http://orcid.org/0000-0003-3029-9624
Figures
Abstract
Background
Staphylococcus aureus (S. aureus) bacteremia (SAB) has high morbidity and mortality, with the development of methicillin-resistant S. aureus (MRSA) and the recognized shortcomings of vancomycin, its management is becoming more complicated. Considering the capability to penetrate cells, tissues and biofilms, rifampin has been used as adjunctive agent to against staphylococcal activity.
Objectives
We performed this meta-analysis, aimed to explore the efficacy of adjunctive rifampin for the treatment of SAB.
Methods
Medical literatures were searched in the Pubmed, Medline, Embase and Cochrane databases up to October 2018. Patients with SAB received treatment with or without rifampin were included. The risk ratio (RR) and 95% confidence intervals (CI) of mortality, rate of bacteriological failure and relapse were estimated.
Results
Seven articles (five randomized controlled trials and two retrospective cohort studies) enrolling 979 and 636 patients of SAB treated with and without rifampin, respectively, were included. There was no difference of mortality between the adjunctive rifampin therapy and standard therapy on SAB (RR: 0.771, 95% CI: 0.442 to 1.347, I2 = 70.4%). In the subgroup analyses, the decreased mortality was observed in the adjunctive rifampin treatment for patients without MRSA infection (RR: 0.509, 95% CI: 0.372 to 0.697, I2 = 8.8%). In addition, there was no difference of the rate of bacteriologic failure (RR: 0.602, 95% CI: 0.198 to 1.825, I2 = 0.0%) or relapse (RR: 0.574, 95% CI: 0.106 to 3.112, I2 = 77.9%) between the adjunctive rifampin therapy and standard therapy on SAB.
Citation: Ma H, Cheng J, Peng L, Gao Y, Zhang G, Luo Z (2020) Adjunctive rifampin for the treatment of Staphylococcus aureus bacteremia with deep infections: A meta-analysis. PLoS ONE 15(3): e0230383. https://doi.org/10.1371/journal.pone.0230383
Editor: Giuseppe Vittorio De Socio, Azienda Ospedaliera Universitaria di Perugia, ITALY
Received: November 3, 2019; Accepted: February 28, 2020; Published: March 19, 2020
Copyright: © 2020 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper.
Funding: This study was funded by the National Key Clinical Specialty Discipline Construction Program of China (2011-873) to HM. No additional external funding was received for this study. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Staphylococcus aureus (S. aureus) is known as an important human pathogen of serious bacterial infections, frequently leads to bacteremia, pneumonia [1], further causes metastatic infections such as infective endocarditis (IE) [2], osteomyelitis [3], skin and soft-tissue infection [1] through the blood migration. Among these infections, S. aureus bacteremia (SAB) has been recognized with significant morbidity and mortality [4,5]. Although anti-staphylococcal β-lactamase-resistant penicillin has been recommended as the mainstay of methicillin-sensitive S. aureus (MSSA) management, with the development of methicillin-resistant S. aureus (MRSA), the management of SAB is becoming even more complicated [6,7]. As the effective therapeutic option for most gram-positive organisms through inhibition of cell wall synthesis, vancomycin has been recommended as the treatment of most infections of MRSA [8,9]. Nevertheless, when considering of its shortcomings such as the increasing minimum inhibitory concentrations (MICs), slow bactericidal activity, poor tissue penetration, reduced activity against biofilm pathogens [10], some other antibiotics with anti-MRSA activity, including linezolid, daptomycin, gentamicin and rifampin, have been suggested as alternatives [11,12]. Among those alternatives, with the capability to penetrate cells and various tissues [13,14], rifampin was regarded as an effective agent to improve antibacterial action and broaden the spectrum of anti-staphylococcal activities [12]. However, the doubt on the use of rifampin in all infections due to S. aureus is well known. Evidence has indicated the benefits of adjunctive rifampin therapy on those S. aureus infections involving prostheses, such as prosthetic valve endocarditis (PVE) and prosthetic joint infection (PJI) [8,9,15,16], in contrast, adding rifampin for the treatment of S. aureus infections not involving inserted medical devices, was not recommend [8,9]. Despite that, as shown in a previous survey, infectious diseases consultants (IDCs) were asked to give treatment choices for a patient with persistent MRSA bacteremia, more than half of IDCs still chose to add rifampin when MIC of vancomycin approaching the limit of the susceptible range [17]. Meanwhile, clinical cases that add rifampin to SAB patients (regardless foreign devices presented or not) were not rare, in regard to evaluation of the efficacy of adjunctive rifampin, two systematic reviews have been published so far, one conducted by Russell CD et al. [18] indicated the possible benefits of adjunctive rifampin on reducing mortality and clinical/bacteriological failure, yet another one [19] drew opposite conclusion. Considering the complicated management of SAB and controversial opinion regarding adjunctive use of rifampin, further research is needed. Therefore, we decided to update present available evidence, by enlarging the numbers of trials and enrolling more subjects, information was collected from studies involving patients with SAB. We aimed to better define the efficacy of adjunctive rifampin for the treatment of SAB, with respect to the rate of death, bacteriological failure and relapse.
Methods
Information sources and search key words
Using the Pubmed, Medline, Embase and Cochrane databases, searches for relevant articles were performed with the following items: (rifampin [Title/Abstract] OR rifampicin [Title/Abstract]) AND (Staphylococcus aureus [Title/Abstract] OR S. aureus [Title/Abstract]). Searches were limited to articles published in English till October 2018. Furthermore, additional references were identified from citations in the articles that were reviewed.
Eligible criteria
The related literatures were evaluated by reviewing the titles and abstracts, and further assessed by reviewing the full texts. Studies involving patients with SAB were included. Participants received two types of therapy: standard therapy (may differed among each study) and standard therapy combined with rifampin, otherwise the treatments were regarded as ineligible. We selected the incidence of death as primary outcome, rate of bacteriologic failure and relapse as secondary outcomes, studies recorded other unsuitable outcomes were not included. Case reports, reviews, notes or comments were excluded.
Data extraction and quality assessment
Information extracted included first author name, year of publication, study design, pathogen, sites of deep infection, daily rifampin dose, duration of rifampin therapy, standard therapy, number of subjects in each group, number of event and nonevent in each group, primary and secondary outcomes. The Cochrane tool for assessing the risk of bias was used to assess the quality of each RCT [20]. The risk of bias was assessed according to seven criteria including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. Each item was judged to obtain an assessment of ‘low risk’, ‘high risk’ or ‘unclear risk’. The quality of each cohort study was assessed according to Newcastle-Ottawa Scale (NOS) [21], the total score ranges from 0 to 9, and a higher score indicates higher quality. Disagreements among the investigators were resolved by review of the assessments to reach consensus. Quality of evidence (QoE) for outcomes reported in the included trials was assessed using the GRADE methodology and GRADE pro (Computer program located at https://www.gradeworkinggroup.org/). The GRADE system offers four categories of the quality of the evidence (i.e. high, moderate, low and very low).
Statistical analysis
Statistical analyses were performed using the Stata Version 15.0 software. Pooled risk ratio (RR) and 95% confidence intervals (CI) for all the outcomes were evaluated, considering the variations of the included studies, random effects model was used in all analyses. The statistical heterogeneity was determined by chi-square test and I2 statistics (P value ≤ 0.10 and/or I2>50% was considered to be significant). To explore the possible sources of heterogeneity, sensitive analysis and subgroup analysis were conducted, subgroups were stratified according to the study designs (cohort study and RCT) and situation of MRSA infection (presence or absence of MRSA infection). Publication bias was visually evaluated using funnel plots and statistically assessed using Egger’s and Begg’s tests. Statistical significance was set at a P value < 0.05 for all analyses.
Results
Searching results
Searches of literatures initially identified 1840 potentially relevant records. Following review of the title and abstract, 1722 records were excluded, and a further 111 were excluded following full-text review to give 7 eligible studies, as shown in Fig 1. The reasons for further exclusion included: review articles (n = 15), case report (n = 11), notes of comments (n = 12), no bacteremia (n = 8), treatment ineligible (n = 29) and no suitable outcomes recorded (n = 36).
Characteristics of the studies
A total of 7 studies [22–28] (five randomized controlled trials and two retrospective cohort studies) published from 1983 to 2017 containing 979 and 636 patients treated with or without rifampin, respectively, were included in the meta-analysis. S. aureus was the only isolated pathogen in studies, information of MRSA was given in five studies but missed in two [22,23]. Deep infections varied among each study, containing pneumonia, endocarditis, osteomyelitis and foreign body infections and so on. Details regarding daily dose and duration of rifampin therapy were given in six studies (ranged from 450 to 1200mg via intravenously or orally) but missed in one [26]. Standard therapy also varied, vancomycin was the commonest used agent, others including oxacillin, penicillin, cefuroxime, daptomycin, and so on. Primary outcome was reported in all studies, rate of bacteriologic was reported in three studies [22,23,28], and three studies [26–28] provided data of relapse rate. The information of the included articles is summarized in Table 1.
Quality assessment
In general, the scores of two retrospective cohort studies are both eight, the risk of bias of RCTs was unclear or low. The lack of blinding of participants and personnel and incomplete outcome data in two studies led to an increase of the risk of bias to some degree, the result of quality assessment is given in Fig 2. Using the GRADE, the overall QoE for all assessed outcomes was rated as moderate to low (S1 Table).
Pool analysis
Primary outcome: Mortality.
Seven studies [22–28] reported the rate of death in SAB patients. Pooled analysis showed there was no difference of mortality between adjunctive rifampin treatment group and control group (RR: 0.771, 95% CI: 0.442 to 1.347, random effects model), a significant heterogeneity was observed (I2 = 70.4%, P = 0.002), as shown in Fig 3.
RR, risk ratio, CI, confidence interval.
Sensitivity analysis showed that removal of each single study did not alter the overall results of pooled analyses (Fig 4). High heterogeneity was partly minimized through further subgroup analysis. Adding rifampin for the treatment of patients without MRSA infection, the rate or mortality was reduced compared to control group (RR: 0.509, 95% CI: 0.372 to 0.697), with low heterogeneity was observed (I2 = 8.8%, P = 0.295). However, there was no statistical difference of mortality in other subgroups, as shown in Table 2.
CI, confidence interval.
Secondary outcomes.
Rate of bacteriologic failure. Three studies [22,23,28] reported the rate of bacteriologic failure in SAB patients. There is no difference of bacteriologic failure between adjunctive rifampin treatment and standard therapy (RR: 0.602, 95% CI: 0.198 to 1.825, random effects model), with no heterogeneity was observed (I2 = 0.0%, P = 0.630), as shown in Fig 5.
RR, risk ratio, CI, confidence interval.
Rate of relapse. Three studies [26–28] reported the rate of relapse in SAB patients. There is no difference of relapse rate between patients treated with and without addition of rifampin after pooling the data with meta-analysis (RR: 0.574, 95% CI: 0.106 to 3.112), a significant heterogeneity was observed (I2 = 77.9%, P = 0.011), as shown in Fig 6.
RR, risk ratio, CI, confidence interval.
Publication bias
There appeared to be funnel plot asymmetry for the incidence of death (Fig 7), but Begg’s and Egger’s test indicated no evidence of publication bias (P Begg: 0.548 and P Egger: 0.334).
SE, standard error, RR, risk ratio.
Discussion
Rifampin is known as an effective antibacterial agent with the ability of penetrating cells and various tissues, againsting intracellular phagocytized S. aureus and preventing the haematogenous dissemination [29,30]. Therefore, it was adjunctively used for the treatment of S. aureus infection, aimed to improve antibacterial action and broaden the spectrum of anti-staphylococcal activity. So far, two systematic reviews evaluating efficacy of adjunctive rifampin therapy for SAB, have been published: one indicated the reduced mortality, clinical or bacteriological failure in adjunctive rifampin group [18], yet another one [19] demonstrated adding rifampin showed no benefits on decreasing survival rates, even further indicated the prevalence of rifampin resistance and prolonged duration of bacteremia. Given the above inconsistent opinion and out of date studies included in both reviews, we aimed to update present evidence by enlarging the accessible studies with our best efforts.
Pooled analyses of our meta analyses showed there is no difference of incidence of mortality, rate of bacteriologic failure or relapse between adjunctive rifampin group and control group. Several explanations exist for the results.
First one should be the development of rifampin resistance, mechanism of which is known as the single bp changes in the b-subunit of the rpoB encoded RNA polymerase [31]. Previous studies already indicated the correlation of rifampin resistance development and decreased microbiological eradication rate [32,33]. Although the resistance was considered most likely to developed when rifampin was used as monotherapy, relevant reports were also not rare in combination therapy [32–36]. Of the included studies, one study [26] demonstrated 9 of 42 patients who received rifampin combination therapy developed rifampin-resistance, longer duration of bacteremia and were less likely to survive than controls. Another one [28] reported rifampin resistance was developed in 2 of 56 patients. However, both studies didn’t further compare the microbiological eradication rate between patients with and without rifampin resistance. In addition, the commonest used standard therapy in the included studies was vancomycin, yet concentration of which was showed varying greatly among organs including heart valve, lung, breast, subcutaneous fat, and muscle tissue [37,38], inversely, rifampin has sustained penetration into the above and other organs [39,40]. Of patients recruited in our meta analyses, most had infection of various organs such as lung, endocardium and so on, therefore, in the case of tissues solely exposed to rifampin, the rapid development of rifampin resistance may be easier developed.
Furthermore, other explanation may be the antagonism effect of rifampin and standard antibiotics when used as clinical combination. Vitro studies investigating the anti-staphylococcal activity of rifampin combination therapy often yielded conflict results, both antagonism and synergy effect were observed [41–46]. This phenomenon may due to the different test system utilized, for instance, different result might be obtained from timed-kill and checkerboard method [47]. Whether two agents show antagonism or synergy effect while combined using may also be affected by the serum concentration: the reduced killing activity was observed when the concentration ratio of standard antibiotic to rifampin was high, but was enhanced at low ratio [45]. This explanation can be illustrated by the results of two included studies: when rifampin was added during the early treatment period which the serum concentration of standard antibiotic was relatively high, a reduction in bactericidal activity was observed [22]; similarly, in another study, patients who failed therapy tended to have higher serum concentration of standard antibiotic than those with a satisfactory therapy response [24].
Moreover, as the potent inducer of the cytochrome p450 system, rifampin is well documented to cause clinically significant drug interactions, including interactions with cardiovascular drugs, antidiabetic agents, antibacterials such as linezolid, moxifloxacin, and so on [48]. A previous study reported a possible interaction between linezolid and rifampin in the combination therapy of MRSA infection, which further leading to the decreased serum levels of linezolid [49]. Nevertheless, none of the included studies evaluating the drug interaction between rifampin and standard antibiotics, whether it existed or how much it contributed to the treatment outcome is uncertain.
Additionally, we tried to explore the possible sources of heterogeneity, subgroups first were stratified according to different study design (cohort study or RCT), in each subgroup, no statistical difference of mortality was detected and the high heterogeneity cannot be minimized. We further conducted subgroup analysis according to the situation of MRSA infection (presence or absence of MRSA infection). Reduced mortality rate of adjunctive rifampin group was only detected in patients without MRSA infection (MSSA bacteremia). However, before we consider the possible benefits of adjunctive rifampin on MSSA bacteremia, a fact shouldn’t be ignored: compared to patients who receive rifampin, the patients treated without rifampin were significantly older, significantly more often had chronic renal failure, a fatal underlying disease or hospital-acquired SAB [25], or had a higher rate of healthcare associated SAB, which might lead to poorer SAB outcome [27].
Meanwhile, two included studies reported other events during treatment: Forsblom E et al. [27] compared the incidence of severe bacteremia and septic shock between short term rifampin therapy (0–13 days) and standard therapy, no difference was observed. In another study [24], one and zero patient developed into septic shock in rifampin group and control group, respectively. Whereas there were insufficient data to define the overall difference regarding those outcomes.
Our meta-analysis was performed based on a highly sensitive and comprehensive search of the literatures, we aimed to update present evidence by identifying as many relevant studies as possible. However, it has some unavoidable limitations. The first one is the small number of included articles. Despite our best efforts to retrieve all related data, with limited well-structured clinical trials to examine the efficacy of rifampin for SAB, fewer literatures were able to meet our stringent inclusion criteria. The high heterogeneity of pooled analysis would be another limit. Although it was partly minimized through subgroup analysis, other factors such as various sites of infection (the presence or absence of medical devices), variation in standard therapy, variation in dose and duration of rifampin treatment, may co-contribute to the high heterogeneity, yet the absence of the related data limited a subgroup analysis to explore further.
Conclusion
Based on our results, insufficient evidence supported the efficacy of adjunctive use of rifampin for treatment of SAB, adding rifampin to standard therapy didn’t decrease the incidence of death, rate of bacteriologic failure and relapse.
Supporting information
S1 Table. GRADE evidence profile summarizing the effect of adjunctive rifampin therapy vs. standard therapy on Staphylococcus aureus bacteremia (SAB).
https://doi.org/10.1371/journal.pone.0230383.s001
(PDF)
References
- 1. Diekema DJ, Pfaller MA, Schmitz FJ, Smayevsky J, Bell J, Jones RN, et al. Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997–1999. Clin Infect Dis 2001; Suppl 2: S114–32.
- 2. Fowler VG Jr, Miro JM, Hoen B, Cabell CH, Abrutyn E, Rubinstein E, et al. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA 2005; 293:3012–21. pmid:15972563
- 3. Lobati F, Herndon B, Bamberger D. Osteomyelitis: etiology, diagnosis, treatment and outcome in a public versus a private institution. Infection 2001; 29:333–6. pmid:11787835
- 4.
Health Protection Agency: Voluntary reporting of Staphylococcus aureus bacteremia in England, Wales, and Northern Ireland January–December 2008. http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1258560519595.
- 5. Wyllie DH, Crook DW, Peto TE. Mortality after Staphylococcus aureus bacteremia in two hospitals in Oxfordshire, 1997–2003: cohort study. BMJ 2006; 333:281. pmid:16798756
- 6. Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 2007; 298:1763–71. pmid:17940231
- 7. Klevens RM, Edwards JR, Tenover FC, McDonald LC, Horan T, Gaynes R. Changes in the epidemiology of methicillin-resistant Staphylococcus aureus in intensive care units in US hospitals, 1992–2003. Clin Infect Dis 2006; 42:389–91. pmid:16392087
- 8. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, 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; 52:285–92. pmid:21217178
- 9. Gould F K, Brindle R, Chadwick P R, Fraise AP, Hill S, Nathwani D, et al. Guidelines (2008) for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the United Kingdom. J Antimicrob Chemother 2009; 63:849–861. pmid:19282331
- 10. Kollef MH. Limitations of vancomycin in the management of resistant staphylococcal infections. Clin Infect Dis 2007; 45 Suppl 3: S191–5.
- 11. Micek ST. Alternatives to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2007; 45 Suppl 3: S184–90.
- 12. Stan Deresinski. Vancomycin in Combination with Other Antibiotics for the Treatment of Serious Methicillin‐Resistant\r, Staphylococcus aureus\r, Infections. Clin Infect Dis 2009; 49:1072–9. pmid:19725789
- 13. Ge Z, Wang Z, Wei M. Measurement of the concentration of three antituberculosis drugs in the focus of spinal tuberculosis. Eur Spine J 2008; 17:1482–7. pmid:18795341
- 14. Darouiche RO, Hamill RJ. Antibiotic penetration of and bactericidal activity within endothelial cells. Antimicrob Agents Chemother 1994; 38:1059–64. pmid:8067738
- 15. 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; 168:805–19. pmid:18443255
- 16. Forrest GN, Tamura K. Rifampin combination therapy for nonmycobacterial infections. Clin Microbiol Rev 2010; 23:14–34. pmid:20065324
- 17. Hageman J. C., Liedtke L. A., Sunenshine R. H., Strausbaugh L. J., McDonald L. C., and Tenover F. C. Management of persistent bacteremia caused by methicillin-resistant Staphylococcus aureus: a survey of infectious diseases consultants. Clin. Infect. Dis 2006; 43:e42–e45. pmid:16886141
- 18. Russell CD, Lawson McLean A, Saunders C, Laurenson IF. Adjunctive rifampicin may improve outcomes in Staphylococcus aureus bacteremia: a systematic review. J Med Microbiol 2014; 63:841–8. pmid:24623637
- 19. Tremblay S, Lau TT, Ensom MH. Addition of rifampin to vancomycin for methicillin-resistant Staphylococcus aureus infections: what is the evidence? Ann Pharmacother 2013; 47:1045–54. pmid:23715070
- 20. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928. pmid:22008217
- 21. Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. 2005. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 31 May 2017.
- 22. Van der Auwera P, Meunier-Carpentier F, Klastersky J. Clinical study of combination therapy with oxacillin and rifampin for staphylococcal infections. Rev Infect Dis 1983; 5 Suppl 3: S515–22. pmid:6356280
- 23. Van der Auwera P, Klastersky J, Thys JP, Meunier-Carpentier F, Legrand JC. Double-blind, placebo-controlled study of oxacillin combined with rifampin in the treatment of staphylococcal infections. Antimicrob Agents Chemother 1985; 28:467–72. pmid:3907494
- 24. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicilin-resistant Staphylococcus aureus endocarditis. An. Int. Med 1991; 115:674–80.
- 25. Ruotsalainen E, Järvinen A, Koivula I, Kauma H, Rintala E, Lumio J, et al. Levofloxacin does not decrease mortality in Staphylococcus aureus bacteremia when added to the standard treatment: a prospective and randomized clinical trial of 381 patients. J Intern Med 2006; 259:179–90. pmid:16420547
- 26. Riedel DJ, Weekes E, Forrest GN. Addition of rifampin to standard therapy for treatment of native valve infective endocarditis caused by Staphylococcus aureus. Antimicrob Agents Chemother 2008; 52:2463–7. pmid:18474578
- 27. Forsblom E, Ruotsalainen E, Järvinen A. Improved outcome with early rifampicin combination treatment in methicillin-sensitive Staphylococcus aureus bacteraemia with a deep infection focus—a retrospective cohort study. PLOS ONE 2015; 10: e0122824. pmid:25874546
- 28. Thwaites GE, Scarborough M, Szubert A, Nsutebu E, Tilley R, Greig J, et al. Adjunctive rifampicin for Staphylococcus aureus bacteremia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2018; 391:668–78. pmid:29249276
- 29. Murdoch MB, Peterson LR. Antimicrobial penetration into polymorphonuclear leukocytes and alveolar macrophages. Semin Respir Infect 1991; 6:112–21. pmid:1771302
- 30. Mandell G L, Vest T K. Killing of Intraleukocytie Staphylococcus aureus by Rifampin: In-Vitro and In-Vivo Studies. J Infect Dis 1972; 125:486–90. pmid:5023643
- 31. Campbell EA, Korzheva N, Mustaev A, Murakami K, Nair S, Goldfarb A, et al. Structural mechanism for rifampicin inhibition of bacterial rna polymerase. Cell 2001; 104:901–12. pmid:11290327
- 32. Jung YJ, Koh Y, Hong SB, Chung JW, Ho Choi S, Kim NJ, et al. Effect of vancomycin plus rifampicin in the treatment of nosocomial methicillin-resistant Staphylococcus aureus pneumonia. Crit Care Med 2010; 38:175–80. pmid:20050336
- 33. Tan CK, Lai CC, Lin SH, Hsueh PR. Vancomycin plus rifampicin for methicillin-resistant Staphylococcus aureus pneumonia benefits only those who have no development of rifampicin resistance during treatment. Crit Care Med 2010; 38:1754–5. pmid:20647809
- 34. Henry NK, Rouse MS, Whitesell AL, McConnell ME, Wilson WR. Treatment of methicillin resistant Staphylococcus aureus experimental osteomyelitis with ciprofloxacin or vancomycin alone or in combination with rifampin. Am J Med 1987; 82:73–5.
- 35. Lai CC, Tan CK, Lin SH, Liao CH, Huang YT, Hsueh PR. Emergence of rifampicin resistance during rifampicin-containing treatment in elderly patients with persistent methicillin-resistant Staphylococcus aureus bacteremia. J Am Geriatr Soc 2010; 58:1001–3. pmid:20722839
- 36. Ju O, Woolley M, Gordon D. Emergence and spread of rifampicin resistant, methicillin-resistant Staphylococcus aureus during vancomycin rifampicin combination therapy in an intensive care unit. Eur J Clin Microbiol Infect Dis 2006; 25:61–2. pmid:16331332
- 37. Stein GE, Wells EM. The importance of tissue penetration in achieving successful antimicrobial treatment of nosocomial pneumonia and complicated skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus: vancomycin and linezolid. Curr Med Res Opin 2010; 26:571–88. pmid:20055750
- 38. Cruciani M, Gatti G, Lazzarini L, Furlan G, Broccali G, Malena M, et al. Penetration of vancomycin into human lung tissue. J. Antimicrob. Chemother 1996; 38:865–9. pmid:8961057
- 39. Kropec A, Daschner FD. Penetration into tissues of various drugs active against gram-positive bacteria. J Antimicrob Chemother 1991; 27:9–15.
- 40. Mindermann T, Zimmerli W, Gratzl O. Rifampin concentrations in various compartments of the human brain: a novel method for determining drug levels in the cerebral extracellular space. Antimicrob Agents Chemother 1998; 42:2626–9. pmid:9756766
- 41. Bayer A S, Lam K. Efficacy of vancomycin plus rifampin in experimental aortic-valve endocarditis due to methicillin-resistant Staphylococcus aureus: in vitro-in vivo correlations. J Infect Dis 1985; 151:157–65. pmid:3965588
- 42. Shelburne SA, Musher DM, Hulten K, Ceasar H, Lu MY, Bhaila I, et al. In vitro killing of community-associated methicillin-resistant Staphylococcus aureus with drug combinations. Antimicrob Agents Chemother 2004; 48:4016–9. pmid:15388469
- 43. Azzam Saleh-Mghir, Nourdine Ameur, Claudette Muller-Serieys, Farid Ismael, Françoise Lemaitre, Laurent Massias, et al. Combination of quinupristin-dalfopristin (Synercid) and rifampin is highly synergistic in experimental Staphylococcus aureus joint prosthesis infection. Antimicrob Agents Chemother 2002; 46:1122–4. pmid:11897604
- 44. Lowy FD, Chang DS, Lash PR. Synergy of combinations of vancomycin, gentamicin, and rifampin against methicillin-resistant, coagulase-negative staphylococci. Antimicrob. Agents Chemother 1983; 23:932–4. pmid:6555016
- 45. Zinner S H, Lagast H, Klastersky J. Antistaphylococcal activity of rifampin with other antibiotics. J Infect Dis 1981; 144:365–71. pmid:6270215
- 46. Norden CW. Experimental chronic staphylococcal osteomyelitis in rabbits: treatment with rifampin alone and in combination with other antimicrobial agents. Rev Infect Dis. 1983; 5(suppl 3): S491–4.
- 47. Bayer AS, Morrison JO. Disparity between timed-kill and checkerboard methods for determination of in vitro bactericidal interactions of vancomycin plus rifampin versus methicillin-susceptible and -resistant Staphylococcus aureus. Antimicrob Agents Chemother 1984; 26:220–3. pmid:6567464
- 48. Baciewicz AM, Chrisman CR, Finch CK, Self TH. Update on rifampin, rifabutin, and rifapentine drug interactions. Curr Med Res Opin 2013;29(1):1–12. pmid:23136913
- 49. Gebhart BC, Barker BC, Markewitz BA. Decreased serum linezolid levels in a critically ill patient receiving concomitant linezolid and rifampin. Pharmacotherapy 2007; 27:476–9. pmid:17316160