U.S. Food and Drug Administration

1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2. 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

3. 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

4. Macrolides • Erythromycin derived in 1952 from strain of Streptomyceserythreus 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

5. 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

6. 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

7. 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

8. 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

9. 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 (Legionnaire’s 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

10. 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.

11. 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

12. Uses of Macrolides in Human Medicine • Legionnaire’s 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

13. 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

14. 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

15. 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

16. 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

17. 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