Adjunctive Rifampin in Staphylococcal Infections – Primer for Bacteremia and Endocarditis

The use of rifampin for staphylococcal infections is a bit controversial. The recommendation seems to be its use on infections involving prosthetic material, such as prosthetic valve endocarditis or prosthetic joint infections. For instance, the AHA infective endocarditis (1) guidelines recommends the addition of rifampin to a regimen consisting of vancomycin to infectious caused by staphylococci in the presence of prosthetic valves or other prosthetic material:

I am not even going to address the use of aminoglycosides here. The same guidelines, however, recommend against the use of rifampin for native-valve endocarditis.

“Moreover, use of rifampin as adjunct therapy for S. aureus NVE has been associated with higher rates of adverse events (primarily hepatotoxicity) and a significantly lower survival rate. Thus, routine use of rifampin is not recommended for treatment of staphylococcal NVE. “

The addition of rifampin tends to be delayed until blood culture clearance to prevent the resistance to rifampin and to allow the main IV antibiotic to penetrate into the cardiac vegetations (2). The rationale behind the use of rifampin comes from a series of in vitro and animal studies that were published back in the mid-80s, most of them in the same issue of Review of Infectious disease. I mention this because, as I get into the articles used to support the adjunctive use of rifampin in staphylococcal infections, keep in mind the following:

1. Most of the support for its use comes from basic science studies. 
2. The clinical data (at least the vast majority) uses cohort studies with different types of diseases being evaluated (prosthetic joint infections or prosthetic valve infections) as well as different doses and combinations of antibiotics being used along with rifampin. This makes a thorough comparison between, lets say the use of vancomycin + rifampin and daptomycin + rifampin (the latter combination not being available until the turn of the 21st century and a more common scenario that is found) very difficult. 
3. Small numbers of participants in trials makes real-world application of such studies very difficult. 

One of the earlier studies on the use of adjunctive rifampin occurred from 1975-1980 (3) where a cohort of 70 patients with Staph epi PVE were retrospectively evaluated. The overall cure rate in this cohort was 57%, with 48/68 episodes requiring valve replacement. A wide combination of approaches were used, with both beta-lactams and vancomycin being combined with either rifampin, gentamicin, or both. While conclusions were difficult to draw, the combination of vancomycin + rifampin was better than the combination between a beta-lactam and rifampin:

The 23 patients who received rifampin were later followed for at least a year (4), with the table published in this paper looking fairly similar to the one above. The effect of the combination was evaluated in 6 of these strains, and found that addition of rifampin to vancomycin increased the serum bactericidal titer at least 8-fold or more in these patients:

An animal study of rabbits (5) against methicillin-resistant staph epi found that the combination of all three antibiotics resulted in the greatest decrease of bacterial titers when compared to each alone, though the combination of vancomycin + rifampin also achieved comparable decrease (p-value for the titers were not different between groups, but the number of sterile vegetations examined between V+R and V+R+G was <0.05):

Another in vitro study (6) using a similar animal model compared rifampin  by itself, cephalothin by itself, and the combination and found that the cephalothin was not quite effective by itself in sterilizing vegetations, however the combination failed to clear the vegetations of 3 rabbits. It should be noted these were all rifampin resistant isolates:

The time kill curves in 10 strains seem to suggest that, using rifampin by itself leads to the  early emergence of resistance, with the addition of gentamicin in this part of the study helping prevent this outcome:

These studies tend to be cited in guidelines when it comes to the recommendation of adding rifampin to prosthetic valve endocarditis. A bit more robust data was also published at around the same time, however it should be noted these studies are quite small to draw any meaningful conclusions. A small prospective randomized study evaluated 56 patients with staphylococcus infection (7) who were treated with either oxacillin alone or in combination with rifampin 300mg twice per day. Those who were methicillin resistant received vancomycin instead. 19 patients in the cohort were bacteremic, with only one of them being cited as having endocarditis. Clinical cure was seen in 67% of patients in the combination group compared to 41% in the monotherapy group (p-value <0.01), with all patients with bacteremia in the combination group having either cure or improvement compared to 56% in the monotherapy group. Another multicenter, randomized controlled trial (8) from the same group performed a similar trial, but with a higher dose of rifampin (600mg twice per day) along with oxacillin/vancomycin or monotherapy with oxacillin/vancomycin. Less than half of the patients had bacteremia. 9% in the combination group and 18% in the monotherapy group had clinical failure, while cure was achieved in 61% of the combination group and 56% in the monotherapy group. Both results were not statistically significant. More patients in the combination group achieved bacteriological cure. Of course, these 2 studies included all comers with any staph infection.

A prospective, randomized trial of 42 patients compared therapy with either vancomycin or vancomycin-rifampin 600mg twice per day (9) in patients with MRSA infective endocarditis. There were no differences in terms of therapeutic failures or deaths between groups, with duration of bacteremia in both groups being roughly the same (though the duration could only be determined in 17 patients):

A retrospective review (10) compared 42 cases of staph aureus IE treated with standard therapy and 42 treated with the addition of rifampin. The number of cases of MRSA and right sided IE were similar between groups, though more patients in the rifampin group received gentamicin (81% vs 17%). There was lower survival and higher duration of bacteremia in the combination group:

When looking at the combination group, 16 patients got rifampin prior to bacteremia clearance and the duration of bacteremia was similar before and after the addition of rifampin. Moreover, the rate of resistance and transaminitis was higher in the combination cohort:

It is difficult to say if the combination group was sicker upfront and hence got “nuked” with medications, but these early data suggest that the benefit, if there is any, of rifampin is likely minimal.  

Two studies evaluated the utility of rifampin as part of native valve endocarditis therapy prior to surgical intervention. In one cohort study (11), 152 cases (91 NVE and 61 PVE) and different approaches were compared, either single agent, double, triple, or partial combination. In those with Staph aureus native valve endocarditis, the addition of any combination was not more likely to result in culture-negative vegetations after adjustment for duration of therapy (OR 0.45, 95% CI 0.12-1.66). Similar results were found for cases of CoNS NVE. Notably, for PVE, there was a trend towards patients who had received any sort of combination therapy to have a culture-negative valve at the time of surgery compared to single-agent therapy (70% vs 43%, p=0.062) with logistic regression analysis finding benefit to any sort of combination (OR 5.9, 95% CI 1.3-27.5), though it should be noted this included aminoglycosides as well as rifampin. A single-center retrospective cohort of 273 patients (12) found that patients who received rifampin tended to be older, have invasive disease or left sided involvement, have methicillin resistance, or have no IVDA and presence of a prosthetic heart valve.  Multivariate model did not find that treatment with rifampin had any impact on the death or reoperation for IE relapse when compared to those who did not get rifampin (HR 0.76, 95% CI 0.44 to 1.32):

The addition of rifampin either pre-op, post-op, or at discharge from the hospital was also not associated with any improvement in the primary outcome of survival free of reoperation:

Two other studies evaluated different combinations of drugs with rifampin for staph aureus infections in general, so these may be less applicable for the use of IE. The first one was a prospective, multicenter trial that compared the use of levofloxacin to standard of care for SAB (13). Rifampin and aminoglycosides could be used if there was a suspicion for IE or a deeper infection. The dose for rifampin was actually only 600mg daily. Primary endpoint was mortality at 28 days and 3 months. 381 patients were included in the trial, with no difference seen in the main primary outcome for mortality benefit at 28 days or 3 months for levofloxacin. In patients with deep infections, however, mortality at 3 months was higher in those who did not get rifampin than those who got it (OR 3.06, 95% CI 1.69-5.54), however those in the standard group (i.e. no levofloxacin) were more likely to get rifampin. Further, older patients, those who had chronic renal failure, or fatal underlying illness were less likely to get rifampin. When looking at all patients with deep infections who were treated with rifampin, there was no difference in the case fatality at 3 months (13% in the rifampin group and 20% in the no rifampin group), suggesting no benefit. An open label trial (14) that compared the combination of fleroxacin-rifampin (an all oral regimen with rifampin dosed at 600mg daily) with standard of care. 130 patients were enrolled, with most having catheter-related bacteremia or a secondary bacteremia. The overall cure rate in the ITT population was similar between groups (78% in the experimental group and 75% in the standard parenteral group), as it was in the microbiologically available patients (86% and 84%):

Not surprisingly, there were more adverse events in the rifampin group (15 vs 5). A more applicable retrospective study (15) evaluated the use of rifampin in Staph aureus with a deep focus of infection. 357 patients were included, of which 27% did not receive adjunctive rifampin. Patients who got any therapy with rifampin had mortality benefit at 60 days and 90 days:

Cox regression analysis found that rifampin therapy, especially rifampin therapy greater than 14 days, was associated with improved 90 day mortality:

It should be noted that patients with methicillin-resistant strains were excluded from the study, so that along with its retrospective natura may hinder its applicability. A more recent, double-blind, RCT evaluated rifampin in both MSSA/MRSA bacteremia (16), where 758 patients were evaluated. Composite outcome of bacteriologically treatment failure, recurrence, or death at 12 weeks was achieved in 17% of the rifampin group and 18% in the placebo group (absolute risk difference -1.4%, 95% CI -7 to 4.3, HR 0.96, 95% CI 0.68 to 1.35):

Notably, the recurrence rate was lower in the rifampin group, but how much of that was due to lack of source control is unknown. 

It should be noted that the only 14 patients in the cohort had some sort of prosthetic valve or joint and 36 had any sort of prosthetic material 

The above trial was evaluated in a meta-analysis of 7 studies (17), which included 979 patients treated with rifampin and 636 patients without it. Of these, two studies evaluated infective endocarditis, and 2 evaluated any sort of prosthetic infection with the duration of rifampin ranging from either 3 days to over 48 days, in addition to standard therapy. In terms of mortality, pooled analysis demonstrated no difference between adjunct rifampin use and control group:

Similarly, there was no difference between groups when it came to rate of bacteriologic failure:

Or relapse:

An older meta-analysis (18) with many of the same studies did not find any convincing results, with multiple conflicting studies, with most of the hard outcomes of clinical cure not achieving statistical significance in the bacteremia studies.

Where does this leave us at the end of the day? As I mentioned, it is incredibly difficult to draw any meaningful conclusions here. The animal studies cited above does suggest some benefit for the combination of rifampin and a glycopeptide for bacteremia, however this does not seem to translate well into clinical efficacy. The earlier cohort studies tend to use different types of antibiotics (some use nafcillin and other types of quinolones) with different doses in multiple different disease states (i.e. pneumonia and bacteremia being included along with endocarditis), which leaves us comparing apples to oranges in terms of diseases. The data of more contemporary studies when it comes to native valve endocarditis suggests (albeit, it suffers from the same issues as earlier studies) there is some harm, with other studies looking at prosthetic valve endocarditis suggesting some benefit after statistical adjustment. While trials like the ARREST trial may have tilted the scale towards not using rifampin in SAB, the lack of patients with prosthetic valve endocarditis leaves us in the same place we started, though a thorough review (19) highlights multiple in vitro data that suggest the role of rifampin in penetrating biofilms in implanted prosthetic material. 

TL;DR

• There is little high-quality clinical evidence for the adjunct use of rifampin overall
• Most of the data is from small cohort studies and animal data
• The use of rifampin in bacteremia or native valve endocarditis is not supported
• Rifampin may have a role in prosthetic valve endocarditis, usually a dose of 600mg twice per day, but keep in mind this is in context of cohort data that included small numbers of patients with PVE.

References:

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