Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Micr

1. Application of Pharmacokinetic and Pharmacodynamic Principles to Otitis Media and other Respiratory Tract Infections Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of Cleveland Cleveland, OH

2. Limitations of outpatient clinical studies in respiratory tract infections • High-rate spontaneous resolution makes it difficult to show 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 Jacobs. Clin Microbiol Infect 2001;7:589–96

3. 1977 FDA Guidance on AOM “In the absence of culture of middle ear fluid, no specific claim can be made regarding the effectiveness of any anti-infective drug”

4. Objectives • Define pharmacokinetics and pharmacodynamics • Correlate serum pharmacokinetic parameters for various drug classes with outcome of infection in outpatient respiratory tract infections • Show examples of these correlations in animal models and in humans • Apply these principles to treatment of otitis media and other respiratory tract infections

5. Impact of limited clinical data and increasing pathogen resistance on choice of antibacterial therapy • There is a need for: • accurate prediction of efficacy • newer dosage regimens • newer antibacterials • revised susceptibility breakpoints • statistically valid clinical studies Jacobs. Clin Microbiol Infect 2001;7:589–96

6. 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) Jacobs. Clin Microbiol Infect 2001;7:589–96

7. Pharmacokinetics Oral ingestion Extracellular compartment of tissues Blood Renal excretion GI Absorption

8. 10 8 Serum Antibiotic Concentration 6 (mcg/mL) 4 2 0 9 11 0 1 2 3 4 5 6 7 8 12 10 Dose Dose Time (hours) Drug Pharmacokinetics in blood

9. Concentration present for 50% of dosing interval (6 h if given q12h) 10 Area under curve 8 Serum Antibiotic Concentration 6 (mcg/mL) 4 2 0 9 11 0 1 2 3 4 5 6 7 8 12 10 Dose Dose Peak serum conc. Time (hours) Pharmacokinetic Parameters

10. Patterns of antibacterial activity Pattern Pharmacodynamic 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 Jacobs. Clin Microbiol Infect 2001;7:589–96

11. Time Above MIC: -Lactams • T>MIC (% of dosing interval) required for the static dose against most organisms in neutropenic mice vary from 25-35% for penicillins and from 30-45% for cephalosporins • The presence of neutrophils reduces the T>MIC required for efficacy by 5-10% • Free drug levels of penicillins and cephalosporins need to exceed the MIC for 35-50% of the dosing interval to produce maximum survival

12. 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 above MIC (%) Craig. Diagn Microbiol Infect Dis 1996; 25:213–217

13. Area under the curve to MIC ratio Peak to MIC ratio 24-hr AUC/MIC and Peak/MIC RatiosCorrelation of serum pharmacokinetics with MIC (susceptibility) of an organism Antibiotic concentration MIC Time 24-hr AUC/MIC is correlated with outcome of infection, the magnitude required for success and MIC at which this occurs becomes the PD breakpoint

14. Relationship between 24 Hr AUC/MIC and mortality for fluoroquinolones against S. pneumoniae in immunocompetent animals 100 80 60 Mortality (%) 40 20 0 100 1 2.5 5 10 25 50 24-hr AUC/MIC

15. 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.

16. Microbiologic outcome of middle ear fluid in experimental acute otitis media in chinchillas due to non-typeable Haemophilus influenzae (NTHI) “After administration of azithromycin at 30 mg/kg as single dailydoses in our chinchilla model of EOM due to NTHI, we were ableto achieve levels in serum and AUCs approximately twice thoseobserved in children treated with 10 mg/kg or with 10, 5, 5,5, and 5 mg/kg as single daily doses and concentrationsin MEF comparable to those reported for children with AOM. Ourobservations provide evidence that current doses of azithromycinadministered to children are likely to have a modest antibacterialeffect on AOM due to NTHI, characterized by a reduction in densityof infection. Maximizing the dosing of azithromycin in childrenhas the potential to improve the microbiologic outcome.” Franz E. Babl, Stephen I. Pelton, and Zhong Li. Experimental Acute Otitis Media Due to Nontypeable Haemophilus influenzae: Comparison of High and Low Azithromycin Doses with Placebo. Antimicrobial Agents and Chemotherapy, 2002, 46:2194-2199

17. 100 80 60 Bacterial eradication (%) 40 PSSP PISP-PRSP 20 H. influenzae 0 0 20 40 60 80 100 Time above MIC (% of dosing interval) Relationship between Time above MIC and bacterial eradication with -lactams in otitis media Craig & Andes, Pediatr Infect Dis J, 1996 Dagan et al studies

18. 100 80 60 Bacterial eradication (%) 40 PSSP 20 H. influenzae 0 0 20 40 60 80 100 Time above MIC (% of dosing interval) Relationship between Time above MIC and bacterial eradication with -lactams in maxillary sinusitis Craig & Andes, Pediatr Infect Dis J, 1996 Gwaltney & Scheld studies

19. Levofloxacin PK/PD correlations134 hospitalized patients with respiratory tract, skin or complicated urinary tract infections treated with 500 mg qd for 5–14 days 100 100 Clinical outcome 90 80 Success 70 60 Failure 50 No. of patients 40 23 30 20 4 3 3 1 10 0 AUC:MIC <25 AUC:MIC 25–100 AUC:MIC >100 Peak:MIC <3 Peak:MIC 3–12 Peak:MIC >12 Clinical failure rate 43% 11.5% 1% Jacobs. Clin Microbiol Infect 2001;7:589–96 [Adapted from Preston et al. JAMA 1998;279:125–9]

20. PK/PD breakpoint ALL ORGANISMS Amoxicillin 2 Amox/clav 2 Cefuroxime axetil 1 Cefprozil 1 Cefixime 0.5 Cefaclor 0.5 Loracarbef 0.5 Azithromycin 0.12 Clarithromycin 0.25 Pharmacodynamic breakpoints (µg/ml) for oral agents used for RTIs

21. NCCLS PK/PD S. pneumoniae H. influenzaeALL ORGANISMS Amoxicillin 2 4 2 Amox/clav 2 4 2 Cefuroxime axetil 1 4 1 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. NCCLS breakpoints (values in µg/ml) 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.

22. Susceptibility of US Isolates at PK/PD breakpoints Percentage of strains susceptible Agent S. pneumoniae H. influenzae M. catarrhalis Amox/clav 9097 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 Levofloxacin 99.8100 99 TMP/SMX* 57 75 9 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)

23. PK/PD breakpoint based on current approved dosing regimens Amoxicillin-clavulanate Susceptible breakpointNCCLS PK/PD S. pneumoniae H. influenzaeALL ORGANISMS Amoxicillin 2 4 2 Amox/clav 2 4 2 Alexander Project USA 2000

24. PK/PD breakpoint based on current approved dosing regimens Cefaclor Susceptible breakpointNCCLS PK/PD S. pneumoniae H. influenzaeALL ORGANISMS Cefaclor 1 8 0.5 Alexander Project USA 2000

25. PK/PD breakpoint based on current approved dosing regimens Cefuroxime axetil Susceptible breakpointNCCLS PK/PD S. pneumoniae H. influenzaeALL ORGANISMS Cefuroxime axetil 1 4 1 Alexander Project USA 2000

26. PK/PD breakpoint based on current approved dosing regimens Cefprozil Susceptible breakpointNCCLS PK/PD S. pneumoniae H. influenzaeALL ORGANISMS Cefprozil 2 8 1 Alexander Project USA 2000

27. PK/PD breakpoint based on current approved dosing regimens Cefixime Susceptible breakpointNCCLS PK/PD S. pneumoniae H. influenzaeALL ORGANISMS Cefixime – 1 0.5 Alexander Project USA 2000

28. PK/PD breakpoint based on current approved dosing regimens Azithromycin Susceptible breakpointNCCLS PK/PD S. pneumoniae H. influenzaeALL ORGANISMS Azithromycin 0.5 4 0.12 Alexander Project USA 2000

29. PK/PD breakpoint based on current approved dosing regimens Clarithromycin Susceptible breakpointNCCLS PK/PD S. pneumoniae H. influenzaeALL ORGANISMS Clarithromycin 0.25 8 0.25 Alexander Project USA 2000

30. PK/PD breakpoint based on current approved dosing regimens Clindamycin Susceptible breakpointNCCLS PK/PD S. pneumoniae H. influenzaeALL ORGANISMS Clindamycin 0.25 NA 0.25 Alexander Project USA 2000

31. PK/PD breakpoint based on current investigational dosing regimens Telithromycin Susceptible breakpointNCCLS PK/PD S. pneumoniae H. influenzaeALL ORGANISMS Telithromycin ? ? 0.5 Nagai AAC 2002, 46:371-7; Pankuch AAC 1998, 42:3032-34

32. PK/PD breakpoint based on current approved dosing regimens Doxycycline Susceptible breakpointNCCLS PK/PD S. pneumoniae H. influenzaeALL ORGANISMS Doxycycline ? ? 0.25 Alexander Project USA 2000

33. PK/PD breakpoint based on current approved dosing regimens Ciprofloxacin Susceptible breakpointNCCLS PK/PD S. pneumoniae H. influenzaeALL ORGANISMS Clarithromycin NA 1 1 Alexander Project USA 2000

34. PK/PD breakpoint based on current approved dosing regimens Levofloxacin Susceptible breakpointNCCLS PK/PD S. pneumoniae H. influenzaeALL ORGANISMS Levofloxacin 2 2 2 Alexander Project USA 2000

35. PK/PD breakpoint based on current approved dosing regimens Trimethoprim-sulfamethoxazole Susceptible breakpointNCCLS PK/PD S. pneumoniae H. influenzaeALL ORGANISMS Trimeth-sulfa 0.5 0.5 0.5 Alexander Project USA 2000

36. Conclusions: antibacterial choice for empiric use in RTI • Most clinical studies do not show clinical differences between agents • PK/PD parameters correlate with bacteriological and clinical outcome in animal models and in humans • PK/PD parameters 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

37. 1977 FDA Guidance on AOM “In the absence of culture of middle ear fluid, no specific claim can be made regarding the effectiveness of any anti-infective drug”

38. New FDA Guidance on AOM • Do we admit there is a problem? • What does it take to fix the problem? • Will we fix the problem? • When will this be achieved?