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

otitis/2002/Dagan day 1 day 4-6 day Day TREATMENT CULTURE TYMPANOCENTESIS a b

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

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) *

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 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)

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

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: , 1997 Dagan et al AAC 44:43-50, 2000 Dagan et al AAC 44:43-50, Pnc - S 4/412/ Pnc - I, R 18/294/ Hi 34/85 7/46 Pncn=111 Hin=131

otitis/2002/Dagan 0 0/280 0/ 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/ /12 Leiberman et al, Pediatr Infect Dis, 20:260-4, 2001

otitis/2002/Dagan 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, days ( Dagan et al AAC 44:43-50, 2000) 5 days ( Dagan et al PIDJ 19:95-104, 2000) 0 8 <= /122/ > 2.0 6/65/ /911/ /3611/

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

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

otitis/2002/Dagan Clinical Failure Clinical success Culture-positive on day /57 (37%) 15/40 (38%) Culture-negative on day 3-7 2/66 (3%) P < /253 (7%) P < 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

otitis/2002/Dagan 0%20%40%60%80%100% Score distribution ≥ score Day Culture (-) (n = 33) 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

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

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

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 = 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%) Day 4-6 No. pathogens = 16 No. patients = 13 PRSP25% ßL (+) HI 50% ßL (-) HI 19% MC6% Leibovitz et al, 40th ICAAC, 2000

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

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

otitis/2002/Dagan NTHi Pnc NTHi + Pnc NG 8.32     2.32 P = n = 392 n = 240 n = 173 n = 198 Mean Clinical Score (  SD) Pre-Treatment

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

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

otitis/2002/Dagan % 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, % Azithro 5 days P < 0.001

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= % with clinical success P=

otitis/2002/Dagan Clinical efficacy in bacterial AOM 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

otitis/2002/Dagan

otitis/2002/Dagan Study 1015 (Single Dose Azithro 30 mg/kg) Conducted by Pfizer by Penicillin Susceptibility Clinical efficacy in bacterial AOM 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%)

otitis/2002/Dagan

otitis/2002/Dagan Clinical Success in Studies Conducted by Pfizer by by Pathogens Clinical efficacy in bacterial AOM 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%)

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

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

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

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

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

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

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

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

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

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