CE: Antibiotic resistance and control strategies

September 1, 2002

Pharmaceutical Representative

September 2002 CE.

This third article in a three-part series provides healthcare representatives with a description of recent threats of antimicrobial resistance, current drug-resistant pathogens that have become problems in the hospital and the community, and strategies to reduce resistance.

J. Peter Rissing, M.D., FACP, FIDSA, chief of Infectious Diseases Section, Sydenstricker Professor of Medicine, Medical College of Georgia, Augusta, GA; and John C. Rotschafer, Pharm.D., FCCP, Section of Clinical Pharmacy, Regions Hospital, and professor, College of Pharmacy, University of Minnesota, St. Paul, MN, served as consultants for this article for the Certified Medical Representatives Institute Inc.

Learning Objectives

* Describe the recent threats of antimicrobial resistance, including: Staphylococcus aureus with reduced susceptibility to vancomycin, the emergence of vancomycin-resistant enterococci and the emergence of multiple-drug-resistant Salmonella enterica.

* List the important resistant pathogens found in the hospital setting and the community setting.

* Explain how antibiotic combinations administered by physicians, minimization of selective pressures that favor the survival and proliferation of resistant bacterial strains, and pharmacist involvement can help in preventing the development and spread of antibiotic resistance.

* Describe the impact of surveillance programs and federal action plans on countering antibiotic resistance.

* Identify new antimicrobial agents and other new developments showing promise against resistant strains of bacteria.

Some antibiotic-resistant bacterial strains represent particularly serious public health threats because the bacteria involved are significant human pathogens and their resistance covers multiple antibiotics, including the most potent agents currently available.

Staphylococcus aureus is the most common cause of surgical wound infections and a major cause of hospital-acquired blood infections. Penicillin was initially successful in treating S. aureus infections, but between 70% and 80% of S. aureus isolates are now resistant to that agent. Methicillin and other semisynthetic penicillins were used successfully to treat penicillin-resistant S. aureus until the 1980s; since then, however, methicillin-resistant S. aureus has become endemic in many hospitals. Strains resistant to cephalosporins, macrolides, quinolones and many other antibiotics have also emerged. For the past 20 years, vancomycin has been the antibiotic of choice for treating methicillin-resistant S. aureus infections. Within the past few years, however, methicillin-resistant S. aureus strains that are also intermediately susceptible to vancomycin have been reported in the United States and Japan.

Vancomycin resistance has emerged among the enterococci, a group of bacteria that frequently cause urinary tract, wound and bloodstream infections in hospital patients. For some time, vancomycin was the only consistently reliable antibiotic available for treating infections caused by multiple-drug-resistant enterococci. Since the mid-1990s, however, vancomycin-resistant strains of enterococci have been emerging, first in Europe and more recently in the United States. Treatment poses a challenge, because the enterococci are already resistant to most other antibiotics.

Salmonella bacteria are responsible for an estimated 800,000 to four million infections in the United States each year, usually taking the form of gastroenteritis following consumption of contaminated food. About 500 fatal Salmonella infections occur in the United States annually.

One of the most common types of pathogenic salmonella is Salmonella enterica of the serotype typhimurium. A multiple-drug-resistant strain of typhimurium, called definitive type 104, has become increasingly widespread in the United Kingdom and has lately been reported in the United States as well. Definitive type 104 is resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides and tetracycline. Furthermore, some isolates of DT104 are now resistant to ciprofloxacin and trimethoprim. Investigators have not determined the sources of the resistant DT104 type of salmonella, but outbreaks in the United Kingdom and the United States have been linked to consumption of contaminated meat and dairy products and direct contact with livestock.

Resistance in the hospital, community

In the hospital environment, there are particularly high levels of antibiotic resistance. In fact, antibiotic resistance has been identified as a major contributor to the illness, death and expense associated with hospital-acquired infections. Few exact data are available, but antibiotic resistance in a single pathogen, Staphylococcus aureus, has been estimated to cost healthcare institutions $122 million annually.

A number of bacterial species have been frequently associated with resistant infections in the hospital setting, including the following:

• Enterococci.

– Major cause of urinary tract infections, wound infections and bacteremia in hospitals.

– Species include Enterococcus faecium, Enterococcus faecalis and others.

• Coagulase-negative staphylococci.

– Most common cause of nosocomial bacteremia associated with prosthesis infections.

– Species include Staphylococcus epidermidis, Staphylococcus haemolyticus.

• Staphylococcus aureus.

• Streptococcus pneumoniae.

– Can cause bacteremia, bronchitis, pneumonia, sinusitis, meningitis and otitis media.

• Klebsiella species.

– Frequent cause of pneumonia and urinary tract infections.

• Pseudomonas aeruginosa.

– Frequent cause of infection in superficial wounds and ulcers.

• Gram-negative rod-shaped bacteria (bacilli).

• Enterobacter.

Some of the resistant bacterial strains emerged in hospitals and later spread into the wider community; others evolved in the community as a result of careless prescribing, poor compliance and other practices. The following are important community-acquired pathogens that have developed resistance to antibiotics:

• Mycobacterium tuberculosis.

– Tuberculosis remains endemic in Asia and is resurgent in Eastern Europe; resistance threatens control programs everywhere.

• Escherichia coli.

– Normal component of intestinal flora in humans and other animals; some strains can cause urinary tract infections, gastroenteritis or other illnesses, especially if sanitary precautions are not observed.

• S. pneumoniae.

– Leading cause of community-acquired pneumonia, meningitis and otitis media.

• Haemophilus influenzae and Moraxella catarrhalis.

– Major causes of acute exacerbations of chronic bronchitis.

• Neisseria gonorrhoeae.

– Pathogen responsible for gonorrhea.

• Helicobacter pylori.

– Gram-negative bacterium; causes infections of gastric mucosa.

Strategies to reduce resistance

Physicians, pharmacists, healthcare institutions and policymakers have adopted a variety of strategies to counter the growing problem of bacterial resistance to antibiotics. As shown in the graphic above, these include antibiotic combinations, minimization of selective pressure, pharmacist involvement, surveillance, a federal action plan and new agents.

Antibiotic combinations. Combinations of antibiotics provide a broad spectrum of activity when the infection involves multiple species of bacteria or, more frequently, when the causative pathogen has not been identified and no single agent is effective against all possibilities. Presumptive treatment of this type is considered essential when the infection is life-threatening, and treatment cannot be delayed while a laboratory identifies the pathogens. Physicians may also prescribe combinations of antibiotics because the agents exhibit synergistic activity. For example, patients with enterococcal endocarditis often receive streptomycin or gentamicin in addition to penicillin G or ampicillin because the combination is associated with a higher cure rate and lower likelihood of relapse than penicillin or ampicillin alone. Finally, combination therapy may be used directly to prevent or counter antibiotic resistance. Multidrug treatment of tuberculosis has become common practice wherever resistant strains are likely to occur.

Minimization of selective pressure. A cornerstone of any plan to combat antibiotic-resistant infections is the minimization of the selective pressures that favor the survival and proliferation of resistant bacterial strains. Thus, physicians are being encouraged to change their prescribing behavior when it comes to antibiotic therapy in the following ways:

• Prescribe fewer antibiotics overall.

• Make sure dosing and duration of therapy are appropriate.

• Follow appropriate diagnostic criteria (e.g., Gram stain, sputum cultures, chest x-rays), and make sure the infection is bacterial rather than viral in origin before prescribing an antibiotic.

• Prescribe more generic antibiotics when available and appropriate instead of brand-name agents to reduce healthcare costs.

• Target a specific narrow-spectrum antibiotic to a certain pathogen.

• If possible, use older antibiotics as first-line treatment.

• Follow switch or step-down treatment protocols in which therapy begins empirically in a hospital, but once the pathogen is identified and its susceptibility known, the physician may either:

– Switch from a broad-spectrum antibiotic to a different agent with specific efficacy against the known pathogen.

– Step down from a combination of three antibiotics to only two, or from two antibiotics to only one.

• Follow national guidelines for appropriate antibiotic usage provided by groups such as the Centers for Disease Control and Prevention, the Infectious Disease Society of America, and the American Thoracic Society.

With increasing frequency, the treatment protocols followed by physicians and the drugs used in these protocols will be approved by a pharmacy and therapeutics committee. In addition, some healthcare institutions have been able to reduce levels of resistance by implementing strict controls on antibiotic use.

Pharmacist involvement. Hospital and community pharmacists are in key positions to promote appropriate antibiotic use in their respective areas. For example, hospital pharmacists can partner with intensive care units and other hospital staff to develop plans to counter nosocomial infections, and they can assist physicians in selecting an appropriate antibiotic class, dosing strategy and route of administration. Community pharmacists' recommendations to consumers and physicians can help guide their behavior toward appropriate antibiotic prescribing and utilization.

Surveillance. Any effective program to counter antibiotic resistance requires accurate information on patterns of antibiotic use and the nature and prevalence of resistant bacterial strains. In the United States, the CDC and local health agencies collect surveillance data on resistant microorganisms and their prevalence. Hospitals, managed care organizations, pharmacy benefit management companies and other healthcare institutions can assist in this effort by providing antibiotic usage and resistance data specific to the localities where they operate.

Federal action plan. In 1999, a task force co-chaired by the CDC, the Food and Drug Administration and the National Institutes of Health formulated a federal action plan to combat antimicrobial resistance. The four focus areas of the plan, followed by brief descriptions, are:

• Surveillance: Use drug susceptibility data; monitor patterns of antibiotic use.

• Prevention and control: Improve diagnostic testing practices; improve use of vaccines; involve nonfederal partners and the public in programs.

• Research: Augment the existing research infrastructure; translate research findings into clinically useful products.

• Product development: Ensure that researchers and pharmaceutical manufacturers are informed of current and projected needs for antimicrobial products.

New agents. The increasing development of bacterial resistance challenges the pharmaceutical industry to discover or develop new antibiotics or modify existing antibiotics to make them less susceptible to known mechanisms of resistance. Agents that inhibit antibiotic-modifying enzymes or inactivate plasmids coding for resistance would be of particular benefit.

The following are some new antibiotic classes and specific agents:

• Linezolid is one of the oxazolidinones, a new class of antimicrobial agents that are active against multiple-drug-resistant staphylococci, streptococci and enterococci.

• Quinupristin and dalfopristin belong to a new class of antibiotics, the streptogramins; each agent alone exhibits bacteriostatic activity, but in combination, they are synergistic and become bactericidal against staphylococci.

• The investigational antibiotic oritavancin (LY333328), which is a semisynthetic glycopeptide that resembles vancomycin in its mechanism of action, but is up to 1,000 times more potent.

• Ketolides, which can be considered fourth-generation macrolides and have been developed for use in respiratory tract infections.

– Telithromycin is close to receiving FDA approval for community-acquired pneumonia in adults, and ABT773 is in phase I trials.

• Daptomycin, a lipopeptide bactericidal for Gram-positive organisms and potentially for enterococci, is in phase II and phase III clinical trials.

• Ertapenem is a second-generation penem approved for the initial empiric treatment of community-acquired and mixed infections.

• New quinolones with broad-spectrum activity are in phase II clinical trials.

Investigators are also developing strategies to improve the effectiveness of existing antibiotics. Beta-lactamase inhibitors such as clavulanic acid and sulbactam have been available for many years. These agents are potent inhibitors of beta-lactamases, the enzymes in resistant organisms that can destroy the activity of many beta-lactam antibiotics, including amoxicillin and ampicillin. Efflux pump inhibitors are also being developed. Other investigators have found that ultrasound can increase the effectiveness of some antibiotics by perturbing or stressing their cell membranes. 

Article Summary

* Isolated cases of Staphylococcus aureus with reduced susceptibility to vancomycin have been reported in Japan and the United States; these and many other strains of S. aureus were already resistant to methicillin and other antibiotics considered reliable in the past.

* Vancomycin resistance is becoming widespread among the enterococci; most enterococci are already resistant to many other antibiotics.

* A strain of Salmonella enterica that is resistant to at least five antibiotics has caused outbreaks of food poisoning in the United Kingdom and the United States.

* In the hospital setting, important resistant pathogens include strains of enterococci, S. aureus, other staphylococci, Streptococcus pneumoniae, Klebsiella, Pseudomonas aeruginosa, various Gram-negative bacilli and Enterobacter.

* In the community setting, important pathogens include resistant strains of Mycobacterium tuberculosis, Escherichia coli, S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae and Helicobacter pylori.

* Strategies to counter bacterial resistance to antibiotics include: antibiotic combinations, minimization of selective pressure, pharmacist involvement, surveillance, a federal action plan and new agents.

• Multidrug therapy has been shown to decrease emergence of resistant strains of tuberculosis.

• Physicians are being encouraged to change their prescribing behavior and to prescribe fewer antibiotics overall.

• Hospital pharmacists can partner with hospital staff to develop plans to counter nosocomial infections, and can assist physicians in selecting an appropriate antibiotic class; community pharmacists' recommendations to physicians and consumers can help guide appropriate use of antibiotics.

• The CDC and local health agencies collect data on prevalence of resistant microorganisms.

• A federal action plan to combat antimicrobial resistance was formulated.

• The pharmaceutical industry is developing new antibiotics or modifying existing antibiotics to make them less susceptible to mechanisms of resistance.

© 2002 The Certified Medical Representatives Institute Inc., Roanoke, VA 24018. All rights reserved. No part of this article may be reproduced by any method or in any form without written permission from the CMR Institute. Reprints of this article are available from the CMR Institute. Request Continuing Education article DR-3.