October 1, 2007

Resistant Staph: Use One Drug or a Combination?

“Vancomycin as a single agent against [methicillin-resistant Staphylococcus aureus (MRSA)] is dead,” declared Dennis L. Stevens, MD, PhD, FIDSA, of the Boise, Idaho Veterans Affairs Medical Center. Today’s serious MRSA infections call for combinations of antibiotics, he argued during the “Clinical Controversies” session at IDSA 2007 this month in San Diego.

Resistance to vancomycin is increasing rapidly, as manifested by minimum inhibitory concentration (MIC) creep, vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-intermediate (VISA), hetero-Stevens quoteresistance, vancomycin tolerance, and slow bacterial killing. Dr. Stevens also noted reports of treatment failure are on the rise. He cited research showing the rate of clinical failure increased as the MIC went up, reaching more than 50 percent when the MIC topped 2 mg/ml (J Clin Microbiol. 2004;42:2398-402).

“Antibiotic susceptibility does not predict success, but it certainly does predict failure,” Dr. Stevens said, adding that failure rates of 50 percent with vancomycin alone are just not acceptable.

Since vancomycin blocks cell-wall synthesis, the drug works best when bacteria are growing rapidly. But he noted that in serious MRSA infections, the bacterial loads are high and these bacteria are not growing rapidly or are in the stationary phase of growth.  Treatment fails as a result. 

“Furthermore,” he added, “vancomycin fails against these toxin-producing bacteria because many bacterial toxins are produced late in the bacterial life cycle (early stationary phase) and drugs such as vancomycin are therefore less effective.” When these drugs do kill bacteria, the bacteria lyse, releasing their toxins. And, Dr. Stevens said, his research has found that drugs active against cell wall production actually increase toxin-gene expression and also increase toxin production.  In sharp contrast drugs like linezolid and clindamycin markedly suppress toxin production at the ribosomal level. (Stevens et al., J Infect Dis. 2007;195:202-211).

Therefore, he concluded, these serious MRSA infections should be treated with a combination of drugs—a protein synthesis inhibitor such as clindamycin, linezolid, or possibly tigecycline; plus either a cell wall agent such as a glycopeptide, or ceftobiprole or daptomycin.

Single Drug Can Still Get Job Done

“Yes, there are a lot of bad diseases that we’re seeing as a result of the newer Staphylococci,” agreed A. W. Karchmer, MD, FIDSA, of Beth Israel Deaconess Medical Center in Boston, in his counterpoint, “but how common are they? They’re just case reports.” While major studies of S. aureus infections have noted increases in MRSA cases, these studies have reported relatively few cases of necrotizing fascitis (Miller et al., NEJM. 2005;352:1445-53) or deaths from invasive disease (Kaplan et al., Clin Infect Dis. 2005;40:1785-91).

Most importantly, he noted, there is limited evidence that using drug combinations improves outcomes. Dr. Karchmer cited a litany of studies in which various drug combinations were no more effective than single drugs, and in several cases the single drug even worked significantly better than the combination. Plus, the additional drug in some cases increased toxicity without improving the outcome.

Dr. Karchmer agreed in theory that combining a toxin-inhibiting drug with a bacteriocidal drug would be a good idea. “But what do we use?” he asked. “At this point in time,” he concluded, “single-drug therapy is…less likely to lead to antagonism, is not going to cause as much collateral damage, and is in all of our experience as efficacious as combination therapy.”

Slides from this session and many others from IDSA 2007 are available online. 

Audio files of individual sessions or a full-conference CD-ROM are available for purchase from Sound Images.

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