Daptomycin, a novel lipopeptide antibiotic derived from Streptomyces roseosporus, is FDA approved for the treatment of complicated skin and skin structure infections (cSSSI).1 It has in vitro bactericidal activity against most clinically relevant Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and vancomycin-resistant enterococcus (VRE).2-5 Its novel mechanism of action involves the disruption of Gram-positive bacterial plasma membranes, and it is bactericidal in a concentration-dependent manner.6 In vitro studies showed that resistance to daptomycin rarely occurs 7; however, since it became available in the United States during 2003, there have been isolated reports of daptomycin resistance in clinical isolates of VRE and MRSA.8-10
Osteomyelitis is a serious complication seen in diabetic patients and other immunosuppressed hosts. It tends to require long antimicrobial treatment and has a high failure rate.11,12 A recent meta-analysis of clinical trials examining antibiotic treatments for osteomyelitis spanning more than 30 years found that most studies did not include a comparator; the report also recognized a lack of information regarding infection staging, surgical treatments, or the presence of orthopedic hardware for participating patients.13 Interestingly, the analysis could not clearly identify the best antibacterial treatment of osteomyelitis but did find that most tested regimens were 6 weeks long. Darley and MacGowan14 reviewed the topic of antibiotics for the treatment of Gram-positive bone and joint infections and cited comparative studies demonstrating improved efficacy with oral fluoroquinolones combined with either rifampin or fusidic acid. Prosthetic-associated infections can occur by inadvertent inoculation at the time of implantation, hematogenous seeding during bacteremia, or by spreading from a nearby infectious focus such as a postoperative surgical infection site.15 A common treatment of infections involving prosthetic joints is a 2-stage prosthetic exchange separated by 6 weeks of intravenous antibiotic therapy.16 However, more often patients with osteomyelitis and joint infections involving MRSA isolates are typically treated with glycopeptide antibiotics such vancomycin or teicoplanin. For many years in the United States, the standard therapy for MRSA has been vancomycin, but more recently other treatment options have become available. However, prospective clinical studies involving these new agents-linezolid, quinupristin-dalfopristin, teicoplanin, and daptomycin-in bone and joint infections caused by MRSA are sparse or nonexistent.15
Of these potential alternatives to vancomycin for the treatment of MRSA infections, daptomycin was most recently approved for use in humans. Clinical studies have demonstrated that it is as effective as standard therapies for cSSSI,17 diabetic foot infections,18 and complicated urinary tract infections.19 Preclinical models of infection have suggested that daptomycin may have antibacterial activity in other infection types including osteomyelitis, endocarditis, and foreign body infections.20-22 Here we present retrospective data collected from 31 patients treated with daptomycin for severe infections involving Gram-positive cocci of native and prosthetic joints, deep spinal wounds resulting from laminectomy procedures, and bone.
PATIENTS AND METHODS
Data from 31 patients with severe Gram-positive infections were collected retrospectively for age, sex, race, underlying illnesses, surgical procedures, culture site and pathogens, duration of daptomycin therapy, adverse effects, previous antibiotics use, and clinical outcomes. All patients treated with daptomycin for an orthopedic-related infection by the authors at 5 separate community hospitals and at an oncology infusion center over a period of 12 months were included in this retrospective review. No patients with orthopedic-related infections were excluded from the chart review; however, patients without conclusive identification of pathogens were not included in the analysis. Each hospital was comparable in size, having approximately 300 beds with advanced cardiac, orthopedic, oncology, and transplant facilities. Three of the facilities were teaching hospitals affiliated with area universities, and actively conducting research. However, patients enrolled in clinical trials of any kind were not included in this chart review study.
To evaluate patient clinical outcomes, the criterion for clinical and microbiologic cure was resolution or improvement in the clinical infections, demonstrated by negative microbiologic culture results, clinical signs, and magnetic resonance imaging (MRI) or computed tomography (CT) scans. Treatment failure was defined as reoccurrence of infection despite antibiotic therapy and appropriate surgical procedures and/or debridement. Cultures were taken directly from bone or prosthetic device during surgery when possible; however, most cultures were taken from wound or laminectomy sites. Surgical interventions included removal of all hardware with repeated incision and debridement of the area until it was deemed clinically free from infection by the surgeon. For some patients, repeat cultures were obtained to determine if any residual microbes were present. Blood cultures were taken routinely from patients with bacteremia. Pathogens were identified, and minimum inhibitory concentrations were determined at a reference laboratory. At follow-up, cultures were obtained for testing when there was a wound or incision available to swab.
In patients who received combination antibiotic therapy to treat single isolate infections, the following criteria were used to assess patient need: (1) patients failed standard surgical debridement more than once, and (2) patients failed standard antimicrobial therapy more than twice. A few patients required concomitant antibiotic therapy for Gram-negative pathogen coverage. As a part of this chart review, patients' laboratory tests were evaluated, including serum creatine phosphokinase levels at admission and discharge, whole blood counts, alanine serum transaminase, and alanine leukocyte transaminase. As part of patients' follow-ups, blood and wound cultures were taken to confirm microbiologic outcome assessments (ie, cure or failure). Routine follow-up evaluations were done 2-4 weeks after the surgical intervention at an outpatient facility. Later follow-up assessments were performed, and in some cases patients have been assessed up to 12 months after receiving daptomycin therapy.
A review of patient demographic information found that the mean age of daptomycin-treated patients was 65 years (N = 31), with a range from 40 to 89 years (Table 1). Fifteen patients (48%) were male, and 15 patients had an underlying diagnosis of diabetes mellitus. The types of infections were as follows: 16 patients had osteomyelitis (2 with concomitant bacteremia), 8 patients had infected prosthetic joints, 6 patients had deeply infected laminectomy wounds without osteomyelitis, and 1 patient had diskitis with bacteremia. Twenty-four patients had infections involving MRSA isolates, 5 had methicillin-sensitive S. aureus (MSSA), and 4 had MRSE. Five patients had mixed MRSA infections, including MRSA with Pseudomonas aeruginosa, coagulase-negative MSSA, S. epidermidis, or Escherichia coli (Tables 1 and 2). Nearly all patients (n = 29) underwent surgery before or upon commencing their treatment with daptomycin; the most common procedure was the removal of hardware and debridement, followed by incision and drainage. Some patients required both procedures. Two patients with osteomyelitis required amputation (Tables 1 and 2). Seven patients with infected joints had their prostheses removed before their failed prior therapy.
Three patients received daptomycin as first-line therapy (Table 2). However, most patients received daptomycin as second- or third-line therapy after failing a prior therapy. Of these patients, 17 included at least 1 course of vancomycin monotherapy, whereas 5 others received vancomycin combined with another agent. Six patients received immediate prior treatment with cefazolin, cephalexin, or levofloxacin monotherapies. The mean duration of all prior therapy types was approximately 30 days.
Daptomycin therapy was successful in 87% (27/31) of the patients who received it, as determined by culture results, clinical signs, and MRI and/or CT scans (Table 3). The mean duration of daptomycin therapy was 38.2 days, with a range of 14-56, and most patients received 6 mg/kg/d of daptomycin intravenously (iv). Seven patients with reduced renal capacity at baseline (glomerular filtration rate of less than 30 mL/min/1.73 m2) were dosed at 4 mg/kg iv every 48 hours. Patients undergoing hemodialysis received antibiotic treatment immediately after dialysis. Twenty-two patients received daptomycin therapy while hospitalized, whereas 9 patients were discharged to receive daptomycin infused intravenously as outpatients (data not shown).
Patient follow-up data are available from a range of 4 to 6 months for osteomyelitis and joint infections and 4 to 12 months for laminectomy patients. To monitor patients' clinical responses and possible relapses, follow-up cultures were obtained in all the laminectomy patients who had hardware removed, and in all the patients with prosthetic joint infections who had reimplantation. At the time of this writing, the average follow-up has been 8-12 months for all patients with osteomyelitis and 10-12 months for at least half of the patients with prosthetic joint infections.
Of patients who were deemed cured after daptomycin therapy, to date none have experienced recurrent or relapsing infections. Of the 4 patients who failed daptomycin monotherapy, 2 were treated successfully with 6 weeks of combined daptomycin (6 mg/kg every 24 hours), vancomycin (1 g every 24 hours), and rifampin (300 mg every 12 hours) therapy. These 2 patients have been free of infection reoccurrence for over 12 months.
Laboratory assessments were performed weekly to evaluate patients' serum creatine phosphokinases and liver transaminases; complete blood counts and metabolic panels were also performed. One patient with diabetes, cardiovascular disease, hypertension, chronic obstructive pulmonary disease, osteoarthritis, and atrial fibrillation experienced myalgia during daptomycin therapy and had a transient elevation in serum creatine phosphokinase levels after 42 days of therapy. Another patient with diabetes and osteoarthritis experienced renal failure while on daptomycin. This patient continued to receive daptomycin after loss of renal function but was dosed 4 mg/kg every 48 hours following hemodialysis treatment. In total, 7 patients with reduced renal capacity were treated with 4 mg/kg every 48 hours. Each of these patients had a successful outcome of their infection with daptomycin therapy.
Infections of the bone and joints are difficult to treat regardless of the etiologic agent. There are special issues to consider, such as drug tissue penetration, biofilm formation, and the maintenance of adequate serum drug levels.23,24 Despite the fact that bone and joint infections are becoming more prevalent as the age of the U.S. population increases and that there is a tremendous need for better antibiotic therapies, the number of prospective, controlled comparative studies in this patient population are few. This may be due to many factors including confounders related to the patient populations. Many patients with bone and joint infections are elderly and have serious and debilitating underlying disease. In fact, top risk factors for prosthetic joint infection in primary arthroplasty are arthritis, diabetes, malnutrition, and obesity.23 Another reason for the shortage of clinical trials in patients with bone and joint infections may be that these trials are very expensive to run: Berbari et al25 estimated the cost of treating an infected prosthetic at more than US$50,000 in 1997. Thus, there are many reasons to account for the dearth of well-controlled clinical studies in patients with bone and joint infections.
An examination of the literature, however, shows that some important studies have been done to demonstrate the safety and efficacy of antibiotics in these difficult infection types. Drancourt et al26 reported in 1997 that for stable MSSA orthopedic implant infections, rifampin combined with fusidic acid (tid) was superior to rifampin combined with ofloxacin (qd), whereas Zimmerli et al27 found that rifampin and ciprofloxacin (bid) were superior to rifampin alone (bid). In bone and joint infections caused by MRSA, there are only a few studies: Trimethoprim/sulfamethoxazole was prospectively studied in patients with orthopedic implant infections, with a 67% success rate (N = 39),28 and in a compassionate use trial, quinupristin/dalfopristin was effective in 77% of patients with MRSA-mixed infections of the bone and joints.29 Prospective clinical trials are few; therefore, reports of clinical experiences at individual institutions regarding antibiotic treatments and regimens can be helpful in assessing drug effects on patient outcomes. In a retrospective chart review, Bassetti et al30 found that 80% of patients were cured after being treated with linezolid (N = 20) after prosthetic joint revision or substitution due to infections. In the current study, daptomycin was an effective treatment in 87% of patients (N = 31) who received it in combination with appropriate surgical interventions.
Here most patients were dosed with daptomycin at 6 mg/kg/d. This is higher than the 4 mg/kg/d dosage recommended for cSSSI on the Cubicin product label (Cubist Pharmaceuticals, Lexington, MA). At the time of this writing, there have been no published studies of daptomycin bone concentration and penetration in patients with infection or without infection. However, the early clinical experiences of the authors and anecdotal evidence from other infectious disease specialists suggested that this higher dose was well tolerated and effective in patients with bone and joint infections. Similarly, we used our experience with other drugs in treating infections of the bone and joints to determine the duration of daptomycin therapy, as there is no published clinical data related to daptomycin therapy with these infection types. In the patients described here, the duration of daptomycin treatment was approximately 6 weeks or 42 days (actual mean duration of therapy 38.2 days).
Vancomycin monotherapy and vancomycin combined with rifampin are the antimicrobials used in the treatment of cSSSI, as well as prosthetic infections that involve MRSA and MRSE. However, no published, peer-reviewed clinical data are available that look prospectively at the safety and efficacy of this modality in patients with orthopedic infections.
Treatment failures that occurred before the institution of daptomycin therapy included patients treated with appropriate antibiotics such as vancomycin for an average of 30 days, ranging from 3 to 8 weeks. This has generally been the accepted standard of care for orthopedic-related infections with resistant Gram-positive infections. Repeated use of vancomycin with and without rifampin has also been used by the authors with variable success.
Due to the retrospective nature of this study, these results are limited by selection biases and the lack of randomized comparative information. Also, it may actually be difficult to determine the role that daptomycin may have played in some of the patients with successful outcomes due to the variable concomitant use of surgical intervention.
Indeed, failure with vancomycin in the treatment of these complicated infections exists, and daptomycin seems to be a good alternative. The ease of the daptomycin dosing regimen, its tolerability, and its relative lack of side effects could make it an attractive alternative to vancomycin. While larger prospective clinical trials in patients with osteomyelitis and prosthetic infections are necessary to further confirm our findings, daptomycin was effective for the treatment of difficult bone and joint infections involving MRSA and MRSE in this patient population.
The authors thank Cubist Pharmaceuticals for thoughtful review of this manuscript.
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