Vancomycin vs. Vancomycin Plus Gentamycin in Treatment of MRSA Infection

Staphylococcus Aureus Clinical Trial

Official title:

Vancomycin Versus Vancomycin Plus Gentamycin For Treating Bacteremic Infection Due to Methicillin-Resistant Staphylococcus Aureus (MRSA)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00304811
• Other study ID #: H-17556
• Status: Completed
• Phase: Phase 4
• First received: March 16, 2006
• Last updated: September 25, 2009
• Start date: January 2006
• Est. completion date: January 2007

Study information

• Verified date: September 2009
• Source: VA Medical Center, Houston
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 160
• Est. completion date: January 2007
• Est. primary completion date: January 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 64 Years

Eligibility

Inclusion Criteria:

• Patients with MRSA in a blood culture processed as standard of care at the VAMC

• Patients or next of kin willing to sign consent to be randomized by social security number to one of the treatments.

Exclusion Criteria:

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind

Related Conditions & MeSH terms

• Staphylococcal Infections
• Staphylococcus Aureus

Intervention

Drug:
• Vancomycin

• Vancomycin plus Gentamicin

• Vancomycin plus Rifampin

• Vancomycin plus Gentamicin plus Rifampin

Locations

Country	Name	City	State
United States	Baylor College of Medicine	Houston	Texas
United States	Michael E. DeBakey Veterans Affairs Medical Center	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
VA Medical Center, Houston	Baylor College of Medicine

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to defervescence (24 hours of temperature <100 degrees F)
Primary	Return of WBC to normal (<10,500)
Primary	negative blood cultures
Primary	discharge