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


DIAGNOSIS OF INTRA-ABDOMINALINFECTION

DIAGNOSIS OF INTRA-ABDOMINALINFECTION

History & Physical Examination

Laboratory Tests

Imaging techniques


OUTLINEOUTLINE

Basic principles

Review of antibiotic choices

Presentation of most recent data on monotherapy

Conclusions


MORTALITY OF INTRA-ABDOMINAL INFECTIONSMORTALITY OF INTRA-ABDOMINAL INFECTIONS

0

20

40

60

LocalizedAbscess

LocalizedPeritonitis

DiffuseSuppurativePeritonitis

CombinedComplicated

Infection

Mortality %


TREATMENT OF INTRA-ABDOMINAL INFECTIONSTREATMENT OF INTRA-ABDOMINAL INFECTIONS

Surgical drainage and correction of pathology

broad spectrum EMPIRIC antibiotic therapy


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.


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.


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



Gm +ve AEROBES

Enterococcus (55%)S. aureus (25%)

Corynebacteria (10%)

S. epidermidis (6%)Others (4%)

RVH Data



ANAEROBES

Bacteroidis sp. (57%)

B. fragilis (27%)

Fusobacteria (6%)Others (9%)

RVH Data


ANTIBIOTICS FOR SURGICAL INFECTIONSANTIBIOTICS FOR SURGICAL INFECTIONS

PenicillinsAminoglycosides

Cephalosporins Metronidazole

Carbapenems Clindamycin

Quinolonnes Vancomycin


PENICILLINSPENICILLINS

Basic structure of Penicillins

Penicillin G

Methicillin

Cloxacillin

Carboxipenicillins

Ureidopenicillins

(Penem nucleus)


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



"More Recent" therapy

UreidoPenicillin

(AntianaerobicAgent)

UreidoPenicillin

(AntianaerobicAgent)

eg Piperacillin 1-2 g q8h

(eg Clindamycin 600 mg q8h)


AMINOGLYCOSIDESAMINOGLYCOSIDES Gentamycin

Tobramycin

Netilmicin

Amikacin

Excellent Gm- activity

(gentamycin)


In vitro Activity of Aminoglycosides - GENTAMYCINIn vitro Activity of Aminoglycosides - GENTAMYCIN

0 20 40 60 80 100 120 140

E. coliEnterobacter


ProteusSeratia


Acinetobacter








"Gold Standard" therapy

Aminoglycoside+

AntianaerobicAgent

Aminoglycoside+

AntianaerobicAgent

eg Gentamycin 2-3 mg/kg q8h

eg Clindamycin 600 mg q8h


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.


CEPHALOSPORINSCEPHALOSPORINS

Penam nucleus

Cephem nucleus

R

R1

First Generation

Second Generation

Third Generation

eg. Cephazolin

eg. Cefoxitin

eg. Cefotaxime


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


ProteusSeratia


Acinetobacter







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


ProteusSeratia


Acinetobacter








"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


QUINOLONESQUINOLONESBasic Structure of Quinolones

Classified according to modifications at X2 and X8

positions.

"True Quinolones"

Norfloxacin

Ciprofloxacin

Enoxacin

Perfloxacin

Ofloxacin


In vitro activity of QUINOLONESIn vitro activity of QUINOLONES

0 5 10 15 20 25 30 35

E. coliEnterobacter


ProteusSeratia


Acinetobacter







ANTIBIOTIC "EFFICACY" STUDIES:INTRAABDOMINAL INFECTIONS


0 20 40 60 80 100

Cephalosporinbased Rx

Aminoglycosidebased Rx

Success Rate %

52-96% range

61-95% range




Problems in Study Design

exclusion criteria not rigid

lack of "illness stratification"

results reporting


CARBAPENEMSCARBAPENEMS

Imipenem- approved for use

Meropenem- phase III clinical trials


In vitro activity of IMIPENEMIn vitro activity of IMIPENEM

0 10 20 30 40 50 60 70

E. coliEnterobacter


ProteusSeratia

CitrobacterP. species

Acinetobacter







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


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


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


Criteria for EligibilityCriteria for Eligibility

> 18 years

No drug hypersensitivity

Normal renal function

Suspected Intraabdominal Infection


Criteria for ExclusionCriteria for Exclusion

Simple Appendicitis

Simple Cholecystitis

Traumatic bowel perforation < 12h

Perforated peptic ulcer < 24 h

Exploration with negative bacterial cultures


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


"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


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+


Outcome ScoringOutcome Scoring

Local Intra-abdominal Infection

Hospitalization


Definition of Rx SuccessDefinition of Rx Success

Initial study driven

antibiotic therapy and an

adequate operation cured

the intraabdominal

infection.


Definition of Rx FailureDefinition of Rx Failure

Survival of < 7 days

Second intervention showed recurrence with initial organisms

Wound Infection developed


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


Demographics of Evaluable Patients -IIDemographics of Evaluable Patients -II

0 4 8 12 16

Malignancy

Alcoholism

Malnutrition

Diabetes

Cirrhosis Tobra/ClindaImipenem

Number of Patients


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


Number of Patients


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


Mean APACHE II Score


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


Number of Patients

Gm -ve aerobes



0 5 10 15 20 25

Candida

S. epidermides

S. aureus

ß-Streptococci

Enterococci

Alpha Strep


Number of Patients

Gm +ve aerobes



0 5 10 15 20 25

Others

Eubacterium spp.

Lactobacillus

Fusobacterium spp.

Peptococci

Clostridium spp.

Bacteroides spp.

B. fragilis


Number of Patients

Anaerobes


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


Number of Patients


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


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


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


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


Analysis of Deaths - IIAnalysis of Deaths - II

APACHE II Score0 4 8 12 16 20 24



Death within 7 days



Analysis of Deaths - IIIAnalysis of Deaths - III

0 10 20 30 40 50



Death within 7 days


Survival Time (days)


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


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


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


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


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.


ANTIBIOTIC OF CHOICE FOR INTA-ABDOMINAL INFECTIONSANTIBIOTIC OF CHOICE FOR

INTA-ABDOMINAL INFECTIONS

Carbapenem

MonoRx

Carbapenem

MonoRx

eg Imipenem 500 mg q6h

antibiotic monotherapy for intraabdominal infections is broad spectrum monotherapy antibiotic...

Documents

antibiotic monotherapy

gml of antibiotic

antibiotic administration

single antibiotic

definitive antibiotic

monotherapy conclusions

q8h slide

gm ve aerobes rvh data