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. Cure at EOT was defined as resolution of signs and symptoms as determined by the treating physician plus improvement of inflammatory markers by ≥75% from baseline and/or bacteriologic eradication. At TOC and LTFU, assessment of cure was based solely on resolution of signs and symptoms. Patients who received oral antibiotics as step-down therapy could be considered cured if they otherwise met these criteria. Improvement was defined as partial resolution of signs and symptoms in the presence of continued positive cultures and/or requiring chronic suppressive therapy with oral antibiotics. Failure was defined as lack of improvement or worsening of signs and symptoms necessitating amputation or a change from daptomycin to an alternative antibiotic. This did not include oral suppressive or step-down therapies, which were classified as previously indicated. If daptomycin was discontinued due to an AE, this was recorded as a failure. Regardless of severity or causal relationship, AEs were recorded if the onset occurred from the first dose of daptomycin through 30 days after completion of daptomycin therapy. Descriptive statistics were calculated for collected data, but statistical hypothesis testing was not planned due to the relatively small numbers of patients in the subgroups analyzed. Although patients with PJI were presumed to have osteomyelitis of the contiguous bone, they were analyzed separately as the PJI group.

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.

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%).

Figure 1

Table 1. Patient Demographics and Infection Characteristics

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).

Figure 2

Table 2. Reasons For Failure in 29 Patients Who Received Prior Antibiotic Therapy

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 S. aureus (MSSA,13.7%), MRCNS (13.7%), and methicillin-susceptible coagulase-negative staphylococci (MSCNS, 8.2%). Other gram-positive organisms were isolated in 16.4% of patients, including Enterococcus faecalis (4 patients), Streptococcus agalactiae and Corynebacterium sp. (1 each), and gram-positive cocci not otherwise specified (5 patients).

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.

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 Klebsiella pneumoniae and persistent MRSA, requiring addition of meropenem. The patient’s original MRSA isolate was susceptible to daptomycin, but testing was not performed on the recurrent isolate. A second patient with a significant history of psychiatric problems and noncompliance had return of osteomyelitis after repeatedly removing his own intravenous catheter. The third patient had return of osteomyelitis due to Staphylococcus epidermidis after initial cure in the presence of retained hardware. The recurrent organism retained its susceptibility to daptomycin, but therapy was changed to vancomycin plus rifampin.

Figure 3

Table 3. Clinical Outcomes After Treatment With Daptomycin

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).

Figure 4

Table 4. Clinical Outcomes After Treatment With Daptomycin, By Hardware Status

Figure 5

Figure 1. Clinical outcomes after treatment with daptomycin, patients with vertebral osteomyelitis.

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.

Figure 6

Table 5. Adverse Events Occurring From the First Dose of Daptomycin Through 30 Days After Completion of Therapy