Daptomycin combinations as alternative therapies in experimental foreign-body infection caused by meticillin-susceptible Staphylococcus aureus
Introduction
The combination of levofloxacin (LVX) plus rifampicin (RIF) is considered the standard reference for oral treatment of acute prosthetic joint infection (PJI) caused by meticillin-susceptible Staphylococcus aureus (MSSA) and managed with debridement and implant retention or with one-stage exchange [1], [2]. The benefits of early RIF administration in this setting are well documented, and the fluoroquinolones have high synergistic efficacy and protect against the development of resistant strains [3], [4], [5], [6]. However, despite optimal therapeutic management, some clinical and microbiological failures occur, especially when implant retention is attempted [2], [4]. Moreover, occasions arise when these drugs often cannot be administered owing to intolerance or allergy, and no adequately evaluated alternatives exist [7].
Daptomycin (DAP) has bactericidal activity against growing and non-growing S. aureus and may be suitable against bacteria embedded within a biofilm [8], [9]. In difficult-to-treat infections in humans, current recommendations encourage the use of DAP at high doses (8–10 mg/kg/day) in combination with other antibiotics [10]. However, the efficacy of such combined therapies has mainly been studied against meticillin-resistant S. aureus (MRSA) strains but has not fully explored in MSSA infection. This is the case for DAP+RIF combination, which has been proposed as one of the most effective anti-MRSA treatments for PJI based on results obtained in experimental models [11], [12], [13]. To date, DAP as anti-MSSA therapy can only be expected to have similar efficacy to that for MRSA, but this has not been confirmed or evaluated in comparison with other anti-MSSA alternative therapies. With this in mind, our group recently evaluated the efficacy of a DAP plus cloxacillin (CLOX) combination using a rat tissue-cage infection model and found that it was as effective as CLOX+RIF, which is the most common intravenous treatment used in the first weeks of PJI [14] caused by MSSA.
The rat tissue-cage infection model is a validated method that can provide relevant information about the pathogenesis and treatment of foreign-body infections (FBIs) [15], [16]. For the present study, this model was used with MSSA infection to test the efficacy of DAP+RIF and DAP+LVX combinations as alternative therapeutic options when the reference LVX+RIF cannot be used.
Section snippets
Micro-organism
MSSA strain ATCC 29213 was used for all in vitro and in vivo studies.
Antimicrobial agents
For in vitro experiments, purified antibiotic powder was re-suspended according to laboratory recommendations. Antibiotics were purchased from the following laboratories: DAP (Novartis, Barcelona, Spain); RIF (Sanofi-Aventis, Madrid, Spain); and LVX (Sigma-Aldrich, Madrid, Spain). For in vivo experiments, the commercial product was diluted to achieve a final volume suitable for administration to rats.
In vitro studies
The medium broth was
24-h kill curves of daptomycin combinations
Most representative results in log and stationary phase for the kill curves are shown in Fig. 1, Fig. 2, respectively. Addition of RIF to DAP in log phase with standard inocula delayed (but did not antagonise) killing by DAP. In stationary phase, 8 mg/L RIF had a bactericidal effect when combined with DAP at 8 mg/L (16× MIC). In log phase with standard inocula, addition of LVX (1× MIC) to DAP (0.25× MIC) resulted in synergism and bactericidal killing. In stationary phase, a slight improvement of
Discussion
The present experimental work demonstrates that DAP+RIF and DAP+LVX combinations have efficacy as potential alternatives in the treatment of MSSA FBI.
LVX (at high doses of 750–1000 mg/day) plus RIF is currently considered the optimal treatment for acute MSSA PJI; its efficacy has been previously described by our own and other groups against experimental staphylococcal FBI [13], [15], [24], [25], [26]. However, alternative therapies have insufficient evidence to support their use in cases where
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