Antibiotic Monotherapy for Intraabdominal Infections IS BROAD SPECTRUM MONOTHERAPY ANTIBIOTIC TREATMENT ADEQUATE FOR INTRAABDOMINAL INFECTIONS ? Nicolas V. Christou Associate Professor of Surgery and Microbiology McGill University

Antibiotic Monotherapy for Intraabdominal Infections DIAGNOSIS OF INTRA-ABDOMINAL INFECTION  History & Physical Examination  Laboratory Tests  Imaging techniques

Antibiotic Monotherapy for Intraabdominal Infections OUTLINE  Basic principles  Review of antibiotic choices  Presentation of most recent data on monotherapy  Conclusions

Antibiotic Monotherapy for Intraabdominal Infections MORTALITY OF INTRA-ABDOMINAL INFECTIONS Localized Abscess Localized Peritonitis Diffuse Suppurative Peritonitis Combined Complicated Infection Mortality %

Antibiotic Monotherapy for Intraabdominal Infections TREATMENT OF INTRA-ABDOMINAL INFECTIONS  Surgical drainage and correction of pathology  broad spectrum EMPIRIC antibiotic therapy

Antibiotic Monotherapy for Intraabdominal Infections ANTIBIOTIC 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 APPROPRIATE EMPIRIC ANTIBIOTIC THERAPY ? 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 INFECTIONS E. coli (59%) K. pneumonia (11%) P. aeruginosa (5%) Enterobacter (5%) P. mirabilis (4%) Other (16%) Gm -ve AEROBES RVH Data

Antibiotic Monotherapy for Intraabdominal Infections SUSPECTED 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 INFECTIONS ANAEROBES Bacteroidis sp. (57%) B. fragilis (27%) Fusobacteria (6%) Others (9%) RVH Data

Antibiotic Monotherapy for Intraabdominal Infections ANTIBIOTICS FOR SURGICAL INFECTIONS  Penicillins  Aminoglycosides  Cephalosporins  Metronidazole  Carbapenems  Clindamycin  Quinolonnes  Vancomycin

Antibiotic Monotherapy for Intraabdominal Infections PENICILLINS Basic structure of Penicillins  Penicillin G  Methicillin  Cloxacillin  Carboxipenicillins  Ureidopenicillins (Penem nucleus)

Antibiotic Monotherapy for Intraabdominal Infections In vitro ACTIVITY of PIPERACILLIN Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic 90

Antibiotic Monotherapy for Intraabdominal Infections ANTIBIOTICS FOR SURGICAL INFECTIONS "More Recent" therapy UreidoPenicillin (Antianaerobic Agent) UreidoPenicillin (Antianaerobic Agent) eg Piperacillin 1-2 g q8h (eg Clindamycin 600 mg q8h)

Antibiotic Monotherapy for Intraabdominal Infections AMINOGLYCOSIDES  Gentamycin  Tobramycin  Netilmicin  Amikacin Excellent Gm- activity (gentamycin)

Antibiotic Monotherapy for Intraabdominal Infections In vitro Activity of Aminoglycosides - GENTAMYCIN Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic 90

Antibiotic Monotherapy for Intraabdominal Infections ANTIBIOTICS FOR SURGICAL INFECTIONS "Gold Standard" therapy Aminoglycoside + Antianaerobic Agent Aminoglycoside + Antianaerobic Agent eg Gentamycin 2-3 mg/kg q8h eg Clindamycin 600 mg q8h

Antibiotic Monotherapy for Intraabdominal Infections Aminoglycoside 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 CEPHALOSPORINS 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 Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic 90

Antibiotic Monotherapy for Intraabdominal Infections In vitro ACTIVITY of 3rd GENERATION CEPHALOSPORINS - CEFOTAXIME Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic 90

Antibiotic Monotherapy for Intraabdominal Infections ANTIBIOTICS 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 QUINOLONES Basic 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 QUINOLONES Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic 90

Antibiotic Monotherapy for Intraabdominal Infections ANTIBIOTIC "EFFICACY" STUDIES: INTRAABDOMINAL INFECTIONS Cephalosporin based Rx Aminoglycoside based Rx Success Rate % 52-96% range 61-95% range

Antibiotic Monotherapy for 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 CARBAPENEMS Imipenem - approved for use Meropenem - phase III clinical trials

Antibiotic Monotherapy for Intraabdominal Infections In vitro activity of IMIPENEM Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic 90

Antibiotic Monotherapy for Intraabdominal Infections COMPARATIVE ACTIVITIES OF VARIOUS ANTIBIOTICS MIC (90) µg/ml Enterobacter cloacae Acinetobacter calcoaceticus P. aeruginosa S. faecalis

Antibiotic Monotherapy for Intraabdominal Infections A Multicenter Comparative Trial of Imipenem/Cilastatin vs Tobramycin/Clindamycin for Intraabdominal Infections 290 Patients Entered Tobra/Clinda Imipenem 81 Patients Evaluable Prospective, randomized, open design

Antibiotic Monotherapy for Intraabdominal Infections Statistical 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 Eligibility  > 18 years  No drug hypersensitivity  Normal renal function  Suspected Intraabdominal Infection

Antibiotic Monotherapy for Intraabdominal Infections Criteria 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 Patients Number of Patients

Antibiotic Monotherapy for Intraabdominal Infections "ILLNESS" STRATIFICATION APACHE II % 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 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 Scoring  Local Intra-abdominal Infection  Hospitalization

Antibiotic Monotherapy for Intraabdominal Infections Definition of Rx Success  Initial study driven antibiotic therapy and an adequate operation cured the intraabdominal infection.

Antibiotic Monotherapy for Intraabdominal Infections Definition 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 - I Tobra/ClindaImipenem Sex (M:F)49:3251:30 Age < >7976

Antibiotic Monotherapy for Intraabdominal Infections Demographics of Evaluable Patients -II Number of Patients

Antibiotic Monotherapy for Intraabdominal Infections Disease Processes Encountered at Initial Operation Number of Patients

Antibiotic Monotherapy for Intraabdominal Infections Mean APACHE II Scores Encountered at Admission Mean APACHE II Score

Antibiotic Monotherapy for Intraabdominal Infections Organisms Encountered in Intra-Abdominal Foci Number of Patients Gm -ve aerobes

Antibiotic Monotherapy for Intraabdominal Infections Organisms Encountered in Intra-Abdominal Foci Number of Patients Gm +ve aerobes

Antibiotic Monotherapy for Intraabdominal Infections Organisms Encountered in Intra-Abdominal Foci Number of Patients Anaerobes

Antibiotic Monotherapy for Intraabdominal Infections Microbiologic Patterns of Encountered Infections Number of Patients

Antibiotic Monotherapy for Intraabdominal Infections Activity of Study Agents: Gm-ve Bacteria MIC (µg/ml) of Antibiotic 90

Antibiotic Monotherapy for Intraabdominal Infections Activity of Study Agents: Anaerobic Bacteria MIC (µg/ml) of Antibiotic 90

Antibiotic Monotherapy for Intraabdominal Infections Overall Deaths, Failures and Predicted Deaths Failures Deaths Predicted APACHE II Range # Enrolled  # patients     

Antibiotic Monotherapy for Intraabdominal Infections Analysis of Deaths - I # Patients

Antibiotic Monotherapy for Intraabdominal Infections Analysis of Deaths - II APACHE II Score

Antibiotic Monotherapy for Intraabdominal Infections Analysis of Deaths - III Survival Time (days)

Antibiotic Monotherapy for Intraabdominal Infections Failure as a Function of APACHE II and Antibiotic Regimen: All Patients Tobra/Clinda Imipenem X = 4.1 p= Cumulative Failures APACHE II Score 2

Antibiotic Monotherapy for Intraabdominal Infections Failure as a Function of APACHE II and Antibiotic Regimen: Gm-ve Organisms Tobra/Clinda Imipenem X = 5.65 p= Cumulative Failures APACHE II Score 2

Antibiotic Monotherapy for Intraabdominal Infections Reasons for Failure # Failures

Antibiotic Monotherapy for Intraabdominal Infections Tobramycin Levels SuccessesFailures Peak Maximum Days to Max Peak (µg/ml + sd) (days + sd) Variable times to adequate Tobramycin levels 

Antibiotic Monotherapy for Intraabdominal Infections Data in support of MONOTHERAPY for surgical infections Results of a Multicenter Trial Comparing Imipenem/Cilastatin to Tobramycin/Clindamycin for Intra-abdominal Infections. Solomkin JS, Dellinger EP, Christou NV, Busuttil RW Ann. Surg 212: , Imipenem vs Tobramycin-Antianaerobe Antibiotic therapy in Intra-abdominal Infections. Poenaru D, De Santis M, Christou NV Can. J. Surg. 33: , 1990.

Antibiotic Monotherapy for Intraabdominal Infections ANTIBIOTIC OF CHOICE FOR INTA-ABDOMINAL INFECTIONS Carbapenem MonoRx Carbapenem MonoRx eg Imipenem 500 mg q6h