Rifampin for biofilm-related Infections

Note from Dr Lee

Ask a clinical pharmacologist

Staphylococcus aureus is a major human pathogen causing various infections ranging from mild to life-threatening in both adults and children,^1,2 and is a significant cause of morbidity in children requiring hospitalization.³ The bacterium colonizes both tissue and artificial surfaces in humans causing chronic persistent infections that are difficult to cure.⁴ These challenging infections include osteomyelitis, endocarditis, indwelling catheter-associated infections, lung infections (particularly in patients with chronic lung disease such as cystic fibrosis), and chronic wounds, which often necessitate surgical interventions and prolonged antibiotic treatment. Thus, there is an unmet clinical need to target S aureus in biofilm-related infections.⁵

Therapies for biofilm-related infection

New antibiotics aimed to overcome S aureus antibiotic resistance are being developed with some already in clinical use in both adults and children.⁶ Specific therapies for biofilm-related infection, however, are scarce. Rifamycins are a class of antibiotics originally shown to be produced by a Gram-positive bacteria Amycolatopsis rifamycinica in 1957 (designated Streptomyces mediterranei at the time).⁷ It has excellent bactericidal activity against susceptible Gram-positive bacteria including S aureus and inhibits bacterial DNA-dependent RNA polymerase independently of bacterial division, resulting in activity against slowly dividing “dormant” organisms.⁸ It is active within acidic environments as well as anaerobic conditions⁹ and accumulates within neutrophils¹⁰ and osteoblasts.¹¹ These properties render rifamycins particularly attractive to be used as therapeutics for biofilm-related infections.

However, the high risk of emergence of rifamycin-resistant mutants requires the concomitant administration of another antibiotic.⁸ Preclinical data from animal models support the use of rifampin, the clinically available derivative of rifamycins, in combination with several antibiotics, such as vancomycin and linezolid.^9,12-14 Early clinical attempts of combination therapy were promising; for example, 2 pediatric cases of endocarditis with failure to control bacteremia with vancomycin showed clearance of infection after addition of rifampin.¹⁵ A prospective double-blind, randomized controlled trial that examined the addition of rifampin to ciprofloxacin for S aureus orthopedic implant infection demonstrated cure without removal of the implant only when rifampin was added to the regimen.¹⁶

However, other studies including 3 randomized controlled trials evaluating the utility of adjunctive rifampin together with cloxacillin, vancomycin, cotrimoxazole, or fusidic acid did not demonstrate any additional benefit.¹⁷ This may be due to interaction and, in some cases, even antagonism between rifampin and these antibiotics.^13,18 Most recently, a large randomized controlled trial involving 758 adults with S aureus bacteremia showed no benefit to adding rifampin over standard antibiotic therapy, although this was associated with a small reduction in bacteriologic failure or recurrence.¹⁹ A deep infection focus was present at baseline in only 301 (40%) participants and 139 (18%) had no established infection focus. The few patients with a deep infection focus or endocarditis included in the trial did substantially better with rifampin, although this trial cannot provide definite answers in these difficult-to-treat scenarios because very few patients were included (of 758 patients, 14 [2%] had prosthetic heart valves or joints and 36 [5%] had implanted vascular devices).

Finally, patients receiving rifampin with a second drug different from flucloxacillin (including other betalactams or vancomycin) had a worse outcome (primary endpoint, 29 [23%] of 127 patients), suggesting that the effect of rifampin could be associated with the companion antibiotic used. Currently, combination therapy with rifampin is recommended by the Infectious Diseases Society of America (IDSA) guidelines for the treatment of the following staphylococcal infections: prosthetic joint infections; infective endocarditis in the presence of prosthetic valves; and ventriculitis and meningitis with hardware.^8,20-23 Some experts recommend the adjunctive use of rifampin for the treatment of methicillin-resistant S aureus (MRSA) even without hardware, particularly for osteomyelitis and central nervous system infections.²⁴

Pharmacokinetics of rifampin

Rifampin is easily absorbed from the gastrointestinal tract and orally administered rifampin results in peak plasma concentrations (C_max) in about 2 to 4 hours.^25,26 Rifampin follows enterohepatic circulation and is metabolized by the liver. Once deacetylated, it can no longer be reabsorbed by the intestines and is eliminated from the body with 60% to 65% of the drug being excreted through feces. Urinary elimination accounts for only about 30% of drug excretion.

The activity of rifampin is concentration dependent, and either C_max or the area under the concentration curve (AUC) divided by the minimal inhibitory concentration (MIC) best correlates with bacterial killing.^25,27 Rifampin shows a nonlinear increase in exposure with dose-saturable biliary excretion.^25,26 On the other hand, autoinduction by rifampin, caused by induction of liver enzymes and transporters, decreases rifampin exposure with time.^26,28 Steady-state is achieved after at least a week of treatment, at which point C_max and the AUC are both reduced to approximately half, compared with the levels following the first dose (for adults: C_max, 5.79 mg/L vs 8.98 mg/L; AUC, 38.73 mg/h/L vs 72.56 mg/h/L).^22,29

Despite the extensive clinical use of rifampin, the optimal daily dose and dosage frequency are not well defined. Adult dosage varies between 300 mg twice daily, 600 mg once daily, 450 mg twice daily, and 900 mg once daily.²² These are adequate in terms of achieving C_max and AUC levels equal to or above the MIC. However, these were not compared with each other in terms of treatment efficacy as well as drug concentration at the site of infection.³⁰

Dosage recommended for children was extrapolated from the adult dosage based on the assumption that the same dose per kg is appropriate across all ages. The limited pharmacokinetic information in children suggests that young children receiving adult-derived dosages have drug exposures significantly lower than adults.^31,32 In fact, children receiving recommended standard dosages of 10 mg/kg demonstrated very low serum rifampin concentrations with a mean AUC of 18.1 mg/h/L at steady-state, which is about half of adult levels.³³ These recommendations also are at least partly based on historical concerns of toxicity with higher rifampin doses and what was then a high cost associated with the manufacturing of the drug.³⁴

Rifampin-related toxicity includes gastrointestinal symptoms, hepatotoxicity, hypersensitivity reactions, and, rarely, severe immunologic reactions including acute renal failure, thrombocytopenia, and “flu-like” syndrome. Severe toxicity with rifampin is infrequent and more recent studies demonstrate that higher doses up to 40 mg/kg are well tolerated in adults.^35-38 Drug interaction is a major consideration as rifampin induces several cytochrome P450 enzymes, particularly CYP2C19 and CYP3A4, and thus increases the hepatic metabolism of numerous agents such as birth control pills, ketoconazole, quinidine, prednisone, oral hypoglycemics (sulfonylureas), digitalis, methadone, warfarin, clarithromycin, and protease inhibitors. One other adverse effect is orange discoloration of secretions, including urine, feces, saliva, sweat, and tears.

Higher doses of rifampin for S aureus infections

Since its introduction in the 1960s, rifampin has been considered the cornerstone of tuberculosis (TB) treatments and was beneficial in shortening the treatment duration. With accumulating data demonstrating increased efficacy of high-dose rifampin for TB,^28,35-38 higher doses of rifampin could be beneficial for S aureus infections as well, particularly when associated with biofilms with foreign materials.

Current recommendations of rifampin dosing in children with biofilm-associated S aureus infection is 10 mg/kg/d to 20 mg/kg/d, given in 1 to 3 doses, with a maximum of 600 mg per dose and 900 mg/d.^20,21,23 Given the pharmacokinetic properties of rifampin in children and the probable lower risk of toxicity, we would favor a higher dose of at least 20 mg/kg/d. Further studies are needed to evaluate the potential of high-dose rifampin to better and even shorten the duration of treatment for biofilm-associated S aureus infections without added safety risks.

References:

1. Rasigade JP, Vandenesch F. Staphylococcus aureus: a pathogen with still unresolved issues. Infect Genet Evo. 2014;21:510-514.

2. Tong SY, Davis JS, Eichenberger E, Holland TL, Fowler VG Jr. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev. 2015;28(3):603-661.

3. Ondusko DS, Nolt D. Staphylococcus aureus. Pediatr Rev. 2018;39(6):287-298.

4. Bhattacharya M, Wozniak DJ, Stoodley P, Hall-Stoodle, L. Prevention and treatment of Staphylococcus aureus biofilms. Expert Rev Anti Infect Ther. 2015;13(12):1499-1516.

5. Richter K, Van den Driessche F, Coenye T. Innovative approaches to treat Staphylococcus aureus biofilm-related infections. Essays Biochem. 2017;61(1):61-70.

6. Sharma R, Francois D, Hammerschlag MR. New antimicrobial agents for the treatment of staphylococcal infections in children. Pediatr Clin North Am. 2017;64(6):1369-1387.

7. Sensi P. History of the development of rifampin. Rev Infect Dis. 1983;5 suppl 3:S402-S406.

8. Perlroth J, Kuo M, Tan J, Bayer AS, Miller LG. Adjunctive use of rifampin for the treatment of Staphylococcus aureus infections: a systematic review of the literature. Arch Intern Med. 2008;168(8):805-819.

9. Norden CW, Shaffer M. Treatment of experimental chronic osteomyelitis due to Staphylococcus aureus with vancomycin and rifampin. J Infect Dis. 1983;147(2):352-357.

10. Mandell GL. The antimicrobial activity of rifampin: emphasis on the relation to phagocytes. Rev Infect Dis. 1983;5 suppl 3:S463-S467.

11. Valour F, Trouiillet-Assant S, Riffard N, et al. Antimicrobial activity against intraosteoblastic Staphylococcus aureus. Antimicrob Agents Chemother. 2015;59(4):2029-2036.

12. Baldoni D, Haschke M, Rajacic Z, Zimmerli W, Trampuz A. Linezolid alone or combined with rifampin against methicillin-resistant Staphylococcus aureus in experimental foreign-body infection. Antimicrob Agents Chemother. 2009;53(3):1142-1148.

13. Dworkin R, Modin G, Kunz S, Rich R, Zak O, Sande M. Comparative efficacies of ciprofloxacin, pefloxacin, and vancomycin in combination with rifampin in a rat model of methicillin-resistant Staphylococcus aureus chronic osteomyelitis. Antimicrob Agents Chemother. 1990;34(6):1014-1016.

14. Thompson JM, Saini V, Ashbaugh AG, et al. Oral-only linezolid-rifampin is highly effective compared with other antibiotics for periprosthetic joint infection: study of a mouse model. J Bone Joint Surg Am. 2017;99(6):656-665.

15. Faville RJ Jr, Zaske DE, Kaplan EL, Crossley K, Sabath LD, Quie PG. Staphylococcus aureus endocarditis. Combined therapy with vancomycin and rifampin. JAMA. 1978;240(18):1963-1965.

16. Zimmerli W, Widmer AF, Blatter M, Frei R, Ochsner PE. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA. 1998;279(19):1537-1541.

17. Coiffier G, Albert JD, Arvieux C, Guggenbuhl P. Optimizing combination rifampin therapy for staphylococcal osteoarticular infections. Joint Bone Spine. 2013;80(1):11-17.

18. Van der Auwera P. Joly P. Comparative in-vitro activities of teicoplanin, vancomycin, coumermycin and ciprofloxacin, alone and in combination with rifampicin or LM 427, against Staphylococcus aureus. J Antimicrob Chemother. 1987;19(3):313-320.

19. Thwaites GE. Scarborough M, Szubert A, et al; United Kingdom Clinical Infection Research Group (UKCIRG). Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2018;391(10121):668-678.

20. Baddour LM. Wilson WR, Bayer AS, et al; American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015;132(15):1435-1486.

21. Tunkel AR. Hasbun R, Bhimraj A, et al. 2017 Infectious Diseases Society of America’s Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis. Clin Infect Dis. February 14, 2017; Epub ahead of print.

22. Sendi P, Zimmerli W. Antimicrobial treatment concepts for orthopaedic device-related infection. Clin Microbiol Infect. 2012;18(12):1176-1184.

23. Osmon DR, Barbari EF, Berendt AR, et al; Infectious Diseases Society of America. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(1):e1-e25.

24. Liu C, Bayer A. Cossrove SE et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011;52(3):285-292.

25. Acocella G. Pharmacokinetics and metabolism of rifampin in humans. Rev Infect Dis. 1983;6 suppl 3:S428-S432.

26. Mandell GL, Bennett JE, Dolin R. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill Livingstone/Elsevier; 2010.

27. Hirai J, Hagihara M, Kato H, et al. Investigation on rifampicin administration from the standpoint of pharmacokinetics/pharmacodynamics in a neutropenic murine thigh infection model. J Infect Chemother. 2016;22(6):387-394.

28. Svensson R.J, Aarnoutse RE, Diacon AH, et al. A population pharmacokinetic model incorporating saturable pharmacokinetics and autoinduction for high rifampicin doses. Clin Pharmacol Ther. 2018;103(4):674-683.

29. Stott KE, Pertinez H, Sturkenboom MGG, et al. Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis. J Antimicrob Chemother. 2018;73(9):2305-2313.

30. O’Reilly T, Kunz S, Sande E, Zak O, Sande MA, Täubr MG. Relationship between antibiotic concentration in bone and efficacy of treatment of staphylococcal osteomyelitis in rats: azithromycin compared with clindamycin and rifampin. Antimicrob Agents Chemother. 1992;36(12):2693-2697.

31. Diacon AH, Patientia RF, Venter A, et al. Early bactericidal activity of high-dose rifampin in patients with pulmonary tuberculosis evidenced by positive sputum smears. Antimicrob Agents Chemother. 2007;51(8):2994-2996.

32. Donald PR, Maritz JS, Diacon A.H. The pharmacokinetics and pharmacodynamics of rifampicin in adults and children in relation to the dosage recommended for children. Tuberculosis (Edinb). 2011;91(3):196-207.

33. Schaaf HS, Willemse M, Cilliers K, et al. Rifampin pharmacokinetics in children, with and without human immunodeficiency virus infection, hospitalized for the management of severe forms of tuberculosis. BMC Med. 2009;7:19.

34. van Ingen J, Aarnoutse RE, Donald PR, et al. Why do we use 600 mg of rifampicin in tuberculosis treatment? Clin Infect Dis. 2011;52(9):e194-e199.

35. Ruslami R, Nijiand HM, Alisjahbana B, Parwati I, van Crevel R, Aarnoutse RE. Pharmacokinetics and tolerability of a higher rifampin dose versus the standard dose in pulmonary tuberculosis patients. Antimicrob Agents Chemother. 2007;51(7):2546-2551.

36. Peloquin CA, Velásquez GE, Lecca L, et al. Pharmacokinetic evidence from the HIRIF Trial to support increased doses of rifampin for tuberculosis. Antimicrob Agents Chemother. 2017;61(8):e00038-17. Erratum in: Antimicrob Agents Chemother. 2017;61(9):e01524-17.

37. Boeree MJ, Diacon AH, Dawson R, et al; PanACEA Consortium. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. Am J Respir Crit Care Med. 2015;191(9):1058-1065.

38. Aarnoutse RE, Kibiki GS, Reither K, et al; PanACEA Consortium. Pharmacokinetics, tolerability, and bacteriological response of rifampin administered at 600, 900, and 1200 milligrams daily in patients with pulmonary tuberculosis. Antimicrob Agents Chemother. 2017;61(11):e01054-17