Vancomycin vs. Vancomycin Plus Gentamycin in Treatment of MRSA Infection
Condition: Staphylococcus Aureus
MeSH terms: Staphylococcal Infections
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to compare the outcome of treatment for bacteremic MRSA
      infection with vancomycin alone, vancomycin plus gentamicin, vancomycin plus rifampin, and
      vancomycin plus gentamicin and rifampin.
    

Detailed description: 
      Treatment of bacteremic infection (infection associated with positive blood cultures) due to
      Staphylococcus aureus has become increasingly problematic as a result of the increasing
      prevalence of strains that are resistant to beta-lactam antibiotics (so-called
      methicillin-resistant Staphylococcus aureus, MRSA). About 70% of hospital-related strains of
      S. aureus are MRSA, and, in the past 4 years, the incidence of MRSA in community-acquired
      infection has risen to about 50%; these data are quite representative of what is being seen
      elsewhere in the United States and other parts of the world.

      Bacteremic MRSA infections are highly problematic for at least two reasons: (1)they are
      serious, with substantial morbidity and about a 25% rate of mortality in middle-aged adults,
      the principal patients in our system; and (2)available antibiotic therapy is suboptimal.

      In the pre-MRSA era (before 1982 in the United States), treatment of bacteremic S. aureus
      infection with a beta-lactam antibiotic such as nafcillin produced a uniform microbiological
      cure (Musher DM, McKenzie SO: Infections due to Staphylococcus aureus. Medicine 56:383-409,
      1977). This means that, in the absence of an untreated focus of infection that required
      surgical removal (such as a myocardial abscess), antibiotics rapidly sterilized the blood
      stream. This does not mean that no one died; deaths from complications of infection remained
      common. But, at autopsy, there was generally no evidence for active infection. Extensive
      literature examined the question of whether gentamicin should be added to nafcillin to treat
      this kind of disease (reviewed critically in DM, Verner EF: Treatment of Infections due to
      Staphylococcus aureus. IN The Staphylococci, Ed. by J Jeljascewicz, Gustave Fischer Verlag,
      Stuttgart, New York, pp.407-419, 1986). Gentamicin produced a synergistic bactericidal effect
      agains S. aureus in vitro and in animal models. In humans, the addition of gentamicin was
      associated with more rapid sterilization of the blood stream, but prolonged gentamicin
      therapy was also associated with nephrotoxicity.

      In contrast, in the MRSA era, treatment with vancomycin is associated with persistence of
      bacteremia (positive blood cultures) and death from active infection. We have recently
      participated in a prospective observational study that documented the association between
      vancomycin treatment, persistently positive blood cultures, and persistence of active
      infection during treatment of S. aureus bacteremia with vancomycin (Chang F-Y, McDonald BB,
      Peacock, Jr. JE, Musher DM, et al. Staphylococcus aureus bacteremia: recurrence and the
      impact of antibiotic treatment in a prospective multicenter study. Medicine 82:333-339,
      2003).

      There appears to be a very close correlation between the outcome of treatment for serious S.
      aureus infection and the bactericidal activity of the treating antibiotic in vitro using
      conventional techniques (Musher DM, Verner EF: Treatment of infections due to Staphylococcus
      aureus. IN The Staphylococci, Ed. by J Jeljascewicz, Gustave Fischer Verlag, Stuttgart, New
      York, pp.407-419, 1986). We recently showed that adding low concentrations of gentamicin to
      vancomycin led to substantial synergistic bactericidal activity against MRSA (Shelburne SA,
      Musher DM, Hulten K, Ceasar H, Lu MY, Bhaila I, Hamill RJ. In-vitro killing of
      community-associated methicillin-resistant Staphylococcus aureus with drug combinations.
      Antimicrob Agents Chemother 48:4016-9, 2004).

      Based in part on the analogy of nafcillin for treating methicillin-susceptible S. aureus
      infection, and in part of in vitro studies such as ours (cited above), some physicians
      regularly add gentamicin to vancomycin for treating MRSA infection. Others, without even the
      in vitro support, add rifampin either instead of gentamicin or together with gentamicin.
      There are no clinical studies to support or to refute any of these clinically motivated
      usages.

      Thus, at present, about one-third of patients with MRSA bacteremia at VAMC are treated with
      vacomycin plus gentamicin, and two-thirds receive vancomycin alone; some in each group
      receive rifampin. The decisionto add gentamicin is made a haphazard fashion. Our proposal is,
      once MRSA has been identified in acceptable regimens by stratifying patients prospectively to
      vancomycin alone or vancomycin plus gentamicin, and further stratifying each of those groups
      to be with or without rifampin.
    

Intervention name(s): Vancomycin; Vancomycin plus Gentamicin; Vancomycin plus Rifampin; Vancomycin plus Gentamicin plus Rifampin
Intervention type(s): Drug; Drug; Drug; Drug
Intervention MeSH terms: Vancomycin; Rifampin; Gentamicins
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single
Keywords: MRSA; Methicillin Resistant Staphylococcus aureus