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Transcript of Antibiotic Monotherapy for Intraabdominal Infections IS BROAD SPECTRUM MONOTHERAPY ANTIBIOTIC...
Antibiotic Monotherapy for Intraabdominal Infections
IS BROAD SPECTRUM MONOTHERAPYANTIBIOTIC TREATMENT ADEQUATE
FOR INTRAABDOMINAL INFECTIONS ?
IS BROAD SPECTRUM MONOTHERAPYANTIBIOTIC TREATMENT ADEQUATE
FOR INTRAABDOMINAL INFECTIONS ?
Nicolas V. Christou
Associate Professor of Surgeryand Microbiology
McGill University
Antibiotic Monotherapy for Intraabdominal Infections
DIAGNOSIS OF INTRA-ABDOMINALINFECTION
DIAGNOSIS OF INTRA-ABDOMINALINFECTION
History & Physical Examination
Laboratory Tests
Imaging techniques
Antibiotic Monotherapy for Intraabdominal Infections
OUTLINEOUTLINE
Basic principles
Review of antibiotic choices
Presentation of most recent data on monotherapy
Conclusions
Antibiotic Monotherapy for Intraabdominal Infections
MORTALITY OF INTRA-ABDOMINAL INFECTIONSMORTALITY OF INTRA-ABDOMINAL INFECTIONS
0
20
40
60
LocalizedAbscess
LocalizedPeritonitis
DiffuseSuppurativePeritonitis
CombinedComplicated
Infection
Mortality %
Antibiotic Monotherapy for Intraabdominal Infections
TREATMENT OF INTRA-ABDOMINAL INFECTIONSTREATMENT OF INTRA-ABDOMINAL INFECTIONS
Surgical drainage and correction of pathology
broad spectrum EMPIRIC antibiotic therapy
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTIC THERAPY OF SURGICAL INFECTIONSANTIBIOTIC THERAPY OF SURGICAL INFECTIONS
Empiric Antibiotic Therapy:
A single antibiotic or a combination of antibiotics providing BROAD SPECTRUM coverage against all possible pathogens.
Definitive Antibiotic Therapy:
Antibiotic administration based on specific culture and sensitivity results.
Antibiotic Monotherapy for Intraabdominal Infections
HOW DOES ONE PICK APPROPRIATEEMPIRIC ANTIBIOTIC THERAPY ?
HOW DOES ONE PICK APPROPRIATEEMPIRIC ANTIBIOTIC THERAPY ?
Use an antibiotic or combination of antibiotics that provides broad spectrum activity to cover all suspected PATHOGENS.
Use an antibiotic or combination of antibiotics that provides broad spectrum activity to cover all suspected PATHOGENS.
Antibiotic Monotherapy for Intraabdominal Infections
SUSPECTED PATHOGENS IN INTRA-ABDOMINAL INFECTIONSSUSPECTED PATHOGENS IN INTRA-ABDOMINAL INFECTIONS
E. coli (59%)K. pneumonia (11%)
P. aeruginosa (5%)
Enterobacter (5%)
P. mirabilis (4%)
Other (16%)
Gm -ve AEROBESRVH Data
Antibiotic Monotherapy for Intraabdominal Infections
SUSPECTED PATHOGENS IN INTRA-ABDOMINAL INFECTIONSSUSPECTED PATHOGENS IN INTRA-ABDOMINAL INFECTIONS
Gm +ve AEROBES
Enterococcus (55%)S. aureus (25%)
Corynebacteria (10%)
S. epidermidis (6%)Others (4%)
RVH Data
Antibiotic Monotherapy for Intraabdominal Infections
SUSPECTED PATHOGENS IN INTRA-ABDOMINAL INFECTIONSSUSPECTED PATHOGENS IN INTRA-ABDOMINAL INFECTIONS
ANAEROBES
Bacteroidis sp. (57%)
B. fragilis (27%)
Fusobacteria (6%)Others (9%)
RVH Data
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTICS FOR SURGICAL INFECTIONSANTIBIOTICS FOR SURGICAL INFECTIONS
PenicillinsAminoglycosides
Cephalosporins Metronidazole
Carbapenems Clindamycin
Quinolonnes Vancomycin
Antibiotic Monotherapy for Intraabdominal Infections
PENICILLINSPENICILLINS
Basic structure of Penicillins
Penicillin G
Methicillin
Cloxacillin
Carboxipenicillins
Ureidopenicillins
(Penem nucleus)
Antibiotic Monotherapy for Intraabdominal Infections
In vitro ACTIVITY of PIPERACILLINIn vitro ACTIVITY of PIPERACILLIN
0 10 20 30 40 50 60 70
E. coliEnterobacter
KlebsiellaP. aeruginosa
ProteusSeratia
CitrobacterMoerganella
Acinetobacter
S. aureusStreptococci
S. epedermidisEnterococci
B. fragilisBacteroides
FusobacteriumAnaerobic cocci
Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic90
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTICS FOR SURGICAL INFECTIONSANTIBIOTICS FOR SURGICAL INFECTIONS
"More Recent" therapy
UreidoPenicillin
(AntianaerobicAgent)
UreidoPenicillin
(AntianaerobicAgent)
eg Piperacillin 1-2 g q8h
(eg Clindamycin 600 mg q8h)
Antibiotic Monotherapy for Intraabdominal Infections
AMINOGLYCOSIDESAMINOGLYCOSIDES Gentamycin
Tobramycin
Netilmicin
Amikacin
Excellent Gm- activity
(gentamycin)
Antibiotic Monotherapy for Intraabdominal Infections
In vitro Activity of Aminoglycosides - GENTAMYCINIn vitro Activity of Aminoglycosides - GENTAMYCIN
0 20 40 60 80 100 120 140
E. coliEnterobacter
KlebsiellaP. aeruginosa
ProteusSeratia
CitrobacterMoerganella
Acinetobacter
S. aureusStreptococci
S. epedermidisEnterococci
B. fragilisBacteroides
FusobacteriumAnaerobic cocci
Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic90
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTICS FOR SURGICAL INFECTIONSANTIBIOTICS FOR SURGICAL INFECTIONS
"Gold Standard" therapy
Aminoglycoside+
AntianaerobicAgent
Aminoglycoside+
AntianaerobicAgent
eg Gentamycin 2-3 mg/kg q8h
eg Clindamycin 600 mg q8h
Antibiotic Monotherapy for Intraabdominal Infections
Aminoglycoside Use - CautionAminoglycoside Use - Caution
Ototoxicity
Nephrotoxicity
Occurs in up to 30% of cases and often is not reversible.
Occurs in up to 5% of cases and is often reversible.
Antibiotic Monotherapy for Intraabdominal Infections
CEPHALOSPORINSCEPHALOSPORINS
Penam nucleus
Cephem nucleus
R
R1
First Generation
Second Generation
Third Generation
eg. Cephazolin
eg. Cefoxitin
eg. Cefotaxime
Antibiotic Monotherapy for Intraabdominal Infections
In vitro ACTIVITY of 2nd GENERATION CEPHALOSPORINS- CEFOXITIN
In vitro ACTIVITY of 2nd GENERATION CEPHALOSPORINS- CEFOXITIN
0 20 40 60 80 100 120 140
E. coliEnterobacter
KlebsiellaP. aeruginosa
ProteusSeratia
CitrobacterMoerganella
Acinetobacter
S. aureusStreptococci
S. epedermidisEnterococci
B. fragilisBacteroides
FusobacteriumAnaerobic cocci
Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic90
Antibiotic Monotherapy for Intraabdominal Infections
In vitro ACTIVITY of 3rd GENERATION CEPHALOSPORINS- CEFOTAXIME
In vitro ACTIVITY of 3rd GENERATION CEPHALOSPORINS- CEFOTAXIME
0 5 10 15 20 25 30 35
E. coliEnterobacter
KlebsiellaP. aeruginosa
ProteusSeratia
CitrobacterMoerganella
Acinetobacter
S. aureusStreptococci
S. epedermidisEnterococci
B. fragilisBacteroides
FusobacteriumAnaerobic cocci
Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic90
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTICS FOR SURGICAL INFECTIONSANTIBIOTICS FOR SURGICAL INFECTIONS
"More Recent" therapy
3 Generation Cephalosporin
+Antianaerobic
Agent
3 Generation Cephalosporin
+Antianaerobic
Agent
eg Cefoperazone 1-2 g q12h
eg Clindamycin 600 mg q8h
rd
Antibiotic Monotherapy for Intraabdominal Infections
QUINOLONESQUINOLONESBasic Structure of Quinolones
Classified according to modifications at X2 and X8
positions.
"True Quinolones"
Norfloxacin
Ciprofloxacin
Enoxacin
Perfloxacin
Ofloxacin
Antibiotic Monotherapy for Intraabdominal Infections
In vitro activity of QUINOLONESIn vitro activity of QUINOLONES
0 5 10 15 20 25 30 35
E. coliEnterobacter
KlebsiellaP. aeruginosa
ProteusSeratia
CitrobacterMoerganella
Acinetobacter
S. aureusStreptococci
S. epedermidisEnterococci
B. fragilisBacteroides
FusobacteriumAnaerobic cocci
Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic90
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTIC "EFFICACY" STUDIES:INTRAABDOMINAL INFECTIONS
ANTIBIOTIC "EFFICACY" STUDIES:INTRAABDOMINAL INFECTIONS
0 20 40 60 80 100
Cephalosporinbased Rx
Aminoglycosidebased Rx
Success Rate %
52-96% range
61-95% range
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTIC "EFFICACY" STUDIES:INTRAABDOMINAL INFECTIONS
ANTIBIOTIC "EFFICACY" STUDIES:INTRAABDOMINAL INFECTIONS
Problems in Study Design
exclusion criteria not rigid
lack of "illness stratification"
results reporting
Antibiotic Monotherapy for Intraabdominal Infections
CARBAPENEMSCARBAPENEMS
Imipenem- approved for use
Meropenem- phase III clinical trials
Antibiotic Monotherapy for Intraabdominal Infections
In vitro activity of IMIPENEMIn vitro activity of IMIPENEM
0 10 20 30 40 50 60 70
E. coliEnterobacter
KlebsiellaP. aeruginosa
ProteusSeratia
CitrobacterP. species
Acinetobacter
S. aureusStreptococci
S. epedermidisEnterococci
B. fragilisBacteroides
FusobacteriumAnaerobic cocci
Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic90
Antibiotic Monotherapy for Intraabdominal Infections
COMPARATIVE ACTIVITIES OF VARIOUS ANTIBIOTICSCOMPARATIVE ACTIVITIES OF VARIOUS ANTIBIOTICS
0 2 4 6 8 10 12 14 16
Imipenem
Piperacillin
Ceftazidime
Tobramycin
0 5 10 15 20 25 30 35 40
Imipenem
Piperacillin
Ceftazidime
Tobramycin
0 2 4 6 8 10 12 14 16 18 20
Imipenem
Piperacillin
Ceftazidime
Tobramycin
0 20 40 60 80 100 120 140
Imipenem
Piperacillin
Ceftazidime
Ampicillin
MIC (90) µg/ml MIC (90) µg/ml
MIC (90) µg/ml MIC (90) µg/ml
Enterobacter cloacaeEnterobacter cloacae Acinetobacter calcoaceticusAcinetobacter calcoaceticus
P. aeruginosaP. aeruginosa S. faecalisS. faecalis
Antibiotic Monotherapy for Intraabdominal Infections
A Multicenter Comparative Trial of Imipenem/Cilastatin vs
Tobramycin/Clindamycin for Intraabdominal Infections
A Multicenter Comparative Trial of Imipenem/Cilastatin vs
Tobramycin/Clindamycin for Intraabdominal Infections
290 Patients Entered290 Patients Entered
143 - Tobra/Clinda143 - Tobra/Clinda 147 - Imipenem147 - Imipenem
81 Patients Evaluable81 Patients Evaluable 81 Patients Evaluable81 Patients Evaluable
Prospective, randomized, open design
Antibiotic Monotherapy for Intraabdominal Infections
Statistical ConsiderationsStatistical Considerations
Assumed failure rate = 25%
Assumed nonevaluability rate = 30%
Sample size to detect a 50% difference in outcome with = .05 and ß = .20
Adequate sample size: n=300
Logistic Regression Analysis, X , and Student's t-tests
2
Antibiotic Monotherapy for Intraabdominal Infections
Criteria for EligibilityCriteria for Eligibility
> 18 years
No drug hypersensitivity
Normal renal function
Suspected Intraabdominal Infection
Antibiotic Monotherapy for Intraabdominal Infections
Criteria for ExclusionCriteria for Exclusion
Simple Appendicitis
Simple Cholecystitis
Traumatic bowel perforation < 12h
Perforated peptic ulcer < 24 h
Exploration with negative bacterial cultures
Antibiotic Monotherapy for Intraabdominal Infections
Reasons for Exclusion of 128 PatientsReasons for Exclusion of 128 Patients
0 10 20 30 40
No Infection
No Intervention
Survival < 48h
<12 h perforation
Medication errors
Inadequate OR
MiscelaneousTobra/Clinda n=61Imipenem n=67
Number of Patients
Antibiotic Monotherapy for Intraabdominal Infections
"ILLNESS" STRATIFICATION"ILLNESS" STRATIFICATION
APACHE II
0
20
40
60
80
100
0-4 5-9 10-14 15-19 20-24 25-29 30-34 35+
% Mortality
APACHE II Ranges
A severity of disease classification system based on acute and chronic physiologic response variables such as :
Pulse, Pressure etc
Oxygenation, pH
Glascow Coma Scale
Antibiotic Monotherapy for Intraabdominal Infections
Drug TherapyDrug Therapy
Imipenem/Cilastatin 500 mg i.v. q6h
Tobramycin 1.5 mg/kg i.v. with interval adjusted for serum creatinine,
Tobramycin levels aimed at : peak > 6 µg/ml and trough < 2 µg/ml
Clindamycin 600 mg i.v. q8h+
Antibiotic Monotherapy for Intraabdominal Infections
Outcome ScoringOutcome Scoring
Local Intra-abdominal Infection
Hospitalization
Antibiotic Monotherapy for Intraabdominal Infections
Definition of Rx SuccessDefinition of Rx Success
Initial study driven
antibiotic therapy and an
adequate operation cured
the intraabdominal
infection.
Antibiotic Monotherapy for Intraabdominal Infections
Definition of Rx FailureDefinition of Rx Failure
Survival of < 7 days
Second intervention showed recurrence with initial organisms
Wound Infection developed
Antibiotic Monotherapy for Intraabdominal Infections
Demographics of Evaluable Patients - IDemographics of Evaluable Patients - I
Tobra/ClindaImipenem
Sex (M:F) 49:32 51:30
Age <50 23 33 50-59 10 16 60-69 24 13 70-79 17 13 >79 7 6
Antibiotic Monotherapy for Intraabdominal Infections
Demographics of Evaluable Patients -IIDemographics of Evaluable Patients -II
0 4 8 12 16
Malignancy
Alcoholism
Malnutrition
Diabetes
Cirrhosis Tobra/ClindaImipenem
Number of Patients
Antibiotic Monotherapy for Intraabdominal Infections
Disease Processes Encountered at Initial OperationDisease Processes Encountered at Initial Operation
0 4 8 12 16 20 24
Stom/Duod
Biliary
Small Bowel
Appendix
Colon
Post-Op
Other
Tobra/ClindaImipenem
Number of Patients
Antibiotic Monotherapy for Intraabdominal Infections
Mean APACHE II Scores Encountered at AdmissionMean APACHE II Scores Encountered at Admission
0 4 8 12 16 20 24
Stom/Duod
Biliary
Small Bowel
Appendix
Colon
Post-Op
Other
Tobra/ClindaImipenem
Mean APACHE II Score
Antibiotic Monotherapy for Intraabdominal Infections
Organisms Encountered in Intra-Abdominal FociOrganisms Encountered in Intra-Abdominal Foci
0 5 10 15 20 25 30 35 40 45 50
Others
M. morgagni
Citrobacter spp.
S. marcencens
Proteus spp.
P. aeruginosa
Klebsiella spp.
Enterobacter spp.
E. coli
Tobra/ClindaImipenem
Number of Patients
Gm -ve aerobes
Antibiotic Monotherapy for Intraabdominal Infections
Organisms Encountered in Intra-Abdominal FociOrganisms Encountered in Intra-Abdominal Foci
0 5 10 15 20 25
Candida
S. epidermides
S. aureus
ß-Streptococci
Enterococci
Alpha Strep
Tobra/ClindaImipenem
Number of Patients
Gm +ve aerobes
Antibiotic Monotherapy for Intraabdominal Infections
Organisms Encountered in Intra-Abdominal FociOrganisms Encountered in Intra-Abdominal Foci
0 5 10 15 20 25
Others
Eubacterium spp.
Lactobacillus
Fusobacterium spp.
Peptococci
Clostridium spp.
Bacteroides spp.
B. fragilis
Tobra/ClindaImipenem
Number of Patients
Anaerobes
Antibiotic Monotherapy for Intraabdominal Infections
Microbiologic Patterns of Encountered InfectionsMicrobiologic Patterns of Encountered Infections
0 10 20 30 40 50 60
Anaerobes Only
Gm+ cocci only
Gm-ve rods only
Mixed
Tobra/ClindaImipenem
Number of Patients
Antibiotic Monotherapy for Intraabdominal Infections
Activity of Study Agents: Gm-ve BacteriaActivity of Study Agents: Gm-ve Bacteria
0 4 8 12 16
Others
Citrobacter spp.
P. aeruginosa
Proteus spp.
Klebsiella
Enterobacter
E.coliTobra/ClindaImipenem
MIC (µg/ml) of Antibiotic90
Antibiotic Monotherapy for Intraabdominal Infections
Activity of Study Agents: Anaerobic BacteriaActivity of Study Agents: Anaerobic Bacteria
0 4 8 12 16 20 24 28 32
Enterococci
Clostridium Spp.
Bacteroides spp.
B. fragilis ClindamycinImipenem
MIC (µg/ml) of Antibiotic90
Antibiotic Monotherapy for Intraabdominal Infections
Overall Deaths, Failures and Predicted DeathsOverall Deaths, Failures and Predicted Deaths
0
10
20
30
40
50
60
0 - 4 5 - 9 10 - 14 15 - 16 20 - 24
FailuresDeaths
Predicted
APACHE II Range
# Enrolled 24 39 36 36 18
# patients
Antibiotic Monotherapy for Intraabdominal Infections
Analysis of Deaths - IAnalysis of Deaths - I
0 2 4 6
Death with Rx Success
Death with Rx Failure
Death within 7 days
Tobra/CLinda (n=14) Imipenem (n=11)
# Patients
Antibiotic Monotherapy for Intraabdominal Infections
Analysis of Deaths - IIAnalysis of Deaths - II
APACHE II Score0 4 8 12 16 20 24
Death with Rx Success
Death with Rx Failure
Death within 7 days
Tobra/CLinda (n=14) Imipenem (n=11)
Antibiotic Monotherapy for Intraabdominal Infections
Analysis of Deaths - IIIAnalysis of Deaths - III
0 10 20 30 40 50
Death with Rx Success
Death with Rx Failure
Death within 7 days
Tobra/CLinda (n=14) Imipenem (n=11)
Survival Time (days)
Antibiotic Monotherapy for Intraabdominal Infections
Failure as a Function of APACHE II and Antibiotic Regimen: All Patients
Failure as a Function of APACHE II and Antibiotic Regimen: All Patients
0
5
10
15
20
25
0 5 10 15 20 25 30 35 40
Tobra/ClindaTobra/Clinda
ImipenemImipenem
X = 4.1 p=0.0429Cumulative
Failures
APACHE II Score
2
Antibiotic Monotherapy for Intraabdominal Infections
Failure as a Function of APACHE II and Antibiotic Regimen: Gm-ve Organisms
Failure as a Function of APACHE II and Antibiotic Regimen: Gm-ve Organisms
0
5
10
15
20
0 5 10 15 20 25 30 35 40
Tobra/ClindaTobra/Clinda
ImipenemImipenem
X = 5.65 p=0.0175CumulativeFailures
APACHE II Score
2
Antibiotic Monotherapy for Intraabdominal Infections
Reasons for FailureReasons for Failure
0 2 4 6 8
Initial Resistance
Adverse Reaction
Wound Infection
Dead with "sepsis"
Fasciitis
Reccurent Abscess
Tobra/Clinda (n=24)Imipenem (n=14)
# Failures
Antibiotic Monotherapy for Intraabdominal Infections
Tobramycin LevelsTobramycin Levels
SuccessesFailures
Peak Maximum 6.4 + 1.9 6.1 + 1.7
Days to Max Peak 3.8 + 2.6 4.6 + 5.2
(µg/ml + sd)
(days + sd)
-
-
-
-
-
-
Variable times to adequate Tobramycin levels
Antibiotic Monotherapy for Intraabdominal Infections
Data in support of MONOTHERAPYfor surgical infections
Data in support of MONOTHERAPYfor surgical infections
Results of a Multicenter Trial ComparingImipenem/Cilastatin to Tobramycin/Clindamycinfor Intra-abdominal Infections.Solomkin JS, Dellinger EP, Christou NV, Busuttil RWAnn. Surg 212:581-591, 1990.
Imipenem vs Tobramycin-AntianaerobeAntibiotic therapy in Intra-abdominalInfections.Poenaru D, De Santis M, Christou NVCan. J. Surg. 33:415-422, 1990.