Daptomycin combinations as alternative therapies in experimental foreign-body infection caused by meticillin-susceptible Staphylococcus aureus

https://doi.org/10.1016/j.ijantimicag.2015.04.004Get rights and content

Highlights

  • Daptomycin combinations in foreign-body infection caused by meticillin-susceptible Staphylococcus aureus were studied.

  • Daptomycin+rifampicin (DAP+RIF) was the most effective treatment.

  • DAP+RIF was more effective than standard levofloxacin+rifampicin (LVX+RIF).

  • There were no differences between LVX+DAP and LVX+RIF combinations.

  • Combined therapies prevented the emergence of resistance.

Abstract

Whilst levofloxacin (LVX) in combination with rifampicin (RIF) is considered the optimal treatment for prosthetic joint infection (PJI) caused by meticillin-susceptible Staphylococcus aureus (MSSA), no therapeutic alternatives have been accurately evaluated. Based on the high effectiveness of the combination of daptomycin (DAP) plus RIF against meticillin-resistant S. aureus (MRSA) in this setting, in this study the efficacy of DAP+RIF and DAP+LVX combinations was tested as alternative therapies for foreign-body infections (FBIs) caused by MSSA. A tissue-cage infection model was performed using an MSSA strain. Male Wistar rats were treated for 7 days with LVX, DAP, RIF or the combinations LVX+RIF, DAP+RIF and DAP+LVX. Antibiotic efficacy was evaluated by bacterial counts from tissue cage fluid (TCF) and the cure rate was determined from adhered bacteria. Resistance was screened. Monotherapies were less effective than combinations (P < 0.05), and resistance to DAP and RIF emerged. DAP+RIF (decrease in bacterial counts in TCF, −4.9 log CFU/mL; cure rate, 92%) was the most effective therapy (P < 0.05). There were no differences between LVX+RIF (−3.4 log CFU/mL; 11%) and DAP+LVX (−3.3 log CFU/mL; 47%). No resistant strains appeared with combined therapies. In conclusion, the combinations DAP+RIF and DAP+LVX showed good efficacy and prevented resistance. DAP+RIF provided higher efficacy than LVX+RIF. These DAP combinations were efficacious alternatives therapies for MSSA FBI. Further studies should confirm whether DAP+RIF may be useful as a first-line therapy in the setting of PJI caused by MSSA.

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

References (30)

  • D.R. Osmon et al.

    Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America

    Clin Infect Dis

    (2013)
  • W. Zimmerli et al.

    Prosthetic-joint infections

    N Engl J Med

    (2004)
  • W. Zimmerli et al.

    Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group

    J Am Med Assoc

    (1998)
  • J. Lora-Tamayo et al.

    A large multicenter study of methicillin-susceptible and methicillin-resistant Staphylococcus aureus prosthetic joint infections managed with implant retention

    Clin Infect Dis

    (2013)
  • A.F. Widmer et al.

    Antimicrobial treatment of orthopedic implant-related infections with rifampin combinations

    Clin Infect Dis

    (1992)
  • A.F. Widmer et al.

    Correlation between in vivo and in vitro efficacy of antimicrobial agents against foreign body infections

    J Infect Dis

    (1990)
  • J. Grosset et al.

    Adverse effects of rifampin

    Rev Infect Dis

    (1983)
  • P.S. Stewart et al.

    Daptomycin rapidly penetrates a Staphylococcus epidermidis biofilm

    Antimicrob Agents Chemother

    (2009)
  • J.N. Steenbergen et al.

    Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections

    J Antimicrob Chemother

    (2005)
  • C. Liu et al.

    Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary

    Clin Infect Dis

    (2011)
  • C. Garrigos et al.

    Efficacy of usual and high doses of daptomycin in combination with rifampin versus alternative therapies in experimental foreign-body infection by methicillin-resistant Staphylococcus aureus

    Antimicrob Agents Chemother

    (2010)
  • A. Saleh-Mghir et al.

    Adjunctive rifampin is crucial to optimizing daptomycin efficacy against rabbit prosthetic joint infection due to methicillin-resistant Staphylococcus aureus

    Antimicrob Agents Chemother

    (2011)
  • A.K. John et al.

    Efficacy of daptomycin in implant-associated infection due to methicillin-resistant Staphylococcus aureus: importance of combination with rifampin

    Antimicrob Agents Chemother

    (2009)
  • C. El Haj et al.

    Comparative efficacy of cloxacillin–daptomycin and the standard cloxacillin–rifampin therapies against an experimental foreign-body infection by methicillin-susceptible Staphylococcus aureus

    Antimicrob Agents Chemother

    (2014)
  • O. Murillo et al.

    Efficacy of high doses of levofloxacin in experimental foreign-body infection by methicillin-susceptible Staphylococcus aureus

    Antimicrob Agents Chemother

    (2006)
  • Cited by (0)

    View full text