Treatment of prosthetic joint infections (PJI) is becoming more challenging because of the increasing prevalence of resistance among gram-positive pathogens, which account for the majority of PJI.13 Daptomycin is a novel cyclic glycopeptide approved by the Food and Drug Administration (FDA) as an antibiotic for complicated skin and skin structure infections resulting from gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE).8,10 Daptomycin is a theoretically attractive option for serious gram-positive PJI because of its unique mechanism of action9 and rapid bactericidal activity against the stationary phases of methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA, which are often present in high density in biofilm on infected hardware. In addition, daptomycin has a relatively long half-life, which makes it suitable for outpatient administration.1,3,9,11
Daptomycin is as active as vancomycin in animal models of chronic MRSA osteomyelitis; both antibiotics are more active than no treatment.6,7 For example, Mader and Adams6 compared daptomycin (4 mg/kg every 12 hours) with vancomycin (40 mg/kg every 6 hours). After treatment, MRSA bone cultures became negative in 7 of 17 daptomycin-treated rabbits, 7 of 18 vancomycin-treated rabbits, and none of 18 control rabbits.6 Rouse and colleagues7 reported analogous outcomes in rats treated with daptomycin at higher doses (50 or 60 mg/kg every 12 hours) and vancomycin at less frequent dosing intervals (40 mg/kg every 12 hours). Luu et al5 also found no difference between histopathologic or microbiological specimens from rats with MSSA osteomyelitis treated with daptomycin (10 mg/kg every 12 hours) or vancomycin (80 mg/kg every 12 hours); however, outcomes in treated groups were no better than in the untreated control group.5 These between-study differences may be attributable to suboptimal dosing in the rat model of MSSA osteomyelitis.
Published clinical experience with daptomycin in patients with PJI is limited.2,4,12 Success occurred in 9 of 10 patients with gram-positive bone and joint infections in the largest series, which was a retrospective analysis without long-term followup.2
We hypothesized daptomycin would be active and well tolerated in patients with PJI caused by gram-positive bacteria. The primary objectives were to evaluate the feasibility of daptomycin in this setting as measured by ability to complete a 6-week course and the ability to obtain successful outcome after long-term followup.
MATERIALS AND METHODS
From June 2004 to January 2005, we administered daptomycin to 12 consecutive adult patients with gram-positive PJI (Table 1), defined as clinical and ancillary diagnostic evidence of an infected prosthesis confirmed by two or more intraoperative tissue cultures for the same organism. Eligible patients were unable to receive standard vancomycin therapy because of resistance, allergy, adverse reaction, or previously failed vancomycin treatment. Exclusion criteria were exposure to systemic antibiotic therapy to which the pathogen was susceptible within 2 weeks of daptomycin administration, and inability to complete at least 6 weeks of therapy. There were seven women and five men who received 6 weeks of daptomycin (Table 1); one patient received a second 6-week course. The mean age was 70.3 years (range, 55-83 years). The pathogens included MRSA (n = 7), methicillin-resistant-coagulase-negative Staphylococcus (n = 4), and MSSA (n = 1). One patient died of an unrelated cause soon after the completion of therapy. In the remaining 11 patients, the mean duration of followup after completion of therapy was 9 months (range, 7-13 months). Written informed consent was not obtained and institutional review board approval was not required because patients were treated according to local standards of care; no clinical interventions were made based on the data collected.
Daptomycin (4 mg/kg/day) was administered intravenously as soon as possible postoperatively and continued for a minimum of 6 weeks. Patients were not to receive any other antibiotics similar to daptomycin during treatment.
The type of surgery depended on the duration of infection and the judgment of the attending orthopaedic surgeon. Patients with signs and symptoms for < 2 weeks were presumed to have acute infection; hardware was retained and treatment comprised incision and drainage, polymer exchange, and, after completing daptomycin, oral suppression with trimethoprim/sulfamethoxazole or minocycline. Patients with signs and symptoms for ≥ 2 weeks were presumed to have chronic infection, which was treated with hardware removal, irrigation and débridement, placement of antibiotic-impregnated cement spacers, daptomycin, and, when infection free, reimplantation. Five patients had acute infection and their hardware was initially retained. Seven patients had chronic infection and their hardware was removed in a 2-stage exchange procedure.
Followup was conducted 5 weeks after the start of treatment and every 2 months thereafter to evaluate response to the therapy by monitoring clinical, laboratory, and microbiologic criteria. The same team of infectious disease (NR) and orthopaedic physicians (LSC and EJM) evaluated clinical signs and symptoms of infection including pain, delayed wound healing, and impaired function of the joint. Laboratory parameters included complete blood count with differential, platelets, basic chemistry profile, and creatinine phosphokinase (CPK) every week during the first 6 weeks of therapy. Patients' erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were obtained at diagnosis, 5 weeks after initiation of therapy, and every 2 months thereafter to assess for continued resolution of infection and/or adverse side effects. If there was ongoing clinical, laboratory, or radiographic evidence of infection after 4 to 6 weeks of daptomycin therapy, repeat joint cultures were performed and appropriate surgical intervention was performed by orthopaedic surgeons (LSC and EJM).
Success was defined as no clinical or radiographic evidence of recurrence, progressive decline in the ESR and CRP levels, and continued improvement of joint function. Failure was defined as clinical evidence of recurrence and positive repeat cultures for the same organism after cessation of therapy. Failure was treated with appropriate surgical intervention and intravenous antibiotics followed by 3 to 6 months of suppression with oral trimethoprim/sulfamethoxazole or minocycline.
All patients completed the planned course of daptomycin therapy. Daptomycin was generally well tolerated. No patient had elevated CPK or cessation of therapy because of adverse side effects.
At followup of 7-13 months, six patients were considered successes. Five had success after the first course of daptomycin therapy with no evidence of recurrent infection, with continued improvement of joint function at followup. Only one patient (#6) considered a success had retained hardware; the pathogen was coagulase-negative Staphylococcus, and the patient remained free of symptoms while on oral suppressive therapy. One patient (#3) failed soon after completing daptomycin therapy and was treated with removal of hardware. Daptomycin was repeated because the pathogen was methicillin-sensitive Staphylococcus aureus infection; this strategy led to success at 8 months followup.
Five patients were considered failures because of clinical evidence of recurrent infection confirmed by intraoperative cultures. Two (#5 and #9) had failures during daptomycin therapy despite removing the hardware and in one (#9) despite increasing the dose of daptomycin to 6 mg/kg/day. The remaining failures were observed at 1, 8, and 10 months in patients with retained hardware.
The pathogen involved for each of the five failures was MRSA, which was susceptible to daptomycin in two patients (#5 and #9). Susceptibility testing was not performed in the patients with late failures. These patients were successfully treated with vancomycin and rifampin (n = 4) or with linezolid (n = 1). The patients with retained hardware (n = 3) were also treated with removal of hardware followed by oral suppressive therapy.
This study was designed to explore the feasibility and efficacy of daptomycin for gram-positive prosthetic joint infections (PJI) by monitoring long-term outcomes in a series of patients treated at our institution. We are unaware of any published prospective study of daptomycin in PJI.
Our study had several limitations. First, this was an observational study; blinding was not possible. Second, this was not a randomized comparison of groups stratified by surgical and medical interventions; all patients received surgical treatment considered the standard of care for PJI13 and daptomycin therapy. Third, we did not perform a power calculation to define the sample size. Fourth, the sample size was small. We described 12 patients, including one who was not available for followup. Fifth, susceptibility testing could not be performed on all samples from patients with failure. Finally, the followup is relative short (7-13 months). Therefore, our findings should be viewed as preliminary.
Daptomycin was generally well tolerated in our patients and in other series.2,4 In our study, five of 11 patients were considered to have success after completing a 6-week course of daptomycin and an additional patient was considered to have success after removal of hardware and completion of a second course of daptomycin. This success rate appears to be lower than in the retrospective analysis by Finney and colleagues,2 who reported success in nine of ten patients, including six of six with osteomyelitis. Pathogens were generally similar; MRSA was the major pathogen in both series and was responsible for all failures. Differences between studies may have contributed to differences in response rates. PJI, a difficult-to-treat infection, was present in all of our patients but in none of those in the other series.2 We followed patients for a mean of 9 months and detected 3 late failures, but followup was not long-term in the other series.2 We minimized possible benefits from previous therapy by requiring a 2-week interval before initiating daptomycin therapy. The interval since previous therapies, administered to all but one patient, was not specified in the other series.2 A carry-over effect may have contributed to the successes in patients receiving short-term therapy, especially in the patient who received only 8 days of daptomycin.
Inadequate dosage of daptomycin may have contributed to failures in both series. Animal data suggest the need for high doses as peak concentrations in infected bone were only 1.3% of simultaneous serum concentrations in rabbits.6 Daptomycin was not detectable in uninfected bone. When our study was initiated, we were not aware of the use of higher doses for difficult-to-treat infections, such as endocarditis. Therefore, the initial dose in our study, 4 mg/kg/day, was based on that for skin and soft tissue infection. After failure of this dose and removal of hardware, the dose was increased to 6 mg/kg/day in one patient; however, these strategies did not result in success. Finney and colleagues2 used 4 or 6 mg/kg once daily or every other day, depending on factors such as the patient's clinical condition, comorbidities, and renal function. They reported underdosing may have led to an epidural abscess in a patient with septic arthritis; the pathogen was MRSA with reduced susceptibility to daptomycin.
Others have reported failure associated with in vitro resistance or reduced susceptibility to daptomycin despite the use of higher doses (6 mg/kg/day). Hayden and colleagues4 reported failure in two patients who had MRSA osteomyelitis and who received daptomycin. One patient was treated with daptomycin and surgical débridement for bacteremic prosthetic knee arthritis; this patient relapsed with bacteremia and vertebral osteomyelitis on day 35 of daptomycin therapy. The second patient was treated with vancomycin followed by 4 weeks of daptomycin for recurrent MRSA bacteremia and sternal osteomyelitis; the patient had recurrent bacteremia 2 weeks after completing therapy.4 Vikram and colleagues12 reported development of bacteremia and clinical progression of MRSA vertebral osteomyelitis during therapy with daptomycin. We did not detect in vitro resistance or reduced susceptibility to daptomycin, but isolates were available for testing from only two of five patients with failure.
Daptomycin was well tolerated in patients with PJI, even with long-term treatment; however, efficacy was uncertain. In vitro data indicating rapid bactericidal activity was not always predictive of favorable outcome in patients with PJI. Our findings suggest that perhaps hardware should be removed to maximize the likelihood of long-term success, even in patients with acute PJI. More studies are needed to determine the optimal dose of daptomycin and role of combination therapy for the treatment of PJI.
We thank Lawrence S. Crossett (LSC), MD, and Edward J. McClain (EJM), III, MD, for performing surgery and monitoring patients for signs and symptoms of infection.
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