Daptomycin for the Treatment of Osteomyelitis and Prosthetic Joint Infection: Retrospective Analysis of Efficacy and Safety in an Outpatient Infusion Center
C Licitra, A Crespo, D Licitra, M Wallis-Crespo
daptomycin, osteomyelitis, outpatient parenteral antimicrobial therapy, prosthesis-related infections
C Licitra, A Crespo, D Licitra, M Wallis-Crespo. Daptomycin for the Treatment of Osteomyelitis and Prosthetic Joint Infection: Retrospective Analysis of Efficacy and Safety in an Outpatient Infusion Center. The Internet Journal of Infectious Diseases. 2010 Volume 9 Number 2.
Data describing the use of daptomycin for osteoarticular infections are limited. We describe our experience with use of daptomycin for outpatient parenteral antimicrobial therapy (OPAT) of osteomyelitis and prosthetic joint infection (PJI). A retrospective analysis was done of patients who received ≥6 mg/kg of daptomycin for ≥2 weeks. All patients had a gram-positive pathogen and confirmed diagnosis of osteomyelitis or PJI. Outcomes were evaluated at end of therapy, test of cure (TOC, 6 months), and long-term follow-up (LTFU), if available. Seventy-three patients (59 osteomyelitis, 14 PJI) met inclusion criteria. The most common pathogens were methicillin-resistant
Chronic osteomyelitis and prosthetic-joint infection (PJI) are challenging to treat, usually requiring a combination of surgical and medical management.1-3 For more than 30 years, vancomycin has been the drug of choice for treatment of osteoarticular infection (OAI) caused by methicillin-resistant strains of
Daptomycin is a cyclic lipopeptide with activity against a wide range of gram-positive pathogens.13 It is indicated for treatment of complicated skin and skin-structure infections and
Based largely on registry data and small case series, daptomycin appears to be safe and effective for OAI.20-28 For example, efficacy of daptomycin was evaluated using a post hoc analysis of an open-label, randomized trial that compared daptomycin with standard therapy for
Materials and Methods
A retrospective chart review was conducted at an outpatient infectious disease practice in Florida. Using ICD-9 codes and the office billing and clinical information systems, the investigators identified patients who had been treated with daptomycin for osteomyelitis or PJI caused by gram-positive organisms and who had ≥6 months of follow-up after the end of therapy. The minimum criteria required for a confirmed diagnosis were identification of a pathogenic gram-positive organism from a culture of the wound, needle aspirate, or surgical sample; clinical findings consistent with OAI (eg, drainage, erythema, pain, swelling); and consistent radiographic and/or histopathologic findings and/or inflammatory markers (latter for PJI only). Patients also had to have received daptomycin at a dose of ≥6 mg/kg for ≥2 weeks and been aged ≥18 years. However, patients who discontinued daptomycin earlier than 2 weeks due to an adverse event (AE) or clinical failure were included and categorized as clinical failures. Concomitant use of potentially synergistic antibiotics was allowed. Patients were excluded if they had mixed gram-positive and gram-negative infections, were receiving chemotherapy, or had been described in previous daptomycin studies.
Data were collected from clinic, hospital, and physician medical records. Information collected included patient demographics, including underlying medical conditions and risk factors for infection; characteristics of the infection, including site of infection, tests and procedures used to support the diagnosis, and prior use of antibiotics that had activity against gram-positive organisms; surgical procedures, antibiotics, post-treatment antibiotic suppression, and ancillary treatments used to manage the infection; clinical outcomes; and AEs.
Osteomyelitis was classified as contiguous or hematogenous in addition to whether the infection was hardware-associated. Because no standardized definitions are accepted, chronicity of infection was assessed by bone pathology results when available; this test provided an objective measurement that a clinical definition could not. Clinical outcomes were assessed at EOT, at the 6-month follow-up (test of cure [TOC]), and, if data were available, at a subsequent, final evaluation (long-term follow-up [LTFU]). The TOC evaluation was obtained by office visit, follow-up with the referring physician, or telephone call. Because definitions are not standardized for outcomes of OAI, the investigators, after much deliberation and based on prior trials, created definitions prior to the start of the trial.
Once patient eligibility was confirmed, a 4-digit identification number was assigned. Precautions were taken to protect the personal information of each patient. The investigators requested and received a Waiver of Consent under the Common Rule and Waiver of Authorization under HIPAA from a central Investigational Review Board.
Patient Demographics and Characteristics of Infection
Beginning in May 2008 and working backwards to January 2003, 1415 patients were screened for study inclusion. Seventy-three patients met all inclusion and exclusion criteria, including 59 with osteomyelitis and 14 with PJI. Basic demographic data are shown in Table 1. The most common underlying medical conditions included hypertension (50.7%), diabetes (28.8%), and heart disease (20.6%), with 21.6% of patients having no underlying illnesses. The most common risk factors for OAI were prior orthopedic procedure (74.0%), recent trauma (37.0%), and previous surgical site infection (15.1%).
During the 6 months prior to the current diagnosis, 29 patients (39.7%) had received antibiotics with activity against gram-positive organisms (Table 2). The most commonly used antibiotics during that time were vancomycin, daptomycin, and ceftriaxone, with some patients receiving multiple agents. The most common reason for failure of prior daptomycin therapy was retention of infection-associated hardware, whereas AEs were the most common cause of vancomycin failure, followed by hardware retention and clinical failure. No differences were observed in cure rates for patients who received or did not receive prior antibiotics (data not shown).
In addition to the positive culture required for study eligibility, the diagnosis of infection was supported by surgical findings (69.9%), radiologic findings (58.9%), and histopathology (38.4%). Culture sources were deep wound (60.3%), bone (31.5%), surface drainage (5.5%), and needle aspirate (2.7%). The most common pathogens were MRSA (46.6%), methicillin-susceptible
The characteristics of the infections are described in Table 1. More than 90% of infections were classified as contiguous; of these cases, 8 were diabetic foot infections. Nearly two-thirds of the osteomyelitis cases were hardware-associated. The most common anatomic sites for osteomyelitis were the vertebra, tibia/fibula, or foot, whereas the majority of PJI were associated with the knee. Among the 35 patients who had bone pathology results, 62.9% had findings consistent with chronic osteomyelitis.
Management of Infection
Sixty-eight patients (93.2%) had daptomycin initiated at a dose of 6 mg/kg, with the remainder (6.9%) receiving 8 mg/kg. Daptomycin was administered once daily to all patients but one, who was dosed every 72 h for a portion of the treatment course due to renal insufficiency. The median length of daptomycin therapy was 49 days (range, 21-183 days).
Thirty-eight patients (52.1%) received concomitant antibiotics with activity against the isolated pathogens for some period of time while on daptomycin, with some patients receiving >1 concomitant agent. Concomitant antibiotics were rifampin (36 patients), gentamicin (5), and oral linezolid, which was used in 1 patient in whom intravenous access was temporarily disrupted. In addition, 20 patients (27.4%) were treated with locally active antibiotics (eg, antibiotic-impregnated beads, bone cement), specifically an aminoglycoside (16 patients) or vancomycin (11 patients). After completing daptomycin therapy, 27 patients (37.0%) received ≥1 oral antibiotics for a median of 28 days (range, 2-371) as either step-down (24 patients) or suppressive therapy (3 patients). Thirteen patients (17.8%) received linezolid for a median duration of 14 days (range, 2-42). Nineteen patients (26.0%) received another oral antibiotic—a tetracycline (12.3%), clindamycin (5.5%), trimethoprim-sulfamethoxazole (4.1%), cefadroxil (4.1%), moxifloxacin (1.4%), or rifampin (1.4%)—for a median of 30 days (range, 7-371). Of the 3 patients who received chronic suppression, 2 patients, 1 each with vertebral and sternal osteomyelitis, received cefadroxil for about 6 months, and 1 patient with PJI who refused surgery received doxycycline for >12 months, remaining on suppression at this time. Management also included ≥1 surgical procedures in 66 patients (90.4%) and wound vacuum-assisted closure in 7 patients (9.6%).
At EOT, 100% of PJI patients and 98.3% of osteomyelitis patients were either cured or improved (Table 3). The one failure in the osteomyelitis group was a patient who discontinued daptomycin due to suspected allergy. A high success rate was maintained at TOC, with all PJI patients and 93.2% of osteomyelitis patients still assessed as cured or improved. An additional 3 osteomyelitis patients were considered failures at this evaluation. One patient had developed recurrent infection with
Data from LTFU were available for 49 patients (67.1%), with a median duration of follow-up for these patients of 15.5 months from EOT (range, 6.0-46.8). Thirty of these patients (41.1%) had durations of follow-up that exceeded 1 year. Cure was seen in 97.4% of patients at LTFU, with the remaining patient assessed as improved. No differences were observed in the cure rates for patients who were followed for 6-12 months compared to those who were followed for >12 months or among the 4 most common pathogens (data not shown).
When analyzed by the status of any infection-associated hardware (Table 4), the majority of patients responded to daptomycin therapy regardless of whether hardware was removed, replaced, or retained. Outcomes were similar in patients who did and did not receive concomitant rifampin. Among osteomyelitis patients, 96.4% (27/28) of patients treated with rifampin were either cured or improved at TOC compared with 90.3% (28/31) of patients who did not receive rifampin. Among PJI patients, all patients were either cured or improved regardless of whether or not rifampin was co-administered. In addition, the subset of patients with vertebral osteomyelitis was analyzed separately, with 94.4%, 88.8%, and 100% of these patients either cured or improved at EOT, TOC, and LTFU, respectively (Figure 1).
Forty-five patients (61.6%) experienced 70 AEs (Table 5). The majority of AEs (78.6%) were considered by the investigators to be unrelated to daptomycin therapy. Daptomycin was discontinued in response to 3 AEs (4.3%)—rash and 2 instances of asymptomatic creatine phosphokinase (CPK) elevation. The drug was safely resumed in both patients with CPK elevation but was permanently discontinued in the patient with rash, who was consequently categorized as a treatment failure. An additional 7 AEs (10.0%) resulted in dose reductions: 2 instances each of renal insufficiency and CPK elevation (occurring in separate patients) and 1 instance each of myalgia, fatigue, and diarrhea. The cases of renal insufficiency were not felt to be related to daptomycin therapy, but doses were reduced per product labeling. The case of fatigue and 1 case of CPK elevation were ongoing at the time of study discontinuation, while the other 5 AEs resolved following dose reduction.
Osteomyelitis is one of the most common indications for OPAT.31 Although vancomycin remains the drug of choice for treatment of osteomyelitis due to methicillin-resistant staphylococci, alternatives are needed for patients in whom vancomycin is not an option due to intolerance, clinical failure, or resistance. Daptomycin possesses several characteristics that make it an attractive option for OPAT, including once-daily administration, short infusion time, and a low incidence of injection-site reactions.14 In addition, staphylococcal OAI may be associated with the production of biofilm, which can significantly hinder the activity of many antibiotics.32 Compared with vancomycin and linezolid, daptomycin has demonstrated greater activity against biofilm-associated
In this study, daptomycin was found to be effective when used as OPAT for the management of osteomyelitis or PJI. At the 6-month (TOC) evaluation, all 14 PJI patients and 55 of 59 osteomyelitis patients were considered to be cured or improved, although these patients represented a population that is difficult to treat. Many patients had chronic osteomyelitis on bone pathology and/or had received prior antibiotic therapy targeting gram-positive organisms. Nearly a third of the osteomyelitis cases involved the vertebrae, and nearly two-thirds were hardware-associated. In addition, LTFU data were available for 49 patients, representing two-thirds of all patients and with a median length of follow-up of approximately 16 months; among these patients, all were cured or improved. Satisfactory clinical success rates were achieved regardless of the status of associated hardware, use of concomitant rifampin, the presence of vertebral osteomyelitis, receipt of prior antibiotics, or duration of follow up.
Furthermore, despite median and maximum durations of therapy of 49 and 183 days, respectively, only 15 AEs occurred that were considered to be possibly or probably related to daptomycin. This included 4 instances of CPK elevation, including 2 in patients treated with the 8-mg/kg dose, reinforcing the need for CPK monitoring. Therapy was discontinued due to AEs in only 3 patients, 2 of whom had daptomycin safely resumed. Gram-negative bacteremia occurred in 8 patients (11.0%), but daptomycin would not be expected to have activity against this group of organisms.
A Phase 2 trial is currently underway to evaluate the efficacy of daptomycin for staphylococcal PJI.34 However, published clinical data regarding use of daptomycin for OAI have been limited to registry data,20-22 case series,23-28 and a post hoc analysis of patients with OAI in a randomized trial of
The current study has several strengths compared with previous publications regarding the use of daptomycin for OAI. To the best of our knowledge, the 73 patients in this chart review constitute the single largest case series of daptomycin for OAI to be published to date. This is more than twice the size of the largest previous case series, which included 31 patients.23 A recent daptomycin registry study included 250 patients with osteomyelitis who were evaluable for efficacy and 327 who were evaluable for safety22; however, outcomes could be assessed only through EOT.
The current study had a longer follow-up period than previous reports, requiring at least 6 months of follow-up for study inclusion. Additional long-term outcomes were available for 67% of patients, with a median duration of follow-up among these patients of nearly 16 months. Most previous case series evaluated outcomes at EOT or at some undefined follow-up period. Balter et al also required ≥6 months of follow-up for study inclusion, but their median duration of follow-up (9 months) was significantly shorter than the current study.27 In addition, all patients in this study were required to have positive cultures as well as other evidence supporting the diagnosis of OAI. Enrollment included many patients with infections that are particularly challenging to treat. Many had chronic osteomyelitis and/or had failed previous antibiotic regimens. Fourteen patients had PJI, and among osteomyelitis patients, nearly two-thirds had associated hardware. Eighteen patients had vertebral osteomyelitis.
However, as with previous reports, the current study is limited by the retrospective, noncomparative nature of the analysis, which prevented standardization of therapies. Concomitant systemic antibiotics with activity against gram-positive pathogens were received by 52% of patients, and 27% were treated with locally active therapy. Daptomycin was dosed at 6 mg/kg in 93% of patients, with the remainder receiving 8 mg/kg; these are the doses that are being evaluated in the prospective trial that is underway. Ancillary treatments and surgical interventions, which are a very important determinant of outcomes, were not controlled. Although the development of nonsusceptibility to daptomycin was not seen, follow-up cultures were not available for 1 patient who failed therapy. Definitions of outcomes are not standardized and, although based on previous studies, were created by the investigators. Although the duration of follow up and size of the LTFU population were greater than previous studies of daptomycin, they remain relatively small.
Outcomes by hardware status were described in Table 4, but placement of patients into these categories was challenging, as patients often had multiple surgical procedures at different times. Thus, patients were categorized according to the best possible description during that time period. Outcomes from different surgical modalities vary considerably depending on the publication, location, surgeon, etc. For example, a recent review suggests retention of hardware plus debridement for selected patients,3 but because our practice is a referral center, few patients would have met these criteria. In addition, there were no differences that we could detect based on hardware status.
At doses of ≥6 mg/kg in the current study, daptomycin was well tolerated and effective as OPAT for the treatment of osteomyelitis and PJI caused by MRSA and other gram-positive organisms. Clinical success was maintained in the majority of patients at both the 6-month and long-term follow-up evaluations, and success was achieved regardless of the presence of hardware or vertebral osteomyelitis or use of concomitant rifampin. This report represents the largest case series with the longest duration of follow-up to date. Patients treated with prolonged courses of daptomycin should have CPK levels monitored regularly and should be assessed for the development of daptomycin nonsusceptibility as clinically indicated. Until confirmatory data are available from an ongoing, prospective, randomized trial, data from case series such as this one provide support to clinicians who wish to use daptomycin for the management of OAIs.
The authors wish to thank Irin Nizam, of the Florida Infectious Diseases Group, for assistance with data collection and entry and Nizam Uddin, PhD, of the University of Central Florida, for assistance with the statistical analysis. Under the direction of the authors, Jeff Kuper, PharmD, of PharmaWrite, LLC (Princeton, NJ) provided assistance in preparing and editing the manuscript.
Conduct of this study and the preparation assistance were funded by a research grant from Cubist Pharmaceuticals, Inc. The design of the study and the collection, analysis, and interpretation of the data were solely the responsibility of the authors. Drs Licitra and Crespo have been on the speakers bureau for Cubist Pharmaceuticals, Inc. Mrs Licitra and Dr Wallis-Crespo have no potential conflicts of interest to report.
The investigators requested and received a Waiver of Consent under the Common Rule and Waiver of Authorization under HIPAA from a central Investigational Review Board.