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Synergy of Fosfomycin with Other Antibiotics for Gram-Positive and Gram-Negative Bacteria Antonia C Synergy of fosfomycin with other antibiotics for Gram-positive and Gram-negative bacteria Antonia C. Kastoris, Petros I. Rafailidis, Evridiki K. Vouloumanou, Ioannis D. Gkegkes, Matthew E. Falagas To cite this version: Antonia C. Kastoris, Petros I. Rafailidis, Evridiki K. Vouloumanou, Ioannis D. Gkegkes, Matthew E. Falagas. Synergy of fosfomycin with other antibiotics for Gram-positive and Gram-negative bacteria. European Journal of Clinical Pharmacology, Springer Verlag, 2010, 66 (4), pp.359-368. 10.1007/s00228-010-0794-5. hal-00570019 HAL Id: hal-00570019 https://hal.archives-ouvertes.fr/hal-00570019 Submitted on 26 Feb 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Eur J Clin Pharmacol (2010) 66:359–368 DOI 10.1007/s00228-010-0794-5 PHARMACODYNAMICS Synergy of fosfomycin with other antibiotics for Gram-positive and Gram-negative bacteria Antonia C. Kastoris & Petros I. Rafailidis & Evridiki K. Vouloumanou & Ioannis D. Gkegkes & Matthew E. Falagas Received: 24 August 2009 /Accepted: 26 January 2010 /Published online: 26 February 2010 # Springer-Verlag 2010 Abstract with other antibiotics. Yet, in the 27 studies providing data for Background The alarming increase in drug resistance and Gram-positive strains (16 for Staphylococcus aureus, 3 for decreased production of new antibiotics necessitate the coagulase-negative staphylococci, 5 for Streptococcus evaluation of combinations of existing antibiotics. Fosfo- pneumoniae, and 3 for Enterococcus spp.), fosfomycin mycin shows no cross-resistance to other antibiotic classes. showed synergy against methicillin-resistant Staphylococcus Thus, its combination with other antibiotics may potentially aureus when combined with cefamandole, cephazolin, show synergy against resistant bacteria. ceftriaxone, ciprofloxacin, imipenem, and rifampicin. Data Objective To evaluate the available published evidence regarding Gram-negative strains reported from 15 studies regarding the in vitro synergistic activity of fosfomycin with (12 exclusively for P. aeruginosa, 2 exclusively for other antibiotic agents against Gram-positive and Gram- Enterobacteriaceae, 1 for both, and 1 for Acinetobacter negative bacteria. baumannii) suggested that fosfomycin showed an estimable Methods PubMed and the Cochrane Library were searched. synergistic effect with gentamicin, amikacin, ceftazidime, Results Forty-one studies, including 34 (82.9%) conducted/ cefepime, ciprofloxacin, levofloxacin, and aztreonam against published before 2000, were eligible for inclusion. The P. aeruginosa. relatively limited number of isolates examined and the Conclusions The synergistic combination of fosfomycin with considerable heterogeneity of the retrieved studies regarding other antibiotics may be a useful alternative treatment option the definitions of synergy and the methodologies used hamper for Gram-negative and Gram-positive infections. Additional conclusive remarks for specific combinations of fosfomycin studies using more stringent definitions of synergy, and studies reporting on the clinical efficacy of fosfomycin combinations in the current era of high antimicrobial resistance are needed. : : : A. C. Kastoris P. I. Rafailidis E. K. Vouloumanou . I. D. Gkegkes : M. E. Falagas Keywords Drug-resistance Synergistic combinations Alfa Institute of Biomedical Sciences (AIBS), Antagonism . MRSA . ESBLs Athens, Greece P. I. Rafailidis : M. E. Falagas Department of Medicine, Henry Dunant Hospital, Introduction Athens, Greece The alarmingly increasing drug resistance rates observed in M. E. Falagas our era limit our armamentarium of antibiotics and necessitate Department of Medicine, Tufts University School of Medicine, Boston, MA, USA the development and evaluation of alternative ways to cope with this issue. Specifically, the renewal of physicians’ interest M. E. Falagas (*) in older and neglected antibiotic agents [1, 2], as well as the Alfa Institute of Biomedical Sciences (AIBS), useofcombinationsofantibioticagentsforthetreatmentof 9 Neapoleos Street, “ ” 151 23 Marousi, Athens, Greece patients with infections may be useful weapons in the e-mail: [email protected] “battle” against antimicrobial resistance. 360 Eur J Clin Pharmacol (2010) 66:359–368 Fosfomycin is an old antibiotic agent that has been used these, 41 studies were considered eligible for inclusion in our for the treatment of uncomplicated urinary tract infections review [9–49]. in many clinical settings [3, 4]. Additionally, data reported from recent studies encourage the use of fosfomycin for the Characteristics of the included studies treatment of infections beyond the urinary tract [5, 6]as well as for infections due to specific categories of resistant Twenty-seven of the 41 included studies provided data bacteria [7, 8]. Consequently, a potential synergistic activity regarding the number of Gram-positive strains for which a of fosfomycin with other antibiotic agents may prove to be synergistic effect of fosfomycin with other selected antibi- an important issue with considerable clinical implications. otic agents was exhibited [10, 13, 15, 19, 21, 23–26, 28–33, In this regard, we aimed to collect and evaluate the 35–44, 46, 47]. Fifteen of the 41 included studies provided available evidence regarding the in vitro synergistic activity data regarding the number of Gram-negative strains for of fosfomycin in combination with other antibiotic agents which a synergistic effect of fosfomycin with other selected against Gram-negative and Gram-positive bacteria. antibiotic agents was exhibited [9, 11, 12, 14, 16–18, 20, 22, 27, 34, 45, 47–49]. One of the 41 included studies provided data regarding the number of Gram-positive as Methods well as Gram-negative strains for which a synergistic effect of fosfomycin with other selected antibiotic agents was Literature search exhibited [47]. The definition of synergy used by the majority of the We searched the PubMed and the Cochrane Library databases. included studies (25 of the 41 included) was the fractional The search strategy applied to these databases was “(fosfo- inhibitory concentration index (FICI), represented by the mycin OR phosphomycin OR phosphonomycin) AND formula FICI=(MIC of fosfomycin in combination/MIC of (synergy OR synergism OR combination OR antagonism).” fosfomycin alone)+(MIC of the antibiotic in combination/ Bibliographies of relevant articles were also hand-searched. MIC of the antibiotic alone), where MIC is the minimal inhibitory concentration. The efficacy time index (ETI) Study selection criteria technique was also used in two of the included studies for the assessment of the synergistic effect of fosfomycin A study was considered as eligible for inclusion if it with the evaluated antibiotics [13, 14]. Detailed data provided data regarding the in vitro use of fosfomycin in regarding the laboratory methods used, the fosfomycin combination with other antibiotic agents against Gram- break points, the definition of synergy used, the antibiotics positive and/or Gram-negative microbial strains. Studies evaluated, as well as the pathogens evaluated along with the written in languages other than English, Spanish, French, site of isolation are presented, when available, in Table 1. German, Italian, or Dutch were excluded. Abstracts from scientific conferences were also excluded. Synergy of fosfomycin with other antibiotics Data extraction Gram-positive strains We extracted data regarding the laboratory methods used, the fosfomycin break point, the susceptibility of the Thirteen studies provided data regarding the in vitro pathogens to fosfomycin, the pathogens isolated, the site synergistic effect of fosfomycin with other antibiotics of isolation, and the type of antibiotics used in the against MRSA strains [13, 19, 26, 29–31, 36, 41–44, 46]. combined therapy. Data regarding the number of bacterial The study examining the largest number of MRSA strains strains for which synergism between fosfomycin and reported a good synergistic effect of fosfomycin with other selected antibiotic agents was observed were also cefamandole and with methicillin (65.5 and 31% of the extracted. 148 tested strains, respectively) [42]. However, the findings of this study were not encouraging regarding the potential synergistic effect of fosfomycin with gentamicin, trimeth- Results oprim, and vancomycin [42]. Two other studies providing data for a considerable number of MRSA strains reported a Selected studies synergistic effect of 100% for the combination of fosfomy- cin with cefamandole [44], and a synergistic effect of Our searches performed in PubMed and the Cochrane Library 94.2% for the combination of fosfomycin with cefazolin generated a total of 411 and 36 articles, respectively. Among [31]. Encouraging relevant data were also reported from Eur J Clin Pharmacol (2010) 66:359–368 361 Table 1 Main characteristics of the studies included in the review First author, Laboratory method Fosfomycin Definition of synergy Antibiotics Pathogens evaluated/site year [ref] break point evaluated of isolation Yamada et Broth microdilution
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