Treatment of Methicillin-Resistant Staphylococcus aureus Infections With a Minimal Inhibitory Concentration of 2 μg/mL to Vancomycin

Michelle L Campbell BA; Dror Marchaim MD; Jason M Pogue PharmD; Bharath Sunkara MD; Suchitha Bheemreddy MD; Pradeep Bathina MBBS; Harish Pulluru MBBS; Neelu Chugh MBBS; Melanie N Wilson BS; Judy Moshos MT; Kimberley Ku BS; Kayoko Hayakawa MD PhD; Emily T Martin MPH PhD; Paul R Lephart PhD; Michael J Rybak PharmD MPH FCCP BCPS; Keith S Kaye MD MPH

Disclosures

The Annals of Pharmacotherapy. 2012;46(12):1587-1597. 

In This Article

Abstract and Introduction

Abstract

Background: Guidelines recommend that agents other than vancomycin be considered for some types of infection due to methicillin-resistant Staphylococcus aureus (MRSA) when the minimum inhibitory concentration (MIC) to vancomycin is 2 μg/mL or more. Alternative therapeutic options include daptomycin and linezolid, 2 relatively new and expensive drugs, and trimethoprim/sulfamethoxazole (TMP/SMX), an old and inexpensive agent.
Objective: To compare the clinical efficacy and potential cost savings associated with use of TMP/SMX compared to linezolid and daptomycin.
Methods: A retrospective study was conducted at Detroit Medical Center. For calendar year 2009, unique adults (age >18 years) with infections due to MRSA with an MIC to vancomycin of 2 μg/mL were included if they received 2 or more doses of TMP/SMX and/or daptomycin and/or linezolid. Data were abstracted from patient charts and pharmacy records.
Results: There were 328 patients included in the study cohort: 143 received TMP/SMX alone, 89 received daptomycin alone, 75 received linezolid alone, and 21 patients received a combination of 2 or more of these agents. In univariate analysis, patients who received TMP/SMX alone had significantly better outcomes, including in-hospital (p = 0.003) and 90-day mortality (p < 0.001) compared to patients treated with daptomycin or linezolid. Patients receiving TMP/SMX were also younger (p < 0.001), had fewer comorbid conditions (p < 0.001), had less severe acute severity of illness (p < 0.001), and received appropriate therapy more rapidly (p = 0.001). In multivariate models the association between TMP/SMX treatment and mortality was no longer significant. Antimicrobial cost savings associated with using TMP/SMX averaged $2067.40 per patient.
Conclusions: TMP/SMX monotherapy compared favorably to linezolid and daptomycin in terms of treatment efficacy and mortality. Use of TMP/SMX instead of linezolid or daptomycin could potentially significantly reduce antibiotic costs. TMP/SMX should be considered for the treatment of MRSA infection with MIC of 2 μg/mL to vancomycin.

Introduction

Methicillin-resistant Staphylococcus aureus (MRSA) is a serious human pathogen,[1] and vancomycin is considered the therapeutic option of choice.[2] In recent years, the minimal inhibitory concentrations (MICs) to vancomycin have increased in MRSA isolates in some regions.[3–5] Recent data demonstrate high rates of clinical and bacteriologic failures, mainly in bloodstream infections (BSIs), when vancomycin is used to treat MRSA strains with an MIC to vancomycin of 2 μg/mL or greater.[2,3,6–12] There is a paucity of evidence guiding the treatment of MRSA infections with MICs at that level; therefore, for infections due to strains of MRSA with MIC to vancomycin of 2 μg/mL or greater, other antimicrobials are often preferred.[1,13] Other therapeutic options for MRSA include newer and expensive agents that have been extensively studied for the treatment of MRSA, such as daptomycin and linezolid, and older inexpensive generic agents including trimethoprim/sulfamethoxazole (TMP/SMX), clindamycin, and fusidic acid. There are few data from controlled studies of the efficacy of these older agents in the treatment of MRSA infection, and there are even fewer data comparing these older agents to newer drugs, such as linezolid and daptomycin.

Because of their low cost and familiarity to health care providers, older antimicrobials are attractive for treatment of MRSA infection. Clindamycin has maintained very good in vitro activity against many strains of MRSA. Because clindamycin is bacteriostatic and is associated with increased rates of inducible resistance,[14] some prescribers are reluctant to use it as monotherapy for severe invasive MRSA infections.[1] In addition, clindamycin use is a significant risk factor for Clostridium difficile infections.[1] Fusidic acid, which recently has become available only as an oral formulation in the US, lacks clinical efficacy data for the treatment of MRSA.[15] In addition, rapid emergence of resistance when fusidic acid is given as monotherapy is a major concern.[16] Additional older therapeutic options such as rifampin and doxycycline are also disadvantageous because of toxicity and lack of controlled efficacy data on use as monotherapy.[17]

TMP/SMX, despite being used as a therapeutic antimicrobial for many years, has not been extensively studied in controlled trials for treatment of infections due to MRSA.[18] There are also limited data pertaining to the optimal dosage to use for specific types of infection. A recent comparative retrospective study of clindamycin and TMP/SMX for the treatment of mild superficial skin and soft-tissue infections (SSTIs) did not reveal significant differences between the efficacy of these agents.[19] Another trial found TMP/SMX to be noninferior to vancomycin for the treatment of MRSA bacteremia in a region where most strains had a vancomycin MIC of 1 μg/mL or less.[20] An older study among intravenous drug users with S. aureus endocarditis found TMP/SMX to be inferior to vancomycin, but not among the subgroup of patients with MRSA infections.[18] Recently, TMP/SMX was reported to be an effective treatment option in the management of osteomyelitis due to MRSA among pediatric patients.[14] Although TMP/SMX is associated with severe allergic reactions and hyperkalemia, there has been renewed interest in its use for MRSA infection, particularly SSTIs.[14]

Southeast Michigan is an endemic region for MRSA with elevated MICs to vancomycin including vancomycin-resistant S. aureus.[21] Thus, alternatives to vancomycin are frequently used for treatment of MRSA infections. The aims of this study were to (1) compare TMP/SMX to daptomycin or linezolid for the treatment of infection due to MRSA with a vancomycin MIC of 2 μg/mL; (2) analyze potential cost savings associated with use of TMP/SMX instead of daptomycin or linezolid for treatment of MRSA infection; and (3) evaluate the susceptibility trends of MRSA strains within our health system against TMP/SMX, daptomycin, and linezolid over a 5-year period.

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