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Pediatric Sepsis: How to Choose
Antibiotics?
Assist. Prof. Wanatreeya Phongsamart, MD
Division of Infectious Diseases
Department of Pediatrics
Faculty of Medicine Siriraj Hospital
Mahidol University
Outline
• Sepsis overview
• Factors to be considered in choosing ATB for
Sepsis
• Principles for empirical antimicrobial therapy
for
• Community-acquired sepsis
• Hospital-acquired sepsis
• Sepsis in immunocompromised children
ผู้ป่วยเด็กชายไทย อายุ 4 ปี ภูมิลาเนา กรุงเทพมหานคร
• Admit 3 พ.ย. 2553
(12 d after last chemotherapy)
• Underlying disease neuroblastoma stage IV
วินิจฉัยเมื่อ พ.ย. 2552
• เริ่ม chemotherapy เมื่อ พ.ค. 2553
• ได้ chemotherapy ครั้งสุดท้าย 21 ต.ค. 2553
(Carboplatin, etoposide, cyclophosphamide)
• 2 วันก่อนมา รพ. – ไข้สูง ถ่ายเหลวเป็นน้้าวันละ 2-3 ครั้ง
คลื่นไส้อาเจียน มีแผลในปาก ซึมลง
Physical Examination ที่ ER
12.30 pm
• V/S: BT 39.8 c, PR 198/min (thready pulse),
BP 105/63 mmHg, RR 40/min
• A Thai boy, irritable, markedly pale
• HEENT: black necrotic crust at lower lip
• Lungs; normal
• Heart: tachycardia, no murmur
14.30 pm
• Pulse เบา, poor tissue perfusion, lethargy
• NSS 20 ml bolus x 2, H/C, CBC was drawn
What is/are the most appropriate
antimicrobial therapy?
A. Ceftazidme + Gentamicin
B. Meropenem
C. Meropenem + Aminoglycoside
D. Meropenem + Aminoglycoside + Vancomycin
E. Meropenem + Aminoglycoside + Vancomycin
+ Amphotericin B
D. Meropenem + Aminoglycoside + Vancomycin
+ Amphotericin B + Acyclovir
Sepsis is a Significant Health Problem
in Children
•
•
•
•
•
In 1995, 42,364 cases/1,586,253 hospitalizations in US
children had severe sepsis
Highest incidence in infants
Hospital mortality: 10.3%
Mean length of stay: 31 days
Estimated annual costs: $1.97 billion
Watson RS. Am J Respir Crit Care Med 2003;167:695–701.
Epidemiology and Mortality
Associated with Sepsis
Mortality rate: 27.8 % in 1979-1984, 17.9% in 1995-2000
• Numbers of Cases of
Sepsis in the US, 1979–
2000
• The incidence of sepsis
and sepsis-related deaths
are increasing
• Overall mortality rate is
declining
• Gram+ bacteria and
fungus are increasingly
common causes of sepsis
Martin GS, et al. N Engl J Med 2003;348(16):1546-54.
•
Mortality rate has varied 36-53% in developing and from
2-20% in developed nations
C.M.F. Mangia. JPID 2009;4:71-6.
Empirical Antimicrobial Therapy for
Sepsis: Factors to be Considered
Dilemma of ID Practice in Seriously Ill
Patients
Inadequate therapy
increases mortality,
length of stay
Excessive antibiotic use
promotes resistance,
toxicity and cost
Inadequate Antimicrobial Therapy: Risk Factor for
Mortality among Critically Ill Patients
42.0%
17.7%
Inadequate Rx
Adequate Rx
Kollef MH. Chest 1999;115:462-74.
• Increased mortality
with initial inadequate
antimicrobal Rx in
serious gram+/- and
Candida spp.
Romero-Vivas J. CID 1995;21:1417–23.
Parkins MD. J Antimicrob Chemother 2007;60:613–8.
Kumar A. Chest 2009 136(5):1237-48.
Empirical Antimicrobial Therapy for
Sepsis
• Factors to be considered:
• Child’s age
• Co-morbidity, underlying disease
• Clinical syndrome, anatomic site of infection
• Gram stain data
• Local epidemiology and resistance pattern
• Organ dysfunction
• PK and PD of antimicrobial agents
Community-Acquired Sepsis
Age group
Pathogens
Neonates
• Bacteria:
Ampicillin + Gentamicin
E. coli & enteric gram
or
Cefotaxime + Gentmicin
negative bacilli
GBS, coagulase negative
Staphylococcus
• Virus: HSV, enterovirus
• Fungus: Candida
1-3 m
• S. pneumoniae, Hib,
Salmonella, N. menngitidis
• GBS, E. coli
3 m-5 y
Cefotaxime/Ceftriaxone
S. pneuminiae, Hib,
Salmonella, N. meningitidis
S . aureus
>5y
S. pneumoniae, S. aureus,
S. pyogenes, Salmonella,
N. meningitidis
Empirical antimicrobial
agents
Cefotaxime +Gentamicin
Cefotaxime/Ceftriaxone
Remarks
• Listeria
monocytogenes is
rare in Thailand
• Consider
acyclovir if HSV is
suspected
Don’t Forget Melioidosis
• Treatment of melioidosis in children traveled /live in NE
Thailand
• Recommended initial treatment of severe melioidosis:
– Ceftazidime (120 mg/kg/d)
– Ceftazidime (1o0 mg/kg/d) + IV co-trimoxazole
– Followed by oral co-trimoxazole + doxycycline
for a total duration of 20 weeks
• Carbapenems provide activity against melioidosis
Lumbiganon P. Pediatr Infect Dis J 2004;23(12):1165-6.
Empirical Antimicrobial Therapy for
Sepsis
• Factors to be considered:
• Child’s age
• Co-morbidity, underlying disease
• Clinical syndrome , anatomic site of infection
• Gram stain data
• Local epidemiology and resistance pattern
• Organ dysfunction
• PK and PD of antimicrobial agents
Etiology of Sepsis In Special
Circumstances
Host
Pathogens
Asplenia
Encapsulated
Cefotaxime/
Ceftriaxone
organisms
(S. pneumoniae, Hib ,
N. meningitidis,
K. pneumoniae),
E. coli, C. carnimorsus
Neutropenic
patients
Enteric gram – bacilli
including P.
aeruginosa,
S. aureus, Candida
Aspergillus spp,
Zygomycosis
Empirical
antimicrobial agents
Ceftazidime+Gent
or Cefipime
or Pip/Tazo
Carbapenem
+ Aminoglycoside
Remarks
• Carbapenem in septic shock
• + Vancomycin if
1) suspected catheter-related
infections
2) known colonization with DRSP,
MRSA
3) Gram+ in H/C
4) Hypotension
5) Severe mucositis (consider)
Hughes WT, et al. CID 2002; 34:730-51.
Lion C, et al. Eur J EPidemiol 1996;12(5):521-33.
Etiology of Sepsis In Special
Circumstances
Host
Pathogens
Empirical
antimicrobial agents
Remarks
B cell defect
S. pneumoniae, Hib, S.
aureus, Salmonella,
Shigella, Campylobacter,
Enterovirus
Cefotaxime/
Ceftriaxone
+ Macrolide
IVIG replacement
CGD
S. aureus, Salmonella,
S. marcescens,
K. pneumonia,
Aspergillus, Nocardia
Cefotaxime/
Ceftriaxone
CMI defect
HIV
Salmonella, Hib, S.
pneumoniae, TB, MAC,
CMV, C. neoformans, P.
maneffei
Cefotaxime/
Ceftriaxone
Complement S. pneumoniae, Hib
deficiency
N. meningitidis
Consider antifungal therapy if
clinically suspected
Cefotaxime/
Ceftriaxone
Feigin RD, eds. Textbook of Pediatric infectious Diseases, 5th ed.
Martire B, et al. Clin Immunol 2008;126(2):155-64.
Empirical Antimicrobial Therapy for
Sepsis
• Factors to be considered:
• Child’s age
• Co-morbidity, underlying disease
• Clinical syndrome , anatomic site of infection
• Gram stain data
• Local epidemiology and resistance pattern
• Organ dysfunction
• PK and PD of antimicrobial agents
Empirical Antimicrobial Regimen
in Sepsis with Meningitis
Age
Pathogens
Empirical
antimicrobial agents
Remarks
NB
GBS, E. coli & enteric gram
negative bacilli, HSV,
enterovirus
Amp + Gent
or Cefotaxime + Gent
•L. monocytogenes is
rare in Thailand
• Consider acyclovir if
HSV is suspected
1-3 m
Hib, S. pneumoniae,
Salmonella, N.
meningitidis, GBS, E. coli
Cefotaxime + Gent
> 3 m-2 y
Hib, S. pneumoniae,
Salmonella, N.meningitidis
>2y
S. pneumoniae,
Salmonella, N.meningitidis
Cefotaxime/
Ceftriaxone +
Vancomycin +
Rifampicin*
* Consider Vancomycin if high risk for resistance (on ATB prophylaxis), severe cases, high number of S. pneumoniae
from CSF gram stain
Add Rifampicin if S. pneumoniae is susceptible and 1) clinically worse 24-48 hr despite Cef+Vanc 2) + subsequent
CSF C/S or failure to eradicate/decrease number of organisms 3) High 3rd Cef MIC (> 4 µg/ml) AAP. Red Book 2009.
Modified from Tunkel AR, et al. CID 2004;39(1):1267-84.
Empirical Antimicrobial Regimen
in Sepsis with Meningitis
Condition
Pathogens
Postneuro Sx
Gram- bacilli including
Pseudomonas, S. aureus,
CNS esp. S. epidermidis
CSF shunt
CNS esp. S. epidermidis, S.
aureus, Gram- bacilli
including Pseudomonas
Empirical
antimicrobial agents
Vancomycin +
Cefepime or
Ceftazidime or
Meropenem
Remarks
Remove VP shunt
Modified from Tunkel AR, et al. CID 2004;39(1):1267-84.
Empirical Antimicrobial Regimen in
Sepsis with Bone and Joint Infections
Age group
Pathogens
Empirical
antimicrobial agents
NB
GBS, Enteric bacilli, S. aureus
Cefotaxime + Gent
1-3 m
GBS, E. coli, S. aureus, GAS,
Hib, Salmonella
> 3m-2 y
S. aureus, GAS, Hib,
Salmonella
>2y
S. aureus, GAS
Cloxacillin + Gent
Adolescent
S. aureus, GAS
Consider GC if sexually active
(arthritis-dermatitis
syndrome)
Cloxacillin + Gent
Cefotaxime/
Ceftriaxone
+ Gent
Remarks
Use 3rd Gen if
Salmonella is
suspected/
isolated
• Ceftriaxone for GC
+ Azithromycin for
C. trachomatis
• Check for STDs
• Treat partner
Empirical Antimicrobial Regimen in Sepsis
with Urinary Tract Infections
Site of
infection
Pathogens
Empirical
antimicrobial agents
UTI
E. coli & enteric gram
negative bacilli
Cefotaxime/
Ceftriaxone+ Gent
Remarks
Empirical Antimicrobial Regimen in Sepsis
with Pneumonia
Age group
Pathogens
NB
GBS, E. coli & enteric
gram negative bacilli
1-3 m
S. pneumonaie , Hib,
GBS, E. coli
Empirical antimicrobial Remarks
agents
Amp + Gent
or Cefotaxime
+ Gent
> 3m-5 y
S. pneumonaie , Hib
(if < 2 y),
S. aureus
Cefotaxime/
Ceftriaxone
+ Gent
>5y
S. pneumoniae, GAS,
S. aureus,
M. pneumoniae,
C. pneumoniae
Cefotaxime/
Ceftri axone
+ Gent
+ Macrolide
*
• Consider oseltamivir
if severe or high-risk*
• Consider macrolide in
severe pneumonia
High risk for severe influenza: 1) children < 2y 2) children with underlying conditions (Chronic pulmonary,
Cardiovascular, Renal, Liver, Neurological, Hematologic, Metabolic disorders (including DM) 3) Immunosuppression
(includingHIV) 4) Women who are or will be pregnant during the influenza season 5) Children (6 mo– 18 y) on longterm aspirin therapy 6) Persons who are morbidly obese (BMI ≥ 40)
CDC. MMWR Early Release 2010;59:1-62.
Empirical Antimicrobial Therapy for
Sepsis
• Factors to be considered:
• Child’s age
• Co-morbidity, underlying disease
• Clinical syndrome , anatomic site of infection
• Gram stain data
• Local epidemiology and resistance pattern
• Organ dysfunction
• PK and PD of antimicrobial agents
Gram Stain Data
•
Gram negative coccobacilli:
– H. influenzae: community acquire
– A. baumannii: hospital acquire
• Lancet-shaped, encapsulted
gram positive diplococci:
S. pneumoniae
Gram Stain Data
•
Gram negative
diplococci:
N. meningitis
•
Septated hyphae
with dichotomous
branching:
Aspergillous spp.
Empirical Antimicrobial Therapy for
Sepsis
• Factors to be considered:
• Child’s age
• Co-morbidity, underlying disease
• Clinical syndrome , anatomic site of infection
• Gram stain data
• Local epidemiology and resistance pattern
• Organ dysfunction
• PK and PD of antimicrobial agents
Antimicrobial Susceptibility of IPD in Children < 5 Y,
Thailand, 2006-2009 (New CLSI Criteria)
N = 64
% Susceptible
100
100
98
96
93.8
94
92.2
90.6
92
90
88
86
84
Penicillin
Cefotaxime
Ofloxacin
Ciprofloxacin
Srifeungfung S, et al. Vaccine 2010;28:3440-4.
Antimicrobial Susceptibility
Common Gram - Pathogens, Thailand, 2008
Pathogens
Antimicrobial agents
% Susceptible
P. aeruginosa
Ceftazidime
Cefipime
Pip/Tazo
Meropenem
Ciprofloxacin
Gent/Amikacin
73
75
85
78
74
73/80
A. baumannii
Cefotaxime
Meropenem
Pip/Tazo
Cefoperazone/Sul
3
33
29
70
http://narst.dmsc.moph.go.th/ars/box/anti2007.pdf
Antimicrobial Susceptibility of Invasive
A. baumannii Isolates, Siriraj Hospital, 2008-2010
N = 73 children
Phongsamart W, Dampanrat W . Unpublished data
3rd Cephalosporin Susceptibility of Invasive
Salmonella Infection, Siriraj Hospital, 2006-2010
(n=64)
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
22.6%
34.5%
50%
100%
100%
77.4%
65.5%
Blood
100%
50%
Urine
CSF
Joint fluid
pus
Stool
non-susceptibility
Phongsamart W, Saihongtong S. Unpublished data
Antimicrobial Resistance
• Common resistant bacterial pathogens
Pathogens
Empirical antimicrobial agents
S. pneumoniae
High dose Cefotaxime
+ Vancomycin + Rif
H. influenzae
Cefotaxime/Ceftriaxone
Salmonella
Cefotaxime/Ceftriaxone
+ Ciprofloxacin*
S. aureus (MRSA)
Vancomycin
E. faecium
Vancomycin+ aminoglycoside
ESBL+ E. coli,
K. pneumoniae
Carbapenem
MDR A. baumannii
Colistin+ sulbactam or carbapenem
* Consider combination in Salmonella meningitis
Empirical Antimicrobial Therapy for
Sepsis
• Factors to be considered:
• Child’s age
• Co-morbidity, underlying disease
• Clinical syndrome , anatomic site of infection
• Gram stain data
• Local epidemiology and resistance pattern
• Organ dysfunction
• PK and PD of antimicrobial agents
Antimicrobial Therapy in Patients
with Renal Impairment
• Avoid nephrotoxic drug
• Adjust dose in most ATB except:
• ATB: Azithromycin, Clindamycin, Tetracycline, Doxycycline,
Minocycline, Metronidazole, Linezolid, Antistaph-penicillin,
Ceftriaxone, Chloramphenicol, Pyrimethamine
• Antifugal agents: Caspofungin, Micafungin, Oral voriconazole,
Itraconazole oral solution
• May need additional dose after dialysis
Sanford Guide to Antimicrobial Therapy 2010, 14th ed.
Drugs that May Require Dosage
Adjustment in Liver Failure
• ATB: Ceftriaxone, Erythromycin, Rifampicin, INH,
Tetracycline, Clindamycin, Chloramphenicol,
Tetracycline, Tigecycline, Metronidazole
• Antifungal agents: Caspofungin, Voriconazole,
Itraconazole
Kumar A. Crit Care Med 2009;25:733-51.
Empirical Antimicrobial Therapy for
Sepsis
• Factors to be considered:
• Child’s age
• Co-morbidity, underlying disease eg.
• Clinical syndrome , anatomic site of infection
• Gram stain data
• Local epidemiology and resistance pattern
• Organ dysfunction
• PK and PD of antimicrobial agents
Pharmacokinetic & Pharmcodynamics
• Bactericidal rather than bacteriostatic ATB in
sepsis/serious infections
• Antimicrobial agents must reach the site of
infection to be effective
• CSF penetration: lipid solubility, nonionized,
lipophilic compounds penetrate BBB well
– Good CSF penetration (enough to Rx):
Pen, Ampi, 3rd & 4th cephalosporin, Carbapenem, Rifampin, Chloram,
Cipro, Levoflox, Metro, Vanco, Fluconazole
– Poor CSF penetration (not enough to Rx):
Aminoglycosides, Macrolides, BL-inhibitors, 1st & 2nd cephalosporins,
Cefoperazone
P. S. McKinnon. Eur J Clin Microbiol Infect Dis 2004;23: 271–288
Pharmacokinetic & Pharmcodynamics
• Intracellular Penetration:
– intracellular organisms: respiratory (Chlamydia
spp., Mycoplasma, Mycobacterium spp.), GI
(Salmonella, Shigella), and others (N.
gonorrheae)
– ATB with intracellular penetration:
fluoroquinolones and macrolides
– β-lactams and aminoglycosides exhibit little/no
intracellular penetration
P. S. McKinnon. Eur J Clin Microbiol Infect Dis 2004;23: 271–288
Pharmacokinetic & Pharmcodynamics
• Volume distribution
• Increase in critically ill patients eg. patients
with expanded ECF, DHF
Higher doses
are needed
• Aminoglycoside
and erythromycin
decrease activity
at acid pH
in abscess
Kumar A. Crit Care Med 2009;25:733-51.
General Principles of Empirical
Antimicrobial Therapy for
Sepsis/Septic Shock
General Principles of Empirical Antimicrobial
Therapy for Sepsis/Septic Shock
• Empiric Rx should approach 100% coverage for the
suspected source of infection
• IV broad spectrum antimicrobial should be initiated
immediately (within 30 mins!!!)
• Initiate high-end dose in life-threatening infection
• Combination therapy is preferred for septic shock
• Narrow regimen within 48-72 hrs once C/S available
or clinically stabilizes
• Early source control
Sharma S, et al. Clin Chest Med 2008;29:677–687.
General Principles of Empirical Antimicrobial
Therapy for Sepsis/Septic Shock
• Empiric Rx should approach 100% coverage for the
suspected source of infection
• IV broad spectrum antimicrobial should be initiated
immediately (within 30 mins!!!)
• Initiate high-end dose in life-threatening infection
• Combination therapy is preferred for septic shock
• Narrow regimen within 48-72 hrs once C/S available
or clinically stabilizes
• Early source control
Sharma S, et al. Clin Chest Med 2008;29:677–687.
Empirical Antibiotic Choice for Sepsis: should
Approach 100% Coverage
• Community-acquired: coverage for DRSP
3rd Cephalosporin+ Aminoglycoside
• Hospital-acquired: coverage for ESBL-producing GNR, P.
aeruginosa,
• Not critically ill: Piperacillin/tazobactam, Cefipime,
Carbapenem + Aminoglycoside
• Seriously ill:
• Carbapenem + Aminoglycoside
• Add colistin if high prevalence/suspected of MDR A.
baumannii
• Add vancomycin to cover MRSA/CoNS if presence of
central line/prosthesis, evidence of line infection,
colonized with MRSA, high prevalence of MRSA
* Empirical antifungal agent is not
recommended routinely
Modified from Paterson DL. CID 2003;36:1006-12.
Bochud PY, et al. Crit Care Med 2004;32:S496-512.
When to Use Carbapenem
• Reserve for
– Serious polymicrobial infections or
– Infections by aerobic Gram negative bacteria resistant to other βlactams
• Use judiciously to avoid resistance in
– Meningitis [initial therapy in countries where cefotaxime-resistant S.
pneumoniae is high (>5%) eg. US]
– Febrile neutropenia (esp. in severe cases or septic shock)
– Nosocomial severe sepsis or ICU infections (stable to AmpC or ESBL)
– Post operative peritonitis/intra-abdominal infection
– Late onset ventilator-associated pneumonia
Bradley JS, et al. Int J Antimicrob Agents 1999;11(2):93-100.
Ayalew K, et al. Ther Drug Monit 2003;25(5):593-9.
When to Use Vancomycin
•
•
•
Treatment of serious infections by β-lactam–resistant gram + bacteria
Vancomycin is less rapidly bactericidal than are cloxacillin in MSSA
Treatment of infections caused by gram+ organisms in patients with
serious β-lactam allergy
Treatment of antibiotic-associated colitis who has
• Failure to metronidazole or
• Severe and potentially life-threatening
•
•
Prophylaxis, recommended by 2007 AHA, for endocarditis following
certain procedures in patients at high risk for MRSA endocarditis or
intolerant to β-lactam
Prophylaxis for major surgical procedures involving implantation of
prosthetic materials or devices (e.g., cardiac and vascular procedures and
total hip replacement) at institutions that have a high rate of infections
caused by MRSA
CDC. MMWR 1995;44(RR-12):1-13.
Antibiotic Management of Febrile Neutropenia
Empiric Therapy
High Risk
Low Risk
Oral
IV
In adults
Ciprofloxacin
+
Amoxiclav
Ceftriaxone
+
Amikacin
Low Risk
• ANC>100
• Normal CXR, LFT, RF
• Neutropenia < 7 day
• Expect neutropenia < 10 d
• No catheter infection
• BM recovery, in remission
• Peak T < 39
• No abdominal pain, CNS
involvement
Vancomycin
Not needed
Vancomycin
Needed
Monotherapy
Cefepime
or
ceftazidime
or
Pip/taz
or
Carbapenem
Modified from IDSA Guidelines 2002. CID 2002;34:730-51
Combination
Therapy
Aminoglycoside
+ Cefepime
or
Ceftazidime
or
Pip/taz
or
Carbapenem
Combination Rx in:
• Complicated cases
• High resistance rate
Vancomycin
+ Cefepime
or
ceftazidime
or
Pip/taz
or
Carbapenem
+ aminoglycoside
Vancomycin indicated in:
Suspected cath-related
Colonized with MRSA
High VRE rate
Septic shock
General Principles of Empirical Antimicrobial
Therapy for Sepsis/Septic Shock
• Empiric Rx should approach 100% coverage for the
suspected source of infection
• IV broad spectrum antimicrobial should be initiated
immediately (within 30 mins!!!)
• Initiate high-end dose in life-threatening infection
• Combination therapy is preferred for septic shock
• Narrow regimen within 48-72 hrs once C/S available
or clinically stabilizes
• Early source control
Sharma S, et al. Clin Chest Med 2008;29:677–687.
Immediate initiation of Effective
Antimicrobial Therapy for Sepsis
• Mortality in sepsis increases
with delay in ATB
administration
• IV antimicrobial therapy
– Should be initiated
immediately after
obtaining c/s
– Should not be withheld
for children who can’t
tolerate LP
Initiation of effective ATB within 1st hour following
onset of septic shock was associated with 79.9%
survival to hospital D/C
Kumar A, et al. Crit Care Med 2006;34:1589-96.
General Principles of Empirical Antimicrobial
Therapy for Sepsis/Septic Shock
• Empiric Rx should approach 100% coverage for the
suspected source of infection
• IV broad spectrum antimicrobial should be initiated
immediately (within 30 mins!!!)
• Initiate high-end dose in life-threatening infection
• Combination therapy is preferred for septic shock
• Narrow regimen within 48-72 hrs once C/S available
or clinically stabilizes
• Early source control
Sharma S, et al. Clin Chest Med 2008;29:677–687.
Antimicrobial Dosage in Sepsis
• Use Maximal recommended dosing in all lifethreatening infections esp. in relatively protected or
poorly perfused sites: CNS
Sharma S, et al. Clin Chest Med 2008;29:677–687.
Recommended Dose of Antimicrobial
Agents in Children with Severe Infections
Dose (mg/kg/d)
Divided
doses/d
Daily adult
dose
Cefotaxime
150-200
3-4
8-10 g
Ceftriaxone
80-100
1-2
4g
Ceftazidime
125-150
3
6g
100-150 of
cefoperazone
2-3
4g
Cefipime
(4th Ceph)
150
3
2-4 g
Cefazolin
(1st Ceph)
100
3
4-6 g
25-40
3-4
1.2-2.7 g
Antimicrobial
agents
Cefoperazone/S
ulbactam
Clindamycin
Comments
300 mg for meningitis
Not approved in chldren
Good CNS penetration but
not approved for meningitis
AAP. Red Bok 2009.
Recommended Dose of Antimicrobial
Agents in Children with Severe Infections
Dose (mg/kg/d)
Divided
doses/d
Daily adult
dose
Cloxacillin
150-200
4-6
4-12
Penicillin
250,000-400,000
U/kg/d
4-6
24 million
U/d
Ampicillin
200-400
4
6-12 g
Piperacillin/
Tazobactam
240-300
3
12-18 g
Ciprofloxacin
30
2
1.0-1.5
Vancomycin
40-60
4
2-4 g
60 mg/kg/d in meningitis
30 for < 12 y
20 for adolescents
3
2
1.2 g
Myelosuppression
Active against E. faecium, E.
faecalis, MRSA, PRSP
Antimicrobial
agents
Linezolid
Comments
Poor CNS penetration
AAP. Red Bok 2009.
Recommended Dose of Antimicrobial
Agents in Children with Severe Infections
Antimicrobial
agents
Dose
(mg/kg/d)
Divided
doses/d
Meropenem
100-120
3
Imipenem
80-100
4
2-4 g
Ertapenem
30
2
1g
Doripenem
500 mg IV q 8
Amikacin
Daily adult
dose
Comments
120 mg/kg/d for meningitis
Not for CNS infection due to risk of
seizures
Approved in 3 m-12 y
Less active against Pseudomonas
spp., Acinetobacter spp., and
gram+cocci
Not approved in children
15-22.5
3
Gentamicin
3-7.5
3
Rifampicin
20
2
1.5 g
600 mg
Should not be used as
monotherapy
Sanford Guide to Antimicrobial Therapy 2010, 14th ed.
AAP. Red Bok 2009.
General Principles of Empirical Antimicrobial
Therapy for Sepsis/Septic Shock
• Empiric Rx should approach 100% coverage for the
suspected source of infection
• IV broad spectrum antimicrobial should be initiated
immediately (within 30 mins!!!)
• Initiate high-end dose in life-threatening infection
• Combination therapy is preferred for septic shock
• Narrow regimen within 48-72 hrs once C/S available
or clinically stabilizes
• Early source control
Sharma S, et al. Clin Chest Med 2008;29:677–687.
Combination vs Monotherapy for
Sepsis
• Monotherapy vs combination therapy with ßlactam + aminoglycoside as empirical for sepsis
• Is as efficacious
• Less nephrotoxic
• Limited studies in severe sepsis/septic shock, small
sample size, rarely used the same ß-lactam in study
vs control group
Despite a lack of clear advantage,
combination empirical therapy with ß-lactam
+ aminoglycoside is preferred
Bochud PY, et al. Crit Care Med 2004;32:S496-512.
Role of Combination Antimicrobial
Therapy
• Broaden coverage
• Prevent emergence of resistance
• Synergistic/Additive effect
• P. aeruginosa: ß-lactam+aminoglycoside
• Enterococcal infection: Ampicillin/Vancomycin+
aminoglycoside
• S. aureus: Cloxacillin+ aminoglycoside/Rifampicin
• Shorten treatment duration
• Steptococcal endocarditis
Kumar A. Crit Care Med 2009;25:733-51.
Mortality Associated with Combination
Antimicrobial Therapy for Septic Shock
•
Combination Rx was associated with
– Decreased 28-d mortality (444 of 1223
[36.3%] vs. 355 of 1223 [29.0%]; HR 0.77;
95% CI 0.67-0.88; p = .0002) for both
Gram-positive and Gram-negative
infections
– Reductions in ICU admission (437 of 1223
[35.7%] vs. 352 of 1223 [28.8%]; OR 0.75;
95% CI 0.63-0.92; p = .0006) and
– Reduction in hospital mortality (584 of
1223 [47.8%] vs. 457 of 1223 [37.4%]; OR
0.69; 95% CI 0.59-0.81; p < .0001).
– Increase inotrope-free days (median and
[interquartile range], 23 [0-28] vs. 25 [028]; p = .007) up to 30 days.
* Combination Rx: β-lactam + aminoglycosides,
fluoroquinolones, or macrolides/clindamycin.
Kumar A, et al. Crit Care Med 2010;38(9):1773-85.
General Principles of Empirical Antimicrobial
Therapy for Sepsis/Septic Shock
• Empiric Rx should approach 100% coverage for the
suspected source of infection
• IV broad spectrum antimicrobial should be initiated
immediately (within 30 mins!!!)
• Initiate high-end dose in life-threatening infection
• Combination therapy is preferred for septic shock
• Narrow regimen within 48-72 hrs once C/S available
or clinically stabilizes
• Early source control
Sharma S, et al. Clin Chest Med 2008;29:677–687.
Strategies for Empirical Antimicrobial
Therapy for Seriously Ill Patients
• Reassess ATB regimen after 48-72 hr on the basis of
microbiological and clinical data
• Narrow down regimen to
• Prevent development of resistance
• Reduce toxicity
• Reduce cost
• Once causative organism and susceptibility is
available, consider d/c aminoglycoside
• Duration of therapy: 7-10 d but guided by clinical
response
Paterson DL, et al. CID 2003;36:1006-12.
General Principles of Empirical Antimicrobial
Therapy for Sepsis/Septic Shock
• Empiric Rx should approach 100% coverage for the
suspected source of infection
• IV broad spectrum antimicrobial should be initiated
immediately (within 30 mins!!!)
• Initiate high-end dose in life-threatening infection
• Combination therapy is preferred for septic shock
• Narrow regimen within 48-72 hrs once C/S available
or clinically stabilizes
• Early source control
Sharma S, et al. Clin Chest Med 2008;29:677–687.
Common Sources of Sepsis/Septic Shock
Requiring Urgent Source Control
•
•
•
•
•
•
•
•
Toxic megacolon or C. difficile
colitis with shock
Ischemic bowel
Perforated viscus
Intra-abdominal abscess
Ascending cholangitis
Gangrenous cholecystitis
Necrotizing pancreatitis with
infection
Bacterial empyema
•
•
•
•
•
•
•
Mediastinitis
Purulent tunnel infections
Purulent foreign body infections
Obstructive uropathy
Complicated
pyelonephritis/perinephric
abscess
Necrotizing soft tissue infections
(necrotizing fasciitis)
Clostridial myonecrosis
Sharma S, et al. Clin Chest Med 2008;29:677–687.
วรทิ ฐ มณีฉ าย ,
WORATITH MANEECHAI
52739270
25/7/2539
Age: 14 year(s) 2 month(s)
M
• A 11-y-old M with ALL, febrile neutropenia developed
septic shock with chest wall necrosis+subcutaneous
emphysema
• Ped sugery consultation for debridement
• Tissue pathology: diffuse skin and muscle gangrene,
C/S: Clostidium septicum
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SIRIRAJ HOSPITAL (PORTABLE)
CHEST
10/10/2553 6:19:55
21957350
S: 439
Z: 0.48
C: 512
W: 1024
cm
IM: 1001
Early Source Control
• Identify infections requiring source control
– Frequently require rapid (<2 hour) radiographic imaging
(often CT scan)
– If clinical findings are supportive, immediate surgical
intervention
• Failure of adequate source control is associated
with increased mortality
• Early surgical intervention has a significant impact
on outcome of rapidly progressive infections, eg.
necrotizing fasciitis
Moss RL. J Pediatr Surg 1996;31:1142–6.
Kumar A, ICAAC Proceedings2004;350:K-1222.
Removal of Foreign body, Catheter at
the Site of Infections
• Remove whenever possible
• Must remove in cases of
• VP-shunt infection
• Long-term catheters: CRBSI associated with
•
Severe sepsis
•
Suppurative thrombophlebitis
•
Endocarditis
•
Failure of ATB therapy (+ H/C > 72 hr after Rx despite
susceptible)
•
Infections due to S. aureus, P. aeruginosa, fungi, or
mycobacteria
Mermel LA., et al. Clin Infect Dis 2009;49:1-45.
Adjunctive Therapy for Sepsis
•
•
•
•
IVIG/IgM-rich immunoglobulin
Hydrocortisone
Activated protein C
Others
Investigations
• CBC: Hct 22.6%, WBC 400/uL, platelet 13,000 /uL
• H/C: Pseudomonas aeruginosa
Susceptibility
Amikacin
Cefepime
Ceftazidime
Ciprofloxacin
Gentamicin
Imipenem
Meropenem
Netilmicin
Piperacillin/tazobactam
S
S
S
S
S
S
S
S
S
Summary
• Patient with sepsis and septic shock must be
evaluated thoroughly
• IV antibiotics should be administered as early
as possible, within 1st hour
• Use broad-spectrum antibiotics against likely
pathogens with good penetration into the
presumed source
• Early source control
Summary
• Reevaluated daily to optimize efficacy,
prevent resistance, avoid toxicity, and
minimize costs
• De-escalation once pathogens and
susceptibilities are available