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      Evaluation of Intravenous Fosfomycin Disodium Dosing Regimens in Critically Ill Patients for Treatment of Carbapenem-Resistant Enterobacterales Infections Using Monte Carlo Simulation

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          Abstract

          There are limited intravenous fosfomycin disodium (IVFOS) dosing regimens to treat carbapenem-resistant Enterobacterales (CRE) infections. This study aimed to use Monte Carlo simulation (MCS) for evaluation of IVFOS dosing regimens in critically ill patients with CRE infections. The dosing regimens in critically ill patients with various creatinine clearance were evaluated with MCS using minimum inhibitory concentration (MIC) distributions of fosfomycin against CRE clinical isolates in Thailand and the 24 h area under the plasma drug concentration–time curve over the minimum inhibitory concentration (AUC 0-24/MIC) of ≥21.5 to be a target for IVFOS. The achieved goal of the probability of target attainment (PTA) and a cumulative fraction of response (CFR) were ≥90%. A total of 129 non-duplicated CRE clinical isolates had MIC distributions from 0.38 to >1024 mg/L. IVFOS 8 g every 8 h, 1 h, or 4 h infusion, could achieve approximately 90% PTA of AUC 0-24/MIC target to treat CRE infections with MICs ≤ 128 mg/L. According to PTA target, an IVFOS daily dose to treat carbapenem-resistant Escherichia coli based on Clinical Laboratory Standards Institute (CLSI) breakpoints for urinary tract infections and one to treatment for CRE infections based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints were 16 g/day and 8 g/day, respectively. All dosing regimens of IVFOS against CRE achieved CFR ≤ 70%. This study proposes the IVFOS dosing regimens based on CLSI and EUCAST breakpoints for the treatment of CRE infections. However, further clinical studies are needed to confirm the results of these findings.

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          Most cited references 36

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          Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

          Therapy of invasive infections due to multidrug-resistant Enterobacteriaceae (MDR-E) is challenging, and some of the few active drugs are not available in many countries. For extended-spectrum β-lactamase and AmpC producers, carbapenems are the drugs of choice, but alternatives are needed because the rate of carbapenem resistance is rising. Potential active drugs include classic and newer β-lactam–β-lactamase inhibitor combinations, cephamycins, temocillin, aminoglycosides, tigecycline, fosfomycin, and, rarely, fluoroquinolones or trimethoprim-sulfamethoxazole. These drugs might be considered in some specific situations. AmpC producers are resistant to cephamycins, but cefepime is an option. In the case of carbapenemase-producing Enterobacteriaceae (CPE), only some “second-line” drugs, such as polymyxins, tigecycline, aminoglycosides, and fosfomycin, may be active; double carbapenems can also be considered in specific situations. Combination therapy is associated with better outcomes for high-risk patients, such as those in septic shock or with pneumonia. Ceftazidime-avibactam was recently approved and is active against KPC and OXA-48 producers; the available experience is scarce but promising, although development of resistance is a concern. New drugs active against some CPE isolates are in different stages of development, including meropenem-vaborbactam, imipenem-relebactam, plazomicin, cefiderocol, eravacycline, and aztreonam-avibactam. Overall, therapy of MDR-E infection must be individualized according to the susceptibility profile, type, and severity of infection and the features of the patient.
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            The Epidemiology of Carbapenem-Resistant Enterobacteriaceae: The Impact and Evolution of a Global Menace.

             Latania K. Logan (corresponding) ,  Robert Weinstein (2017)
            Carbapenem-resistant Enterobacteriaceae (CRE) are a serious public health threat. Infections due to these organisms are associated with significant morbidity and mortality. Mechanisms of drug resistance in gram-negative bacteria (GNB) are numerous; β-lactamase genes carried on mobile genetic elements are a key mechanism for the rapid spread of antibiotic-resistant GNB worldwide. Transmissible carbapenem-resistance in Enterobacteriaceae has been recognized for the last 2 decades, but global dissemination of carbapenemase-producing Enterobacteriaceae (CPE) is a more recent problem that, once initiated, has been occurring at an alarming pace. In this article, we discuss the evolution of CRE, with a focus on the epidemiology of the CPE pandemic; review risk factors for colonization and infection with the most common transmissible CPE worldwide, Klebsiella pneumoniae carbapenemase-producing K. pneumoniae; and present strategies used to halt the striking spread of these deadly pathogens.
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              Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: a prospective evaluation.

              Intensive care unit (ICU)-acquired infections as a result of multidrug-resistant Gram-negative pathogens remain a serious problem in critically ill patients. Adult ICU patients who received intravenous fosfomycin were prospectively examined to assess its safety and effectiveness as an adjunct to the antimicrobial therapy of life-threatening infections caused by carbapenem-resistant Klebsiella pneumoniae. Fosfomycin was administered intravenously in 11 patients for treatment of hospital-acquired infections caused by carbapenem-resistant K. pneumoniae. Fosfomycin (2-4 g every 6 h) was administered in combination with other antibiotics. The mean +/- SD duration of treatment was 14 +/- 5.6 days. All patients had good bacteriological and clinical outcome of infection. All-cause hospital mortality was two out of 11 (18.2%) patients. No patient experienced adverse events related to the administration of fosfomycin. Intravenous fosfomycin may be a beneficial and safe adjunctive treatment in the management of life-threatening ICU-acquired infections caused by carbapenem-resistant K. pneumoniae.
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                Author and article information

                Journal
                Antibiotics (Basel)
                Antibiotics (Basel)
                antibiotics
                Antibiotics
                MDPI
                2079-6382
                18 September 2020
                September 2020
                : 9
                : 9
                Affiliations
                [1 ]Division of Clinical Pharmacy, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand; pannee@ 123456nmu.ac.th (P.L.); wichit.nos@ 123456mahidol.ac.th (W.N.)
                [2 ]Department of Pharmacy, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok 10300, Thailand
                [3 ]Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand; thitima.w@ 123456pharm.chula.ac.th (T.W.); sang.u@ 123456pharm.chula.ac.th (S.U.)
                [4 ]Department of Pharmacy Practice, College of Pharmacy, Rangsit University, Pathum Thani 12000, Thailand; taniya.p@ 123456rsu.ac.th
                [5 ]Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand; rongpong.p@ 123456chula.ac.th
                [6 ]Antimicrobial Resistance and Stewardship Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; tanittha.c@ 123456chula.ac.th
                [7 ]Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
                Author notes
                [* ]Correspondence: preecha.mon@ 123456mahidol.ac.th ; Tel./Fax: +66-2-644-8694
                Article
                antibiotics-09-00615
                10.3390/antibiotics9090615
                7558518
                32961833
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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