Role of Rifampin for Treatment of Orthopedic Implant Related Staphylococcal Infections

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 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 ciprofloxacinrifampin 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. JAMA. 1998;279:1537-1541 ORTHOPEDIC DEVICES are used for bone fixation or joint replacement. Orthopedic device related infections are rare, but they carry a high morbidity for the patientandarecostly. 1-6 Traditionally,the management of such infections includes resection arthroplasty or removal of fixation devices. 1,3,4,7 Observational studies For editorial comment see p 1575. showed that despite prolonged (4-6 weeks) intravenous treatment with lactam antibiotics and subsequent longterm 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 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). A listing of the additional institutions and investigators who participated in the Foreign-Body Infection (FBI) Study Group Trial appears at the end of this article. Presented in part at the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, La, September 15-18, 1996. Reprints: Werner Zimmerli, MD, Division of Infectious Diseases, University Hospital, Petersgraben 4, CH- 4031 Basel, Switzerland (e-mail: zimmerliw@ubaclu.unibas.ch). JAMA, May 20, 1998 Vol 279, No. 19 Rifampin for Treatment of Staphylococcal Infections Zimmerli et al 1537

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,thereisnotasinglecontrolled, 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 Atstudyentry, anytypeofrevisionsurgery 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. Attherevision, implantswereleftinplace (inclusion criteria). Thorough debridement was followed by suction irrigation drainage or drainage alone. In osteosynthesis cases, open-wound therapy was allowedasanalternative. Therewasnocase 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 hoursintravenously) pluseitherrifampin (1 coated 450-mg tablet every 12 hours) orplacebo(1matchedcoatedtabletevery 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 treatmenthadtobestoppedifthepatient 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 gramnegative 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. 1538 JAMA, May 20, 1998 Vol 279, No. 19 Rifampin for Treatment of Staphylococcal Infections Zimmerli et al

Table 1. Study Population Characteristic Rifampin Combination (n=18) Placebo Combination (n=15) Mean (SD) age, y 66 (15) 67 (15) Sex, male:female 9:9 5:10 Implant Hip prosthesis 5 3 Knee prosthesis 3 4 Osteosynthesis 10 8 Microbiology Staphylococcus aureus (0/26 methicillin resistant) 15 11 Staphylococcus epidermidis (2/7 methicillin resistant) 3 4 Initial intravenous treatment Flucloxacillin 13 13 Vancomycin 5 2 Median duration of infection,* d (range) 5 (0-19) 4 (0-21) *Duration of signs and symptoms of infection prior to enrollment in the study. One patient had methicillin-resistant S epidermidis; 4 patients had methicillin-sensitive S aureus and allergy. One patient had methicillin-resistant S epidermidis; 1 had methicillin-sensitive S aureus and allergy. Disease-Free Survival 1.00 0.95 Ciprofloxacin- Rifampin Group 0.90 Ciprofloxacin- 0.85 Placebo Group 0.80 0.75 0.70 0.65 0.60 0 200 400 600 800 1000 1200 14001600 Time After Randomization, d Figure 1. Kaplan-Meier estimates of the cumulative risk of failure according to the treatment group. The risk of failure was lower in the ciprofloxacinrifampin group than in the ciprofloxacin-placebo group (P.02). Microbiology The isolates were identified by standardtechniques. 28 Minimalinhibitoryconcentrations of the study drugs were determined by E-test (AB BIODISKA, Solna, Sweden) at the principal study center. All isolates were collected and stored inskimmilkat 70 Cformoleculartyping in case of treatment failure. For this purpose, pairs of isolates were characterized bythecontour-clampedhomogenouselectricalfieldsmodificationofpulsed-fieldgel electrophoresis, after digestion of chromosomal DNA with low-frequency cutting enzymes (SmaI and EagI). 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 2 test 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). Outcome Figure 1 shows the Kaplan-Meier plot of disease-free survival in the 24 patients who completed the study according to theprotocol.thecureratewas12(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. We also performed an intention-totreat 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. Intherifampincombinationarm 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 withinafewdayswithareduceddose(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 agreetostoptherapyattherequiredtime point according to the study protocol. In the placebo combination arm, reasons for dropping out were an adverse event (nausea), noncompliance, and a protocol violation. Seven of 9 dropout patientswere subsequently treatedwith rifampin 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). JAMA, May 20, 1998 Vol 279, No. 19 Rifampin for Treatment of Staphylococcal Infections Zimmerli et al 1539

Table 2. Outcome of Dropout Patients Initial Therapy Therapy After Dropout Cure Without Removal of the Device* Flucloxacillin or vancomycin and rifampin Ciprofloxacin and rifampin (n=4) 3/4 followed by ciprofloxacin and rifampin Ciprofloxacin and clindamycin (n=1) 1/1 Ciprofloxacin (n=1) 0/1 Flucloxacillin and placebo followed by Ciprofloxacin and rifampin (n=2) 2/2 ciprofloxacin and placebo Amoxicillin clavulanic acid and rifampin (n=1) 0/1 *Removal due to persisting infection was defined as failure. Partly rifampin in reduced dose (300 mg twice a day). Superinfection with enterococci after dropping out (secondary mixed infection). 1 2 Microbiological Analysis of Treatment Failures Fourmethicillin-sensitiveSaureusand 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 minimalinhibitoryconcentrationofciprofloxacin 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). COMMENT We found a superiority of the rifampin combination regimen compared with the 3 4 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 EagI. Lane ST is the molecular weight standard (Staphylococcus aureus NCTC 8325 DNA digested with SmaI). kb indicates kilobase. ST 674 361 260 208 175 135 117 kb 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 antimicrobialagentsineffective. 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 Emergenceofresistancetorifampin 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 theinfectionbeforedebridement is themajor cause of treatment failure. However, in these studies, the antibiotic therapy was not standardized and did not include rifampin. Nevertheless, itisconceivablethat 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 1540 JAMA, May 20, 1998 Vol 279, No. 19 Rifampin for Treatment of Staphylococcal Infections Zimmerli et al

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. References 1. Lew DP, Waldvogel FA. Osteomyelitis. N Engl J Med. 1997;326:999-1007. 2. Schutzer SF, Harris WH. Deep-wound infection after total hip replacement under contemporary aseptic conditions. J Bone Joint Surg Am. 1988;70: 724-727. 3. NIHConsensusDevelopmentPanelonTotalHip Replacement. Total hip replacement. JAMA. 1995; 273:1950-1956. 4. Garvin KL, Hanssen AD. Infection after total hip arthroplasty. J Bone Joint Surg Am. 1995;77:1576-1588. 5. Zych GA, Hutson JJ. Diagnosis and management of infection after tibial intramedullary nailing. Clin Orthop. 1995;315:153-162. 6. Gustilo RB, Merkow RL, Templeman D. The management of open fractures. J Bone Joint Surg Am. 1990;72:299-304. 7. Morscher E, Herzog R, Bapst R, Zimmerli W. Management of infected hip arthroplasty. Orthop Int. 1995;3:343-351. 8. Tsukayama DT, Estrada R, Gustilo RB. Infection after total hip arthroplasty. J Bone Joint Surg Am. 1996;78:512-523. 9. WolfeSW,FiggieMP,InglisAE,BohnWW,Ranawat CS. Management of infection about total elbow prostheses. J Bone Joint Surg Am. 1990;72:198-212. 10. Schoifet SD, Morrey BF. Treatment of infection after total knee arthroplasty by débridement with retention of the components. J Bone Joint Surg Am. 1990;72:1383-1390. 11. Rasul AT, Tsukayama D, Gustilo RB. Effect of time on onset and depth of infection on the outcome of total knee arthroplasty infections. Clin Orthop. 1991;273:98-103. 12. Burger RR, Basch T, Hopson CN. Implant salvage in infected total knee arthroplasty. Clin Orthop. 1991;273:105-111. 13. Hartman MB, Fehring TK, Jordan L, Norton HJ. Periprosthetic knee sepsis: the role of irrigation and debridement. Clin Orthop. 1991;273:113-118. 14. Tsukayama DT, Wicklund B, Gustilo RB. Suppressive antibiotic therapy in chronic prosthetic joint infections. Orthopedics. 1991;14:841-844. 15. Wilson MG, Kelley K, Thornhill TS. Infection as a complication of total knee-replacement arthroplasty. J Bone Joint Surg Am. 1990;72:878-883. 16. Brandt CM, Sistrunk WW, Duffy MC, et al. Staphylococcus aureus prosthetic infection treated withdebridementandprosthesisretention. ClinInfect Dis. 1997;24:914-919. 17. McGraw JM, Lim E. Treatment of open tibial shaft fractures: external fixation and secondary intramedullary nailing. J Bone Joint Surg Am. 1988; 70:900-911. 18. Ochsner PE, Brunazzi MG. Intramedullary reaming and soft tissue procedures in treatment of chronic osteomyelitis of long bones. Orthopedics. 1994;17:433-440. 19. Salvati EA, Snall RD, Brause BD, Pellicci PM. Infections associated with orthopedic devices. In: Sugarman B, Young EJ, eds. Infections Associated With Prosthetic Devices. Boca Raton, Fla: CRC Press Inc; 1984:181-218. 20. Dellamonica P, Etesse-Carsenti H, Bernard E, Mondain V, Durant J, Argenson C. Pefloxacin in the treatment of bone infections associated with foreign material. J Antimicrob Chemother. 1990;26(suppl B):199-205. 21. Steckelberg JM, Osmon DR. Prosthetic joint infections. In: Bisno AL, Waldvogel FA, eds. Infections Associated With Indwelling Medical Devices. 2nd ed. Washington, DC: ASM Press; 1994:259-290. 22. Tshefu K, Zimmerli W, Waldvogel FA. Shortterm rifampin administration in the prevention/ eradication of foreign body infection. Rev Infect Dis. 1983;5(suppl 3):S474-S480. 23. Widmer AF, Frei R, Rajacic Z, Zimmerli W. Correlation between in vivo and in vitro efficacy of antimicrobial agents against foreign-body infections. J Infect Dis. 1990;162:96-102. 24. Zimmerli W, Frei R, Widmer AF, Rajacic Z. Microbiological tests to predict treatment outcome in experimental device-related infections due to Staphylococcus aureus. J Antimicrob Chemother. 1994;33:959-967. 25. Blaser J, Vergères P, Widmer AF, Zimmerli W. In-vivo verification of an in-vitro model of antibiotic 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 placebocoated 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). treatment of device-related infection. Antimicrob Agents Chemother. 1995;39:1134-1139. 26. Widmer AF, Gächter A, Ochsner PE, Zimmerli W. Antimicrobial treatment of orthopedic implantrelated infections with rifampin combinations. Clin Infect Dis. 1992;14:1251-1253. 27. Drancourt M, Stein A, Argenson JN, Zannier A, Curvale G, Raoult D. Oral rifampin plus ofloxacin for treatment of Staphylococcus-infected orthopedic implants. Antimicrob Agents Chemother. 1993; 37:1214-1218. 28. Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, eds. Manual of Clinical Microbiology. 6th ed. Washington, DC: ASM Press: 1995. 29. Pfaller MA, Hollis RJ, Sader HS. PFGE analysis of chromosomal restriction fragments. In: Isenberg HD, ed. Clinical Microbiology Procedures Handbook: Supplement 1. Washington, DC: ASM Press; 1992:1-12. 30. Dupont WD, Plummer WDJ. Power and sample size calculations: a review and computer program. Control Clin Trial. 1990;11:116-128. 31. Cox DR, Oakes D. Analysis of Survival Data. London, England: Chapman & Hall; 1990. 32. Zimmerli W, Lew PD, Waldvogel FA. Pathogenesis of foreign body infection: evidence for a local granulocyte defect. J Clin Invest. 1984;73:1191-1200. 33. Gristina AG. Biomaterial-centered infection: microbial adhesion versus tissue integration. Science. 1987;237:1588-1595. 34. Gristina AG. Biofilms and chronic bacterial infections. Clin Microbiol Newslett. 1994;16:171-176. 35. DworkinRJ,SandeMA,LeeBL,ChambersHF. Treatment of right-sided Staphylococcus aureus endocarditis in intravenous drug users with ciprofloxacin and rifampin. Lancet. 1989;2:1071-1073. 36. Heldman AW, Hartert TV, Ray CR, et al. Oral antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: prospective randomized comparison with parenteral therapy. Am J Med. 1996;101:68-76. 37. Hooper DC, Wolfson JS. Fluoroquinolone antimicrobial agents. N Engl J Med. 1991;324:384-394. JAMA, May 20, 1998 Vol 279, No. 19 Rifampin for Treatment of Staphylococcal Infections Zimmerli et al 1541