Clinical OutcomeHigh doses of daptomycin (10 mg/kg/d) plus rifampin for the treatment of staphylococcal prosthetic joint infection managed with implant retention: a comparative study
Introduction
Prosthetic joint infection (PJI) is a fearsome complication after joint replacement (Ariza et al., 2008, Zimmerli et al., 2004). It frequently requires prosthesis removal and long courses of antimicrobials. However, in acute cases, a treatment comprising debridement, antibiotics, and implant retention (DAIR) may be attempted (Ariza et al., 2008, Byren et al., 2009, Zimmerli et al., 2004), thus sparing the patient further surgery and loss of bone stock.
Staphylococcus aureus is the most likely etiology of acute PJI. In the DAIR setting, the antimicrobial treatment of choice is semisynthetic penicillins followed by long courses of rifampin plus fluoroquinolones (Ariza et al., 2008, Zimmerli et al., 2004). However, methicillin-resistant S. aureus (MRSA), frequently resistant to fluoroquinolones, is not uncommon in this context (Lora-Tamayo et al., 2013a, Peel et al., 2012). We recently observed that MRSA-PJI had a similar overall prognosis to that of methicillin-susceptible strains if rifampin was administered. However, we also observed that failure during treatment was more frequent in MRSA-PJI than in methicillin-susceptible S. aureus (MSSA)–PJI, suggesting that rifampin combinations without fluoroquinolones were less effective in avoiding relapse (Lora-Tamayo et al., 2013a). Currently, the best treatment for fluoroquinolone-resistant strains remains uncertain.
Daptomycin is a recently introduced lipopeptide that has been approved for skin and soft-tissue infection and for bacteremia and endocarditis (Enoch et al., 2007, Moise et al., 2009a).Its high bactericidal activity against Gram-positive microorganisms, including both planktonic and biofilm-embedded bacteria (Enoch et al., 2007, Murillo et al., 2009, Stewart et al., 2009), may also make it suitable for treatment of PJI. However, its activity is concentration-dependent (Enoch et al., 2007, Moise et al., 2009a, Safdar et al., 2004). The emergence of resistance along with clinical and microbiological failure has been reported with currently approved doses of 4–6 mg/kg/d (Fowler et al., 2006, Marty et al., 2006, Sharma et al., 2008) and also in the setting of PJI (Rao and Regalla, 2006). Current opinion supports the use of higher doses of daptomycin (8–10 mg/kg/d) combined with a second drug in order to optimize its activity and avoid the emergence of resistance (Gould et al., 2013, Moise et al., 2009a, Moise et al., 2009b).
Rifampin is key in the treatment of staphylococcal orthopedic device infections (Lora-Tamayo et al., 2013a, Zimmerli et al., 1998, Zimmerli et al., 2004), and several experimental models have found the combination of high doses of daptomycin (equivalent to 8–10 mg/kg/d in humans) with rifampin to be the most effective treatment for foreign body–related infections caused by MRSA (Garrigos et al., 2010, Saleh-Mghir et al., 2011). Significantly, the combination also avoided the emergence of resistance (Garrigos et al., 2010, Saleh-Mghir et al., 2011).
There is little clinical information regarding the efficacy and safety of high doses of daptomycin in combination with rifampin in the setting of PJI due to methicillin-resistant Staphylococcus managed with DAIR (Corona Pérez Cardona et al., 2012, Jogun et al., 2013). We aimed to assess the efficacy and safety of daptomycin (10 mg/kg/d) plus rifampin in this clinical setting.
Section snippets
Setting and patients
This retrospective observational study was performed in 5 Spanish hospitals between 2010 and 2012. All cases of fluoroquinolone-resistant staphylococcal postsurgical PJI managed with DAIR and high doses of daptomycin plus rifampin as first-line therapy were included in the analysis. A minimum of 15 days of treatment with the combination was required to assess its efficacy. The decision of treatment with daptomycin plus rifampin was taken at the discretion of the assisting medical team.
Results
Twenty patients presenting acute infection and undergoing DAIR were treated with daptomycin and rifampin as first-line therapy. Of these, 2 (10%) did not complete the initially scheduled treatment with the combination due to persistent vomiting caused by rifampin within the first 15 days, finally leading to its withdrawal [1 (5%) of them developed acute renal injury, and later rhabdomyolysis due to daptomycin].
Thus, 18 patients were analyzed for clinical and microbiological cure: 13 (72%) were
Discussion
This is the first study addressing the efficacy and safety of a 6-week course of parenteral daptomycin at high doses plus rifampin as first-line therapy for acute staphylococcal PJI managed with DAIR. Clinical failure was recorded in 50%. In accordance with previous works by our group (Cobo et al., 2011, Lora-Tamayo et al., 2013a, Rodríguez et al., 2010), our definition of clinical failure is quite broad, thus mirroring the complexity of patients with PJI. This definition may overestimate the
Conclusion
In summary, we present the first case series of PJI treated with DAIR and the combination of daptomycin at high doses (10 mg/kg/d) plus rifampin as first-line therapy. Treatment tolerance was good, and clinical and microbiological outcomes were comparable to previous regimes used for these infections. It is not clear whether prolonging antimicrobial therapy might have improved outcomes. Interestingly, the failure rate during therapy was lower than that previously reported, and no resistant
Conflict of interest disclosure
All authors declare that no direct external support, grants, or another ways of funding have been received for this study. They also declare that nonrelated with the present article, JL-T has received honoraria and travel grants for scientific purposes for public speaking from Novartis and advisory board from Pfizer; JP-R is a speaker, is a consultant, or received grant support from Astellas, Cubist, Bayer, and Pfizer; DR-P declares having received honoraria from Pfizer and Novartis as payment
Acknowledgments
We thank Michael Maudsley for revising the English manuscript. The preliminary results of this study were reported in part at the XVII Congress of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC, Zaragoza, Spain, 2013). JL-T was supported by a grant from the Instituto de Salud Carlos III [FI09/00943]. AR was supported by a grant from the Instituto de InvestigaciónBiomédica de Bellvitge.
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