Daptomycin, a semisynthetic lipopeptide antibiotic, was approved by the US Food and Drug Administration in September 2003 for the treatment of complicated skin and soft tissue infections caused by Staphylococcus aureus (methicillin-susceptible and methicillin-resistant [MRSA]), vancomycin-susceptible Enterococcus faecalis, Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus dysgalactiae.1,2 More recently, it was approved for the treatment of Staphylococcus aureus bacteremia and right-sided endocarditis.3,4 Off-label use of daptomycin occurs commonly, and clinicians are increasingly using this new antibiotic to treat bone and joint infections when approved antibiotics fail or cause adverse events. The failure of daptomycin to eradicate MRSA in a patient with septic arthritis of the shoulder and osteomyelitis of the humerus prompted us to review our clinical experience with this agent in the treatment of bone and joint infections. We summarize treatment outcomes for this case and 10 additional cases in which daptomycin was used for the treatment of bone and/or joint infections at our institution from September 2003 through June 2006.
MATERIALS AND METHODS
We retrospectively reviewed the medical records of patients at Beth Israel Deaconess Medical Center, a 585-bed teaching hospital in Boston, Massachussetts, from September 2003 through June 2006 to determine whether daptomycin had been used to treat other cases of bone and/or joint infections. Institutional review board approval was obtained for medical record review. We reviewed the outcomes of these cases and determined whether isolates with reduced susceptibility to daptomycin were isolated. A bone or joint infection was defined on the basis of having one of the following: (1) bone pathology consistent with osteomyelitis, (2) radiological studies (magnetic resonance imaging [MRI] or bone scan) consistent with osteomyelitis in the setting of documented bacteremia, or (3) a positive culture from a bone or joint obtained under sterile conditions. Data collected included demographic information, microorganisms isolated, dose of daptomycin administered, duration of treatment, and initial and on-treatment susceptibilities to daptomycin. Response to therapy was categorized as successful (completion of planned course with clinical response and no relapse of infection within 3 months of stopping daptomycin), unsuccessful (failure to clear infection after appropriate treatment course or relapse of infection within 3 months of cessation of daptomycin), or not evaluable (inadequate length of treatment with daptomycin or lack of follow-up information). Data regarding patient allergies and treatment with prior antibiotics were collected. When prior antibiotics were used, reasons for changing to daptomycin were recorded.
During the study period, 12 courses of daptomycin were used for the treatment of 11 distinct cases of bone and/or joint infections. Two separate courses were administered to 1 patient with a relapse of infection in which daptomycin treatment ultimately failed. These were combined to count as 1 case resulting in 1 clinical failure. Six patients were women and 5 were men with an average age of 56 years. In each case, infection was caused by Staphylococcus species (9 MRSA, 1 methicillin-susceptible Staphylococcus aureus, 1 coagulase-negative Staphylococcus [CNS]). In 3 patients, daptomycin was the initial antibiotic selected for treatment. Each of these patients had a prior documented intolerance to vancomycin and/or linezolid. In the other 8 cases, each patient was treated first with an alternative antibiotic and switched to daptomycin after an adverse event (n = 6), lack of clinical resolution (n = 1), or increasing minimum inhibitory concentration (MIC) to the first antibiotic (n = 1). Treatment was successful in 3 cases, unsuccessful in 4 cases, and not evaluable in 4 cases. The 4 cases categorized as not evaluable included 2 that had no follow-up recorded after starting daptomycin and 2 that received an inadequate length of treatment with daptomycin. In the latter 2 cases, daptomycin was not discontinued secondary to side effects, toxicity, or documented failure. Table 1 describes the outcomes in the 7 cases in which a full treatment course of daptomycin was used.
Daptomycin nonsusceptibility developed in one of the treatment failures (4b, Table 1). Details regarding this patient are as follows: the patient is a middle-aged woman who had undergone open reduction and internal fixation for a closed fracture of the right humerus. Postoperatively, she was noted to have extrusion of the fixation pins, and all hardware was removed. She subsequently developed MRSA bacteremia and, because of a history of an adverse reaction to vancomycin, was treated with 2 weeks of linezolid. Ten days after completion of linezolid, she presented with increasing pain in the right shoulder. Septic arthritis was confirmed with MRSA cultured from a surgical debridement specimen. Linezolid was restarted for a planned 6-week course. However, because of leukopenia and thrombocytopenia, therapy was changed to daptomycin (6 mg/kg per day intravenously) 4 weeks into the linezolid course. Eleven days after completing the remaining 2-week course of daptomycin, fever and pain in the shoulder recurred. Operative cultures from a bone debridement grew MRSA susceptible to daptomycin by E-test (MIC = 0.25 μg/mL). Treatment with daptomycin was initiated again (second course). The patient underwent repeat debridement on day 32 of the second course of daptomycin therapy because of worsening shoulder pain and fever. Operative cultures again grew MRSA; however, the organism was nonsusceptible to daptomycin by E-test (MIC = 4 μg/mL with MIC less than 1 μg/mL, defined as susceptible by Clinical and Laboratory Standards Institute break points5). This result was confirmed by agar dilution testing at a reference laboratory (Focus Diagnostics, Inc, Cypress, Calif). Antibiotics were changed to quinupristin/dalfopristin (6-week course), followed by minocycline (9-week course). The patient underwent extensive debridement with resection of the proximal humerus and placement of a tobramycin-impregnated spacer 2 weeks after stopping the minocycline for definitive cure at an outside hospital. Operative cultures at that time, 4 months after stopping daptomycin, again grew MRSA susceptible to daptomycin by E-test, with an MIC of 0.75 μg/mL. The patient was given vancomycin and developed a diffuse, generalized rash, but was able to complete 12 weeks of therapy. She was then treated with 7 months of minocycline therapy followed by a shoulder replacement.
We identified 7 patients in whom a full course of daptomycin was used for the treatment of staphylococcal bone and joint infections. In all 7 patients, medical treatment was accompanied by appropriate surgical debridement. Treatment was successful in 3 (43%) of 7 cases, defined as clinical resolution of symptoms with no recurrence of infection after discontinuation of daptomycin (duration of follow-up, mean 7.3 months; range, 6-9 months). Treatment with daptomycin was unsuccessful in 4 (57%) of the 7 cases, with daptomycin nonsusceptibility developing during treatment in 1 case, as detailed previously. In this case, a follow-up culture 4 months after discontinuation of daptomycin again grew MRSA, this time, susceptible to daptomycin. This relapse isolate was recovered at an outside institution, and thus we were unable to confirm its identity with the initial MRSA isolate. However, because the culture was taken from the same site in a patient who had been on near continuous antibiotic treatment, the assumption that this finding represents persistence of the same MRSA strain seems reasonable. Although this apparent "reversion" back to susceptible has not been previously documented in clinical practice, it has been exhibited in early in vitro studies.8,9 There was no clear relationship between treatment outcome and daptomycin dosing in our study.
Of note, in these 7 cases, 2 (no. 5 and 7) involved MRSA infections that were treated with vancomycin before initiation of daptomycin. Both resulted in unsuccessful treatment outcomes. Recent data suggest that some MRSA strains that develop reduced susceptibility to vancomycin also demonstrate increased MICs to daptomycin.10-13 Vancomycin-intermediate Staphylococcus aureus resist vancomycin by cell wall thickening, a phenomenon which may confer cross-resistance with daptomycin by decreasing the drug's access to the cell membrane. In fact, it has been shown that the reduction of daptomycin susceptibility correlates with the incremental increase of cell wall thickness.11 These findings suggest that patients heavily exposed to vancomycin before use of daptomycin may be at increased risk of clinical failure with daptomycin, if populations of vancomycin-intermediate Staphylococcus aureus have emerged.
In early phase II and III clinical trials, a daptomycin resistance rate of less than 0.2% was noted.14 Although the mechanism for the development of resistance is still not understood, recent evidence suggests that mutations or insertions in genes mediating production of MprF, a lysylphosphatidylglycerol synthetase, YycG, a histidine kinase, or RNA polymerase subunits may play a role.15 A recent report describing whole-genome sequencing of a series of increasingly vancomycin nonsusceptible MRSA clinical isolates from a patient exposed to drugs including vancomycin and rifampin, but not daptomycin, also found mutations in rpoC and the Yyc gene cluster, adding to a growing body of evidence that there may be commonalities in the selection for resistance against these 2 drugs, despite that current understanding that they have differing mechanisms of action.16 Since US Food and Drug Administration approval, several cases of documented daptomycin nonsusceptibility have been published or reported in abstracts,3,17-23 5 of which involved bone and joint infections. In all 5 cases, MRSA was the etiologic organism, and daptomycin (dosed at 6 mg/kg) was started after vancomycin failed to clear the infection. In all but 1 case, daptomycin susceptibility was initially confirmed, yet nonsusceptibility developed after prolonged therapy. In the remaining case, de novo daptomycin nonsusceptibility was documented. In 3 of the 5 cases, increased MICs to vancomycin were also documented at the time of failure. Our patient (no. 4) was not treated with vancomycin before daptomycin. The MIC to vancomycin was less than or equal to 1 μg/mL in the daptomycin nonsusceptible strain, suggesting that prior vancomycin exposure is not required for the emergence of daptomycin nonsusceptibility.
It is not yet clear if the use of additional antibiotics in combination with daptomycin might improve its efficacy in the treatment of bone and joint infections. In vitro studies have shown the possibility of synergy between daptomycin and β-lactams, gentamicin, or rifampin.24-26 Three recent case reports were published of MRSA bone and joint infections that were successfully treated with both daptomycin and rifampin or with the combination of daptomycin, vancomycin, and rifampin.27,28 In all 3 cases, the patient had failed standard therapy with vancomycin and either gentamicin or rifampin, and in 2 cases had also failed daptomycin monotherapy at 6 mg/kg daily.
Several reports and reviews have discussed the efficacy of daptomycin in treating bone and joint infections.29-36 The reported success rates have varied from 50% to 96%. This variability is most likely caused by differences in the definitions of clinical success, types of bone and joint infections treated, infecting microorganisms, doses of daptomycin used, extent of adjunctive therapy such as debridement, hardware removal, and synergistic antibiotics, the small number of patients evaluated, and retrospective nature of most reports. Only 1 prospective study has been presented to date. Rao and Regalla31 followed 12 patients with prosthetic joint infections who were treated with daptomycin 4 mg/kg per day for 6 weeks. Six of 12 patients were considered successfully treated, defined as no clinical evidence of recurrence and continued improvement of joint function (mean follow-up time, 5 months; range, 0-9 months). Five were categorized as treatment failures (2 despite hardware removal), and one was unknown.
Additional data regarding the use of daptomycin in the treatment of osteomyelitis comes from animal models.37,38 In the first study, a rabbit model of MRSA osteomyelitis was used to compare the efficacy of daptomycin with that of vancomycin. After a 28-day antibiotic course, treatment was successful in 41% of daptomycin- and 39% of vancomycin-treated rabbits. There was no difference between daptomycin- and vancomycin-treated rabbits with regard to the number of viable bacteria remaining in bone. Vancomycin levels in bone were higher than daptomycin levels, although the significance of this finding was not clear. Daptomycin is 90% to 93% protein bound, a factor which may hinder penetration into some tissue compartments, including bone. More recently, Rouse et al38 studied MRSA chronic osteomyelitis in the rat model. After a 21-day treatment course, there was no significant difference in the median log10 colony-forming unit per gram of MRSA in bone from daptomycin (2 doses evaluated to simulate area under the curve in humans after administration of 6 mg/kg or 8 mg/kg)- and vancomycin-treated rats.
The limitations of this study include the retrospective design and the small number of patients evaluated. In addition, the results from these daptomycin-treated patients were not compared with any control group. Although the cases failing therapy meet the criteria for clinical failure, defined in the "Methods" section, microbiological failure was not documented in 1 of the 4 cases (no. 7). Although microbiological relapse was documented in 2 cases (no. 4 and 6), we do not have molecular typing to prove that the failure isolate was the same as the original infecting organism. With any case of chronic osteomyelitis, adequate debridement is an important component of therapy. Although all cases of osteomyelitis presented, both acute and chronic, had debridement performed, it is impossible to evaluate if inadequate debridement played a role in any of the cases of clinical failure.
Regardless of antibiotic choice, bone and joint infections are difficult to eradicate. In 1 study that evaluated 215 patients with MRSA infections who were appropriately treated with vancomycin, osteomyelitis was independently associated with both clinical failure and relapse.39 There are currently no prospective, randomized, published data comparing daptomycin with other antibiotics in the treatment of bone and joint infections in humans. However, Cubist Pharmaceuticals is planning a randomized study comparing the efficacy and safety of daptomycin given at a dose of 6 mg/kg or 8 mg/kg per day intravenously with those of a comparator group, vancomycin or teicoplanin, in subjects undergoing surgery for osteomyelitis associated with an infected prosthetic hip or knee joint caused by MRSA and/or CNS.40 Based on the available evidence published in abstracts and case reports of daptomycin nonsusceptibility developing in patients treated for bone and joint infections, we suggest caution in using daptomycin for this indication, particularly in the setting of recent vancomycin exposure. If daptomycin is used, our data and those of others, indicate that clinicians should monitor closely for signs of persistent infection and repeatedly culture affected sites to test for continued daptomycin susceptibility when clinical improvement is slow or lacking.
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