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Selection of antibiotics for acute otitis media: Application of pharmakokinetic and pharmacodynamic principles

Selection of antibiotics for acute otitis media: Application of pharmakokinetic and pharmacodynamic principles. Michael R. Jacobs, MD, PhD Professor of Pathology Case Western Reserve University Director of Clinical Microbiology University Hospitals of Cleveland Cleveland, OH. 60. 50.

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Selection of antibiotics for acute otitis media: Application of pharmakokinetic and pharmacodynamic principles

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  1. Selection of antibiotics for acute otitis media: Application of pharmakokinetic and pharmacodynamic principles Michael R. Jacobs, MD, PhD Professor of Pathology Case Western Reserve University Director of Clinical Microbiology University Hospitals of Cleveland Cleveland, OH

  2. 60 50 Resistant MIC > 2.0 g/ml Intermediate MIC = 0.12–1.0 g/ml 40 33 29 34 30 % Penicillin resistant 25 3 8 20 10 8 7 10 17 6 16 15 5 5 14 13 13 4 3.8 11 3 2 2 0 1979 1980 1981 1982 1983 1984 1985 1986 1987 1997 1998 1999 2000 1988–89 1990–91 1992–93 1994–95 Year S. pneumoniae Penicillin SusceptibilityUnited States 1979–20001–4 1. Doern GV. Am J Med 1995; 99(suppl 6B):3S–7S. 2. Jacobs MR et al. Antimicrob Agents Chemother 1999; 43:1901–1908. 3. Jacobs MR et al. ICAAC 1999, poster C-61. 4. Jacobs MR. USA Alexander Project data 2000

  3. Temporal Trends in Macrolide Resistance Among Invasive Streptococcus pneumoniae Isolates and Macrolide Use USA 1993-1999 Hyde, TB, et al. JAMA 2001; 286: 1857-1862

  4. Agent MIC90 (ug/ml) % Susceptible* 1973-85 1995-98 1973-85 1995-98 Amoxicillin .03 2 100 91 Amox-clav .03 2 100 92 Cefuroxime .5 >4 100 54 Cefprozil .5 16 100 55 Clarithromycin .03 >2 98 63 Azithromycin .12 >4 98 63 S. pneumoniae: susceptibility of middle ear fluid isolates in two time periods* *Based on PK/PD breakpoints Jacobs M PIDJ 2000;19:S 47 1973-85: N=50; 1995-98: N=440

  5. Agent MIC90 (ug/ml) % Susceptible* 1973-85 1995-98 1973-85 1995-98 Amoxicillin >8 >8 84 54 Amox-clav .5 1 100 97 Cefuroxime 1 2 94 76 Cefprozil 8 16 6 14 Clarithomycin 16 16 2 0 Azithromycin 2 2 2 0 H. influenzae: susceptibility of middle ear fluid isolates in two time periods* *Based on PK/PD breakpoints Jacobs M PIDJ 2000;19:S 47 1973-85: N=50; 1995-98: N=271

  6. Acute otitis media studies in children

  7. The role of antibacterials is to eradicate the causative organisms from the site of infection Dagan R. Personal communication

  8. Outpatient clinical studies in respiratory tract infections • High rate of spontaneous resolution makes it difficult to show clinical differences between agents • Bacteriologic outcome studies are not often performed due to necessity for invasive procedure (ear, sinus or lung tap) to obtain specimen • Most studies are therefore designed to show “equivalent” clinical outcome between established and new agents • Inadequacies of agents studied are therefore often not apparent Marchant C. et al. J Pediatr 1992; 120:72–77.

  9. Sample sizes required to detect differences between antibacterial drugs for acute otitis mediaComparison of bacteriologic vs clinical outcomes in trials of two drugs (half the patients would be in each arm of a study) Marchant C. et al. J Pediatr 1992; 120:72–77.

  10. Azithromycin in AOM: clinical outcome at end of therapy studies • Four studies using a common comparator were compared1-4 • Study designs differed • two were clinical diagnosis and outcome1,3 • one was bacteriologic diagnosis, clinical outcome2 • one was bacteriologic diagnosis and outcome4 • Patient ages in these studies differed: the first three were 0.5–15 years old (mean 4–6 years), while the fourth was 0.5-4 years (mean 1.3 years) • Sample sized required for studies to be powered to show differences between agents were determined based on calculations published by Marchant et al.5 1McLinn S. et al. Pediatr Infect Dis J 1996; 15, supp1: S3–9 2Aronovitz G. et al. Pediatr Infect Dis J 1996; 15, supp1: S15–19 3Khurana C.et al. Pediatr Infect Dis J 1996; 15, supp1: S24–29 4Dagan R. et al. Pediatr Infect Dis J 2000; 19:95–104 5Marchant C. et al. J Pediatr 1992; 120:72–77

  11. Azithromycin in AOM: clinical outcome at end of treatment Comparator Azithro Mean age (range) years ? (1-15) 4.0 (2-15) 5.7 (0.5-12) 1.3 (0.5-4) N evaluable at EOT 553 (82%) 92 (54%) 444 (84%) 143 (60%) P value for clin. outcome 0.64 0.10 0.42 0.023 No. of patients needed to show: 60% vs 90% bact. efficacy 2000 800 2000 800 clin/100 bact 30% vs 90% bact. efficacy 542 234 542 100 clin/30 bact

  12. Using pharmacokinetics and pharmacodynamics to predict bacterial efficacy

  13. Evaluating antibacterial efficacy using pharmacokinetics and pharmacodynamics • Pharmacokinetics (PK) • serum concentration profile • penetration to site of infection • Pharmacodynamics (PD) • susceptibility – MIC (potency) • concentration- vs time-dependent killing • persistent (post-antibiotic) effects (PAE)

  14. Patterns of antibacterial activity PatternPharmacodynamic correlate Time-dependent killing Time above MIC and minimal to moderate (T > MIC) persistent effects Time-dependent killing AUC/MIC ratio and prolonged persistent effects Concentration-dependent AUC/MIC ratio killing and prolonged or persistent effects Peak/MIC ratio

  15. Relationship between time above MIC and efficacy in animal infection models infected with S. pneumoniae 100 Penicillins Cephalosporins 80 60 Mortality after 4 days of therapy (%) 40 20 0 0 20 40 60 80 100 Time serum conc. is above MIC (%) Craig W. Diagn Microbiol Infect Dis 1996; 25:213–217.

  16. 100 80 Bacterial eradication day 4-6 of therapy (%) Spontaneous resolution of H. influenzae* 60 PSSP PISP-PRSP 40 H. influenzae Spontaneous resolution of S. pneumoniae* 20 0 0 20 40 60 80 100 Time serum conc. is above MIC (% of dosing interval) Relationship between time above MIC and bacterial eradication with -lactams in otitis media Craig W., Andes D. Pediatr Infect Dis J 1996; 15:255–259. Dagan R. et al. studies *Howie, V. Clin Pediatr 1972, 11:205-214].

  17. 34/34 35/38 76/79 30/30 28/30 40/75†‡ 19/30 10/28† 17/75† Azithromycin therapy Microbiologic outcome of middle ear fluid in experimental acute otitis media in chinchillas due to non-typeable Hemophilus influenzaeF E Babl, S I Pelton, Z Li. Experimental Acute Otitis Media Due to Non-typable Haemophilus Influenzae: Comparison of High and Low Dose Azithromycin with Placebo. Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Canada, August 2000 and submitted for publication † ‡ † † * Number of ears; denominator changes due to  in # of animals † p<0.05 Rx vs. placebo ‡ p<0.05 30 vs. 120 mg/kg

  18. Median CFU by treatment group inmiddle ear fluid in experimental acute otitis media in chinchillas due to non-typeable Hemophilus influenzae F E Babl, S I Pelton, Z Li. Experimental Acute Otitis Media Due to Non-typable Haemophilus Influenzae: Comparison of High and Low Dose Azithromycin with Placebo. Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Canada, August 2000 and submitted for publication Azithromycin therapy † p<0.05 Rx vs. placebo ‡ p<0.05 30 vs. 120 mg/kg † † †‡ †

  19. 100 10 H. Influenzae MIC90 2 g/mL 1 Concentration (g/mL or g/g) 0.1 Plasma: 50 mg/kg Single doseLung: 50 mg/kg Single dosePlasma: 50 mg/kg Multiple doseLung: 50 mg/kg Multiple dose 0.01 0.001 0 4 8 12 16 20 24 Hours after dose Azithromycin concentrations in plasma and lung after single and multiple 50 mg/kg oral dosing in rats. These levels are about twice those achieved in humans Adapted from Mitten M. et al. Antimicrob Agents Chemother 2001; 45: 2585–2593.

  20. 100 10 1 Concentration (g/mL or g/g) 0.1 Plasma: 50 mg/kg Single doseLung: 50 mg/kg Single dosePlasma: 50 mg/kg bid Multiple doseLung: 50 mg/kg bid Multiple dose 0.01 0.001 0 4 8 12 16 20 24 Hours after dose Clarithromycin concentrations in plasma and lung after single and multiple 50 mg/kg oral dosing in rats. These levels are about twice those achieved in humans H. Influenzae MIC90 16 g/mL Adapted from Mitten M. et al. Antimicrob Agents Chemother 2001; 45: 2585–2593.

  21. AZI, CLARI approved human dosing provides PK similar to approx. 25 mg/kg/d in this model S. pneumoniae and H. influenzae pneumonia in rats:ED50 based on 3 log10 reduction in cfu/lung MIC (g/ml) Adapted from Mitten et al. Antimicrob Agents Chemother 2001; 45: 2585–2593

  22. S. pneumoniae and H. influenzae pneumonia in rats:ED50 based on 3 log10 reduction in cfu/lung H. influenzae Macrolide resistant S. pneumoniae (efflux) Macrolide susceptible S. pneumoniae ED50 of macrolide resistant (ribosomal methylase) S. pneumoniae: >100 mg/kg/d MIC (g/ml) Adapted from Mitten et al. Antimicrob Agents Chemother 2001; 45: 2585–2593

  23. S. pneumoniae and H.influenzae pneumonia in rats:ED50 based on  3 log10 reduction in cfu/lung At dosing comparable to dosing in humans: • Azithromycin and clarithromycin were able to reduce inoculum by  3 log10 cfu/lung for macrolide susceptible S. pneumoniae • Azithromycin and clarithromycin were NOT able to reduce inoculum by  3 log10 cfu/lung for H influenzae or for macrolide non-susceptible S. pneumoniae (erm and mef mechanisms) Mitten M. et al. Antimicrob Agents Chemother 2001; 45: 2585–2593.

  24. Macrolide R (ermB): MIC90 ≥ 32 g/mL; AUC:MIC ratio < 0.1 Macrolide R (mefE): MIC90 = 8 g/mL; AUC:MIC ratio 0.4 Haemophilus: MIC90 = 1 g/mL; AUC:MIC ratio = 3 PK/PD bkpt. 0.12 g/mL M. cat: MIC90 = 0.12 g/mL Macrolide S: MIC90 = 0.06 g/mL; AUC:MIC ratio = 50 Azithromycin10 mg/kg day 1; 5 mg/kg d 2–5 32 16 8 4 2 Serum conc.(g/mL) 1 0.5 AUC = 3 mg.h/L 0.25 0.12 0.06 12 hr 24 hr 0 Adapted from Drusano G. et al. J Chemother 1997; 9(suppl 3):38–44.

  25. NCCLS*PK/PD + S. pneumoniae H. influenzaeALL ORGANISMS Amoxicillin 2 –2 Amox/clav 2 4 2 Cefuroxime axetil 1 4 1 Cefdinir 0.5 1 0.5 Cefprozil 2 8 1 Cefixime – 1 0.5 Cefaclor 1 8 0.5 Loracarbef 2 8 0.5 Azithromycin 0.5 4 0.12 Clarithromycin 0.25 8 0.25 Pharmacodynamic vs NCCLSbreakpoints (µg/mL) *M100-S11, National Committee for Clinical Laboratory Standards, 2001. +Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32.

  26. Susceptibility of Isolates at PK/PD and NCCLS breakpoints Percentage of strains susceptible Agent S. pneumoniae H. influenzae M. catarrhalis Amox/clav90 97 100 Amoxicillin 90 61 14 Cefaclor 27 2 5 Cefixime 57 99 100 Cefpodoxime 63 99 64 Cefprozil 64 18 6 Cefuroxime 64 79 37 Cefdinir‡ 61 97 100 Azithromycin 67 0 100 Clindamycin* 89 NA NA Doxycycline 76 20 96 Levofloxacin99.8 100 99 TMP/SMX* 57 75 9 90 100 NA 90 63 NA 46 82 NA 55 100 NA 63 100 NA 67 86 NA 65 98 NA 61 99 NA 68 97 NA 89 NA NA 76 NA NA 99.8 100 NA 57 75 NA Based on M100-S11, National Committee for Clinical Laboratory Standards, 2001; Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32. ‡Jacobs M. (unpublished)

  27. NCCLS* PK/PD+ Bkpt %S Bkpt %S Amoxicillin 2 90 2 90 Amoxicillin/clav 2 90 2 90 Clindamycin 0.25 89 NA NA S. pneumoniae: oral agents approved or recommended for AOM with 90% of recent US strains susceptible at NCCLS orPK/PD breakpoints (µg/mL) *M100-S11, National Committee for Clinical Laboratory Standards, 2001. +Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32.

  28. NCCLS* PK/PD+ Bkpt %S Bkpt %S Amoxicillin/clav 4 100 2 97 Cefdinir‡ 1 99 0.5 97 Cefixime 1 100 0.5 100 Cefpodoxime 2 100 0.5 99 Cefuroxime axetil 4 98 1 80 Cefprozil 8 86 1 18 Loracarbef 8 90 0.5 10 Azithromycin 4 97 0.12 0 H. influenzae: oral agents approved or recommended for AOM with 90% of recent US strains susceptible at NCCLS orPK/PD breakpoints (µg/mL) *M100-S11, National Committee for Clinical Laboratory Standards, 2001. +Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32. ‡ Data from Jacobs M. (unpublished).

  29. MIC that includes 90% of H. influenzae MIC that includes 90% of S. pneumoniae Azithromycin MICs(S. pneumoniae and H. influenzae) Jacobs et al. ICAAC 1999 poster C-61.

  30. Efficacy animal models equivalent to current dosing Efficacy in animal models equivalent to 4X current dosing PK/PD breakpoint based on current approved dosing Azithromycin MICs(S. pneumoniae and H. influenzae) Jacobs et al. ICAAC 1999 poster C-61.

  31. Conclusions: Antibacterial choice for empiric use in acute otitis media • Most clinical studies are too small to show clinical differences between agents • PK/PD parameters correlate with bacteriological and clinical outcome in animal models and in humans, and can be used to select agents with maximum potential for bacterial eradication • Currently available agents vary significantly in achieving PK/PD parameters necessary for bacterial eradication • Few oral agents approved for pediatric use are active against 90% of current US strains of the key otitis media pathogens at approved dosing regimens • Bacteriologic outcome studies in children and animal studies have repeatedly validated these conclusions

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