Efficacy of linezolid compared to vancomycin in an experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus in ventilated pigs*

Martínez-Olondris, Pilar; Rigol, Montserrat; Soy, Dolors; Guerrero, Laura; Agustı́, Carlos; Quera, M.; Bassi, Gianluigi Li; Esperatti, Mariano; Luque, Néstor; Liapikou, Manto; Filella, Xavier; Marco, Francesc; Bellacasa, Jordi Puig de la; Torres, Antoni

doi:10.1097/ccm.0b013e31822d74a2

Cited by 37 publications

(32 citation statements)

References 9 publications

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“…The preference for linezolid and clindamycin over vancomycin in this setting is based upon the hypothesis that linezolid and clindamycin, which suppress toxin production, may improve survival with this specific infection, for which toxin production is a key virulence factor. This improved survival has been demonstrated in a rabbit model of necrotizing MRSA pneumonia (754) and in a pig pneumonia model (755). Two retrospective studies suggest that there may be a clinical benefit for suppression of toxins in such cases (756,757).…”

Section: Managementmentioning

confidence: 91%

Staphylococcus aureus Infections: Epidemiology, Pathophysiology, Clinical Manifestations, and Management

et al. 2015

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SUMMARY Staphylococcus aureus is a major human pathogen that causes a wide range of clinical infections. It is a leading cause of bacteremia and infective endocarditis as well as osteoarticular, skin and soft tissue, pleuropulmonary, and device-related infections. This review comprehensively covers the epidemiology, pathophysiology, clinical manifestations, and management of each of these clinical entities. The past 2 decades have witnessed two clear shifts in the epidemiology of S. aureus infections: first, a growing number of health care-associated infections, particularly seen in infective endocarditis and prosthetic device infections, and second, an epidemic of community-associated skin and soft tissue infections driven by strains with certain virulence factors and resistance to β-lactam antibiotics. In reviewing the literature to support management strategies for these clinical manifestations, we also highlight the paucity of high-quality evidence for many key clinical questions.

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Section: Managementmentioning

confidence: 91%

Staphylococcus aureus Infections: Epidemiology, Pathophysiology, Clinical Manifestations, and Management

et al. 2015

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“…Among the infections produced by this pathogen, health care-and ventilator-associated pneumonia is associated with the most dismal outcomes, and S. aureus is now recognized as the most commonly implicated organism (28,50). Recent experimental and clinical investigations suggest the potential advantage of treatment with the oxazolidinone linezolid for this disease state due to potency against MRSA and penetration into the infection site relative to vancomycin and daptomycin (12,16,24,30,36,38,(56)(57)(58). The present studies were designed to characterize the PK/PD relationships of a new oxazolidinone, TR-701, for treatment of these infections.…”

Section: Discussionmentioning

confidence: 99%

Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model

Lepak

Marchillo

Pichereau

et al. 2012

Antimicrob Agents Chemother

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Staphylococcus aureus has become a leading cause of community-and hospital-acquired pneumonia. Furthermore, infection with community-and health care-acquired strains of methicillinresistant S. aureus (MRSA) is increasingly common and limits antimicrobial options (13,25,29,31). Tedizolid phosphate (TR-701) is a novel oxazolidinone prodrug. The active moiety, tedizolid (TR-700), exhibits potent activity against Gram-positive bacteria, including MRSA (48). The goals of our studies were to identify the pharmacodynamic (PD) target (AUC/MIC ratio) for TR-700 against methicillin-susceptible S. aureus (MSSA) and MRSA strains in a neutropenic murine pneumonia model and compare the PD targets of TR-700 to that of the only FDA-approved oxazolidinone antibiotic, linezolid. MATERIALS AND METHODSBacteria, media, and antibiotics. Eleven isolates of S. aureus were utilized for these experiments. The strains included four MSSA strains (ATCC 6538P, ATCC 25923, ATCC 29213, and ATCC Smith), one hospital-acquired MRSA strain (ATCC 33591), and six community-acquired MRSA strains (MW2, R2527, 04-045, 04-154, 05-051, and UW 307109). Organisms were grown, subcultured, and quantified in Mueller-Hinton broth (Difco Laboratories, Detroit, MI) and Mueller-Hinton agar (Difco Laboratories, Detroit, MI). Linezolid was obtained from the University of Wisconsin pharmacy. Tedizolid (TR-700) and tedizolid phosphate (TR-701) were supplied by the manufacturer (Trius Therapeutics, San Diego, CA). Prior to in vivo treatment studies, TR-701 was dissolved in sterile water at the appropriate drug concentrations. TR-700 was dissolved in sterile dimethyl sulfoxide (DMSO) and diluted with medium to the appropriate concentration for in vitro susceptibility testing.In vitro susceptibility studies. The MICs of linezolid and TR-700 were determined three times in duplicate using Clinical and Laboratory Standards Institute (CLSI) microdilution methods M07-A8 (15). The duplicates were identical, and the final results were reported as the median value of the three MIC tests (see Table 1).Murine infection model. All animal studies were approved by the Animal Research Committees of the University of Wisconsin and William S. Middleton Memorial VA Hospital. Six-week-old, specific-pathogenfree, female ICR/Swiss mice weighing between 24 and 27 g (Harlan Sprague-Dawley, Indianapolis, IN) were used for all studies. Three mice were utilized for each treatment and control group. Mice were rendered neutropenic (absolute neutrophil count of Ͻ100/mm 3 ) by injecting cyclophosphamide (Mead Johnson Pharmaceuticals, Evansville, IN) intraperitoneally 4 days (150 mg/kg of body weight) and 1 day (100 mg/kg) prior to experimental infection. Previous studies have shown that this regimen produces persistent neutropenia in this animal model for 5 days (3). Broth cultures of freshly plated bacteria were grown to logarithmic phase. The inoculum for each organism was diluted to a 0.3 absorbance at 580 nm. Viable plate count confirmation of the inoculum ranged from 10 6 to 10 7 CFU/ml. Anima...

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“…Therefore, its administration by CI would be a reasonable mode of administration. CI of vancomycin in a pig lung model showed evidence for increased efficacy [53], but clinical experience is limited [54,55]. A clinical trial in intensive care unit (ICU) patients did not show better outcome using CI but it was associated with an earlier achievement of desired trough concentrations, and concentrations were more stable over time [56].…”

Section: Heteroresistancementioning

confidence: 99%

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

Edwards

Andini

Esposito

et al. 2014

Journal of Global Antimicrobial Resistance

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Efficacy of linezolid compared to vancomycin in an experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus in ventilated pigs*

Abstract: In this animal model of MRSA pneumonia, linezolid showed a better efficacy than vancomycin showed because of a better pharmacokinetics/pharmacodynamics index.

Cited by 37 publications

References 9 publications

Staphylococcus aureus Infections: Epidemiology, Pathophysiology, Clinical Manifestations, and Management

Staphylococcus aureus Infections: Epidemiology, Pathophysiology, Clinical Manifestations, and Management

Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

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