JAC Advance Access published online on November 13, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm437
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Outcomes with daptomycin versus standard therapy for osteoarticular infections associated with Staphylococcus aureus bacteraemia
1 Division of Infectious Diseases, Duke Clinical Research Institute, Durham, NC, USA 2 Division of Geographic Medicine and Infectious Diseases, Tufts New England Medical Center, Boston, MA, USA 3 Johns Hopkins University School of Medicine, Baltimore, MD, USA 4 Cubist Pharmaceuticals, Lexington, MA, USA 5 Independent Consultant, Newton, MA, USA 6 Drexel University College of Medicine, Philadelphia, PA, USA 7 Wayne State University School of Medicine, Detroit, MI, USA 8 Denver Health Medical, Denver, CO, USA 9 Cleveland Clinic, Cleveland, OH, USA 10 Beth Israel Deaconess Medical Center, Boston, MA, USA
* Corresponding author. Tel: +1-919-668-8077; Fax: +1-919-668-7103; E-mail: lalan002{at}mc.duke.edu
Received 25 July 2007; returned 27 August 2007; revised 11 October 2007; accepted 12 October 2007
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Abstract |
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Objectives: To evaluate the clinical characteristics, treatment and outcomes of patients with osteoarticular infections (OAIs) associated with Staphylococcus aureus bacteraemia (SAB).
Methods: The clinical characteristics and outcomes for patients with OAI were described using a post hoc analysis of an open label, randomized trial comparing daptomycin with standard therapy (vancomycin or anti-staphylococcal penicillin with initial gentamicin) for the treatment of SAB.
Results: OAI occurred in 32 of 121 patients (21 daptomycin and 11 standard therapy) with complicated SAB (18 septic arthritis, 9 vertebral osteomyelitis and 7 others). Two patients had osteomyelitis in more than one site. Success rates seen in two groups were as follows: vertebral osteomyelitis [3/5 (60%) daptomycin versus 0/2 (0%) comparator], septic arthritis [7/11 (64%) versus 3/5 (60%)], sternal osteomyelitis [3/3 (100%) versus 1/2 (50%)] and long bone osteomyelitis [0/1 (0%) versus 1/1 (100%)]. Success rates in both treatment groups improved with surgical therapy. Creatine phosphokinase elevations to >500 IU/L occurred in one patient on daptomycin who discontinued therapy, whereas renal impairment developed in three patients on standard therapy, two of whom discontinued therapy. Two patients treated with daptomycin and one patient on vancomycin had increases in S. aureus MICs to daptomycin and vancomycin, respectively. Three patients treated with daptomycin died following completion of therapy, with mortality attributed to multiple co-morbid conditions and inadequate debridement of OAIs in these patients. No deaths were reported in the standard therapy group.
Conclusions: Daptomycin may be considered an alternative to standard therapy in the treatment of patients with complicated SAB and OAI.
Key Words: osteomyelitis , septic arthritis , complicated bacteraemia , treatment
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Introduction |
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Staphylococcus aureus is a common cause of osteoarticular infections (OAIs). Bacteraemia may be associated with S. aureus OAIs either due to the haematogenous seeding of joints and/or bone or due to haematogenous spread from an osteoarticular source. Treatment for S. aureus OAI and bacteraemia is challenging because of the need for prolonged antibiotic therapy and the risk for haematogenous complications. Although previous reports have evaluated the risk factors and outcomes for patients with OAI, data from prospective studies evaluating the epidemiology, clinical presentation, microbiological features (including susceptibility of isolates by MIC testing), treatment and outcomes of OAI associated with bacteraemia are incomplete.1
New anti-staphylococcal antibiotics have recently been shown to be effective in complicated skin and soft tissue infections, pneumonia and bacteraemia.2–5 Although successful treatment of staphylococcal osteomyelitis with linezolid and daptomycin has been reported, most of these data are in the form of individual case reports and retrospective case series.6,7 The paucity of data from randomized controlled trials, suboptimal outcomes and emergence of resistant strains highlight the need to test standard therapy against new agents for the treatment of OAI associated with S. aureus bacteraemia (SAB).
The purpose of the current investigation is to describe the epidemiology, clinical features and outcomes of patients with SAB and OAI enrolled in an open-label, randomized, multinational trial comparing daptomycin with standard therapy for the treatment of SAB.2 This study provides a unique opportunity to evaluate OAI given the prospective data collection, objective clinical and microbiological endpoints and relatively long-term follow-up of patients.
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Patients and methods |
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Patient characteristics and outcomes
The design and results of the international, open-label randomized controlled trial of therapy for SAB have been previously reported.2 Briefly, patients were randomized to treatment with daptomycin (6 mg/kg of body weight intravenously once daily) or standard therapy with either vancomycin (1 g every 12 h with appropriate dose adjustment) or an anti-staphylococcal penicillin (nafcillin, oxacillin or flucloxacillin 2 g every 4 h) depending on the susceptibility of the causative strain. All patients randomly assigned to standard treatment were to receive gentamicin (1 mg/kg intravenously every 8 h or adjusted on the basis of renal function) for the first 4 days. Patients were required to be treated for a minimum of 4 weeks, with the total duration of treatment left to the discretion of the treating physician.
The investigators evaluated patients at baseline and assessed response to therapy at the end of therapy and at 6 weeks following the end of therapy. All patients deemed to be treated successfully at the 6 week visit underwent additional follow-up at 12 weeks following the end of therapy to ensure that a relapse of infection did not occur. A committee blinded to treatment allocation evaluated each case to ascertain diagnoses and outcomes.
All patients with complicated bacteraemia in the modified intention-to-treat population (mITT) were evaluated for the presence of OAI. Complicated SAB was defined by the isolation of S. aureus from blood cultures on at least 2 separate days through study day 5, metastatic infection, or infection involving prostheses not removed within 4 days. Patients with definite endocarditis were excluded from this analysis. Individual case report forms and patient data summaries were reviewed with attention to risk factors, physical examination findings, culture results and interventions such as drainage and debridement in order to describe the epidemiology, clinical features and outcome of each infection.
Two unblinded investigators (H. W. B. and T. L.) reviewed all cases of complicated bacteraemia from the original trial to establish the diagnosis of OAI, based on strict clinical criteria defined below.8
- Septic arthritis: signs and symptoms of arthritis (pain, erythema, swelling and limitation of joint movement) and one or more of the following: (i) positive synovial fluid culture for S. aureus, (ii) X-ray, MRI or bone scan findings suggestive of infection, or (iii) purulence observed during arthroscopy or surgery of the involved joint.
- Vertebral osteomyelitis: clinical signs of infection such as persistent back pain, tenderness to palpation, movement restriction, radicular pain with associated sensory changes or weakness plus either positive culture for S. aureus on bone biopsy and/or suggestive radiographic findings on CT scan, MRI or bone scan.
- Osteomyelitis: persistent bone pain, erythema or tenderness and one or more of the following: (i) positive culture on bone biopsy; (ii) suggestive radiographic findings on CT scan, MRI or bone scan; and (iii) operative findings suggestive of infection.
- Contiguous OAI: any associated wound infection (following surgery or trauma) or cellulitis at the site of OAI occurring within 2 weeks prior to diagnosis.
- Haematogenous OAI: patients were presumed to have haematogenous OAI if they did not have any contiguous focus of infection associated with the site of OAI.
Statistical analysis was restricted to descriptive methods and results summarized as incidence estimates, given the limited number of patients and retrospective nature of this analysis. We compared the clinical characteristics and risk factors for patients with and without OAI. For patients with OAI, we evaluated the incidence of different types of OAIs. In addition, clinical outcomes of patients with OAIs were compared according to their randomized antibiotic therapy. The outcome at 6 weeks following end of therapy was the primary efficacy endpoint. A successful outcome was defined as complete resolution of symptoms and signs of OAI following completion of antibiotic therapy. Patients who failed due to persisting or relapsing S. aureus infection, clinical failure or death were considered failures in this analysis. We also examined adverse events in patients treated for OAI.
Ethics approval and patient consent
The institutional review board at each site approved the protocol, and all patients or their authorized representatives provided written informed consent.
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Results |
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Of the 246 randomized patients, 235 comprised the mITT population: 120 patients assigned to daptomycin and 115 assigned to standard therapy. One hundred and twenty-one (51%) patients in the mITT population had complicated SAB (60 treated with daptomycin and 61 treated with standard therapy). OAIs were identified in 32 patients with complicated SAB: 21 (35%) in those randomized to treatment with daptomycin and 11 (18%) in those treated with standard therapy (7 patients treated with anti-staphylococcal penicillin therapy and 4 patients with vancomycin) (Table 1).
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Eleven of 32 patients (34%) with OAI and 33 of 89 patients (37%) without OAI had complicated bacteraemia because of methicillin-resistant S. aureus (MRSA). The median duration of bacteraemia prior to study entry was 3.5 days for patients with OAI and 3.0 days for patients without OAI (Table 2). The types and sites of OAI are listed in Table S1 [available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)].
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Outcomes
Outcomes of patients with OAI treated with daptomycin and standard therapy are presented in Table 3. At 6 weeks following the end of therapy, a successful outcome was documented in 14 of 21 (67%) patients with OAI in the daptomycin group and 6 of 11 patients (55%) treated with standard therapy (absolute difference, 12%; 95% confidence interval –23.5 to 47.8%). Success was observed in 15 of the 23 patients with septic arthritis, sternal osteomyelitis or long bone osteomyelitis, with 12 successes among the 16 patients who underwent surgical debridement (75%), compared with 3 successes among the 7 patients who did not (43%). The number of successes and failures by OAI type and whether or not intervention was received are shown in Figure 1. Patients with haematogenous vertebral osteomyelitis were treated with antibiotics alone. Two post-laminectomy patients underwent surgery for the treatment of vertebral osteomyelitis: one was treated successfully with daptomycin and one failed standard therapy.
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MIC data
Four patients had MRSA isolates with a baseline vancomycin MIC of 1 mg/L. Of these, two were treated with vancomycin: one patient failed treatment, whereas the other was non-evaluable. Among the two patients treated with daptomycin, one was treated successfully and one failed therapy.
S. aureus isolates from patients in both treatment groups developed increased MICs during therapy with daptomycin and vancomycin, respectively. In 2 of the 21 daptomycin patients, S. aureus [1 MRSA and 1 methicillin-susceptible S. aureus (MSSA)] daptomycin MICs increased to 2 mg/L from a baseline of 0.25 mg/L during or following therapy. One of these patients failed treatment despite surgical intervention, whereas the other was treated successfully. The patient who failed therapy was hospitalized with recurrent MRSA bacteraemia and left knee septic arthritis. He underwent arthroscopic irrigation and drainage once and received a 3 week course of daptomycin, and no further drainage was performed. Twenty days following the last dose of daptomycin, he was re-admitted with recurrent S. aureus bacteraemia (blood culture isolate with daptomycin MIC 2 mg/L) and left knee septic arthritis. The patient who was successfully treated with daptomycin, despite a rise in MIC values, developed MSSA vertebral osteomyelitis following spinal surgery. Isolates with an increased MIC (2 mg/L) were obtained from lumbar wound culture 13 days after initiation of daptomycin. She received 74 days of daptomycin and underwent serial debridements with a successful outcome.
A comparator patient with MRSA bacteraemia and sternal osteomyelitis developed an increase in vancomycin MIC while receiving vancomycin. On day 3 of therapy, the S. aureus blood isolate had a vancomycin MIC of 2 mg/L following baseline MIC of 0.25 mg/L. He underwent aggressive surgical debridement along with antibiotic therapy and was cured.
Among patients with OAI, 3 of the 21 patients in the daptomycin group died, all after completion of therapy. One of these patients had multiple co-morbidities and developed MRSA bacteraemia, vertebral osteomyelitis and multiple psoas abscesses but was unable to undergo debridement because of his co-morbid conditions. He failed treatment with a 2 week course of daptomycin and died 3 weeks later from pulmonary embolism. The second patient developed MRSA bacteraemia following bilateral lung reduction surgery. He received 3 days of daptomycin and then switched to vancomycin due to concerns for MRSA pneumonia. His course was complicated by sternal wound dehiscence requiring debridement, bacteraemia and pneumonia, and he died 4 weeks later because of respiratory failure. The third patient had a history of chronic osteomyelitis of the left shoulder. Although disarticulation of the left shoulder was recommended by the patient's physicians, the patient declined. She received daptomycin for 3 days before care was withdrawn and died because of sepsis and multi-organ failure. There were no deaths reported among patients on standard therapy.
Most adverse events in the two treatment groups were mild to moderate in severity, resolved during continued treatment, and were considered to be unrelated to the study medications by the investigators. Reports of renal impairment, including interstitial nephritis, toxic nephropathy, acute pre-renal failure, acute or chronic renal failure or renal tubular necrosis were more common in patients on standard therapy [3 patients (27%) versus no patients in the daptomycin arm]. In order to examine this issue in a more objective manner, laboratory data were reviewed for evidence of renal impairment. The proportion of patients with clinically significant decreases in renal function during treatment (defined as a decrease in the creatinine clearance to <50 mL/min or a decrease of more than 10 mL/min from a baseline creatinine clearance of <50 mL/min) was greater in the standard therapy arm [3/10 patients (30%) versus 1/19 patients (5%) in the daptomycin arm].
Creatine phosphokinase (CPK) levels >500 IU/L occurred in one patient on daptomycin. This patient had a baseline CPK of 771 IU/L and discontinued daptomycin therapy after 10 days due to CPK levels greater than 10 times the upper limit of normal (5548 IU/L). No symptoms suggestive of myopathy such as muscle aches or weakness were reported.
Of the 21 patients who received daptomycin, 2 (10%) discontinued therapy because of a drug-related adverse event, as did 4 (36%) of the 11 patients who received standard therapy. In the daptomycin group, one patient discontinued therapy because of a drug rash, whereas the other discontinued therapy because of CPK elevation (described earlier). In the standard therapy arm, four patients discontinued therapy: a drug rash was reported in two patients (one received 32 days and the other received 6 days of anti-staphylococcal penicillin) and renal dysfunction occurred in two patients (one received 11 days of semi-synthetic penicillin, whereas the other received 35 days of vancomycin; both were treated with initial gentamicin).
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Discussion |
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To the best of our knowledge, this study represents the largest cohort of patients with SAB and OAI studied prospectively. Important observations were made in this post hoc analysis. First, most OAIs were present at the time of enrolment prior to initiation of study antibiotics. Comparable success rates were observed among patients treated with daptomycin versus standard therapy for vertebral osteomyelitis, septic arthritis, sternal osteomyelitis and long bone osteomyelitis. Success rates in both treatment groups were improved by adequate debridement of the infected bone or joint. Our findings suggest that daptomycin may be effective in the treatment of OAI associated with staphylococcal bacteraemia. Additional well-designed and adequately powered studies are required to evaluate the efficacy of daptomycin in the treatment of OAI.
Treatment limiting nephrotoxicity occurred more frequently in the standard therapy group. However, this is likely due to the use of gentamicin as part of the study regimen for the treatment of complicated bacteraemia. Gentamicin therapy is not standard of care for OAIs without ongoing bacteraemia.
Decreased drug susceptibility was noted in both successes and failures in the two groups. Luperchio et al.10 recently presented data on isolates with daptomycin MIC shifts from patients who failed therapy during the clinical trial. Pre- and post-therapy isolates responded to daptomycin exposure in time–kill assays, and the drug exposure required to treat each isolate in a neutropenic mouse model was less than the clinical exposure to daptomycin based on each patient's pharmacokinetic data. Patients with MIC shifts who failed therapy could not or did not undergo adequate drainage of infected foci, highlighting the importance of appropriate adjunctive therapy during treatment of SAB complicated by OAI.
Most patients had signs and symptoms of OAI prior to initiation of study antibiotics, although the diagnosis was not confirmed until after initiation of therapy. We believe that almost all patients had OAI associated with bacteraemia and did not develop OAI as a haematogenous complication while on study antibiotics. The two patients diagnosed with OAI >2 weeks after last dose of study therapy were likely due to other causes (non-compliance and diagnostic difficulty because of co-morbid conditions, respectively). There was no evidence to suggest that daptomycin patients developed more complications of bone and joint infections during therapy.
Our study has a number of limitations because of the infrequent occurrence of OAI and the inherent difficulty in promptly diagnosing these infections. The small number of patients with OAI in the study limits our ability to detect differences in outcomes between the two treatment groups. In addition, we were unable to evaluate the mean duration of treatment for the different types of OAIs because of the limited number of patients who completed therapy and could be evaluated. The open-label nature of the study may have introduced bias, although this was minimized by providing objective endpoints and use of a blinded adjudication committee to establish the final diagnosis and outcome assessments. Another limitation was the lack of long-term follow-up, as OAIs are known to relapse several months to years after the initial episode. Lastly, given the retrospective nature of this analysis, we were unable to obtain further details regarding risk factors in patients developing post-surgical OAI such as peri-operative prophylactic antibiotics or assess additional factors affecting treatment outcomes such as vancomycin trough levels.
In conclusion, our results demonstrate that daptomycin may be effective in the treatment of OAI associated with SAB and that further studies are warranted.
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Funding |
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This study is supported by Cubist Pharmaceuticals.
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Transparency declarations |
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Drs H. W. B., G. R. C., E. A., A. W. K., V. G. F., D. P. L. and S. E. C. have served as consultants for Cubist Pharmaceuticals. Drs T. L. and Z. A. K. are supported by Cubist Pharmaceuticals. Ms M. C. is a consultant for Cubist Pharmaceuticals. Dr G. A. V. was an employee of Cubist Pharmaceuticals during the study. Dr V. G. F. reports having received grant support from Inhibitex, Merck, Nabi and Theravance; Dr G. R. C., from Inhibitex, Merck and Theravance; Dr E. A., from Tenet Healthcare Foundation; Dr A. W. K., from Cubist, Merck, Theravance and Pfizer; Dr D. P. L., from Cubist; Dr S. J. R., from Cubist; and Dr S. E. C., from Merck. Dr V. G. F. reports having received lecture fees from Cubist, Nabi and Pfizer; Dr H. W. B. from Novartis, Pfizer, Schering-Plough and Cubist; Dr A. W. K., from Cubist; Dr C. S. P., from Ortho-McNeil; Dr D. P. L., from Cubist; and Dr S. J. R., from Wyeth and Cubist. No other potential conflict of interest relevant to this article was reported.
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Supplementary data |
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Table S1 is available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/).
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Footnotes |
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Deceased—please see the Acknowledgements section. 
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Acknowledgements |
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Dr E. Abrutyn passed away a few months prior to the submission of this paper. He was a key participant in the study design and analysis and was also involved in manuscript preparation.
In addition to the authors, the following persons participated in the S. aureus Endocarditis and Bacteraemia Study. Patient Enrolment: Amarillo, TX—R. Akins; Atlanta—H. Albrecht; Denver—M. Barron, M. Bessesen; Fargo, ND—P. Carson; New York—D. Fierer; Danville, PA—M. Foltzer; St Louis—D. Goodenberger; Winston-Salem, NC—K. High; Manhasset, NY—B. Hirsch; Besançon Cedex, France—B. Hoen; Buffalo, NY—C. Hsiao; San Francisco—H. Lampiris; Philadelphia—M. Levison, B. Suh; Bethlehem, PA—T. P. Le; Leuven, Belgium—W. Peetermans; Chicago—D. Pitrak, J. P. Quinn, J. Segreti; Louisville, KY—J. Ramirez; Boston—P. A. Rice; Regensburg, Germany—B. Salzberger; Cumberland, MD—J. Stone; Akron, OH—J. Tan; Rochester, MN—Z. Temesgen. Data and Safety Monitoring Committee: New York—K. Freeman; Charleston, SC—J. John Jr; Springfield, MA—D. Longworth. Cubist Pharmaceuticals Study Team: J. Alder, D. Anastasiou, R. Arbeit, J. Aziz, K. Blackerby, E. Campanaro, B. Eisenstein, J. Lufkin, S. Luperchio, C. Otradovec, C. Rundlett, U. Stoutenburgh, G. Thorne and P. Tipirneni.
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References |
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