Macrolide-Resistant Streptococcus pneumoniae : What is the Public Health Impact?

1. Macrolide-Resistant Streptococcus pneumoniae:What is the Public Health Impact? John H. Powers, M.D. Lead Medical Officer Antimicrobial Drug Development and Resistance Initiatives Office of Drug Evaluation IV Center for Drug Evaluation and Research U.S. Food and Drug Administration

2. Introduction • Background on drug development for resistant pathogens • Discuss public health implications of macrolide-resistant Streptococcus pneumoniae (MRSP) • characteristics of an organism of public health importance • review data on MRSP related to characteristics • in vitro data • pharmacokinetics and pharmacodynamics • human data on clinical failures

3. Introduction • Two separate questions in today’s meeting • Is Ketek safe and effective? • Should Ketek garner a claim against macrolide-resistant Streptococcus pneumoniae (MRSP)? • First must address whether MRSP is of clinical significance • Several requests but to date no drug sponsor has received an indication for MRSP

4. Background • Several meetings addressing drug development for resistant pathogens • February 2002 advisory committee meeting • November 19-20 workshop with IDSA and PhRMA • Requests to develop list of pathogens for which there is public need for drug development • Public health importance of various organisms would vary over time • changing epidemiology of infections • availability of alternative drug therapies • e.g. penicillin-resistant Staphylococcus aureus

5. Background • Characteristics of organisms of public health importance for drug development 1. incidence/prevalence of organisms in disease 2. virulence of organism in question 3. drug commonly used to treat infection in the population under study 4. availability of alternative therapies for the disease 5. organisms resistant to multiple drug classes 6. drug is essential to prevent spread of organism in population 7. correlation of in vitro resistance with clinical failures

6. Background • Clear cut cases of organisms of public health importance for which indications for resistance claims already granted • methicillin-resistant S. aureus • vancomycin-resistant enterococci • penicillin-resistant Streptococcus pneumoniae • Less clear cut • macrolide-resistant Streptococcus pneumoniae

7. 1. Prevalence • prevalence of MRSP increasing in active surveillance study in invasive isolates from Atlanta from 16% in 1994 to 32% in 1999 • level of ermAM resistance remained stable while majority of increase made up by mefE resistance • MICs for mefE resistant isolates increased from 21% with MIC >8 mcg/mL in 1995 to 94% with >8 mcg/mL and 63% with >16 mcg/mL in 1999 • Gay et al. J Infect Dis 2000:182:1417-24.

8. 1. Prevalence • Raises two related questions: • How is resistance to macrolides defined in vitro? • Is the population with invasive disease the same population that would be treated with oral antimicrobials on an outpatient basis?

9. In vitro resistance • Some controversy over breakpoints for macrolides • pre-1996 NCCLS breakpoints for erythromycin • >1 mcg/mL to <4 mcg/mL for intermediate • >4 mcg/mL for resistant • NCCLS breakpoints post-1996 • 0.5 mcg/mL for intermediate • >1 mcg/mL for resistant • Jorgensen et al J Clin Micro 1996;34:2679-84.

10. In vitro • Arguments for raising breakpoints • incubation or organisms in ambient environments as compare to CO2 lowers MIC by up to two tube dilutions • Gerardo Antimicrob Agents Chemo 1996;40:2413-5. • mixing of 50% human serum in media also lowers MIC by several tube dilutions • Hardy Antimicrob Agents Chemo 1988;32:1710-9 • pharmacokinetics of macrolides which concentrate in WBCs and endothelial lining fluid • Arguments for lowering breakpoints • pharmacodynamic studies in animals • Tessier Antimicrob Agents Chemo 2002;46:1425-34.

11. Populations • Guidelines recommend oral outpatient therapy for patients with mild disease and no comorbidities (PSI class 1 or 2) • Bartlett et al. Clin Infect Dis 2000;31:347-82. • Risk factors for macrolide resistance include age >65 and multiple comorbidities • Ewig et al Am J Resp Crit Care Med 1999;159:1835-42. • Would patient populations who would harbor resistant organisms be appropriate populations to receive oral therapy?

12. 2. Virulence • S. pneumoniae clearly a virulent organism and can cause serious invasive disease • several studies show inverse relationship of invasive disease with antimicrobial resistance • Linnares et al Clin Cinfect Dis 1992;15:99-105. • Pallares et al. N Engl J Med 1995;333:474-80. • Outpatient mortality from community-acquired pneumonia is low • class 1 mortality = 0.1% • class 2 mortality = 0.6% • Fine MJ et al. NEJM 1997;336:243-50

13. 3. Common drug • Macrolides commonly used to treat upper respiratory tract infections and mild-moderately severe community acquired pneumonia (CAP) • Macrolides rarely used as sole therapy to treat severe CAP • 62% of hospitalized patients received cephalosporin plus macrolide • none received a macrolide as sole therapy • Ewig et al. Am J Resp Crit Care Med 1999;159:1835-42. • Macrolides not used to severe sequelae i.e. meningitis

14. 4. Alternative therapies • Some MRSP are also resistant to other drug classes used to treat pneumonia • 15% of MRSP highly resistant to PCN (MIC >2 mcg/mL) • another 19% of MRSP intermediate to PCN • Gay et al. J Infect Dis 2000;182:1417-24. • Data imply that third generation cephalosporins and high dose penicillin may still be effective for many of these organisms • Heffelfinger et al. Arch Intern Med 2000;160:1399-1408. • Are there data to indicate that patients actually fail therapy more often with macrolides for MRSP infection?

15. 5. Cross-resistance to other drug classes • Of PRSP organisms, 48% are MRSP • PRSP also predicts resistance to clindamycin (11.8%), tetracyclines (35.5%) and TMP-SMX (71.1%) • Doern et al. Clin Infect Dis 1998;27:764-70. • Of MRSP, 15 % are PRSP • Are these organisms more correctly called “drug resistant S. pneumoniae” (DRSP) than PRSP? • Does drug activity against PRSP accurately predict activity against MRSP and other forms of resistance as well?

16. 6. Control of Disease in Population • 87% of PRSP isolates are included in 23 valent pneumococcal vaccine • 66% of serotypes included in 7 valent vaccine • Gay et al. J Infect Dis 2000;182:1417-24. • Vaccine may result in decrease in invasive disease • How will this impact of drug resistant disease given inverse relationship of invasiveness and drug resistance?

17. 7. Correlation of In Vitro Results with Clinical Outcomes • Paucity of data on clinical outcomes in patients who receive macrolides for MRSP • Almost no data on diseases other than community acquired pneumonia (CAP) • no reports on patients with acute bacterial sinusitis (ABS) • few reports on patients with acute bacterial exacerbations of chronic bronchitis (AECB) show no increased failures

18. 7. Correlation of In Vitro Results with Clinical Outcomes • Several case reports of failures of macrolide therapy • usually small numbers of cases • retrospective, uncontrolled or case-controlled • some patients were not appropriate for oral therapy • can natural history or other factors explain failures? • Tells us failures do occur but more relevant question is are failures more likely to occur in patients receiving macrolides for MRSP than MSSP? • Complicated by inherent difference in patients harboring resistant organisms (older and more comorbidities) • Kays Diag Micro Infect Dis 2002;43:163-5. • Kelley Clin Infect Dis 2000;31:1008-11. • Lonks Clin Infect Dis 2002;35:556-9.

19. 7. Correlation of In Vitro Results with Clinical Outcomes • Are there reasons why patients with MRSP may still be clinical cures when treated with macrolides? • Concentrations in endothelial lining fluid (ELF) and WBCs exceed serum concentrations • may exceed MIC of mefE mutants • contribution of host immune system in younger patients with no comorbidities who are candidates for oral therapy • according to some authors “clinically relevant” breakpoints for macrolides may be higher than current NCCLS standard

20. 7. Correlation of In Vitro Results with Clinical Outcomes • Are there reasons why patients with MRSP may fail clinically when treated with macrolides? • Concentrations in WBC and ELF may still not be high enough for some isolates, especially ermAM mutants • several reports show poor lung tissue levels of azalides in healthy volunteers despite high ELF concentrations • some studies in immunocompromised animals show failure of bacterial eradication with MRSP treated with macrolides • breakpoint for macrolides based in PD parameters may be lower than current NCCLS standard

21. PRO rising MICs even for mefE mutants macrolides are commonly used for CAP MRSP may be resistant to other drug classes Case reports of clinical failures with MRSP CON mefE most prominent and can dose for cure concentrations in ELF and WBCs exceed MIC for some isolates alternative therapies are available No studies directly evaluating impact of MRSP on outcome Significant or Not?

22. Conclusions • Does the data support granting indications for any drug for MRSP at this point in time? Should this vary depending on indication (e.g. CAP, ABS, AECB) • If so, how would this affect other drugs which have asked for this claim previously? • Would granting claims for MRSP at this time affect physicians prescribing patterns? Is this appropriate as this time? • Does granting an indication for PRSP de facto mean the drug must be effective for MRSP as well?