By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
SYNOPSIS: Clear evidence of benefit from adjunctive administration a β-lactam and/or a glycopeptide in the treatment of prosthetic valve endocarditis due to staphylococci is lacking. Current guidelines need to be reassessed.
SOURCE: Ryder JH, Tong SYC, Gallagher JC, et al. Deconstructing the dogma: Systematic literature review and meta-analysis of adjunctive gentamicin and rifampin in staphylococcal prosthetic valve endocarditis. Open Forum Infect Dis 2022;9:ofac583.
Both European and U.S. guidelines recommend that treatment of staphylococcal prosthetic valve endocarditis (PVE) include gentamicin and/or rifampin in addition to a backbone of a β-lactam or glycopeptide. Ryder and colleagues addressed these guideline recommendations by performing a systematic review and meta-analysis of published studies.
The authors identified four relevant studies, two published in 1983 (both with the same first author), and one each in 2018 and 2021. The etiologic pathogen was Staphylococcus aureus in 154 (44.9%) and coagulase negative Staphylococcus (CoNS) in 189 (55.1%). The backbone antibiotic was reported in only three studies, and this was a glycopeptide in 94 (57.7%) and a β-lactam in 69 (42.3%). Rifampin was prescribed in 242 (70.3%) of the 343 patients in the four studies, while gentamicin was given to 108/163 (61.3%) in the three studies with this information. Of the total of 343 patients in the four studies, 137 (39.9%) underwent surgery.
The authors concluded that adding gentamicin to regimens containing rifampin was not associated with a reduced risk of clinical failure (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.39 to 2.46). Similarly, adding rifampin to a regimens containing gentamicin did not reduce the risk of clinical failure (OR, 1.29; 95% CI, 0.71 to 1.33). Relapse of infection was not affected by the addition of either adjunctive antibiotic. Limited safety data were reported, but one study reported that adverse effects led to rifampin discontinuation in almost one-third of patients.
Having found a lack of evidence of benefit in the context of known potential harm, Ryder and colleagues suggested that current guideline recommendations be critically reevaluated — and that the issue can only be settled with a prospective randomized clinical trial.
COMMENTARY
In 2009, I pointed out that in one of the 1983 studies mentioned earlier, of the seven patients with Staphylococcus epidermidis PVE who did not undergo surgery, vancomycin was judged by the authors to be ineffective based on failure in the only patient who received it as monotherapy.1 I also pointed out that, in a prospective cohort study of 69 patients with PVE due to coagulase negative staphylococci (CoNS) published in 2009 (two-thirds methicillin-resistant), there was no statistically significant difference regarding in-hospital mortality related to adjunctive administration of rifampin and/or an aminoglycoside.1 In following the literature, I have long been convinced that the recommendation of combination therapy is without basis and may, in fact, be dangerous. Thus, there is no clear evidence of benefit, but there is known toxicity associated with the use of aminoglycosides and rifampin.
As Ryder and colleagues pointed out, the current U.S. and European guidelines are “based on expert opinion, foreign body infection animal models with culture-based outcomes, or clinical studies that do not evaluate clinically relevant outcomes (e.g., mortality and toxicity.” It is clearly time to reassess.
REFERENCE
- Deresinski S. Vancomycin in combination with other antibiotics for the treatment of serious methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2009;49:1072-1079.
