High doses of daptomycin (10 mg/kg/d) plus rifampin for the treatment of staphylococcal prosthetic joint infection managed with implant retention: a comparative study

Abstract

We aimed to analyze the efficacy and safety of high doses of daptomycin (10 mg/kg/d) plus rifampin (D10 + R) for prosthetic joint infection (PJI). This was an observational retrospective multicenter study (2010–2012) including all patients with acute PJI by fluoroquinolone-resistant staphylococci managed with implant retention and D10 + R. Twenty cases were included: 2 (10%) were withdrawn due to toxicity, leaving 18 cases for efficacy evaluation: 13 (72%) women, age 79 years (range 58–90). Clinical failure was observed in 9 (50%) patients: in 5 cases, staphylococci were recovered (28% of microbiological failures); no modification of daptomycin-MIC was observed. These 18 cases were compared with 44 matched historical cases: failure rate was similar, but whereas in the historical series, failure occurred fundamentally during therapy, in the present series, it was recorded after discontinuation of antibiotics. In summary, D10 + R may be the initial treatment of choice for PJI by fluoroquinolone-resistant staphylococci managed with implant retention.

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.