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

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

8. Drug Pharmacokinetics in blood Serum Antibiotic Concentration 0 2 4 6 8 10 012345678 Time (hours) (mcg/mL) 9 10 11 12 Dose

9. Pharmacokinetic Parameters Serum Antibiotic Concentration 0 2 4 6 8 10 012345678 Time (hours) (mcg/mL) 9 10 11 12 Dose Concentration present for 50% of dosing interval (6 h if given q12h) Area under curve Peak serum conc.

10. 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 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. 020406080100 0 20 40 60 80 100 Time above MIC (%) Penicillins Cephalosporins Mortality after 4 days of therapy (%) Craig. Diagn Microbiol Infect Dis 1996; 25:213–217 Relationship between Time above MIC and efficacy in animal infection models infected with S. pneumoniae

13. 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 24-hr AUC/MIC and Peak/MIC Ratios Correlation of serum pharmacokinetics with MIC (susceptibility) of an organism Area under the curve to MIC ratio Peak to MIC ratio

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

15. At dosing comparable to dosing in humans: Azithromycin and clarithromycin were able to reduce inoculum by  3 log 10 cfu/lung for macrolide susceptible S. pneumoniae Azithromycin and clarithromycin were NOT able to reduce inoculum by  3 log 10 cfu/lung for H influenzae or for macrolide non-susceptible S. pneumoniae (erm and mef mechanisms) S. pneumoniae and H. influenzae pneumonia in rats: ED 50 based on  3 log 10 reduction in cfu/lung Mitten M. et al. Antimicrob Agents Chemother 2001; 45 : 2585–2593.

16. “After administration of azithromycin at 30 mg/kg as single daily doses in our chinchilla model of EOM due to NTHI, we were able to achieve levels in serum and AUCs approximately twice those observed in children treated with 10 mg/kg or with 10, 5, 5, 5, and 5 mg/kg as single daily doses and concentrations in MEF comparable to those reported for children with AOM. Our observations provide evidence that current doses of azithromycin administered to children are likely to have a modest antibacterial effect on AOM due to NTHI, characterized by a reduction in density of infection. Maximizing the dosing of azithromycin in children has 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 Microbiologic outcome of middle ear fluid in experimental acute otitis media in chinchillas due to non-typeable Haemophilus influenzae (NTHI)

17. Relationship between Time above MIC and bacterial eradication with  - lactams in otitis media 20 40 60 80 100 Time above MIC (% of dosing interval) 020406080100 Bacterial eradication (%) 0 PSSP PISP-PRSP H. influenzae Craig & Andes, Pediatr Infect Dis J, 1996 Dagan et al studies

18. Relationship between Time above MIC and bacterial eradication with  - lactams in maxillary sinusitis Craig & Andes, Pediatr Infect Dis J, 1996 Gwaltney & Scheld studies 20 40 60 80 100 Time above MIC (% of dosing interval) 020406080100 Bacterial eradication (%) 0 PSSP H. influenzae

19. Clinical failure rate 43%11.5% 1% Levofloxacin PK/PD correlations 134 hospitalized patients with respiratory tract, skin or complicated urinary tract infections treated with 500 mg qd for 5–14 days Jacobs. Clin Microbiol Infect 2001;7:589–96 [Adapted from Preston et al. JAMA 1998;279:125–9] 4 3 23 3 100 1 0 10 20 30 40 50 60 70 80 90 100 No. of patients AUC:MIC <25 Peak:MIC <3 AUC:MIC 25–100 Peak:MIC 3–12 AUC:MIC >100 Peak:MIC >12 Success Failure Clinical outcome

20. PK/PD breakpoint ALL ORGANISMS Amoxicillin2 Amox/clav2 Cefuroxime axetil1 Cefprozil1 Cefixime0.5 Cefaclor 0.5 Loracarbef 0.5 Azithromycin0.12 Clarithromycin0.25 Pharmacodynamic breakpoints (µg/ml) for oral agents used for RTIs

21. NCCLSPK/PD S. pneumoniae H. influenzaeALL ORGANISMS Amoxicillin242 Amox/clav242 Cefuroxime axetil141 Cefprozil281 Cefixime–10.5 Cefaclor 180.5 Loracarbef 280.5 Azithromycin0.540.12 Clarithromycin0.2580.25 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/clav9097100 Amoxicillin906114 Cefaclor2725 Cefixime5799100 Cefpodoxime639964 Cefprozil64186 Cefuroxime647937 Cefdinir ‡ 6197100 Azithromycin670100 Clindamycin*89NANA Doxycycline762096 Levofloxacin99.810099 TMP/SMX*57759 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. Amoxicillin-clavulanate Alexander Project USA 2000 PK/PD breakpoint based on current approved dosing regimens Susceptible breakpoint NCCLSPK/PD S. pneumoniae H. influenzaeALL ORGANISMS Amoxicillin242 Amox/clav242

24. Cefaclor Alexander Project USA 2000 PK/PD breakpoint based on current approved dosing regimens Susceptible breakpoint NCCLSPK/PD S. pneumoniae H. influenzaeALL ORGANISMS Cefaclor 180.5

25. Cefuroxime axetil Alexander Project USA 2000 PK/PD breakpoint based on current approved dosing regimens Susceptible breakpoint NCCLSPK/PD S. pneumoniae H. influenzaeALL ORGANISMS Cefuroxime axetil141

26. Cefprozil Alexander Project USA 2000 PK/PD breakpoint based on current approved dosing regimens Susceptible breakpoint NCCLSPK/PD S. pneumoniae H. influenzaeALL ORGANISMS Cefprozil281

27. Cefixime Alexander Project USA 2000 PK/PD breakpoint based on current approved dosing regimens Susceptible breakpoint NCCLSPK/PD S. pneumoniae H. influenzaeALL ORGANISMS Cefixime–10.5

28. Azithromycin Alexander Project USA 2000 PK/PD breakpoint based on current approved dosing regimens Susceptible breakpoint NCCLSPK/PD S. pneumoniae H. influenzaeALL ORGANISMS Azithromycin0.540.12

29. Clarithromycin Alexander Project USA 2000 PK/PD breakpoint based on current approved dosing regimens Susceptible breakpoint NCCLSPK/PD S. pneumoniae H. influenzaeALL ORGANISMS Clarithromycin0.2580.25

30. Clindamycin Alexander Project USA 2000 PK/PD breakpoint based on current approved dosing regimens Susceptible breakpoint NCCLSPK/PD S. pneumoniae H. influenzaeALL ORGANISMS Clindamycin0.25NA0.25

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

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

33. Ciprofloxacin Alexander Project USA 2000 PK/PD breakpoint based on current approved dosing regimens Susceptible breakpoint NCCLSPK/PD S. pneumoniae H. influenzaeALL ORGANISMS ClarithromycinNA11

34. Levofloxacin Alexander Project USA 2000 PK/PD breakpoint based on current approved dosing regimens Susceptible breakpoint NCCLSPK/PD S. pneumoniae H. influenzaeALL ORGANISMS Levofloxacin222

35. Trimethoprim-sulfamethoxazole Alexander Project USA 2000 PK/PD breakpoint based on current approved dosing regimens Susceptible breakpoint NCCLSPK/PD S. pneumoniae H. influenzaeALL ORGANISMS Trimeth-sulfa0.50.50.5

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?