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R. Dagan The Pediatric Infectious Disease Unit Soroka University Medical Center

Double Tympanocentesis Studies: Bridging from Bacteriological Outcome to Studies with Clinical Outcome. R. Dagan The Pediatric Infectious Disease Unit Soroka University Medical Center Ben-Gurion University Beer-Sheva, Israel. b. a. TYMPANOCENTESIS. CULTURE. TREATMENT. day 1. day 4-6.

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R. Dagan The Pediatric Infectious Disease Unit Soroka University Medical Center

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  1. Double Tympanocentesis Studies: Bridging from Bacteriological Outcome to Studies with Clinical Outcome R. Dagan The Pediatric Infectious Disease Unit Soroka University Medical Center Ben-Gurion University Beer-Sheva, Israel

  2. b a TYMPANOCENTESIS CULTURE TREATMENT day 1 day 4-6 day 10-12 Day 21-30

  3. (1) In AOM, is there any difference between drugs in regard to bacteriologic eradication on day 4-6?

  4. 84% 52% * % persistence placebo cefac(40) cef-axet(40) Ts CROx1(50) Azith(3;5d) amox/augm(40-50) CROx3(50) Gati(10) AugES-600(90) * for amoxicilline only

  5. ceftriaxone (4) gatifloxacin (1) cefixime (2) amox/clav - 90 (1) cefpodox (1) TMP/SMX (2) cefur-axet (2) amp/amox (7) amox/clav - 45 (4) cefaclor (6) cefprozil (1) azithro (2) erythro (1) clarithto (1) Failure Rate to Eradicate H. influenzae in AOM: Studies with a 2nd Tympanocentesis Performed on Day 2-6 of Tx placebo (1*) 50 0 100 *Number of studies Failure rate (%)

  6. (2) Can double tap studies determine an MIC concentration cut-off, above which a given drug is not bacteriologically efficacious ?

  7. 62 52 40 21 15 10 9 2/22 4/41 4/19 18/29 34/85 7/46 Pnc - S Pnc - I, R Hi Placebo Cefaclor vs. Cefuroxime-Axetil: Bacteriology and Organism-specific Bacteriological Failure CEF - AXET CECL 84 Pnc n=111 Hi n=131 % bacteriologic failures Placebo Dagan et al, J Infect Dis 176:1253-1259, 1997 Dagan et al AAC 44:43-50, 2000

  8. 73 50 0 0 0/9 11/15 0/28 6/12 Bacteriologic Failure Rate (day 4-5) TMP/SMX as an Example of “All-or-Non Phenomenon” MIC<=0.5 mcg/ml 84 MIC >0.5 mcg/ml 52 % bacteriologic failures Pnc Placebo Pnc Hi Placebo Hi Leiberman et al, Pediatr Infect Dis, 20:260-4, 2001

  9. 6/6 3 days (Dagan et al AAC 44:43-50, 2000) 100 0.25 5 days (Dagan et al PIDJ 19:95-104, 2000) 0.25 5/8 11/17 23/36 11/18 5/9 65 64 63 61 56 2/25 0/12 8 0 <= 0.25 > 2.0 0.5 - 1 2.0 - 4.0 Bacteriologic Failure Rate (day 4-6) for Azithromycin Pnc Hi 100 90 84 80 70 60 52 % with bacteriological failure 50 40 30 20 10 0 Placebo Placebo Azithromycin MIC (µg/ml) For placebo - Howie, Clin Pediatr 11:205-14,1972

  10. Pnc Hi P = .036 P = .004 N = 87 N = 20 N = 14 N = 57 N = 22 N = 4 Penicillin MIC (µg/ml) Augmentin MIC (µg/ml) Bacteriological Failures of Pnc and Hi Treated by Augmentin ES-600 by MIC Dagan et al, Pediatr Infect Dis, 20:829-37, 2001 % with bacteriological failure

  11. (3) Is there a relation between bacteriologic eradication on day 4-6 and clinical outcome ?

  12. 17/253 (7%) P < 0.001 15/40 (38%) 2/66 (3%) P < 0.001 21/57 (37%) Culture-positive on day 3-7 Culture-negative on day 3-7 Clinical vs. Bacteriological Outcome of Children with AOM with Initial Positive MEF Cx Clinical Failure Clinical success Carlin et al J Pediatr 118:178-83, 1991 Dagan et al Pediatr Infect Dis J 17:776-82, 1998

  13. Score distribution Day 4-6 score 6 46 45 Culture (-) (n = 33) ≥ 4 P < 0.001 2 - 4 0-1 34 55 11 Culture (+) (n = 35) 0% 20% 40% 60% 80% 100% 0 1 2 3 TEMPERATURE (ºC)<38.0 38.0-38.5 38.6-39.0 >39.0 IRRITABILITYabsent mild moderate severe TUGGINGabsent mild moderate severe REDNESS absent mild moderate severe BULGINGabsent mild moderate severe* A * Including draining pus Dagan et al Pediatr Infect Dis J 17:776-82, 1998 B

  14. (4) Can we determine by double tap studies if an organism is not important in AOM

  15. H. Influenzae is deemed by some clinicians/antibiotic manufacturers as being not important, although prevalent, in AOM

  16. No. pathogens = 56 No. patients = 43 No. pathogens = 16 No. patients = 13 MC 6% GAS 2% MC 2% PRSP 25% ßL (-) HI 19% PRSP 30% ßL (-) HI 36% 1 1 1 3 4 17 20 4 13 8 PSSP 7% ßL (+) HI 50% ßL (+) HI 23% Day 4-6 Day 1 No. ßL (+) organisms = 9/16 (56%) No. ßL (+) organisms = 14/56 (25%) P=0.04 High Dose Amoxicillin (80mg/Kg/d): MEF Pathogens in Bacteriologic Failure Leibovitz et al, 40th ICAAC, 2000

  17. Does NTHi Cause a Less Severe AOM? Clinical score 0 1 2 3 TEMPERATURE (ºC)<38.0 38.0-38.5 38.6-39.0 >39.0 IRRITABILITYabsent mild moderate severe REDNESS absent mild moderate severe BULGINGabsent mild moderate severe* * Including draining pus Maximal score = 12 Modified from Dagan et al Pediatr Infect Dis J 17:776-82, 1998

  18. Mean Clinical Score ( SD) Pre-Treatment n = 240 Cx (-) 7.73  2.32 P = 0.003 Cx (+) 8.21  2.17 n = 762

  19. Mean Clinical Score ( SD) Pre-Treatment 7.73  2.32 n = 240 NG 8.06  2.20 n = 173 NTHi + Pnc P = 0.018 n = 198 8.14  2.11 Pnc n = 392 8.32  2.19 NTHi

  20. Eradication Failure 4.79  3.71 P = 0.0034 n=43 NTHi + Pnc n=98 6.53  2.93  Clinical score 5.75  3.08 P = 0.13 n=36 ∆ between day 1 and day 4-6 Pnc n=143 6.55  2.79 P = 0.0001 5.29  3.14 n=85 NTHi 6.89  2.76 n=254 4 4.5 5 5.5 6 6.5 7 7.5 Score Mean ( SD) Difference in Total Score Between 1st & 2nd Visit

  21. (5) Can we bridge between double tap studies and studies with clinical outcome?

  22. 87% P < 0.001 48% 39% Amox/clav 45mg/Kg Azithro 5 days Placebo NTHi Eradication Rate: Amox/Clav (45mg/kg) vs. Azithromycin 90 80 70 60 50 Bacterial eradication rate 40 30 20 10 0 Dagan et al PIDJ 19:95-104, 2000

  23. 91 86 P=0.01 80 86 P=0.023 65 70 % with clinical success 90 68 87 39 83 49 Clinical Success: Amox/Clav (45mg/kg) vs. Azithromycin Azithromycin Augmentin Hi alone Pnc alone Total Dagan et al PIDJ 19:95-104, 2000

  24. Clinical Success: Amox/Clav (45mg/kg) vs. Azithromycin Amox/clav - 45mg/Kg (87%) Amox/clav - 45mg/Kg (86%) Azithro (80%) Azithro (65%) Pnc Hi Placebo Dagan et al PIDJ 19:95-104, 2000 Bacteriologic efficacy in bacterial AOM Clinical efficacy in bacterial AOM Clinical efficacy in “clinical” AOM 100 90 80 70 % Success 60 50 40 30 20 Marchant et al, J Pediat 120:72-7, 1992

  25. Pnc Pen-S (95%) Pnc Pen-I (75%) Pnc Pen-R (67%) Placebo Study 1015 (Single Dose Azithro 30 mg/kg) Conducted by Pfizer by Penicillin Susceptibility Bacteriologic efficacy in bacterial AOM Clinical efficacy in bacterial AOM Clinical efficacy in “clinical” AOM 100 90 80 70 % Success 60 50 40 30 20 Marchant et al, J Pediat 120:72-7, 1992

  26. 3 days - Pnc (94%) Single dose - Pnc (88%) 3 days - Hi (69%) Single dose - Hi (64%) Placebo Clinical Success in Studies Conducted by Pfizer by by Pathogens Bacteriologic efficacy in bacterial AOM Clinical efficacy in bacterial AOM Clinical efficacy in “clinical” AOM 100 90 80 70 % Success 60 50 40 30 20 Marchant et al, J Pediat 120:72-7, 1992

  27. (6) How do double tap studies help in understanding the best timing for clinical outcome determination?

  28. b a c TYMPANOCENTESIS CULTURE TREATMENT day 1 day 4-6 day 10-12 (EOT) Day 21-30 (TOC)

  29. NG 20 (18%) True bacteriologic relapse 30 (28%) New Infection 58 (54%) Clinical Recurrence After Completion of Rx vs Bacteriologic Relapse Leibovitz et al, 40th ICAAC, Toronto. 2000 Clinical recurrence After bacteriologic eradication N=108

  30. Hi  Hi (n = 34) New Relapse New Acquisition vs Persistence of Pathogens in Clinical Recurrence of AOM in Relation to Initial AOM Isolate* Leibovitz et al, 40th ICAAC, Toronto. 2000 Pnc  Pnc (n = 38) * Verified by serotype and PFGE for Pnc and PFGE for Hi

  31. b a c TYMPANOCENTESIS CULTURE TREATMENT day 1 day 4-6 day 10-12 (EOT) Day 21-30 (TOC)

  32. b a TYMPANOCENTESIS CULTURE TREATMENT day 1 day 4-6 EOT >>>>TOC

  33. (7) Are the patients that are studied in double tap studies different than those in purely clinical studies?

  34. Patients in whom antibiotics are most needed Yes,Patients that are Studied in Double Tap Studies Are Different than Those in Pure Clinical Studies • Most are < 2yrs of age • Tympanic membrane bulging + pus • Positive Cx • Enriched for more complex AOM • Otitis prone • Recent antibiotic use • DCC attendance • Older siblings • genetics

  35. Conclusions 1) Double tap studies clearly demonstrate a considerable difference between drugs in regard to their ability to eradicate the pathogens within 3-5 days 2) Double tap studies can determine an MIC concentration cut-off, above which a given drug is not bacteriologically efficacious 3) Bacteriologic eradication within 3-5 days and clinical outcome correlate

  36. Conclusions (cont’d) • 4) Double tap studies demonstrate that H. influenzae is an important pathogen in AOM • 5) We can bridge between double tap studies and studies with clinical outcome • Double tap studies help in understanding that the best timing for clinical outcome determination is EOT rather than TOC • The patients that are studied in double tap studies are those who need antibiotics more often than patients enrolled in purely clinical studies

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