ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Dec. 2010, p. 5161–5166 0066-4804/10/$12.00 doi:10.1128/AAC.00027-10 Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Vol. 54, No. 12
Safety and Efficacy of Moxifloxacin Monotherapy for Treatment of Orthopedic Implant-Related Staphylococcal Infections䌤 Rafael San Juan,1* Ana Garcia-Reyne,1 Pedro Caba,2 Fernando Chaves,3 Carlos Resines,2 Fernando Llanos,2 Francisco Lo ´pez-Medrano,1 Manuel Lizasoain,1 and Jose Maria Aguado1 Unit of Infectious Diseases,1 Department of Traumatology,2 and Department of Clinical Microbiology,3 University Hospital 12 de Octubre, Madrid, Spain Received 7 January 2010/Returned for modification 12 January 2010/Accepted 14 September 2010
The rifampin-ciprofloxacin combination is recommended for treatment of orthopedic implant-related staphylococcal infections to avoid the emergence of ciprofloxacin resistance; however, the efficacy of this combination is limited by the tolerability problems associated with the use of rifampin. Moxifloxacin is a quinolone up to 10 times more active against staphylococci than ciprofloxacin and the risk of resistance development during monotherapy against staphylococci is theoretically lower for moxifloxacin, but information regarding its use in bone infections is lacking. The aim of the present study was to evaluate the safety and clinical efficacy of moxifloxacin monotherapy in patients with orthopedic implant-related staphylococcal infections. From June 2006 to April 2009, all patients with culture-proven infection by quinolone-sensitive staphylococcal strains associated with orthopedic implants at our institution were included in a management protocol that mostly included specific surgery, 1 to 2 weeks of an intravenous course of cloxacillin-cefazolin or vancomycin, and long-term therapy with moxifloxacin (400 mg/day for 3 months). Cure was defined as (i) a lack of clinical signs and symptoms of infection, (ii) a C-reactive protein level less than 5 mg/liter, and (iii) absence of radiological signs of loosening or infection at the latest follow-up visit. Failure was defined as (i) persisting clinical and/or laboratory signs of infection or (ii) persisting or new isolation of the initial microorganism. A total of 48 patients with a median follow-up of 716 days (range, 102 to 1,613 days) were included in the study. Complete drug compliance was achieved in all but two patients (4.2%), who required drug discontinuation because of side effects (diarrhea and dizziness). No moxifloxacin-induced arrhythmia was reported. Twenty patients had joint prosthesis infections (5 acute-onset infections and 15 chronic infections), and 28 patients had osteosynthesis material infections (4 acute-onset infections and 24 chronic infections). The etiologies were methicillin-sensitive Staphylococcus aureus in 33 patients and a coagulase-negative staphylococcus (CoNS) in 15. Surgical management was performed for the majority of patients (37/48; 77%), and the implant was retained in 21 patients (43.8%). The global cure rate was 38/46 (82.6%), and the cure rate for patients with implant retention was 15/21 (71.4%). The global cure rate for the 32 patients with a minimum follow-up of 2 years was 80%. Of the eight cases of relapse, we obtained microbiological confirmation in six cases, and all bacteria recovered were quinolone susceptible. Monotherapy with moxifloxacin seems to be an effective, safe, and easy alternative for the long-term treatment of orthopedic implant-related staphylococcal infections by quinolone-sensitive strains. Comparative studies with rifampin-containing regimens are warranted.
therapy with ciprofloxacin was inferior to therapy with the rifampin-ciprofloxacin combination mainly due to the emergence of ciprofloxacin resistance (27). Moxifloxacin is a quinolone up to 10 times more active than ciprofloxacin against staphylococci and the risk of resistance development during monotherapy is theoretically lower for moxifloxacin (4), but information regarding its use in orthopedic implant-related staphylococcal infections is lacking. The aim of the present study was to evaluate the safety and clinical efficacy of moxifloxacin monotherapy in patients with staphylococcal orthopedic implant-related infections.
Infection of orthopedic implants complicates 1 to 4% of implanted articular prostheses (26) and 2 to 30% of patients in whom osteosynthesis material had been implanted (28), with Staphylococcus aureus and coagulase-negative staphylococci (CoNS) being the main causative microorganisms. Cure of such orthopedic implant-associated infections mostly depends on surgical debridement and implant removal but also depends on the administration of long-term antibiotic therapy. Rifampin-containing regimens are currently recommended for long-term oral antibiotic treatment in patients with orthopedic implant-related staphylococcal infections, in view of the results of a single randomized study which demonstrated that mono-
MATERIALS AND METHODS Study population. This is an observational descriptive study including all patients with a diagnosis of orthopedic device-related infection due to quinolonesusceptible S. aureus or CoNS hospitalized from June 2006 to April 2009 in the orthopedic infection ward of a 1,300-bed tertiary teaching hospital in Madrid, Spain. The patients were included in a consensus management protocol, approved by University Hospital 12 de Octubre Review Board, between orthopedic
* Corresponding author. Mailing address: Infectious Diseases Unit, Hospital Universitario Doce de Octubre, Carretera de Andalucía Km. 5.4, Madrid 28041, Spain. Phone: 34-913908000, ext. 1712. Fax: 34914695775. E-mail:
[email protected]. 䌤 Published ahead of print on 20 September 2010. 5161
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ANTIMICROB. AGENTS CHEMOTHER. TABLE 1. Characteristics of the 48 patients included in the study Characteristic
Value
Sex (% male/% female) ................................................................................................................................................................................... Mean ⫾ SD age (yr)......................................................................................................................................................................................... Mean ⫾ SD Charlson comorbidity index ......................................................................................................................................................
52.1/47.9 58.8 ⫾ 2.6 0.8 ⫾ 0.2
No. (%) of patients in the following McCabe and Jackson group of underlying disease: Nonfatal.......................................................................................................................................................................................................... 39 (81.3) Ultimately fatal.............................................................................................................................................................................................. 9 (18.8) Rapidly fatal................................................................................................................................................................................................... 0 No. (%) of patients with an underlying disease conditioning immune suppressiona............................................................................... 13 (27.1) No. (%) of patients with the following type of orthopedic implant: Osteosynthesis materialb............................................................................................................................................................................... 28 (58.3) Hip prosthesis ................................................................................................................................................................................................ 9 (18.8) Knee prosthesis ............................................................................................................................................................................................. 10 (20.8) Shoulder prosthesis ....................................................................................................................................................................................... 1 (2.1) No. (%) of patients with the following timing of infection: Early infection ............................................................................................................................................................................................... 6 (12.5) Late chronic infection................................................................................................................................................................................... 33 (68.8) Late hematogenous infection ...................................................................................................................................................................... 3 (6.3) Finding in prosthetic joint revision............................................................................................................................................................. 6 (12.5) No. (%) of patients with the following etiology of infection: Staphylococcus aureus ................................................................................................................................................................................... 33 (68.8) CoNS............................................................................................................................................................................................................... 15 (31.2) Median (range) no. of days of i.v. antibiotic treatmentc ............................................................................................................................. 12.6 (1–31) Median (range) no. of days of oral moxifloxacin treatment ....................................................................................................................... 78 (24–223) No. (%) of patients with: Adverse events with moxifloxacin treatment ............................................................................................................................................. 3 (6.3) Adverse events requiring moxifloxacin withdrawal................................................................................................................................... 2 (4.2) Surgical debridement with or without implant removal .......................................................................................................................... 37 (77.1) Retention of implant .................................................................................................................................................................................... 21 (43.8) Median (range) no. of days of follow-up .......................................................................................................................................................716 (102–1,613) No. (%) of patients with global cure Per ITT ........................................................................................................................................................................................................... All patients (n ⫽ 46) .................................................................................................................................................................................... Patients with implant retentiond (n ⫽ 20)................................................................................................................................................. Patients with S. aureus infection (n ⫽ 33)................................................................................................................................................. Patients with CoNS infection with global cure (n ⫽ 14).........................................................................................................................
38 (79.1) 38 (82.6) 15 (71.3) 26 (78.8) 12 (86)
Diabetes mellitus (n ⫽ 1), liver cirrhosis (n ⫽ 1), connective tissue diseases (n ⫽ 4), oncological disease (n ⫽ 5), and HIV infection (n ⫽ 2). Tibia (n ⫽ 12), femur (n ⫽ 4), foot (n ⫽ 4), radius-cubitus (n ⫽ 3), humerus (n ⫽ 3), and pelvis (n ⫽ 2). Intravenous vancomycin and cloxacillin-cefazolin, followed by moxifloxacin for a total of 3 months. d Implant retention was performed in 15 cases of S. aureus infection and 4 cases of CoNS infection. a b c
surgeons and infectious disease specialists. The protocol consisted of surgical treatment, when possible (extensive debridement of bone and soft tissues, removal of foreign material, and two-stage exchange of the prosthesis), and antibiotic treatment. The antibiotic treatment was initiated with parenteral cloxacillin or cefazolin (preceded by vancomycin, until the results of susceptibility studies were available) for 1 to 2 weeks and was followed by moxifloxacin at 400 mg orally daily in order to complete a total of 3 months of antibiotic treatment. Patients with antecedents of cardiac arrhythmias and/or conduction disorders or with basal electrocardiography findings suggesting these disorders were excluded from the protocol. Written informed consent was required for all patients receiving long-term moxifloxacin treatment. Definitions. For the diagnosis of infection, growth of S. aureus in at least one deep sample of synovial fluid or periprosthetic tissue or growth of CoNS in at least two deep samples of synovial fluid or periprosthetic tissue plus demonstration of the presence of neutrophils in a patient with compatible clinical symptoms (except in cases where infection was a finding during prosthetic joint revision; see below) was required. Infections were classified as follows: (i) early postoperative infections were those diagnosed within the first 30 days after the surgery, (ii) late chronic
infections were those diagnosed after 30 days after the surgery with clinical data suggesting chronicity, (iii) hematogenous infections were those that represented hematogenous seeding of the joint from another primary site with no previous dysfunction of the prosthesis, and (iv) a finding in prosthetic joint revision of growth of S. aureus in at least one deep sample of synovial fluid or periprosthetic tissue or at least two deep samples of synovial fluid or periprosthetic tissue with growth of CoNS plus demonstration of the presence of neutrophils in a prosthesis exchange procedure from a patient without a previous diagnosis of prosthesis infection. We considered clinically evaluable patients to be those who completed moxifloxacin treatment and/or those who did not complete moxifloxacin treatment because of failure. Cure was defined as (i) a lack of clinical signs and symptoms of infection, (ii) a C-reactive protein level of less than 5 mg/liter, and (iii) the absence of radiological signs of loosening or infection at the latest follow-up visit. Failure was defined as (i) persisting clinical and/or laboratory signs of infection or (ii) persisting or new isolation of the initial microorganism at the latest follow-up visit. The global cure rate was calculated by dividing the number of patients considered cured by the number of all clinically evaluable patients (excluding those
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TABLE 2. Comparative data according to type of infected implant Value by implant type Characteristic
Sex (% male/% female) Mean ⫾ SD age (yr) Mean ⫾ SD Charlson comorbidity index No. (%) of patients in the following McCabe and Jackson group of underlying disease: Nonfatal Ultimately fatal Rapidly fatal No. (%) of patients with underlying diseases conditioning immune suppressionb No. (%) of patients with the following timing of infection: Early infection Late chronic infection Late hematogenous infection Finding in prosthetic joint revision No. (%) of patients with the following etiology of infection: Staphylococcus aureus CoNS Median (range) no. of days of i.v. antibiotic treatmentc Median (range) no. of days of oral moxifloxacin treatment No. (%) of patients with surgical debridement with or without implant removal No. (%) of patients with implant retentiond Median (range) no. of days of follow-up No. of patients with global cure per ITT/total no. of patients (%) No. of patients with global cure/total no. of patients (%) (n ⫽ 46)
Osteosynthesis material (n ⫽ 28)
Prosthesis (n ⫽ 20)
64.3/35.7 50.5 ⫾ 12 0.6 ⫾ 1.5
35/65 68 ⫾ 12 0.9 ⫾ 1.3
25 (89.3) 3 (10.7) 0
14 (70) 6 (30) 0
4 (14.3)
9 (45)
4 (14.3) 24 (85.7) 0
2 (10) 9 (45) 3 (15) 6 (30)
22 (78.6) 6 (21.4)
11 (55) 9 (45)
11 (1–31) 82 (24–212) 20 (71.4)
14 (5–28) 77 (48–223) 17 (85)
13 (46.4) 568 (102–1,326) 21/28 (75) 21/27 (78)
P valuea
0.001
0.04
0.007
8 (40) 854 (107–1,613) 17/20 (85) 18/19 (95)
Only P values of ⬍0.1 are shown. Diabetes mellitus, liver cirrhosis, chronic renal failure, rheumatoid arthritis, oncological disease, and HIV infection. Intravenous vancomycin and cloxacillin-cefazolin, followed by moxifloxacin for a total of 3 months. d Implant retention was performed in 15 cases of S. aureus infection and 4 cases of CoNS infection. a b c
patients who did not complete moxifloxacin treatment because of adverse events). For the cure rate according to intention to treat (ITT), we also considered failures to be those patients who did not complete moxifloxacin treatment because of adverse events. Clinical follow-up. Relevant information about each patient’s demographics, comorbidity, type of implant (osteosynthesis material, prosthesis), clinical manifestations, surgical treatment, microorganism isolated, antimicrobial therapy, adverse events of moxifloxacin (including a per protocol electrocardiogram before and during therapy), and outcome was prospectively recorded and retrospectively analyzed. After the patients were discharged, they were followed up monthly while they were receiving treatment. Once the treatment was finished, they were reviewed every 3 months, at which time the clinical response was recorded. If no recent clinical data were available, the patients or their closest relatives were contacted by telephone. Microbiology methods. Bone samples obtained during surgery were cultured in 5% horse blood, chocolate, and MacConkey agar plates and in thioglycolate medium. S. aureus and CoNS were identified using conventional methods. Ciprofloxacin and levofloxacin MICs were determined according to the CLSI guidelines (2) with a microdilution method (7). We assumed moxifloxacin susceptibility in ciprofloxacin- and levofloxacin-susceptible isolates. Statistical analysis. Continuous variables were expressed as the means and standard deviations or the medians and interquartile ranges (IQRs). The continuous variables were compared by using the Mann-Whitney U test, and the comparison of proportions was done by using the 2 test or Fisher’s exact test, when necessary. Analysis of cure was performed by intention to treat or for the clinically evaluable population, as indicated in the Results. Survival was defined as the interval from the end of the antibiotic therapy to the relapse. All patients who had not relapsed by the date of the last analysis were censored. Kaplan-Meier
survival curves were calculated globally and for each potentially prognostic variable (etiology, type of implant). The log-rank test was applied to evaluate the influence of each variable. Statistical significance was defined as a two-tailed P value of 0.05. The analysis was done with the SPSS program (version 13.0; SPSS, Inc., Chicago, IL).
RESULTS Forty-eight patients with quinolone-sensitive S. aureus or CoNS orthopedic implant-related infections reported between June 2006 and April 2009 at our institution were included in the present study. Only one patient was excluded from the protocol because of basal electrocardiogram abnormalities. As is shown in Table 1, 25 (52%) were male (mean age, 58.8 ⫾ 2.6 years), and 13 (27%) had some underlying condition associated with immunosuppression (4 with connective tissue diseases, 1 with liver cirrhosis, 2 with human immunodeficiency virus infection, 5 with neoplasia, and 1 with diabetes) and a mean Charlson comorbidity index under 1 (0.8 ⫾ 0.2). The type of orthopedic implant with osteomyelitis is also summarized in Table 1: osteosynthesis material (58.3%), hip prosthesis (18.8%), knee prosthesis (20.8%), and a shoulder prosthesis in one patient (2.1%). The majority of patients included had late chronic infection
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FIG. 2. Kaplan-Meier estimates of the cumulative risk of failure after treatment with moxifloxacin, according to the etiology of the episodes.
FIG. 1. Kaplan-Meier estimates of the cumulative risk of failure after treatment with moxifloxacin.
(33, 68.8%), six patients had an infection in a prosthetic joint revision (12.5%), six patients had an early infection (12.5%), and three patients had a late hematogenous infection (6.3%). As is shown in Table 2, patients with prosthesis infections were significantly older and had more underlying diseases conditioning immunosuppression than patients with osteosynthesis material infections. On the other hand, late chronic infection was more frequently reported in patients with osteosynthesis material infections. The majority of the cases were due to S. aureus (33, 68.8%). All S. aureus and CoNS strains were susceptible to oxacillin (MIC ⱕ 1 mg/liter) and levofloxacin (MIC ⱕ 1 mg/liter). The majority of the patients underwent some type of surgical intervention (37, 77.1%), and total or partial retention of the implant occurred in 21 patients (43.8%). Moxifloxacin was administered for a median of 78 days. Treatment compliance was excellent in all but two patients (4.2%; 95% confidence interval [CI], 0 to 9.5%), who developed side effects conditioning treatment withdrawal (one patient with Clostridium difficile-associated colitis and one patient with persistent moxifloxacin administration-related dizziness). No electrocardiogram abnormalities were reported during moxifloxacin treatment. The overall median follow-up was nearly 24 months (716 days; range, 102 to 1,613 days). Two patients (4%) were considered lost (with the last evaluations being at 8 and 13 months after therapy), and one patient (2%) died of nonrelated causes during follow-up. The global cure rate per ITT was 79.1% (38/48; 95% CI, 67 to 90%). Thirty-eight of 46 clinically evaluable patients were considered cured (82.6%; 95% CI, 71 to 93%) at the latest follow-up visit. Patients managed with implant retention had lower global cure rates than those managed with complete implant removal, although the differences did not reach statistical significance (15/217 [1.3%] and 23/25 [92%], respectively; P ⫽ 0.1). A total of 32 patients had a minimum follow-up of 2
years, and the cure rate in the 30 clinically evaluable patients was 80% (95% CI, 65.4% to 94.6%). The cure rate per ITT in this subgroup of patients was 68.8% (95% CI, 52.4% to 85.2%). Figure 1 shows the Kaplan-Meier plot of the disease-free survival in the 48 patients. According to the survival function obtained, the cumulative probability of being free of relapse at 2 years of follow-up was 0.8 (95% CI, 0.73 to 0.86). In Fig. 2 and 3, comparative survival curves according to the etiology of the episodes and the type of infected implant, respectively, are also shown. Overall, eight cases of relapse occurred (16.6%). As is shown in Table 3, the overall median time to relapse was 291 days (range, 44 to 711 days). The majority of the infected implants were osteosynthesis material, and six out of eight patients had been managed with implant retention. Isolation of the relapsing microorganism was achieved in six patients, with S. aureus being the microorganism in most of them (n ⫽
FIG. 3. Kaplan-Meier estimates of the cumulative risk of failure after treatment with moxifloxacin, according to the type of infected implant.
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TABLE 3. Clinical and microbiological data for the 8 patients with treatment failure due to relapse of infectiona Age (yr)/sex
Underlying disease
49/F 29/M 49/M 54/M 46/F 62/M 60/M 71/M
NR NR NR NR NR NR Neoplasia Diabetes
a b
Type of implant
Osteosynthesis Osteosynthesis Osteosynthesis Osteosynthesis Osteosynthesis Osteosynthesis Hip prosthesis Hip prosthesis
material material material material material material
Etiology
S. aureus S. aureus S. aureus S. aureus CoNS CoNS S. aureus S. aureus
Initial surgical management
None Debridement Debridement Debridement None Debridement Debridement Debridement
⫹ implant retention ⫹ implant retention ⫹ total removal ⫹ implant retention ⫹ implant retention ⫹ total removal
Time to relapse (days)
Microbiological findings
71 291 468 711 44 355 109 155
S. aureus Cips S. aureus Cips S. aureus Cips S. aureus Cips Noneb CoNS Cips S. aureus Cips Noneb
M, male; F, female; NR, nonrelevant; Cip, ciprofloxacin; s, susceptible. Only clinical criteria were used to determine a relapse.
5). In all the cases, the isolated strain in the relapse episode was susceptible to ciprofloxacin and levofloxacin. DISCUSSION Here we report on our experience with the long-term use of moxifloxacin not combined with rifampin in a population of patients with orthopedic implant-related staphylococcal infections, including infections of osteosynthesis material and prostheses. Although most of the patients had poor prognostic factors (almost 70% of them had chronic forms of S. aureus infections, and 44% were managed with implant retention), the efficacies of moxifloxacin treatment were 82.6% globally (80% for patients with at least 2 years of follow-up) and 71% for patients managed with implant retention. These results are similar to those reported for several series of patients with orthopedic implant-related infections in which long-term treatment with ciprofloxacin/ofloxacin plus rifampin was administered (5, 6, 10, 17, 19, 21, 23, 24). In a recently published descriptive study of a population with characteristics similar to ours, long-term treatment with levofloxacin plus rifampin showed efficacy of about 70% (2, 3). To the best of our knowledge, there is no previously published clinical information regarding the clinical efficacy of new quinolones in monotherapy for the treatment of staphylococcal osteoarticular infection. The in vitro antistaphylococcal activity of quinolones in biofilms is good (9, 13, 15, 18), and the findings of some previous animal experimental studies support the efficacy of moxifloxacin monotherapy in bone staphylococcal infections (11, 12). Nevertheless, there is scarce information regarding the potential influence of some pharmacokinetic properties of moxifloxacin, which has a high level of protein binding, resulting in the attainment of relatively low free drug concentrations with the standard dose. In a recently published study (14), monotherapy with high doses of levofloxacin in an experimental model of foreign body-associated staphylococcal infection was superior to therapy with the combination of levofloxacin and rifampin, and no resistant strains were reported (14). Although according to a recently reported systematic review analysis there is no definitive evidence of the effectiveness of adding rifampin to treat staphylococcal osteoarticular infections (16), combination of rifampin with quinolones is currently recommended for long-term oral treatment of orthopedic implant-related staphylococcal infections (8, 20, 26). This
recommendation is made partially on the basis of the excellent in vitro properties of rifampin against staphylococci embedded in biofilms (1, 22, 25) but is mostly supported by the results from the randomized study performed by Zimmerli et al. (27). That study demonstrated that the failure rate was higher in patients with orthopedic implant-related staphylococcal infections treated with ciprofloxacin monotherapy than in those treated with the combination rifampin-ciprofloxacin due to the emergence of ciprofloxacin resistance (which occurred in 5 of the 6 patients with treatment failure). In the present study, a total of 8 patients relapsed, but treatment failure was not due to the emergence of quinolone resistance in any of them. Other factors, mostly implant retention, were probably implicated (Table 3). Therefore, in view of these findings we can postulate that the protective effect of rifampin on the emergence of quinolone-resistant staphylococci is not necessary when more active antistaphylococcal quinolones such as moxifloxacin are administered, as has been previously suggested in recent experimental studies (14). On the other hand, addition of rifampin poses an increased risk of adverse effects and relevant pharmacological interactions, including bactericidal antagonism, determined in time-kill experiments, between quinolones and rifampin (1, 14). The simplicity of the single daily dose of moxifloxacin administered in our study favors excellent treatment compliance and a very low rate of side effects (4.2%). In addition, interaction with other drugs frequently concomitantly administered to these patients was not a limiting factor, as could have been the case if rifampin-containing regimens had been used. Some limitations of the present study deserve specific consideration. As occurs in all descriptive studies trying to analyze the efficacy of antibiotic treatment in this type of infection, it is difficult to attribute a specific role to antibiotics when taking into account the fact that many other factors influence the outcome, as do the specific clinical characteristics and surgical management of the patients. The number of patients included was relatively limited, and therefore, extrapolation of our results should be done with caution. Finally, although the median follow-up time for the patients was about 2 years, a longer follow-up probably could have led to a slightly higher rate of reported cases of relapse. In conclusion, long-term monotherapy with moxifloxacin appears to be safe and effective for the treatment of orthopedic implant-related staphylococcal infections, and it does not seem to be related to the development of intratreatment quinolone
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resistance. Further studies are needed to prospectively compare the efficacy of the use of moxifloxacin alone with the efficacy of the combined use of rifampin and quinolones for the treatment of orthopedic implant-related staphylococcal infections. ACKNOWLEDGMENTS This study was supported by the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III—FEDER, Spanish Network for the Research in Infectious Diseases (REIPI RD06/0008). We do not have a commercial or other associations that might pose a conflict of interest (e.g., pharmaceutical stock ownership, consultancy, advisory board membership, relevant patents, or research funding). REFERENCES 1. Bahl, D., D. A. Miller, I. Leviton, P. Gialanella, M. J. Wolin, W. Liu, R. Perkins, and M. H. Miller. 1997. In vitro activities of ciprofloxacin and rifampin alone and in combination against growing and nongrowing strains of methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 41:1293–1297. 2. Barberan, J., L. Aguilar, G. Carroquino, M. J. Gimenez, B. Sanchez, D. Martinez, and J. Prieto. 2006. Conservative treatment of staphylococcal prosthetic joint infections in elderly patients. Am. J. Med. 119:993.e7–e10. 3. Barberan, J., L. Aguilar, M. J. Gimenez, G. Carroquino, J. J. Granizo, and J. Prieto. 2008. Levofloxacin plus rifampicin conservative treatment of 25 early staphylococcal infections of osteosynthetic devices for rigid internal fixation. Int. J. Antimicrob. Agents 32:154–157. 4. Bogdanovich, T., D. Esel, L. M. Kelly, B. Bozdogan, K. Credito, G. Lin, K. Smith, L. M. Ednie, D. B. Hoellman, and P. C. Appelbaum. 2005. Antistaphylococcal activity of DX-619, a new des-F(6)-quinolone, compared to those of other agents. Antimicrob. Agents Chemother. 49:3325–3333. 5. Brandt, C. M., M. C. Duffy, E. F. Berbari, A. D. Hanssen, J. M. Steckelberg, and D. R. Osmon. 1999. Staphylococcus aureus prosthetic joint infection treated with prosthesis removal and delayed reimplantation arthroplasty. Mayo Clin. Proc. 74:553–558. 6. Callaghan, J. J., R. P. Katz, and R. C. Johnston. 1999. One-stage revision surgery of the infected hip. A minimum 10-year followup study. Clin. Orthop. Relat. Res. 369:139–143. 7. Clinical and Laboratory Standards Institute. 2007. Performance standards for antimicrobial susceptibility testing, 17th informational supplement: M100-S17. Clinical and Laboratory Standards Institute, Wayne, PA. 8. Del Pozo, J. L., and R. Patel. 2009. Clinical practice. Infection associated with prosthetic joints. N. Engl. J. Med. 361:787–794. 9. Frank, K. L., E. J. Reichert, K. E. Piper, and R. Patel. 2007. In vitro effects of antimicrobial agents on planktonic and biofilm forms of Staphylococcus lugdunensis clinical isolates. Antimicrob. Agents Chemother. 51:888–895. 10. Hope, P. G., K. G. Kristinsson, P. Norman, and R. A. Elson. 1989. Deep infection of cemented total hip arthroplasties caused by coagulase-negative staphylococci. J. Bone Joint Surg. Br. 71:851–855. 11. Kalteis, T., J. Beckmann, H. J. Schroder, M. Handel, J. Grifka, N. Lehn, and
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