# Presentation: 852995

## 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*

## 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

## 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**

## 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***

## 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**

## 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***** **

## 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.

## 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?**

## 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.

## 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.**

## 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?**

## 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**

## 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**

## 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?

## 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?**

## 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?**

## 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**

## 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.**

## 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**

## 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**

## Significant or Not?

- 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

## 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?**