Despite limited data regarding the utility of rifampin in the treatment of native valve S. aureus
IE, our study indicates that it is still frequently used for this infection at our institution. A recent survey suggests that this practice appears to occur frequently (11
). Despite using rifampin as an adjunctive treatment in combination with other therapy for native valve S. aureus
IE, there was a high incidence of the development of S. aureus
isolates resistant to rifampin, especially if patients were bacteremic at initiation (9 of 16 patients [56%]). HCV-infected patients who received rifampin often developed significant elevations of their hepatic transaminases. Additionally, unrecognized significant drug interactions were often overlooked (52%). Lastly, cases receiving rifampin with standard antibiotic therapy may have been more severely ill, since they had longer durations of bacteremia, were more likely to require surgery, and were less likely to survive than controls.
We found that rifampin is often added to standard antibiotic therapy for the treatment of native valve S. aureus
IE at our institution. The most recent guidelines from the American Heart Association/Infectious Diseases Society of America for the treatment of native valve S. aureus
IE currently do not recommend adding this agent to standard therapy, and in fact, they recommend against routine use of rifampin for this infection (1
). However, the review by Hawkins et al. (12
) and the survey by Hageman et al. (11
) suggest that clinicians are still likely to add rifampin to patients who appear severely ill or have protracted bacteremia. Continued use of rifampin for this indication may reflect a perceived benefit for more-complicated S. aureus
infections, such as left-sided, native valve IE with prolonged bacteremia.
The development of S. aureus
isolates resistant to rifampin is a well-recognized disadvantage of its use for S. aureus
), and it has recently been shown at the genetic level to occur after only a single dose of rifampin in a patient with MRSA endocarditis (24
). In our study, rifampin-resistant isolates developed in 56% of cases who were bacteremic at initiation of rifampin therapy, while there were no resistant isolates in cases who received rifampin after clearance of bacteremia. It is possible that more cases actually acquired rifampin-resistant isolates but were not detected, since follow-up cultures were performed only as clinically indicated and not systematically. This problem has been noted in other studies in which rifampin was added to standard therapy for serious S. aureus
). The optimal timing for addition of rifampin (e.g., after clearance of bacteremia) to reduce the risk of developing resistance has not been shown prospectively, but some experts recommend waiting to add rifampin until after blood cultures have cleared (3
), and our data support this approach.
Rifampin has numerous potential adverse effects, including anaphylaxis, gastrointestinal symptoms, hemolytic anemia, thrombocytopenia, acute renal failure, uveitis, and rash, in addition to hepatic toxicity (9
). In this study, patients with elevations in hepatic transaminases had underlying HCV infection and baseline elevations above the upper limit of normal, which may have predisposed them to this adverse effect; therefore, rifampin use should be initiated with caution in this patient population. Other studies that have added rifampin to standard therapy have also seen higher incidences of elevated transaminases or hepatitis in the rifampin groups (18
). Without clear documentation in most patient charts, it was not possible to determine whether rifampin led to other adverse effects.
Because rifampin is a potent inducer of the cytochrome P-450 system, potential drug-drug interactions are numerous (6
). We found that unrecognized drug-drug interactions occurred in more than half (52%) of the patients in the rifampin group. Failure by clinicians to recognize rifampin's many drug-drug interactions could lead to higher rates of toxicity from rifampin itself or from the other drugs whose action is potentiated by decreased clearance and subsequently increased serum levels.
We cannot conclude whether the addition of rifampin to standard therapy for native valve S. aureus
IE affects patient outcomes. Our data suggest that patients who received rifampin were less likely to have survived the episode of S. aureus
IE than those who did not. One possible explanation for this finding is that patients who received rifampin had a more severe illness than those who did not; APACHE II scores were higher in rifampin-treated patients, though this difference was not statistically significant. When outcomes were analyzed by APACHE II scores, however, no difference between groups was found. In a retrospective study, it is difficult to isolate rifampin's effect on the outcome from other variables. The prospective randomized trial by Levine et al. (18
) also showed that rifampin plus vancomycin was no better than vancomycin alone for treatment of MRSA IE, though that trial was likely underpowered to detect a true difference. One possibility for a lack of benefit from rifampin is that there is a negative interaction between the standard antibiotic therapy and rifampin such that serum levels of the former are reduced or its serum bactericidal activity for S. aureus
is decreased. This possibility has been illustrated in vitro in previous studies with oxacillin (29
), nafcillin (10
), vancomycin (10
), and teicoplanin (10
We also found that patients who received rifampin had significantly longer total durations of bacteremia than did controls (median of 5.2 versus 2.1 days; P
< 0.001). When these results were analyzed by whether bacteremia had cleared at the time of rifampin initiation, cases receiving rifampin before clearance of bacteremia still had statistically significantly longer durations of bacteremia than controls (median of 4.0 days versus 2.1 days; P
= 0.004). Levine et al. (18
) also found a longer median duration of bacteremia (9 versus 7 days) in the rifampin group in their prospective, randomized controlled trial, though this trend was not statistically significant. A recent retrospective, case-control study comparing outcomes of patients with persistent S. aureus
bacteremia (>7 days) to those with nonpersistent S. aureus
bacteremia (<3 days) also found that patients in the former group were more likely to receive either rifampin or gentamicin (odds ratio = 8.10), although they did not clarify the proportion receiving each drug (12
). Thus, in our retrospective study, it is difficult to separate the effect of rifampin on the duration of bacteremia from the severity of illness; the fact that cases receiving rifampin before clearance of bacteremia still had significantly longer durations of bacteremia than controls may indicate that severity of illness played less of a role.
There are several potential limitations to this study. First, these results are based on patients from a single institution, and so the use of rifampin at our institution may not be generalizable to other institutions. The matched-cohort design of this study would have benefited from a larger control group to reduce confounding variables, especially confounding by indication, whereby patients with longer durations of bacteremia were the ones receiving rifampin; furthermore, a prospective trial would have made the findings more robust. Also, our study was not large enough to discern a difference between outcomes for patients with methicillin-sensitive S. aureus versus MRSA IE. More cases than controls received gentamicin, which also may have impacted the results—the fact that cases were more likely to have been prescribed gentamicin may be an indicator that they appeared sicker to clinicians; however, gentamicin is not generally noted to be hepatotoxic or to interfere with the cytochrome P-450 system, and so the toxicity and drug interaction findings of this study were unlikely to be affected by its use. Lastly, we could not determine the reasoning for why rifampin was added to standard therapy, because this information was rarely if ever documented by the treating clinicians in the patient's medical chart.
Our results suggest that adding rifampin to standard antibiotic therapy for the treatment of native valve S. aureus IE should be done with caution, especially if the patient has not cleared the bacteremia or is HCV infected. Potential problems of hepatotoxicity, drug-drug interactions, and the emergence of resistant S. aureus isolates should prompt a careful risk-benefit assessment before adding rifampin to standard antibiotic therapy for the treatment of native valve S. aureus IE until further clinical studies are performed.