Preserving the Effectiveness of Antibiotics

ANTIBIOTICS ARE EXTRAORDINARY MEDICINE AND ARE often curative. In general, antibiotics are remarkably free of adverse effects, eradicating the microorganism and usually leaving the host unaffected. Because antibiotics are typically well tolerated and effective, they are often used when the diagnosis of a bacterial infection is unclear. The liberal use of antibiotics has contributed to antibiotic resistance—a problem that has become a crisis. As a drug class, antibiotics are virtually unique because once an antibiotic is released for wide-scale use, its efficacy diminishes. In contrast, aspirin, one of the oldest drugs, is as effective an analgesic today as the first time it was used. The same cannot be said of penicillin. In the 1950s, the use and overuse of penicillin resulted in penicillin resistance. In the 1960s and 1970s, the use and overuse of gentamicin resulted in gentamicin resistance. In the 1980s and 1990s, the use and overuse of ciprofloxacin resulted in ciprofloxacin resistance. The observation has been repeatedly made, yet clinicians do not seem to be learning from the mistakes that continue to occur with each new antibiotic. In this issue of JAMA, Sanchez Garcia and colleagues described an outbreak of linezolid-resistant Staphylococcus aureus (LRSA) in an intensive care unit (ICU) and identified a rarely described mechanism of linezolid resistance. The authors demonstrated that use of linezolid was associated with this novel resistance mechanism in clinically significant ICU infections that affected 12 patients, causing ventilator-associated pneumonia in 6 and bacteremia in 3. Linezolid is a member of the oxazolidinone class of antibiotics used to treat a variety of gram-positive bacteria, including methicillin-resistant S aureus (MRSA). MRSA has limited therapeutic options, especially considering that susceptibility to vancomycin has become an increasing concern. Physicians hoped linezolid would help replete the inadequate arsenal of antibiotics for MRSA, but it is not a panacea. Chief among linezolid’s limitations has been adverse effects, which are most serious in the long term (ie, use 2 weeks) and include thrombocytopenia and neuropathy. The latter is often irreversible. Linezolid resistance among MRSA has been uncommon, restricted to isolated reports until this investigation. In the study by Sanchez Garcia and colleagues, the laboratory analysis suggested that some molecular evolution of the resistance mechanism may have occurred. The outbreak was associated largely with 1 clone of LRSA in a Spanish hospital. However, at least 1 patient harbored a clone of LRSA that was different than the predominant clone in the outbreak. Even more worrisome, the cfr gene that was responsible for the linezolid resistance in MRSA was found in 2 coagulase-negative Staphylococci isolates. The evolution and transmission of linezolid resistance to another species in the relatively short period of the outbreak suggest that other institutions may be managing their own version of LRSA in the near future, particularly if linezolid is frequently used. The feature that provides a measure of relief from the study by Sanchez Garcia et al is the apparent control of the outbreak both with infection-control measures and control of linezolid use. The authors described total ICU consumption of linezolid as 202 defined daily doses in April 2008. Following their investigation, use of linezolid declined to 25 defined daily doses in July 2008. The defined daily doses in April suggest liberal use of the drug, although there is no description of guidelines for linezolid use in the ICU and whether the use of linezolid was appropriate. The authors also did not describe how the substantial reduction in linezolid use was achieved, but such a significant decrease in linezolid use suggests that much of the use in April probably could have been changed to another antibiotic or even eliminated. No one doubts the importance of infection-control practices in limiting outbreaks with antibiotic-resistant organisms, but optimizing antibiotic use remains essential for successful control of such outbreaks. Several reasons support the need for controls over antibiotic use, also known as antibiotic stewardship. First, the supply of different types of antibiotics has dwindled. New antibiotics have never been easy to find. However, pharmaceutical companies have recently curtailed or eliminated antibiotic discovery. Since the beginning of 2008, the US Food and Drug Administration