Division of Infectious Diseases

Take Home Points:

• Rifampin should not be used to treat S. aureus native valve endocarditis. 
• There is currently low-quality evidence that suggests potential benefit for using rifampin to treat prosthetic valve endocarditis caused by S. aureus and only limited reports of outcomes from infections with commonly used bioprosthetic valves. The need for improved therapy in this serious infection is great. 
• Safety concerns warrant further investigation to adequately weigh the risks versus benefits and optimal dosing of using adjunctive rifampin for treatment of prosthetic valve endocarditis caused by S. aureus.

Background

Staphylococcus aureus is now considered to be the most common causative organism of infective endocarditis (IE).¹ Every patient with a S. aureus bloodstream infection is at high risk of IE because the organism harnesses the ability to form structured biofilm matrices on indwelling medical devices and host tissue, which allows it to evade immune system defense mechanisms and impede penetration of antimicrobial drugs.² This is just one mechanism that contributes to the significant virulence of S. aureus. 

Findings from several in vitro and in vivo studies have provided a strong theoretical framework regarding rifampin’s unique pharmacokinetic and pharmacodynamic profile and its clinical utility for treating S. aureus infections.³ Rifampin’s high volume of distribution, ability to penetrate biofilms, and bactericidal activity against staphylococci make it a seemingly advantageous choice for treating S. aureus IE.⁴ However, resistance develops rapidly to rifampin when used alone so it should always be in combination with other antimicrobials. Recommendations for the treatment of staphylococcal IE depend on whether prosthetic material is involved, and rifampin is only recommended in select circumstances. 

Guidelines for Staphylococcal Native Valve Endocarditis (NVE) 

For the treatment of staphylococcal NVE, the most current guidelines from the American Heart Association & Infectious Diseases Society of America (AHA/IDSA) recommend against the routine use of rifampin for staphylococcal NVE. Instead, 6 weeks of intravenous (IV) anti-staphylococcal penicillins (nafcillin/oxacillin) or cefazolin for oxacillin-susceptible strains and IV vancomycin or daptomycin monotherapy for oxacillin-resistant strains.¹

Why Isn’t Rifampin Recommended for S. aureus NVE?

The utilization of rifampin as adjunctive therapy for NVE caused by S. aureus has been shown to lead to increased rates of hepatotoxicity and overall mortality.¹ Riedel and colleagues conducted a retrospective, matched-cohort study to compare clinical outcomes between 42 patients who had received adjunctive rifampin and 42 patients who received standard therapy for treatment of S. aureus NVE. They found that patients treated with rifampin had decreased survival at 30 days or hospital discharge (79% versus 95%; P = 0.048), increased median length of hospital stay (21.3 days versus 14.7 days; P = 0.09), and increased median length of bacteremia (5.2 days versus 2.1 days; P < 0.001). In addition, patients that received rifampin were more prone to have elevated hepatic transaminases (9 cases versus 1 case; P = 0.014). Although, the authors of this article note that these elevations were only observed in patients with underlying hepatitis C virus (HCV) infection who had baseline levels exceeding the upper limit of normal.⁵

Guidelines for Staphylococcal Prosthetic Valve Endocarditis (PVE) 

PVE due to S. aureus has been estimated to have a mortality rate of >45%.⁶ Due to the significant mortality and morbidity that is associated with PVE caused by S. aureus, combination antimicrobial therapy including rifampin is advised per AHA/IDSA guidelines.¹ They recommend IV anti-staphylococcal penicillins or cefazolin for oxacillin-susceptible strains and IV vancomycin for oxacillin-resistant strains, in combination with IV gentamicin during the first 2 weeks and IV or by mouth (PO) rifampin for the total duration of 6 weeks.^1,7 The European Society of Cardiology (ESC) guidelines have very similar recommendations for the treatment of staphylococcal PVE; however, they suggest a daily dose of rifampin 900-1200 mg IV or PO in 2 or 3 divided doses. They also note that some experts recommend delaying the initiation of rifampin after 3-5 days until bacteremia has cleared.⁶ This is because of the risk of resistance developing during the stage of infection when bacteria are dividing in the bloodstream.

Why is Rifampin Recommended for S. aureus PVE?

The AHA/IDSA guideline recommendation to use rifampin is based on its activity against S. aureus and animal models. In the animal models, rats received subcutaneous implants to mimic prosthetic hardware and were subsequently inoculated with bloodstream isolates of methicillin-resistant S. aureus (MRSA). The findings of this study suggest that combination antimicrobial regimens containing rifampin are superior to single-drug regimens for sterilization of indwelling hardware infected with MRSA.⁸ However, the appropriateness of extrapolating this data to the treatment of IE in humans is somewhat debated.

Uncertainties Surrounding the Use of Rifampin

Timing of rifampin initiation

The reasoning for ESC’s recommendation to delay initiation of rifampin until clearance of bacteremia is due to in vitro observations of antagonistic effects against replicating bacteria and synergistic effects on dormant bacteria when combining rifampin with oxacillin.^6,9 An additional in vitro study conducted by Zinner et al. showed that rifampin had synergistic effects on low concentrations of oxacillin, but antagonistic effects on high concentrations of oxacillin.¹⁰

Rifampin dosing

AHA/IDSA guidelines note that their recommended dose of 300 mg three times daily is not supported by any pharmacokinetic studies.¹ In a 2020 survey of 557 infectious diseases physicians in the United States and Canada, 91% reported using rifampin to treat staphylococcal PVE; however, the majority (55%) of respondents reported that they had used a dose of 300 mg twice daily.¹¹ Inconsistencies regarding dosing of rifampin and various in vitro studies showing its highly variable pharmacokinetic and pharmacodynamic profile highlight the need for additional studies.

Is Rifampin Use Associated with Better Outcomes for the Treatment of S. aureus PVE?

A retrospective analysis performed by Drinkovic and colleagues showed that the rate of valve sterilization was not significantly different in patients with S. aureus PVE who were treated with rifampin versus those that were not (67% versus 63%).¹² More recently, Le Bot et al. conducted a multicenter observational retrospective cohort study to assess the impact of using rifampin for treatment of staphylococcal PVE. Baseline characteristics were similar between the group that received rifampin and the group that did not receive rifampin. However, MRSA was more prevalent in patients treated with rifampin (21.9% versus 6.0%; P = 0.04). After multivariate analysis, they found only 3 variables that were independently associated with 1-year mortality: cerebral emboli, definite IE based on the modified Duke criteria, and MRSA. Of the 180 patients enrolled in this study, 114 of them had PVE due to S. aureus. They found no significant difference in in-hospital, six-month, and one-year mortalities and no significant difference in relapse rate between the 64 patients who received rifampin-based combination treatment and the 50 patients who did not receive rifampin. However, they did show that patients treated with rifampin had a significantly longer length of hospital stay than those that did not receive rifampin (42.8 + 20.1 days versus 30.7 + 14.7 days; P = 0.0006). The authors of this study also point out that a substantial proportion (43.9%) of patients with staphylococcal PVE did not receive rifampin.⁷ This may reflect an evolving clinical approach to treating IE in which rifampin-based combination therapy is seemingly falling out of favor; however, due to the limited sample size and large period (2000-2018) in which data were collected for this retrospective analysis, it is difficult to make this presumption. Moreover, data in this study were obtained from 3 referral centers located in western France. Thus, their findings may not be representative of practice patterns in other European countries or the United States. 

Rifampin: Warnings & Precautions

A key concern with rifampin is its potent cytochrome P-450 (CYP) system-inducing effects. It has its most potent inducing effects on CYP3A4, but it has also been shown to induce CYP2C9, CYP2C19, CYP1A2, UDP-glucuronyltransferase (UGT), and P-glycoprotein (P-gp).¹³ Consequently, rifampin is a common perpetrator of drug-drug interactions. Below is a table of major relevant drug-drug interactions.^13-15 Significant interactions exist with a long list of other drugs that are not shown.

Interacting Drug	Effect	Reference(s)
Anticonvulsants -Lamotrigine -Phenytoin -Valproic acid	↑Clearance ↑Clearance ↑Clearance	13, 15 13, 15 13, 15
Antibiotics -Cefazolin -Doxycycline -Linezolid -Moxifloxacin	↑Risk of bleeding ↑Clearance ↓Exposure ↓Exposure	13 14, 15 13, 14 13, 14
Antifungals -Caspofungin -Fluconazole -Isavuconazonium -Itraconazole -Ketoconazole -Voriconazole	↓Exposure ↑Metabolism ↓Exposure (Contraindicated) ↓Exposure ↓Exposure ↓Exposure (Contraindicated)	13, 14, 15 13, 14, 15 13 13 13 13
Antiretrovirals -Bictegravir -Cabotegravir -Dolutegravir -Elvitegravir -Raltegravir -Ritonavir	↓Exposure (Contraindicated) ↓Exposure (Contraindicated) ↓Exposure ↓Exposure  ↓Exposure ↓Exposure (Contraindicated)	13 13 13 13 13 13, 14
Cardiovascular Agents -Amiodarone -Carvedilol -Digoxin -Diltiazem -Metoprolol	↑Metabolism  ↓Exposure ↓Oral bioavailability ↑Metabolism  ↓Exposure	13, 15 13, 15 13, 15 13, 15 15
Anticoagulants -Warfarin -Apixaban -Rivaroxaban	↓Exposure ↓Exposure ↓Exposure	13, 15 13 13

Mechanical heart valves place patients at high risk for valvular thrombosis and therefore necessitate lifelong anticoagulation with warfarin. Bioprosthetic heart valves are less durable than mechanical valves; however, they are less thrombogenic and only require 3 months of anticoagulation following placement.¹⁶ Direct oral anticoagulants (DOACs) such as rivaroxaban and apixaban are sometimes used off-label for patients with bioprosthetic heart valves.¹⁷Nonetheless, drug-drug interactions become a concern when rifampin is used to treat PVE in the setting of oral anticoagulation due to its tendency to decrease exposure of warfarin and DOACs, subsequently reducing their efficacy. This risk can be more readily mitigated in patients taking warfarin by routinely monitoring international normalized ratio (INR) and adjusting its dose accordingly. The interaction between DOACs and rifampin is more challenging to manage due to the limited ability to monitor. In addition to anticoagulants, the use of rifampin is contraindicated with several antiretrovirals and antifungals. This makes rifampin a much less appealing agent for any indication in patients with HIV and/or certain fungal infections. 

Discoloration of bodily fluids is a common yet benign side effect of rifampin. Despite having a relatively mild side effect profile, the use of rifampin has been associated with serious adverse effects such as hepatotoxicity and interstitial nephritis.¹⁴ This, along with its effects on CYP450 enzymes, should be taken into consideration when determining if rifampin can be safely used to treat patients with PVE caused by S. aureus. 

Conclusions

The European and American guidelines that were both published in 2015 strongly recommend the use of adjunctive rifampin for treatment of staphylococcal PVE. Despite the extensive uptake of this practice, it has not yet been shown to be effective. Additional clinical trials will be needed to better elucidate the clinical utility of rifampin in staphylococcal PVE. Furthermore, drug-drug interactions and patient-specific factors such as renal and hepatic function should be heavily considered when determining if rifampin can be safely used for staphylococcal PVE in individual patients.

References:

1. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: Diagnosis, antimicrobial therapy, and management of complications. Circulation. 2015;132(15):1435-1486. doi:10.1161/cir.0000000000000296 
2. Vor L, Rooijakkers SH, Strijp JA. Staphylococci evade the innate immune response by disarming neutrophils and forming biofilms. FEBS Letters. 2020;594(16):2556-2569.doi:10.1002/1873-3468.13767 
3. Perlroth J, Kuo M, Tan J, Bayer AS, Miller LG. Adjunctive use of rifampin for the treatment of Staphylococcus aureus infections. Archives of Internal Medicine. 2008;168(8):805. doi:10.1001/archinte.168.8.805 
4. Adema JL, Ahiskali A, Fida M, Mediwala Hornback K, Stevens RW, Rivera CG. Heartbreaking Decisions: The Dogma and Uncertainties of Antimicrobial Therapy in Infective Endocarditis. Pathogens. 2023; 12(5):703. https://doi.org/10.3390/pathogens12050703
5. Riedel DJ, Weekes E, Forrest GN. Addition of rifampin to standard therapy for treatment of native valve infective endocarditis caused by staphylococcus aureus. Antimicrobial Agents and Chemotherapy. 2008;52(7):2463-2467. doi:10.1128/aac.00300-08 
6. Habib G, Lancellotti P, Iung B. 2015 ESC guidelines on the management of infective endocarditis: A big step forward for an old disease. Heart. 2016;102(13):992-994. doi:10.1136/heartjnl-2015-308791 
7. Le Bot A, Lecomte R, Gazeau P, Benezit F, Arvieux C, Ansart S, Boutoille D, Le Berre R, Chabanne C, Lesouhaitier M, Dejoies L, Flecher E, Chapplain JM, Tattevin P, Revest M. Is Rifampin Use Associated With Better Outcome in Staphylococcal Prosthetic Valve Endocarditis? A Multicenter Retrospective Study. Clin Infect Dis. 2021 May 4;72(9):e249-e255. doi: 10.1093/cid/ciaa1040. PMID: 32706879.
8. Lucet JC, Herrmann M, Rohner P, Auckenthaler R, Waldvogel FA, Lew DP. Treatment of experimental foreign body infection caused by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 1990 Dec;34(12):2312-7. doi: 10.1128/AAC.34.12.2312. PMID: 2128441; PMCID: PMC172053.
9. Van der Auwera P, Klastersky J. In vitro study of the combination of rifampin with oxacillin against Staphylococcus aureus. Rev Infect Dis. 1983 Jul-Aug;5 Suppl 3:S509-14. doi: 10.1093/clinids/5.supplement_3.s509. PMID: 6635442.
10. Zinner SH, Lagast H, Klastersky J. Antistaphylococcal activity of rifampin with other antibiotics. J Infect Dis. 1981 Oct;144(4):365-71. doi: 10.1093/infdis/144.4.365. PMID: 6270215.
11. Huang G, Gupta S, Davis KA, Barnes EW, Beekmann SE, Polgreen PM, Peacock JE Jr. Infective Endocarditis Guidelines: The Challenges of Adherence-A Survey of Infectious Diseases Clinicians. Open Forum Infect Dis. 2020 Aug 24;7(9):ofaa342. doi: 10.1093/ofid/ofaa342. PMID: 32964063; PMCID: PMC7489528.
12. Drinkovic D, Morris AJ, Pottumarthy S, MacCulloch D, West T. Bacteriological outcome of combination versus single-agent treatment for staphylococcal endocarditis. Journal of Antimicrobial Chemotherapy. 2003;52(5):820-825. doi:10.1093/jac/dkg440 
13. Rifampin. In: Clinical Pharmacology [database on the Internet]. Tampa (FL): Elsevier; 2023 [cited 2023 Jun 3]. Available from: www.clinicalpharmacology.com. Subscription required to view.
14. Forrest GN, Tamura K. Rifampin combination therapy for nonmycobacterial infections.Clinical Microbiology Reviews. 2010;23(1):14-34. doi:10.1128/cmr.00034-09 
15. Pai MP, Momary KM, Rodvold KA. Antibiotic drug interactions. Medical Clinics ofNorth America. 2006;90(6):1223-1255. doi:10.1016/j.mcna.2006.06.008 
16. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: A report of the american college of cardiology/american heart association joint committee on clinical practice guidelines. Circulation. 2021;143(5). doi:10.1161/cir.0000000000000923 
17. Kalra A, Raza S, Jafry BH, et al. Off-label Use of Direct Oral Anticoagulants in Patients Receiving Surgical Mechanical and Bioprosthetic Heart Valves. JAMA Netw Open. 2021;4(3):e211259. doi:10.1001/jamanetworkopen.2021.1259