Activity Of Fosfomycin In Combination Research Articles

In Vitro and In Vivo Synergism of Fosfomycin in Combination with Meropenem or Polymyxin B against KPC-2-Producing Klebsiella pneumoniae Clinical Isolates.

Fosfomycin disodium is a potential therapeutic option to manage difficult-to-treat infections, especially when combined with other antimicrobials. In this study, we evaluated the activity of fosfomycin in combination with meropenem or polymyxin B against contemporaneous KPC-2-producing K. pneumoniae clinical isolates (KPC-KPN). Synergistic activity was assessed by checkerboard (CKA) and time-kill (TKA) assays. TKA was performed using serum peak and trough concentrations. The activity of these combinations was also assessed in the Galleria mellonella model. Biofilm disruption was assessed by the microtiter plate technique. CKA resulted in an 8- to 2048-fold decrease in meropenem MIC, restoring meropenem activity for 82.4% of the isolates when combined with fosfomycin. For the fosfomycin + polymyxin B combination, a 2- to 128-fold reduction in polymyxin B MIC was achieved, restoring polymyxin B activity for 47% of the isolates. TKA resulted in the synergism of fosfomycin + meropenem (3.0-6.7 log10 CFU/mL decrease) and fosfomycin + polymyxin B (6.0-6.2 log10 CFU/mL decrease) at peak concentrations. All larvae treated with fosfomycin + meropenem survived. Larvae survival rate was higher with fosfomycin monotherapy (95%) than that observed for fosfomycin + polymyxin B (75%) (p-value < 0.0001). Finally, a higher biofilm disruption was observed under exposure to fosfomycin + polymyxin B (2.4-3.4-fold reduction). In summary, we observed a synergistic effect of fosfomycin + meropenem and fosfomycin + polymyxin B combinations, in vitro and in vivo, against KPC-KPN, as well as biofilm disruption.

In vitro Synergistic Activities of Fosfomycin in Combination with Other Antimicrobial Agents Against Carbapenem-Resistant Escherichia coli Harboring bla NDM-1 on the IncN2 Plasmid and a Study of the Genomic Characteristics of These Pathogens.

PurposeThe spread of New Delhi metallo-β-lactamase (NDM) encoded by the blaNDM gene has been a global health crisis for many years. Most of blaNDM-harboring bacteria commonly carry various antimicrobial resistance (AMR) genes on their chromosomes or plasmids, leading to limited treatment options. Thus, we aimed to evaluate the synergistic effects of fosfomycin in combination with other antimicrobial agents against blaNDM-harboring carbapenem-resistant Escherichia coli (CREC) and to characterize the whole-genome and plasmid sequences of these pathogens.MethodsThirty-eight CREC isolates were collected from patients in the Medicine Ward, Songklanagarind Hospital, Thailand. The activity of fosfomycin in combination with other antimicrobial agents against CREC isolates harboring blaNDM on the plasmid was evaluated using the checkerboard method. In this method, the serial dilutions of two antibiotics were mixed with the cultured CREC, the mixtures were incubated, and FICI was calculated to interpret the synergistic activity of the combination. The whole-genome and particular plasmids of these pathogens were sequenced using next-generation sequencing. Sequence analysis, especially on antimicrobial resistance (AMR) genes, mobile-genetic elements (MGEs), and virulence genes was performed using many bioinformatics tools.ResultsOf the E. coli 38 isolates, only 3 isolates contained the blaNDM-1 gene, which is located on the IncN2 plasmid. The combinations of fosfomycin with aminoglycosides, colistin, tigecycline, sitafloxacin, and ciprofloxacin were synergies against blaNDM-1-harboring CREC isolates. Genomic analysis revealed that these isolates harbored many β-lactam resistance genes and other AMR genes that may confer resistance to aminoglycoside, fluoroquinolone, rifampicin, trimethoprim, sulfonamide, tetracycline, and macrolide. Also, various MGEs, especially the blaNDM-1-bearing IncN2 plasmid, were present in these isolates.ConclusionOur study demonstrated some synergistic effects of antimicrobial combination against CREC isolates harboring blaNDM-1 on the IncN2 plasmid. Also, our data on the whole-genome and plasmid sequences might be beneficial in the control of the spread of blaNDM-1-harboring CREC isolates. The linkages between blaNDM-1-carrying plasmid, patient information, and time of collection will be elucidated to track the horizontal gene transfer in the future.

In vitro synergistic activity of fosfomycin in combination with other antimicrobial agents against carbapenem-resistant Klebsiella pneumoniae isolated from patients in a hospital in Thailand

IntroductionCarbapenem-resistant Klebsiella pneumoniae (CRKP) causes high morbidity and mortality worldwide. The purpose of the study was to assess the synergistic activity of fosfomycin in combination with other antimicrobial agents against CRKP isolated from patients in Songklanagarind Hospital, Thailand. MethodsA total of 35 K. pneumoniae isolates were obtained from patients in Songklanagarind Hospital. The MICs of imipenem and meropenem were determined in all isolates by broth microdilution. In all CRKP isolates, the presence of carbapenemase and extended-spectrum β-lactamase (ESBL) genes was investigated by PCR, while the production of these enzymes was determined by combined disk test. In the carbapenemase-genes-negative CRKP isolates, the porin loss and efflux pump were characterized by SDS-PAGE and broth microdilution, respectively. Finally, the synergistic effects of fosfomycin and other antimicrobial agents were evaluated by checkerboard analysis. ResultsTwenty-one of 35 K. pneumoniae isolates were classified as CRKP. Most of CRKP isolates carried blaNDM-1 (n = 18), blaSHV (n = 21), blaCTX-M (n = 21), and blaTEM (n = 16). In fosfomycin-based combination, the result showed that the highest synergistic activity in this study was observed in the combination of fosfomycin and gentamicin (61.9%). ConclusionThese findings suggested that the fosfomycin and gentamicin combination might be useful as a possible treatment option for CRKP infection.

In vitro synergistic activity of fosfomycin in combination with meropenem, amikacin and colistin against OXA-48 and/or NDM-producing Klebsiella pneumoniae

Objective: Carbapenemase-producing Klebsiella pneumoniae (CPKp) infections are increasing worldwide. We investigated the in vitro synergistic activity of fosfomycin (FOS) with meropenem (MRP), amikacin (AMK) and colistin (COL) against OXA-48 and/or New Delhi metallo-beta-lactamase (NDM)-producing Kp blood isolates. Materials and Methods: Seventeen CPKp blood isolates were studied. The broth microdilution method was used for COL, MRP and AMK susceptibilities, while agar dilution for FOS. Synergy was tested by agar dilution chequerboard technique and also was confirmed by a time-kill assay for FOS/MRP and FOS/COL using three representative isolates that were found to be synergistic. Results: FOS in combination with MRP was found to be the most synergistic (15/17 strains, 88%), while 29% and 41% with AMK and COL, respectively. Antagonism was only determined in 2 isolates with the COL/FOS. Conclusions: The MRP/FOS combination demonstrated synergistic activity against CRKp, especially against the two common enzyme-producing isolates in Turkey (OXA-48 and NDM).

Evaluation of the Bactericidal Activity of Fosfomycin in Combination with Selected Antimicrobial Comparison Agents Tested against Gram-Negative Bacterial Strains by Using Time-Kill Curves.

The effects of combining fosfomycin with various antimicrobial agents were evaluated in vitro by broth microdilution checkerboard and time-kill kinetic studies. Checkerboard analyses were used to evaluate the following 30 Gram-negative isolates: 5 Pseudomonas aeruginosa, 5 Acinetobacter baumannii-Acinetobacter calcoaceticus species complex, and 20 Enterobacteriaceae isolates. No isolate exhibited antagonism when fosfomycin was tested in combination, and synergy was observed in more than 25% of the drug combinations tested. The most frequent instances of synergy occurred when testing fosfomycin with β-lactams. Two isolates of Pseudomonas aeruginosa, 2 of Klebsiella pneumoniae, and 1 of the A. baumannii-A. calcoaceticus species complex that exhibited synergy when fosfomycin was tested in combination were subjected to time-kill kinetic analyses for confirmation. Time-kill assays confirmed synergistic activity. These data indicated that combination therapy with fosfomycin may be beneficial.

Antibacterial activity of fosfomycin in combination with eight antimicrobial agents against carbapenem-resistant Enterobacteriaceae

Objective To investigate the antimicrobial activity of fosfomycin combined with other antibiotics against carbapenem-resistant enterobacteriaceae(CRE). Methods A total of 233 non-repititive CRE isolates were collected from January 2010 to December 2014 from 4 hospitals, including Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou Traditional Chinese Medicine Hospital, Zhejiang Provincial People's Hospital and Second Hospital of Jiaxing. Antimicrobial susceptibility of fosfomycin, imipenem, meropenem, cefepime, ceftazidime, ceftriaxone, cefperazone-sulbactam, piperacillin-tazobactam, ciprofloxacin, amikacin, tobramycin, polymyxin B and tigecycline were determined by agar dilution method. Synergistic effect between fosfomycin and other antibiotics, including meropenem, cefepime, ceftazidime, cefperazone-sulbactam, ciprofloxacin, amikacin, tobramycin and tigecycline against 30 CRE isolates was determined by chequerboard assay.Chi-Square test was used for statistical analysis, and the difference was statistical significant when P<0.05. Results An overall 45.1%(105/233) of 233 CRE isolates were resistant to fosfomycin. Among which, Klebsiella spp. possessed the highest resistance rate (61.9%, 73/118), followed by Enterobacter spp. (50%, 15/30), Serratia marcescens (25%, 7/28), and Escherichia coli (8.2%, 4/49). Fosfomycin in combination with tigecyclin showed best activity against CRE isolates with a synergy rate of 76.7%(23/30). Fosfomycin and aminoglycosides also presented good activity against CRE isolates with synergy rate of 53.3%(16/30) to 70.0%(21/30). Synergism was observed only in 30%(9/30) of CRE isolates for the combination of fosfomycin and ciprofloxacin. As for the combination of fosfomycin and β-lactam antibiotics, even less synergism was observed (0%-3.3%)(1/30). No antagonism was demonstrates among all of the combinations. Conclusions Fosfomycin demonstrates certain in vitro activity against CRE isolates. A combination of fosfomycin and tigecyclin or aminoglycosides shows good activity, which suggests a new strategy in the campaign against serious infections caused by CRE.(Chin J Lab Med, 2016, 39: 629-632) Key words: Enterobacteriaceae; Fosfomycin; Anti-bacterial agents; Drug therapy, combination; Drug synergism; Drug resistance, bacterial

In vitro activity of fosfomycin in combination with colistin against clinical isolates of carbapenem-resistant Pseudomas aeruginosa.

The shortage of effective antibiotics against carbapenem-resistant Pseudomonas aeruginosa (CRPA) poses a public health threat. Combination treatment may represent a good choice for treating infections caused by CRPA. The aim of this study was to evaluate the in vitro efficacy of fosfomycin in combination with colistin against clinical CRPA isolates. Eighty-seven isolates were collected from three hospitals in China. The checkerboard method and time-kill assay were used to assess the interactions between fosfomycin and colistin. The fosfomycin/colistin combination displayed synergistic and partial synergistic activity against 21.84% and 27.59% of the isolates, respectively. Antagonism was not observed. In combination, the colistin MIC values were ⩽0.5 μg ml(-1) for 91.95% of the isolates. This result differed significantly from those obtained using a single agent treatment (The colistin MIC values were ⩽0.5 μg ml(-1) for only 25.29% of the isolates). In addition, the time-kill assay demonstrated that the fosfomycin/colistin combination treatment exerted bactericidal effects against five isolates and that the regrowth observed after colistin monotherapy was prevented. In summary, the combination of fosfomycin and colistin demonstrated synergistic activity against the CRPA isolates tested in this study. Furthermore, fosfomycin may potentially widen the therapeutic window of colistin, suggesting that this combination could be applied clinically to control infections caused by CRPA.

In vitro activity of fosfomycin in combination with linezolid against clinical isolates of methicillin-resistant Staphylococcus aureus

The objective of this paper was to investigate the in vitro effects of fosfomycin combined with linezolid against methicillin-resistant Staphylococcus aureus (MRSA). A total of 102 MRSA isolates isolated from clinical specimens of human infections from three hospitals in China were studied. The microdilution checkerboard method was used to determine whether combinations act synergistically against these isolates. The susceptibility results for fosfomycin and linezolid were interpreted according to the guidelines of the Clinical and Laboratory Standards Institute. Synergy and indifference were defined as a fractional inhibitory concentration index of ⩽0.5 and >0.5 but ⩽4, respectively. The combination of fosfomycin and linezolid demonstrated the following interactions: 98.04% (100/102) synergism; 1.96% (2/102) indifference; no antagonism was seen. Thus, the combination between fosfomycin and linezolid shows synergism for most of the MRSA isolates tested in this study. If these findings are confirmed in further in vitro or in vivo studies, the above combination could be tested clinically for difficulty to treat MRSA infections, particularly those warranting prolonged oral therapy.

In vitro activity of fosfomycin in combination with imipenem, meropenem, colistin and tigecycline against OXA 48–positive Klebsiella pneumoniae strains

Carbapenem resistance due to OXA-48 enzymes in Klebsiella pneumoniae is increasing particularly in the Middle Eastern and European regions. Treatment options are limited. The aim of this study was to evaluate the in vitro synergistic activity of fosfomycin in combination with imipenem, meropenem, colistin and tigecycline against OXA-48 producing K. pneumoniae strains.Twelve carbapenem-resistant OXA-48 producing K. pneumoniae isolates were enrolled in this study. Synergistic activity of fosfomycin combined with imipenem, meropenem, colistin, and tigecycline was assessed by chequerboard method.The combination of fosfomycin was synergistic with imipenem, meropenem and tigecycline with the ratios of 42%, 33%, and 33%, respectively. Whilst the combination of fosfomycin with colistin was fully antagonistic against all of the strains, there was no statistically significant difference between the in vitro synergistic activities of fosfomycin in combination with imipenem, meropenem and tigecycline combinations (P > 0.05).Fosfomycin in combination with other agents can be preferred against multidrug resistant K. pneumoniae strains.

In vitro activity of fosfomycin in combination with various antistaphylococcal substances.

Using the chequerboard technique we studied the in vitro activity of the broad spectrum antibiotic fosfomycin in combination with vancomycin, rifampicin, linezolid, quinupristin/ dalfopristin, cefazolin, meropenem and moxifloxacin against two Staphylococcus epidermidis strains (ATCC 12228, DSM 3269) and five Staphylococcus aureus isolates (ATCC 29213, DSM 683, DSM 46320, GISA 323/93, MRSA 3558/00). The phenomena of 'trailing' and 'skipped wells' did not present a problem. Synergy was the most common effect of all drugs tested in combination with fosfomycin; only combination with vancomycin showed antagonism for two of seven isolates. Using a killing-curve technique fosfomycin showed cidal activity, where increasing the drug concentration above the MIC did not enhance killing velocity. Inhibitory concentrations of vancomycin plus fosfomycin against DSM 46320 caused effects identical to those observed with vancomycin alone. The combination of fosfomycin plus linezolid exerted the bacteriostatic effect found with linezolid alone. Fosfomycin plus quinupristin/dalfopristin exhibited the bactericidal effect found with fosfomycin alone (in contrast to the rapidly bactericidal effect of quinupristin/dalfopristin). Electron microscopy showed that fosfomycin given in combination with linezolid, quinupristin/dalfopristin or moxifloxacin (substances that do not cause morphological alterations when given alone) resulted in 'cauliflower-shaped' distortion as caused by fosfomycin alone. Our in vitro data indicate considerable potential for fosfomycin used in combination with other antistaphylococcal antimicrobials, especially linezolid or quinupristin/dalfopristin.

In vitro activity of fosfomycin combined with ceftazidime, imipenem, amikacin, and ciprofloxacin against Pseudomonas aeruginosa.

The in vitro activity of fosfomycin in combination with ceftazidime, imipenem, amikacin, or ciprofloxacin was studied by an agar plate checkerboard method against 40 clinical isolates of Pseudomonas aeruginosa with various antibiotic resistance profiles. Fosfomycin/ciprofloxacin appeared to be the most effective combination (synergy 15%, addition 80%, indifference 5%), followed by fosfomycin/amikacin (synergy 7.5%, addition 52.5%, indifference 40%), fosfomycin/imipenem (addition 37%, indifference 63%), and fosfomycin/ceftazidime (addition 20%, indifference 80%). The effects of the combinations were not significantly influenced by the antibiotic susceptibility patterns of the strains.