Efficacy of linezolid versus a pharmacodynamically optimized vancomycin therapy in an experimental pneumonia model caused by methicillin-resistant Staphylococcus aureus

Docobo-Pérez, Fernando; López-Rojas, Rafael; Domínguez-Herrera, Juan; Jiménez-Mejías, M E; Pichardo, C.; Ibáñez-Martínez, José; Pachón, Jerónimo

doi:10.1093/jac/dks142

Cited by 25 publications

(15 citation statements)

References 33 publications

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“…Using an experimental murine model of MRSA pneumonia, our group found that an optimized dose of vancomycin (AUC/ MIC ratio Ն 400) was more efficacious than lower doses of vancomycin in the clearance of bacteria from lungs and blood, even though it could not demonstrate a higher survival rate (20). In clinical studies, an AUC/MIC ratio around 400 is related to the best survival rate or to clinical success in patients with S. aureus bacteremia, although other thresholds have been observed (10,17,18,21).…”

Section: Vancomycin Pharmacodynamics and Its Implications For Drug Momentioning

confidence: 99%

Optimizing the Clinical Use of Vancomycin

Álvarez

López-Cortés

Molina

et al. 2016

Antimicrob Agents Chemother

190

124

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Pharmacists published specific guidelines about vancomycin dosage and monitoring. However, these guidelines have not been updated in the past 6 years. This review analyzes the new available information about vancomycin published in recent years regarding pharmacokinetics and pharmacodynamics, serum concentration monitoring, and optimal vancomycin dosing in special situations (obese people, burn patients, renal replacement therapy, among others). Vancomycin efficacy is linked to a correct dosage which should aim to reach an area under the curve (AUC)/MIC ratio of >400; serum trough levels of 15 to 20 mg/liter are considered a surrogate marker of an AUC/MIC ratio of >400 for a MIC of <1 mg/liter. For Staphylococcus aureus strains presenting with a MIC >1 mg/liter, an alternative agent should be considered. Vancomycin doses must be adjusted according to body weight and the plasma trough levels of the drug. Nephrotoxicity has been associated with target vancomycin trough levels above 15 mg/liter. Continuous infusion is an option, especially for patients at high risk of renal impairment or unstable vancomycin clearance. In such cases, vancomycin plasma steady-state level and creatinine monitoring are strongly indicated. Vancomycin has traditionally been used as a first-line agent for treating methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive beta-lactam-resistant bacteria (1), which are frequent etiologies of severe health-related infections (2, 3).Although the effectiveness of vancomycin is supported by more than 5 decades of use and multiple studies, the clinical and microbiological scenario in which it is used is always changing. Attaining an appropriate dosage of vancomycin for S. aureus infections might be difficult due to the clinical impact of the creep in the MIC of vancomycin and heteroresistance among MRSA strains, or due to complex pharmacokinetic and pharmacodynamic (PK/PD) situations. In this context, the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists (SIDP) introduced a practice guideline in 2009 (4), marking a milestone in vancomycin therapy. However, several questions, such as the optimal dosing in some special clinical situations (e.g., with renal replacement therapies or in burn patients or obese patients), the role of continuous infusion, or the renal toxicity when the suggested vancomycin serum levels are achieved, remain unanswered. The present review mainly focuses on these issues. VANCOMYCIN PHARMACODYNAMICS AND ITS IMPLICATIONS FOR DRUG MONITORINGThe killing effect of vancomycin is characterized by a slow mode of action and is further hampered by a large bacterial inoculum, a stationary growth phase, and anaerobic conditions (5, 6). Although several pharmacodynamic parameters have been proposed to determine vancomycin activity, data from experimental and clinical studies have selected the area under the curve (AUC)/ MIC ratio as the best parameter to predict the...

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Section: Vancomycin Pharmacodynamics and Its Implications For Drug Momentioning

confidence: 99%

Optimizing the Clinical Use of Vancomycin

Álvarez

López-Cortés

Molina

et al. 2016

Antimicrob Agents Chemother

190

124

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“…Treatment of these infections is complicated by the fact that ϳ50% of S. aureus isolates from patients with pneumonia are methicillin-resistant S. aureus (MRSA), thereby reducing safe and effective treatment options (1). While vancomycin (VAN) is the primary therapy for MRSA pneumonia, the mortality rate in pneumonia patients treated with vancomycin remains high, and the emergence of intermediate resistance to glycopeptides potentially limits the usefulness of this class of antibiotics (3)(4)(5). Linezolid (LZD) is currently the only other drug with anti-MRSA activity that is approved for the treatment of nosocomial pneumonia in the United States and Europe (4,6).…”

mentioning

confidence: 99%

Assessment of an Anti-Alpha-Toxin Monoclonal Antibody for Prevention and Treatment of Staphylococcus aureus-Induced Pneumonia

Liu¹,

Hilliard²,

Shi³

et al. 2014

Antimicrob Agents Chemother

160

174

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Alpha-toxin (AT) is a major virulence factor in the disease pathogenesis of Staphylococcus aureus. We previously identified a monoclonal antibody (MAb) against AT that reduced disease severity in a mouse dermonecrosis model. Here, we evaluate the activity of an affinity-optimized variant, LC10, in a mouse model of S. aureus pneumonia. Passive immunization with LC10 increased survival and reduced bacterial numbers in the lungs and kidneys of infected mice and showed protection against diverse S. aureus clinical isolates. The lungs of S. aureus-infected mice exhibited bacterial pneumonia, including widespread inflammation, whereas the lungs of mice that received LC10 exhibited minimal inflammation and retained healthy architecture. Consistent with reduced immune cell infiltration, LC10-treated animals had significantly lower (P < 0.05) proinflammatory cytokine and chemokine levels in the bronchoalveolar lavage fluid than did those of the control animals. This reduction in inflammation and damage to the LC10-treated animals resulted in reduced vascular protein leakage and CO 2 levels in the blood. LC10 was also assessed for its therapeutic activity in combination with vancomycin or linezolid. Treatment with a combination of LC10 and vancomycin or linezolid resulted in a significant increase (P < 0.05) in survival relative to the monotherapies and was deemed additive to synergistic by isobologram analysis. Consistent with improved survival, the lungs of animals treated with antibiotic plus LC10 exhibited less inflammatory tissue damage than those that received monotherapy. These data provide insight into the mechanisms of protection provided by AT inhibition and support AT as a promising target for immunoprophylaxis or adjunctive therapy against S. aureus pneumonia.

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“…Some studies using pneumonia animal models have demonstrated that linezolid was more effective than vancomycin toward this type of infection due to its better penetration into the lung. Therefore, it was suggested that linezolid might be chosen for MRSA pneumonia cases with increased vancomycin minimum inhibitory concentration ( Docobo-Pérez et al 2012 , Martinez-Olondris et al 2012 , Rodvold & McConeghy 2014 ). Daptomycin, which is a cyclic lipopeptide, was launched in the USA in 2003 for the treatment of skin/soft tissue infections (SSTI) caused by MRSA and other microorganisms and good results have been reported for this drug for the treatment of BSI and endocarditis caused by these microorganisms ( Rodvold & McConeghy 2014 ).…”

mentioning

confidence: 99%

The multifaceted resources and microevolution of the successful human and animal pathogen methicillin-resistant Staphylococcus aureus

Figueiredo

Ferreira

2014

Mem. Inst. Oswaldo Cruz

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Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most important bacterial pathogens based on its incidence and the severity of its associated infections. In addition, severe MRSA infections can occur in hospitalised patients or healthy individuals from the community. Studies have shown the infiltration of MRSA isolates of community origin into hospitals and variants of hospital-associated MRSA have caused infections in the community. These rapid epidemiological changes represent a challenge for the molecular characterisation of such bacteria as a hospital or community-acquired pathogen. To efficiently control the spread of MRSA, it is important to promptly detect the mecA gene, which is the determinant of methicillin resistance, using a polymerase chain reaction-based test or other rapidly and accurate methods that detect the mecA product penicillin-binding protein (PBP)2a or PBP2’. The recent emergence of MRSA isolates that harbour a mecA allotype, i.e., the mecC gene, infecting animals and humans has raised an additional and significant issue regarding MRSA laboratory detection. Antimicrobial drugs for MRSA therapy are becoming depleted and vancomycin is still the main choice in many cases. In this review, we present an overview of MRSA infections in community and healthcare settings with focus on recent changes in the global epidemiology, with special reference to the MRSA picture in Brazil.

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Efficacy of linezolid versus a pharmacodynamically optimized vancomycin therapy in an experimental pneumonia model caused by methicillin-resistant Staphylococcus aureus

Cited by 25 publications

References 33 publications

Optimizing the Clinical Use of Vancomycin

Optimizing the Clinical Use of Vancomycin

Assessment of an Anti-Alpha-Toxin Monoclonal Antibody for Prevention and Treatment of Staphylococcus aureus-Induced Pneumonia

The multifaceted resources and microevolution of the successful human and animal pathogen methicillin-resistant Staphylococcus aureus

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