MacrolideResistant Streptococcus pneumoniae: What is the Public Health Impact

1
Macrolide-Resistant Streptococcus
pneumoniaeWhat 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

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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

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Introduction

• Two separate questions in todays 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

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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

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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

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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

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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 20001821417-24.

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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?

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In vitro resistance

• Some controversy over breakpoints for macrolides
• pre-1996 NCCLS breakpoints for erythromycin
• 1 mcg/mL to
• 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 1996342679-84.

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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 1996402413-5.
• mixing of 50 human serum in media also lowers
  MIC by several tube dilutions
• Hardy Antimicrob Agents Chemo 1988321710-9
• pharmacokinetics of macrolides which concentrate
  in WBCs and endothelial lining fluid
• Arguments for lowering breakpoints
• pharmacodynamic studies in animals
• Tessier Antimicrob Agents Chemo 2002461425-34.

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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 200031347-82.
• Risk factors for macrolide resistance include age
  65 and multiple comorbidities
• Ewig et al Am J Resp Crit Care Med
  19991591835-42.
• Would patient populations who would harbor
  resistant organisms be appropriate populations to
  receive oral therapy?

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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 19921599-105.
• Pallares et al. N Engl J Med 1995333474-80.
• Outpatient mortality from community-acquired
  pneumonia is low
• class 1 mortality 0.1
• class 2 mortality 0.6
• Fine MJ et al. NEJM 1997336243-50

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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
  19991591835-42.
• Macrolides not used to severe sequelae i.e.
  meningitis

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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 20001821417-24.
• 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
  20001601399-1408.
• Are there data to indicate that patients actually
  fail therapy more often with macrolides for MRSP
  infection?

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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 199827764-70.
• 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?

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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 20001821417-24.
• Vaccine may result in decrease in invasive
  disease
• How will this impact of drug resistant disease
  given inverse relationship of invasiveness and
  drug resistance?

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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

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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 200243163-5.
• Kelley Clin Infect Dis 2000311008-11.
• Lonks Clin Infect Dis 200235556-9.

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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

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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

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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

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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?