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      Fosfomycin: the characteristics, activity, and use in critical care

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          Abstract

          Fosfomycin (C 3H 7O 4P) is a phosphonic acid derivative representing an epoxide class of antibiotics. The drug is a re-emerging bactericidal antibiotic with a wide range of actions against several Gram-positive and Gram-negative bacteria. Among the existing antibacterial agents, fosfomycin has the lowest molecular weight (138 Da), which is not structurally associated with other classes of antibiotics. In intensive care unit (ICU) patients, severe soft tissue infections (STIs) may lead to serious life-threatening problems, and therefore, appropriate antibiotic therapy and often intensive care management (ICM) coupled with surgical intervention are necessary. Fosfomycin is an antibiotic primarily utilized for the treatment of STIs in ICUs. Recently, fosfomycin has attracted renewed interest for the treatment of serious systemic infections caused by multidrug-resistant Enterobacteriaceae. In some countries, intravenous fosfomycin has been prescribed for various serious systemic infections, such as acute osteomyelitis, nosocomial lower respiratory tract infections, complicated urinary tract infections, bacterial meningitis, and bacteremia. Administration of intravenous fosfomycin can result in a sufficient concentration of the drug at different body regions. Dose modification is not required in hepatic deficiency because fosfomycin is not subjected to enterohepatic circulation.

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          Most cited references 57

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          Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship.

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            Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis.

            The use of combination antimicrobial therapy for bacteraemia caused by Gram-negative bacilli is controversial. We did a meta-analysis of published studies to determine whether a combination of two or more antimicrobials reduces mortality in patients with Gram-negative bacteraemia. Criteria for inclusion were: analytic studies of patients with documented Gram-negative bacteraemia that included patients receiving a single antibiotic (monotherapy) and patients receiving two or more antibiotics (combination therapy). Data on mortality (outcome) had to be provided. A pooled odds ratio was calculated with the random effects model of DerSimonian and Laird. Assessment of heterogeneity was done with the Breslow-Day test and reasons for heterogeneity were explored. 17 studies met the inclusion criteria, five prospective cohort studies, two prospective randomised trials, and ten retrospective cohort studies. Most studies used beta-lactams or aminoglycosides alone and in combination. The summary odds ratio was 0.96 (95% CI 0.70-1.32), indicating no mortality benefit with combination therapy. Subgroup analyses adjusting for year of publication, study design, and severity of illness did not change the results. Considerable heterogeneity was present in the main analyses. Analysis of only Pseudomonas aeruginosa bacteraemias showed a significant mortality benefit (OR 0.50, 95% CI 0.30-0.79). Our analysis does not support the routine use of combination antimicrobial therapy for Gram-negative bacteraemia, beyond settings where infection by P aeruginosa is strongly suspected or more than one drug would be desirable to assure in-vitro efficacy.
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              Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of fosfomycin for the treatment of patients with systemic infections.

              The advancing antimicrobial drug resistance in common bacterial pathogens, along with the relative shortage of new antibacterial agents, call for the re-evaluation of available therapeutic options. Fosfomycin is an established treatment option for uncomplicated urinary tract infections. Here we review and evaluate the main pharmacokinetic and pharmacodynamic parameters of intravenously administered fosfomycin with regard to its use for systemic infections. Fosfomycin is a relatively small, hydrophilic agent with almost negligible serum protein binding. It is excreted unchanged in urine, achieving high concentrations for a prolonged period. Fosfomycin has good distribution into tissues, achieving clinically relevant concentrations in sites such as serum, soft tissue, lungs, bone, cerebrospinal fluid and heart valves. Fosfomycin has shown antimicrobial activity against biofilms, particularly in combination with fluoroquinolones. It also exerts immunomodulatory effects, mainly on lymphocyte and neutrophil function. Potentially useful properties of fosfomycin regarding its use in combination regimens include reduction in the expression of certain penicillin-binding proteins and attenuation of nephrotoxicity caused by several antimicrobial agents. In conclusion, the pharmacokinetic and pharmacodynamic properties of fosfomycin do not preclude its use for various types of systemic infections and suggest further research on relevant clinical applications of this agent.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2019
                27 March 2019
                : 15
                : 525-530
                Affiliations
                [1 ]Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran, tayebehfarhadi@ 123456yahoo.com
                [2 ]Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
                [3 ]Department of Microbiology, Shiraz Branch, Islamic Azad University, Shiraz, Iran
                Author notes
                Correspondence: Tayebeh Farhadi, Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran 19569-44413, Iran, Tel/fax +98 212 610 9931, Email tayebehfarhadi@ 123456yahoo.com
                Article
                tcrm-15-525
                10.2147/TCRM.S199119
                6441553
                © 2019 Hashemian et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Review

                Medicine

                intensive care management, soft tissue infections, fosfomycin

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