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TABLE OF CONTENTS Use the page numbers and your mouse to navigate the file! Date of revision: 5 May 2014 INTRODUCTION ........................................................................................................ IV Hospital medicines list (HML) and antimicrobial guidelines ..................................... v Infectious Disease Service: Consultation Policy ..................................................... vi Prescribing and endorsement of medicines deemed “Specialist” medications within the Pharmac Community Schedule ........................................................................ vii Acknowledgements................................................................................................. vii Principles of empiric antimicrobial prescribing ....................................................... viii Antimicrobial cost awareness ................................................................................. ix BLOOD CULTURES – WHEN, WHY, HOW ............................................................... 1 Procedures to follow after notification of a positive blood culture ............................ 2 Management Of Patients With Positive Blood Cultures........................................... 4 Management of Confirmed Staphylococcus aureus Bacteraemia ........................... 6 TREATMENT GUIDELINES FOR COMMON CONDITIONS IN ADULT PATIENTS .... 7 IDENTIFICATION AND MANAGEMENT OF SEVERE SEPSIS ................................. 8 NEUTROPENIC FEVER IN ADULT PATIENTS ....................................................... 13 NEUTROPENIC FEVER IN PAEDIATRIC PATIENTS ............................................. 15 CARDIOVASCULAR SYSTEM INFECTIONS .......................................................... 17 Infective Endocarditis (IE) ...................................................................................... 17 CENTRAL NERVOUS SYSTEM INFECTIONS ........................................................ 20 Community-Acquired Meningitis in Adults1 ............................................................ 20 Herpes Simplex Encephalitis ................................................................................. 22 EAR, NOSE AND THROAT INFECTIONS ................................................................ 24 Acute Otitis Media.................................................................................................. 24 Acute Sinusitis ....................................................................................................... 25 Chronic Sinusitis .................................................................................................... 26 Pharyngitis ............................................................................................................. 27 RESPIRATORY TRACT INFECTIONS ..................................................................... 28 Exacerbations of COPD And Chronic Bronchitis ................................................... 28 Pneumonia............................................................................................................. 29 Tuberculosis .......................................................................................................... 33 Influenza ................................................................................................................ 34 GASTROINTESTINAL TRACT AND INTRA-ABDOMINAL INFECTIONS ............... 35 Dental and Gingival Infections ............................................................................... 35 Acute Peritonitis ..................................................................................................... 36 Cholecystitis / Cholangitis ...................................................................................... 37 Acute Pancreatitis/Severe Necrotising Pancreatitis............................................... 38 Infectious Diarrhoea............................................................................................... 39 Clostridium difficile disease ................................................................................... 40 Typhoid / Paratyphoid Fever.................................................................................. 41 Helicobacter Pylori Infection .................................................................................. 42 URINARY TRACT INFECTIONS .............................................................................. 43 Cystitis ................................................................................................................... 43 Uncomplicated pyelonephritis ................................................................................ 44 Complicated UTI .................................................................................................... 45 Ciprofloxacin prescribing policy ............................................................................. 46 GENITAL TRACT INFECTION .................................................................................. 47 Pelvic Inflammatory Disease ................................................................................. 48 Bacterial Vaginosis ................................................................................................ 49 Candidosis / Vulvo-Vaginitis .................................................................................. 50 Chlamydial Cervicitis / Urethritis ............................................................................ 51 Genital Herpes Simplex ......................................................................................... 52 Gonorrhoea............................................................................................................ 53 Non-Gonococcal Urethritis..................................................................................... 54 Trichomoniasis....................................................................................................... 55 Syphilis .................................................................................................................. 55 SKIN, MUSCLE AND BONE INFECTIONS .............................................................. 56 Osteomyelitis - Acute ............................................................................................. 56 Septic Arthritis - Non Prosthetic Joint .................................................................... 57 Septic Arthritis - Prosthetic Joint ............................................................................ 57 Bites and Clenched Fist Injuries ............................................................................ 58 Compound Fractures ............................................................................................. 59 Cellulitis - Simple ................................................................................................... 60 Cellulitis - Complicating Ulcer ................................................................................ 61 Necrotising Fasciitis or Synergistic Gangrene ....................................................... 62 Mastitis / Breast Abscess....................................................................................... 63 Wound Infections ................................................................................................... 64 EYE INFECTIONS .................................................................................................... 65 Blepharitis .............................................................................................................. 65 Conjunctivitis.......................................................................................................... 66 TRAVELLERS’ INFECTIONS ................................................................................... 67 Malaria ................................................................................................................... 67 TREATMENT GUIDELINES FOR COMMON CONDITIONS IN PAEDIATRIC PATIENTS .................................................................................................................... 69 Cellulitis ................................................................................................................. 69 Conjunctivitis Neonatorum ..................................................................................... 70 Epiglottitis .............................................................................................................. 70 Meningitis............................................................................................................... 71 Osteomyelitis - Acute ............................................................................................. 73 Otitis Media – Acute............................................................................................... 74 Periorbital / Orbital Cellulitis................................................................................... 75 Pharyngitis ............................................................................................................. 76 Pneumonia............................................................................................................. 77 Pyelonephritis ........................................................................................................ 78 Urinary Tract Infections.......................................................................................... 79 Aminoglycoside Dosing In Children ....................................................................... 80 GUIDELINES FOR EFFECTIVE USE OF ANTIMICROBIAL DRUGS ........................ 83 INFORMATION ON SELECTED ANTIMICROBIAL DRUGS .................................... 83 Antibacterial Drugs ................................................................................................ 84 Antiviral Drugs ....................................................................................................... 91 Antifungal Agents................................................................................................... 92 DOSING, PHARMACOKINETICS AND PHARMOCODYNAMICS ........................... 95 Gentamicin: Principles of Usage and dosing ......................................................... 97 Vancomycin Dosing ............................................................................................. 102 Metronidazole Dosing .......................................................................................... 103 Beta-Lactam Dosing ............................................................................................ 104 IMPAIRED RENAL FUNCTION .............................................................................. 105 HEPATIC INSUFFICIENCY .................................................................................... 109 OBESE PATIENTS ................................................................................................. 110 PREGNANCY AND LACTATION ............................................................................ 111 Drugs in Pregnancy ............................................................................................. 111 Drugs in Lactation ................................................................................................ 112 ORAL ANTIMICROBIAL THERAPY........................................................................ 115 Switch Therapy .................................................................................................... 115 Selecting an Appropriate Oral Antimicrobial Drug ............................................... 116 ii PROPHYLACTIC USE OF ANTIMICROBIAL DRUGS ............................................. 118 SURGICAL PROPHYLAXIS.................................................................................... 118 ENDOCARDITIS PROPHYLAXIS ........................................................................... 123 Antibiotic Regimens ............................................................................................. 123 SPLENECTOMY ..................................................................................................... 125 Prevention of Severe Infections ........................................................................... 125 Treatment Of Post-Splenectomy Sepsis.............................................................. 125 APPENDICES ............................................................................................................. 126 OUTPATIENT INTRAVENOUS THERAPY ............................................................. 126 Long Term IV Antibiotics...................................................................................... 126 Short Term IV Therapy ........................................................................................ 126 Chronic/Speciality Patients Requiring IV Therapy ............................................... 126 Community Cellulitis Protocol .............................................................................. 127 LOCAL RESISTANCE PATTERNS TO ANTIMICROBIAL DRUGS ....................... 128 Infection incidence summary report 2013 ............................................................ 135 MRSA Management ............................................................................................ 141 BLOOD AND BODY FLUID EXPOSURES ............................................................. 146 NOTIFIABLE DISEASES IN NEW ZEALAND ......................................................... 148 How To Notify A Notifiable Disease ..................................................................... 149 iii INTRODUCTION This booklet is intended as a guide for the initial treatment of common conditions. It takes into account agreed best practice in clinical infectious disease nationally and internationally, uses local antimicrobial sensitivities to offer empiric (“best guess”) antibiotic choices and complies with Pharmac regulations in relation to restricted antimicrobials http://www.pharmac.health.nz/medicines/hospital-pharmaceuticals. This document has been developed by Waikato District Health Board (Waikato DHB) specifically for its own use. Use of this document and any reliance on the information contained therein by any third party is at their own risk. Recommendations are based on current (March 2014) international clinical practice and may sometimes differ from product registration information. This handbook has been developed in association with the Waikato Hospital clinical services and is approved for use within Waikato District Health Board. We trust that you will find these guidelines helpful. Paul Huggan Graham Mills Infectious Diseases Physicians Chris Mansell Clinical Microbiologist iv Hospital medicines list (HML) and antimicrobial guidelines 1. The Hospital Medicines List (HML) – Section H of the Pharmaceutical Schedule came into effect on 1July 2013. The HML lists the pharmaceuticals which are funded for use in DHB hospitals in NZ. Prescribing within DHB hospitals must conform to the regulations set out in the HML. See: http://www.pharmac.health.nz/medicines/hospital-pharmaceuticals. 2. Many antimicrobials listed in the HML are now restricted to the approval of ID and clinical microbiology staff (and a limited number of other specialists in some circumstances). 3. Drugs listed on the HML and listed in this antimicrobial guideline are indicated with a superscript H (e.g. meropenemH) and are automatically approved for use for the condition and duration stated. 4. For drugs, listed on the HML but not in this antimicrobial guideline (or for indications, duration or doses not covered in this guideline), treating clinicians will have to seek approval from a clinical infectious disease specialist or clinical microbiologist before the drug can be dispensed from pharmacy. The haematology and intensive care units are specifically exempted as a formal multi-disciplinary team approach, involving infectious diseases and clinical microbiology exists. 5. For drugs not listed on the HML (or indications not listed on the HML), treating clinicians will have to seek approval from a clinical infectious disease specialist or clinical microbiologist AND approval from PHARMAC (following their Rapid Assessment or NPPA process) before the drug will be ordered by pharmacy. See: http://www.pharmac.health.nz/tools-resources/forms/named-patientpharmaceutical-assessment-nppa-forms#nppaapplication 6. The New Zealand Health and Disability Services (Infection Prevention and Control) Standards – Infection Control Management (NZS 8134.3:2008) includes a requirement to promote the prudent prescribing of antibiotics. For Waikato DHB to comply with this standard, ongoing auditing of the use of antibiotics is required. This handbook will form the antibiotic standard that our practice will be audited against. 7. Guidelines can only provide guidance and are not a substitute for thoughtful clinical decision making and common sense. The guideline authors acknowledge that the antibiotic choices suggested here will be appropriate in 90% of the patients, 90% of the time. For that reason, any HML antimicrobial can be prescribed with the approval of a senior medical officer for the first 24 hours of a patient’s hospital admission. Beyond 24 hours, restricted pharmaceuticals will only be dispensed with the approval of a named infectious disease or clinical microbiologist (see Infectious Disease Service: Consultation Policy). v Infectious Disease Service: Consultation Policy 1. The infectious disease and microbiology departments have limited resources and at the time of writing cannot provide routine in-person consultation for all patients. Telephone consultation will often be the only option and is always available. 2. Telephone advice is potentially unsafe and therefore only appropriate if the details of a case are transmitted accurately and the outcome of the conversation documented and properly interpreted by the referrer (http://www.medicalprotection.org/uk/sessionalgp-issue-6) 3. Antimicrobial prescribing requires a broad understanding of the patient’s clinical background, early progress, likely management and prognosis. The referrer retains medico-legal responsibility for prescribing and must interpret telephone advice in the light of their superior knowledge of the patient (i.e. renal function, drug allergies). 4. Therefore, where information and advice is sought by telephone, the ID consultant should only be contacted by a senior member of the referring clinical team, i.e. registrar or consultant. 5. The outcome of the conversation must be documented in the clinical record by the referrer. Email may be used to reach an appropriate recommendation for complex cases. 6. Subsequent updates and advice can be sought by other members of the team provided the ID consultant who provided the initial opinion is available to discuss the case. vi Prescribing and endorsement of medicines deemed “Specialist” medications within the Pharmac Community Schedule To be funded in community some medicines require endorsement on the prescription – to state that the medicine is written by or recommended by a specialist. PHARMAC has revised endorsement requirements when prescribing medications classified as “Retail pharmacy–Specialist”, which came into effect on the 1st July 2013. Any “Retail pharmacy-Specialist” medications (as defined in the schedule) will only be eligible for subsidy if the prescription is either signed by a relevant specialist or recommended by a relevant specialist. If recommended then the prescription needs to be endorsed with either: i) The words “recommended by [name of Specialist and year of authorisation]” and signed; or ii) Endorsed with the word ‘protocol’ which means “initiated in accordance with DHB hospital approved protocol” Current antimicrobials affected by these policies include: • Cefoxitin, Cefuroxime, ClindamycinH, Colistin, TB medications including rifampicin, fluconazole, fusidic acid and ketoconazole. A help desk has been set up for any PHARMAC queries relating to the Hospital Medicine List: email [email protected] phone 0800 66 00 50 or fax 64 4 974 7819. Source: Pharmacy Services Memorandum, 19 June 2013 Acknowledgements The following documents have been helpful in the production of this handbook and are gratefully acknowledged: Antibiotic Guidelines, Victorian Medical Postgraduate Foundation Inc, 14th Edition, 2010. Canterbury District Health Board Antimicrobial Guidelines 16th Edition 2012 Guide to Pathogens and Antibiotic Treatment 7th Edition, Selwyn Lang, 2004. New Zealand Pharmaceutical Schedule, Pharmac, December 2013. Principles and Practice of Infectious Diseases, Mandell, Douglas, Bennett, 7th Edition, 2010. vii Principles of empiric antimicrobial prescribing Always remember that an alternative to the recommendations in this guideline is always available and is only a phone-call or a good textbook away. In most cases, antimicrobial treatment is initiated before a causative organism is known. A major role of microbiological laboratory testing is to enable the spectrum of the antibiotic used to be narrowed with confidence. Remember that restraint in the use of all antimicrobials is the best way to ensure their continuing efficacy. The principles of prescribing remain straightforward, but the ever-increasing number of alternatives has made the task complex. The following concepts underpin prescribing: Efficacy: Therapy has to be effective for the suspected condition in the majority of circumstances. Although efficacy is an over-riding concern, the problem that we encounter is not so much a lack of choice, but too many regimens that are equally effective. Tolerability: The choice has to have an acceptable side effect profile and ease of administration. Some of the most difficult antibiotic selection problems arise, not from resistant organisms, but when a patient has contraindications to several classes of drugs. It is important to document the nature of any adverse reaction so that a patient is not inadvertently re-exposed, nor unnecessarily disadvantaged in future by a label of “drug allergy”. Economically Sound: Given the wide choice and the constraints on health spending, cost has to be considered if two products are similar. With the movement to generic antibiotics, many antibiotics have become considerably cheaper in recent years. Remember that an effective oral regimen is always superior to an intravenous regimen. Ecological Impact: Awareness is needed of the impact of antibiotic selection pressure on the hospital environment and beyond. Ignoring this will lead to ever increasing resistance problems. The choices that have been made in this handbook reflect these concepts. The aim of this guideline is to provide effective first-line therapy for all patients. viii Antimicrobial cost awareness Cost awareness is an important factor that needs to be considered in choosing antibiotics. Agents of similar efficacy can vary in cost by greater than a 1000% - yet often because of pharmaceutical company marketing efforts, the more expensive agent is chosen. Remember that a non-marketed antibiotic does not mean an ineffective antibiotic. Often it is simply that the patent has run out! The dosage regimen used for cost comparison is an indication only and should not be used as a dosing guideline for all infections. The stated costs in this table are based on hospital acquisition costs as at August 2012 and should be seen as approximate only. Prices are subject to change over time. Drug Route Av. Adult Dose* Hospital Cost Cost/Unit Cost/Day ($) ($) ANTIBACTERIALS Cephalosporins Cephalexin 500mg Cefaclor 250mg Cephazolin 500mg Cefotaxime 1g Cefoxitin 1g Cefuroxime axetil 500mg Cefuroxime 750mg Ceftriaxone 1g CeftazidimeH 1g H Cefepime 1g PO PO IV/IM IV/IM IV/IM PO IV/IM IV/IM IV/IM IV/IM 250mg q6h 250mg q8h 1g q6h 1g q8h 1g q6h 500mg q12h 750mg q8h 1g q24h 1g q8h 1g q12h 0.45 0.25 1.60 1.56 11.00 0.59 1.39 2.10 6.49 8.80 0.89 0.74 6.40 4.67 44.00 1.18 4.18 2.10 19.47 17.60 500mg 1g 500mg PO IV/IM PO 500mg q8h 1g q8h 500mg q8h 0.05 2.19 0.13 0.15 6.57 0.39 1.2g IV 1.2g q8h 1.65 4.95 500mg 600mg 500mg 1g 4.5g PO IV/IM PO IV IV/IM 500mg q6h 600mg q6h 500mg q6h 1g q6h 4.5g q8h 0.23 1.15 0.15 1.43 12.00 0.93 4.60 0.60 5.71 36.00 3.1g IV/IM 3.1g q6h 18.00 72.00 1g 1g IV/IM IV/IM 1g q8h 1g q24h 21.00 70.00 63.00 70.00 Penicillins Amoxycillin Amoxycillin Amoxycillin/ clavulanate Amoxycillin/ clavulanate Penicillin V Benzylpenicillin Flucloxacillin Flucloxacillin Piperacillin/ tazobactamH Ticarcillin/ clavulanateH Carbapenems MeropenemH ErtapenemH * Calculations based on body weight of 70kg ix Drug Route Av. Adult Dose* ANTIBACTERIALS Aminoglycosides Gentamicin 80mg TobramycinH 80mg H Amikacin 500mg IV/IM IV/IM IV/IM 400mg q24h 400mg q24h 1g q24h 0.65 5.86 77.00 3.25 29.32 154.00 Glycopeptides VancomycinH 500mg TeicoplaninH 400mg IV IV/IM 1g q12h 400mg q24h 3.58 113.39 14.32 113.39 400mg PO 400mg q6h 0.17 0.68 1g IV 1g q6h 10.93 43.72 300mg 250mg 500mg PO PO PO 300mg q24h 500mg q12h 1g stat 0.29 0.30 2.98 0.29 1.20 5.95 Fluoroquinolones Norfloxacin 400mg H Ciprofloxacin 500mg CiprofloxacinH 200mg H Moxifloxacin 400mg PO PO IV PO 400mg q12h 500mg q12h 200mg q12h 400mg q24h 0.15 0.11 4.10 10.40 0.31 0.21 8.20 10.40 Nitroimidazoles Metronidazole 500mg Metronidazole 500mg Metronidazole 400mg IV PR PO 500mg q12h 500mg q12h 400mg q12h 2.46 2.45 0.18 4.92 4.90 0.36 Tetracyclines Doxycycline 100mg PO 100mg q24h 0.03 0.03 150mg 600mg 480mg 480mg PO IV/IM PO IV 300mg q6h 600mg q8h 960mg q12h 960mg q12h 0.62 16.00 0.04 22.00 4.95 48.00 0.16 88.00 50mg 300mg PO PO 50mg q8h 300mg q24h 0.22 0.18 0.66 0.18 Macrolides Erythromycin ethylsuccinate Erythromycin lactobionate Roxithromycin ClarithromycinH AzithromycinH Miscellaneous ClindamycinH ClindamycinH Cotrimoxazole Cotrimoxazole Fusidic Acid Nitrofurantoin Trimethoprim * Calculations based on body weight of 70kg x Hospital Cost Cost/Unit Cost/Day ($) ($) Drug Route Av. Adult Dose* ANTIBACTERIALS Antituberculins Isoniazid 100mg Pyrazinamide 500mg Rifampicin 600mg PO PO PO 300mg q24h 2000mg q24h 600mg q24h 50mg 50mg IV IV 50mg 200mg 100mg 100mg 200mg 250mg 200mg 200mg ANTIVIRALS Acyclovir Hospital Cost Cost/Unit Cost/Day ($) ($) 0.20 0.59 3.81 0.60 2.36 3.81 50mg q24h 200mg q24h 27.41 345.00 27.41 1380.00 IV PO IV PO PO PO PO IV 50mg q24h 200mg q24h 200mg q24h 100mg q24h 200mg q24h 250mg q24h 200mg q12h 200mg q12h 667.50 0.48 5.68 0.28 1.27 0.13 59.80 217.46 667.50 0.48 11.36 0.28 1.27 0.13 119.60 434.92 200mg PO 0.08 0.40 Acyclovir 400mg PO 0.12 0.59 Acyclovir 800mg PO 0.21 1.05 Acyclovir 250mg IV ValganciclovirH 450mg PO Ganciclovir 500mg IV Foscarnet 6000mg IV 200mg 5 times daily 400mg 5 times daily 800mg 5 times daily Indication dependent Indication dependent Indication dependent Indication dependent ANTIFUNGALS AmphotericinH Amphotericin liposomalH CaspofunginH Fluconazole Fluconazole ItraconazoleH Ketoconazole Terbinafine VoriconazoleH VoriconazoleH * Calculations based on body weight of 70kg xi 5.10 50.00 76.00 140.00 BLOOD CULTURES – WHEN, WHY, HOW Bloodstream infection represents a serious and potentially life threatening stage of an infective process where the infection is no longer contained within an organ space or system. Depending on the organism involved bloodstream infections carry a high morbidity and mortality risk. A blood culture is a diagnostic test. The performance of the test changes dramatically based on factors that alter sensitivity and specificity: How to increase true positives ( sensitivity) Take blood cultures before administering antibiotics in all but the sickest patients • especially important in endocarditis and patients in whom fever may not relate to infection (i.e. PE, drug fever, burns, pancreatitis) Fill each blood culture bottle properly • standard culture bottle: 10ml • paediatric culture bottle: 3ml • myco-flytic cultures: 5ml How to increase false positives (↓ specificity) Culture through peripheral lines, central lines and PICC lines without taking peripheral cultures at the same time • vascular access cultures are frequently contaminated by colonising organisms Take all bottles from a single draw • this preserves sensitivity but doesn’t help to diagnose contamination if cultures are positive Fail to adhere to aseptic technique Take more cultures • take a minimum of 4 but ideally 6 bottles for culture (3 aerobic + 3 anaerobic) from 2 separate draws Take cultures from each lumen of a vascular access device if a suspected source of infection Take blood cultures from patients with no indication to have the test Good blood culture technique, adequate sampling and interpretation of positive results are the responsibility of all clinicians and nurses involved in patient care. Failing to secure a microbiologic diagnosis exposes the patient to harm both through use of inappropriate antibiotics and/or failure to link an organism to an underlying diagnosis (ie Streptococcus bovis as an indicator of underlying bowel cancer). Optimal diagnosis of bacteremia/fungemia is achieved with 3 aerobic/anaerobic sets of blood cultures (see below). Sequential sensitivity (%) of blood cultures for monomicrobial bacteremia/fungemia J Clin Micro 2007; 45: 3546-48 Microorganism Staphylococcus aureus Coagulase negative staphylococci Enterococcus spp Streptococci Escherichia coli Klebsiella pneumoniae Pseudomonas aeruginosa Candida albicans Candida glabrata Cumulative number of blood cultures drawn 1 2 3 87 93 100 71 98 100 68 87 100 85 100 65 90 100 76 88 100 62 94 100 60 83 100 80 100 1 Procedures to follow after notification of a positive blood culture Interpretation of Laboratory Reports Positive blood cultures are phoned through when the organism has grown in the blood culture bottle and has been gram-stained. The following table gives some guidance to interpreting the gram-stain description of the organism. Initially this is all the information that will be available, as the organism then needs to grow on agar plates overnight before it can be identified further. Antimicrobial susceptibility and identification to species level take a further 12-48 hrs. A rapid coagulase test will often give an indication that a gram-positive coccus is Staphylococcus aureus 2- 4 hrs after the initial gram stain result is available. All positive blood culture results should be followed up urgently. If a doctor receives a report for a patient that is not directly under his/her care, it is the responsibility of the doctor to check that suitable treatment is under way. 2 Interpretation of Blood Culture Gram Stain Reports Description of Gram Stain Most Serious Possible Cause of Infection Most Likely Cause of Infection Other Possible Causes of Infection - Clusters Staph. aureus Coagulase-negative Staph (usually contaminant) Micrococcus Aerococcus Anaerobic gram- positive Coccus - Pairs (diplococci) - Chains Strep. pneumoniae Strep. pneumoniae Group A Strep Group B Strep Viridans strep group GRAM-POSITIVE BACILLI Listeria monocytogenes Bacillus anthracis Diphtheroids (Corynebacteria or Propionibacterium acnes - both are usually contaminants). GRAM-NEGATIVE COCCI Neisseria meningitidis Neisseria meningitidis - Pairs (diplococci) Neisseria meningitidis E. coli-like organisms (Coliform) e.g. Klebsiella, Enterobacter, Proteus, Serratia, Yersinia Neisseria meningitidis Coliform e.g. E. coli Klebsiella, Enterobacter, Proteus, Serratia, Yersinia Campylobacter fetus Candida albicans Campylobacter jejuni Candida albicans GRAM-POSITIVE COCCI GRAM-NEGATIVE BACILLI - Curved YEAST 3 Group C or G Strep Strep milleri or Strep anginosus Anaerobic gram-positive coccus Erysipelothrix Bacillus sp (Aerobic spore-forming grampositive bacillus) Clostridium (Anaerobic spore-forming grampositive bacillus) Commensal Neisseria Strep pneumoniae Anaerobic gram-negative cocci Gram-negative coccobacilli e.g. Kingella, Acinetobacter sp Neisseria gonorrhoeae Pseudomonas-like organisms Stenotrophomonas maltophilia Anaerobic gramnegative bacilli e.g. Bacteroides sp Aeromonas Haemophilus Other Candida sp e.g. C. krusei, C. glabrata Management Of Patients With Positive Blood Cultures 1. Possible Staphylococcus aureus bacteraemia (Gram positive cocci in clusters in a patient with sepsis) • • • • • • • Visit within 2 hr unless diagnosis has been made and antibiotic already given. Repeat blood cultures (all lumens of IV lines plus peripheral). Sample obvious sites of infection. Check notes for MRSA alert and susceptibility of previous isolates. Antibiotic of choice is IV flucloxacillin 1-2g every 6 hours. Discuss with any other medical teams involved and notify patient’s own team next day. Staph aureus infection can lead to significant complications from inadequate therapy. For this reason, Waikato Hospital has specific guidelines on how to manage this condition (see below). 2. Possible Meningococcal bacteraemia (Any Gram-Negative Cocci) • • Urgently phone ward to check whether IV ceftriaxone 1g every 12 hours or any other antibiotic is being given. If diagnosis has not already been made, then visit patient urgently (<1hr). 3. Possible Gram-Negative Sepsis (Any Gram-Negative Bacilli) • • • • • • • • • • Urgently phone ward to check whether any IV antibiotic is being given. If patient is stable and has already been treated, visit within 4 hr to document in notes. Briefly check the patient. Check that specimens have been sent: urine for culture + dipstick, swab any wounds, sputum if available, diarrhoea if present, ideally more than one set of blood cultures before antibiotics, gentamicin levels. Notify patients’ own team first thing next working day. If diagnosis has not already been made or if antibiotics have not yet been given, visit urgently (<1hr). Assess urinary tract, genital tract, abdomen, respiratory tract, recent surgical sites, recent antibiotic history and gentamicin level results if available. If UTI give gentamicin 5mg/kg IV once daily. If abdominal infection, give gentamicin 5mg/kg IV daily + amoxycillin 1g IV every 6 hours + metronidazole 500 mg IV every 12 hours. If PID, take cervical bacterial and chlamydial swabs and urine for chlamydia, give Augmentin and doxycycline and refer to O&G. 4 4. Possible Pneumococcus Infection (Gram-Positive Diplococci) • • • • • • Urgently phone ward to check whether any antibiotic is being given. If diagnosis has not already been made or if antibiotics have not yet been given, visit urgently (<1hr). Check that the following tests have been done and whether any results are available: ABG, FBC, CXR, sputum, ± repeat blood cultures, check ears and sinuses, possibility of meningitis. If patient is stable and has already been started on treatment, visit within 4 hours to record details of test results in notes. Briefly check patient. Appropriate antibiotics include any penicillin or cephalosporin. Ciprofloxacin or macrolides such as erythromycin alone are not adequate. Consult General Medical or Respiratory team if patient is under the care of another team. 5. Suspected Endocarditis or Subacute PUO Associated With Any Murmur or Embolic Symptom (Streptococci or Staph. aureus, for patient with any abnormal valve). • • Visit patient within 4 hours. Check the following tests have been done: • 3 sets of blood cultures, preferably from different sites. • Perform a clinical review for changing murmur, decompensated heart failure, sepsis syndrome and emboli, particularly cerebral. • Discuss with General Medicine or Cardiology before giving further antibiotics or arranging TTE or TOE. 6. Apparent Contaminant (Coagulase Negative Staph or Gram-Positive Bacilli from patient who is well) • • • • Check patient history and confirm organism involved. Carefully repeat blood cultures if necessary (see blood culture guidelines). Do not attribute coagulase negative staphylococci, viridans streptococci or unidentified gram positive bacilli to contamination if the patient is ill or has a prosthetic heart valve or implanted endovascular device (ie pacemaker). Update consultant responsible for patient. 5 Management of Confirmed Staphylococcus aureus Bacteraemia BACKGROUND Staphylococcus aureus bacteraemia (SAB) is a common problem in Health Waikato patients with about a hundred positive cultures every year. An audit of local practice recently identified several problems in the management of SAB with common underinvestigation and inadequate IV antibiotic treatment. Approach to Management ID consultation is not mandatory at Waikato DHB but is encouraged, particularly if there is any doubt as to the source of bacteraemia, the adequacy of initial response to treatment or the final duration of therapy (see below). 1) Notification of blood cultures positive for Staphylococcus aureus. The requesting doctor will be notified as soon as the blood culture becomes positive and the patient’s consultant is to be notified after confirmation of SAB with a standard letter. 2) Use of echocardiography All patients with signs of endocarditis or community-onset SAB (blood cultures positive within 48 hours of hospital admission) should undergo trans-thoracic echocardiography. Trans-oesophageal echocardiography should be considered on a case by case basis but is usually required for patients with prosthetic heart valves or permanent pacemakers. Discuss with an infectious disease specialist if in doubt. 3) Further investigation • • • Cultures should be repeated at 48-72 hours Direct investigations according to the clinical presentation and dominant findings Deep sources of SAB that are commonly missed include: spinal osteomyelitis/discitis, septic arthritis, renal and psoas abscesses, infection of implanted devices (i.e. pacemaker wires) and thrombophlebitis. 4) Antibiotic treatment and duration In general, patients should receive 2 weeks of intra-venous antibiotics before cessation of treatment is considered. Stopping treatment after 2 weeks is reasonable providing all of the following are satisfied; • • • Complete, focused clinical investigation has effectively ruled out deep-seated infection that would mandate longer periods of treatment by standard guidelines (i.e. endocarditis, prosthetic device or graft infection, spinal osteomyelitis/discitis) There has been a complete clinical response with negative blood cultures at 48-72 hours. No ongoing symptoms, clinical or laboratory findings exist that raise suspicion of deep infection (i.e. new back pain) The duration of intravenous therapy for patients with bacteraemia in the setting of a deep focus of infection depends on the nature of the underlying infection and is usually longer than two weeks. All cases of clinical concern should be discussed with an infectious disease specialist. 6 TREATMENT GUIDELINES FOR COMMON CONDITIONS IN ADULT PATIENTS 7 IDENTIFICATION AND MANAGEMENT OF SEVERE SEPSIS Sepsis is the systemic response to infection. Septic patients present in all areas of the hospital and diagnosis is frequently delayed. Delays in diagnosing and treating sepsis can contribute to the progression of severe sepsis, defined as sepsis in the presence of organ failure or tissue hypoperfusion. The following guide outlines how to identify each of these disorders and the ACTION to take if sepsis/severe sepsis are confirmed. Identifying and managing the septic patient Sepsis = confirmed/suspected infection AND 2 or more SIRS criteria: Temp >38C or <36C, HR>90, RR>20 or PaCO2<32mmHg, WBC>12,000 or <4000 or “left shift” ACTION: • • • • • • • Secure IV access and run fluid Give supplemental oxygen to maintain SpO2 above 93% Send new bloods for FBC, renal panel, LFT, venous blood gas (arterial in hypoxic patients) and lactate, draw 3 sets of blood cultures Request diagnostic tests to confirm diagnosis Prescribe antibiotic according to guideline and ensure patient receives first dose within one hour of review Recheck clinical observations/ADDS within 2 hours Ensure that nursing staff and the registrar in charge of the patient are informed of change in patient’s condition and any treatment plans. Discuss these with the consultant in charge as necessary Review investigations – is this severe sepsis? IN HOSPITAL MORTALITY 10-50% Severe sepsis = sepsis AND new organ dysfunction AND/OR hypoperfusion AND/OR hypotension *Hypotension = SBP <90mmHg, MAP <70 or >40mmHg decrease in SBP from patient baseline Organ dysfunction = change in mental status (new confusion or delirium); increase in oxygen requirements; new rise in creatinine above 175 micromol/L; urine output <0.5ml/kg/hr for 2 hours despite adequate fluids; platelets <100; INR >1.5 or aPTT>60 sec; total bilirubin > 34 micromol/L; serum lactate >2 mmol/L ACTION: • • • • • As for sepsis but stay with the patient to ensure that all steps completed; focus on resuscitation end points of normalised lactate after 4 hours, adequate urine output, improvement in conscious level, oxygenation and blood pressure Give 500ml NSaline over 15 minutes and repeat up to 2 litres as necessary Move quickly to identify, debride and drain all accessible sources of infection as soon as possible, including out of normal office hours Ensure your consultant is involved and get ICU/HDU input early if the patient is eligible for intensive organ support. Note: hypotension is often a late sign in sepsis – the normotensive patient with organ dysfunction is at high risk of in-hospital mortality 8 “Best Guess” Antibiotic Choice in Severe Sepsis Empiric antibiotic therapy should ideally be based on localising symptoms and signs of infection. If none are present, the diagnostic tests required for localisation should be performed as soon as possible. All empiric antibiotic regimens are intended for 24 to 72 hours only and should be modified as soon as possible based on clinical progress, pathogen identification and susceptibility testing. 1) Sepsis - community onset: unknown site Pathogens: Gram-negative organisms, Staphyloccus aureus, Neisseria meningitidis, Streptococcus pneumoniae DRUG DOSE (for normal renal function) Empiric Cefriaxone 2g IV q12 hourly and Gentamicin See gentamicin dosing guidelines Treatment Duration: This is an empiric initial therapy only and should only continue for the first 48 hours and should be altered at that time based on microbiology results 9 2) Sepsis + Urinary Tract INFECTION (Pyelonephritis, renal/perinephric abscess) For immunocompetent patients presenting with lower urinary tract infection without systemic toxicity, refer to the section on urinary tract infection. Cystitis associated with the sepsis syndrome +/- flank or loin pain is by definition a complicated urinary tract infection – initial treatment should be with an IV agent. Pathogens: Enterobacteriaceae, Pseudomonas aeruginosa. DRUG DOSE Empiric Amoxicillin 1g IV q8 hrly and Gentamicin Refer to gentamicin dosing guidelines 10 3) Sepsis + Skin and soft tissue infection Pathogens: Staphylococcus aureus, Group A Streptococci. DRUG DOSE Empiric – cellulitis/myositis Flucloxacillin 1,2 2g iv 6 hourly Empiric – deep ulceration or suspicion of necrotising fasciitis2 Benzylpenicillin 2.4g iv q4h and CeftazidimeH 2g iv q8h and ClindamycinH 600mg IV q8h 1 There is no need to combine flucloxacillin and benzylpenicillin in soft tissue infection; flucloxacillin has excellent activity against Group A Streptococci. 2 Use only for clinically severe infections – apply LRINEC Score and consider surgical review if ≥6 - revise diagnosis after 24-48 hours, consult readily for cases of gangrene, necrotising fasciitis and infected ulceration in diabetics and patients with vascular compromise of affected limb. 4) Sepsis and hepatobiliary disease/obstruction Pathogens: Enterobacteriaceae, Anaerobes, Enterococcus DRUG DOSE Ceftriaxone 2g IV q24 hourly and Metronidazole 500mg iv inf 12 hourly 11 5) Sepsis with peritonitis Pathogens: Enterobacteriaceae, anaerobes, enterococci DRUG DOSE Cefuroxime1,2 750mg IV q8 hourly and Metronidazole 500mg IV q8 hourly and if pelvic inflammatory disease suspected Doxycycline 100mg PO q12 hourly 1 Adjust in renal impairment: eGFR 10-20ml/min give 750mg bd. eGFR <10ml/min give 750mg daily. 2 Most patients with treated/resolving peritonitis can complete therapy with oral coamoxyclavulanate unless microbiologic evidence of resistant infection. 6) Sepsis + line infection (including central lines) Pathogens: Coagulase-negative staphylococci, Staphylococcus aureus, Gram-negative rods, Candida sp. DRUG DOSE Flucloxacillin 2g iv 6 hourly1 and Gentamicin 1 Refer to gentamicin dosing guidelines Line-associated MRSA infection is currently very unusual at WDHB facilities. Empiric vancomycin is not recommended. 7) Sepsis + suspected meningitis See section on central nervous system infections (below) 12 NEUTROPENIC FEVER IN ADULT PATIENTS Definition Neutropenic fever is a body temperature ≥38.3oC or ≥38.0oC on two occasions over at least one hour in a patient who is severely neutropenic (i.e. neutrophil count < 0.5 x 109 /L). Principles Of Therapy • • • • • • • All patients who become febrile whilst severely neutropenic must be assessed by medical staff within 20 minutes of the fever (as defined above) developing. Treatment is empiric. Antibiotic therapy is commenced without an isolated organism or even possible site of infection. Antibiotic choice must be broad spectrum, particularly covering gram-negative organisms, which carry a high morbidity and mortality. Currently, all antibiotics are given intravenously with a high degree of urgency. The first dose of intravenous antibiotics should be given within 30 minutes. Patients on Ward M5 at Waikato Hospital will be routinely reviewed by their consultant each day. For patients in other locations (especially at T Hospitals), the relevant haematologist or oncologist should be contacted within 24 hours of admission or commencing treatment for neutropenic fever to discuss ongoing management. After hours, or at weekends, this should be discussed with the on-call consultant. First Line Therapy Summary Providing there is no known allergy, severe renal impairment (estimated creatinine clearance less than 30ml/min) or previous use of cisplatin, the recommended combination treatment is tobramycinH and piperacillin/tazobactamH (Tazocin). Alternative regimens, as described below, must be used for patients in whom the usual first line therapy is likely to cause severe toxicity. If there is any uncertainty, the haematologist or oncologist on- call should be contacted for discussion. 1. Usual First Line Therapy (Tazocin® and TobramycinH) TazocinR (Piperacillin + Tazobactam) The conventional starting dose in adults is 4.5g 8 hourly IV. Adjustments of dosage are made for severe renal impairment i.e. if creatinine clearance less than 30ml/min, use 4.5g 12 hourly. 13 TobramycinH In adults this should be commenced with a single dose of 5 mg/kg IV, regardless of gender or age. TobramycinH can be discontinued if blood cultures are negative for Pseudomonas aeruginosa or other multi-drug resistant pathogens. Doses should be calculated using ideal body weight (IBW), or actual weight, if this is less than IBW. If actual weight is >20% above IBW, dosing should be based on the Obese Dosing Weight (ODW). The dosing interval should be in accordance with estimated creatinine clearance, based on an extended interval regimen (see section on aminoglycoside dosing). Beware of continuing aminoglycosides for prolonged periods of time given the complication of renal toxicity and ototoxicity which are more likely to occur with treatment durations of more than seven days. 2. Patients with Penicillin Allergy but without Anaphylaxis (CefepimeH and TobramycinH) CefepimeH is a fourth generation cephalosporin with slightly broader spectrum activity than ceftazidimeH. The usual dose is 2 g 12 hourly IV. Cross allergy with penicillins is estimated to be less than five percent. Usually, the benefits of highly potent gram-positive cover will outweigh the possible risk of allergic reactions. Tobramycin should be commenced with a single dose of 5 mg/kg IV, regardless of gender or age. TobramycinH can be discontinued if blood cultures are negative for Pseudomonas aeruginosa or other multi-drug resistant pathogens. Doses should be calculated using ideal body weight (IBW), or actual weight, if this is less than IBW. If actual weight is >20% above IBW, dosing should be based on the Obese Dosing Weight (ODW). The dosing interval should be in accordance with estimated creatinine clearance as per the Cockcroft formula, based on an extended interval regimen (see guidelines on Aminoglycoside dosing). Beware of continuing aminoglycosides for prolonged periods of time given the complication of renal toxicity and ototoxicity which are more likely to occur with treatment durations of more than seven days. 3. Patients Receiving Nephrotoxic Drugs or Previously Treated with Cisplatin Monotherapy with IV cefepimeH 2g 12 hourly is recommended. 4. Patients with Severe Renal Impairment (Calculated creatinine clearance <30ml/min) Monotherapy with IV cefepimeH 1g 12 hourly is recommended for treatment of patients with severe renal failure. Aminoglycosides and intravenous vancomycin are not usually recommended for treatment of patients with severe renal failure. However, they may be used in life-threatening situations after consultation with the specialist on call. Subsequent Changes in Antimicrobial Therapy Changes from first line therapy will be made by the Haematology or Oncology team, with the guidance of a departmental protocol. Antibacterial spectrum may be widened, antifungal or antiviral therapy may be added or treatment may be narrowed or discontinued in light of laboratory results or changes in the patient’s clinical condition. If a change in antimicrobial therapy appears indicated out of hours, please discuss with the haematologist or oncologist on call. 14 NEUTROPENIC FEVER IN PAEDIATRIC PATIENTS Protocol adapted from Auckland Starship Hospital Protocol for Treatment of Febrile Neutropenia in Children for use at Waikato Hospital (May 2005). Definitions • Fever: Temperature > 38.0°C on two consecutive occasions within 2 hours, or >38.5°C on one occasion. • Neutropenia: A neutrophil count of <0.5 x 109/L Evaluation Of Patient • Examine patient. • Obtain CBC. • Culture blood from all lumens for bacteria and fungi and indicate which culture bottle contains blood from which lumen. • Peripheral culture should be taken if possible. • Culture other sites as clinically indicated. • Order CXR/urine specimens, as clinically indicated. Risk Groups RISK FACTORS Absolute neutrophil count LOW RISK 0.1 – 0.5 x 109/L HIGH RISK <0.1 x 109/L Duration of neutropenia <7 days >7-10 days Comorbidity Nil Toxic/clinical focus/ High-dose Ara-C Treatment i) • • • Low Risk First line therapy is cefepimeH 50 mg/kg/dose 8-12 hourly (max 4g/day) Evaluate after 48 hours. - If afebrile with negative cultures and still neutropenic, discharge home on once daily IV ceftriaxone 80 mg/kg/day (max 2g/day). This can be given by District Nurse until neutrophil and platelet counts start to increase or until absolute neutrophil count >0.5 x 109/L. - If still febrile with negative cultures, reassess and re-culture. Add tobramycinH 5mg/kg/dose 24 hourly. Note: TobramycinH/Ceftriaxone is inadequate for Pseudomonas. If still febrile at 96 hours, consider consulting ID team (Auckland Starship Hospital) for reassessment and individualised therapy. 15 ii) High Risk • • • • First line therapy is tobramycinH 5mg/kg/dose 24 hourly and Timentin (ticarcillin/clavulanate) 75mg/kg/dose (ticarcillin) 6 hourly (max 12g/day). Evaluate after 48 hours. - If afebrile with negative culture and still neutropenic, consider discharge home to return to ward or outreach for once daily iv ceftriaxone 80mg/kg/day (max 2g/day) and tobramycinH (5 mg/kg/dose). - District nurse not to give. - Such patients will need a daily medical review, temperature and CBC. - Antibiotics should continue until absolute neutrophil count >0.5 x 109/L. - If still febrile with negative cultures, reassess and reculture. - Add IV vancomycin 20-30 mg/kg/dose 8 or 12 hourly (max 2g/day). If still febrile at 96 hours, consult ID team (Auckland Starship Hospital) for reassessment. - Consider meropenemH (20-40 mg/kg/dose) 8 hourly (max 3g/day). If still febrile at 5-7 days, consider amphotericinH 0.5mg/kg/day, increasing to 1.5mg/kg/day, or fluconazole, if there is renal impairment. Monitoring Levels • • Vancomycin TobramycinH (8 hourly dosing) • TobramycinH (daily dosing) Troughs only prior to the 4th dose. Peak after 3rd dose and trough prior to the 4th dose. Trough prior to 2nd dose – refer to Aminoglycoside nomogram 16 CARDIOVASCULAR SYSTEM INFECTIONS Infective Endocarditis (IE) The diagnosis and management of IE rests on coupling positive blood cultures with evidence of endocardial involvement in an infective process. This forms the basis of the major Duke criteria for diagnosis of IE, which are a useful clinical guide. In suspected IE, take a minimum of 3 sets of blood cultures (6 bottles, 3 aerobic and 3 anaerobic) drawn from 2 venepuncture sites more than one hour apart. Take all blood cultures before any antibiotics are given. If antibiotics have been given within two weeks take 6 sets of blood cultures. Duke criteria for diagnosis of endocarditis [Clin Infect Dis 2000; 30: 633-8] Definitive diagnosis • Histologic or microbiologic studies of valve tissue confirming endocarditis OR • 2 major clinical criteria; or • 1 major clinical criterion and 3 minor criteria; or • 5 minor clinical criteria Possible diagnosis • 1 major criterion and 1 minor criterion; or • 3 minor criteria. Rejected diagnosis • Firm alternate diagnosis explaining evidence of infective endocarditis syndrome or • Resolution of infective endocarditis syndrome with antibiotic therapy for ≤4 days; or • No pathologic evidence of infective endocarditis at surgery or autopsy, with antibiotic therapy for ≤4 days; or • Does not meet criteria for possible infective endocarditis, as above. Major Clinical Criteria 1. Major Microbiologic Criteria • Typical micro-organisms consistent with IE from 2 separate blood cultures: Viridans streptococci, Streptococcus bovis, HACEK organisms, Staphylococcus aureus or community-acquired enterococci in the absence of a primary focus; or • Micro-organisms consistent with IE from persistently positive blood cultures, defined as follows: - At least 2 positive cultures of blood samples drawn >12 h apart; or - All of 3 sets of blood cultures or - A majority of ≥4 separate cultures of blood with first and last sample drawn at least 1 hour apart. • or single positive blood culture for Coxiella burnetti or antiphase I IgG antibody titre>1:800 17 2. Evidence of endocardial involvement A. Echocardiogram positive for IE • TOE is recommended in patients with: - prosthetic valves, rated at least “possible IE” by clinical criteria, or - complicated IE (perivalvular abscess or poor clinical response to treatment); • TTE is the first test in other patients, with positive results defined as: - oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; or - Abscess; or - New partial dehiscence of prosthetic valve. B. New valvular regurgitation (worsening or changing of pre-existing murmur not sufficient) Minor Criteria 1. Predisposition • Predisposing heart condition or intravenous drug use. 2. Fever • Temperature >38oC 3. Vascular phenomena • • • • • • Major arterial emboli Septic pulmonary infarcts Mycotic aneurysm Intracranial haemorrhage Conjunctival haemorrhages Janeway's lesions. 4. Immunologic phenomena • • • • Glomerulonephritis Osler’s nodes Roth’s spots Positive rheumatoid factor 5. Microbiological evidence • Positive blood culture that does not meet a major criterion as noted above, or • Serological evidence of active infection with organism consistent with IE except as indicated above. 18 Empiric Treatment for Suspected Endocarditis: DRUG Empiric1 (a) Native Valve Benzylpenicillin and Gentamicin and Flucloxacillin (b) Prosthetic Valve VancomycinH and Gentamicin DOSE 1.8g iv 4 hourly 3 mg /kg iv q24 hourly2 2g iv 4 hourly 30mg/kg/day (Up to 1.5g iv inf 12 hourly) 3 mg /kg iv q 24 hourly2 1 Consult Cardiology Specialist and Infectious Disease specialists upon confirmation of endocarditis or to direct investigation and treatment. 2 Low-dose gentamicin (3mg/kg q24 hourly) is used in synergy with other agents to treat endocarditis and is continued for 14 days in most cases. Check a trough level before giving the second dose and every 48 hours during the first week of treatment. Counsel patients regarding symptoms of vestibular dysfunction and discuss with ward pharmacist if either i) trough level >1 mg/L or ii) renal function deteriorates. Specific Therapy for Endocarditis • • Refer to relevant summaries available on UptoDate Discuss with an infectious disease specialist once microbiology results available 19 CENTRAL NERVOUS SYSTEM INFECTIONS Community-Acquired Meningitis in Adults1 Empiric 1 DRUG/DOSE in Normal Renal Function Day 1 1. In all cases Ceftriaxone2 2g IV q12 hourly 2.Are Gram positive cocci resembling streptococcus seen in CSF (see below)? If yes, add to ceftriaxone: Dexamethasone 10mg IV (0.15mg/kg in children) with antibiotics3 plus Vancomycin 30mg/kg/day in divided doses (up to 1.5g q12 hourly) 3. Is L.monocytogenes a possibility (see risk factors below)? If yes, add to ceftriaxone: Amoxicillin 2g IV q 4hrly or in penicillin allergic patients Trimethoprim/Sulfamethoxazole 5mg/kg based on trimethoprim component IV q 8 hourly Day 2 onwards Streptococcus pneumoniae: +ve Gram stain of CSF: positive blood culture; pneumococcal antigen test on CSF3 Ceftriaxone 2g IV q12h and VancomycinH (until penicillin susceptibility known) and Dexamethasone if commenced3 30mg/kg/day in divided doses (up to 1.5g q12 hourly) Neisseria meningitidis Ceftriaxone 2g IV q24h For clearance of nasopharyngeal Neisseria meningitidis in close contacts4 Rifampicin 600mg PO 12 hourly for 2 days or Ceftriaxone 250mg IM as single dose Listeria monocytogenes Amoxycillin and 2g IV q4 hourly Gentamicin See gentamicin dosing guideline 20 • • • • CT prior to LP if: - Impaired level of consciousness or lateralising neurological signs - Features of raised intracranial pressure - New onset seizures - Shocked - Sinus or ear infections. If LP cannot be performed immediately, start antibiotics. For patients with severe penicillin allergy or known mild-moderate penicillin allergy who require cover for L.monocytogenes, see “First Dose Empiric Antibiotic Guidelines in Adults” and/or consult an infectious disease specialist. Carefully consider possible aetiologies in all cases • Streptococcus pneumoniae: children; base of skull fracture, sinus or middle ear infection; seizure; rapid onset with reduced consciousness at presentation • Listeria monocytogenes: pregnancy, immunosuppression (CLL or Lymphoma, high dose steroids, transplant), cirrhosis and those older than 60 • Neiserria meningitides: should be covered in all cases until microbiology results available • Haemophilus influenzae: should be covered in all cases until microbiology results available. Important cause of meningitis in children and young adult but becoming less common due to vaccination 1 Discussion with an infectious disease or microbiology specialist is recommended. Third generation cephalosporins are inactive in meningitis caused by L. monocytogenes. 3 Due to the possibility of resistance, Health Waikato policy determines that evidence of pneumococcal meningitis (gram positive cocci resembling streptococci seen in CSF) requires treatment with both ceftriaxone and vancomycin until sensitivity results become available ceftriaxone alone if sensitive. Treatment with dexamethasone 10mg IV (0.15mg/kg in children) at the time of the first dose of antibiotic is recommended for meningitis due to Streptococcus pneumoniae as it is considered to improve outcomes in both adults and children. If initial investigations confirm S.pneumoniae meningitis dexamethasone is continued at the dose above q6hrly for 4 days. There is no evidence that delayed starting of dexamethasone i.e. more than four hours after starting antibiotics, is helpful (N Engl J Med. 2004;351(18):1849). 4 Prophylaxis is not recommended routinely for medical personal except those who have had intimate exposure such as occurs with unprotected mouth to mouth resuscitation, intubation or suctioning before antibiotic therapy was begun. Community contacts of N.meningitidis meningitis are determined by the Medical Officer of Health. 2 Treatment Duration: Meningococcal disease 3 days. Streptococcus pneumoniae 7-10 days. Staphylococcus or Listeria Minimum of 14 days. 21 Herpes Simplex Encephalitis • Consider if altered consciousness, seizures, or focal neurology. • Fever and personality changes are uniformly present in Herpes simplex encephalitis. • LP usually abnormal with the presence of mononuclear cells. • EEG may be characteristic. • PCR testing is very sensitive and specific but should not be ordered prior to knowledge of LP findings. Pathogen: Herpes simplex. Drug Treatment: DRUG DOSE Empiric Aciclovir 10 mg/kg iv 8 hourly Treatment Duration: 14 –21 days Notes: • Most patients with biopsy-proven HSV encephalitis present with a focal encephalopathic process characterised by altered mentation and decreasing levels of consciousness with focal neurologic findings, including dysphasia, weakness and paraesthesia. Fever and personality changes are uniformly present. • Approximately two-thirds of patients with biopsy-proven disease develop either focal or generalised seizures. • Herpes simplex PCR on CSF is a very sensitive and specific diagnostic test. It will usually only be performed with the presence of mononuclear cells in CSF. • It is therefore important to make all efforts to confirm the diagnosis. • All suspected cases of Herpes simplex encephalitis should be reviewed by the Infectious Diseases Physician or Virologist so that PCR testing can be performed in a timely manner 22 Brain Abscess In the immunocompetent, most brain abscesses are polymicrobial with microaerophilic cocci, including Streptococcus anginosus/milleri, and anaerobic bacteria predominating. However, where the likely site of origin is the ear, enteric Gramnegative bacilli are commonly involved, while after trauma or surgery, Staphylococcus aureus predominates. In the immunocompromised, Nocardia species, Toxoplasma gondii and fungi such as Cryptococcus species, Aspergillus species or Scedosporium species are more lily to occur. Modify therapy on the basis of Gram stain and culture results. Durations of IV treatment from 2 to 6 weeks are used and depend on surgical drainage, clinical response and radiological evidence of resolution. Drug Treatment: DRUG DOSE Empiric 1 Metronidazole 500mg IV 8-hourly plus Ceftriaxone 2g iv 12 hourly For postneurosugical brain abscess VancomycinH 1.5g IV 12hourly plus CeftazidimeH 2g IV 8-hourly 23 EAR, NOSE AND THROAT INFECTIONS Acute Otitis Media • • • • True acute otitis media may be either viral or bacterial, but in either case is usually a self-limiting disease (60% of placebo-treated children become pain-free in 24 hours and 80% of cases resolve without antibiotics). Provision of adequate analgesia is necessary. Treatment with antibiotics should be considered only after a 24 hour trial of analgesia. The NNT is 16; i.e. 16 children need to be treated at first presentation to prevent one child experiencing pain at 2 to 7 days. Pathogens: Common: Viral, Streptococcus pneumoniae, Haemophilus influenzae. Other: Streptococcus pyogenes, Moraxella catarrhalis, Staphylococcus aureus. Drug Treatment: DRUG DOSE Empiric Amoxycillin 500mg po 8 hourly Patients with penicillin allergy Cotrimoxazole1 960mg po 12 hourly Beta-lactamase producing organisms (known or suspected) Amoxycillin/clavulanate 1 500/125mg po 8 hourly Avoid cotrimoxazole in pregnancy. Beware with use of cotrimoxazole in the elderly. Treatment Duration: 5 days. 24 Acute Sinusitis • • Sinus congestion often occurs with viral infection or allergy, which require no antibacterial treatment. Antibiotic therapy should be considered when at least 3 of the following features are present: - persistent (greater than a week) mucopurulent nasal discharge - facial pain - poor response to decongestants - tenderness over the sinuses, especially unilateral maxillary tenderness - tenderness on percussion of maxillary molar and premolar teeth. - Fever 38.4º or more Pathogens: Common: Viral, Streptococcus pneumoniae, Haemophilus influenzae. Other: Moraxella catarrhalis, Staphylococcus aureus, Gram-negative bacilli, anaerobes. Drug Treatment: DRUG DOSE Empiric Amoxycillin 500mg po 8 hourly Patients with penicillin allergy Doxycycline2, or Cotrimoxazole 3 100mg po 12 hourly 960mg po 12 hourly Pathogens Known Beta-lactamase producing organisms or anaerobes Amoxycillin/clavulanate 500/125mg po 8 hourly Staphylococcus aureus Flucloxacillin4 500/125mg po 8 hourly 2 Avoid doxycycline in both pregnancy and children. Avoid cotrimoxazole in pregnancy and the elderly. 4 For treatment of patients with penicillin allergy - see Empiric treatment. 3 Treatment Duration: At least 10 days. 25 Chronic Sinusitis Pathogens: NB: Microbiological diagnosis requires a biopsy or sterile aspirate Common: Anaerobes, Streptococci, Staphylococcus aureus. Other: Gram-negative bacilli, Pseudomonas aeruginosa. Drug Treatment: DRUG DOSE Empiric Amoxycillin/clavulanate 500/125mg po 8 hourly Patients with penicillin allergy Doxycycline1, or Cotrimoxazole 2 100mg po 12 hourly 960mg po 12 hourly Pathogens Known Pseudomonas aeruginosa (proven) Ciprofloxacin1, H 500mg po 12 hourly Staphylococcus aureus Flucloxacillin3 500mg po 8 hourly 1 Avoid doxycycline and ciprofloxacin in both pregnancy and children. Avoid cotrimoxazole in pregnancy. 3 For treatment of patients with penicillin allergy - see Empiric treatment. 2 Treatment Duration: At least 14 days. Note: Consider referral to the ENT Service as structural abnormalities may be present. 26 Pharyngitis • • • Most cases of pharyngitis are caused by viral infection and therefore do not require antibiotic therapy. A bacterial cause of acute sore throat is more common in children aged 3 to 13 years (30-40%), than in children aged less then 3 years (5-10%) or adults (5-15%). The four diagnostic features suggestive of Streptococcus pyogenes infection are: - fever >38 C - tender cervical lymphadenopathy - tonsillar exudate - no cough Sore throats, though mostly viral, need to be taken seriously in New Zealand, where a high rate of endemic rheumatic fever persists. As the sequelae of rheumatic fever are so serious (including permanent cardiac impairment or death), the small chance of a sore throat being caused by GAS, and potentially leading to rheumatic fever, cannot be overlooked in clinical decision-making. Those at greatest risk are Maori or Pacific peoples between the age of 3-45 living in lower socioeconomic areas of North Island. See: http://www.nzma.org.nz/journal/122-1301/3746/algorithms.pdf Pathogens: Common: Viral, Streptococcus pyogenes. Other: Corynebacterium diphtheriae, Chlamydia pneumoniae, Neisseria gonorrhoea, Mycoplasma pneumoniae. Drug Treatment: DRUG DOSE Empiric Phenoxymethylpenicillin 500mg po 12 hourly Patients with penicillin allergy Roxithromycin 300mg po daily Pathogens Known Streptococcus pyogenes Phenoxymethylpenicillin 500mg po 12 hourly Other organisms, or penicillin allergy Roxithromycin 300mg po daily Treatment Duration: 10 days Note: Diphtheria infections require urgent referral to a Specialist. 27 RESPIRATORY TRACT INFECTIONS Exacerbations of COPD And Chronic Bronchitis Pathogens: Common: Viruses, Streptococcus pneumoniae, Haemophilus influenzae. Other: Moraxella catarrhalis. Antibiotics have only been shown to be effective when all 3 cardinal symptoms of acute bacterial exacerbations are present: increased dyspnoea, increased sputum volume and sputum purulence. Drug Treatment: DRUG DOSE Empiric1 Smokers Amoxycillin/clavulanate 500/125mg po 8 hourly Non Smokers Amoxycillin 500mg po 8 hourly Patients with penicillin allergy Doxycycline2 100mg po 24 hourly Pathogens Known Streptococcus pneumoniae Amoxycillin 500mg po 8 hourly Penicillinase- producing Haemophilus influenzae or Moraxella catarrhalis Amoxycillin/clavulanate 500/125mg po 8 hourly 1 2 Empiric treatment is often used in moderate to severe exacerbations. Avoid doxycycline in pregnancy and children. Treatment Duration: Variable depending on clinical response. Notes: • • There is no indication for IV therapy in the treatment of chronic bronchitis. If pneumonia is diagnosed, refer to pneumonia protocol. 28 Pneumonia Pathogens: Common: Streptococcus pneumoniae. Other: Haemophilus influenzae, Mycoplasma pneumoniae, Legionella pneumophila, Staphylococcus aureus, Moraxella catarrhalis, Klebsiella pneumoniae, Chlamydia pneumoniae. The choice of antibiotic for CAP is usually empirical, because the clinical presentation and CXR appearances are not sufficiently specific to direct therapy against any one of the likely causative organisms, and stand microbiological tests have a relatively low yield. Community Acquired - Mild / Moderate Disease (CURB Score ≤2) Drug Treatment: DRUG DOSE Empiric Amoxycillin 1g po 8 hourly 1 g iv 8 hourly1 Patients with COPD or smokers Amoxycillin/Clavulanate 1g/200mg iv 8 hourly1 500/125mg po 8 hourly Patients with penicillin allergy Roxithromycin 1 300mg po daily IV therapy is usually only necessary when concerns are held regarding absorption of oral antibiotics. Treatment with “atypical agents” is not usually recommended in mild/moderate pneumonia Treatment Duration: Usually 5 - 7 days depending on severity. Aspiration pneumonia 10 days Atypical pneumonia 14 days 29 Community Acquired - Severe Disease (CURB Score ≥3) Definition: Community acquired pneumonia with at least two of the following CURB-65 risk factors: - Confusion - Urea >7mmol/l - Respiratory rate > 30/min - Diastolic BP < 60mmHg - Age >65years Drug Treatment: DRUG Erythromycin and Amoxycillin/clavulanate DOSE 1g iv inf q6 hourly 1g/200mg iv q8 hourly Treatment Duration: 7-10 days, although most patients will change to oral therapy within 24 hours. Notes: • Most patients admitted to hospital will not have severe disease by the above definition. • Most patients will be able to change to oral therapy within 24 hours. If no pathogen is identified and the patient is improving, change iv amoxycillin/ clavulanate to oral amoxycillin 1g 8hrly and change IV erythromycin to oral macrolide e.g. roxithromycin 300 mg daily. • CXR changes will persist despite appropriate therapy for up to eight weeks (dependent on age of patient and underlying lung condition). • The new fluoroquinolone agents are not recommended for empiric management of pneumonia at Waikato Hospital. They are not on the HML for the management of pneumonia unless highly resistant pneumococci are proven. • Erythromycin iv produces a high rate of phlebitis and may require central line administration if prolonged administration is planned. 30 Hospital Acquired pneumonia Nosocomial or hospital-acquired pneumonia is defined as pneumonia that is not incubating at the time of admission to hospital and develops in a patient hospitalised for longer than 48 hours. Most bacterial HAP occurs by microaspiration of bacteria colonising the oropharynx or upper gastrointestinal tract of the patient. The spectrum of potential pathogens associated with HAP may differ from that of community-acquired pneumonia (CAP) as hospitalised patients more frequently develop colonisation of the oropharynx with aerobic Gram-negative bacilli, and may also be at greater risk of multiresistant hospital pathogens such as MRSA, ESBL etc. Hospital Acquired – Mild or Moderate Despite the change in spectrum of organisms, the use of amoxicillin/clavulanate monotherapy remains appropriate Hospital Acquired – Severe Infection only Drug Treatment: DRUG DOSE Gentamicin See gentamicin dosing guideline and Amoxycillin/Clavulanate 1g/200mg iv 8 hourly and Erythromycin 1g iv inf 6 hourly1 1 The need for erythromycin is confined to empirical treatment of legionella. If this has been excluded erythromycin can be discontinued. Treatment Duration: 10 days 31 Aspiration Pneumonia Drug Treatment: DRUG DOSE Amoxycillin/Clavulanate 1g/200mg iv 8 hourly or ClindamycinH 600mg iv inf 8 hourly Treatment Duration: 10 days. Community / Hospital Acquired Infection-Pathogens Known Drug Treatment: DRUG DOSE Streptococcus pneumoniae Amoxycillin 1g po 8 hourly 1 g iv 8 hourly Staphylococcus aureus Flucloxacillin or Vancomycin 1, H 1g iv 6 hourly 1g iv inf 12 hourly2 Klebsiella pneumoniae Cefuroxime 750mg iv 8 hourly Legionella pneumophila, Mycoplasma pneumoniae Erythromycin 500mg – 1g iv inf 6 hourly 1 2. If methicillin-resistant, or patient has severe penicillin allergy Adjust vancomycin dosing for renal function. Treatment Duration: Variable dependent on patient characteristics. Notes: • • • Streptococcus pneumoniae still remains the most common cause of pneumonia and must be adequately covered by any regime chosen. If Legionella pneumophila is suspected, use high dose macrolide therapy. Please seek Infectious Diseases advice. Legionella PCR can be undertaken on serum, sputum or BAL at Waikato Hospital. Although pneumococcal resistance is increasing, clinical trials suggest that amoxycillin still remains adequate treatment for pneumonia, as drug levels still exceed the MIC levels of the resistant organism (less than 5% of pneumococci show high level resistance – May 2012). 32 Tuberculosis • • • • Tuberculosis is a notifiable disease- notify to Medical Officer of Health ext 2065 Treatment of tuberculosis is a specialised area and should involve respiratory physician and public health input to ensure adequate treatment and contact tracing occurs. Liver function, serum creatinine, electrolytes, are essential blood tests that should be checked before treatment. Liver function should be monitored routinely. Pathogen: Mycobacterium tuberculosis. Drug Treatment: • • • • Multiple antitubercular drug therapy is initiated primarily to guard against the existence and/or emergence of resistant organisms. The current recommendations are for a short course, i.e. Six months of therapy in pulmonary tuberculosis. Extra-pulmonary Tb often requires longer courses. This consists of an initial two months of therapy using 3 or 4 drugs, the aim of which is to obtain a rapid decrease in the number of viable organisms, followed by a further four months of therapy with 2 drugs, rifampicin and isoniazid, to eradicate any remaining organisms. The initial regimen must contain pyrazinamide for the short course to be effective. DRUG Rifampicin1 and Isoniazid 1,2,3 and Pyrazinamide1 ± Ethambutol 1,4,5,6 DOSE Wt <50kg, 450mg po mane for 6 months Wt ≥50kg, 600mg po mane for 6 months 300mg po mane for 6 months Wt <50kg, 1.5g po mane for 2 months Wt ≥50kg, 2g po mane for 2 months 15mg/kg po mane for 2 months, or until sensitivity results return 1 Four drugs are given daily in those with previous TB therapy, those from high incidence countries and those with extensive disease. i.e. Rifampicin, Isoniazid, Pyrazinamide and Ethambutol. 2 Combination tablets of Isoniazid and Rifampicin exist in NZ – Rifinah 150 (Rifampicin 150mg/Isoniazid 100mg) and Rifinah 300 (Rifampicin 300mg/Isoniazid 150mg) 3 Pyridoxine 25mg po is usually given daily while on isoniazid to prevent neurotoxicity. 4 Ethambutol (the 4th drug) can be omitted from NZ born patients without prior treatment. 5 Ethambutol is not recommended for children under 6 years. 6 Visual acuity with a Snellen chart and red-green vision should be checked prior to commencement of ethambutol and regularly throughout treatment Treatment Duration: At least 6 months Notes: • Intermittent supervised therapy is often given in twice or three times week regimens and is preferred for infectious pulmonary tuberculosis. • Always check dosages (Refer to Guidelines for Tuberculosis Control in NZ 2010) http://www.immune.org.nz/sites/default/files/factsheets/guidelines-tuberculosiscontrol-new-zealand%202010.pdf 33 Influenza • • • • • • • • • The typical clinical syndrome caused by Influenza virus infection is an abrupt onset of fever, myalgia and cough. Many cases are less typical, however. Most cases of “Influenza – like illness” are caused by other agents. Influenza may mimic meningococcal disease – be wary when making a clinical diagnosis Influenza usually circulates as a distinct epidemic for 4 to 6 weeks each winter. Superinfection with bacteria such as Haemophilus influenzae and Staphylococcus aureus can cause severe pneumonia and these should be covered in empiric treatment. Neuraminidase inhibitors such as oseltamivir, if administered early, reduce severity and duration of illness and reduce viral shedding and may be considered in specific circumstances. They are not Pharmac funded. Outbreaks can occur on hospital wards and in long-term care facilities. Nasopharyngeal swab for direct immunoflourescence is available within Waikato Hospital. This is available 6 days a week during influenza season. Sensitivity is 60-80%. Acute and convalescent serology is also available to make a retrospective diagnosis of influenza. 34 GASTROINTESTINAL TRACT AND INTRA-ABDOMINAL INFECTIONS Dental and Gingival Infections For tooth abscess, inflamed wisdom tooth area or root canal infection, local treatment includes removal of the dental pulp from the related tooth or extraction of the tooth, as well as drainage of the abscess when fluctuant. With mild disease, antibiotics are often not required. • • Pathogens: Common: Mixed aerobic and anaerobic oral flora. Drug Treatment: DRUG DOSE Empiric Amoxycillin/Clavulanate 500/125mg orally tds or Clindamycin1, H 1 300mg orally tds For patients with penicillin allergy. Treatment Duration: 3 - 5 days 35 Acute Peritonitis Pathogens: Common: Enterobacteriaceae, Enterococcus, Anaerobes. Other: Streptococcus milleri (especially in abscesses). Drug Treatment: DRUG DOSE Cefuroxime1,2 750mg IV q8 hourly and Metronidazole 500mg IV q8 hourly and if pelvic inflammatory disease suspected Doxycycline 100mg PO q12 hourly Treatment Duration: 5 - 10 days Notes: • Consult Specialist to discuss management of patients with severe penicillin allergy. • Various treatment strategies are suggested in the literature using single, dual and triple combinations. • All strategies appear equally effective with the proviso that the drug regimen used has activity against Enterobacteriaceae and Bacteroides fragilis. • Cefuroxime covers the majority of Enterobacteriaceae involved in acute peritonitis. • Abscesses may require longer therapy and/or drainage. • If a patient has improved clinically on cefuroxime/metronidazole and has had the underlying cause of peritonitis adequately treated, oral co-amoxyclavulanate can usually be given to complete a course of antibiotics provided there is no microbiologic evidence to the contrary. 36 Cholecystitis / Cholangitis Pathogens: Common: Enterobacteriaceae, Enterococcus. Drug Treatment: DRUG DOSE Gentamicin See gentamicin dosing guideline and Augmentin 1.2g IV q8 hourly2 Patients with mild penicillin allergy or significant renal dysfunction Ceftriaxone 1g iv 24 hourly and Metronidazole 1 500mg iv inf 12 hourly If IV therapy is still indicated after three days consider augmentin or piperacillin/tazobactamH 4.5g IV 8 hourly as monotherapy depending on clinical response. Treatment Duration: 5 - 10 days Note: Consult Specialist to discuss management of patients with severe penicillin allergy. 37 Acute Pancreatitis/Severe Necrotising Pancreatitis • • Antibiotics are not indicated in the initial management of acute pancreatitis. Antibiotics can be considered on a case by case basis for patients with severe necrotising pancreatitis (defined by CT) or suspected pancreatic abscess Pathogens: Common: Enterobacteriaceae, Enterococcus, Anaerobes. 38 Infectious Diarrhoea • • • The first priority in management is to ensure adequate fluid and electrolyte replacement. Routine administration of antibiotics is not indicated and may be harmful in certain situations. Discuss antibiotic administration with an infectious disease specialist or clinical microbiologist. Pathogens: Common: Campylobacter jejuni (73%). Salmonella sp (non typhi) (7%), Shigella sp (1%). Other: (<1%) Yersinia enterocolitica, Vibrio parahaemolyticus, Plesiomonas shigelloides. Drug Treatment: DRUG Pathogens Known DOSE Campylobacter jejuni Usually self-limiting, routine use of antibiotics not recommended1 Usually self-limiting, routine use of antibiotics not recommended2 Metronidazole 2g po daily for 3 days Usually self-limiting in immunocompetent host. No role for antimicrobial therapy Salmonella species (non-typhi)2,3 Giardia Cryptosporidiosis3 1 Consider therapy if high fever or bloody diarrhoea with Norfloxacin 400mg 12hrly Treatment may lead to an increased risk of clinical relapse. If treatment required Ciprofloxacin 500mg 12hrly is usually the treatment 3 Infectious disease consultation in immuno-compromised host, very severe illness or bacteraemia. 2 Treatment Duration: Variable. 39 Clostridium difficile disease • • • Send stool for antigen testing in patients with a diarrhoeal illness occurring more than 48 hours after hospital admission or with a history of antibiotic use. 5% of Clostridium difficile infection occurs in patients without a history of antibiotic use and this proportion may rise during hospital-based epidemics. Do not underestimate the potential for Clostridium difficile to cause severe disease. In all cases but especially the elderly, provide careful supportive care with attention to hydration and nutrition. SEVERE DISEASE • Use PO or NG vancomycin as a first-line agent in any patient with a clinically severe illness. • Severe disease is defined as two or more of: age>60, T>38.3, serum albumin <25g/L, TWC>15 cells/mL. DRUG DOSE Empiric Metronidazole 400mg po 12 hourly or VancomycinH 125mg po 6 hourly Treatment Duration: 14 days. 40 Typhoid / Paratyphoid Fever Pathogens: Salmonella typhi, Salmonella paratyphi. Drug Treatment: DRUG DOSE Empiric AzithromycinH 1g po daily 10 days or Ceftriaxone 2g IV daily Treatment Duration: 5 - 10 days. Notes: Salmonella typhi resistance to ciprofloxacin has increased to the point that it is no longer first line therapy. If patient is still febrile at 5 days suspect resistance. 41 Helicobacter Pylori Infection Pathogen: Helicobacter pylori. • All patients with positive tests for H.pylori infection should undergo eradication therapy. • For eradication regimes refer to the New Zealand Formulary. • Most regimes consist of an acid suppressant such as Omeprazole 20mg bd along with two antibiotics eg amoxicillin 1g bd and clarithromycin 500mg bd or amoxicillin 1g bd and metronidazole 400mg tds or clarithromycin 500mg bd and metronidazole 400mg bd. • Test for cure: treatment failure is increasingly recognised and predicts relapse of ulcer disease. Request H.pylori faecal antigen test one month following triple therapy – inform patient of the following recommendations and include them in the discharge summary to GP; i) perform test one month following completion of eradication therapy, ii) patient must not be taking antibiotics, antacids, or acid-suppressants in the two weeks preceding the test, iii) re-treat according to the New Zealand Formulary for patients with positive stool antigen tests. 42 URINARY TRACT INFECTIONS Urinary tract infection as a clinical entity is a source of considerable confusion, resulting in significant over-use of antibiotics. The following rules of thumb are used by infectious disease physicians to aid decision-making: 1. Only pregnant women and patients undergoing genitourinary tract instrumentation are treated for asymptomatic bacteriuria. In the absence of symptoms we do not treat bacteriuria in elderly patients, diabetics, patients undergoing joint arthroplasty, patients with indwelling urinary catheters or patients with positive assays for leucocytes/nitrites on dipstick testing. 2. Urinary tract infection is an unlikely cause of delirium in elderly patients without genito-urinary symptoms or systemic evidence of sepsis. 3. A “complicated” urinary tract infection is defined by the presence of underlying conditions that increase the risk of treatment failure (see below). This does not include acute first episodes of pyelonephritis in healthy young women with only mild to moderate symptoms. Cystitis • • • • Cystitis is the syndrome of frequency and dysuria in women1. It is due to bacterial infection in 70-80% of cases. Patients with bacterial cystitis usually have pyuria. Men with cystitis should be evaluated thoroughly for sexually transmitted infection (STI) and structural abnormalities of the male genito-urinary tract.1 Refer to STI guidelines or treat as “complicated” urinary tract infection if STI ruled out. Pathogens: Cystitis in women: Escherichia coli, Staphylococcus saprophyticus. Drug Treatment: DRUG DOSE Empiric Trimethoprim2 600mg po stat, or 300mg po daily for three days If resistant to trimethoprim3 Nitrofurantoin 200mg po stat, or 100mg po 12 hourly for three days Amoxycillin/clavulanate 500/125mg po 12 hourly Pathogens Known Alternatives used according to sensitivities. 1 Urinary tract infections in men are often associated with infection of the posterior urethra, prostate or epididymis. 2 Avoid trimethoprim and norfloxacin during pregnancy. Amoxycillin/clavulanate 43 3 500/125mg 12 hourly or cephalexin 500mg 12 hourly are suitable alternatives. Trimethoprim resistance is present in 20% of E.coli but 50% of women with resistant isolates responding to treatment. Treat women with resistant isolates who have not already responded to trimethoprim. Treatment Duration: 3 days Uncomplicated pyelonephritis A proportion of non-pregnant young women with clinical evidence of pyelonephritis can be managed in the community. In this situation, ciprofloxacin 500mg bd is an appropriate agent even in severe cases (Lancet 2012; 380: 484-90) and is approved without ID or microbiology approval as follows; 1. The patient has been reviewed or discussed with an Emergency Department SMO to confirm the diagnosis of pyelonephritis vs cystitis1. The name of the SMO must be written on the prescription. 2. The patient is female, non-pregnant and has received an intravenous dose of antibiotic (gentamicin or ceftriaxone) 3. The patient has been able to absorb food and fluids over a period of observation in the emergency department 4. The patient is accompanied by a competent carer for the first 24 hours of treatment. 5. The patient and carer have been counselled regarding the need to continue antibiotics and to re-present to hospital if fever persists beyond 48 hours, symptoms worsen or vomiting prevents absorption of antibiotics. 1 Patients with cystits (ie frequency and dysuria without documented fever, back pain or sepsis) should receive treatment according to cystitis guidelines. 44 Complicated UTI • Complicated urinary tract is defined by the presence of factors that increase the risk of treatment failure. This includes; • Diabetes; pregnancy; renal failure; known obstruction or structural lesions of the urinary tract; recent instrumentation; indwelling catheter or nephrostomy; immunosuppression; renal transplant patients; male patients • Organ imaging (usually ultrasound or non-contrast CT urogram) should be considered in the following cases: • Men with recurrent bacterial cystitis or pyelonephritis • Patients with bacteraemia or if acute pyelonephritis follows an atypical course (ie persistent severe toxicity/septic shock despite antibiotics) • UTIs become closely spaced • UTIs occur prior to commencement of sexual activity • Persistent haematuria following resolution of infective symptoms Pathogens: Escherichia coli, other coliforms, enterococcus spp, Pseudomonas aeruginosa. Drug Treatment: Scenario 1: the patient has a complicated urinary tract infection requiring admission and no contraindications to gentamicin. Rx: Gentamicin 5mg/kg; follow gentamicin dosing guidelines. Scenario 2: the patient has a complicated urinary tract infection with absolute or relative contraindications to gentamicin (including pregnancy) Rx: Ceftriaxone 2g daily; check culture and sensitivity results daily Scenario 3: gentamicin or ceftriaxone have been given for 48 hours and culture results are available Rx: Switch to an appropriate oral agent once the patient is clinically improving Scenario 4: gentamicin or ceftriaxone have been given for 48 hours and there are no culture results available Switch to one of the following regimes if the patient is clinically improving and continue to follow culture results: • • Augmentin 625mg PO 8 hourly Cotrimoxazole 480mg PO 12 hourly (avoid in pregnancy) Treatment Duration: Use IV therapy until satisfactory clinical response, followed by oral therapy when tolerated for a total of 7 days. Longer courses may be required in the presence of an abscess, prostatitis or an obstructed urinary tract system. Consult urology or infectious diseases. 45 Ciprofloxacin prescribing policy 1. Ciprofloxacin is a restricted pharmaceutical 2. Ciprofloxacin will be dispensed in accordance with the “restricted pharmaceutical policy” and without ID/Microbiology approval in the following situations a. Uncomplicated pyelonephritis in women presenting to the emergency department (see above) b. Men with suspected prostatitis and cultures proving a ciprofloxacin susceptible organism c. Prophylaxis for TRUS biopsy (TRUS to be written on prescription) d. Treatment of ciprofloxacin susceptible Pseudomonas aeruginosa in a patient with a clinical diagnosis of complicated urinary tract infection or respiratory tract infection e. Other rare scenarios as outlined within this document 46 GENITAL TRACT INFECTION Genital tract infections usually require more than antibiotic therapy; e.g. full sexual history, partner tracing, appropriate specimen taking and examination, specialist knowledge, support, education and counselling. For these reasons, discussion with or referral to the Sexual Health Service, Health Waikato is recommended. For discussion or urgent referral, phone ext. 98732 or 98753, or fax referrals to ext. 98892. Note that the clinic runs on an appointment basis, rather than a walk-in service. Patients can book their own appointments, on 07 839 8732. The service aims to see all patients within 48 hours. 47 Pelvic Inflammatory Disease Pathogens: Common: Neisseria gonorrhoea, Chlamydia trachomatis, Enterobacteriaceae, Streptococci sp, Anaerobes. Other: Clostridium perfringens, Group A Streptococci. Drug Treatment: DRUG Inpatient Regimens A. Cefoxitin and Doxycycline3 followed by Doxycycline3 and Metronidazole4 B. ClindamycinH and Gentamicin followed by ClindamycinH, or Doxycycline3 and Metronidazole4 DOSE 1,2 2g iv tds 100mg po bd 100mg po bd 400mg po bd 900mg iv tds 2mg/kg loading dose iv followed by 1.5 mg/kg 8 hourly or 7mg/kg iv daily5 450mg po qds 100 mg po bd 400mg po bd Outpatient Regimen Ceftriaxone, or 500 mg im stat Ciprofloxacin6, H 500 mg po stat followed by Doxycycline3 100 mg po bd and Metronidazole4 400mg po bd 1 All antibiotic regimens are evidence-based and are of similar efficacy. 2 Patients known to be allergic to one of the suggested regimens should be treated with an alternative. 3 Avoid doxycycline in pregnancy and children. 4 Metronidazole is included to improve coverage for anaerobic bacteria. Anaerobes are of relatively greater importance in patients with severe PID and metronidazole may be discontinued in those patients with mild or moderate PID who are unable to tolerate it. 5 Adjust dosing interval of gentamicin for renal function. 6 Avoid ciprofloxacin in pregnancy and children. Treatment Duration: 14 days total therapy. In-patient intravenous therapy should be continued for 24 hours after clinical improvement and then switched to oral. 48 Bacterial Vaginosis Pathogen: Gardnerella vaginalis. Other: Mixed anaerobes, e.g. Mobiluncus, Bacteroides, Mixed aerobes, e.g. Staphylococcus and Streptococci. Drug Treatment: DRUG DOSE Empiric Metronidazole 2g po stat or 400mg po 12 hourly for 7 days1 1 If stat treatment is unsuccessful. Treatment Duration: See dosage above. Notes: • • • G.vaginalis isolation per se should not be treated. Treatment is indicated only with Gram-stain confirmation of bacterial vaginosis ± symptoms e.g. malodorous vaginal discharge. Screen for all other sexually transmitted diseases. Empirical partner treatment for Gardnerella has no effect on reducing recurrence rate in women, but it may be advisable to exclude other infections e.g. non-specific urethritis in sexual partners. 49 Candidosis / Vulvo-Vaginitis Pathogen: Candida albicans. Drug Treatment: DRUG DOSE Empiric Clotrimazole 500mg pv stat, or 100mg pv nocte for 6 nights Recurrent infections Consider monthly therapy with: ItraconazoleH or 200mg po 12 hourly for one day Fluconazole 150mg po stat Treatment Duration: See dosage above. Notes: • Make sure diagnosis is correct. • Treating the male partner does not reduce the frequency of recurrences in women; men should therefore only receive treatment if symptomatic. • Exclude predisposing factors, e.g. urine dip stick for glycosuria. • If frequent recurrences (>4 per year), refer to Sexual Health Clinic or combined Gynae/Skin Clinic for review. 50 Chlamydial Cervicitis / Urethritis Pathogen: Chlamydia trachomatis. Drug Treatment: DRUG DOSE Empiric AzithromycinH or 1gm po stat1 Doxycycline2 100mg po bd for 7 days 1 2 Stat treatment is possible due to the long half-life of azithromycinH. Avoid doxycycline in pregnancy and children. Treatment Duration: See dosage above. Note: Sexual partners (i.e. within the last 3 months) need to be screened for STDs and treated for Chlamydia without delay i.e. without waiting for their test results, to avoid further transmission of infection. 51 Genital Herpes Simplex Pathogen: Herpes simplex. Drug Treatment: DRUG DOSE Empiric Acyclovir 200mg po 5 times daily Treatment of superinfection Cotrimoxazole1 960mg po 12 hourly 1 Avoid cotrimoxazole in pregnancy. Treatment Duration: 5 days. Notes: • • • • Simple recurrences (secondary attacks) do not always require acyclovir tablets. Severe HSV infection (e.g. in immunocompromised patients, insulin-dependent diabetics) may require IV acyclovir. Suppressive therapy is indicated when confirmed recurrences are frequent (>6-8 per year), severe or associated with significant psychological morbidity – usual dosage is 400mg po bd. Consider referral for specialist advice or counselling. 52 Gonorrhoea Pathogen: Neisseria gonorrhoea. Drug Treatment: DRUG DOSE Empiric Ceftriaxone 500mg im stat and either: Doxycycline 1,2 or 100mg po 12 hourly for 7 days AzithromycinH 2,3 1 g po as a single dose 1 2 Avoid doxycycline in pregnancy and children. The doxycycline or azithromycinH is given to cover Chlamydia, which co-exists with gonorrhoea in 40-50% cases. This should be given, even if the Chlamydia test is negative, as false-negative Chlamydia tests have been reported in this situation. Treatment Duration: See dosage above. Notes: • • • The incidence of penicillin- resistant Neisseria gonorrhoea means that penicillin or amoxycillin should be reserved for known penicillin-sensitive strains. Ceftriaxone (500mg stat IM) is now used due to high rates of ciprofloxacin resistance. If sensitivity results are known at time of treatment Ciprofloxacin 500mg stat is an oral alternative. Pharyngeal and uncomplicated rectal gonorrhoea can be treated successfully with a single stat dose of ceftriaxone or ciprofloxacin (if the organism is sensitive). Sexual partners (i.e. within the last 3 months) need to be screened for STDs and treated for gonorrhoea without delay, i.e. without waiting for their test results, to avoid further transmission of infection. 53 Non-Gonococcal Urethritis (Non-Specific Urethritis, NSU) Pathogens: Common: Chlamydia trachomatis, Ureaplasma urealyticum. Other: Trichomonas vaginalis, Herpes simplex (less than 5% of cases of NSU) Various skin bacteria. Drug Treatment: DRUG DOSE Empiric Doxycycline1 100mg po 12 hourly for 7 days or AzithromycinH 1 g po stat dose Pathogens Known Trichomonas vaginalis Metronidazole 2g po stat Herpes simplex Acyclovir 1 200mg po 5 times daily for 7 days Avoid doxycycline in pregnancy and children. Treatment Duration: See dosage above. Note: Screen and treat partners as for Chlamydia infection. 54 Trichomoniasis • Trichomonas vaginalis causes vaginitis and occasionally urethritis in males. Pathogen: Trichomonas vaginalis. Drug Treatment: DRUG DOSE Empiric Metronidazole 2g po stat for females or 400mg po bd for 7 days for male contacts Treatment Duration: See dosage above. Syphilis Pathogen: Treponema pallidum. Drug Treatment: See note below. Treatment Duration: Depending on stage of disease. Note: The management of syphilis usually requires specialist knowledge. Therefore regimens have not been included. Referral to Sexual Health Service, Health Waikato (07) 8398732 is recommended for people with reactive syphilis serology. 55 SKIN, MUSCLE AND BONE INFECTIONS • • • • There is no role for the combined usage of flucloxacillin and penicillin. The belief that flucloxacillin is able to cover Staphylococcus aureus and not Streptococcus pyogenes is incorrect. The MIC90 of flucloxacillin for Streptococcus pyogenes is 0.4µg/ml. This concentration is extremely easy to achieve. No randomised studies show the need for both agents http://emj.bmj.com/content/22/5/342.full If anaerobic cover is required, the use of metronidazole is preferred. Metronidazole will cover Clostridium tetani if this is being considered. For suspected bone infections, all efforts should be made to obtain material for culture before any antibiotics are given to the patient. In the absence of severe systemic upset it is unlikely that delays for microbial sampling will lead to clinical deterioration – a definitive microbiologic diagnosis is of the greatest value to the patient. Osteomyelitis - Acute Pathogens: Common: Staphylococcus aureus (> 80%), Streptococci species. Other: Enterobacteriaceae, Pseudomonas aeruginosa. Drug Treatment: DRUG DOSE Empiric Flucloxacillin Patients with mild penicillin allergy Cephazolin 2g iv 6 hourly, then 1g po 6 hourly 1g iv 6 hourly Patients with severe penicillin allergy ClindamycinH 450mg iv inf 8 hourly, then 450mg po 8 hourly Treatment Duration: • Minimum duration is 6 weeks in adults. • IV therapy should be given for 14 days in adults and then changed to oral therapy. Children with acute osteomyelitis can be treated with very brief IV courses (suggested by some authorities as a minimum of 3 days). Notes: • • Chronic osteomyelitis diagnosis and treatment - refer Specialist. MRSA osteomyelitis - seek Infectious Diseases advice. 56 Septic Arthritis - Non Prosthetic Joint Pathogens: Common: Staphylococcus aureus, Group A streptococcus. Other: Neisseria gonorrhoea. Drug Treatment: DRUG DOSE Empiric See empiric therapy for Osteomyelitis Treatment Duration: Duration of total treatment is 4 weeks, including at least 7 days IV therapy. Notes: • • Joint washout usually required - refer Specialist. Prosthetic joint infections - refer Specialist. Septic Arthritis - Prosthetic Joint The proportion of prosthetic hips that become infected is 0.5-1%, knees 1-2% and elbows 4-9%. Treatment always involves a combination of surgery and antibiotics; antibiotics are seldom successful when used alone. If possible all antibiotic therapy should be withheld until appropriate diagnostic samples have been collected. Eradication of infection is most likely to be achieved if the prosthesis and all associated foreign material are removed, together with devitalised tissue and infected bone. Debridement and retention is only recommended as a possibility in early infection (<3 months after primary implantation). 57 Bites and Clenched Fist Injuries Bites and clenched fist injuries can often become infected. In all cases a patient’s tetanus immunisation status must be assessed. All bites should be cleaned and debrided and irrigated. Elevation and immobilisation are recommended. Not all bites require antibiotic therapy. Antibiotics are usually reserved for serious bites, especially those more than 4 hours old; involving the hand; or associated with deep puncture wounds or crush injury. • • • • Pathogens: Usually multiple, including anaerobes, Staphylococcus aureus, Streptococci species, Pasteurella multocida (cats and dogs) and Eikenella corrodens (humans). Drug Treatment: DRUG DOSE Empiric Amoxycillin/clavulanate 500/125mg po 8 hourly Patients with severe infection Amoxycillin/clavulanate 1g/200mg iv 8 hourly Patients with penicillin allergy Cotrimoxazole1 and Metronidazole 960mg po 12 hourly 400mg po 12 hourly or ClindamycinH alone 1 450mg iv inf 8 hourly or 450mg po 8 hourly Avoid cotrimoxazole in pregnancy and the elderly. Treatment Duration: At least 5 days. Note: • Severe infection or poor response to above regimens may also require surgery. 58 Compound Fractures The patient with a compound fracture should have their immune status to tetanus assessed. Prophylaxis or early treatment should be given. Pathogens: Common: Staphylococcus aureus Drug Treatment: DRUG DOSE 1 Empiric Flucloxacillin2 2g iv 6 hourly, then 500mg po 6 hourly Patients with mild penicillin allergy Cephazolin 1g iv 8 hourly followed by Cephalexin 500mg po 8 hourly Patients with severe penicillin allergy ClindamycinH 450mg iv inf 8 hourly, then 450mg po 8 hourly The duration of antibiotic treatment in compound fractures should be for 1 to 3 days. If presentation is delayed (>8 hours), presumptive early treatment should be given for 5 to 7 days, but continued for longer if bone infection is established. 2 If wound soiling or tissue damage is severe and/or devitalised tissue is present, use amoxicillin/clavulanate 1.2 gm IV 8 hourly instead of flucloxacillin. 59 Cellulitis - Simple Pathogens: Common: Streptococcus pyogenes. Other: Staphylococcus aureus, Enterobacteriaceae, anaerobes. Drug Treatment: DRUG DOSE 1 Empiric Flucloxacillin2 1g po 6 hourly or 1g iv 6 hourly, then 1g po 6 hourly Patients with mild penicillin allergy Cephazolin 1g iv 8 hourly followed by Cephalexin 500mg po 8 hourly Patients with severe penicillin allergy ClindamycinH 450mg iv inf 8 hourly, then 450mg po 8 hourly Pathogens Known Streptococcus pyogenes Benzylpenicillin 1.2g iv 4 hourly followed by Penicillin V 500mg po 6 hourly Staphylococcus aureus Flucloxacillin alone As for empiric treatment 1 As the distinction between Streptococcal and Staphylococcal cellulitis is often difficult on clinical grounds, empiric therapy is directed against both organisms. Treatment Duration: • Usual total duration of treatment at least 5 days, depending on response. • 2IV therapy should only be used for those who are systemically ill or systemically well but with a co-morbidity such as peripheral vascular disease, chronic venous insufficiency or morbid obesity which may complicate or delay resolution of their infection. Note: • • There is no role for the combined usage of flucloxacillin and penicillin in any circumstance. If anaerobic cover is required, the use of metronidazole is preferred. Metronidazole will cover Clostridium tetani if this is being considered. 60 Cellulitis - Complicating Ulcer • • Complicating ulcer caused by diabetes, vascular disease. Usually involves multiple organisms. Pathogens Common: Streptococcus pyogenes, Staphylococcus aureus, Enterobacteriaceae, Anaerobes. Drug Treatment: DRUG DOSE Empiric Amoxycillin/clavulanate alone 1g/200mg iv 8 hourly, then 500mg po 8 hourly Patients with mild penicillin allergy Cefuroxime 750mg iv 8 hourly and Metronidazole 500mg iv inf 8 hourly followed by Cephalexin 500mg po 8 hourly and Metronidazole 400mg po 12 hourly Patients with severe penicillin allergy Gentamicin See gentamicin dosing guideline and ClindamycinH 450mg iv inf 8 hourly Treatment Duration: Minimum duration of total treatment is 10 days (longer treatment is often required). Use IV therapy initially for severe infections. 61 Necrotising Fasciitis or Synergistic Gangrene • • • • • • Necrotizing soft-tissue infections are characterised by rapidly progressing inflammation and necrosis of skin, subcutaneous fat and fascia, and sometimes muscle. Clinical clues to early recognition are: oedema beyond the area of erythema, skin vesicles, crepitus, the absence of lymphangitis and lymphadenitis, severe systemic toxicity and pain out of keeping with clinical findings. These are severe, life threatening infections. If clinical suspicion or LRINEC score 6 or more call urgently for surgical help. Antibiotics do not substitute for adequate debridement and there is no proven role for imaging – therefore do not delay surgical consultation. Neither antibiotics nor hyperbaric oxygen substitute for surgical debridement. Consult infectious disease and intensive care specialties early. Pathogens: Common: Mixed aerobes and anaerobes, including Escherichia coli, Bacteroides fragilis, Streptococcus pyogenes and Staphylococcus aureus. Drug Treatment: DRUG DOSE Empiric Benzylpenicillin 2.4g iv q4h and CeftazidimeH 2g iv q8h and ClindamycinH 600mg IV q8h Patients with mild penicillin allergy MeropenemH 1g IV q8h Patients with severe penicillin allergy CiprofloxacinH 400mg IV q12h and ClindamycinH 600mg IV q6h 62 Mastitis / Breast Abscess Pathogens: Common: Staphylococcus aureus (if lactating), anaerobes (if not lactating). Other: Diphtheroids. Drug Treatment: DRUG DOSE Empiric Lactating Flucloxacillin 500mg po 8 hourly Non-lactating Amoxycillin/clavulanate 500/125mg po 8 hourly Patients with penicillin allergy ClindamycinH 450mg po 8 hourly Treatment Duration: 5 days. Note: Failure of symptoms to improve after 2 to 3 days suggests other pathogens or an abscess, requiring review, surgical drainage and bacteriological examination of the pus. 63 Wound Infections POST-OPERATIVE Local measures such as surgical drainage and irrigation with sodium chloride 0.9% will usually suffice. Topical antibiotics may cause skin hypersensitivity and the emergence of resistant organisms, and are not recommended. For mild to moderate infection with surrounding cellulitis, use: Flucloxacillin 500mg orally, 6 hourly. Alternatively, if Gram-negative organisms are suspected or known to be involved, use Amoxycillin/Clavulanate 500/125mg 8 hourly. For more severe infections particularly where systemic symptoms are present, use: Flucloxacillin 2g IV 6 hourly or Cephazolin 1g IV 8 hourly. If Gram-negative organisms are suspected or known to be involved, add Gentamicin 5mg/kg IV daily (adjust dose for renal function, see gentamicin dosing guideline). Episiotomy Infections Infection of the episiotomy site is an uncommon occurrence. Overall, only 0.1% of episiotomies become infected, although this rate increases to 1% to 2% for episiotomies complicated by third- or fourth- degree extensions. Management is as per postoperative wound infections where gram-negative organisms may be involved i.e. Amoxycillin + clavulanate 500/125mg 8 hourly. Very rarely necrotising fasciitis may occur which requires surgery and management as per the necrotising fasciitis protocol. 64 EYE INFECTIONS Blepharitis • • • Blepharitis is an inflammation of the lid margins. Lid hygiene is an important adjunct to antimicrobial therapy. Remove crusts with warm compresses prior to administration of eye drops or eye ointment. If in doubt about the need for antibiotics seek advice from Ophthalmology. Pathogens: Common: Staphylococcus aureus. Drug Treatment: DRUG DOSE Empiric Chloramphenicol Eye drops 0.5% 1-2 drops in affected eyes(s) 2-3 hourly initially or Eye ointment 1% Applied to the affected eye(s) 6 hourly 250mg po 6 hourly Patients with lid abscesses Add to empiric treatment: Flucloxacillin Treatment Duration: At least 7 days 65 Conjunctivitis Pathogens: May be mixed, including Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Group A Streptococci, Neisseria gonorrhoea, Chlamydia trachomatis, viruses. Drug Treatment: DRUG DOSE Empiric: Chloramphenicol Eye drops 0.5% 1-2 drops in both eyes 2-3 hourly initially or Eye ointment 1% applied to both eyes 6 hourly Pathogens Known Neisseria gonorrhoea 1 Ceftriaxone 1 g iv stat or 125mg iv stat in neonate Chlamydia trachomatis 1 Doxycycline 2 100mg po 12 hourly 1 gm po stat dose or AzithromycinH 1 2 Treat sexual partners for N. gonorrhoea and C. trachomatis infections. Avoid doxycycline in pregnancy and children. Treatment Duration: Non-Chlamydia infections 5 days Chlamydia infections 3 weeks 66 TRAVELLERS’ INFECTIONS Malaria • • • Malaria must be considered in any patient who has visited a malarious area and presents with a febrile illness. Malaria treatment can be complex in some circumstances (critical illness, pregnant or splenectomised patients, issues of anti-malarial drug resistance etc.). Involve an infectious disease specialist in the patient’s care and follow-up. Pathogens: Common: Plasmodium falciparum, Plasmodium vivax Other: Plasmodium ovale, Plasmodium malariae, Plasmodium knowelsi Diagnosis and Decision to Admit • Thick and thin blood films together with a blood sample collected into an EDTA tube should be sent to the laboratory for examination. A single negative blood film does not exclude the diagnosis of malaria, particularly if antimalarials or antibiotics have been taken recently. Patients with exposure and an intermittent fever should be admitted and serial (usually up to three) EDTA samples taken during consecutive febrile episodes for thick/thin film assessment. • All patients with clinically complicated or laboratory diagnosed Plasmodium falciparum malaria should be admitted for the first 24 hours of treatment due to the potential for rapid deterioration. • Patients with uncomplicated Plasmodium vivax do not need to be admitted but close follow-up is necessary. Assessment for complicated disease1 • Complicated malaria is defined clinically - both Plasmodium falciparum and Plasmodium vivax can cause complicated disease. All patients with complicated malaria should be admitted to hospital. • Manifestations of complicated malaria relate to adherence of parasitized RBC to small blood vessels, leading to microcirculatory obstruction, leakage and organ dysfunction: >5% parasitized RBC, altered conscious level, respiratory distress, jaundice, oliguria, vomiting, severe anemia, hemodynamic collapse, acidosis, hepatic failure. Drug Treatment: DRUG DOSE Complicated – treat in HDU/ICU2 ArtesunateH 2.4mg/kg iv on admission and repeat at 12 hours and 24 hours, then once daily until oral therapy is possible. Follow iv therapy with artemether +lumefantrine 20+120mg 4 tablets orally with fatty food or full-fat milk at 0,8,24,36,48 and 60 hours, making a total adult dose of 24 tablets in 6 doses. 67 Plasmodium falciparum – uncomplicated Artemether+lumefantrine or Atovaquone+proquanil4 20+120mg 4 tablets orally with fatty food or full-fat milk at 0, 8, 24, 36, 48 and 60 hours, making a total adult dose of 24 tablets in 6 doses 250+100mg tablets, 4 tablets orally with fatty food or full-fat milk daily for 3 days Plasmodium vivax Chloroquine sulphateH, 6 then (once G6PD status available) 1g (4 x 250mg tabs) stat PO, followed by 500 mg PO 6 hours later, then 500mg PO on days 2 and 3. 6 Primaquine 30mg po, daily with food for 2 weeks 1 http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf 2 IV artesunateH is the preferred treatment for severe plasmodium falciparum infection. This drug is unregistered. It is now available on-site at Waikato Hospital. It is also available within Auckland hospital pharmacy department and rapid access by courier is possible. 4 Malarone [Atovaquone/proguanil (250mg/100mg)] should only be used if they did not take this medication as prophylaxis. 6 Severe haemolysis may occur with G6PD-deficient patients – check G6PD status before prescribing Treatment Duration: Dependent on Plasmodium species (see above). 68 TREATMENT GUIDELINES FOR COMMON CONDITIONS IN PAEDIATRIC PATIENTS Doses in this section are given in mg/kg/dose. Please note that dosage for children should never exceed the usual adult dosage. Cellulitis Pathogens: Common: Streptococcus pyogenes. Other: Staphylococcus aureus, Enterobacteriaceae, anaerobes. Drug Treatment: DRUG DOSE Empiric Flucloxacillin 25 mg/kg/dose iv 6 hourly 30 mg/kg/dose iv 6 hourly 7. 5 - 15 mg/kg/dose po 4 times daily Pathogens Known Streptococcus pyogenes Benzylpenicillin followed by Penicillin V Treatment Duration: At least 5 days, depending on clinical course. Notes: • • Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage. 69 Conjunctivitis Neonatorum Pathogens: Common: Neisseria gonorrhoea, Chlamydia trachomatis. Other: Staphylococcus aureus, Pseudomonas aeruginosa. Drug Treatment: DRUG DOSE Empiric Ceftriaxone 30 mg/kg/dose iv 24 hourly 20 mg/kg/dose po 4 times daily for 2 weeks Pathogens Known Chlamydia trachomatis Erythromycin succinate Treatment Duration: 7 - 14 days Notes: • • Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage. Epiglottitis Pathogens: Common: Haemophilus influenzae type b. Drug Treatment: DRUG DOSE Empiric Cefotaxime or Ceftriaxone 50 mg/kg/dose iv 8 hourly (max 2g per dose) 100 mg/kg/dose iv stat, then 50 mg/kg daily (max 2g daily) Treatment Duration: 7 – 10 days. Notes: • • Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage. 70 Meningitis Consider dexamexethasone 0.15mg/kg/dose 6 hourly for 16 doses, commencing one hour prior to antibiotics, if Streptococcus pneumoniae or Haemophilus influenzae suspected. Pathogens: Common: Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae. Neonatal: Group B Streptococci, Escherichia coli, Listeria. Other: Staphylococcus aureus. Neonatal: Streptococci, coagulase-negative and positive Staphylococci, Klebsiella, Enterobacter, Pseudomonas. Drug Treatment: DRUG DOSE Empiric 0 - 3 Months Amoxycillin 50-100 mg/kg/dose iv Age 1 week Age 2-4 weeks Age >4 weeks 12 hourly 8 hourly 6 hourly and Cefotaxime 50 mg/kg/dose iv Age 1 week Age 2-4 weeks Age >4 weeks 12 hourly 8 hourly 6 hourly Empiric: >3 Months1 Ceftriaxone Pathogens Known Pseudomonas CeftazidimeH 100 mg/kg/dose iv stat, then once daily (max 4g/day, 2g/dose) 50 mg/kg/dose iv Age 1 week Age 2-4 weeks 12 hourly 8 hourly Streptococcus pneumoniae 2 Ceftriaxone 100 mg/kg/dose iv stat, then once daily (max 4g/day, 2g/dose) and VancomycinH 15mg/kg/dose iv 6 hourly (max 3g/day) Benzylpenicillin 3 60 mg/kg/dose iv 4 hourly Neisseria meningitidis Benzylpenicillin 60 mg/kg/dose iv 4 hourly Haemophilus influenzae Ceftriaxone 100 mg/kg/dose iv stat, then 50mg/kg/dose iv once daily 71 1 If organisms are seen on the gram-stain, then therapy may be directed accordingly. Due to increasing resistance, Health Waikato policy determines that a positive gramstain suggestive of Streptococcus pneumoniae now requires treatment with both ceftriaxone and vancomycin, until sensitivity results become available. Use both agents until sensitivity results available, then reduce to ceftriaxone or benzylpenicillin alone. 3 For penicillin-sensitive organisms. 2 Treatment Duration: Neonatal: Group B Streptococci Meningococcal Pneumococcal Haemophilus 21 days, or 14 days after CSF sterilisation, whichever is longer 14 - 21 days 4 days 7 - 10 days 7 - 14 days Notes: • • Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage. 72 Osteomyelitis - Acute Pathogens: Common: 0 -2 months: 2 months-2 years: >2 years: Group B Streptococci, Staphylococcus aureus, E. coli. Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae B, Group B Streptococci. Staphylococcus aureus, Streptococci, E coli. Other: Salmonella, anaerobes, fungi. Drug Treatment: DRUG DOSE Empiric: 0-2 months Flucloxacillin 25-50 mg/kg/dose iv Age 1 week 12 hourly Age 2-4 weeks 8 hourly Age >4 weeks 4-6 hourly and Cefotaxime 50 mg/kg/dose iv 8 hourly 25-50 mg/kg/dose iv 4-6 hourly 50 mg/kg/dose iv 8 hourly Pathogens Known Staphylococcus aureus Flucloxacillin 25-50 mg/kg/dose iv 4-6 hourly E. coli Cefotaxime 50 mg/kg/dose iv 8 hourly 50 mg/kg/dose iv 8 hourly 100 mg/kg/dose iv 24 hourly Empiric: >2 months Flucloxacillin and Cefotaxime H. influenzae Cefotaxime or Ceftriaxone Treatment Duration: 4-6 weeks Oral antibiotics may be commenced after 3-7 days of iv treatment, depending on clinical course. Notes: • • Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage. 73 Otitis Media – Acute Prior to commencing antibiotics consider whether antibiotic treatment is actually needed – in uncomplicated Otitis Media watchful waiting has a high success rate without the side effects of antibiotics. Pathogens: Common: Streptococcus pneumoniae, Haemophilus influenzae. Other: Streptococcus pyogenes, Moraxella catarrhalis, Staphylococcus aureus. Drug Treatment: DRUG DOSE Empiric: Amoxycillin 25 mg/kg/dose po/iv 8 hourly or Sulphamethoxazole/ trimethoprim 20/4 mg/kg/dose po 12 hourly or Amoxycillin/clavulanate 10/2.5-20/5 mg/kg/dose po/iv 8 hourly Treatment Duration: 5 days Notes: • • • With increasing pneumococcal resistance, cefaclor is no longer recommended, as it is active only against fully sensitive strains. Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage. 74 Periorbital / Orbital Cellulitis Pathogens: Common: Streptococcus pneumoniae, Group A Streptococci, Haemophilus influenzae B, Staphylococcus aureus. Drug Treatment: DRUG DOSE Empiric Flucloxacillin 25 mg/kg/dose iv 6 hourly and Cefuroxime 50 mg/kg/dose iv 8 hourly followed by Amoxycillin/clavulanate 10/2.5-20/5 mg/kg/dose po 8 hourly Treatment Duration: IV therapy for a minimum of 48 hrs, then continue with oral therapy. Total duration of therapy at least 7 days. Notes: • • Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage. 75 Pharyngitis Most cases of pharyngitis in preschool children are due to viral infection and do not require antibiotic treatment. Before commencing antibiotics obtain a bacterial pharyngeal throat swab. Review bacterial culture 3-4 days before deciding whether to continue antibiotics for a full 10-day course. The four diagnostic features suggestive of Streptococcus pyogenes infection are: • Fever >38oC • Tender cervical lymphadenopathy • Tonsillar exudate • No cough Pathogens: Common: Viruses, Streptococcus pyogenes. Other: Mycoplasma pneumoniae, Haemophilus influenza B, Corynebacterium diphtheriae. Drug Treatment: DRUG DOSE Empiric Penicillin V 15 mg/kg/dose po 3 times daily or Erythromycin 10 mg/kg/dose po 6-8 hourly Treatment Duration: 10 days. Notes: • • Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage. 76 Pneumonia Most Lower Respiratory Tract infections in children are viral. Pathogens: Common: 0-3 months: 3 months: Group B Streptococci, Staphylococcus aureus, Listeria, Chlamydia, Gram-negative bacilli. Viruses, Streptococcus pneumoniae. Other: Streptococci, Staphylococcus aureus, Haemophilus influenzae, Mycoplasma pneumoniae, Klebsiella, Pseudomonas aeruginosa, Mycobacterium tuberculosis. Drug Treatment: DRUG DOSE Empiric: 0-3 months Amoxycillin 50 mg/kg/dose iv and Gentamicin 2-2.5 mg/kg/dose iv 8 hourly 30 mg/kg/dose iv 4-6 hourly Penicillin V 15 mg/kg/dose po 6 hourly or Erythromycin succinate 20 mg/kg/dose po 6-8 hourly Age 1 week 12 hourly Age 2-4 weeks 6 hourly Age >4 weeks 3 hourly Empiric: >3 months Benzylpenicillin or Treatment Duration: 7 days. Notes: • • • • • • If suspicious of Staphylococcal infections, use flucloxacillin 25 mg/kg/dose iv 6 hourly. Use erythromycin only if likely penicillin allergy, or mycoplasma pneumoniae infection suspected. If severely unwell, use broad-spectrum antibiotic cover e.g. cefuroxime 50mg/kg iv 8 hourly. Legionella pneumophila is extremely rare in immunocompetent children. Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage. 77 Pyelonephritis Pathogens: Common: E. coli, Proteus sp., Klebsiella. Other: Staphylococcus aureus, Pseudomonas, Serratia. Drug Treatment: DRUG DOSE Empiric: Amoxycillin and Gentamicin 1 50 mg/kg/dose iv 6 hourly 7 mg/kg/dose iv 24 hourly, or 2 -2.5 mg/kg/dose iv 8 hourly1 Appropriate for children under one year of age. (See section on Aminoglycoside dosing in children). Treatment Duration: 10 days. Notes: • • Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage. 78 Urinary Tract Infections Pathogens: Common: E. coli , Proteus sp., Klebsiella. Other: Staphylococcus aureus, Pseudomonas, Serratia. Drug Treatment: DRUG DOSE Empiric: Sulphamethoxazole/trimethoprim 12.5/2.5-25/5 mg/kg/dose po twice daily or Cefaclor 10-15 mg/kg/dose po 8 hourly Pathogens Known As per sensitivities Treatment Duration: 7-10 days, followed by chemoprophylaxis (dependent on organism) while awaiting renal investigations, or if otherwise indicated. Notes: • • Doses in this section are given in mg/kg/dose. Dosage for children should never exceed the usual adult dosage. 79 Aminoglycoside Dosing In Children The Paediatric Department has moved to use “extended interval dosing” of aminoglycosides in children over one year of age. For children, extended interval usually means once daily dosing. Neonates, children under one year and patients with infective endocarditis have been excluded. Gentamicin is given at a dose of 5 mg/kg/day IV over 10-15 minutes. Monitoring Of Aminoglycoside Levels 8 Hourly Dosing Regimens When treating patients >3 months of age with normal renal function and who are on concurrent antibiotics (for synergy), peak/trough levels need not be done routinely. Peak concentrations are of no benefit if drug is infused over >1 hour. • Indications for Peak/Trough Levels: - • Age <3 months Critically ill Patients receiving concurrent nephrotoxins Pneumonia, cystic fibrosis No clinical response after >24 hours of appropriate doses Burns Indications for Trough Levels: - Patients receiving unusually high doses (>3 mg/kg/dose) - Renal failure - After 5th dose, if concerned about potential nephrotoxicity. (Also obtain baseline serum creatinine and repeat on days 5-7 of therapy). • - Indications for Additional Trough Concentrations: Dose adjusted Treatment duration >10 days Additional nephrotoxic drugs being used Renal insufficiency High MIC isolate 24 Hourly Dosing Regimens There is no need to measure peak concentrations. Concentrations may be measured at 8 hours (or 10 hours) post dose. If >3.5 µg/ml at 8 hours (or >2 µg/ml at 10 hours), then decrease dose. 80 Dosage Schedules Of Antimicrobial Drugs Used In Paediatric Patients Note that amounts recommended are mg/kg per dose. Do not exceed recommended dose for adults. Drug Penicillins Penicillin G, crystalline Penicillin G, procaine Penicillin V Flucloxacillin Amoxycillin Amoxycillin Amoxycillin/clavulanate Route Mild to Moderate Infections Severe Infections PiperacillinH Piperacillin/tazobactamH Ticarcillin/clavulanateH IV/IM IM PO PO/IV PO IV PO IV IV IV IV 25 mg/kg 6 hourly 25-50 mg/kg 12-24 hourly (max 2.4g/day) 5-12.5 mg/kg 6-8 hourly 12.5-50 mg/kg 6 hourly 7.5-15 mg/kg 8 hourly Inappropriate 7.5-15 mg/kg 8 hourly 7.5-15 mg/kg 8 hourly Inappropriate Inappropriate Inappropriate 50 mg/kg 4-6 hourly (max 12g/day) Inappropriate Inappropriate 50 mg/kg 4-6 hourly Inappropriate 50 mg/kg 4 hourly Inappropriate 7.5-15 mg/kg 8 hourly 50 mg/kg 6 hourly or 100 mg/kg 8 hourly Cephalosporins Cephalothin Cephazolin Cephalexin Cefoxitin Cefaclor Cefuroxime Cefotaxime Ceftriaxone IV/IM IV/IM PO IV/IM PO IV/IM IV/IM IV/IM 10-20 mg/kg 6 hourly 10-15 mg/kg 8 hourly 6-12.5 mg/kg 6 hourly Inappropriate 10-15 mg/kg 8 hourly Inappropriate Inappropriate Inappropriate 40 mg/kg 4 hourly 25 mg/kg 6 hourly Inappropriate 25 mg/kg 4-6 hourly Inappropriate 50 mg/kg 6-8 hourly 50 mg/kg 6 hourly 50-100 mg/kg 12-24 hourly, (max 2g/dose or 4 g/day) Dosage Schedules Of Antimicrobial Drugs Used In Paediatric Patients, cont. Drug Carbapenems MeropenemH Route Mild to Moderate Infections Severe Infections IV Inappropriate 20-40 mg/kg every 8 hours IV Inappropriate 5 mg/kg 6-8 hourly PO PO PO PO 7.5-12.5 mg/kg 6 hourly 7.5-12.5 mg/kg 6 hourly 7.5-12.5 mg/kg 6 hourly 7.5-12.5 mg/kg 6 hourly Inappropriate Inappropriate Inappropriate Inappropriate IV/IM PO 5-10 mg/kg 6 hourly 5-10 mg/kg 6 hourly 10-20 mg/kg 6 hourly Inappropriate Glycopeptides VancomycinH IV Inappropriate 15 mg/kg 8 hourly (max 500 mg/dose) Aminoglycosides Gentamicin TobramycinH IV/IM IV/IM Inappropriate Inappropriate 5-7 mg/kg 24 hourly 5-7 mg/kg 24 hourly IV PO PR PR 5-10 mg/kg 8 hourly 5-10 mg/kg 8 hourly 1-5 years: 250 mg/kg 8 hourly 6-12 years: 500 mg/kg 8 hourly 10 mg/kg 6 hourly 10 mg/kg 6 hourly Macrolides Erythromycin lactobionate Erythromycin base Erythromycin ethyl succinate Erythromycin stearate Erythromycin estolate Lincosamides ClindamycinH Nitroimidazoles Metronidazole 82 GUIDELINES FOR EFFECTIVE USE OF ANTIMICROBIAL DRUGS INFORMATION ON SELECTED ANTIMICROB DRUGS Most conditions requiring antimicrobial treatment can be managed using esta drugs. This is reflected in the recommendations made in the body of this bookle comments (not intended to be comprehensive) are made on the various cla antibacterial, antiviral and antifungal agents. 83 Antibacterial Drugs Beta-Lactams Penicillins, cephalosporins including cephamycins, monobactams and the carbapenems, are structurally related and share bactericidal activity primarily directed at the bacterial cell wall. Most beta-lactams are relatively safe, except in those patients hypersensitive to them. Penicillins Narrow Spectrum Penicillins These are mainly active against Gram-positive organisms and anaerobes but are inactivated by beta-lactamases produced by staphylococci and some other organisms. Benzylpenicillin (penicillin G) is administered parenterally. It still remains the treatment of choice for a number of infections. Procaine penicillin is an intramuscular preparation designed to extend the half-life of benzylpenicillin. It provides adequate levels for up to 24 hours but only against highly susceptible organisms. Benzathine penicillin is given intramuscularly and provides low levels of benzylpenicillin for up to 4 weeks. Phenoxymethylpenicillin (penicillin V) is acid-stable and thus may be given orally. It is intrinsically less active than benzylpenicillin. Antistaphylococcal Penicillins Flucloxacillin is stable to beta-lactamase produced by staphylococci. Anaerobic activity is minimal to none, while these agents do not cover enterococci. Flucloxacillin is reliably absorbed by the oral route, although preferably taken on an empty stomach. It is generally well tolerated but has recently been found to be associated with cholestatic jaundice in some patients. This can manifest up to 6 weeks after treatment and may last for months. It is more commonly seen in elderly patients. This propensity should not prevent use of this excellent anti-staphylococcal drug in patients with serious infections. Methicillin-resistant Staphylococcus aureus (MRSA) should be regarded as clinically resistant to all beta-lactams, irrespective of laboratory reports of susceptibility. Conversely, the treatment of choice for methicillin-sensitive Staphylococcus aureus (MSSA) is a beta-lactam antibiotic, not a glycopeptide. In New Zealand, many MRSA are not multi-resistant and therapy with macrolides, cotrimoxazole or tetracyclines may be efficacious (see separate section on MRSA management page 136). The practice of combining flucloxacillin with penicillin frequently occurs. There is hardly ever an instance when this is necessary. The belief that you are able to cover Staphylococcus aureus with flucloxacillin and not Streptococcus pyogenes is incorrect. Although it is true that the MIC90 of Streptococcus pyogenes to penicillin is 0.015µg/ml, the MIC90 of Streptococcus pyogenes to flucloxacillin is still excellent at 0.4µg/ml. This concentration is extremely easy to achieve. No randomised studies show the need for both agents. If anaerobic cover is required, the use of metronidazole is preferred. Metronidazole will cover Clostridium tetani if this is being considered. 84 Broad-Spectrum Aminopenicillins Amoxycillin has greater activity than benzylpenicillin against some Gram-negative organisms, e.g. Escherichia coli, Haemophilus influenzae but are destroyed by betalactamase producing strains. It is the agent of choice against enterococci. Antipseudomonal Penicillins Piperacillin and Ticarcillin (no longer marketed in NZ) are the only penicillins available that have activity against Pseudomonas aeruginosa. They are more expensive than most other penicillins. Beta-Lactamase Inhibitors Clavulanic acid, and tazobactam inhibit the β-lactamase enzymes produced by Staphylococcus aureus and Bacteroides fragilis; and also the ubiquitous TEM enzyme, found in Escherichia coli, Neisseria gonorrhoea and Haemophilus influenzae. They possess little inherent antibacterial activity, but in combination with penicillins such as amoxycillin, ticarcillin and piperacillin, they significantly extend their spectrum of activity. These combinations should be reserved for the treatment of organisms in which resistance to the beta-lactam antibiotic component is due to enzymes that these agents can inhibit. It should be noted that for Pseudomonas aeruginosa, the addition of a beta-lactamase inhibitor offers no increased activity. The combinations are often more expensive than the beta-lactam antibiotics alone. Amoxycillin/clavulanic acid can cause diarrhoea and cholestasis, which occur more frequently than with amoxycillin alone. Carbapenems Imipenem/cilastatin, meropenem and ertapenem are available in New Zealand. Due to inactivation by a renal dipeptidase, imipenem is formulated in combination with the dipeptidase inhibitor, cilastatin. This preparation has wide activity against enteric Gram-negative rods and Pseudomonas aeruginosa, comparable to that of aminoglycosides, and, in addition, has excellent activity against anaerobes including Bacteroides fragilis, and many Gram-positive organisms. However, it is not active against MRSA or some strains of Pseudomonas species. These drugs are expensive and should not be regarded as a first-line agent. Meropenem is resistant to renal dipeptidase and can therefore be given alone. It also attains better levels in CSF than imipenem and the risk of seizures is said to be less than with imipenem. At Waikato Hospital, carbapenems are restricted to the Haematology/Oncology ward and Intensive Care. Meropenem is currently the major carbapenem used at Waikato Hospital. Ertapenem has a narrower spectrum of activity; Pseudomonas and Acinetobacter spp. are resistant. Its advantage is that it has a long half-life allowing for once a day administration. Ertapenem is currently on the Waikato Hospital formulary for use with ESBL infections. Monobactams AztreonamH is a member of this family of beta-lactams. This compound is inactive against Gram-positive organisms and anaerobes but is highly active against the majority of aerobic Gram-negative bacteria, including beta-lactamase producing Haemophilus influenzae, enteric Gram-negative rods and Pseudomonas species, including those resistant to aminoglycosides. It can be given to people with severe penicillin hypersensitivity, as there is little cross sensitisation. It is expensive and has so far found little place in treatment of infections within WDHB. 85 Cephalosporins and Related Drugs For ease of understanding, the cephalosporins have been divided into four classes or "generations" which reflect their spectrum of activity and price. Widespread use of cephalosporins has been linked with the increasing prevalence of infections due to methicillin-resistant Staphylococcus aureus (MRSA), vancomycinresistant enterococci (VRE), drug-resistant Streptococcus pneumoniae (DRSP) and multiresistant Gram-negative organisms. First Generation Cephalosporins Cephalexin / cefaclor / cephradine and cephazolin are “first generation drugs” which have a similar range of antimicrobial activity. They are active against penicillinaseproducing staphylococci and their Gram-negative spectrum includes Escherichia coli and Klebsiella species among the enteric Gram-negative rods. They are not active against Enterococcus faecalis or Listeria monocytogenes. Cefaclor has greater activity against Haemophilus influenzae and some authorities class this agent as a secondgeneration drug. No first generation cephalosporin has useful activity against the Gram-negative anaerobe, Bacteroides fragilis, nor against Gram-negative aerobes such as Serratia, Enterobacter or Pseudomonas. Second Generation Cephalosporins Cefuroxime is a "second generation drugs" which is more stable to some Gramnegative beta-lactamases. Cefuroxime’s spectrum of activity encompasses methicillinsensitive staphylococcus and the common respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. In addition, it exhibits activity against Klebsiella pneumoniae, Proteus mirabilis and Escherichia coli. Enterobacter, Pseudomonas and Acinetobacter species are usually resistant. Cefuroxime is active against fully sensitive Streptococcus pneumoniae and is not as effective as amoxycillin against intermediate or high-level penicillin-resistant strains. Cephamycins Cefoxitin is cephalosporin-like, but in fact, make up a separate class known as cephamycins. It is resistant to the extended spectrum beta-lactamases of gramnegative organisms. Cefoxitin is less active against gram-positive organisms, particularly against Staphylococcus aureus compared to the second-generation cephalosporins. It has greater activity against Bacteroides fragilis (60% to 70% of strains have been reported to be susceptible) than second generation cephalosporins. These drugs have a limited role in therapy and have traditionally been used for prophylaxis, although metronidazole provides superior cover for anaerobes than cefoxitin. Third and Fourth Generation Cephalosporins Cefotaxime, ceftriaxone, ceftazidimeH, and cefepimeH are "third and fourth generation drugs" which have an extended spectrum of activity covering the majority of the enteric Gram-negative rods. Ceftriaxone has a considerably longer half-life than other members of this group. The activity of these drugs against Bacteroides fragilis is considerably less than the cephamycins. Third generation cephalosporins are less active against Gram-positive organisms than are earlier generations. None has clinically useful activity against enterococci or MRSA. However, unlike earlier cephalosporins, which do not enter the cerebrospinal fluid (CSF) in therapeutically useful concentrations, third generation drugs have been effective in meningitis because of better penetration and higher intrinsic activity. Some organisms, e.g. Serratia, Citrobacter and Enterobacter species, have inducible beta-lactamases and resistance can develop during treatment. Combination therapy with an aminoglycoside has been 86 suggested for serious infections with these organisms. CeftazidimeH and cefepimeH have valuable activity against Pseudomonas aeruginosa, with cefepimeH having improved gram-positive activity compared with ceftazidimeH. Both drugs are inactivated by the ESBL enzymes. Penicillin Hypersensitivity and Cross-Reactivity Between 1% and 10% of penicillin courses result in manifestations interpreted as due to hypersensitivity. Anaphylaxis, angio-oedema and urticaria due to immunoglobulin E (IgE) directed against penicillin-derived antigens occur within 72 hours, often within minutes. Later manifestations (non-IgE) include fever, haemolysis and serum sickness-like reactions, but rashes are by far the most common. Delayed hypersensitivity may present up to 14 days after initiation of the antibiotic with erythema multiforme, toxic erythema or toxic epidermal necrolysis. Unless rashes are urticarial they may not represent acute hypersensitivity reactions and they may not recur. This is particularly so with rashes associated with amoxycillin. Immediate reactions may be serious or fatal, although fatal reactions are usually associated with parenteral rather than oral routes. Thus, a detailed history of penicillin reactions should always be sought before a course of penicillin is commenced. A history of an immediate hypersensitivity reaction (urticaria, angioedema, bronchospasm, or anaphylaxis within one hour of drug administration) contraindicates further exposure to penicillin and other beta-lactam drugs apart from aztreonamH unless desensitisation has been undertaken. Late manifestations are only a relative contraindication, although rashes, especially if associated with amoxycillin, are much less predictive of future problems. Cross-reaction to cephalosporins occurs in 1-8% of penicillin-allergic individuals. Carbapenem cross-reactivity can also occur at a similar rate to cephalosporins, whereas aztreonamH cross-reactivity does not occur. Skin Prick Testing Skin prick testing for penicillin allergy is not undertaken at Waikato Hospital or in the Hamilton region. Auckland Hospital Clinical Immunology service do provide testing, when a good clinical indication is present. Testing is performed with penicillin metabolites against which most specific IgE is directed: penicilloyl (major determinant); and penicilloate and penilloate (minor determinants). Negative skin test results using major and minor determinants reassure patients and carers that the risk of lifethreatening penicillin allergy is negligible. There is a <0.1% risk of anaphylaxis after penicillin administration to a patient with a history of penicillin allergy and a negative skin prick test. This is a similar risk to that of patients who do not have a positive history. Desensitisation It is possible to desensitise individuals. Desensitisation is appropriate for patients who require penicillin treatment who have a history of penicillin allergy with a positive skin prick test or a history of penicillin allergy when skin prick testing is not available. If there has been a history of a life-threatening drug hypersensitivity, desensitisation should be carried out in a hospital setting, with an intravenous line in situ in the patient and resuscitation equipment available, including oxygen and adrenaline. Heart rate and blood pressure should be monitored every 15 minutes with continuous observation of the patient. Intensive Care should be made aware prior to commencing the protocol. 87 Where non-life threatening features (e.g. rash) have occurred, desensitisation may occur on an outpatient basis with regular observation and telephone contact available, and with an action plan for hypersensitivity reactions in place. Protocols are available from the Pharmacy Department who will be involved in making up the solutions. The process involves administration of incremental doses of penicillin – oral followed by IV – given every 15 - 30 minutes. The whole process takes 5 to 6 hours. This process of acute desensitisation is effective and relatively safe. The first therapeutic dose should be given within 4 hours of the end of the desensitisation procedure. The state of desensitisation induced does not last longer than the penicillin course that is administered immediately after the desensitisation process. Aminoglycosides Aminoglycosides usage has reduced over the last two decades as toxicity issues have clarified and alternative antibiotics have become available. For a comprehensive discussion on their role at Waikato Hospital please go to page 97. Tetracyclines Tetracyclines all have a broad spectrum of activity, which includes Gram-positive and Gram-negative bacteria, Chlamydia, Rickettsia, Mycoplasma, Spirochaetes, some Mycobacteria and some Protozoa. Their main use is in the treatment of pelvic inflammatory disease, acne, periodontal disease, exacerbations of chronic obstructive pulmonary disease, brucellosis, plague, cholera and Lyme disease. Tetracyclines are contraindicated in pregnancy and lactation and in children <8-12 years of age. Minocycline and doxycycline each have a longer half-life and absorption is not significantly affected by the presence of food. Sulphonamides and Trimethoprim Sulphonamides now have limited use. Sulphamethoxazole in cotrimoxazole, the combined formulation with the dihydrofolate reductase inhibitor trimethoprim, has in the past, found widespread use as a broad-spectrum agent, particularly in respiratory and urinary tract infections. However, the combination is associated with significant serious adverse effects due to the sulphonamide, especially in the elderly. Given that trimethoprim alone is highly effective in the treatment of urinary tract infections, the combination drug should be restricted to the few clinical situations where it is the drug of choice. These include the treatment and prophylaxis of Pneumocystis carinii infection, the treatment of Nocardia infection, the treatment of Listeria monocytogenes infections in patients with penicillin hypersensitivity and treatment of MRSA infections. Fluoroquinolones This class of antibiotic has a broad spectrum of antimicrobial activity, good bioavailability, excellent penetration into tissues, long serum half-lives, and are generally well tolerated. Their major downfall is the alarming development of resistance with the use of these agents. They should be reserved for treatment of infections resistant to other agents or where an oral agent with this particular antibacterial spectrum is required. Resistance to these fluoroquinolones has commonly occurred, especially where they have been widely used, principally in infections caused by Staphylococcus aureus, Pseudomonas aeruginosa, enteric Gramnegative rods, Campylobacter species and Neisseria gonorrhoeae. Quinolones are inappropriate for first line empiric therapy of common infections such as cellulitis, pharyngitis, otitis media, sinusitis, respiratory tract infections, urinary tract infections or acute osteomyelitis. 88 Norfloxacin is used in the treatment of urinary tract and gastrointestinal infection. CiprofloxacinH has a wider range of therapeutic activity against Gram-negative bacilli including Haemophilus influenzae, enteric Gram-negative rods, Pseudomonas aeruginosa, some Gram-positive cocci, Gram-negative cocci, and various species of Mycobacteria. They generally have poor activity against streptococci and in general should not be considered as the preferred therapy of gram-positive infections. Fluoroquinolone therapy is not advocated as first-line therapy for S. aureus osteomyelitis. Because of excellent bioavailability, oral use is the preferred route in most circumstances and in fact 750mg orally has a preferred pharmacodynamic profile than 400mg iv. Concomitant administration of iron, aluminium, calcium or magnesiumcontaining medicines can significantly reduce the gastrointestinal absorption of orally administered quinolones. Therefore, a gap of at least two hours should be allowed between these agents. Dairy foods containing large amounts of calcium will also reduce absorption. Quinolones damage the joints of immature animals and therefore should be used with caution in children under 14 years. Considerable experience in cystic fibrosis has shown that they can be used safely in the appropriate clinical situation. The extended spectrum fluoroquinolone moxifloxacin with increased activity against Streptococcus pneumoniae (including drug-resistant strains) are available in New Zealand, but are restricted in both the HML and in the community. This drug has increased activity against Gram-positive bacteria (including streptococci) and wide activity against Gram-negative aerobes (but inferior to ciprofloxacin against pseudomonas). It has good activity against anaerobes and most pathogens causing atypical pneumonia. Resistance is already beginning to be seen with these newer agents, which may limit their future. Currently, the role for these newer fluoroquinolones is extremely limited. Ciprofloxacin prescribing policy Ciprofloxacin is a restricted pharmaceutical in New Zealand Ciprofloxacin will be dispensed in accordance with the “restricted pharmaceutical policy” and without ID/Microbiology approval in the following situations only a. Uncomplicated pyelonephritis in women presenting to the emergency department (see above) b. Men with suspected prostatitis and cultures proving a ciprofloxacin susceptible organism c. Prophylaxis for TRUS biopsy (TRUS to be written on prescription) d. Treatment of ciprofloxacin susceptible Pseudomonas aeruginosa in a patient with a clinical diagnosis of complicated urinary tract infection or respiratory tract infection e. Other rare scenarios as outlined within this document Usage outside these indications requires ID/Microbiology approval. Macrolides The macrolides include erythromycin, roxithromycin, clarithromycinH and azithromycinH. They have a wide spectrum of activity covering Gram-positive cocci, Legionella, Bordetella, Corynebacteria, Gram-negative cocci, Mycoplasma, Chlamydia and both Gram-positive and Gram-negative anaerobes. They are not active against Gram89 negative rods. The newer macrolides have more reliable absorption and longer halflives, allowing less frequent dosing. They attain high intracellular concentrations that confer theoretical benefits in the treatment of intracellular pathogens. They also cause adverse effects less frequently than erythromycin. Erythromycin in all of its oral formulations has variable absorption and frequent GI side effects. The only parenteral formulation, erythromycin lactobionate, frequently causes pain and phlebitis. Intravenous doses should be administered slowly to minimise local reactions and also to avoid arrhythmia. Erythromycin should not be given intramuscularly. Several oral preparations are available, including erythromycin base, the stearate, and the estolate forms. Although the blood levels achieved with these forms vary somewhat, when the agents are used against very sensitive organisms, these minor differences are not believed to be clinically significant. Erythromycin ethylsuccinate has different absorption characteristics to other forms of erythromycin and therefore higher oral doses are needed to achieve therapeutic effects. 400mg erythromycin as the ethylsuccinate provides serum concentrations similar to those provided by 250mg erythromycin as the base, stearate or estolate. Unfortunately no one formulation seems to cause substantially less GI upset than others. Erythromycin may produce interactions with other drugs by inhibiting hepatic metabolism via the cytochrome P450 enzyme system. It can also prolong the QT interval. Waikato District Health Board is now only stocking Erythromycin ethylsuccinate so whenever oral erythromycin is referred to in this document it is the succinate form. Roxithromycin is an alternative to oral erythromycin. It has good oral bioavailability and may cause less gastrointestinal upset than erythromycin, but is slightly more expensive. It is fully funded on the Pharmaceutical Schedule. Clarithromycin, unlike other macrolides, has a microbiologically active metabolite. It is generally suitable for indications similar to those of erythromycin. It has activity against Mycobacterium avium complex and is used in combination with other agents for the treatment of this infection in patients with AIDS. It is not fully funded (except under special authority for specific indications such as Helicobacter pylori). AzithromycinH has good in vitro activity against a wider range of organisms than erythromycin. It is more active against Haemophilus influenzae. It has good oral bioavailability and in particular rapid and sustained uptake by tissues. Once daily dosage of this drug is generally acceptable. AzithromycinH can be used for the usual indications of erythromycin and also for Neisseria gonorrhoea and chlamydial genital tract infections. It is also used for the treatment of cerebral toxoplasmosis in patients with AIDS. AzithromycinH has recently been used for uncomplicated typhoid fever (Clin Infect Dis 2004;38:951-957). It is currently fully funded for urethritis and cervicitis due to Chlamydia trachomatis. Glycopeptides VancomycinH and teicoplaninH are effective only against gram-positive organisms. They play an important role in the treatment of methicillin-resistant organisms and in treating severe infection with susceptible organisms in patients who are hypersensitive to penicillin. Glycopeptides are not as effective as Beta-lactam antibiotics in the treatment of sensitive Staphylococcus aureus. Vancomycin is given by intravenous infusion over at least 1 hour to avoid producing the "red man syndrome". TeicoplaninH can be given by intramuscular injection or by slow intravenous injection or infusion. TeicoplaninH is considerably more expensive (ten times the price), no more efficacious, with a similar toxicity profile and should only be considered as a second-line agent or for community IV therapy. 90 Oral Vancomycin should not be used as first line therapy in Clostridium difficile diarrhoea. It should be reserved for severe cases unresponsive to metronidazole. Lincosamides Clindamycin is active against Gram-positive aerobes and most anaerobes. Although clindamycin has received a great deal of attention as a cause of C. difficile diarrhoea, this condition is now recognised to complicate almost all antibiotic therapy. It should be used as a second choice in those who cannot tolerate conventional therapy. It also has a role to play in the management of Toxoplasma gondii infection. Both oral and intravenous formulations are available. The oral formulation has 90% bioavailability. The intravenous formulation is expensive but is rarely required in someone with a functioning GI tract. Linezolid Linezolid is an oxazolidinone. It is effective against Gram-positive organisms including MRSA, coagulase-negative staphylococci, vancomycin-resistant enterococci, and penicillin-resistant strains of Streptococcus pneumoniae. Dosing is twice daily. Myelosuppression is common with prolonged administration and haematology should be monitored weekly. Peripheral neuropathy has also been seen with prolonged therapy. The drug is also known to have monoamine oxidase inhibitory activity. It is available in both oral and IV formulations. It is extremely expensive and is not on the WDHB formulary or PHARMAC funded. Its usage within WDHB will only be after discussion with the Infectious Diseases Service. The major value of this new therapy will probably be in the long-term management of chronic infections with multi-resistant Gram-positive organisms. Currently, other options usually exist for this indication. A monitoring programme to avoid adverse reactions has recently been published in Antimicrob Agents Chemother 2006;50:1599-602. Nitroimidazoles Metronidazole has a spectrum of activity that encompass Gram-negative anaerobes such as Bacteroides fragilis, Gram-positive anaerobes such as Clostridium species and anaerobic protozoa including Trichomonas vaginalis, Giardia lamblia and Entamoeba histolytica. Metronidazole is available as an intravenous preparation; however excellent absorption means that tablets or suppositories can often be used instead. Metronicazole may cause a disulfiram-like reaction with alcohol. Recommended dosage for metronidazole is 400mg orally or 500mg IV with a 12-hourly dosing schedule. This is based on pharmacokinetic data and minimum inhibitory concentrations of the pathogens involved, rather than formal clinical studies. Rifampicin Apart from its important role as an anti-tuberculous and anti-leprosy agent, rifampicin is used to eradicate nasopharyngeal carriage of N. meningitidis, H. influenzae and S. aureus, and as an adjunct to other antibiotics in serious staphylococcal infection. Rifampicin causes red discoloration of body fluids and occasional influenza-like symptoms and hepatotoxicity. It interferes with oral contraceptive metabolism. Antiviral Drugs Purine Nucleoside Analogues Aciclovir is active against Herpes simplex virus and to a lesser extent Varicella-zoster virus. It is the drug of choice for severe infections caused by these viruses. Intravenous doses should be administered slowly. ValacyclovirH and famciclovir, which have longer half-lives, are no longer funded in New Zealand. 91 Ganciclovir is used for the treatment of serious cytomegalovirus infections in immunocompromised patients. Unfortunately, it has dose-dependent bone marrow suppressive effects. The drug also has demonstrated mutagenicity in mammalian cells and carcinogenic potential in animals. Solutions for iv infusion must therefore be prepared in a biohazard cabinet (currently prepared at Waikato Hospital by Baxter). Neuraminidase Inhibitors Zanamivir and Oseltamivir can shorten the duration of influenza symptoms by about one day if commenced within 48 hours of the onset of symptoms. Both drugs are neuraminidase inhibitors. Zanamivir is produced in a diskhaler format (and should be used with caution in severe asthmatics) while Oseltamivir is an oral medication. The advantages of one over the other are still to be clarified by further trials. These agents are not funded by Pharmac. Antiretroviral Drugs The last decade has seen an explosion in the number of anti-retroviral therapies specific for HIV infection become available. There were seven nucleoside analogue reverse transcriptase inhibitors (NRTIs), two non-nucleoside reverse transcriptase inhibitors (NNRTIs), six protease inhibitors, one integrase inhibitor and an HIV fusion inhibitor currently funded for use within New Zealand as at August 2012. Antiretroviral prescribing can only be undertaken by named specialist. At the time of publication only Dr Jane Morgan and Dr Graham Mills were approved to initiate antiretroviral therapy. Antifungal Agents The number of systemic antifungal agents has grown considerably during the last decade. The newer agents are usually confined to specific infections in the setting of immunocompromised individuals. Polyenes Amphotericin BH is a polyene compound that remains the treatment of choice for most serious fungal infections having the broadest spectrum of any antifungal compound currently marketed. The major action of amphotericin BH is to damage the membrane of fungal cells. It has significant and serious side effects, predominantly renal toxicity. Consultation with an infectious diseases physician or clinical microbiologist is advised concerning its use. Liposomal amphotericinH is less toxic but is extremely expensive (up to $3000 per day dependent on dose used). Evidence of increased efficacy against fungal infection compared with the standard preparation of amphotericin ΒH is anecdotal only. It is likely to be used only in extremely exceptional circumstances after prior use of standard amphotericin ΒH when significant toxicity has occurred and alternative antifungal agents are not appropriate. AmphotericinH has a long half-life (up to 15 days). It is initially given once daily, although once control of fungal sepsis has been achieved, alternate day dosing can be used. Dosage modifications of amphotericin BH are not required in patients with renal insufficiency, in keeping with the low renal excretion of the drug. Hypersensitivity to amphotericinH is common and consists of headache, fever, severe rigors, chills, malaise, muscle and joint aches, and hypotension. Symptoms subside within 4 hours after discontinuance. The occurrence of this side effect decreases with continued therapy. 92 Intravenous hydrocortisone (50-100 mg) and promethazine can be given prior to commencing the amphotericinH infusion, although the hypersensitivity reactions are, in part, dose-related. The patients should be closely observed during the first dose, but daily incrementation of the dose is not necessary. Regular monitoring of serum electrolytes, renal function and full blood count is essential. AmphotericinH is usually infused in 500 ml 5% dextrose, although for volume-restricted patients, amphotericin BH can be given in a concentration of 0.5mg/ml of 5% dextrose. It is typically infused via a central line as peripheral venous administration may predispose patients to develop phlebitis because of the irritant effect of amphotericin BH. IV administration of 0.5 to 1L sodium chloride 0.9% prior to the amphotericin infusion is strongly recommended. When commencing amphotericinH, a slow infusion is recommended over 6 hours. If the patient tolerates this for two successive doses without any evidence of an allergic response occurring, then the infusion can be shortened down to a 2 - hour infusion for subsequent doses. AmphotericinH is nephrotoxic, although impaired renal function is generally reversible after discontinuation of therapy. Irreversible renal damage is rare. One must be cautious about using amphotericinH in combination with aminoglycosides, vancomycin, cisplatin or cyclosporin. Imidazoles Clotrimazole, econazole, ketoconazole and miconazole are broad-spectrum antifungal drugs, which are used in mucocutaneous candidiasis, dermatophytosis and tinea versicolor. Clotrimazole has some activity against trichomonas, and ketoconazole shampoo is used in the treatment of seborrhoeic dermatitis and dandruff. Ketoconazole is active against a variety of fungal infections, particularly yeasts. It has acid-dependent oral absorption (similar to itraconazole) and is not significantly excreted in the urine. Hepatotoxicity may occur and liver function tests need to be monitored monthly. It blocks steroid synthesis and may lead to hypoadrenalism and reduction in testosterone levels. Ketoconazole has significant interactions with other drugs that are metabolised in the liver by CYP3A4 isoforms of the cytochrome P450 enzymes. Triazoles Fluconazole has a narrow spectrum of antifungal activity, and clinical use is usually limited to treatment of Candida species. It has good tissue penetration, including penetration into the central nervous system. It is well absorbed following oral administration. Itraconazole absorption is increased with acidic drinks and food. Itraconazole has a similar spectrum to fluconazole, except for increased activity against filamentous fungi such as Aspergillus species. Itraconazole has significant interactions with other drugs that are metabolised in the liver by the cytochrome P450 enzymes. Fluconazole has a lesser effect on the same pathway. VoriconazoleH and PosaconazoleH are newer triazole antifungals structurally related to fluconazole with a spectrum of action similar to itraconazole. They can be used for the treatment of invasive aspergillosis, and serious infection with Candida species, Scedosporium species and Fusarium species. VoriconazoleH is available both as oral and intravenous preparations, with an oral bioavailability of 96%. As voriconazoleH is eliminated via a cytochrome P450 pathway, the potential for drug interactions is high. VoriconazoleH is expensive and should be restricted to patients with proven invasive aspergillosis intolerant or unresponsive to amphotericin ΒH. VoriconazoleH is active 93 against Aspergillus species, Scedosporium apiospermum and Fusarium species. PosaconazoleH (currently only available in an oral formulation) is active against Candida and Aspergillus species. It also has activity against Coccidioides immitis, Fusarium, Histoplasma, Zygomycetes and phaeohyphomycetes. Caspofungin CaspofunginH is the first in a new class of antifungal agents called the echinocandins, which inhibit β-1,3-D-glucan synthesis in the cell wall in a novel way. It is used in the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies, such as amphotericinH or voriconazoleH. It is administered by slow IV infusion. It is not available in oral formulation. Flucytosine Flucytosine is a fluorinated pyrimidine analogue, with antifungal properties. It is available for oral or parenteral use although it is unregistered in New Zealand and requires a Section 29 application. It is mainly used in a synergistic combination with amphotericinH against Cryptococcus neoformans. High serum levels, which often occur with renal impairment, are associated with bone marrow toxicity and monitoring of serum concentrations is therefore advised. Terbinafine Terbinafine is fungicidal for many dermatophytes. It is well absorbed from the gut and is of value in treating fungal infections of the skin and nail. It should be used with caution in patients with hepatic diseases. It may be used topically. 94 DOSING, PHARMACOKINETICS AND PHARMOCODYNAMICS The pharmacology of antimicrobial therapy can be separated into distinct components. The first of these is pharmacokinetics, which deals with the absorption, distribution, metabolism and elimination of antimicrobials. It is these factors that determine the time course of antimicrobial concentrations in serum and tissues for a given dosing regimen. Pharmacodynamics, the second component, is concerned with the relationship between concentration and the antimicrobial effect. IMPORTANT PHARMACODYNAMIC PRINCIPLES 1. The minimum inhibitory concentration is the minimum in vitro concentration of antibiotic required to prevent inoculum growth. The MIC predicts bacteriologic response to therapy. 2. Post-antibiotic effect is the recognised in vitro and in vivo inhibition of growth despite sub-MIC levels of antibiotics. It is recognised that increasing the peak level of an antibiotic will also increase the post-antibiotic effect. The effect varies depending on class of antimicrobial agent and pathogen. An example of postantibiotic effect is shown below. Antibiotic Beta-lactam Vancomycin Aminoglycoside Quinolone Staphylococci 3h 4h 3h 3h Pseudomonas 0h N/A 6h 6h 3. The relationship between tissue levels and serum levels. As most infections occur in tissues and the common bacterial pathogens are extracellular, interstitial fluid concentrations at the site of infection are the prime determinants of efficacy. Most tissue sites within the body can be described as having a large capillary surface area across which antimicrobials diffuse into a relatively small volume of interstitial fluid. Drug concentrations at these sites will show little lag and therefore antibiotic levels will be very close to serum concentrations. Some tissue sites such as blister, pleural, peritoneal and synovial fluids have a lower ratio of surface area to volume than most other tissues. Concentrations at these sites will therefore lag behind those in serum, resulting in lower peak concentrations but higher trough levels. 4. Two major patterns of bactericidal activity are now recognised. These are termed "concentration-dependent killing" and "time-dependent killing". An understanding of these concepts will have a major impact on how antibiotics are prescribed. Concentration-dependent bactericidal activity is characterised by a greater extent and rate of bactericidal activity with higher drug concentrations. Figure 1 demonstrates this characteristic. This pattern of killing is observed with the aminoglycosides, fluoroquinolones, and metronidazole. 95 Concentration K3 K2 K1 MIC ………………………………….………..………….…..…… Time Fig 1: Concentration Dependent Bactericidal Activity Rate of Kill K3 > K2 > K1 Concentration Time-dependent bactericidal activity is characterised by a saturation of the rate of killing at concentrations near the MIC. Thus, high concentrations will not kill the organism faster or more extensively than low concentrations. The duration of exposure rather than the concentration is the major determinant of the extent of killing. This pattern of bactericidal activity is seen with beta-lactams, vancomycin, macrolides and clindamycin. Figure 2 demonstrates this characteristic. Furthermore, animal studies have revealed that maximal efficacy for an antibiotic with time-dependent bactericidal activity can be achieved when serum levels are above the MIC for only 60% of the dosing interval, and as low as 25% for some organisms. K0 K0 K0 MIC …………………………………………..…………………….. Time Fig 2: Time-Dependent Bactericidal Activity Rate of Kill K0 is constant The pharmacodynamic characteristics described reveal that the time course of antimicrobial activity varies markedly for different antimicrobials and can not be based solely on half-life of the antibiotic or the MIC data for a particular organism. It is with this in mind that the dosing guidelines for various antibiotics have been defined. Much of this pharmacodynamic data is relatively new, differing from some of the traditional dosing approaches used in the past. 96 Gentamicin: Principles of Usage and dosing Aminoglycosides have previously played a very important role in the management of infectious diseases. They continue to play a role in empiric therapy (due to their potency and low levels of resistance), and a small number of other specific indications where alternatives are not available. Their toxicity profile has lead to a major reduction in usage in recent years and as a result, specialist advice should be sought to weigh the risks and benefits of aminoglycoside courses that are longer than 3 days. Gentamicin, tobramycinH and amikacinH are active against aerobic Gram-negative bacilli including Pseudomonas and are amongst the most rapidly bactericidal drugs available for treatment of aerobic Gram-negative sepsis. Anaerobes are resistant. Alone they are inactive against enterococci, but in combination with penicillin (or amoxycillin) are synergistic. Gentamicin plus penicillin (or amoxycillin) is bactericidal for most enterococci. Although aminoglycosides are active against most staphylococci and may be life-saving in unsuspected staphylococcal sepsis, they should not be used alone to treat staphylococcal infections, because resistance commonly develops. Gentamicin are no longer the aminoglycoside of choice for hospital-acquired aerobic Gram-negative sepsis, but are still used as the initial empiric therapy until the organism and sensitivity profile of the organism has been identified. TobramycinH produces greater in vitro activity than gentamicin against Pseudomonas aeruginosa, but not other aerobic Gram-negative bacteria and is nine times more expensive. All aminoglycosides are potentially ototoxic and nephrotoxic, with clinically significant adverse effects more likely with advancing age or pre-existing renal impairment. Pharmacodynamic Properties The aminoglycosides demonstrate a property known as concentration-dependent killing. Clinical studies have demonstrated that achievement of high peak serum concentrations of the aminoglycoside relative to the minimum inhibitory concentration of the micro-organism being treated, is the major determinant of the clinical response to the aminoglycosides. This optimisation of the Peak : MIC ratio, can best be obtained by the “extended interval" administration of aminoglycosides, which result in high peak concentrations of the drug (peak target ~ 20 µg/ml). In addition to this property of the aminoglycosides, these drugs also demonstrate a property known as the post-antibiotic effect, which may be defined as a period of time after complete removal of the antibiotic during which there is no growth of the target organism. Although "extended interval" dosing of aminoglycosides may result in a period of up to 12 hours during which there are no detectable serum concentrations of the drug, this property of the aminoglycosides allows for “extended interval” dosing without compromising therapeutic efficacy. This has now been confirmed by a large number of studies. Drug Toxicity The major determinant of aminoglycoside-induced renal and ototoxicity is the accumulation of these agents within both the renal cortex and the perilymph of the inner ear, respectively. Uptake and accumulation of aminoglycosides into renal cortical tissue demonstrates saturable kinetics. The saturable feature of these kinetics makes peak aminoglycoside concentrations irrelevant when considering tissue accumulation of the drug. Less frequent dosing of aminoglycosides allows for trough levels of the drug to fall well below the threshold for binding to their tissue receptors. This also 97 allows for the back-diffusion of aminoglycosides from the renal cortex and inner ear that may theoretically limit drug toxicity. Toxicity may still occur in some cases where target levels have been adhered to, particularly after prolonged courses and in preexisting renal failure. We stress again that as a result of toxicity issues, specialist advice should be sought to weigh the risks and benefits of aminoglycoside courses that are longer than 3 days. AMINOGLYCOSIDES: DOSING AND MONITORING Contraindications • Previous vestibular or auditory toxicity due to aminoglycoside • Serious hypersensitivity reaction to aminoglycoside (rare) Precautions, particularly if used beyond three days • Pre-existing conductive hearing problem or vestibular problem • Neuromuscular disorders • Chronic liver disease or cholestasis (bilirubin > 90 micromole/L) • Chronic renal failure or deteriorating renal function Alternative agents • 3rd and 4th generation cephalosporins eg ceftriaxone, ceftazidimeH or cefepimeH (the latter two are active against Pseudomonas) • Fluroquinolones eg ciprofloxacinH (not moxifloxacin) • Carbapenems e.g. meropenemH or ertapenemH (use is restricted for ecological and stewardship reasons). Dual agent therapy • With another active agent for severe Pseudomonal infection • With penicillin or amoxicillin for endocarditis Administration IV infusion over 30 min. • Neuromuscular blockade may occur with rapid administration. The standard dose size is 5 mg/kg of “dosing weight” • “Dosing weight” is “ideal body weight” or an adjusted “obese dosing weight” (see below). • Round the dose to the nearest 20 or 40 mg for adults. • Adjustment within the range 3 – 7 mg/kg may be required for specific patients (see below). • An initial stat dose of 5 mg/kg may be given safely to most patients and subsequent doses adjusted the next day. The standard dose interval is 24 hr • In most cases, adjusting the interval is the preferable way to manage dosing. • Use the nomogram below to adjust the interval. • Adjustment within the range 16-48 hr may be necessary, guided by monitoring levels. • Intervals in multiples of 12 hr are most convenient and foolproof. • If intervals beyond 48 hr are indicated, change to another agent. • Renal function is the main determinant of dosing interval. • 8 hrly dosing may be used in specific situations such as endocarditis synergy and for neonates, in pregnancy and >20% burns. • Close monitoring and dose by dose adjustment is required in renal failure (CrCl < 30mL/min) and alternative agents are preferred. 98 Monitoring Courses over 3 days: consult with infectious diseases specialist as to the benefits versus risks. Consider monitoring renal function, vestibular and auditory function. Toxicity (particularly ototoxicity) may occur with long term use even if serum gentamicin levels are satisfactory. It is not necessary to measure drug levels if renal function is normal and the course is < 48 hr. Frequency of monitoring • Initial test: after 24-72 hr of treatment • Long term monitoring: weekly with additional 3 x weekly serum creatinine • Recheck aminoglycoside levels if renal function improves or declines significantly. • Dose adjustment: remeasurement is often useful at 24 – 48 hr intervals until a stable satisfactory dose is established. The ideal time to measure levels is 8 – 12 hr post dose but levels between 6 and up to 14 hours post-dose can be used. • Suitable when renal function is mildly impaired ie CrCl > 30ml/min • Usually gives a measurable non zero figure. • Will pick up cases with slow clearance and those with large Vd. • Minor errors in recording the administration and sampling times won’t severely affect interpretation. • Target level 2-7 mg/L, depends on time of sampling relative to last dose. See nomogram. Measure peak and trough levels if difficulty is encountered. • eg unusual Vd or body composition, changing or unpredictable renal function, if significant drug accumulation is suspected • Peak sample: 30 min after end of 30 min infusion. • Target: gent and tobraH 10-20 mg/L, amikacinH 40-60 mg/L • Trough sample: within 2 hr of next dose. • Target: gent & tobra < 1mg/L, amikacinH < 4 mg/L • For 8 hrly dosing, gent & tobra targets are peak: 5-10, trough <2 (4x time this for amikacinH). How to adjust doses • Try for simple, conventional dose sizes and intervals to minimise administration errors. • The Clinical Microbiologist or Infectious Diseases Physician is available to discuss cases. • First, try to adjust the interval, using the nomogram. • Second, adjust the dose size if necessary. • Third, take peak and trough levels if a satisfactory result is not achieved after a couple of days (sooner if problems are anticipated). • Fourth, change to an alternative agent if satisfactory levels can’t be readily achieved. 99 Calculation of Dose Size • Use “Ideal Body Weight” (IBW) to calculate the dose, or the actual body weight (if less than IBW). IBW (male) = 50kg + 0.9kg for each cm >150cm in height IBW (female) = 45.5kg + 0.9kg for each cm >150cm in height • If an individual is > 20% above IBW, dosing should be based on the obese dosing weight (ODW) which is calculated: ODW = IBW + 0.4 (Actual BW IBW). Ideal Body Weight Chart Height Males (kg) 155 cm / 5’2” 55 160 cm / 5’4” 60 165 cm / 5’6” 64 170 cm / 5’8” 68 175 cm / 5’10” 73 180 cm / 6’0” 78 185 cm / 6’2” 82 190 cm / 6’4” 87 195 cm / 6’6” 91 Females (kg) 50 55 60 64 69 73 78 82 87 Aminoglycoside Starting Doses for Special Cases Special Cases Starting Dose for Extended Interval Dosing (24 – 48 hrly) mg/kg/day for gent or tobra For amikacinH, multiply by 4 Neonates incl premature 3 Infants and Children < 10 y 7 10 - 29 y 6 30 - 60 5 > 60 y 4 Endocarditis, Streptococcal 3 (gentamicin only) and Enterococcal Determination of Initial Dosing Interval • The initial dosing interval is determined from the eGFR. • The initial dose interval is then selected according to guidelines below: Creatinine Clearance (mL/min) >60 45-60 30-45 <30 Initial Dosing Interval 5mg/kg for gentamicin and tobramycinH. AmikacinH doses are 4x those. q24 h q36 h q48 h Consider alternative antibiotic. One stat dose then seek specialist advice. 100 Nomogram for Dose Interval Adjustment • Start with the time the sample was taken after the most recent dose, read up to the measured aminoglycoside level and adjust the dose interval to that shown. • If the measured level is undetectable, next time measure the peak level; increasing to 7mg/kg may be helpful. Note: This nomogram may be used for either gentamicin or tobramycinH and is calibrated for a dose of 5 mg/kg. For amikacinH, multiply plasma concentration and dose given by 4. Source: Therapeutic Guidelines Antibiotic 13th ed 2006. 101 Vancomycin Dosing It is now recognised that Vancomycin is a safe drug that has been underdosed over the last fifty years since its introduction into clinical medicine. The way to assure optimum dosing is to measure trough levels. Current recommendations are that the target for trough levels should be 15±5 µg/ml. The MIC values for most Staphylococcus aureus are 0.5-1 µg/ml and for Enterococci and Coagulase Negative Staphyloccci may range up to 2 µg/ml. In cases of serious infection, the MIC should be checked because at levels of 2 or 4 µg/ml vancomycin will not be so effective. With MRSA, small moderately resistant subpopulations (heterogenous Vancomycin Intermediate S aureus, hVISA) may occur, which are difficult to detect in the laboratory and may result in therapeutic failure. Prolonged, subtherapeutic vancomycin dosing appears to allow such strains to emerge in an individual patient during treatment. If the patient does not improve on vancomycin, repeat cultures should be obtained and the case discussed with the laboratory so the organism may be sent to a reference laboratory to check for occult resistance. Fully Vancomycin Resistant Enterococci (VRE) and S. aureus (VRSA) due to VanA or VanB have MIC ≥ 32 µg/ml. VRE has been recognised in recent outbreaks within Auckland hospital (2007) and Waikato hospital (2008). Vancomycin must be given intravenously for systemic infections. It is not absorbed when given orally and IM injections cause tissue necrosis. Ototoxic and nephrotoxic effects of this drug are now considered to be minimal and not related to specific serum concentrations. However, vancomycin appears to potentiate the ototoxicity and nephrotoxicity of aminoglycosides. Careful monitoring is required when administering vancomycin together with an aminoglycoside or other drugs that are known to be cause ototoxicity or nephrotoxicity. Usual Dose The usual adult starting dose is 1.5g for those with creatinine clearance >90 mL/min and 1.0g for those with creatinine clearance <90mL/min. The dosing interval is usually 12 hourly, but less frequent administration is used in those with renal impairment. Vancomycin should be infused slowly over at least one hour to avoid anaphylactoid reactions and the ‘red man’ syndrome. Dosing Interval As vancomycin is cleared solely by the kidney, an assessment of the patient’s renal function is required for determining the appropriate dosing interval. The initial dosage interval will be determined from an estimate of creatinine clearance. Creatinine Clearance (ml/min) Dosing Interval > 60 20-60 < 20 q12 h q24 h Repeat dose when Vanc level is 1020µg/ml 102 Monitoring • • • • • The primary aim of vancomycin monitoring is to ensure that dosing is adequate. Peak levels are not performed, since they are not useful in predicting efficacy and do not predict toxicity. Trough levels should usually be performed in those who have been on vancomycin therapy for greater than 72 hours, but earlier measurements may be required in: - Patients with high (e.g. burn patients) or low (<50ml/min) creatinine clearance. - Patients receiving concurrent treatment with other nephrotoxic drugs (e.g. aminoglycosides, amphotericin BH). - Patients with infections at sites where there is reduced penetration of vancomycin (e.g. endocarditis, meningitis, pneumonia). When trough levels are taken, the aim is to maintain a trough level of 15±5 µg/ml. Trough levels should be drawn immediately before the next dose. If the first vancomycin level is taken prior to achieving steady state (i.e. after three or four doses), the trough level may be misleading. Adjusting the Dose Dose adjustments should be done in a simple linear way. For example, if the trough concentration is 8µg/ml, the dose should be adjusted by a factor of 15/8 or 1.9 fold. In some pateints dose adjustment may result in doses above those recommended for starting doses. As a general rule, the maximum dose is likely to be less than 2gm 12 hourly. Beware - taking the first trough level too early (prior to achieving steady state) or through a line diluted with saline may lead to inappropriate interpretation of the trough level. Monitoring Renal Function Check renal function periodically during the therapy, if the duration of therapy exceeds 72 hours. If signs of renal impairment develop, or if drug accumulation occurs, or trough levels fall too low, the dose must be reassessed. Metronidazole Dosing Metronidazole, a nitroimidazole derivative, is a well-established antimicrobial for the prevention and treatment of anaerobic infections. Despite having a long serum elimination half-life of about 8 hours (range 6-12 hours), metronidazole has traditionally been administered every 6-8 hours. It has never been determined that such a frequency is necessary. Furthermore, dosing metronidazole every 6-8 hours will lead to drug accumulation after prolonged use, especially if there is liver impairment. It has been shown that a dose of 500mg every 12 hours is sufficient to maintain serum concentrations of the drug above the minimal inhibitory concentration (MIC) of most anaerobic pathogens for the duration of the dosing interval. There is also some limited data to suggest that metronidazole may have a post-antibiotic effect against certain anaerobic bacteria. Metronidazole’s bactericidal activity is based on concentrationdependent killing. All dosing recommendations in this booklet are based upon daily or twelve hourly dosing of metronidazole. Metronidazole has excellent oral bioavailability (95-100%) and the iv route should only be used when oral or rectal administration is not possible. 103 Beta-Lactam Dosing Beta-lactam antibiotics are frequently given in inappropriately high dosages. The treatments of meningitis and endocarditis are the only indications for "high" dosage, as serum levels may not necessarily reflect levels in the infected tissue. For most other infections, the magnitude of the peak level is no longer deemed relevant. Timedependent killing means that the time above the MIC is the determinant of success. Examples of this would include ceftazidimeH for a sensitive Pseudomonas aeruginosa where 1g 8 hourly is more than adequate and ceftriaxone for systemic gram-negative infections where 1g 24 hourly is satisfactory. 104 IMPAIRED RENAL FUNCTION Renal impairment may lead to the accumulation of toxic levels of antimicrobial drugs and/or their metabolites. The following table contains dosage recommendations for common antimicrobials. To make best use of the recommendations in the following table, it is necessary to calculate creatinine clearance (CrCl) as an estimate of glomerular filtration rate (GFR). eGFR using the CKD-EPI formula since March 2013. The CKD-EPI formula will not accurately predict clearance in patients with rapidly changing renal function. In the presence of diminished renal function, doses may be altered by reducing the dose or by extending the interval between doses. Legend For Dosage Guidelines (See following tables) 1 Method of dosage adjustment: D = Dose adjustment I = Dosage interval adjustment. 2 Monitoring of levels recommended to determine precise dosage requirements. 3 Dosage for intraperitoneal administration. 4 Dosage in mg/L of filtrate removed. 5 nd = no data. 6 n/a = not applicable. 7 No supplement means that the dose given is the same as for GFR< 12 ml/min. 8 Dose after means that the dose given is the same as for GFR < 12 ml/min and it should be withheld until after dialysis on days of dialysis. * + Agents (often) used in combination, see also companion agent Monitor for myelosuppression HAEMO Intermittent Haemodialysis CAPD Continuous Ambulatory Peritoneal Dialysis 105 Antimicrobial Therapy In Patients With Impaired Renal Function (i) Drug Aciclovir AmikacinH Amoxycillin Amoxycillin/ Clavulanate AmphotericinH AzithromycinH AztreonamH Benzylpenicillin Cefaclor CefepimeH Cefotaxime Cefoxitin CeftazidimeH Ceftriaxone Cefuroxime Cephalexin Cephalothin Cephamandole Cephazolin Chloramphenicol ChloroquineH Dose Adjustment for Renal Failure by GFR (ml/min) Adjustment > 50 ml/min 10 - 50 ml/min < 10 ml/min Method2 D&I 8 hourly 12-24 hourly 50% 24-hourly D&I 50-100% 50% 24 hourly2 to 30% 48 hourly2 2 30% 48 hourly I 6-8 hourly 8-12 hourly 24 hourly D&I normal 8-12 hourly 50% 12 hourly D D D D I I D&I I I I I I D normal normal normal normal normal normal 6 hourly 8 hourly 8-12 hourly normal normal 6 hourly 6 hourly 6 hourly 8 hourly normal normal normal normal 50-75% 75% normal 50% 12 hourly 12 hourly 8-12 hourly 12-24 hourly normal normal 6 hourly 6-8 hourly 6-8 hourly 12 hourly normal normal normal normal 25% 20-50% normal 25% 24 hourly 24 hourly 24 hourly 50% 24 hourly normal 50% 24 hourly 8-12 hourly 12 hourly 12 hourly 24 hourly normal 50% Doses for Dialysis Supplement for Supplement or Dose (D) HAEMO for CAPD 8 dose after no supplement7 dose after8,2 15-20 mg/L of dialysate3 (D)2 dose after8 dose after8 dose for GFR 0.2-1 dose for GFR 0.2-1 nd5 no supplement7 no supplement7 dose after8 dose after8 dose after8 dose after8 dose after8 dose after8 dose after8 normal dose after8 dose after8 dose after8 dose after8 dose after8 no supplement7 no supplement7 no supplement7 no supplement7 no supplement7 no supplement7 dose for GFR 0.2-1 (D) no supplement7 no supplement7 no supplement7 no supplement7 normal no supplement7 no supplement7 no supplement7 no supplement7 dose for GFR 0.2-1 no supplement7 no supplement7 Antimicrobial Therapy In Patients With Impaired Renal Function (ii) Drug CiprofloxacinH ClarithromycinH ClindamycinH Co-trimoxazole2,+ Dose Adjustment Method2 I D D&I Adjustment for Renal Failure by GFR (ml/sec) > 50 ml/min 10 - 50 ml/min < 10 ml/min 12 hourly normal normal 12 hourly 12-24 hourly 75% normal 50% 12 hourly Doxycycline Erythromycin Ethambutol Flucloxacillin Fluconazole Flucytosine Fusidic acid Ganciclovir+ Gatifloxacin D I D&I D I I D normal normal 24 hourly 6 hourly normal 6-8 hourly2 normal 12 hourly normal normal normal 24-48 hourly 8 hourly 50% 12-24 hourly2 normal 24-48 hourly 50% 24 hourly 50% normal Avoid 50% 24 hourly (on dialysis) normal 50-75% 48 hourly 50% 8 hourly 50% 24 hourly2 normal 48 hourly 50% Gentamicin2 Imipenem/cilastatinH Isoniazid ItraconazoleH Ketoconazole Mebendazole Mefloquine Metronidazole MeropenemH Minocycline MoxifloxacinH D&I D&I D D&I - normal normal normal normal normal normal normal normal 8 hourly normal normal 100% 36-48 hourly 50% 8-12 hourly normal normal normal normal normal normal 50-100% 12 hourly normal normal avoid 50% 12 hourly normal normal normal normal normal normal 50% 24 hourly normal normal 107 Doses for Dialysis Supplement for Supplement or Dose (D) HAEMO for CAPD 8 dose after 250 mg 8 hourly (D) dose after8 no supplement7 no supplement7 no supplement7 dose after8 no supplement7 no supplement7 no supplement7 dose after8 no supplement7 dose after8 dose after8,2 no supplement7 dose after8 Dose after as per 0.2-1.0ml/sec dose after8,2 dose after8 dose after8 no supplement7 no supplement7 no supplement7 no supplement7 dose after8 dose after8 no supplement7 no data no supplement7 no supplement7 no supplement7 no supplement7 no supplement7 no supplement7 nd5 no supplement7 As for 0.2-1.0mL/sec 4-8 mg/L of dialysate3,2 (D) nd5 no supplement7 no supplement7 no supplement7 nd5 no supplement7 no supplement7 nd5 no supplement7 no data Antimicrobial Therapy In Patients With Impaired Renal Function (iii) Drug Nitrofurantoin Norfloxacin Phenoxymethylpenicillin Piperacillin TazobactamH Praziquantel Pyrazinamide Pyrimethamine+ Quinine Rifabutin Rifampicin Roxithromycin Sulphadiazine+ Dose Adjustment Method2 I D normal 12 hourly normal avoid 12-24 hourly normal avoid 24 hourly normal Doses for Dialysis Supplement for Supplement or Dose (D) HAEMO for CAPD avoid avoid no supplement7 no supplement7 dose after8 no supplement7 I normal 8 hourly 12 hourly dose after8 no supplement7 D I I normal normal normal 8 hourly normal normal normal 6 hourly normal 50% normal 24 hourly normal 50-100% normal Avoid if possible 12 hourly 24 hourly 72 hourly no supplement7 no data no supplement7 dose after8 no supplement7 no supplement7 no supplement7 nd5 nd5 no data no supplement7 no supplement7 no supplement7 no supplement7 no supplement7 nd5 12 hourly 24 hourly normal normal normal 8-12 hourly normal normal normal Avoid if possible 8 hourly 18 hourly 48 hourly dose after8 no supplement7 no supplement7 no supplement7 normal 8-12 hourly normal 50-100% 24 hourly2 normal 12-24 hourly 48 hourly avoid normal 50% 24 hourly to 30% 48 hourly2 normal 24-48 hourly 48 hourly avoid normal 30% 48 hourly2 no supplement7 avoid dose after8 dose after8,2 no supplement7 avoid normal 3-4 mg/L of dialysate3 (D)2 Sulphamethoxazole*,+ I H Teicoplanin After dose on day 4 (I) Terbinafine I Tetracycline I Tinidazole TobramycinH, 2 D&I Trimethoprim Vancomycin2, H I Adjustment for Renal Failure by GFR (ml/sec) > 50 ml/min 10 - 50 ml/min < 10 ml/min 108 avoid dose after8 every 4-10 days no supplement7 no supplement7 no supplement7 HEPATIC INSUFFICIENCY Although many antibiotics are metabolised in the liver and a few are excrete significant extent, in the bile, precise guidelines for dosing in hepatic insufficie unavailable. There is no test of hepatic function, equivalent to creatinine cleara renal insufficiency, on which to base dosage adjustments. It is prudent to avoi with known hepatotoxicity when possible in those with hepatic failure. For manufacturer’s recommendations consult www.medsafe.govt.nz 109 OBESE PATIENTS Antibiotic dosing is routinely adjusted for weight, but does not often take account of the variable proportions of tissues that comprise the body’s mass. The effect of obesity on the pharmacokinetics of antimicrobials is not very well understood. The volume of distribution of antibiotics in fat is only about 0.3 to 0.4 that of other tissues. The dosing weight is therefore often calculated as the ideal body weight plus 0.3-0.4 the difference between actual and ideal body weight. Since there is likely to be considerable individual variation, in the case of potentially toxic drugs e.g. aminoglycosides, levels should be measured and doses adjusted accordingly. 110 PREGNANCY AND LACTATION Drugs in Pregnancy During the first 2 weeks of development, the embryo is thought to be resistant to any teratogenic effects of drugs. The critical period of embryonic development, when the organ systems develop starts at about 17 days after conception and is complete by 60 to 70 days. Exposure to certain drugs during this period can cause major birth defects. However, some drugs can interfere with functional development of organ systems and the central nervous system in the second and third trimesters and produce serious consequences. All drugs should be avoided if possible in the first 12 weeks of pregnancy. If drugs are to be prescribed, the benefits to the mother and/or foetus must be considerable. Discrepancies between recommendations on the safety of antimicrobials in pregnancy are a reminder that all prescribing involves risks and benefits that are often difficult to quantify. Manufacturers' recommendations tend to err on the side of caution and their warnings frequently reflect theoretical concerns or insufficient data rather than proven toxicity. No antimicrobial is absolutely contraindicated in all circumstances in pregnancy but the table below may allow choice of a safer alternative or raise the possibility of deferring treatment. Refer to the Description of Foetal Risk Categories (below) when prescribing any antimicrobial medications for women who are pregnant or lactating. Description Of Foetal Risk Categories A Controlled studies show no risk. Adequate, well-controlled studies in pregnant women have failed to demonstrate risk to the foetus. B No evidence of risk in humans. As experience of effects of drugs in this category in humans is limited, results of toxicological studies to date (including reproduction studies in animals) are indicated by allocation to one of three sub-groups: B1 Studies in animals have not shown evidence of an increased occurrence of foetal damage. B2 Studies in animals are inadequate or may be lacking, but available data show no evidence of any increased occurrence of foetal damage. B3 Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans. C Risk cannot be ruled out. Human studies are lacking, and animal studies are either positive for foetal risk or lacking as well. However, potential benefits may justify the potential risk. D Positive evidence of risk. Investigational or postmarketing data shows risk to the foetus. Nevertheless, potential benefits may outweigh the potential risk. X Contraindicated in pregnancy. Studies in animals or humans, or investigational or postmarketing reports have shown foetal risk that clearly outweighs any possible benefit to the patient. Drugs that have such a high risk of causing permanent damage to the foetus should not be used in pregnancy or when there is a possibility of pregnancy (ie avoid in woman of childbearing potential unless effective contraception is assured). 111 Drugs in Lactation The benefits of breastfeeding are sufficiently important to recommend that breastfeeding should be discontinued or discouraged only when there is substantial evidence that the drug taken by the mother will be harmful to the infant and that no therapeutic equivalent can be given. Most antimicrobial drugs are only excreted to a minimal extent in breast milk, and in most cases the dosage to which the infant is ultimately exposed is very low and is well below the therapeutic dose level for infants. For this reason there are few antimicrobial drugs that are totally contraindicated whilst breastfeeding. 112 Antimicrobial Drugs In Pregnancy And Lactation (i) Drug Category ANTIBACTERIALS Penicillins Use in Pregnancy (Foetal Risk Category) A/B1 Use in Lactation Safe Caution high dose IV Safe Safe Caution high dose IV Safe Cephalosporins Beta-lactamase inhibitors (e.g. clavulanate) Erythromycin (Do not use estolate during pregnancy - increased risk of maternal hepatoxicity) ClindamycinH A/B1 B Nitrofurantoin A Roxithromycin Aminoglycosides (Potential for foetal 8th nerve toxicity) Chloramphenicol (Avoid near term - risk of Grey Baby syndrome) ClarithromycinH (Foetal toxicity in primates) Fusidic acid Metronidazole and other nitroimidazoles (Avoid during first trimester) B1 D Safe, monitor infant for diarrhoea Avoid in premature infants. Caution with G6PD deficiency infants Safe Safe A Not recommended B3 Safe C B2 Rifampicin (Neonatal bleeding, give Vitamin K if used during last few weeks of pregnancy) Trimethoprim (Avoid use in first trimesterteratogenic) Nalidixic acid C Safe Produces a bitter taste in milk Withhold breast-feeding for 24hrs after high dose or IV Safe B3 Safe A VancomycinH Tetracyclines (Discoloration of teeth, inhibition of bone growth, maternal hepatotoxicity) Sulphonamides e.g. cotrimoxazole, sulphamethoxazole (Avoid near term - risk of kernicterus) Fluoroquinolones e.g. ciprofloxacin, norfloxacin (Damage to developing cartilage in animal models) B2 D Caution especially in neonatal period Safe Short course is safe C Safe B3 Caution, monitor infant for diarrhoea A A 113 Antimicrobial Drugs In Pregnancy And Lactation (ii) Drug Category ANTIFUNGALS Amphotericin BH Fluconazole ItraconazoleH Ketoconazole ANTIVIRALS Aciclovir Ganciclovir Antiretrovirals (Therapy for HIV infection has not been associated with foetal risk and prevents transmission. Expert advice recommended). Use in Pregnancy (Foetal Risk Category) Use in Lactation B3 D B3 B3 Uncertain Safe Uncertain Uncertain B3 D Safe Insufficient data Contraindicated in HIV positive women 114 ORAL ANTIMICROBIAL THERAPY Switch Therapy The excellent pharmacokinetics and spectra of activity of many oral antimicrobial agents now enable the physician to choose an alternate approach to the treatment of infection in selected patients without compromising clinical outcome. Timely conversion from intravenous to oral agents has been referred to as switch, step-down or sequential therapy. This has been shown to be successful in the management of infections including those of the respiratory tract, skin and soft tissue, and bone and joint. In addition to reducing the costs of treatment, this approach to the management of infectious disease can be an important component in the provision of optimal patient care. Oral agents are generally much less expensive than parenteral; in addition, hidden costs such as plasma drug and toxicity monitoring, IV sets and specialised equipment, nursing and pharmacy time and wastage are avoided. In some patients, the antimicrobial may be given by mouth from the outset of treatment; this will depend upon the disease state, its severity and patient characteristics. Advantages • • • • • Eliminates the risk of adverse events associated with intravenous therapy, such as phlebitis and increased fluid burden. Increases patient comfort and acceptance of therapy and permits increased patient mobility. Increases the potential for completion of treatment as an outpatient, allowing earlier discharge from hospital. Decreases the risk and severity of allergic reactions. Reduces treatment costs. Guidelines Patients eligible for conversion from parenteral to oral therapy should meet the following criteria: • Patient is tolerating oral or NG nutrition or is receiving medication by mouth or NG tube. • Patient has a functional gastrointestinal tract. • Signs and symptoms related to the infection have resolved or are improving. • Patient does not fall within the parameters of exclusion as described below. • Patients should be excluded from immediate consideration for Switch Therapy if they meet any of the following criteria: - Patient has an infection in which the continuation of parenteral therapy is indicated, such as endocarditis, meningitis, line sepsis or Staphylococcus aureus, or Enterococcus spp. bacteraemia. - Patient has febrile neutropenia. Response to oral medication may be unreliable e.g. in the presence of continuous NG suction, malabsorption syndrome, ileus, protracted vomiting and severe diarrhoea. Treatment should be reinstated with the original parenteral regimen if continued improvement in the patient's clinical status is not apparent on oral therapy. 115 Selecting an Appropriate Oral Antimicrobial Drug The choice of oral antimicrobial agent should reflect the sensitivities of the microorganism(s) involved. In the absence of a cultured pathogen, the oral agent should be chosen with consideration of the most likely causative organism and its usual sensitivities. It is not necessary to choose an oral agent from the same antimicrobial class as the parenteral agent being replaced. The following examples of regimen conversion are representative only and are not intended to be comprehensive. Doses will vary according to the clinical circumstances and patient characteristics. IV Drug and Representative Dose Amoxycillin 1g q6h Amoxycillin/ 1.2g q8h clavulanate Cephazolin 1g q8h Cefuroxime 750mg q8h CiprofloxacinH ClindamycinH Erythromycin Flucloxacillin Gentamicin Metronidazole 400mg q12h 300-600mg q8h 500-1000mg q6h 1-2g q6h 400mg q24h 500mg q12h Oral Drug and Representative Dose Amoxycillin 500mg q8h Amoxycillin/ 500mg q8h clavulanate Cephalexin 500mg q8h Amoxycillin/ 500mg q8h clavulanate CiprofloxacinH 500-750mg q12h H Clindamycin 300-450mg q6h Erythromycin 800mg q6h Flucloxacillin 500-1000mg q6h H Ciprofloxacin 500mg q12h Metronidazole 400mg q12h 116 Bioavailability Of Oral Antimicrobials Drug Oral Absorption (%) Dose (mg) Peak (µg/ml) Half-Life (hr) Protein Binding (%) Taken with Meals ANTIBACTERIALS Penicillins Amoxycillin Amoxycillin/clavulanate Flucloxacillin Penicillin V 60-89 60 50 35-70 500 500 500 500 5.0 4.8 7-14 3-5 1 1 0.5 0.5 17 18 95 35 Yes Yes No No Cephalosporins Cephalexin Cephradine Cefaclor 90 90 50 500 500 500 15-18 16 13 0.5-1.3 1.3 0.8 5-15 6-20 22-25 Yes No No Fluoroquinolones CiprofloxacinH Gatifloxacin MoxifloxacinH 69-85 96 89 750 400 400 4.0 4.2-4.6 4.5 3-5 7-8 10-14 20-40 20 50 Yes No No Macrolides Erythromycin base Erythromycin stearate 18-45 18-45 250 500 0.3-1.0 0.4-1.9 1.4 70-74 Roxithromycin 80 150 6 12 90% No Yes No 100 200 200 250 500 1.8-2.9 3.7-6.7 2-3 1.5-2.2 3.0-4.3 18 93 Yes 11-26 8.5 76 65 Yes No 600 250 500 160/ 800 5.3 5 10 2/40 2.4 6-14 85-94 20 Yes Yes 11/9 44/ 70 Yes Tetracyclines Doxycycline 90-100 Minocycline Tetracycline 95-100 75-80 Miscellaneous ClindamycinH Metronidazole 85-90 90-100 Trimethoprim / Sulphamethoxazole 85-90 ANTIVIRALS Aciclovir 15-30 200 0.3-0.9 2.2-5.0 9-33 Yes ANTIFUNGALS Fluconazole 90 11-12 Yes Variable 4.5-8 10 3-4.5 24 Ketoconazole 100 200 200 6.5-9.6 84-99 Yes 117 PROPHYLACTIC USE OF ANTIMICROBIAL DRUGS SURGICAL PROPHYLAXIS Appropriate antimicrobial prophylaxis significantly decreases the incidence of postoperative infection following certain surgical procedures. The antibiotic regimen chosen for these procedures should be directed against the most likely infecting organism(s) (and not necessarily against every potential pathogen) and be designed so that the total number of organisms is decreased but not necessarily eliminated. Most post-surgical infections are due to the patient’s own organisms. In hospitalised patients, this may include multiresistant organisms, so the following recommendations may need to be individualised. Prophylaxis is the use of antibiotics to prevent infections at the surgical site. This must be distinguished from their use in early treatment, where infection is already established although not necessarily evident preoperatively (e.g. removal of a perforated appendix). Major Indications for use of Prophylactic Antibiotics • • Operations in which the risk of post-operative wound infection are high e.g. cleancontaminated surgical procedures. Operations in which the wound infection rate is relatively low but the consequences of infection are significant e.g. prosthetic implants. Principles for timing of Antibiotic Administration For effective antimicrobial prophylaxis, the drug must be present in the tissues in adequate concentration at the onset and throughout the operative procedure. To achieve this goal, the initial dose must be administered parenterally in the immediate pre-operative period (within 30 minutes) before the operation. Delaying initial dosing until the post-operative period or giving the antibiotics too far in advance of the procedure are both associated with an increased wound infection rate. Rectally administered metronidazole should be given 2 to 4 hours before surgery. VancomycinH requires a slower infusion that should be completed just prior to induction. Route(s) of Administration Intravenous administration is the optimal method to ensure adequate tissue levels during the operative procedure. In certain instances rectal or oral administration is appropriate. Duration of Antibiotic Treatment The critical period for successful prophylaxis is the 4 hours following implantation of organisms into a wound. In general, a single dose of parenteral antibiotic is sufficient 118 for most surgical procedures lasting less than 4 hours. A second dose may be necessary under the following circumstances: • A delay in starting the operation. • If the operation is prolonged so that it continues beyond four hours. • In specific circumstances e.g. amputation of an ischaemic limb. Giving more than 1 or 2 doses postoperatively is not advised, except where specifically recommended. Established infection should of course be treated. Note: • Prophylactic antibiotics are only one factor that determines the risk of infection. Other factors of equal or even greater importance are surgical technique, the duration of surgery, the duration of pre-operative stay, shaving the operation site (if this must be done, do so immediately pre-operatively), repeat surgical procedure, obesity, immune compromise and a variety of other host factors (eg diabetes). • Excessively long courses of 'prophylactic' antibiotic, whether before or after surgery, select for resistant organisms and may increase the risk of infection. The practice of continuing prophylactic antibiotics until surgical drains have been removed is both illogical and of unproven benefit. Choice of Antibiotic There are several considerations when selecting an antimicrobial regimen for prophylaxis: • Antibiotics should have a spectrum of activity, which includes the pathogens most frequently responsible for wound infection following a given operation. • The antibiotics need not be active against every micro-organism present in the initial bacterial inoculum, as some of the micro-organisms may not contribute to the development of wound infection. • Consideration should be given to the serum half-life of the antibiotic and local hospital antimicrobial susceptibility patterns. Routine use of vancomycinH prophylaxis is strongly discouraged to prevent selection pressure for VRE and VRSA. However, vancomycin should replace the cephalosporin or penicillin component of a regimen when preoperative patients are infected or colonised with an MRSA strain either currently or in the recent past. The following tables contain surgical prophylaxis regimens that have been approved for use by the respective Clinical Directors at Waikato Hospital. 119 Antibiotic Prophylaxis for Surgical Procedures (i) Type of Surgery Likely Pathogens Suggested Regime(s) GENERAL SURGERY Contaminated or potentially contaminated wounds Abdominal surgery, including upper and lower GI tract, appendix and biliary tract and laparoscopic surgery Anaerobic bacteria, Streptococci, Aerobic Gram-negative bacilli Metronidazole (child:12.5mg/kg up to) 500mg IV, ending the infusion at the time of induction plus Cephazolin (child: 25mg/kg up to) 1g IV at the time of induction (2g IV if >80kg). A second dose of cephazolin is administered for prolonged procedures (greater than 4 hours), or if significant blood loss has occurred Severe penicillin allergy Gentamicin 3mg/kg IV (based on lean body mass) and metronidazole 500mg IV at induction Clean surgery Hernia (with prosthetic material), varicose veins Staphylococcus aureus, Staphylococcus epidermidis Cephazolin 1g IV (2g IV if >80kg) at induction. A second dose is administered for prolonged procedures (greater than 4 hours) or if significant blood loss has occurred Thyroid and Parathyroid surgery Staphylococcus aureus, Staphylococcus epidermidis Flucloxacillin 1g IV at induction. Breast surgery Staphylococcus aureus, Staphylococcus epidermidis (occasional anaerobes) Amoxycillin/clavulanate 1g/200mg IV at induction Note: Not all GI surgery needs prophylaxis. There is no indication for prophylaxis in uncomplicated cholecystectomies in patients younger than 60 as Antibiotic Prophylaxis For Surgical Procedures (ii) Type of Surgery Likely Pathogens Suggested Regime(s) VASCULAR SURGERY Staphylococcus aureus, Staphylococcus epidermidis (occasional gram-negative bacilli) Cephazolin 1g IV (2g IV if >80kg) at induction. A second dose is administered for prolonged procedures (greater than 4 hours) or if significant blood loss has occurred. LOWER LIMB AMPUTATION This carries a small but important risk of clostridial infection. Use Cephazolin 1g IV (2g IV if >80kg) at induction plus metronidazole 500mg (child: 12.5mg/kg up to 500mg) IV ending at the time of induction and then 12 hourly for 24 hours. CARDIOTHORACIC SURGERY Staphylococcus epidermidis, Staphylococcus aureus Aerobic Gram-negative organisms Cephazolin 1g IV (2g IV if >80kg) at induction. A second dose is administered for prolonged procedures (greater than 4 hours), or if significant blood loss has occurred. NEUROSURGERY Staphylococcus epidermidis, Staphylococcus aureus Cephazolin 1g IV (2g IV if >80kg) at induction only. ORTHOPAEDIC SURGERY Staphylococcus epidermidis, Staphylococcus aureus Cephazolin 2g IV (3g IV if >120kg) at induction only. Allow 5 minutes to elapse between administration of antibiotic and application of a tourniquet. A second dose is administered for prolonged procedures (greater than 4 hours). Severe penicillin allergy or patients known to be colonised with MRSA Vancomycin 500mg infused over at least one hour Head And Neck Mixed anaerobic and anaerobic upper respiratory tract flora Amoxycillin/clavulanate 1g/200mg IV at induction Rhinoplasty +/- cartilage graft Staphylococcus species Flucloxacillin 1g IV at induction Ear or sinus surgery with potential for dural breach Mixed aerobic and anaerobic upper respiratory tract flora Amoxycillin/clavulanate 1g/200mg IV at induction Contaminated major ear or sinus surgery Mixed aerobes and anaerobic upper respiratory tract flora Amoxycillin/clavulanate 1g/200mg IV at induction EAR, NOSE AND THROAT SURGERY 121 Antibiotic Prophylaxis For Surgical Procedures (iii) Type of Surgery Likely Pathogens Suggested Regime(s) OBSTETRIC & GYNAECOLOGICAL SURGERY Hysterectomy Anaerobes, Gram negative bacilli, Group B Strep, and enterococci Cephazolin 1g IV (2g IV if >80kg) at induction plus metronidazole 500mg IV, ending the infusion at the time of induction. Severe penicillin allergy Gentamicin 3mg/kg IV (based on lean body mass) and Metronidazole 500mg IV at induction or 1g PR 1 hour pre-operatively. Caesarean section. Gram negative bacilli, Group B Strep, and enterococci Cephazolin 1g IV (2g IV if >80kg) immediately after clamping of the cord. The recommendation to delay the timing of antibiotics, therefore avoiding exposure to the neonate, may assist in the assessment of potential sepsis in the neonate. There is no evidence that Cephazolin given at induction causes either toxicity or allergy in the neonate. General Aerobic Gram-negative bacilli, Enterococcus faecalis, Staphylococci Gentamicin 3mg/kg IV (based on lean body mass) Cystectomy Aerobic Gram-negative bacilli, Enterococcus faecalis, Staphylococci and anaerobes Gentamicin 3mg/kg IV (based on lean body mass) and Metronidazole 500mg IV at induction or 1g PR 1 hour pre-operatively OPTHALMOLOGY SURGERY Staphylococcus epidermidis, Staphylococcus aureus Cephazolin 1g IV (2g IV if >80kg) at induction only. There is now evidence that antibiotics are beneficial for prophylaxis of wound sepsis as well as endometritis for all caesarean sections, elective or nonelective. UROLOGICAL SURGERY Orbital Trauma and Orbital Implants 122 ENDOCARDITIS PROPHYLAXIS A revolution in the recommendations for endocarditis prophylaxis has occurred during the last decade highlighted by the 2007 publication of the American Health Association “Prevention of endocarditis” guidelines - Circulation 2007;116:1736-1754. These evidence based guidelines are radically different from previous guidelines and have markedly reduced the indications for endocarditis prophylaxis acknowledging that the frequency, magnitude and duration of bacteraemia from dental and other procedures is in fact very similar to that which occurs from everyday activities. As a result, the need for specific endocarditis prophylaxis around dental and other operative procedures has been markedly reduced. The Waikato DHB has therefore created new endocarditis prophylaxis guidelines, adapted from the recommendations made within the AHA guidelines and 2008 NICE guidelines (http://www.nice.org.uk/CG064). The NZ heart foundation guidelines are as follows. http://www.ttophs.govt.nz/vdb/document/312 Cardiac Conditions associated with the highest risk of adverse outcome from endocarditis for which prophylaxis is reasonable • Prosthetic cardiac valve or prosthetic material used for cardiac valve repair. • Prior episode(s) of infective endocarditis. • Specific congenital heart disease only - Unrepaired cyanotic CHD, including palliatie shunts and conduits - Completely repaired congenital heart defect with prosthetic material or device during the first 6 months after the procedure - Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device • Cardiac transplantation recipients who develop cardiac valvulopathy • Rheumatic valvular heart disease Prophylaxis is not reasonable or recommended in any of the following circumstances: - Native valvular heart disease (except for those with previous infective endocarditis) - Mitral valve prolapse or hypertrophic cardiomyopathy - Previous coronary artery bypass graft surgery - Presence of a cardiac pacemaker - There is also no role for antibiotic prophylaxis in those with prosthetic joints. Dental Procedures for which Prophylaxis is reasonable when the above highest risk cardiac conditions are present • All dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa. Endocarditis prophylaxis solely to prevent IE is no longer recommended for any Respiratory, GI or GU procedures. It is important to state that antibiotic therapy remains important in treating active infections. Antibiotic Regimens Antibiotics are aimed at Streptococcus viridans species. Standard regimen: Amoxycillin 2g (children 50mg/kg up to 2g) po 30 to 60 minutes before the procedure. Patients with penicillin allergy: Clindamycin 600mg (children 20mg/kg up to 600mg) po 30 to 60 minutes before the procedure. “Until publication of the recent AHA (Wilson et al. 2007) guidelines, antibiotic prophylaxis was universally prescribed to cover dental and other interventional procedures in patients at risk of infective endocarditis (IE). There are, accordingly, a large number of patients with a long history of taking antibiotic prophylaxis against IE for dental procedures for whom it is no longer considered appropriate. The information and support needs for such patients are likely to be significant because they will need to be fully informed about the risks and benefits of antibiotic prophylaxis in order to make an informed decision not to continue to take it.” NICE guideline comment 2008 124 SPLENECTOMY After splenectomy, people are at risk of severe infection, particularly from a small range of encapsulated bacteria. About 70% of these post splenectomy sepsis episodes occur in the first 5 years. Adults may be at less risk than children. The most common organisms are Streptococcus pneumoniae and Haemophilus influenzae type B, with Neisseria meningitidis and S. aureus causing a few cases only. Malaria is a recognised risk which travellers should be warned about. Australasian guidelines have been published in Internal Medicine Journal 38 (2008) 349–356. Prevention of Severe Infections Measures to prevent severe infections post-splenectomy include: • Use of spleen-sparing procedures in trauma. • Vaccination • Prophylactic antibiotics. Vaccination(see website for advice) http://www.immune.org.nz/sites/default/files/resources/ProgrammeFundedPrePostSplenectomy201302 27V03Final.pdf This should ideally be done 2 weeks before an elective splenectomy. Post splenectomy, response is believed to be better if given more than 2 weeks after the operation. Recommended vaccinations include: • • • • Pneumococcal 23-valent, 5 yearly. For children, a 13-valent conjugate vaccine is available which is more efficacious than the 23 valent polysaccharide vaccine. Haemophilus influenzae Type B. This should be given as per routine schedule for children, but is unlikely to benefit adults who have a much lower incidence of disease, presumably due to preexisting immunity. This vaccine doesn’t protect against the non-typable H. influenzae, which causes adult respiratory tract infections. Meningococcal vaccine. Meningococcal ACYW-135 is recommended. The New Zealand custom-made serogroup B vaccine is no longer available. Influenza vaccine seems sensible and could be offered annually. Prophylactic Antibiotics Penicillin for “a few years” has been used, but there is no consensus that it is worthwhile, particularly for adults. There are no guidelines for dose, but amoxycillin has theoretical advantages with better coverage of Haemophilus and better pharmacokinetics from oral dosing. For the motivated, informed patient who wishes to use prophylaxis, amoxycillin 250 mg daily (20mg/kg daily for children <5 years) for 3 - 5 years would be reasonable, although there is no evidence-based literature to support this. Patient education is vitally important and the following site provides a good resource for patients. http://www.patient.co.uk/health/preventing-infection-after-splenectomy-or-if-you-do-nothave-a-working-spleen Treatment Of Post-Splenectomy Sepsis It would be reasonable for a patient to hold a supply of oral amoxycillin for prompt treatment of sepsis, but immediate simultaneous presentation to hospital would also be necessary. Ceftriaxone would be the drug of choice at hospital presentation. Treatment of fulminant sepsis may be unsuccessful even when initiated promptly. 125 APPENDICES OUTPATIENT INTRAVENOUS THERAPY To ensure the safe and co-ordinated care of a patient who is discharging into the community on IV therapy the Community Resource Nurse (CRN) must be contacted. (The ward Clinical Nurse Leader will be able to do this). Nursing policies related to community IV therapy exist within the following link http://ourintranet/WDHB/Nursing+and+Midwifery/IV+Therapy+Medicine+Management/Discharge+Pl anning.htm Sections within this link include: How to Discharge Home Your Patient on IV Therapy - Procedure to discharge into the community on long term intravenous antibiotic therapy Elastomeric Infusor Order Forms - Waikato infusor order form and Elastomeric infusor information The CRN will facilitate discharge planning. There are 23 District Nurses based within WDHB, and all are able to manage IV therapy. Long Term IV Antibiotics e.g. Joint infections, Endocarditis. A District Nurse can administer once daily IV antibiotics e.g. ceftriaxone. If administration is more frequent than this, the patient/parent is required to self-administer, or have a continuous infusion pump (we use elastomeric pumps within the Waikato DHB). A central venous catheter line or PICC line is usually required. Only certain antibiotics are fully subsidised for patients in the community. Check with Pharmacy Department to see whether it will be necessary to make an application for funding through Hospital Exceptional Circumstances (HEC). Applications forms for HEC funding are available from Pharmacy. The WDHB IV Manual, Section A10, has a pre-discharge checklist and skills mastery list, essential for all IV discharges. Short Term IV Therapy e.g. Completion of antibiotic course for meningitis (up to 7 days). As above, but a peripheral line is adequate. Chronic/Speciality Patients Requiring IV Therapy e.g. Cystic Fibrosis, Haematology patients. 126 Contact the ward Clinical Nurse Leader or Clinical Nurse Educator – specialist areas will have relevant protocols for chronic patients. Community Cellulitis Protocol This is for short-term antibiotics (three days) in the community via a peripheral line for simple cellulitis. This protocol is used by Waikato and T Hospital Emergency Departments and is now available to all GPs in the region. 127 LOCAL RESISTANCE PATTERNS TO ANTIMICROBIAL DRUGS Antimicrobial therapy is usually commenced before the causative organism is known with certainty. The choice of agent for this “empiric therapy” depends on knowing the likely organisms and their likely susceptibility. The Treatment Guidelines for Common Conditions section of this handbook includes notes on the anticipated etiologic organisms. Frequently, the organism is identified in the laboratory before susceptibility test results are available. Most organisms are reasonably predictable in their antimicrobial susceptibility and frequently the antibiotic spectrum used can be narrowed once their identity is known. Susceptibility results for the individual patient’s organism often allow it to be narrowed further. Definitions: • “Susceptible” means that recommended doses of the antibiotic should be effective in commonly encountered conditions. Many other factors can influence therapeutic success, e.g. site of infection, presence of prosthetic material or immunosuppression. • “Resistant” means that an alternative agent should be considered. • “Intermediate” or “reduced susceptibility” means that in favourable circumstances, the antibiotic may be effective. Increased doses may be required. Common Organisms in Sepsis The following data is presented as a guide to the most common organisms expected in severe sepsis. These organisms are grouped according to their predictable susceptibility patterns. 128 Gram-Positive Bacteria Staphylococcus aureus Flucloxacillin remains the drug of choice. About 10% are MRSA. Check the hospital alerts system and previous lab results because many cases of MRSA infection in previously recognised carriers. Coagulase-Negative Staphylococci These are frequently contaminants and don’t require treatment. Streptococcus pneumoniae These respond well to high dose penicillin or cephalosporins. Invasive isolates are almost always susceptible but low level resistance is not uncommon in respiratory tract isolates Beta Haemolytic Streptococci (Group A B C G and S. anginosus) These are uniformly susceptible to penicillin. Viridans Streptococci These are also uniformly susceptible to penicillin. If MIC >0.1 µg/ml in endocarditis, gentamicin may be required in addition. Most blood culture isolates occur in the context of mucosal barrier injury or polymicrobial abscesses. Enterococci 129 These are intrinsically more resistant than streptococci. A penicillin is the agent of choice. They are intrinsically resistant to cephalosporins, cotrimoxazole and erythromycin. There has not been any evidence of vancomycin resistance in the Waikato for nearly a decade. Vancomycin is often the only alternative. For urinary tract infections, nitrofurantoin is often satisfactory. Gram-Negative Bacteria Coliforms (E. coli, Klebsiella, Proteus, Enterobacter, Serratia) These are mostly reasonably susceptible to antibiotics, with two exceptions: 1. ESBL producing (cephalosporin resistant) E. coli and Klebsiella pneumoniae, which are typically also multi resistant to gentamicin, cotrimoxazole and ciprofloxacin. Use of any of these agents allows ESBL strains to spread to new patients. Oral options are few (Fosfomycin may be of use for urinary tract infections due to ESBLs and is available with Infectious Diseases input), but amikacin, ertapenem and meropenem are usually active. 2. Potential AmpC producing species (Enterobacter, Serratia, Citrobacter, Providencia, Morgaella). Although initially testing susceptible in the lab, these can develop resistance to cephalosporins after 3 or 4 days treatment so an early change to another agent is recommended once the species is known. Pseudomonas species Severe sepsis may be treated with dual antibiotics, including an aminoglycoside, antipseudomonal penicillin or cephalosporin or a fluoroquinolone. Acinetobacters A rare cause of sepsis. antibiotics. Isolates from the Waikato are usually susceptible to several standard Stenotrophomonas maltophilia Low pathogenicity, sometimes associated with central line infection, highly multiresistant. They are usually susceptible to cotrimoxazole. Neisseria meningitidis Uniformly susceptible to ceftriaxone and all penicillins. Haemophilus influenzae H. influenza serotype B invasive disease has virtually been eradicated by vaccination. All our isolates are “non typeable” and susceptible to amox-clav and cephalosporins but a few show low level resistance of uncertain clinical significance. Anaerobic Bacteria (Bacteroides, Clostridia, Propionibacteria and many others) Usually present as part of a polymicrobial infection. Full identification to species level and susceptibility testing are technically difficult and taken 1-2 weeks, so not usually performed. Most clinical isolates of all species in NZ are susceptible to amox-clav and to meropenem. Gram negative anaerobes (Bacteroides, fusobacterium) are almost all covered by metronidazole and gram positives (Clostridia) by clindamycin. It is not usually necessary to cover all anaerobes; treatment of coliforms and streptococci is the priority. A few life threatening pure anaerobic infections (eg Lemierres disease, tetanus) require infectious disease consultation. Yeast Candida albicans and Candida parapsilosis Predictably susceptible to fluconazole. 130 Other Candida species are often resistant to fluconazole e.g. C. glabrata and C. krusei. 131 Antimicrobial Susceptibility of Common Blood Culture Isolates Waikato Hospital 2013 Recommended antibiotics for E. coli bacteraemia in order of preference: Ceftriaxone Gentamicin Ciprofloxacin (If above drugs contraindicated or resistant) Ertapenem (If multidrug resistant eg ESBL) Recommended antibiotics for E. coli infection at other sites: Cotrimoxazole Amoxycillin or amox-clav Nitrofurantoin (urine only) Ciprofloxacin (If above drugs contraindicated or resistant) 132 Recommended antibiotics for S. aureus in order of preference: Flucloxacillin Cotrimoxazole (if oral therapy is appropriate) Vancomycin (if MRSA and resistant to cotrimoxazole) Erythromycin or clindamycin (for non life threatening conditions) Amox-clav (if broader spectrum cover is required) Cephalosporins (If past adverse reaction to penicillins but cephalosporins have been tolerated) Note: mupirocin is only used for clearing nasal carriage. Note: Coagulase negative staphylococci are normal skin flora and of low pathogenicity. Most isolates from blood culture are contaminants. A diagnosis of true infection (eg CVL or prosthetic joint) requires two or three positive specimens from a sterile site. Note: Only 30 isolates of P. aeruginosa were found in blood cultures over 12 months. Isolates from urine, sputum and wounds tend to be more resistant but are often colonisers or contaminants. 133 Resistance to any antibiotic can develop after prolonged treatment. Report prepared by: Dr Chris Mansell Microbiology department 134 Infection incidence summary report 2013 (MRSA, ESBL, Clostridium difficile, VRE & MDRO) Methicillin Resistant Staphylococcus Aureus (MRSA) (For MRSA Incidence Graph see Appendix 1) There were 755 cases of MRSA reported to Infection Control during 2013. This is an increase of 61 cases from 2012, and an on-going upward trend for a number of years. Cases include Hospital acquired (HA) , community acquired (CA) MRSA and those reported to us by the community laboratories. Pathlab results accounted for 54% of notifications (409 cases), approximately the same percentage as 2012. 56 cases (7%) were identified as nosocomial to Waikato DHB services and 36 cases (5%) were categorised as ‘possible’. Nosocomial cases were identified in practically all wards including the rural hospitals. The majority of identified cases were community acquired at 651 (86%), while those which were unable to be determined as either HA or CA, were grouped in the unknown category with 12 cases (2%). These are the same approximate percentages as 2012. Positive specimens came from a range of sources including screening swabs, wounds, urine, blood cultures, sputum, tissue and aspirates. The reason specimens were collected was unknown in 53% of isolates, this is due to the notification from Pathlab and the limited information provided. Clinical signs and symptoms (37%) were the next most common reason for collection, with screening only accounting for 8% of isolates identified. The AK3 strain was the commonly identified this year at 20% of all isolates, with WSPP1 and EMRSA-15 being the next most common at 7% each. This is an increase from last year for AK3 by 2% and a decrease for both WSPP1 & EMRSA-15 from 13% and 8% respectively. Currently Waikato DHB chooses to send all their multi resistant isolates to ESR for typing whereas Pathlab and other DHB’s do not, therefore 54% of our strains were classified as ‘not sent’ or ‘unknown’. There was an almost even split in results for male (49%) and female (51%), and patients ranged in age from less than 1 to 98 years old. Extend Spectrum Beta Lactamase (ESBL) (For ESBL Incidence Graph see Appendix 2) There were 286 new patients identified with ESBL isolates in 2013. Organisms identified included E. coli, E. cloacae, Klebsiella pneumonia, Klebsiella oxytoca and Proteus mirabilis. Isolate specimens included blood cultures, urine, faeces, sputum, wound swabs, rectal swabs, and tissue samples. Urine was the most common specimen (73%) that ESBL was identified from, with rectal screening swabs accounting for 18% of ESBL’s identified. These isolates were identified to us are from within Waikato DHB facilities (including rural hospitals), from the community (Pathlab) and from other District Health Boards. Just over half of the isolates were identified at Pathlab (53%). 81% of isolates were defined as community acquired, 12% as hospital acquired, and 6% possibly hospital acquired. The remaining 1% was not able to be identified in any of the above classifications, so were grouped into the unknown category. Hospital acquired increased 3% from 2012; this may be attributable to the start of the ESBL outbreak at Rhoda Read Continuing Care facility in December 2013. 18% of specimens were collected for screening purposes, which tie in with 18% of ESBL’s being identified from rectal screening swabs. 41% of specimens were taken for clinical signs and 135 symptoms, and 41% were unknown, these are commonly the Pathlab results where no clinical information is available. These are very similar to last year’s specimens. Patients ranged in age from less than 1 to 95 years old, with 72% (142) being female, an increase of 3% from 2012. All isolates in 2013 were multi-resistant. Clostridium difficile associated diarrhoea (CDAD) (For Clostridium difficile Incidence Graph see Appendix 3) From 1st January 2013 to 31st December 2013, data was collected on 84 patients with faeces positive for C. difficile. These figures include patient samples and tests undertaken for outside agencies. The definition used to define nosocomial infection is; 1. Hospital-Acquired (HA): patient with CDAD symptom onset more than 24 hours after admission to Health Care Facility (HCF). 2. Community onset-HCF associated (CO-HCFA): patient with CDAD symptom onset in the community or 48 hours or less after admission to a HCF, provided that symptom onset was less than 4 weeks after the last discharge from a HCF. 3. Community-acquired (CA): patient with symptom onset in the community or 48 hours or less after admission to any HCF providing symptom onset was more than 12 weeks after the last discharge form a HCF. 4. Indeterminate disease: patient who does not fit any of the above criteria for an exposure setting e.g. patient who has symptom onset in the community buy: patient who does not fit any of the above criteria for an exposure setting e.g. patient who has symptom onset in the community but who has discharged from the same or other HCF 4-12 weeks before symptom onset. The 84 cases is a decrease from 131 cases in 2012. Of the 84 cases with CDAD, 41 (49%) were defined as hospital-acquired, 17 (20%) CO-HCFA, 6 (7%) were of indeterminate disease, and 20 (23%) community-acquired. The incidence of hospital-acquired and community acquired cases decreased from 2012, while the number of CO-HFCA and indeterminate cases increased. The highest numbers of cases were identified in the fourth quarter with increase being in community acquired cases. The age of patients with CDAD ranged from 20 to 98 years of age, with a mean age was 67 years for all CDAD. Infants under the age of 2 years were excluded from the surveillance. Patients with CDAD were identified in 25 clinical areas across Waikato DHB. Ward M5 had the highest number of patients identified with CDAD in their area, with the majority being CO-HCFA, while Ward M3 had the highest incidence of hospital-acquired infections. The two major risk factors for development of CDAD are exposure to the organism and exposure to antibiotics, particularly third generation cephalosporins. Other risk factors include altered bowel function e.g. following bowel surgery and/or altered nutrition. 78% of CDAD cases received antibiotics which is a slight increase from 2012, while only 7% of cases had exposure to C.difficle, a significant decrease from 24% in 2012. 25% of CDAD cases experienced bowel surgery / bowel infection or impaired nutrition, the same as last year, and no cases required bowel surgery as a result of C.difficle infection complications. Vancomycin Resistant Enterococci (VRE) There were two cases of VRE identified in 2013, both were E.faecium species, and identified from a faecal sample and rectal screening swab. Both cases had been overseas prior to admission. The first case was a 27 year old female who presented with diarrhoea & vomiting two days after surgery at Braemar Hospital, having returned from holidaying in Bali 10 days prior. The second case was an 88 year old male who was transferred to Waikato Hospital directly from an Australian hospital, following an admission and surgery for a fractured neck of femur. 136 Multi Drug Resistant Organism (MDRO) There was one case of a multi-drug resistant organism reported in 2013, the organism a Pseudomonas aeruginosa was identified from aortic graft tissue following the patient suffering from recurrent pseudomonas bacteraemia’s throughout 2012. Compiled by Lisa Maxwell (CNS) on behalf of Infection Prevention & Control Team 137 Appendix 1: MRSA Incidence Graph Waikato DHB MRSA Incidence Colonised and clinical infections 800 Unknown 700 NOT STATED DISTINCT BORSA 600 Not sent Untypeable 500 Other Strains AKH3 TANS 2 400 WSPP 2 WSPP 1 USA 300 300 AK3 WR/AK1 200 AkH4 EMRSA 1 5 100 0 1989 1990 1991 1992 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 Appendix 2: Extended Spectrum Beta Lactamase Incidence Graph 139 Appendix 3: Clostridium difficile Incidence Graph 140 MRSA Management The control of MRSA is important because the alternatives to beta-lactams are more toxic, more expensive and less effective. New Zealand is in the fortunate position where beta lactams can be confidently used as initial treatment in conditions where S. aureus infection is suspected. In 2013 about 10% of S. aureus from blood cultures at Waikato Hospital were MRSA, although this figure fluctuates depending on local outbreaks. In many parts of the world, over 30% of S. aureus is MRSA. Patients found to be positive are isolated or cohorted and receive appropriate treatment and follow up. MRSA Strain Types in the Waikato 2011 to 2013 Chris Mansell and Lynne McLeod have recently undertaken a major work looking at MRSA strains at Waikato Hospital. They have undertaken the following three analyses using 1107 MRSA cases over the last three years. Analysis What strains of MRSA are present in the Waikato? What are the antibiotic sensitivity profiles of each strain? Can the strain be deduced from the antibiotic sensitivity pattern? As can be seen from the following tables, the predominant strains at Waikato Hospital are AK3, EMRS15 and WSPP strains. Most of the MRSA strains encountered in the Waikato can be treated with cotrimoxazole if oral therapy is required. 141 142 143 An alternative way of looking at the antibiogram is whether the resistance profile can determine the strain type. It appears from the following figures that EMRSA-‐15 is relatively distinct based on Ciprofloxacin resistance and erythromycin susceptibility. However AkH4 is not as predictable based on the antibiogram. 144 AK3 can be recognised reasonably well when resistance to fusidic acid and susceptibility to mupirocin is present. The management of MRSA outbreaks is directed by the Infection Control Team and may vary for each particular outbreak. The location, type of clinical service, staffing and strain of MRSA will influence strategies for isolation, screening and decolonisation. 145 BLOOD AND BODY FLUID EXPOSURES Needlestick injuries and mucous membrane splashes are the most common recognised incidents where healthcare workers may be exposed to infectious diseases. Pathogens of major concern include Hepatitis B, Hepatitis C and HIV. In some circumstances, prophylaxis or monitoring may be indicated after exposure to Neisseria meningitidis, Hepatitis A virus, bites, sexual assault, Tuberculosis, Varicella (non-immune pregnant or immunosuppressed people), Haemophilus influenzae type B, Influenza, Rabies, biological weapons. These cases should be discussed with an appropriate specialist. Procedures for dealing with Needlestick and Mucous Membrane Exposures Similar procedures should be used for dealing with needlestick injuries and mucous membrane exposures, although risk of infection following mucous membrane exposure is much lower. Blood contact with intact skin is not a risk exposure. A “Body Fluid Exposure Pack” is available to guide management. Packs are available at Health and Safety, Emergency Department, Delivery Suite and Theatre First Aid Measures • • • • • • Wash and gently encourage bleeding. Attend to injuries. Document identity of source and exposed people. Arrange for a doctor, Health and Safety advisor or other trained person (e.g. Clinical Nurse Leader) to manage the incident, arranging collection of specimens, checking results and ensuring follow-up. In general, people should not manage their own exposure incident. The incident form included within the “Exposure Pack” needs to be completed and sent to health and safety to ensure process is complete and appropriate follow-up put in place. Routinely obtain blood (request form included in “Exposure Pack”) from both source and exposed people and test both for: - HBsAg - Anti-HBs - Anti-HBc - Anti-HCV - HIV antigen and antibody Assess risk status of source person. Are they likely to be early in acute infection with one of the 3 viruses or is blood not available for testing? Clarify Hepatitis B immunisation status of the exposed person. Health and Safety will help with this on receipt of the incident form. Management of Documented Exposures HBV • • • Risk of infection for a non-immune exposed person is 5-30%, depending on the HBeAg status of the source. HBV immunoglobulin is given within 72 hrs if exposed person is non-immune. HBV vaccination is commenced. 146 HCV • • • Risk of infection is approximately 3%. Exposed person is monitored for development of Hepatitis C, particularly asymptomatic infection. If infection occurs, treatment of acute Hepatitis C may be initiated. HIV • • • • • • Risk of infection is approximately 0.3%, but considerably less if the source is having effective antiretroviral treatment and has an undetectable HIV viral load. HIV infection is now a manageable chronic condition with excellent life expectancy and quality of life for those diagnosed and under care. Prophylaxis should generally not be given unless a definite exposure has occurred. Antiretroviral prophylaxis have side effects and the risk/benefit analysis needs to be undertaken The ideal time frame for administration is thought to be within 2 hours, but sometimes longer delays are unavoidable. Only a “specialist experienced in the treatment of patients with HIV as approved and named by the Ministry of Health” may prescribe antiretroviral prophylaxis. The people to contact (through Waikato Hospital telephonist) are, in order: - Dr Graham Mills or Dr Paul Huggan, Infectious Disease Physicians. - Dr Jane Morgan, Sexual Health Physician. - Auckland Hospital Infectious Disease Service (available 24hr). Please persist in making contact with one person on this list if source blood is HIV positive to assess need for urgent commencement of antiretroviral therapy. A starter pack is available within the Waikato Hospital emergency department. 147 NOTIFIABLE DISEASES IN NEW ZEALAND Notifiable Infectious Diseases Under The Health Act 1956 And Tuberculosis Act 1948 Infectious Diseases Notifiable to a Medical Officer of Health and Local Authority (Public Health staff will notify the Local Authority where required). Acute gastroenteritis* Campylobacteriosis Cholera Cryptosporidiosis Giardiasis Hepatitis A Legionellosis Listeriosis Meningoencephalitis = primary amoebic Salmonellosis Shigellosis Typhoid and paratyphoid fever Yersiniosis * Not every case of acute gastroenteritis is necessarily notifiable - only those where there is a suspected common source or from a person in a high risk category, (e.g. food handler, child care worker, etc.) or single cases of chemical, bacterial, or toxic food poisoning such as botulism, toxic shellfish poisoning (any type) and disease caused by verocytotoxic E. coli. Infectious Diseases Notifiable to Medical Officer of Health Acquired Immunodeficiency Syndrome Arboviral diseases Creutzfeldt Jakob Disease and other Spongiform encephalopathies Haemophilus Influenzae B Hepatitis C Hydatid disease Leptospirosis Measles Neisseria meningitidis invasive disease Plague Rabies Rickettsial diseases Severe Acute Respiratory Syndrome (SARS) Tetanus Anthrax Brucellosis Diphtheria Hepatitis B Hepatitis (viral) - not otherwise specified Leprosy Malaria Mumps Pertussis Poliomyelitis Rheumatic fever Rubella Tuberculosis (all forms) Viral haemorrhagic fevers Yellow fever Diseases Notifiable to Medical Officer of Health (Other than Notifiable Infectious Diseases) Cysticercosis Lead absorption equal to or in excess of Taeniasis 15µg/dL (0.72µmol/L) ** Trichinosis Poisoning arising from chemical Decompression sickness contamination of the environment **Blood lead levels to be reported to the Medical Officer of Health (15µg/dL or 0.72µmol/L) are for environmental exposure. Where occupational exposure is suspected, please notify OSH through the NODS network. 148 How To Notify A Notifiable Disease (Include Suspected Cases) During times of increased incidence practitioners may be requested to report with informed consent, to their local Medical Officer of Health cases of communicable diseases not on this list. Notification by phone is preferred, since the Ministry of Health notification forms have too little information. Contact Phone Numbers: Normal Office Hours (0800 - 1700) Waikato Hospital ext 22065 or 22020 Hamilton region (07) 8581065 Outside Hamilton region 0800 800 977 For specific advice, ring phone numbers above or contact On Call Medical Officer of Health 021 359 650 Dr Antia Bell 021 473 854 Dr Felicity Dumble 021 359 646 Dr Richard Wall 021 831 137 Facsimile for Public Health 07 838 2382 After Hours and Weekends Phone Waikato Hospital operators and ask for the Medical Officer of Health on-call or phone 021 359650. 149
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