U.S. Food and Drug Administration

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U.S. Food and Drug Administration

• Notice Archived Document
• The content in this document is provided on the
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  maintained and may be outdated.

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Importance of Macrolides in Human Medicine

• John H. Powers, MD
• 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 macrolide antimicrobials
• Background on ranking process of importance of
  antimicrobials in human medicine
• Ranking process applied to macrolides
• Uses of macrolides in human medicine

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Macrolides

• Erythromycin derived in 1952 from strain of
  Streptomyces erythreus from soil in Philippines
• Structure
• 14-membered macrocyclic lactone ring
• Related azalide class has 15-membered ring
• FDA approved drugs
• erythromycin
• clarithromycin
• azithromycin
• dirithromycin
• telithromycin

Structure of erythromycin
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Importance of Antimicrobials in Human Medicine

• Desire to preserve usefulness of antimicrobials
  of greatest importance in treatment of human
  disease
• Guidance 152 includes categorization of drugs
  based on relative importance in human medicine
• drugs ranked as critically important, highly
  important or important in human medicine based on
  several factors
• considered in hazard identification and
  consequence assessments of Guidance
• Joint CVM-CDER team developed criteria for
  categorization of drugs

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Importance of Antimicrobials in Human Medicine

• Developing criteria important to ensure fair
  approach and lack of bias in ranking
• Criteria presented at open public meeting in
  October 2002 and Anti-Infective Drugs Advisory
  Committee (AIDAC) meeting in January 2003
• Criteria refined based on AIDAC advice with input
  from animal health industry at open public
  hearing part of meeting
• Ranking based solely on importance of drugs in
  human medicine and not degree of transmissibility
  of resistance from animals to humans

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Importance of Antimicrobials in Human Medicine

• Criteria
• 1) Antimicrobial used to treat enteric pathogens
  that cause food borne disease
• 2) Sole therapy or one of few alternatives to
  treat serious human disease or drug is essential
  component among many antimicrobials in treatment
  of human disease
• 3) Antimicrobials used to treat enteric pathogens
  in non-food-borne disease
• 4) No cross-resistance within drug class and
  absence of linked resistance with other drug
  classes
• 5) Difficulty in transmitting resistance elements
  within or across genera and species of organisms

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Importance of Antimicrobials in Human Medicine

• Drugs that meet criteria 1 AND 2 considered
  critically important
• Drugs that meet criteria 1 OR 2 considered highly
  important
• Drugs that meet any of criteria 3, 4 , or 5
  considered important

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Importance of Antimicrobials in Human Medicine

• Ranking of macrolides
• treatment of diarrheal disease due to
  Campylobacter species
• macrolides are one of few alternatives in
  treating potentially lethal diseases
• treatment of community-acquired pneumonia due to
  Legionella pneumophila (Legionnaires Disease)
• treatment of pertussis due to Bordetella
  pertussis (whooping cough) in children and adults
• Treatment and prevention of disseminated
  infection due to Mycobacterium avium in patient
  with AIDS
• fulfills both criteria 1 and 2 critically
  important

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Uses of Macrolides in Human Medicine

• Disease caused by Campylobacter species
• Disease caused by Campylobacter species are among
  the most common bacterial infections in the world
• Can cause both diarrheal and systemic illness and
  
• Complications of diarrheal disease e.g.
  Guillain-Barre syndrome and reactive arthritis
• One of most common cause of bloody diarrhea in
  the U.S.

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Uses of Macrolides in Human Medicine

• Disease caused by Campylobacter species
• Self-resolving disease most common but can cause
  fatal disease at the extremes of age and in
  immunocompromised hosts
• Treatment recommended in patients with more
  severe forms of disease like dysentery -
  treatment appears more effective when given early
  in course of illness
• Macrolides are drugs of choice
• studied in placebo controlled trials
• recommended by IDSA Guidelines
• alternatives such as quinolones and tetracyclines
  are not recommended in some patient populations
  such as children

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Uses of Macrolides in Human Medicine

• Legionnaires Disease
• intracellular pathogen Legionella pneumophila
• causes potentially lethal form of pneumonia
• initial description in 1976 outbreak 34 out of
  182 persons died
• subsequent studies show pneumonia due to L.
  pneumophila to be the second most common cause of
  pneumonia in patients admitted to ICUs with
  mortality of approximately 20
• macrolides and quinolones only drugs proven
  effective in treatment of disease, with most
  experience with macrolides

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Uses of Macrolides in Human Medicine

• Disease due to Mycobacterium avium -
  intracellulare complex
• disseminated disease usually occurs in patients
  with advanced AIDS, pulmonary disease in non-AIDS
• widespread organ involvement in liver, spleen,
  and other organs
• disease consists of fever, drenching night
  sweats, and weight loss, anemia requiring blood
  transfusions
• usual course without treatment is progressive
  clinical deterioration although not direct cause
  of death
• Mainstay of prevention is clarithromycin or
  azithromycin treatment with these drugs plus
  ethambutol

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Uses of Macrolides in Human Medicine

• Pertussis
• disease caused by Bordetella pertussis most
  commonly known as whooping cough
• causes 40 million cases worldwide and 360,000
  deaths in data from 1994 with increases in some
  countries due to lack of vaccination
• most common in children but up to 20 - 30 of
  adults with prolonged cough may have the disease
• macrolides considered drugs of choice

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Uses of Macrolides in Human Medicine

• Other uses of macrolides
• prevention of recurrence of peptic ulcer disease
  due to Helicobacter pylori
• commonly used as one of many alternatives in
  upper respiratory tract diseases and pneumonia
• one macrolide is the best selling antibiotic
  worldwide demonstrating how commonly these drugs
  are used

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Macrolide Resistance

• Resistance occurs by two mechanisms
• efflux pump due to mefA mutation - low level
  resistance with cross resistance to other
  macrolides that may remain susceptible to
  clindamycin and streptogramins, telithromycin in
  some cases
• ribosomal mutation in ermB - high level
  resistance that may confer resistance to all
  macrolides (with potential exception of
  telithromycin for some organisms), clindamycin
  and streptogramins
• Clinical significance of resistance varies with
  organism and disease setting
• appears to be clinically meaningful in some
  diseases like disseminated MAC, PUD with H.
  pylori
• clinical significance in upper respiratory
  disease less clear

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Conclusions

• Macrolides are important drugs in the treatment
  and prevention of human disease
• According to criteria discussed at previous
  meetings, macrolides are ranked as critically
  important in human medicine
• Macrolides treat or prevent disease due to
  gastrointestinal pathogens
• Macrolides either the sole or one of few
  therapies used to treat a variety of infections