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IS BROAD SPECTRUM MONOTHERAPY ANTIBIOTIC TREATMENT ADEQUATE FOR INTRAABDOMINAL INFECTIONS ?

IS BROAD SPECTRUM MONOTHERAPY ANTIBIOTIC TREATMENT ADEQUATE FOR INTRAABDOMINAL INFECTIONS ?. Nicolas V. Christou. Associate Professor of Surgery and Microbiology. McGill University.  History & Physical Examination  Laboratory Tests  Imaging techniques.

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IS BROAD SPECTRUM MONOTHERAPY ANTIBIOTIC TREATMENT ADEQUATE FOR INTRAABDOMINAL INFECTIONS ?

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  1. IS BROAD SPECTRUM MONOTHERAPYANTIBIOTIC TREATMENT ADEQUATEFOR INTRAABDOMINAL INFECTIONS ? Nicolas V. Christou Associate Professor of Surgery and Microbiology McGill University

  2. History & Physical Examination Laboratory Tests Imaging techniques DIAGNOSIS OF INTRA-ABDOMINALINFECTION

  3. Basic principles Review of antibiotic choices Presentation of most recent data on monotherapy Conclusions OUTLINE

  4. MORTALITY OF INTRA-ABDOMINAL INFECTIONS Mortality % Diffuse Suppurative Peritonitis Combined Complicated Infection Localized Peritonitis Localized Abscess

  5.  broad spectrum EMPIRIC antibiotic therapy TREATMENT OF INTRA-ABDOMINAL INFECTIONS  Surgical drainage and correction of pathology

  6. A single antibiotic or a combination of antibiotics providing BROAD SPECTRUM coverage against all possible pathogens. ANTIBIOTIC THERAPY OF SURGICAL INFECTIONS Empiric Antibiotic Therapy: Definitive Antibiotic Therapy: Antibiotic administration based on specific culture and sensitivity results.

  7. Use an antibiotic or combination of antibiotics that provides broad spectrum activity to cover all suspected PATHOGENS. HOW DOES ONE PICK APPROPRIATEEMPIRIC ANTIBIOTIC THERAPY ?

  8. SUSPECTED PATHOGENS IN INTRA-ABDOMINAL INFECTIONS RVH Data Gm -ve AEROBES Other (16%) P. mirabilis (4%) Enterobacter (5%) P. aeruginosa (5%) E. coli (59%) K. pneumonia (11%)

  9. SUSPECTED PATHOGENS IN INTRA-ABDOMINAL INFECTIONS RVH Data Gm +ve AEROBES Others (4%) S. epidermidis (6%) Corynebacteria (10%) S. aureus (25%) Enterococcus (55%)

  10. SUSPECTED PATHOGENS IN INTRA-ABDOMINAL INFECTIONS RVH Data ANAEROBES Others (9%) Fusobacteria (6%) B. fragilis (27%) Bacteroidis sp. (57%)

  11. PenicillinsAminoglycosides Cephalosporins Metronidazole Carbapenems Clindamycin Quinolonnes Vancomycin ANTIBIOTICS FOR SURGICAL INFECTIONS

  12. Penicillin G Methicillin Cloxacillin Carboxipenicillins Ureidopenicillins PENICILLINS (Penem nucleus) Basic structure of Penicillins

  13. In vitro ACTIVITY of PIPERACILLIN Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic 90

  14. ANTIBIOTICS FOR SURGICAL INFECTIONS "More Recent" therapy eg Piperacillin 1-2 g q8h UreidoPenicillin (Antianaerobic Agent) (eg Clindamycin 600 mg q8h)

  15. Gentamycin Tobramycin Netilmicin Amikacin AMINOGLYCOSIDES (gentamycin) Excellent Gm- activity

  16. In vitro Activity of Aminoglycosides - GENTAMYCIN Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic 90

  17. ANTIBIOTICS FOR SURGICAL INFECTIONS "Gold Standard" therapy Aminoglycoside + Antianaerobic Agent eg Gentamycin 2-3 mg/kg q8h eg Clindamycin 600 mg q8h

  18. Aminoglycoside Use - Caution  Ototoxicity Occurs in up to 30% of cases and often is not reversible. Nephrotoxicity Occurs in up to 5% of cases and is often reversible.

  19. CEPHALOSPORINS First Generation eg. Cephazolin Penam nucleus Second Generation eg. Cefoxitin R R1 Third Generation eg. Cefotaxime Cephem nucleus

  20. In vitro ACTIVITY of 2nd GENERATION CEPHALOSPORINS- CEFOXITIN Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic 90

  21. In vitro ACTIVITY of 3rd GENERATION CEPHALOSPORINS- CEFOTAXIME Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic 90

  22. ANTIBIOTICS FOR SURGICAL INFECTIONS "More Recent" therapy rd 3 Generation Cephalosporin + Antianaerobic Agent eg Cefoperazone 1-2 g q12h eg Clindamycin 600 mg q8h

  23. "True Quinolones" Norfloxacin Ciprofloxacin Enoxacin Perfloxacin Ofloxacin QUINOLONES Basic Structure of Quinolones Classified according to modifications at X2 and X8 positions.

  24. In vitro activity of QUINOLONES Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic 90

  25. ANTIBIOTIC "EFFICACY" STUDIES:INTRAABDOMINAL INFECTIONS Cephalosporin based Rx 52-96% range Aminoglycoside based Rx 61-95% range Success Rate %

  26. exclusion criteria not rigid lack of "illness stratification" results reporting ANTIBIOTIC "EFFICACY" STUDIES:INTRAABDOMINAL INFECTIONS Problems in Study Design

  27. CARBAPENEMS Imipenem - approved for use Meropenem - phase III clinical trials

  28. In vitro activity of IMIPENEM Minimal Inhibitory Concentration (MIC in µg/ml) of Antibiotic 90

  29. COMPARATIVE ACTIVITIES OF VARIOUS ANTIBIOTICS Acinetobacter calcoaceticus Enterobacter cloacae MIC (90) µg/ml MIC (90) µg/ml S. faecalis P. aeruginosa MIC (90) µg/ml MIC (90) µg/ml

  30. A Multicenter Comparative Trial of Imipenem/Cilastatin vsTobramycin/Clindamycin for Intraabdominal Infections Prospective, randomized, open design 290 Patients Entered 147 - Imipenem 143 - Tobra/Clinda 81 Patients Evaluable 81 Patients Evaluable

  31. 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 Statistical Considerations 2

  32. > 18 years No drug hypersensitivity Normal renal function Suspected Intraabdominal Infection Criteria for Eligibility

  33. Simple Appendicitis Simple Cholecystitis Traumatic bowel perforation < 12h Perforated peptic ulcer < 24 h Exploration with negative bacterial cultures Criteria for Exclusion

  34. Reasons for Exclusion of 128 Patients Number of Patients

  35. A severity of disease classification system based on acute and chronic physiologic response variables such as : "ILLNESS" STRATIFICATION % Mortality APACHE II • Pulse, Pressure etc • Oxygenation, pH • Glascow Coma Scale APACHE II Ranges

  36. 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 Drug Therapy + Clindamycin 600 mg i.v. q8h

  37. Local Intra-abdominal Infection Hospitalization Outcome Scoring

  38. Initial study driven antibiotic therapy and an adequate operation cured the intraabdominal infection. Definition of Rx Success

  39. Survival of < 7 days Second intervention showed recurrence with initial organisms Wound Infection developed Definition of Rx Failure

  40. Tobra/Clinda Imipenem 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 - I

  41. Demographics of Evaluable Patients -II Number of Patients

  42. Disease Processes Encountered at Initial Operation Number of Patients

  43. Mean APACHE II Scores Encountered at Admission Mean APACHE II Score

  44. Organisms Encountered in Intra-Abdominal Foci Gm -ve aerobes Number of Patients

  45. Organisms Encountered in Intra-Abdominal Foci Gm +ve aerobes Number of Patients

  46. Organisms Encountered in Intra-Abdominal Foci Anaerobes Number of Patients

  47. Microbiologic Patterns of Encountered Infections Number of Patients

  48. Activity of Study Agents: Gm-ve Bacteria MIC (µg/ml) of Antibiotic 90

  49. Activity of Study Agents: Anaerobic Bacteria MIC (µg/ml) of Antibiotic 90

  50. Overall Deaths, Failures and Predicted Deaths # patients  Failures Deaths  Predicted     APACHE II Range # Enrolled 24 39 36 36 18

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