Pharmacy Council of Guyana CE Session Dr. Shamdeo Persaud Chief Medical Officer g Background - Antibiotics Importance of appropriate use Why overprescribe and Antibiotic Abuse Rational use of Antibiotics Indications for antibacterial therapy What antibiotics Factors considered while prescribing antibiotics Methods of administration of antimicrobials R i t Resistance tto A Antimicrobial ti i bi l Agents A t Factors contributing to antimicrobial resistance Control of use of antimicrobial agents g CMO, November 2010 Antibiotics are considered as one of the greatest discovery of the twentieth century. In the p pre-antibiotic era,, infectious diseases accounted for significant morbidity and mortality and invasive medical procedures were fraught with the risk of infection. Antibiotics are Life Saving drugs.. CMO, November 2010 The first antimicrobials were discovered in the mid-20's and many new molecules were discovered between 1960 and 1980. This 'golden era of antibiotics' saw a dramatic fall in the mortality from infections. Since the 80's, not many new class of molecules have been discovered and the funding into antimicrobial i i bi l research h iis on the h d decline li CMO, November 2010 “The miracle seems to be short lived.” Irresponsible and erratic use of these medicines resulted in the development of drug resistance by many organisms i and d deaths d th due d to hospital-acquired infections is on the rise. In the U U.S., S mortality due to nosocomial infections is now 4 times that due to road traffic accidents CMO, November 2010 "Antibiotics have been ggiven for everything from headaches to ingrown toenails; theyy are swallowed, sucked, injected and smeared; they are ppainted on cuts, dumped into wounds, fed to the chickens and pigs and spread p on the floors f off the hospital wards." Dr. Richard Novick CMO, November 2010 % of 70-80% prescriptions for antimicrobials are probably b bl written itt unnecessarily Why do doctors overprescribe antibiotics? p CMO, November 2010 y easy y to scribble a p p It is very prescription but it takes courage to avoid unnecessary prescriptions. Inability to make a fairly accurate clinical diagnosis Inability to convince the patient about the nature and simplicity of the illness Some doctors may harbour a notion that it is better to give i ""something thi powerful“ f l“ (Shot (Sh t Gun G therapy). th ) The fact remains that most patients do not demand any yp particular prescription p p from their doctor and many are indeed happy if they are explained about their problem and prescribed as less drugs as p possible. CMO, November 2010 Some doctors may have a fear that f h if they h do d not prescribe, their 'next door' colleague may prescribe these 'powerful' drugs and get all the credit for 'curing' cu g tthee pat patient. e t. To avoid this 'loss of practice' they tend to prescribe p these 'powerful' remedies. This is another face of 'defensive' practice. CMO, November 2010 Some patients with halfknowledge will insist on a prescription for antibacterials so as to "get better at the earliest" (because they are "very busy and have no time to lie down in bed") or to "avoid any hassles", particularly in cases of children and the elderly. It is the duty of the doctor to resist any such pressures, some doctors d may yield i ld to these pressures, often to appease the patients and to 'save' their practice CMO, November 2010 With many pharmaceutical companies and medical representatives, it is t ti i natural t l to t come under d some pressure for prescribing Companies seem to mislead the doctors about the indications suppress the facts on adverse effects and hide indications, the facts on cost of therapy. dangerous trend of 'combining' antibacterials and marketing g them for imaginary g y diseases. Many of the so called 'newer' antibiotics (which are in fact nothing more than modifications of existing molecules) are priced exorbitantly (even hundred times more than their older congeners) become rather fashionable to prescribe these drugs, with many doctors feeling that 'costlier must be better'. CMO, November 2010 Most Common Situations Fever: It is a manifestation of hundreds of diseases, infective and non-infective. Antibacterials DO NOT have any beneficial effects in cases of fever due to non-bacterial causes. Self-limiting viral infections are the commonest infectious causes for fever and antibacterials have no role to play in their management CMO, November 2010 y the commonest illness Sore throat: It is p probably where antibacterials are misused the most. Although it accounts for 13% of all office visits, it h been has b found f d in i various i studies t di that th t only l 8 to t 20% of persons with a sore throat make a visit to a general practitioner (and in the other 80 80-90% 90% it cures spontaneously!). Sore Throat Score 1. Tonsillar exudate 2. Swollen anterior cervical nodes 3. A history of a fever of more than 380 C. 4. Lack of a cough. T Two or more – Throat Th t swab b and d antibotics tib ti CMO, November 2010 Diarrhoea: It is another condition where antibacterials are often over-prescribed. p While there are many causes for diarrhoea, infective and non-infective, the fact remains that most of them are self-limiting and require only adequate rehydration. In all doubtful cases, a stool examination should be done for ova, cyst, blood and h hanging i drop d if cholera h l is i suspected. t d CMO, November 2010 Antibiotics are the most important weapons in our hands. Each one of them have been invented after spending considerable id bl amount off time, i energy and money. Therefore, we cannot afford to lose them. We must exercise considerable restraint in prescribing antibacterials and restrict their use to only certain definite indications. CMO, November 2010 1. 2. 3. Definitive therapy: This is for proven bacterial infections Empirical p therapy: py Strong g indication in critical cases Prophylactic p y therapy: py Indicated and p proven to prevent an infection for which a treat exist CMO, November 2010 This is for p proven bacterial infections. Antibiotics are drugs to tackle bacteria and hence should be restricted for the treatment of bacterial i f ti infections only. l Based on the reports, a narrow spectrum, least toxic toxic, easy to easy-toadminister and cheap drug should be prescribed. CMO, November 2010 Should be restricted to critical cases When time is inadequate for identification and isolation off th the b bacteria t i and d reasonably strong doubt of bacterial infection exists: septicemic p shock// sepsis p syndrome immunocompromised patients with severe y infection systemic hectic temperature, neutrophilic leukocytosis, raised ESR etc. CMO, November 2010 Antimicrobial prophylaxis is administered to susceptible patients to prevent specific infections that can cause definite detrimental effect. These include antitubercular prophylaxis, prophylaxis anti rheumatic prophylaxis, anti endocarditis prophylaxis and prophylactic use of antimicrobials in invasive medical procedures etc. In all these situations, only narrow spectrum and specific drugs are used. used It should be remembered that there is NO single prophylaxis to 'prevent all' possible bacterial infections. infections CMO, November 2010 There are more than 100 antibacterials available today, and each one has its own spectrum of activity, adverse effect profile and cost. The doctor should consider many factors before prescribing an antibacterial agent so as to make the treatment most effective with least adverse effects and cost. CMO, November 2010 Site of infection Type of infection Severity of infection Isolate and its sensitivity Source of infection Host factors Drug related factors CMO, November 2010 Rule Of The Thumb, infections above the diaphragm Cocci and Gram (+); infections below - Bacilli and Gram (-) () Above the diaphragm: Upper respiratory tract infections like pharyngitis B l the Below th diaphragm: di h E Examples l include i l d urinary i tract t t infection Certain sites where the infection difficult to treatment: Meningitis M i iti (i (impenetrable t bl bl blood-brain db i b barrier), i ) Chronic prostatitis (non-fenestrated capillaries), Intra-ocular infections (non-fenestrated capillaries), Abscesses (thick wall, acidic pH, hydrolyzing enzymes etc.), Aardiac and intra intra-vascular vascular vegetations (poor reach and penetration) penetration), Osteomyelitis (avascular sequestrum) etc. Higher dose, more frequent administration, longer duration and antibacterial combinations may have to be used. CMO, November 2010 Infections can be localised or extensive;; mild or severe; superficial p or deep p seated; acute, sub acute or chronic extracellular or intracellular. For extensive, severe, deep seated, chronic and intracellular infections, higher and more frequent dose, dose longer duration of therapy therapy, combinations, lipophilic drugs may have to be used. CMO, November 2010 Life threatening and rapidly fatal infections. Bacteremia / septic B t i / pyemia i / sepsis i syndrome d ti shock; h k Abscesses in lung/ brain/ liver/ pelvis/ intra-abdominal; Meningitis/ endocarditis/ pneumonias/ pyelonephritis/ puerperal sepsis; Severe soft tissue infections / gangrene and hospital acquired infections) g In such situations the drug absorption, distribution and excretion could be altered due to tissue hypoxia, changes in hemodynamics, renal and hepatic perfusion, GI absorption etc. g dynamics y can also be altered due to acidosis,, altered p permeability, y, The drug presence of hydrolysing enzymes at the site of infection etc. In such situations, possibility of infection with multiple organisms and of drug resistance make the choice difficult CMO, November 2010 g y significant g Ideal management of any bacterial infection requires culture and sensitivity study of the specimen. If the situation permits, permits antibacterials can be started only after the sensitivity report is available. Narrow spectrum, least toxic, easy to administer and cheapest of the effective drugs should be chosen. If the patient is responding to the drug that has already been started, it should not be changed even if th the in i vitro it reportt suggests t otherwise th i CMO, November 2010 y acquired q Community infections are less likely to be resistant whereas h hospital h it l acquired infections are likely to be resistant and more difficult to treat (e.g. P d Pseudomonas, MRSA etc.). CMO, November 2010 g of the p Age patient Infants: Chloramphenicol (can cause grey baby syndrome) and sulfa (can cause kernicterus) are contraindicated. Below the age of 8 years: Tetracyclines are contraindicated because they are known to discolour the teeth. B l Below the h age off 18 years: All fluoroquinolones fl i l are contraindicated because they are known to cause arthropathy by damaging the growing cartilage. Elderly: In the elderly elderly, achlorhydria may affect absorption of antibacterial agents. Drug elimination is slower, requiring dose adjustments. Ototoxicity of aminoglycosides may be increased in the aged CMO, November 2010 immune status In patients with extremes of age, HIV infection, diabetes mellitus, neutropenia, splenectomy, using corticosteroids or immunosuppressants, immunosuppressants patients with cancers / blood dyscrasias, ONLY bactericidal drugs should be used. It iis iindeed d dd debatable b t bl whether h th antibacterials tib t i l should h ld be used to treat infections like aspiration pneumonia, UTI, catheter infections, infections through life supportt systems, t pressure sores etc. t iin patients ti t who h are terminally ill (brain dead, patients with massive stroke, terminal cancers, advanced age, terminal AIDS etc.). t ) CMO, November 2010 p g y and lactation pregnancy Drugs with known toxicity or un-established safety like tetracyclines, quinolones, streptomycin, erythromycin estolate and clarithromycin y are contraindicated in all trimesters and sulfa, nitrofurantoin and chloramphenicol are contraindicated in the last trimester. Drugs with limited data on safety like aminoglycosides, azithromycin, ih i clindamycin, li d i vancomycin, i metronidazole, id l trimethoprim, rifampicin and pyrazinamide should be used with caution when benefits overweigh the risks. Penicillins cephalosporins, Penicillins, cephalosporins INH and ethambutol are safe in pregnancy. In lactating mothers sulfa, tetracyclines, metronidazole, nitrofurantoin and quinolones are contraindicated CMO, November 2010 Associated conditions like renal failure, hepatic failure, epilepsy etc. should be considered in choosing the antibacterial agent. agent Renal failure: Tetracyclines are absolutely contraindicated; aminoglycosides, cephalosporins, fluoroquinolones and sulfa are relatively contraindicated; t i di t d penicillins, macrolides, vancomycin, metronidazole, INH, ethambutol and rifampicin are relatively safe. It is better to avoid combinations of cephalosporins p p and aminoglycosides in these patients because both these classes of drugs can cause nephrotoxicity. Hepatic failure: N drugs No g are absolutely y contraindicated;; chloramphenicol, p , erythromycin estolate, fluoroquinolones, pyrazinamide, rifampicin, INH and metronidazole are relatively contraindicated Penicillins, cephalosporins, ethambutol and aminoglycosides are safe. CMO, November 2010 1. 2. 3. 4. Hypersensitivity: in patients with prior history of hypersensitivity h iti it the th concerned d antibacterial tib t i l agentt should h ld be avoided. Adverse reactions: Certain adverse reactions warrant discontinuation of therapy and the doctor should adequately educate the patients on these adverse effects. Interactions: Interactions with food and other concomitant drugs g should be considered before instituting g antibacterial therapy so as to maximize efficacy and minimize toxicity. Cost: The cost of therapy should be considered in choosing the antibacterial agent. It should always be remembered that just because a particular drug is expensive, expensive it need not be superior than the cheaper ones. For example, cheaper drugs like doxycycline or co-trimoxazole would be as effective as the costlier cephalosporins in the management g off LRTI. CMO, November 2010 Route of administration Dosage Frequency and duration of administration Combinations CMO, November 2010 The route of administration depends on the site, type and severity of the infection and the availability of a suitable drug. drug Oral route - most preferred, easy and cheap, but it may not be reliable in all circumstances, particularly in patients with severe infections, noncompliant patients, in the presence of vomiting etc. Certain drugs like the aminoglycosides and most 3rd generation cephalosporins are not available for oral administration. Intramuscular route - generally restricted for the administration of procaine and benzathine penicillin and single shot of ceftriaxone; the p is not very y reliable and it is p painful and disliked by y the absorption patients. Intravenous route - best for the management of severe and deep-seated infections since it ensures adequate serum drug levels. Procaine penicillin and benzathine penicillin should never be given I.V. However, some d drugs are not available il bl ffor parenterall use (e.g. ( most macrolides, lid sulfa, lf tetracyclines). Topical: Antibacterials are also used topically, but drugs used for systemic administration should not be used in skin ointments. CMO, November 2010 p Dose depends on: age of the patient weight of the patient associated conditions like pregnancy renal and hepatic failure and site type and severity of infection. Generally the dose should be higher in cases of severe, deep-seated infections and in pregnancy and lower in cases of renal failure. While unnecessary overdosage only adds to the cost and adverse effects, there should not be any compromise i on adequate d t dose. d CMO, November 2010 q y of administration: The drug g should be Frequency administered 4-5 times the plasma half-life to maintain adequate therapeutic concentrations in the serum throughout the day. day Frequency can be increased in cases of severe, deep seated and sequestrated infections and reduced in cases of renal and hepatic failure. failure Duration: Duration of therapy depends on the site, type yp and severity y of infection. ((e.g. g Tonsillitis-10 days; bronchitis-5-7 days; UTI-single shot to 21 days; lung abscess-2-8 weeks; tuberculosis-6-24 months etc.). etc ) CMO, November 2010 Antibacterial combinations can be useful in the following situations: 1. To sharpen the effect: Synergistic combination of two static drugs - e.g. Combination of Trimethoprim and Sulfamethoxazole - CoTrimoxazole 2. Treatment of infections with multiple organisms: Mixed infections in lung abscess, peritonitis, soiled wounds etc., naturally require multiple antibiotics for complete clearance of the infection - Penicillins (for gram positive and certain anaerobes) + Aminoglycosides (for gram negative); metronidazole for bacteroides etc. 3. To prevent resistance: The classic example is the antitubercular therapy. h 4. To overcome resistance: Examples include Penicillins + b lactamase inhibitors/b lactamase resistant penicillins for S. aureus; / p p + aminoglycosides gy for Pseudomonas etc. Penicillins/cephalosporins The following combinations are irrational, not useful or even harmful: Combinations of bactericidal with bacteristatic drugs (e.g. (e g Penicillins with tetracyclines); Combinations of drugs with similar toxicity (e.g. chloramphenicol and sulfa) Combining drugs for non-existing ‘mixed infections’ (e.g. tablets of ciprofloxacin + metronidazole CMO, November 2010 Resistance to antimicrobial agents is one of the greatest problems faced by the medical community. These powerful weapons, developed by spending millions of dollars and years of dedicated research, have been rendered less effective or totally ineffective only because of our own negligence and complacence complacence. CMO, November 2010 Organism Resistance Gram Positive cocci Methicillin resistant Staph. p aureus and coagulase g negative Staphylocci, penicillin resistant Pneumococci, macrolide resistant Streptococci, vancomycin resistant Enterococci Gram negative cocci Gram negative bacilli A id fast Acid f t bacilli b illi Penicillin, quinolone resistant gonococci Enterobacteriaccae resistant to B lactams and B lactamase inhibitors, multi drug resistant pathogens include Shigella, E. Coli, Salmonella. M lti d Multi drug resistant i t t M. M tuberculosis t b l i CMO, November 2010 yap p Antimicrobial resistance,, initially problem in hospitals and developing countries, today affects the world at large. The WHO reports that the antimicrobial agents are used by too many people to treat the wrong kind of infection in the wrong dosage and for the wrong period of time. Increase in poverty, over crowded living areas, crowded day care centers have all contributed in spreading the resistant bacterial infection. The tremendous increase in the size of the high risk populations because of immunocompromise, the increased frequency of invasive medical interventions and prolonged survival of patients with chronic debilitating disease have amplified the problem CMO, November 2010 Inability of the drug to reach the organisms Inactivation of the drug Alteration in the target Resistance may be acquired by mutation and passed onto the next generations. It may also be acquired by horizontal transfer from a donor cell by y transformation,, transduction or conjugation. CMO, November 2010 g methods can be used to control The following the use of antimicrobial agents in hospitals: Education programmes like staff conferences, lectures and audiovisual programmes Availability l b l off clinical l l pharmacist consultants l Control of contact between pharmaceutical representatives and staff physicians and of various sponsorships from companies Restriction of hospital formulary to minimum number of agents needed for most effective therapy Availability of diagnostic microbiology laboratory sensitivity tests and appropriate selection of sensitivity tests for organism and site Automatic stop orders for specific high-cost agents and written justification for high-cost agents CMO, November 2010 Thank You! CMO, November 2010