Adjunctive Use of Rifampin for the Treatment of Staphylococcus Aureus Infections: a Systematic Review of the Literature

Home , Etest, Glycylcycline, Novobiocin, Rokitamycin, Sisomicin, Sitafloxacin

REVIEW ARTICLE Adjunctive Use of Rifampin for the Treatment of Staphylococcus aureus Infections A Systematic Review of the Literature

Joshua Perlroth, MD; Melissa Kuo, MD; Jennifer Tan, MHS; Arnold S. Bayer, MD; Loren G. Miller, MD, MPH

Background: Staphylococcus aureus causes severe life- efit of adjunctive rifampin use, particularly in osteomy- threatening infections and has become increasingly com- elitis and infected foreign body infection models; however, mon, particularly methicillin-resistant strains. Rif- many studies failed to show a benefit of adjunctive therapy. ampin is often used as adjunctive therapy to treat S aureus Few human studies have addressed the role of adjunc- infections, but there have been no systematic investiga- tive rifampin therapy. Adjunctive therapy seems most tions examining the usefulness of such an approach. promising for the treatment of osteomyelitis and prosthetic device–related infections, although studies were Methods: A systematic review of the literature to iden- typically underpowered and benefits were not always seen. tify in vitro, animal, and human investigations that compared single antibiotics alone and in combination with Conclusions: In vitro results of interactions between rif- rifampin therapy against S aureus. ampin and other antibiotics are method dependent and often do not correlate with in vivo findings. Adjunctive Results: The methods of in vitro studies varied substan- rifampin use seems promising in the treatment of clini- tially among investigations. The effect of rifampin therapy cal hardware infections or osteomyelitis, but more de- was often inconsistent, it did not necessarily correlate with finitive data are lacking. Given the increasing incidence in vivo investigations, and findings seemed heavily de- of S aureus infections, further adequately powered in- pendent on the method used. In addition, the quality of vestigations are needed. data reporting in these investigations was often subop- timal. Animal studies tended to show a microbiologic ben- Arch Intern Med. 2008;168(8):805-819

TAPHYLOCOCCUS AUREUS INFEC- more limited than those for methicillin- tions are common, severe, and susceptible S aureus strains. Further- associated with significant more, treatment failure with standard morbidity and mortality. therapies for MRSA is common.13-15 There Staphylococcus aureus is the is a need to better understand the effi- mostS common cause of skin and soft- cacy of antimicrobial therapies for MRSA tissue infections and is a frequent cause of and difficult-to-treat S aureus infections. serious infections such as health care– Rifampin, a broad-spectrum antimicro- associated bloodstream infections,1,2 device- bial agent that is bactericidal against S au- Author Affiliations: Division of associated infections,3,4 and osteomyeli- reus, achieves high intracellular levels and Infectious Diseases tis.5,6 Worldwide, S aureus is the most is one of the few antimicrobial agents that (Drs Perlroth, Bayer, and common cause of infective endocarditis.7,8 can penetrate biofilms and kill organisms Miller) and Los Angeles 16-18 Biomedical Research Institute Of concern, the number of infections in the sessile phase of growth. Its use (Ms Tan and Dr Miller), caused by methicillin-resistant S aureus as monotherapy has been abandoned be- Department of Medicine, (MRSA) continues to rise. In intensive care cause of the rapid development of resis- Harbor-UCLA Medical Center, units, the proportion of S aureus infec- tance, which is prevented by combina- Torrance, California, tions that are MRSA in the United States tion with another active antibiotic. St Mary Medical Center, Long has been increasing by 3% per year, and Combination therapy with rifampin has Beach (Dr Kuo), and Division MRSA now constitutes more than 60% of been used to treat S aureus infections.19,20 of Infectious Diseases, David S aureus strains that cause infections.9 Nevertheless, it has been commonly used Geffen School of Medicine at Methicillin-resistant S aureus has been re- adjunctively to treat S aureus infec- the University of California, 19,20 Los Angeles (Drs Bayer and cently implicated as the causative agent of tions. However, data to support this Miller). Dr Kuo is now with life-threatening community-acquired in- practice are limited and are typically based Division of Infectious Diseases, fections such as sepsislike syndromes, nec- on small clinical studies or basic in vitro Department of Medicine, rotizing pneumonia, and necrotizing fasci- investigations. To our knowledge, there University of California, Irvine. itis.10-12 Therapeutic options for MRSA are has been no attempt to synthesize the lit-

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 erature that has examined the effi- DATA EXTRACTION RESULTS cacy of rifampin therapy against S aureus. To this aim, we con- Each investigator was blinded to the ducted a systematic review of the use other investigator’s data extraction. The The results of the literature search of rifampin as adjunctive therapy to 2 reviewers independently rejected or ac- and the reasons for exclusion from treat S aureus infections. cepted each abstract based on the inclu- the systematic review are summa- sion and exclusion criteria. Article texts rized in the Figure. To facilitate of selected abstracts were reviewed, as review of our findings, results are METHODS were article texts of abstracts that could summarized herein as in vitro in- not be excluded based on abstract re- vestigations, animal investigations, LITERATURE SEARCH view alone. All disagreements between the abstractors as to whether the article and human investigations. should be included were settled by a To identify in vitro, animal, and hu- third independent reviewer (L.G.M.). IN VITRO INVESTIGATIONS man subject data regarding the efficacy Data from each trial were entered onto of rifampin as adjunctive therapy for the a standardized form, verified for accu- treatment of S aureus, 2 independent re- We identified 72 publications com- racy, and input into a computerized da- viewers (J.P. and M.K.) searched paring antibiotic efficacy with and tabase. Information extracted included PubMed, Cochrane Library, and study design, antibiotics tested, num- without rifampin using in vitro mod- EMBASE for publications containing the ber of subjects, year of publication, du- els (Table 1). Of 164 individual text phrases Staph* AND rifamp*. These ration of follow-up, clinical setting (in antibiotic trials in these 72 publica- terms were used to avoid ignoring ar- vitro, animal, or human), and interven- tions, 41 trials tested both methicillin- ticles with permutations of the words tion (dosage, frequency, and duration of susceptible S aureus and MRSA Staphylococcus and rifampin, (eg, Staph therapy or exposure). Abstracted data in- aureus or rifampicin). All abstracts were strains. We found that methods used cluded the outcome (eg, mortality, clini- printed for review. The search was lim- to determine the nature of the anti- cal failure, and colony count after treat- ited to English-language articles pub- biotic interactions were heteroge- ment) and the time of evaluation of lished between January 1, 1966, and neous and included E test, time-kill treatment outcome. Discrepancies in January 31, 2006. We reviewed only curves, checkerboard assays, serum data between abstractors were identi- manuscripts relating to S aureus and not fied and resolved via discussion among bactericidal activity, and ex vivo in- coagulase-negative staphylococci. We the investigators. For human studies, 2 tracellular bactericidal activity. Even also contacted several experts in the field independent reviewers (M.K. and J.T.) within-method differences (eg, among of adjunctive rifampin therapy to deter- reviewed the 8 human subject trials and time-kill studies) were substantial in mine if there were any pertinent re- assigned them Jadad scores; disagree- terms of the media used, the inocu- cently published meeting abstracts or ments between the reviewers were settled 4 9 published articles that we missed by our lum (from 10 to 10 bacteria), the by a third independent reviewer systematic review. growth phase (ie, stationary vs log (L.G.M.). phase), the temperature of inoculation (from 36°C to 38°C), the time the INCLUSION AND EXCLUSION CFU outcomes were quantified (from CRITERIA STATISTICAL ANALYSIS 6 to 48 hours after inoculation), and An investigation was included in our sys- For investigations that did not perform the concentration of the antibiotics tematic analysis if it met each of the fol- statistical analyses but reported re- used (0.25 to many times the mean lowing criteria: (1) the organism under sults, we attempted to perform statisti- inhibitory concentration). study was S aureus; (2) the study de- cal analyses. For investigations compar- Methodological variability was re- sign compared the efficacy of 1 or more ing dichotomous outcomes, we flected in the inconsistent interactions antibiotics alone and in combination performed ␹2 or Fisher exact test. For reported. Many studies using time-kill with rifampin; (3) the study outcome as- studies comparing means, if standard de- assays failed to report results in terms sessed quantitative bacterial measure- viations and group sample sizes were of synergy or antagonism, presenting ments, cure rates (or eradication of colo- available, we performed Wilcoxon rank the data only graphically and without nization), or staphylococcal-related sum test. We did not perform analyses statistical analysis.21-25 Definitions of mortality; and (4) outcome data were ex- from investigations that reported re- plicitly reported. By the nature of our sults of statistical tests or contained in- synergy, antagonism, or indifference methods, we excluded studies report- adequate information for us to perform inindividualinvestigationsdidnotnec- ing the efficacy of rifampin therapy alone tests of significance. We initially planned essarily correlate with those of other compared with other antibiotics, the ef- to perform a meta-analysis of results but in vitro studies26-30 or were not pro- ficacy of rifampin as prophylaxis to pre- abandoned this method because study vided.31 Some investigations used cat- vent infections in uninfected hosts, or outcome heterogeneity was substantial egoriesof“additive”interactions26,32-34; the use of rifampin-impregnated de- (eg, in vivo studies variably used out- others did not specify the interaction vices or catheters. Also excluded were comes of cure rates, proportion of ster- other than as “not synergistic,”35 “not articles not containing original re- ile cultures, decrease in colony- antagonistic,”36 “improved,”37,38 “research (eg, reviews, editorials, case re- forming units [CFUs], and others). In duced,”39 or “enhanced.”40 Some did ports, abstracts, and letters). We also ex- addition, performing a meta-analysis was 41,42 amined the bibliographies of selected problematic because of the large num- notreporteachspecificinteraction. review articles for original research ar- ber of strata in disease studied (eg, bac- As shown in Table 1, many of the an- ticles that may have contained refer- teremia and abscess) and in treatment tibiotics tested with rifampin had in- ences of articles that were missed by our (␤-lactam antibiotics, glycopeptides, consistent outcomes. Some authors search criteria. fluoroquinolones, and others). noted that different concentrations of

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 antibiotics changed the nature of the interaction.30,36,43,44 Several investiga- 1293 Excluded from 249 Non–English language manuscript tionsrevealeddifferentinteractionsde- systematic review 117 Review language/or clinical guidelines∗ 1464 Articles screened pendingonthemethodused(time-kill 3 Editorial 30,33,37,45,46 35 Case report or case series vs checkerboard). Some in- 5 Comments vestigators attempted to validate in 884 Inappropriate comparison for present vitro findings with in vivo models or review† clinical outcomes.18,25,35-37,47,48 Because outcome definitions were heterogeneous and often missing, we thought 70 Excluded from 17 Review article it was hazardous and likely inappro- 171 Articles reviewed in systematic review 26 Non–Staphylococcus aureus investigation detail 1 Letter priate to summarize data or to state 11 Irrelevant‡ general conclusions from the in vitro 4 Inappropriate comparison for present review investigations. 8 Not comparative 2 Case report 101 Studies included in 1 Primary antibiotic not reported ANIMAL INVESTIGATIONS systematic review

In the animal models, between- study differences included the dos- Figure. Flow diagram of results of the literature search for comparative studies of the additive effect of rifampin, including in vitro investigations, animal investigations, and human investigations. The ing route, dosing frequency, antibi- schematic indicates how many hits were found on the search, the number of articles excluded from the otic dosages, S aureus strain used, systematic review, and the reasons for exclusion from the systematic review. *Review was determined to animal model investigated, timing be unlikely to yield references relating to adjunctive rifampin therapy for Staphylococcus aureus of outcome assessment, end point infections based on the abstract (eg, review of treatment of S aureus colonization). †Inappropriate comparisons for the systematic review included studies relating to biofilm diffusion, pharmacokinetics, studied (eg, microbiologic or cure), descriptive ecology, S aureus prophylaxis, treatment of colonization, non–S aureus organisms, clinical and duration between bacterial in- microbiology methods, review of medication adverse events, comparison of intravenous and oral oculation and therapy initiation therapies, antibiotic effects on virulence factor production, compartmental pharmacokinetics and pharmacodynamics, investigations of antibiotic-impregnated catheters or devices, observational (Table 2). Many studies did not re- investigations of antibiotic use and antimicrobial resistance, and epidemiologic investigations (including port statistical analyses. To facili- epidemiology of antimicrobial resistance, molecular epidemiologic studies, and descriptive molecular tate description of the animal inves- analyses). In addition, noncomparative studies and conference abstracts were excluded. ‡Irrelevant studies for the systematic review included studies or articles relating to treatment of colonization or tigations, we first stratified models pharmacokinetics. In addition, errata and conference abstracts were excluded. by disease and then by primary antibiotic treatment. In peritonitis models, we identi- Of 16 antibiotics used in 12 pub- ported a similar benefit (although the fied 3 studies. Of 2 investigations of lications pertaining to endocarditis, 7 therapeutic groups were directly fluoroquinolones, one noted that showed superiority of combination compared with control groups in- combination therapy resulted in a therapy, 4 showed superiority of stead of with each other but none- larger decrease in CFUs per millili- monotherapy, and 5 showed no dif- theless can be compared in a post ter and sterilization of fluid but did ference. Dual therapy was superior in hoc manner).55 not report a statistical analysis.47 The terms of decreases in CFUs or valve In osteomyelitis models, 16 anti- other investigation of fluoroquino- sterilization in trials using vancomy- biotic trials were reported in 8 pub- lones used the same end points and cin,48 cloxacillin,52 ciprofloxacin,23 lications. Statistical analyses re- found the fluoroquinolone-rifampin quinupristin-dalfopristin,52 teicopla- vealed significant reductions in combination to be superior.49 A third nin,51 and daptomycin.53 However, in positive bone cultures,56 increases in investigation stated that there was in- other investigations, dual therapy with sterile bone cultures,35,37,56-58 or re- difference or a simple additive effect vancomycin was indifferent,31,54 and ductions in CFUs per gram.58,59 In 2 when oxazolidinones were com- dual therapy with ciprofloxacin was treatment groups from 1 publica- bined with rifampin.50 worse than monotherapy.23 Dual tion, no discrete numbers were re- Two investigations examined skin therapy with oxazolidinones had in- ported in the text of the publica- and soft-tissue infections (without consistent results, with decreases in tion.60 No trial demonstrated worse hardware). One abscess model dem- CFUs reported only with low doses clinical or microbiological results in onstrated that adjunctive rifampin of linezolid.21,50 Taken in sum, inves- dual-therapy arms. with teicoplanin resulted in dimin- tigations of dual therapy with ␤- Nine treatment comparisons pre- ished CFU decrease compared with lactam antibiotics tended to show im- sented in 4 publications of device- teicoplanin monotherapy.51 The other proved microbiological outcomes as or hardware-associated infections abscess model showed that cipro- opposed to survival or valve steriliza- with adjunctive rifampin therapy floxacin plus rifampin was no more tion (Table 2). were identified. In an abscess model effective as either antibiotic alone.89 In S aureus bacteremia models, an with implanted foreign material, dual A third study of cloxacillin in a mas- investigation showed a benefit to therapy with rifampin and either titis model found that dual therapy re- adding rifampin to methicillin or tri- vancomycin, ciprofloxacin, fleroxa- sulted in statistically significant CFU methoprim.55 In a survival study cin, or teicoplanin showed superi- decreases in 3 experiments but no sig- using single-dose penicillin or tri- ority in terms of cure rate.18 Fleroxa- nificant difference in a fourth.25 methoprim, the same authors re- cin-rifampin was superior in another

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Staphylococcus aureus Strain Tested Method Interaction Reported Source Oxacillin 4 MS TK Indifference (Ͻ2-log reduction) Fass and Helsel,39 1987 25 MS TK Not antagonism Brandt et al,36 1994 1 MR plus GR TK Indifference Perdikaris et al,54 1995 20 MS TK Antagonism, indifference Watanakunakorn and Tisone,75 1982 1 MS TK Antagonism, indifference Sande and Johnson,76 1975 8 MS TK Antagonism, indifference, synergy Van der Auwera and Klastersky,77 1983 5 MR, 5 MS TK, CB, SBA Antagonism, indifference, synergy Zinner et al,30 1981 5 MR, 5 MS TK, CB, SBA Antagonism (high oxacillin), synergy (low oxacillin) Zinner et al,30 1981 10 MS TK Antagonism, indifference, synergy Lorian et al,78 1983 11 MR, 64 MS SBA Antagonism, indifference, synergy Maduri Traczewski et al,79 1983 1 MR, 1 MS TK, TK Indifference (MR, MS), antagonism (MS depending Cappelletty et al,80 1996 on antibiotic concentration) Cloxacillin 1 MS TK Indifference Craven and Anderson,25 1981 Methicillin 1 MS TK, CB Indifference Zinner et al,30 1981 Nafcillin 10 MS TK, SBA Antagonism Hackbarth et al,22 1986 2 MS Endothelial cells, CB MBC improved (decreased 4 times) Darouiche and Hamill,38 1994 20 MS CB Antagonism, indifference, synergy Tuazon et al,28 1978 20 MS TK Antagonism, indifference Watanakunakorn and Tisone,75 1982 1 MR, 1 MS TK Indifference Sato et al,64 1985 Ampicillin-Sulbactam 1 MR, 1 MS (hGISA) TK, E test, FIC Synergy (TK), indifference (TK, E test, FIC) Tsuji and Rybak,81 2006 Cefdinir 3 MS TK, CB Indifference (TK, CB), synergy (CB) Marchese et al,46 1995 Cefazolin-Cefpirome 1 MS TK Not antagonism Brandt et al,36 1994 Cephalothin 1 MS CB Indifference Norden,56 1983 5 MR, 5 MS TK, CB, SBA Antagonism, synergy Zinner et al,30 1981 Cefotiam 1 MS CB Synergy (FIC), antagonism (FBC) Zinner et al,30 1981 Ceftazidime 91a CB (FIC) Synergy, additive Simon and Littschwager,82 1985 Imipenem-Meropenem 16 MR, 22 MS TK, CB Indifference, synergy Debbia et al,83 1986 5 MR, 5 MS CB Synergy, additive Ferrara et al,26 1989 Imipenem 13 MR Defibrinated blood TK Indifference Traub et al,34 1987 Ciprofloxacin 2 MR, 8 MS TK Antagonism, indifference Røder and Gutschik,84 1989 3 MR, 2 MS TK Antagonism, indifference Van der Auwera and Joly,44 1987 2 MS TK Antagonism Kaatz et al,23 1989 1a Intracellular (monocytes) Indifference Smith et al,85 2000 1a TK, CB Indifference Gradelski et al,86 2001 10 MR, 10 MS CB Antagonism, indifference, synergy Chow et al,87 1991 1a CB Indifference Zimmerli et al,18 1994 1a Intracellular (PMNs), TK Synergy Røder et al,88 1991 2 MR, 2 MS TK Antagonism (log phase), additive (stationary phase) Bahl et al,32 1997 10 MS TK, SBA Antagonism Hackbarth et al,22 1986 2 MR, 2 MS SBA Antagonism (appears, no formal statistics done) Weinstein et al,24 1991 2 MS Endothelial cells, CB Indifference Darouiche and Hamill,38 1994 1 MS TK, in PMNs Appears indifference, “enhanced” Bamberger et al,47 1991 1 MR TK, CB Indifference (TK), synergy (CB) Kang et al,33 1994 1 MS TK, CB Indifference (TK), antagonism (CB) Kang et al,33 1994 13 MR Defibrinated blood TK Indifference Traub et al,34 1987 2a CB Additive Coe et al,89 1995

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Staphylococcus aureus Strain Tested Method Interaction Reported Source Ofloxacin 1 MR TK, CB Antagonism (TK), antagonism (CB) Kang et al,33 1994 1 MS TK, CB Additive (TK), antagonism (CB) Kang et al,33 1994 13 MR Defibrinated blood TK Indifference Traub et al,34 1987 1a In PMNs at 2 h Appears synergy Bamberger et al,49 1997 Levofloxacin 1 MR TK, CB Indifference (TK), synergy (CB) Kang et al,33 1994 1a Intracellular (monocytes) Indifference Smith et al,85 2000 1 MR, 1 MS TK Indifference Chambers et al,90 1999 1 MR, 1 MS TK Indifference (MR), appears indifference (MS) Palmer and Rybak,40 1996 Sitafloxacin-Trovafloxacin 14 MR TK Synergy (some), others unclear Giamarellou-Bourboulis et al,41 1999 Fleroxacin 10 MR, 10 MS CB Indifference Chow et al,87 1991 1a CB Indifference Zimmerli et al,18 1994 1 MR TK Antagonism at 6 h, indifference at 24 h Lucet et al,62 1990 1 MR TK Antagonism at 1-3 h, indifference at 6-24 h Chuard et al,61 1991 Pefloxacin 4 MR, 4 MS TK Appears antagonism (“reduced”) Fass and Helsel,39 1987 10 MS TK, SBA Antagonism Hackbarth et al,22 1986 Gatifloxacin 1a TK, CB Indifference Gradelski et al,86 2001 Temafloxacin 1 MR TK Antagonism Hessen et al,31 1990 2 MR, 2 MS TK (MR, MS), CB (MR) Indifference (TK), antagonism (CB) Carsenti-Etesse et al,91 1993 Vancomycin 20 MR, 30 MS TK Antagonism, indifference, synergy Watanakunakorn and Guerriero,29 1981 3 MR, 2 MS TK Antagonism, indifference, synergy Van der Auwera and Joly,44 1987 1 MR TK Antagonism Lucet et al,62 1990 1a TK, CB Antagonism (TK), no synergy (CB) Norden and Chaffer,35 1983 6a TK, CB Indifference, synergy Varaldo et al,92 1984 20 MS CB Indifference, antagonism, partial synergy Tuazon et al,28 1978 33 MR, 20 MS CB Synergy Tuazon and Miller,42 1984 35 MR, 11 MS TK Indifference, antagonism Shelburne et al,93 2004 13 MR Defibrinated blood TK Additive Traub et al,34 1987 4 MR TK Appears antagonism (“reduced”) Fass and Helsel,39 1987 60 S aureus, non–S aureus CB Indifference, synergy in 1 S aureus Varaldo et al,94 1983 1 MR, 1 MS (hGISA) TK, E test, FIC Indifference Tsuji and Rybak,81 2006 1a CB Indifference Zimmerli et al,18 1994 1 MR TK Indifference Perdikaris et al,54 1995 1 MR TK Synergy Bayer and Lam,48 1985 1 MR CB Antagonism Bayer and Lam,48 1985 26 MR TK, CB Synergy (TK), antagonism (TK, CB), indifference (TK) Bayer and Morrison,74 1984 22 MS TK, CB Synergy (TK), antagonism (TK, CB), indifference (TK) Bayer and Morrison,74 1984 1 MR, 1 MS TK Synergy (“slightly enhanced”) Palmer and Rybak,40 1996 5 MR, 5 MS CB, TK Indifference Zinner et al,30 1981 10 MS TK, SBA Indifference, antagonism Hackbarth et al,22 1986 2 MS Intracellular MBC Improved (MBC decreased 16 times) Darouiche and Hamill,38 1994 3 VISA, 1 MR TK Indifference Hershberger et al,95 1999 1 MR TK Synergy Saleh-Mghir et al,63 2002 1 MR, 1 GISA TK Antagonism Mercier et al,96 2002 37 MR CB Indifference Foldes et al,97 1983 1 MR TK Antagonism Hessen et al,31 1990 5 MR TK, CB Synergy, indifference Walsh et al,98 1986 1 MR, 1 MS TK Synergy (MR), indifference (MS), antagonism Cappelletty et al,80 1996 (MR/MS, depending on antibiotic concentration) 15 MR, 21 MS TK Indifference Darouiche et al,99 1995 1 MR, 1 MS TK Indifference Sato et al,64 1985 LY333328 (Glycopeptide) 1 MR TK Synergy Mercier et al,100 1997

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Staphylococcus aureus Strain Tested Method Interaction Reported Source Teicoplanin 3 VISA, 1 MR TK Indifference (VISA), synergy (MR) Hershberger et al,95 1999 13 MR Defibrinated blood TK Additive Traub et al,34 1987 1a CB Indifference Zimmerli et al,18 1994 10 MSSA TK, SBA Indifference, antagonism Hackbarth et al,22 1986 5 MR, 5 MS TK, SBA Indifference Van der Auwera and Joly,44 1987 5 MR, 5 MS SBA (TK) Indifference Van der Auwera and Klastersky,101 1987 Sisomicin 1 MS TK, CB “Improved” (TK), synergy (CB) Norden,37 1975 1 MS CB Synergy Norden,56 1983 Teichomycin 33 MR, 20 MS CB (MBC) Synergy Tuazon and Miller,42 1984 60 S aureus, non–S aureus CB Indifference, synergy in 1 S aureus Varaldo et al,94 1983 Coumermycin 3 MR, 2 MS TK Antagonism, indifference Van der Auwera and Joly,44 1987 13 MR Defibrinated blood TK Indifference Traub et al,34 1987 20 MR, 20 MS TK Antagonism, indifference, additive Van der Auwera and Klastersky,102 1986 Quinupristin-Dalfopristin 6 MR TK Synergy Sambatakou et al,103 1998 1 MR TK Synergy Saleh-Mghir et al,63 2002 2 MS, 7 MR TK Synergy (MR), indifference (MS, MR) Fuchs et al,104 2001 1 MR, 1 MS (hGISA) TK, E test, FIC Indifference Tsuji and Rybak,81 2006 Linezolid-Oxazolidinones 3 MR TK Indifference Mulazimoglu et al,105 1996 5 MR, 5 MS TK Indifference Grohs et al,106 2003 4 MR TK Indifference, synergy Jacqueline et al,107 2003 1 MR, 1 MS (hGISA) TK, E test, FIC Indifference Tsuji and Rybak,81 2006 1 MR TK Indifference Dailey et al,21 2003 Trimethoprim 24a CB Antagonism Kerry et al,108 1975 1 MS CB Antagonism Norden,56 1983 10 MS TK, SBA Antagonism, indifference, synergy Hackbarth et al,22 1986 Trimethoprim-Sulfamethoxazole 13 MR Defibrinated blood TK Indifference Traub et al,34 1987 Fusidic Acid 20 MR TK, CB Synergy, indifference Farber et al,109 1986 1a Intracellular (PMNs), TK Synergy Røder et al,88 1991 1a TK Synergy (nongrowing and rapid) Schierholz et al,72 1998 24 MR, 11 MS TK Antagonism (high concentration of rifampin), Drugeon et al,43 1994 synergy (low concentration of rifampin) 13 MR Defibrinated blood TK Indifference Traub et al,34 1987 5 MR, 5 MS CB Antagonism, indifference, synergy Zinner et al,30 1981 37 MR CB Indifference Foldes et al,97 1983 Fosfomycin 19 MR CB Indifference, synergy Hamilton-Miller and Maple,27 1992 3 MR, 2 MS TK, CB Indifference (TK), synergy (CB) Grif et al,45 2001 6a TK Antagonism, indifference Quentin et al,110 1987 Novobiocin 10 MR, 10 MS CB Indifference (MR, MS), synergy (MR) Chow et al,87 1991 13 MR Defibrinated blood TK Additive Traub et al,34 1987 20 MR SBA Not stated Standiford et al,111 1993 5 MR TK, CB Synergy indifference Walsh et al,98 1986 15 MR, 21 MS TK Indifference (MR, MS), antagonism (MR) Darouiche et al,99 1995 10 MR TK, CB Indifference (TK, CB), synergy (TK), antagonism (TK) Johnston et al,112 1987 Tigecycline 1 MR, 1 GISA TK Indifference Mercier et al,96 2002 Clindamycin 10 MR, 10 MS CB Antagonism, indifference, synergy Chow et al,87 1991 5 MR, 5 MS CB Antagonism, indifference, synergy Zinner et al,30 1981

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Staphylococcus aureus Strain Tested Method Interaction Reported Source Clindamycin 10 MR, 10 MS CB Antagonism, indifference, synergy Chow et al,87 1991 5 MR, 5 MS CB Antagonism, indifference, synergy Zinner et al,30 1981 Minocycline 10 MR, 10 MS CB Indifference, synergy, antagonism Chow et al,87 1991 5 MR, 5 MS TK, CB Synergy, indifference Zinner et al,30 1981 2 MS Intracellular MBC Improved (decreased 4 times) Darouiche and Hamill,38 1994 24 MR, 26 MS CB (FIC) Synergy, indifference Segreti et al,113 1989 15 MR, 21 MS TK Indifference Darouiche et al,99 1995 Daptomycin 1 MR, 1 MS (hGISA) TK, E test with FIC Indifference Tsuji and Rybak,81 2006 Erythromycin 1a TK Synergy (nongrowing), indifference (rapid) Schierholtz et al,72 1998 Mupirocin 1a TK Synergy (nongrowing and rapid) Schierholtz et al,72 1998 CL 331 002 (Glycylcycline) 1 MR, 1 MS TK Indifference, synergy (depending on antibiotic concentration) Cappelletty et al,80 1996 Tetrahydroxy-8-Lavandulyl-Flavanone 21 MR CB Partial synergy defined as FIC 0.5-1.0 Sato et al,114 1995

Abbreviations: CB, checkerboard microdilution assay; FBC, fractional bactericidal concentration; FIC, fractional inhibitory concentration; GISA, glycopeptide-intermediate S aureus; GR, gentamicin-resistant; hGISA, heterogeneous glycopeptide-intermediate S aureus; MBC, minimum bactericidal concentration; MR, methicillin-resistant S aureus; MS, methicillin-susceptible S aureus; PMNs, polymorphonuclear leukocytes; SBA, serum bactericidal activity; TK, time-kill curve assay; VISA, vancomycin-intermediate S aureus. a Not stated if MRSA or MSSA.

trial measuring sterilization of ab- decreases in mean log10 bacteria/ years. The mean Jadad score of the scess fluid.61 A study of vancomy- gland (5.7±0.2 vs 5.0±0.2).25 Some studies was 2 (median, 1 [range 0-5]), cin and fleroxacin showed de- other significant differences were One study65 did not separate S au- creased CFUs in abscess fluid and on likewise of unclear clinical signifi- reus from coagulase-negative staphy- foreign material with adjunctive rif- cance (data not shown). lococcal infections in its intent-to- ampin.62 An infected partial knee re- treat analysis, although the differences placement model testing vancomy- HUMAN INVESTIGATIONS between groups in the as-treated cin or quinupristin-dalfopristin analysis could be determined. showed a significant reduction of Of 7 identified trials in humans that ␤-Lactam antibiotics (oxacillin or CFUs in bone with adjunctive rif- compared antibacterial therapy with nafcillin) were studied in 4 trials. Oxa- ampin and a higher proportion of or without rifampin, 6 were prospec- cillin was used in 2 trials of hetero- animals with sterile bone cul- tive randomized trials, 2 were pla- geneous infection types and resulted tures.63 Finally, in a meningitis cebo controlled, and 1 was retrospec- in significantly improved cure rates model, rifampin added to nafcillin tive (some were of combined designs) in one66 but not another.67 Nafcillin or vancomycin added modest de- (Table 3). Antibiotics used in the in- was studied in 2 osteomyelitis trials creases in colony counts but no im- vestigations (in varying dosages), demonstrating that dual therapy was provement with sterilization of ce- were vancomycin, pefloxacin, cipro- equivalent to monotherapy in one rebrospinal fluid cultures.64 floxacin, oxacillin, fleroxacin, and study68 but superior in another.69 Some investigators attempted to nafcillin. Rifampin doses varied (typi- Vancomycin was used in 2 stud- correlate in vitro and in vivo effects cally 600-1200 mg/d). Study popu- ies66,67 (in which oxacillin therapy was of rifampin therapy. Commonly, a lations were small (15-65 patients) also analyzed) and as the primary contradiction or poor correlation and diverse in terms of comorbidi- study drug in an endocarditis trial of was found between the 2 meth- ties (malignant neoplasms, trauma, MRSA.70 In the first 2 trials, vanco- ods.18,36,37,47,48 We should note, while and previous surgery), sites of infec- mycin-rifampin dual therapy was su- some animal investigations’ out- tion (wound, osteomyelitis, and bac- perior in terms of cure or improve- comes achived statistical signifi- teremia), and acuity of infection ment66 and for bacteriologic success.67 cance, the clinical significance of dif- (acute to many years in the case of os- For the endocarditis investigation, ferences are unclear. For example, teomyelitis). End points were hetero- there was no difference in outcome in an investigation of mastitis in a geneous and included cure, clinical with adjunctive rifampin.70 mouse model, adjunctive rifampin improvement, and persistence of bac- In a trial of treating hardware when added to cloxacillin was as- teremia. Duration of follow-up var- infections with fluoroquinolones, sociated with a significant (PϽ.05) ied from several days to more than 3 clinical cure was achieved more

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P Value Staphylococcus Treatment Time of (Monotherapy Primary Antibiotic aureus Strain Duration, Evaluation, vs Dual Dosage Rifampin Dosage Tested Animal Disease d d Therapy) Source Ciprofloxacin 30 mg/kg IM every 8 h 20 mg/kg IM every 8 h MSSA Rabbit Peritonitis (IP 8 8, 14 NR, Ͻ.001b Bamberger et al,47 ping-pong 1991 ball) Ofloxacin 30 mg/kg IM every 8 h 20 mg/kg IM every 8 h MSSA Rabbit Peritonitis (IP 88,14 Ͻ.05, Ͻ.001 Bamberger et al,49 ping-pong 1997 ball) U-100592 and U-100766 2 Novel oxazolidinones Fixed combination MRSA Mouse Peritonitis 4 6 .08, .07 Ford et al,50 1996

based on ED50 Ciprofloxacin 4 mg/kg SQ every 2 h 0.004 mg/kg SQ every Not stated Mouse Abscess 1 1 .54b Coe et al,89 1995 24 h Teicoplanin 12.5 mg/kg SQ every day 10 mg/kg every day MSSA Rat Abscess (no 77Ͻ.01 Arioli et al,51 1986 hardware), “granuloma pouch” Cloxacillin 1 mg 25 µg MSSA Mouse Mastitis 0.75 0.75 Ͻ.05, Ͻ.001, Craven and Ͼ.05, Ͻ.02 Anderson,25 1981 Nafcillin 200 mg/kg IM 3 5 mg/kg SQ twice a day MSSA Rabbit Endocarditis 3 3 NR, .99b Brandt et al,36 1994 times a day Penicillin 150 000 U/kg IM 35 mg/kg IM 4 times MSSA Rabbit Endocarditis 1-3, 4-6, 1-3, 4-6, .2b, .073b,.3b, Sande and twice a day a day 7-12 7-12 .1b, .19b Johnson,76 1975 Cloxacillin 60 mg/kg SQ every 6 h, 20 mg/kg IV every MSSA Rabbit Endocarditis 3 3 Ͻ.03, .23b, Zak et al,52 1983 100 mg/kg SQ every 12 h, 20 mg/kg IV .12b, .05 6 h, 200 mg/kg SQ every 12 h, 2 mg/kg every 6 h IV every 12 h Cefazolin 50 mg/kg IM 3 times 5 mg/kg SQ twice a day MSSA Rabbit Endocarditis 3 3 Ͻ.01, .074b Brandt et al,36 1994 a day Cefpirome 40 mg/kg SQ 3 times 5 mg/kg SQ twice a day MSSA Rabbit Endocarditis 3 3 Ͻ.01, .51b Brandt et al,36 1994 a day Vancomycin 60 mg/kg IM every 12 h 6 mg/kg IM every 12 h MRSA Rat Endocarditis 5 5 Ͼ.05 Hessen et al,31 1990 15 mg/kg IV twice a day 10 mg/kg IM MRSA Rabbit Endocarditis 3, 7, 14 3, 7, 14 Ͻ.05, Ͻ.005, Bayer and Lam,48 twice a day Ͼ.05 1985 15 mg/kg IV every 12 h 10 mg/kg IM MRSA Rabbit Endocarditis 6, 12 6, 12 Ͼ.05 Perdikaris et al,54 twice a day 1995 Temafloxacin 100 mg/ kg gavage 6 mg/kg IM every 12 h MRSA Rat Endocarditis 5 5 NR, .37b Hessen et al,31 1990 every 12 h Teicoplanin 40 mg/kg SQ every day 2.5 mg/kg orally MSSA Rat Endocarditis 5 6 Ͻ.01 Arioli et al,51 1986 every day Ciprofloxacin 25 mg/kg IV every 8 h 10 mg/kg IM MSSA (2 Rabbit Endocarditis 6 6 Ͻ.001, Ͻ.05 Kaatz et al,23 1989 every day strains) Levofloxacin 20 mg/kg IM twice a day 5 mg/kg IM twice MRSA, MSSA Rabbit Endocarditis 4 4 Ͻ.01, Ͻ.05 Chambers et al,90 a day 1999

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P Value Staphylococcus Treatment Time of (Monotherapy Primary Antibiotic Rifampin aureus Strain Duration, Evaluation, vs Dual Dosage Dosage Tested Animal Disease d d Therapy) Source Linezolid 25 mg/kg orally 5 mg/kg IM MSSA Rabbit Endocarditis 5 5 Ͻ.05, .18b, Dailey et al,21 2003 3 times a day, 50 3 times a day .54b mg/kg orally 3 times a day, 75 mg/kg orally 3 times a day Quinupristin-Dalfopristin 30 mg/kg IM 10 mg/kg IM MRSA, MSSA Rabbit Endocarditis 4 4 Ͻ.001, Ͼ.05 Zarrouk et al,115 every 8 h every 8 h 2001 Daptomycin 40 mg/kg SQ 25 mg/kg IM MRSA Rat Endocarditis 5 5 .006 Sakoulas et al,53 every day every day 2003 Penicillin 260 mg/kg IP 20 mg/kg IP MSSA Mouse Bacteremia 1 Dose 1 Ͻ.001b Mandell and every day Moorman,55 1980 Methicillin 7.8 mg/d every day 0.4 mg/d IP MSSA Mouse Bacteremia 10 10, 30 Ͻ.05b Mandell and every day Moorman,55 1980 Trimethoprim 20 mg/kg IP 20 mg/kg IP MSSA Mouse Bacteremia 1 Dose 1 Ͻ.001b Mandell and Moorman,55 1980 0.6 mg IP every day 0.4 mg/d IP MSSA Mouse Bacteremia 10 10, 30 Ͻ.001b, NR Mandell and every day Moorman,55 1980 Vancomycin 50 mg/kg IM 5 mg/kg SQ MRSA Rat Osteomyelitis 21 21, 49 Ͻ.001b Henry et al,116 1987 twice a day every day 60 mg/kg SQ 40 mg/kg SQ MSSA Rabbit Osteomyelitis 14, 28 70 Ͻ.001b Norden and twice a day every day Shaffer,35 1983 60 mg/kg SQ 60 mg/kg SQ MRSA Rat Osteomyelitis 21-30 (mean, 4 Ͼ.05, .002 Dworkin et al,59 twice a day every day 24.2) 1990 30 mg/kg SQ 40 mg/kg orally MRSA Rabbit Osteomyelitis 28 56 NR Yin et al,60 2005 twice a day twice a day Cephalothin 50 mg/kg SQ 40 mg/kg SQ MSSA Rabbit Osteomyelitis 28 70 Ͻ.001 Norden,56 1983 3 times a day every day Ciprofloxacin 50 mg/kg SQ 10 mg/kg IM MRSA Rat Osteomyelitis 21 21, 49 Ͻ.01, .53b Henry et al,116 1987 twice a day every day 30 mg/kg SQ 10 mg/kg IM MRSA Rat Osteomyelitis 21-30 (mean, 4 Ͼ.05, Ͻ.002 Dworkin et al,59 twice a day every day 24.2) 1990 Pefloxacin 60 mg/kg SQ 10 mg/kg IM MRSA Rat Osteomyelitis 21-30 (mean, 4 Ͼ.05, Ͻ.01 Dworkin et al,59 twice a day every day 24.2) 1990 Trimethoprim 40 mg/kg SQ 40 mg/kg SQ MSSA Rabbit Osteomyelitis 28 70 NR Norden,56 1983 4 times a day every day 40 mg/kg SQ 40 mg/kg SQ MSSA Rabbit Osteomyelitis 7, 14 70 Ͻ.005 Norden and Keleti,57 4 times a day every day 1980 Sisomicin 10 mg/kg SQ 40 mg/kg SQ MSSA Rabbit Osteomyelitis 28 70 NR Norden,56 1983 every day every day 10 mg/kg SQ 40 mg/kg SQ MSSA Rabbit Osteomyelitis 28 70 Ͻ.001b Norden,37 1975 twice a day every day Gentamicin 5 mg/kg SQ 40 mg/kg SQ MSSA Rabbit Osteomyelitis 14, 28 70 Ͻ.001b Norden,37 1975 twice a day every day Clindamycin 90 mg/kg orally 20 mg/kg SQ MSSAc Rat Osteomyelitis 21 21 Ͻ.01, Ͻ.05b O’Reilly et al,58 1992 every 8 h every day

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P Value Staphylococcus Treatment Time of (Monotherapy Primary Antibiotic Rifampin aureus Strain Duration, Evaluation, vs Dual Dosage Dosage Tested Animal Disease d d Therapy) Source Azithromycin 50 mg/kg orally 20 mg/kg SQ MSSAc Rat Osteomyelitis 21 21 Ͻ.05 O’Reilly et al,58 1992 every day every day Tigecycline 14 mg/kg SQ 40 mg/kg MRSA Rabbit Osteomyelitis 28 56 NR Yin et al,60 2005 twice a day orally twice a day Vancomycin 7.5 mg/kg IP 12.5 mg/kg IP MSSA Guinea Abscess (Teflon tissue 414Ͻ.001 Zimmerli et al,18 twice a day twice a day pig cage) 1994 50 mg/kg IP 25 mg/kg IP MRSA Rat Abscess (Teflon tissue 67Ͻ.001b Lucet et al,62 1990 twice a day twice a day cage, coverslips) Teicoplanin 3.3 mg/kg IP 12.5 mg/kg IP MSSA Guinea Abscess (Teflon tissue 410Ͻ.001 Zimmerli et al,18 twice a day twice a day pig cage) 1994 Ciprofloxacin 5 mg/kg IP 12.5 mg/kg IP MSSA Guinea Abscess (Teflon tissue 410Ͻ.001 Zimmerli et al,18 twice a day twice a day pig cage) 1994 Fleroxacin 5 mg/kg IP 12.5 mg/kg IP MSSA Guinea Abscess (Teflon tissue 410Ͻ.001 Zimmerli et al,18 twice a day twice a day pig cage) 1994 50 mg/kg IP 25 mg/kg IP MRSA Rat Abscess (Teflon tissue 67Ͻ.001b, Lucet et al,62 1990 twice a day twice a day cage, coverslips) Ͻ.01b 50 mg/kg IP 25 mg/kg IP MRSA Rat Abscess (Teflon tissue 21 28 Ͻ.001 Chuard et al,61 1991 twice a day twice a day cage, coverslips) Vancomycin 60 mg/kg IM 10 mg/kg IM MRSA Rabbit Partial knee 710Ͻ.01, Ͻ.05b Saleh-Mghir et al,63 twice a day twice a day replacement 2002 Quinupristin-Dalfopristin 30 mg/kg IM every 10 mg/kg IM MRSA Rabbit Partial knee 710Ͻ.01, Ͻ.001b Chuard et al,61 1991 8hr twice a day replacement Nafcillin 40 mg/kg IV loading 100 mg/kg SQ MSSA, MRSA Rabbit Meningitis 8 h 8, 24 h NR, .91b, Saleh-Mghir et al,63 dose, then Ͼ.99b 2002 40 mg/kg/h Vancomycin 10 mg/kg IV loading 100 mg/kg SQ MSSA, MRSA Rabbit Meningitis 8 h 8, 24 h NR, .79b, .87b Sato et al,64 1985 dose, then 10 mg/kg/h

Abbreviations: ED50, median effective dose; IM, intramuscular; IP, intraperitoneal; IV, intravenous; MRSA, methicillin-resistant S aureus; MSSA, methicillin-susceptible S aureus; NR, not reported; NS, not statistically significant; SQ, subcutaneous. aMany of the animal investigations examined multiple clinical and/or microbiologic outcomes. Therefore, some study findings are represented by PՆ1. bStatistics performed by data abstractors of the systematic review and not reported in the original article. cAssumed to be MSSA.

often with dual therapy in a study with coagulase-negative Staphylo- COMMENT (P=.002).65 Cure rates were supe- coccus infections. In another trial rior in an as-treated analysis for using pefloxacin for osteomyelitis those receiving dual therapy com- or septic arthritis infections, there Rifampin is an antibiotic of great in- pared with monotherapy (P=.04).65 was no advantage to adjunctive rif- terest in the face of rising incidence, The investigation also showed a ampin therapy, although the cure morbidity, and mortality of S aureus trend toward a benefit for the rates in the monotherapy arm were infections. There is a strong theoretic rifampin-containing therapy (16 of high, creating a ceiling effect.71 In foundation as to why rifampin may 18 cured vs 9 of 15 cured, P=.10) summary, human trials investigat- provideimportantclinicaladvantages. in the intent-to-treat analysis of ing adjunctive rifampin use have Specifically, rifampin has bactericidal patients who did not have their occasionally demonstrated a ben- activity, concentrates well intracellu- hardware removed, although this eficial result in terms of clinical or larly,38 and penetrates biofilms, kill- analysis included some patients bacteriologic cure rates. ing S aureus in sessile and planktonic

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Staphylococcus Rifampin Jadad aureus Strain Dosage Dosage Study Design Disease Score Tested Outcome P Value Source Oxacillin or Vancomycin 3 g IV every 6 h 300 mg IV Randomized Cellulitis, wound, 1 MSSA, Clinical cure (MSSA); .10b, .002a,b Van der Auwera (oxacillin) or 1 g every 12 h prospective pneumonia, MRSA failure to respond et al,66 1983 IV every 12 h urinary tract (MRSA) (vancomycin) infection, endocarditis, bacteremia, osteomyelitis, other 3 g IV 4 times a 600 mg Orally Randomized Wound, bacteremia, 1 MSSA, Cure/improvement/ .60a,b, Ͻ.05 Van der Auwera day (oxacillin) or twice a day prospective, osteomyelitis, MRSA failure; bacteriologic et al,67 1985 1 g IV every 12 h placebo- septic arthritis, failure (vancomycin) controlled catheter related, empyema, pneumonia, other Vancomycin 1 g IV every 12 h 600 mg Orally Randomized Endocarditis (proven 3 MRSA Duration of bacteremia; Ͼ.05, Ͼ.05 Levine et al,70 every day prospective or probable) duration of fever 1991 (cohort analysis) Pefloxacin No standard dosing Not stated Retrospective Osteomyelitis, septic 0 Not stated Clinical cure (TJA); .83a, Ͼ.99a Desplaces and review arthritis with clinical cure (OIF) Acar,71 1988 hardware Ciprofloxacin 750 mg Orally 450 mg Orally Randomized Orthopedic hardware 5 MSSA Cure (as treated .075a, .91a, Zimmerli et al,65 every 12 h every 12 h prospective, infection analysis); cure .10 1998 placebo- negative explanted controlled hardware; cure without hardware removal (intent to treat) Nafcillin 30 mg/kg IV 300-600 mg Randomized Osteomyelitis 1 Not stated Possible cure (6 mo); Ͼ.99a, Norden et al,68 every 4 h Orally every prospective Possible cure Ͼ.99a 1983 8-12 h (12 mo) 30 mg/kg IV 300-600 mg Randomized Osteomyelitis 3 MSSA Probable cure; .061a, .37a, Norden et al,69 every 4 h Orally every prospective remission; definite .41a, .45a, 1986 8-12 h relapse; persistent Ͼ.99a infection; overall favorable response

Abbreviations: IV, intravenously; MRSA, methicillin-resistant S aureus ; MSSA, methicillin-susceptible S aureus ; NS, not significant; OIF, osteosynthesis internal fixation; TJA, total joint arthroplasty. aStatistics performed by data abstractors of the systematic review and not reported in the original article. bP values differ from those reported in the article because original calculations were in error.

(log) growth phases.18,32,47,72 To exam- ity) often correlated poorly, an obser- fects of rifampin commonly had con- ine the clinical benefit of rifampin, we vation previously noted.30,37,45,46,48,73,74 tradictory results or were poorly systematicallyidentifieddataobtained Methods often differed at other levels correlated. One group examining from in vitro studies, animal models, suchasinoculumused,outcomestud- MRSA found vancomycin-rifampin and human trials that examined the ied, and experiment duration.26-30 For- antagonism by checkerboard assay efficacy of adjunctive use of rifampin malstatisticalfindingswerefrequently and then in a subsequent animal en- forthetreatmentofSaureusinfections. unreported.21-23 Therefore,itseemsthat docarditis model found that rifampin- We found that investigations using in for in vitro investigations results are treated animals had decreased bacte- vitro methods tested rifampin com- heavilymethoddependent.Thisraises rial burden on valves and higher cure bined with many antibiotic classes. In a serious question as to whether in rates. The investigators then down- addition, we found that methods were vitro models of the efficacy of combi- played concerns that in vitro antago- heterogeneous, although the time-kill nationantibiotictherapywithrifampin nism might predict similar in vivo in- or checkerboard dilution assays against S aureus have relevance in the teractions.48 More recent studies have were most commonly used. Findings treatment of clinical infections. not tied in vivo to in vitro investiga- amongmethodtypes(time-kill,check- Likewise, studies18,36,37,47,48 that ex- tions, perhaps acknowledging that erboard, and serum bactericidal activ- amined both in vitro and in vivo ef- discrepant findings are common. Un-

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 til there are clear data as to which in ment of prosthetic device infec- myelitis, hardware-associated infec- vitro models have the most rel- tions and bone infections in human tions, and perhaps infections caused evance for specific types of clinical in- studies and animal models. In other by MRSA strains. Given the rising fections (and such studies are prob- disease states, data are less promis- global incidence of MRSA infec- ably challenging to perform), the role ing or are not well explored in hu- tions, there is an urgent need to may be little for in vitro models of ad- man investigations. Further clini- better define the role of rifampin for junctive rifampin therapy for cal studies may choose to build on the treatment of clinical S aureus S aureus other than to ensure that the promising in vivo data or clinical infections. study strain is rifampin susceptible. studies noted in our review. The animal models reviewed Although our findings demon- included the following 5 principal strate that adjunctive rifampin use Submitted for Publication: March types of infection: peritonitis, endo- is not strongly supported with clini- 26, 2007; final revision received Sep- carditis, osteomyelitis, bacteremia, cal or high-quality relevant animal tember 6, 2007; accepted Septem- and device- or hardware-related or basic clinical data, there are 2 im- ber 7, 2007. infections. Most investigations portant observations worth noting. Correspondence:LorenG.Miller,MD, examined rifampin used with fluo- First, rifampin use does not seem an- MPH, Division of Infectious Diseases, roquinolones, glycopeptides, and tagonistic to other antibiotics in hu- Harbor-UCLA Medical Center, 1000 ␤-lactam antibiotics. Dual therapy man studies. Second, although rif- W Carson St, Bin 466, Torrance, CA was significantly better than mono- ampin seems to be well tolerated in 90509 ([email protected]). therapy in some investigations in most patients with S aureus infec- Author Contributions: Study con- terms of outcomes such as bone tions, some degree of intolerance oc- cept and design: Perlroth and Miller. sterilization, bacterial counts, and curs. In the study by Zimmerli et al,65 Acquisition of data: Perlroth, Kuo, cure rates, regardless of the disease 3 of 18 patients stopped rifampin Tan, and Miller. Analysis and inter- or animal model used. More spe- therapy temporarily because of nau- pretation of data: Perlroth, Kuo, Tan, cifically, the fluoroquinolone- sea, although rifampin was success- Bayer, and Miller. Drafting of the rifampin combination was gener- fully reintroduced at a lower dos- manuscript: Perlroth, Kuo, Tan, ally efficacious in peritonitis and age. Two subjects discontinued the Bayer, and Miller. Critical revision of device-related infections, with study because of exanthems, al- the manuscript for important intellec- inconsistent results (indifference or though nausea prompted discon- tual content: Perlroth, Kuo, Bayer, benefit) in the osteomyelitis and tinuation in a subject treated with and Miller. Statistical analysis: Miller. endocarditis models. On the other monotherapy. Subjectively, we con- Obtained funding: Miller. Adminis- hand, the glycopeptides were not clude that rifampin therapy may be trative, technical, and material sup- more effective when combined reasonable in infections in which port: Perlroth, Tan, and Miller. Study with rifampin in osteomyelitis and cure rates are not high, assuming pa- supervision: Miller. endocarditis studies but generally tients are at low risk for toxic ef- Financial Disclosure: None re- resulted in better microbiological fects from rifampin or significant ported. and clinical outcomes in foreign drug-drug interactions (eg, with an- Funding/Support: This study was body–related (abscess or prosthetic ticoagulants and immunosuppres- supported in part by grant R01 device) infections. sive medications). In cases in which CCR923419 from the Centers for Few human trials to date have di- rifampin treatment may compro- Disease Control and Prevention (Dr rectly compared outcomes with and mise patient safety, the use of this Miller). without rifampin. Among the trials medication is questionable given that Additional Contributions: James we identified, the median Jadad score the benefit of rifampin remains Steckelberg, MD, Donald Levine, was 1, and the range was 0 to 5, sug- poorly defined. MD, and Paul Holtom, MD, assisted gesting that the quality of pub- In summary, we found that in- with identifying abstracts and articles lished trials varies considerably. vestigations of rifampin adjunctive that could have been missed by our Cure rates were often higher in the therapy for S aureus infection are systematic review. Amy J. Chatfield, adjunctive rifampin arms, but stud- plagued by numerous limitations. MLS, and Penny Coppernoll-Blach, ies were typically underpowered to There are situations in which ad- MLS, assisted with the EMBASE da- detect differences between groups. junctive rifampin therapy seems tabase. However, no study indicated a trend promising, but none in which ben- toward worse outcomes with ad- efit is definitively established. We REFERENCES junctive rifampin therapy. also found that in vitro models seem Because of the limitations noted, to contribute little to our under- 1. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, it is challenging to draw conclu- standing of the role of rifampin in Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of sions from studies of rifampin in vivo given that results are heavily 24,179 cases from a prospective nationwide sur- terms of its role as adjunctive therapy method dependent. Adequately veillance study [published corrections appear in in infected patients. Nevertheless, powered clinical studies need to be Clin Infect Dis. 2004;39(7):1093 and our review identified clinical sce- performed to assess outcomes with 2005;40(7):1077]. 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