Use Of Daptomycin In The Treatment Of Prosthetic Joint Infections: A Prospective Observational Study Of 30 Patients With Infected Prosthetic Joint Infections
S Antony, I Tiscareno-Grajeda, G Misenhiemer, J Heyderman
daptomycin, methicillin-resistant, prosthetic joint infections
S Antony, I Tiscareno-Grajeda, G Misenhiemer, J Heyderman. Use Of Daptomycin In The Treatment Of Prosthetic Joint Infections: A Prospective Observational Study Of 30 Patients With Infected Prosthetic Joint Infections. The Internet Journal of Infectious Diseases. 2008 Volume 7 Number 1.
This prospective, observational study evaluated daptomycin, a lipopeptide antibiotic active against most Gram-positive bacteria, in prosthetic joint infections. Thirty patients received daptomycin for a mean of 37 days. Most patients received daptomycin 4 or 6 mg/kg/day as second- or third-line therapy after failing prior therapy; three patients with reduced renal capacity at baseline received 4 mg/kg q48h. At 6 to 12 months' posttreatment follow-up, 20 patients (66%) had no clinical, laboratory, or radiographic signs of recurrent infection. Ten patients (33%), all of whom were infected with methicillin-resistant
A novel cyclic lipopeptide, daptomycin has been shown to have in vitro bactericidal activity against antibiotic-resistant Gram-positive bacteria such as methicillin-resistant
Despite the large volume of successful replacement surgeries for hip, knee, shoulder, and elbow joints, prosthetic joint infection (PJI) is a relatively rare but devastating complication associated with significant morbidity and health care utilization costs. Approximately 60% of PJIs occur by direct contamination during the operative procedure . Rates of PJI range from 0.5–1.0% for hip replacements, 0.5–2% for knee replacements, and < 1% for shoulder replacements [20–22]. In addition to lengthy hospital stays, surgical interventions and antimicrobial therapy add to the patient's risk of further complications and disability [23,24]. The pathogenesis of PJIs is influenced by microorganisms adhering to each other to form a biofilm, a process mediated by the polysaccharide intercellular adhesion encoded by the
Guidelines for the management of PJIs have not yet been published, although the Infectious Diseases Society of America (IDSA) is preparing new guidelines for publication in 2008. In clinical practice, patients with PJIs involving MRSA isolates are often treated with a glycopeptide antibiotic such as vancomycin, which has been the standard therapy for MRSA infections for many years in the United States. However, the continued utility of vancomycin for MRSA infections, despite its sustained in vitro microbiologic inhibitory activity, is being questioned . The detection of reduced susceptibility to vancomycin by routine susceptibility testing is unreliable, and vancomycin non-susceptibility is probably underreported . While high-level resistance remains rare, an evolutionary change in
The cyclic lipopeptide antibacterial agent daptomycin is the most recently introduced alternative to vancomycin for the treatment of MRSA infections. Clinical studies have demonstrated that daptomycin is as effective as standard therapies for cSSSI , diabetic foot infections , and complicated urinary tract infections . Preclinical models of infection have suggested that daptomycin may have antibacterial activity in other types of infection, including osteomyelitis and foreign body infection due to
Materials and Methods
Thirty patients treated with daptomycin for a severe, Gram-positive PJI during a 12-month period were included in this prospective observational study. Data were collected with respect to age, sex, race, underlying illnesses, surgical procedures, culture site and pathogens, duration of daptomycin therapy, dosage, adverse effects, previous antibiotic use, and clinical outcomes. When possible, cultures were taken directly from the prosthetic device during surgery. Surgical interventions included removal of all hardware and repeated incision and debridement of the area until it was deemed clinically free from infection by the surgeon. Repeat cultures were obtained from some patients to determine if residual microbes were present. Clinical and microbiologic cure was defined as resolution or improvement of clinical infections, as demonstrated by negative microbiologic culture results, clinical signs, and magnetic resonance imaging (MRI) or computed tomography (CT) scans. Treatment failure was defined as recurrence of infection despite antibiotic therapy and appropriate surgical procedures and/or debridement. Laboratory testing included serum creatinine phosphokinase (CPK) levels (at admission and discharge), whole blood counts, alanine aminotransaminase, and aspartate aminotransferase. Routine follow-up evaluations were undertaken 2–4 weeks after the surgical intervention. Later follow-up assessments were performed, in some cases up to 12 months after a patient had received daptomycin therapy.
The mean age of daptomycin-treated patients was 67.3 years (range, 41–88 years) (Table 1). Seventeen patients (57%) were male, and 16 patients (53%) had an underlying diagnosis of diabetes mellitus. Twenty-three of the 30 patients (77%) had infections involving MRSA isolates, 4 (13%) had methicillin-sensitive
At 12-month follow-up, daptomycin therapy was successful in 67% (20/30) of the patients who received it (Table 3). A cure rate of 66% was achieved in 13 patients with total knee arthroplasty infections; 13 patients (61%) with total hip arthroplasty infections were cured. The cure rate among 3 patients with total elbow arthroplasty infections was 66%; 1 patient with a total shoulder arthroplasty infection was cured. Of patients who were deemed cured after daptomycin therapy, none to date have experienced a recurrent or relapsing infection. One patient with diabetes experienced myalgia during daptomycin therapy and had a transient elevation in serum CPK levels after 14 days of therapy, which resulted in discontinuation of treatment. Of the 10 patients who failed daptomycin therapy, all had MRSA infection, and 9 had received previous antimicrobial therapy (vancomycin, n = 3; cephalosporin, n = 3; linezolid, n = 2; trimethoprim-sulfamethoxazole, n = 1). Three of the 10 patients (30%) who failed daptomycin therapy had not had their prostheses surgically removed.
To date, there have been no published studies of bone concentration and penetration of daptomycin in patients with or without infection, and no study has assessed the safety profile of daptomycin beyond 42 days. In the current study, IV daptomycin in combination with appropriate surgical interventions was effective in 66% of the patients who received it. While the recommended dose for daptomycin in the treatment of cSSSI is 4 mg/kg/day , 73% of patients in this study were dosed at 6 mg/kg/day (i.e., the approved dosage for treatment of
There are few other randomized, controlled clinical studies of antimicrobial treatment for patients with PJIs, despite the increasing prevalence of this type of infection in an aging population. Rifampicin has been shown to have excellent activity on slow-growing and implant-adherent staphylococci [39,40], and is frequently combined with a quinolone to prevent emergent staphylococcal resistance. The combination of rifampin and ciprofloxacin has been shown to be superior to rifampin alone for the treatment of orthopedic implant-related staphylococcal infections . Controlled clinical trials of newer quinolones in the treatment of PJIs have not been completed.
Because of its oral bioavailability and activity against MRSA and VRE, the oxazolidinone linezolid is a possible alternative treatment for PJIs . A European study of linezolid for the treatment of Gram-positive prosthetic hip and knee infections, including MRSA, resulted in 16 of 20 (80%) not needing further surgical substitution of prosthesis or surgical joint revision; 4 patients (20%) had relapsing infections . A more recent study of linezolid in 51 patients with orthopedic infections (23 with PJIs) resulted in clinical and microbiologic failure in only 1 patient (2%). Seventeen infections (33%) required long-term suppression after remission, most often because of retained hardware. One patient developed reversible optic and irreversible peripheral neuropathy after 24 months of treatment with linezolid .
The 67% overall treatment success rate of daptomycin found in this trial should be viewed in the context of current rates of successful treatment of MRSA PJIs. A 2007 retrospective prognostic study determined the effect of methicillin resistance on the outcome of patients with PJIs caused by
Suresh J. Antony, MD,1205 N. Oregon, El Paso, TX 79902; Phone: (915) 533-4900; Fax: (915) 533-4902; E-mail:email@example.com