# Presentation: 916727

##  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***

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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.**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**