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Otitis/2002/Dagan R. Dagan The Pediatric Infectious Disease Unit Soroka University Medical Center Ben-Gurion University Beer-Sheva, Israel Beer-Sheva,

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Presentation on theme: "Otitis/2002/Dagan R. Dagan The Pediatric Infectious Disease Unit Soroka University Medical Center Ben-Gurion University Beer-Sheva, Israel Beer-Sheva,"— Presentation transcript:

1 otitis/2002/Dagan R. Dagan The Pediatric Infectious Disease Unit Soroka University Medical Center Ben-Gurion University Beer-Sheva, Israel Beer-Sheva, Israel Double Tympanocentesis Studies: Bridging from Bacteriological Outcome to Studies with Clinical Outcome

2 otitis/2002/Dagan day 1 day 4-6 day 10-12 Day 21-30 TREATMENT CULTURE TYMPANOCENTESIS a b

3 otitis/2002/Dagan (1) In AOM, is there any difference between drugs in regard to bacteriologic eradication on day 4-6?

4 otitis/2002/Dagan cefac (40) cef-axet (40) amox/augm (40-50) CROx1 (50) CROx3 (50) Azith (3;5d) Ts placebo * for amoxicilline only 84% 52% % persistence Aug ES-600 (90) Gati (10) *

5 otitis/2002/Dagan placebo (1*) Failure rate (%) *Number of studies Failure Rate to Eradicate H. influenzae in AOM: Studies with a 2 nd Tympanocentesis Performed on Day 2-6 of Tx 50 0100 amox/clav - 45 (4) amp/amox (7) cefur-axet (2) TMP/SMX (2) cefpodox (1) cefixime (2) ceftriaxone (4) amox/clav - 90 (1) gatifloxacin (1)

6 otitis/2002/Dagan (2) Can double tap studies determine an MIC concentration cut-off, above which a given drug is not bacteriologically efficacious ?

7 otitis/2002/Dagan 84 Placebo52 CEF - AXETCECL Cefaclor vs. Cefuroxime-Axetil: Bacteriology and Organism-specific Bacteriological Failure % bacteriologic failures Dagan et al, J Infect Dis 176:1253-1259, 1997 Dagan et al AAC 44:43-50, 2000 Dagan et al AAC 44:43-50, 2000 910 Pnc - S 4/412/22 2162 Pnc - I, R 18/294/19 1540 Hi 34/85 7/46 Pncn=111 Hin=131

8 otitis/2002/Dagan 0 0/280 0/9 84 52 PncPlacebo PncHiPlacebo Hi MIC<=0.5 mcg/ml MIC >0.5 mcg/ml % bacteriologic failures Bacteriologic Failure Rate (day 4-5) TMP/SMX as an Example of “All-or-Non Phenomenon” 73 11/15 50 6/12 Leiberman et al, Pediatr Infect Dis, 20:260-4, 2001

9 otitis/2002/Dagan 84 52 0 10 20 30 40 50 60 70 80 90 100 PlaceboPlacebo PncHi % with bacteriological failure Azithromycin MIC (µg/ml) Bacteriologic Failure Rate (day 4-6) for Azithromycin For placebo - Howie, Clin Pediatr 11:205-14,1972 3 days ( Dagan et al AAC 44:43-50, 2000) 5 days ( Dagan et al PIDJ 19:95-104, 2000) 0 8 <= 0.25 0/122/25 100 63 > 2.0 6/65/8 56 61 0.5 - 1 5/911/18 64 65 2.0 - 4.0 23/3611/17 0.25 0.25

10 otitis/2002/Dagan 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 P =.004 N = 87N = 20N = 14 Penicillin MIC (µg/ml) Pnc N = 57N = 22N = 4 P =.036 Augmentin MIC (µg/ml) Hi

11 otitis/2002/Dagan (3) Is there a relation between bacteriologic eradication on day 4-6 and clinical outcome ?

12 otitis/2002/Dagan Clinical Failure Clinical success Culture-positive on day 3-7 21/57 (37%) 15/40 (38%) Culture-negative on day 3-7 2/66 (3%) P < 0.001 17/253 (7%) P < 0.001 Carlin et al J Pediatr 118:178-83, 1991 Dagan et al Pediatr Infect Dis J 17:776-82, 1998 Clinical vs. Bacteriological Outcome of Children with AOM with Initial Positive MEF Cx

13 otitis/2002/Dagan 0%20%40%60%80%100% Score distribution ≥ 4 2 - 4 0-1 score Day 4-6 64645 Culture (-) (n = 33) 345511 Culture (+) (n = 35) P < 0.001B 0123 TEMPERATURE (ºC) 39.0 IRRITABILITYabsentmildmoderatesevere TUGGING absentmildmoderatesevere REDNESS absentmildmoderatesevere BULGING absentmildmoderatesevere* A * Including draining pus Dagan et al Pediatr Infect Dis J 17:776-82, 1998

14 otitis/2002/Dagan (4) Can we determine by double tap studies if an organism is not important in AOM

15 otitis/2002/Dagan H. Influenzae is deemed by some clinicians/antibiotic manufacturers as being not important, although prevalent, in AOM

16 otitis/2002/Dagan High Dose Amoxicillin (80mg/Kg/d): High Dose Amoxicillin (80mg/Kg/d): MEF Pathogens in Bacteriologic Failure PRSP30% MC2% No. pathogens = 56 No. patients = 43 13 20 4 17 11 Day 1 PSSP7% ßL (+) HI 23% ßL (-) HI 36% GAS2% P=0.04 No. ßL (+) organisms = 14/56 (25%) No. ßL (+) organisms = 9/16 (56%) 8 3 1 4 Day 4-6 No. pathogens = 16 No. patients = 13 PRSP25% ßL (+) HI 50% ßL (-) HI 19% MC6% Leibovitz et al, 40th ICAAC, 2000

17 otitis/2002/Dagan 0123 TEMPERATURE (ºC) 39.0 IRRITABILITYabsentmildmoderatesevere REDNESS absentmildmoderatesevere BULGING absentmildmoderatesevere* * Including draining pus Modified from Dagan et al Pediatr Infect Dis J 17:776-82, 1998 Maximal score = 12 Does NTHi Cause a Less Severe AOM? Clinical score

18 otitis/2002/Dagan Cx (+) 8.21  2.17 7.73  2.32 P = 0.003 n = 762 n = 240 Cx (-) Mean Clinical Score (  SD) Pre-Treatment

19 otitis/2002/Dagan NTHi Pnc NTHi + Pnc NG 8.32  2.19 8.14  2.11 8.06  2.20 7.73  2.32 P = 0.018 n = 392 n = 240 n = 173 n = 198 Mean Clinical Score (  SD) Pre-Treatment

20 otitis/2002/Dagan Mean (  SD) Difference in Total Score Between 1 st & 2 nd Visit P = 0.0001 P = 0.0034 P = 0.13 Failure 5.75  3.08 n=36 5.29  3.14 n=85 n=43 4.79  3.71 Clinical score  NTHi Pnc NTHi + Pnc 44.555.566.577.5 Score Eradication 6.55  2.79 n=143 6.89  2.76 n=254 n=98 6.53  2.93 ∆ between day 1 and day 4-6

21 otitis/2002/Dagan (5) Can we bridge between double tap studies and studies with clinical outcome?

22 otitis/2002/Dagan 0 10 20 30 40 50 60 70 80 90 87% Amox/clav 45mg/Kg 48% Placebo Bacterial eradication rate NTHi Eradication Rate: Amox/Clav (45mg/kg) vs. Azithromycin Dagan et al PIDJ 19:95-104, 2000 39% Azithro 5 days P < 0.001

23 otitis/2002/Dagan Clinical Success: Amox/Clav (45mg/kg) vs. Azithromycin Azithromycin Dagan et al PIDJ 19:95-104, 2000 Hi alone Pnc alone Total Augmentin P=0.023 86 70 % with clinical success 91 65 86 80 P=0.01 8739 9068 8349

24 otitis/2002/Dagan Clinical efficacy in bacterial AOM 20 30 40 50 60 70 80 90 10 0 Bacteriologic efficacy in bacterial AOM Placebo Clinical efficacy in “clinical” AOM % Success Marchant et al, J Pediat 120:72-7, 1992 Clinical Success: Amox/Clav (45mg/kg) vs. Azithromycin Dagan et al PIDJ 19:95-104, 2000 Azithro (65%) Amox/clav - 45mg/Kg (86%) Azithro (80%) Amox/clav - 45mg/Kg (87%) Pnc Hi

25 otitis/2002/Dagan

26 otitis/2002/Dagan Study 1015 (Single Dose Azithro 30 mg/kg) Conducted by Pfizer by Penicillin Susceptibility Clinical efficacy in bacterial AOM 20 30 40 50 60 70 80 90 10 0 Bacteriologic efficacy in bacterial AOM Placebo Clinical efficacy in “clinical” AOM % Success Marchant et al, J Pediat 120:72-7, 1992 Pnc Pen-S (95%) Pnc Pen-I (75%) Pnc Pen-R (67%)

27 otitis/2002/Dagan

28 otitis/2002/Dagan Clinical Success in Studies Conducted by Pfizer by by Pathogens Clinical efficacy in bacterial AOM 20 30 40 50 60 70 80 90 10 0 Bacteriologic efficacy in bacterial AOM Placebo Clinical efficacy in “clinical” AOM % Success Marchant et al, J Pediat 120:72-7, 1992 Single dose - Pnc (88%) 3 days - Pnc (94%) Single dose - Hi (64%) 3 days - Hi (69%)

29 otitis/2002/Dagan (6) How do double tap studies help in understanding the best timing for clinical outcome determination?

30 otitis/2002/Dagan day 1 day 4-6 day 10-12 (EOT) Day 21-30 (TOC) TREATMENT TYMPANOCENTESIS CULTURE a b c

31 otitis/2002/Dagan NG 20 (18%) True bacteriologic relapse 30 (28%) New Infection 58 (54%) Clinical Recurrence After Completion of Rx vs Bacteriologic Relapse Clinical recurrence After bacteriologic eradication N=108 Leibovitz et al, 40th ICAAC, Toronto. 2000

32 otitis/2002/Dagan New Acquisition vs Persistence of Pathogens in Clinical Recurrence of AOM in Relation to Initial AOM Isolate* Pnc  Pnc (n = 38) Hi  Hi (n = 34) * Verified by serotype and PFGE for Pnc and PFGE for Hi RelapseNew Leibovitz et al, 40th ICAAC, Toronto. 2000

33 otitis/2002/Dagan day 1 day 4-6 day 10-12 (EOT) Day 21-30 (TOC) TREATMENT TYMPANOCENTESIS CULTURE a b c

34 otitis/2002/Dagan day 1 day 4-6 TREATMENT TYMPANOCENTESIS CULTURE a b EOT >>>>TOC

35 otitis/2002/Dagan (7) Are the patients that are studied in double tap studies different than those in purely clinical studies?

36 otitis/2002/Dagan Yes, Patients that are Studied in Double Tap Studies Are Different than Those in Pure Clinical Studies Most are < 2yrs of ageMost are < 2yrs of age Tympanic membrane bulging + pusTympanic membrane bulging + pus Positive CxPositive Cx Enriched for more complex AOMEnriched for more complex AOM Otitis proneOtitis prone Recent antibiotic useRecent antibiotic use DCC attendanceDCC attendance Older siblingsOlder siblings geneticsgenetics Patients in whom antibiotics are most needed

37 otitis/2002/Dagan 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

38 otitis/2002/Dagan 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 6)Double tap studies help in understanding that the best timing for clinical outcome determination is EOT rather than TOC 7)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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