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Role of Rifampin for Treatment of Orthopedic Implant–Related Staphylococcal Infections
A Randomized Controlled Trial
Werner Zimmerli, MD;
Andreas F. Widmer, MD, MSc;
Marianne Blatter, MD;
R. Frei, MD;
Peter E. Ochsner, MD;
for the Foreign-Body Infection (FBI) Study Group
JAMA. 1998;279:1537-1541.
ABSTRACT
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Context.— Rifampin-containing regimens are able to cure staphylococcal implant-related infections based on in vitro and in vivo observations. However, this evidence has not been proven by a controlled clinical trial.
Objective.— To evaluate the clinical efficacy of a rifampin combination in staphylococcal infections associated with stable orthopedic devices.
Design.— A randomized, placebo-controlled, double-blind trial conducted from 1992 through 1997.
Setting.— Two infectious disease services in tertiary care centers in collaboration with 5 orthopedic surgeons in Switzerland.
Patients.— A total of 33 patients with culture-proven staphylococcal infection associated with stable orthopedic implants and with a short duration of symptoms of infection (exclusion limit <1 year; actual experience 0-21 days).
Intervention.— Initial debridement and 2-week intravenous course of flucloxacillin or vancomycin with rifampin or placebo, followed by either ciprofloxacin-rifampin or ciprofloxacin-placebo long-term therapy.
Main Outcome Measures.— Cure was defined as (1) lack of clinical signs and symptoms of infection, (2) C-reactive protein level less than 5 mg/L, and (3) absence of radiological signs of loosening or infection at the final follow-up visit at 24 months. Failure was defined as (1) persisting clinical and/or laboratory signs of infection or (2) persisting or new isolation of the initial microorganism.
Results.— A total of 18 patients were allocated to ciprofloxacin-rifampin and 15 patients to the ciprofloxacin-placebo combination. Twenty-four patients fully completed the trial with a follow-up of 35 and 33 months. The cure rate was 12 (100%) of 12 in the ciprofloxacin-rifampin group compared with 7 (58%) of 12 in the ciprofloxacin-placebo group (P=.02). Nine of 33 patients dropped out due to adverse events (n=6), noncompliance (n=1), or protocol violation (n=2). Seven of the 9 patients who dropped out were subsequently treated with rifampin combinations, and 5 of them were cured without removal of the device.
Conclusion.— Among patients with stable implants, short duration of infection, and initial debridement, patients able to tolerate long-term (3-6 months) therapy with rifampin-ciprofloxacin experienced cure of the infection without removal of the implant.
INTRODUCTION
ORTHOPEDIC DEVICES are used for bone fixation or joint replacement. Orthopedic device–related infections are rare, but they carry a high morbidity for the patient and are costly.1-6 Traditionally, the management of such infections includes resection arthroplasty or removal of fixation devices.1, 3-4,7 Observational studies showed that despite prolonged (4-6 weeks) intravenous treatment with  -lactam antibiotics and subsequent long-term oral therapy, the failure rate with retention of the device is between 32% and 82%.8-16 Among the best results are those of Tsukayama et al,8 who reported a failure rate of only 13 (32%) of 41 devices in patients with early postoperative and hematogenous infection after hip arthroplasty. However, in this study the polyethylene insert of the acetabular component was replaced in all patients. High failure rates (69%-77%) were reported in 3 series.10, 14, 16 In these studies, risk factors for failure were a long history of infection and a delayed debridement.
Osteomyelitis associated with fracture fixation devices occurs more frequently than infection after joint replacement.5-6,17-18 The incidence of infection after internal fixation of closed fractures should not exceed 1% to 2%, whereas the infection of open fractures can be higher than 30% depending on the type of fracture.5-6,19 The treatment of infected bone fixation devices usually requires device removal and stabilization with an external fixation device. The success rate of Staphylococcus aureus device–related infection with a quinolone was only 20% (1/5) despite treatment for 6 months.20
Hitherto, there is not a single controlled, randomized clinical trial evaluating the value of the antibiotic treatment of orthopedic device–related infection. In most studies, only surgical procedures, not antimicrobial therapies, are described.4-18,21 Results from our animal model for implant-associated infection demonstrated the clear superiority of rifampin combinations.22-25 In addition, a prospective pilot study showed the success rate of rifampin combinations in orthopedic implant–associated staphylococcal infections to be 82% (9/11).26 These results were confirmed in a larger series showing a success rate with ofloxacin plus rifampin of 62% (13/21) without removal of the device.27
Our study question was to estimate the cure rate of a conservative approach with a controlled trial. Therefore, we conducted this double-blind, randomized clinical trial evaluating the role of rifampin in patients with a stable orthopedic implant infected with S aureus or coagulase-negative staphylococci.
METHODS
Study Design and Population
Eligible for this study were patients who had a diagnosis of orthopedic device–related infection due to S aureus or coagulase-negative staphylococci established by arthrocentesis or surgical revision. Only subjects in whom the stable implant was kept in place were included. All consecutive patients treated by the infectious diseases consultants of the study centers were asked to participate in the study. The following exclusion criteria were applied: lack of written informed consent, symptoms for more than 1 year before randomization, age younger than 16 years, less than 2 years of expected survival, predictable inability to comply with the treatment and follow-up visits, known or suspected allergy to quinolones and/or rifampin, mixed infection with microorganisms other than staphylococci, staphylococci resistant to ciprofloxacin and/or rifampin, removal of the implant before randomization, clinical or radiological signs of implant loosening, refusal to discontinue wearing soft contact lenses during treatment period, refusal to discontinue hormonal contraception during treatment period, and an antimicrobial treatment of more than 2 weeks after the microbiologically established diagnosis. In addition, patients who took less than 85% of the study medication were excluded a posteriori (poor compliance) and were regarded as dropouts. Patients were randomly assigned to antimicrobial combination treatment (see below) either with rifampin or with placebo, using a computer-generated list distributed to the study centers in sealed envelopes. Patients were randomized by blocks of 4, stratified into groups of patients with knee protheses, hip protheses, or fixation devices. The study was approved by the local ethics committees of the University Hospitals, Basel and Geneva, Switzerland. Written informed consent was required for all study patients.
Assessment of Effectiveness and Toxic Effects
The patients were clinically assessed at enrollment in the study, at weeks 1 and 2, then once monthly to month 6, then at 9, 12, and 24 months, or until failure of the treatment or death of the patient. All patients including dropouts were scheduled for a final evaluation at the end of the study. Radiological evaluation was performed at study enrollment, after 1 and 2 years, or on removal of the device. During treatment, the following laboratory parameters were determined at least twice a month: C-reactive protein, hemoglobin, erythrocytes, platelets, differential white blood cell count, and liver enzymes.
Treatment
At study entry, any type of revision surgery was encouraged except the removal of the device (exclusion criteria). Only cases with radiological (n=33) and intraoperative (n=29) evidence of stability of the implant or the prosthesis were included in the study. Fifteen cases in the rifampin group and 14 in the placebo group had revision surgery for infection. At the revision, implants were left in place (inclusion criteria). Thorough debridement was followed by suction irrigation drainage or drainage alone. In osteosynthesis cases, open-wound therapy was allowed as an alternative. There was no case where gentamicin beads were used.
During the initial 2 weeks, patients were treated with flucloxacillin (2 g every 6 hours intravenously) or, in case of methicillin resistance or an allergy to penicillin, with vancomycin (1 g every 12 hours intravenously) plus either rifampin (1 coated 450-mg tablet every 12 hours) or placebo (1 matched coated tablet every 12 hours). This initial 2-week course with a standard intravenous treatment was chosen to minimize the risk of emergence of ciprofloxacin resistance. An oral form of rifampin and an identical placebo was provided by Ciba-Geigy Ltd, Basel, Switzerland. Patients were informed that body fluids can turn orange with placebo or drug. After 2 weeks, flucloxacillin or vancomycin was replaced by ciprofloxacin (750 mg every 12 hours by mouth), whereas the rifampin or placebo was continued. Patients with hip prostheses and internal fixation devices were treated for 3 months, those with knee prostheses for 6 months. After this time, antimicrobial treatment had to be stopped if the patient had no clinical signs and symptoms of infection and the C-reactive protein level was below 5 mg/L for at least 6 weeks. The surgeon was encouraged to remove osteosynthesis material after stopping antimicrobial therapy for at least 1 week, provided that the material was no longer required for stability. The whole implant was sent to the microbiology laboratory. Identification of the same microorganism was considered as failure.
Study End Points
Cure was defined as the lack of clinical signs and symptoms of infection (fever, local pain, redness, warmth, sinus tract infection, fever), a C-reactive protein level below 5 mg/L, and the absence of radiological signs of loosening, pseudoarthrosis (in case of fixation device), or dislocation of the artificial joint at the final follow-up visit 24 months after start of the treatment. In case of the removal of the internal fixation device because of sufficient stability, cure was defined as the absence of the infecting agent of the cultured implant. For this purpose, the entire device was cultured in trypticase soy broth and sonicated in case of no growth after 48 hours of incubation. Sonication was delayed since gram-negative microorganisms could be killed by sonication and superinfection could therefore be missed. Confirmed failure was defined as isolation of the initial microorganism (persistence or relapse) in the culture of intraoperative tissue specimens, synovia, or device. A probable failure was defined as clinical signs and symptoms of local infection, or an otherwise unexplained high C-reactive protein level (>50 mg/L) without microbiological documentation of infection.
Microbiology
The isolates were identified by standard techniques.28 Minimal inhibitory concentrations of the study drugs were determined by E-test (AB BIODISKA, Solna, Sweden) at the principal study center. All isolates were collected and stored in skim milk at -70°C for molecular typing in case of treatment failure. For this purpose, pairs of isolates were characterized by the contour-clamped homogenous electrical fields modification of pulsed-field gel electrophoresis, after digestion of chromosomal DNA with low-frequency cutting enzymes (SmaI and Eag I).29
Statistical Analysis
Cure rates of orthopedic device–related infections with the standard regimen range from 20% to 30% without removal of the device.10, 12, 14, 16 Experimental data and uncontrolled case series with rifampin combinations indicated a cure rate between 70% and 90%.26-27 The sample size was calculated with the following assumptions:  was set at .05, the power at 80%, the probability of cure with standard treatment at 20%, and the probability of cure with study treatment at 75%. A sample size of more than 30 subjects was calculated, with an estimated dropout rate of 20%.30
Time to failure was estimated with the Kaplan-Meier method, and compared between groups by the log-rank test.31 Categorical variables were compared by the  2test or the Fisher exact test. The independent safety monitor was the only one who was aware of the type of blinded study drug. A P value of <.05 (2-tailed) was considered significant.
RESULTS
Study Population
Patients enrollment started in May 1992, and the last follow-up visit was performed in November 1997, or at the removal of the device if failure occurred. After randomization of 33 patients, the investigators were asked by the safety advisor to stop randomization because all failures occurred in the same group.
The 2 groups were similar in demographic characteristics, type of devices, and infecting agents (Table 1). In the rifampin combination group, 12 of the 18 infections occurred within 2 months after implantation of the device, compared with 7 of the 15 in the placebo combination group. However, the duration of infectious signs and symptoms was short and similar in both groups, ie, all infections occurred either early after intraoperative contamination (<2 months) or late as a consequence of hematogenous seeding (Table 1). Twenty-four patients fully completed the trial and 9 dropped out for various reasons but received further follow-up (see below).
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Table 1.—Study Population
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Outcome
Figure 1 shows the Kaplan-Meier plot of disease-free survival in the 24 patients who completed the study according to the protocol. The cure rate was 12 (100%) of 12 in the rifampin combination arm, and 7 (58%) of 12 in the placebo combination arm, with a median follow-up of 35 (range, 24-46 months) and 33 (range, 15-41 months) months, respectively. The definite proof for cure of a device-related infection is the negative broth culture of the whole explanted foreign body after antimicrobial therapy.23-24 This unambiguous test was performed in 8 of the 10 patients with fixation devices in the ciprofloxacin-rifampin group and in 2 of 6 patients in the ciprofloxacin-placebo group. In the former group, all 8 implant cultures were negative; in the latter group, 1 of 2 implant cultures showed growth of the initial pathogen. All 5 failures were microbiologically confirmed (see below); all had flucloxacillin as the initial intravenous therapy.
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Figure 1.—Kaplan-Meier estimates of the cumulative risk of failure according to the treatment group. The risk of failure was lower in the ciprofloxacin-rifampin group than in the ciprofloxacin-placebo group (P<.02).
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We also performed an intention-to-treat analysis. Sixteen (89%) of the 18 patients of the rifampin combination arm and 9 (60%) of 15 patients of the placebo combination arm were cured without removal of the implant before the end of the antimicrobial therapy (P=.10). In the 2 patients from the former group in whom treatment failed, rifampin therapy was stopped after 8 weeks, in 1 patient due to an exanthema; in the other patient, the dose of rifampin was reduced after 3 weeks because of nausea.
Dropout Patients
As expected for a long-term study, a considerable percentage of patients dropped out. All dropouts had an identical follow-up observation as did the treated patients. In the rifampin combination arm 6 of the 18 patients dropped out, and in the placebo combination arm 3 of the 15 (P=.45, Table 2). In the rifampin combination arm, in 3 patients rifampin therapy had to be temporarily discontinued due to severe nausea, but could be continued within a few days with a reduced dose (300 mg every 12 hours). In 2 other patients, rifampin therapy was definitely stopped due to an allergic exanthema. One patient dropped out due to protocol violation because the orthopedic surgeon did not agree to stop therapy at the required time point according to the study protocol.
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Table 2.—Outcome of Dropout Patients
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In the placebo combination arm, reasons for dropping out were an adverse event (nausea), noncompliance, and a protocol violation. Seven of 9 dropout patients were subsequently treated withrifampin combinations, 3 of them with a reduced dose. The success rate among the rifampin-treated dropout patients of both groups together was 5 (71%) of 7 without removal of the device during antimicrobial therapy (Table 2).
Microbiological Analysis of Treatment Failures
Four methicillin-sensitive S aureus and 1 methicillin-sensitive S epidermidis isolates were cultured from the 5 failures in the ciprofloxacin-placebo group. The isolates at failure were compared with the initial isolates by susceptibility testing and molecular subtyping. In 4 of these isolates (3 S aureus and 1 S epidermidis), the minimal inhibitory concentration of ciprofloxacin increased 3- to 8-fold to 4 mg/L, and in 1 failure S aureus remained susceptible to ciprofloxacin. The analysis of the chromosomal DNA of the ciprofloxacin-resistant strains by pulsed-field gel electrophoresis showed identity of all bands, indicating emergence of quinolone resistance during prolonged ciprofloxacin monotherapy of the pathogen isolated at randomization (Figure 2).
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Figure 2.—Pulsed-field gel electrophoresis of chromosomal DNA from 4 ciprofloxacin-resistant isolates from patients with failure. DNA from 4 pairs (lanes 1-4) of ciprofloxacin-resistant isolates (A indicates initial and B, at the time of failure) was digested with Eag I. Lane ST is the molecular weight standard (Staphylococcus aureus NCTC 8325 DNA digested with Sma I). kb indicates kilobase.
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COMMENT
We found a superiority of the rifampin combination regimen compared with the ciprofloxacin monotherapy. Foreign bodies are favorite sites for bacterial persistence due to a local host-defense defect.32 In addition, the biofilm and the low growth rate of surface-adherent microorganisms render many antimicrobial agents ineffective.23-24,33-34 Therefore, most orthopedic surgeons remove all foreign material in case of an infected arthroplasty.1, 3-4,7 The superiority of rifampin in the animal model could be explained by its high efficacy on adherent and stationary-phase staphylococci.23-25 The excellent results of the rifampin combination in this study confirm previous data from animal models and observational studies.22-27 In addition, this combination has also been shown to be efficacious in right-sided endocarditis due to S aureus.35-36 However, there are no controlled studies on the role of rifampin in nonmycobacterial infection.
Our results confirm the high risk of emergence of resistance of staphylococci to quinolones when used as monotherapy.37 Emergence of resistance to rifampin was not observed in a single case in our study. Recurrent infections were exclusively caused by the original strain, as confirmed by molecular typing of both the original and consecutive isolates. This indicates that bacteria may persist despite initial clinical response to antibiotic treatment. Therefore, surface adhering staphylococci seem to be highly resistant even to prolonged quinolone monotherapy, as previously suggested by animal experiments and observational studies.20, 23-24 The present study shows that the rifampin-quinolone combination was highly efficacious, not only in eliminating device-associated staphylococci, but also in preventing the emergence of ciprofloxacin resistance.
Our results cannot be generalized to every type of orthopedic implant–associated infection. According to the inclusion criteria, all devices were stable. Loosening of the infected device precludes an antimicrobial therapy without removing or exchanging the implant.4 Despite the fact that we allowed the inclusion of patients with up to 1 year of infection, the median duration of signs and symptoms of infection was only 4 and 5 days, respectively, with a maximum of 21 days. According to Schoifet and Morrey,10 the long duration of the infection before debridement is the major cause of treatment failure. However, in these studies, the antibiotic therapy was not standardized and did not include rifampin. Nevertheless, it is conceivable that the treatment with retention is only successful in patients with a short interval before therapy. In our study, only patients with early (<2 months after surgery) or acute hematogenous infection were treated. Therefore, we can only speculate that patients with chronic orthopedic device–related infections can also be successfully treated with ciprofloxacin plus rifampin with retention of the device.
Dropouts were mainly observed in the combination treatment group. All dropout patients had an identical follow-up as the other cases. Seven dropout patients were subsequently treated with rifampin combinations, 3 of them with a reduced dose due to nausea as the main adverse event. Six of 7 rifampin-treated patients had a successful outcome, 5 of them without removal of the device—supporting the main conclusion. Compliance was excellent in both groups as checked by pill counting. Only 1 patient dropped out due to insufficient compliance (<85% of the study medication).
This is the first randomized, controlled clinical trial evaluating a conservative treatment approach to staphylococcal device–related infection with rifampin. It confirms the in vitro and experimental animal data,23-25 as well as the results of observational clinical studies.26-27 In conclusion, orthopedic device–related infections due to rifampin- and ciprofloxacin-susceptible staphylococci can be cured without removal of the device, given the implant is stable, the duration of infection is short, an initial debridement is performed, and the patient tolerates long-term therapy.
AUTHOR INFORMATION
Presented in part at the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, La, September 15-18, 1996.
This study was funded with an educational grant from Bayer Ltd, Zürich, Switzerland.
We are indebted to the study patients for their participation; Oto Zak, MD, for the Safety Monitoring of this double-blind study; H. Braun, MD, Bayer Ltd for an educational grant; and Ciba-Geigy Ltd for providing rifampin and the matched placebo-coated tablets. In addition to the authors, the following institutions and investigators participated in the Foreign-Body Infection (FBI) Study Group trial: J. Fabbri, MD, and T. Bregenzer, MD, the Division of Infectious Diseases, University Hospitals, Basel, Switerland, in collaboration with E. Morscher, MD, and A. Gächter, MD, the Orthopedic Department, University Hospitals, Basel (22 patients enrolled), with the Clinic of Orthopedic Surgery, Liestal, Switzerland (5 patients enrolled), and the Clinic of Surgery, Zofingen, Switzerland (3 patients enrolled); and D. P. Lew, the Division of Infectious Diseases, Geneva, Switzerland, in collaboration with the Orthopedic Department, University Hospital, Geneva (3 patients enrolled).
Reprints: Werner Zimmerli, MD, Division of Infectious Diseases, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland (e-mail: zimmerliw{at}ubaclu.unibas.ch).
From the Division of Infectious Diseases, Department of Internal Medicine (Drs Zimmerli and Blatter), Division of Clinical Epidemiology (Dr Widmer), and Bacteriology Laboratory (Dr Frei), University Hospitals, Basel, Switzerland; and Clinic of Orthopedic Surgery, Kantonsspital, Liestal, Switzerland (Dr Ochsner).
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Antagonistic Effect of Rifampin on the Efficacy of High-Dose Levofloxacin in Staphylococcal Experimental Foreign-Body Infection
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In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Studies of the Mode of Action in Staphylococcus aureus
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Antimicrob. Agents Chemother. 2008;52:2313-2323.
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Adjunctive Use of Rifampin for the Treatment of Staphylococcus aureus Infections: A Systematic Review of the Literature
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Arch Intern Med 2008;168:805-819.
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Virulence characteristics of community-associated Staphylococcus aureus and in vitro activities of moxifloxacin alone and in combination against community-associated and healthcare-associated meticillin-resistant and -susceptible S. aureus
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J Med Microbiol 2008;57:452-456.
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Comparative Study of the Effects of Pyridoxine, Rifampin, and Renal Function on Hematological Adverse Events Induced by Linezolid
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Antimicrob. Agents Chemother. 2007;51:2559-2563.
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Efficacy of a Novel Rifamycin Derivative, ABI-0043, against Staphylococcus aureus in an Experimental Model of Foreign-Body Infection
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Antimicrob. Agents Chemother. 2007;51:2540-2545.
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Efficacy of High Doses of Levofloxacin in Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus
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Antimicrob. Agents Chemother. 2006;50:4011-4017.
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In Vitro Activity of Novel Rifamycins against Rifamycin-Resistant Staphylococcus aureus
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The management of peri-prosthetic infection in total joint arthroplasty
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Multiple Combination Bactericidal Testing of Staphylococcal Biofilms from Implant-Associated Infections
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Antimicrob. Agents Chemother. 2006;50:55-61.
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Diagnosis and treatment of prosthetic aortic graft infections: confusion and inconsistency in the absence of evidence or consensus
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Extra-Articular Resection of the Hip with a Posterior Column-Preserving Technique for Treatment of an Intra-Articular Malignant Lesion. A Report of Two Cases
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JBJS 2005;87:2768-2774.
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Monitoring in vivo fitness of rifampicin-resistant Staphylococcus aureus mutants in a mouse biofilm infection model
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J Antimicrob Chemother 2005;55:528-534.
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Treatment of infected retained implants
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Prosthetic-Joint Infections
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NEJM 2005;352:95-97.
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Place of newer quinolones and rifampicin in the treatment of Gram-positive bone and joint infections
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Silver nanoparticles and polymeric medical devices: a new approach to prevention of infection?
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J Antimicrob Chemother 2004;54:1019-1024.
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Prosthetic-Joint Infections
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NEJM 2004;351:1645-1654.
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Risk factors for anaemia in patients on prolonged linezolid therapy for chronic osteomyelitis: a case-control study
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Antibiotic treatment of Gram-positive bone and joint infections
Darley and MacGowan
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Treatment of Infections Associated with Surgical Implants
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Trends in the treatment of orthopaedic prosthetic infections
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Rapid Direct Method for Monitoring Antibiotics in a Mouse Model of Bacterial Biofilm Infection
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Antimicrob. Agents Chemother. 2003;47:3130-3137.
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Efficacy of Linezolid plus Rifampin in an Experimental Model of Methicillin-Susceptible Staphylococcus aureus Endocarditis
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Comparative efficacy of daptomycin and vancomycin in the therapy of experimental foreign body infection due to Staphylococcus aureus
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Vancomycin Treatment Failure Associated with Heterogeneous Vancomycin-Intermediate Staphylococcus aureus in a Patient with Endocarditis and in the Rabbit Model of Endocarditis
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Diagnosis and Management of Infection After Total Knee Arthroplasty
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Multicentre surveillance of antimicrobial resistance in enterococci and staphylococci from Colombian hospitals, 2001-2002
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Single and Combination Antibiotic Susceptibilities of Planktonic, Adherent, and Biofilm-Grown Pseudomonas aeruginosa Isolates Cultured from Sputa of Adults with Cystic Fibrosis
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Discoloration of Intraocular Lens Subsequent to Rifabutin Use
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Comparison of Levofloxacin, Alatrofloxacin, and Vancomycin for Prophylaxis and Treatment of Experimental Foreign-Body-Associated Infection by Methicillin-Resistant Staphylococcus aureus
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Combination of Quinupristin-Dalfopristin (Synercid) and Rifampin Is Highly Synergistic in Experimental Staphylococcus aureus Joint Prosthesis Infection
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Fluoroquinolones
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Antimicrobial Resistance: Guidelines for the Practicing Orthopaedic Surgeon
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Linezolid Therapy of Staphylococcus aureus Experimental Osteomyelitis
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Infection of a Hip Prosthesis by Actinomyces naeslundii
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Efficacy of Levofloxacin for Experimental Aortic-Valve Endocarditis in Rabbits Infected with Viridans Group Streptococcus or Staphylococcus aureus
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Rifampin for Staphylococcal Infections of Orthopedic Prostheses
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