Fosfomycin Research Articles

Susceptibility to rifaximin and other antimicrobial agents of bacteria isolated from acute gastrointestinal infections in Mexico

BackgroundBacterial resistance may hamper the antimicrobial management of acute gastroenteritis. Bacterial susceptibility to rifaximin, an antibiotic that achieves high fecal concentrations (up to 8,000μg/g), has not been evaluated in Mexico. ObjectiveTo determine the susceptibility to rifaximin and other antimicrobial agents of enteropathogenic bacteria isolated from patients with acute gastroenteritis in Mexico. Material and methodsBacterial strains were analyzed in stool samples from 1,000 patients with diagnosis of acute gastroenteritis. The susceptibility to rifaximin (RIF) was tested by microdilution (<100, <200, <400 and <800μg/ml) and susceptibility to chloramphenicol (CHL), trimethoprim-sulfamethoxazole (T-S), neomycin (NEO), furazolidone (FUR), fosfomycin (FOS), ampicillin (AMP) and ciprofloxacin (CIP) was tested by agar diffusion at the concentrations recommended by the Clinical & Laboratory Standards Institute and the American Society for Microbiology. ResultsIsolated bacteria were: enteropathogenic Escherichia coli (E. coli) (EPEC) 531, Shigella 120, non-Typhi Salmonella 117, Aeromonas spp. 80, enterotoxigenic E. coli (ETEC) 54, Yersinia enterocolitica 20, Campylobacter jejuni 20, Vibrio spp. 20, Plesiomonas shigelloides 20, and enterohemorrhagic E. coli (EHEC 0:157) 18. The overall cumulative susceptibility to RIF at <100, <200, <400, and <800μg/ml was 70.6, 90.8, 99.3, and 100%, respectively. The overall susceptibility to each antibiotic was: AMP 32.2%, T-S 53.6%, NEO 54.1%, FUR 64.7%, CIP 67.3%, CLO 73%, and FOS 81.3%. The susceptibility to RIF <400 and RIF <800μg/ml was significantly greater than with the other antibiotics (p<0.001). ConclusionsResistance of enteropathogenic bacteria to various antibiotics used in gastrointestinal infections is high. Rifaximin was active against 99-100% of these enteropathogens at reachable concentrations in the intestine with the recommended dose.

Fosfomycin: A First-Line Oral Therapy for Acute Uncomplicated Cystitis.

Fosfomycin is a new agent to Canada approved for the treatment of acute uncomplicated cystitis (AUC) in adult women infected with susceptible isolates of E. coli and Enterococcus faecalis. We reviewed the literature regarding the use of oral fosfomycin for the treatment of AUC. All English-language references from 1975 to October 2015 were reviewed. In Canada, fosfomycin tromethamine is manufactured as Monurol® and is available as a 3-gram single dose sachet. Fosfomycin has a unique chemical structure, inhibiting peptidoglycan synthesis at an earlier site compared to β-lactams with no cross-resistance with other agents. Fosfomycin displays broad-spectrum activity against ESBL-producing, AmpC-producing, carbapenem-non-susceptible, and multidrug-resistant (MDR) E. coli. Resistance to fosfomycin in E. coli is rare (<1%). Fosfomycin is excreted unchanged in the urine by glomerular filtration with peak urinary concentration ~4000 µg/mL and remains at concentrations >100 µg/mL for 48 hours after a single 3-gram oral dose. No dosage adjustments are required in elderly patients, in pregnant patients, or in either renal or hepatic impairment. Fosfomycin demonstrates a favorable safety profile, and clinical trials have demonstrated efficacy in AUC that is comparable to ciprofloxacin, nitrofurantoin, and trimethoprim-sulfamethoxazole. Fosfomycin's in vitro activity against common uropathogens, including MDR isolates, its favorable safety profile including pregnancy patients, drug interactions, and clinical trials data demonstrating efficacy in AUC, has resulted in Canadian, US, and European guidelines/authorities recommending fosfomycin as a first line agent for the treatment of AUC.

In vitro synergism of magnolol and honokiol in combination with antibacterial agents against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA).

BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) is a problematic pathogen posing a serious therapeutic challenge in the clinic. It is often multidrug-resistant (MDR) to conventional classes of antibacterial agents and there is an urgent need to develop new agents or strategies for treatment. Magnolol (ML) and honokiol (HL) are two naturally occurring diallylbiphenols which have been reported to show inhibition of MRSA. In this study their synergistic effects with antibacterial agents were further evaluated via checkerboard and time-kill assays.MethodsThe susceptibility spectrum of clinical MRSA strains was tested by the disk diffusion method. The minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of ML and HL were assayed by broth microdilution. The synergy was evaluated through checkerboard microdilution and time-killing experiments.ResultsML and HL showed similar activity against both MSSA and MRSA with MIC/MBC at 16 ~ 64 mg/L, with potency similar to amikacin (AMK) and gentamicin (GEN). When they were used in combination with conventional antibacterial agents, they showed bacteriostatic synergy with FICIs between 0.25 ~ 0.5, leading to the combined MICs decreasing to as low as 1 ~ 2 and 1 ~ 16 mg/L for ML (HL) and the agents, respectively. MIC50 of the combinations decreased from 16 mg/L to 1 ~ 4 mg/L for ML (HL) and 8 ~ 128 mg/L to 2 ~ 64 mg/L for the antibacterial agents, which exhibited a broad spectrum of synergistic action with aminoglycosides (AMK, etilmicin (ETM) and GEN), floroquinolones (levofloxacin (LEV), ciprofloxacin and norfloxacin), fosfomycin (FOS) and piperacillin. The times of dilution (TOD, the extent of decreasing in MIC value) were determined up to 16 for the combined MIC. A more significant synergy after combining was determined as ML (HL) with AMK, ETM, GEN and FOS. ML (HL) combined with antibacterial agents did not show antagonistic effects on any of the ten MRSA strains. Reversal effects of MRSA resistance to AMK and GEN by ML and HL were also observed, respectively. All the combinations also showed better dynamic bactericidal activity against MRSA than any of single ML (HL) or the agents at 24 h incubation. The more significant synergy of combinations were determined as HL (ML) + ETM, HL + LEV and HL + AMK (GEN or FOS), with △LC24 of 2.02 ~ 2.25.ConclusionML and HL showed synergistic potentiation of antibacterial agents against clinical isolates of MRSA and warrant further pharmacological investigation.

Susceptibilidad de las bacterias aisladas de infecciones gastrointestinales agudas a la rifaximina y otros agentes antimicrobianos en México

Bacterial resistance may hamper the antimicrobial management of acute gastroenteritis. Bacterial susceptibility to rifaximin, an antibiotic that achieves high fecal concentrations (up to 8,000μg/g), has not been evaluated in Mexico. To determine the susceptibility to rifaximin and other antimicrobial agents of enteropathogenic bacteria isolated from patients with acute gastroenteritis in Mexico. Bacterial strains were analyzed in stool samples from 1,000 patients with diagnosis of acute gastroenteritis. The susceptibility to rifaximin (RIF) was tested by microdilution (<100, <200, <400 and <800μg/ml) and susceptibility to chloramphenicol (CHL), trimethoprim-sulfamethoxazole (T-S), neomycin (NEO), furazolidone (FUR), fosfomycin (FOS), ampicillin (AMP) and ciprofloxacin (CIP) was tested by agar diffusion at the concentrations recommended by the Clinical & Laboratory Standards Institute and the American Society for Microbiology. Isolated bacteria were: enteropathogenic Escherichia coli (E. coli) (EPEC) 531, Shigella 120, non-Typhi Salmonella 117, Aeromonas spp. 80, enterotoxigenic E. coli (ETEC) 54, Yersinia enterocolitica 20, Campylobacter jejuni 20, Vibrio spp. 20, Plesiomonas shigelloides 20, and enterohemorrhagic E. coli (EHEC 0:157) 18. The overall cumulative susceptibility to RIF at <100, <200, <400, and <800μg/ml was 70.6, 90.8, 99.3, and 100%, respectively. The overall susceptibility to each antibiotic was: AMP 32.2%, T-S 53.6%, NEO 54.1%, FUR 64.7%, CIP 67.3%, CLO 73%, and FOS 81.3%. The susceptibility to RIF <400 and RIF <800μg/ml was significantly greater than with the other antibiotics (p<0.001). Resistance of enteropathogenic bacteria to various antibiotics used in gastrointestinal infections is high. Rifaximin was active against 99-100% of these enteropathogens at reachable concentrations in the intestine with the recommended dose.

Actividad in-vitro de fosfomicina, sola o en combinaciones, frente a aislamientos clínicos de Pseudomonas aeruginosa resistentes a carbapenémicos

IntroductionThe increase in microorganisms showing patterns of multi-drug resistance or even pan-drug resistance is of growing concern. Fosfomycin (FO) is well known to be active against a wide variety of microorganisms, including highly resistant strains of Pseudomonas aeruginosa (P. aeruginosa), and can also synergistically act with other molecules. MethodsThis study examines the in vitro activity shown by FO against 120 strains of carbapenem-resistant P. aeruginosa using an agar dilution and a gradient diffusion test. Possible synergistic effects of the combinations of FO/amikacin and FO/ciprofloxacin were also examined using E-test and time-kill techniques. ResultsAccording to the epidemiological cut-off value (ECOFF) issued by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), our results indicate that over three-quarters of the strains tested would be susceptible to FO treatment, especially if combined with another antimicrobial. The FO/ciprofloxacin combination had a synergistic effect on 40% of the clinical isolates, while for FO/amikacin this effect was only observed in 12% of the isolates. ConclusionThe appearance of carbapenem-resistant P. aeruginosa strains requires the evaluation by combination therapy. This report suggests that the FO/ciprofloxacin combination can be useful, showing a synergistic effect in 40% of the isolates.

MP20-11 ANTIMICROBIAL SUSCEPTIBILITIES OF URINARY EXTENDED SPECTRUM BETA-LACTAMASE-PRODUCING ESCHERICHIA COLI AND KLEBSIELLA PNEUMONIAE TO FOSFOMYCIN IN HEALTH CARE ASSOCIATED URINARY TRACT INFECTION

INTRODUCTION AND OBJECTIVES: The appearance of extended-spectrum beta-lactamase (ESBL)-producing gram negative bacteria in urinary tract infections (UTIs) constitutes an important therapeutic challenge. The aim of this study was to describe drug susceptibility profiles of (ESBL)-producing gram-negative isolates recovered from urine samples. We also determined the antimicrobial coresistance to several agents, including fosfomycin METHODS: Retrospective analysis of 29,584 urine culture results obtained during January 2008 to December 2013 at Chonnam National Hwasun Hospital in Korea was done. The computerized database was used to identify ESBL-positive urine samples. A total of 869 ESBL positive strains were identified during the study period. We analyzed E. coli and Klebsiella isolates obtained from urine cultures and duplicate isolates; and no fosfomycin tests were excluded. The cases were further categorized according to UTI definition [community acquired (CA) UTI, health care-associated (HCA) UTI and hospital acquired (HA) UTI] and urology sample. ESBLisolates were stratified according their origin into two groups: Urology and non-Urology isolates RESULTS: Antimicrobial susceptibilities of the strains for fosfomycin were tested in 277 ESBL-positive strains: 217 ESBL-EC and 60 ESBL-KP. The most effective agents were carbapenem, such as imipenem and meropenem. The least active substances were ciprofloxacin (20.7%), Levofloxacin (22.7%), Trimethoprim-sulfamethoxazole (34.3%), and ampicillin-clavulanate (42.9 %). Overall, 243/277 (87.7%) of the isolates tested were susceptible to fosfomycin tromethamine. Higher fosfomycin sensitivity in E. coli (94.9%) were observed compared to Klebsiella (61.7%) (p1⁄40.001). ESBL-positive isolates from urological (68 isolates) and nonurological patients (209 isolates) showed similar susceptibility profiles. Except for carbapenem, CA-UTI showed higher sensitivity to fosfomycin (100%) and nitrofurantoin (93.1%), HCA-UTI showed higher sensitivity to amikacin (94.1%) and HA-UTI showed an overall poor sensitivity to antibiotics. CONCLUSIONS: Fosfomycin could be an alternative treatment option for UTIs related to ESBL-producing E. coli spp. and CA-UTI, but not for ESBL-producing Klebsiella spp. Antimicrobial susceptibilities in ESBL producing UTI was different to UTI classification. Fosfomycin showed decreased sensitivity in HCA-UTI and HA-UTI.

MP20-12 RECENT ANTIBIOTIC TREATMENT AND THE RISK OF POST-OUTPATIENT CYSTOSCOPY URINARY TRACT INFECTION

INTRODUCTION AND OBJECTIVES: The appearance of extended-spectrum beta-lactamase (ESBL)-producing gram negative bacteria in urinary tract infections (UTIs) constitutes an important therapeutic challenge. The aim of this study was to describe drug susceptibility profiles of (ESBL)-producing gram-negative isolates recovered from urine samples. We also determined the antimicrobial coresistance to several agents, including fosfomycin METHODS: Retrospective analysis of 29,584 urine culture results obtained during January 2008 to December 2013 at Chonnam National Hwasun Hospital in Korea was done. The computerized database was used to identify ESBL-positive urine samples. A total of 869 ESBL positive strains were identified during the study period. We analyzed E. coli and Klebsiella isolates obtained from urine cultures and duplicate isolates; and no fosfomycin tests were excluded. The cases were further categorized according to UTI definition [community acquired (CA) UTI, health care-associated (HCA) UTI and hospital acquired (HA) UTI] and urology sample. ESBLisolates were stratified according their origin into two groups: Urology and non-Urology isolates RESULTS: Antimicrobial susceptibilities of the strains for fosfomycin were tested in 277 ESBL-positive strains: 217 ESBL-EC and 60 ESBL-KP. The most effective agents were carbapenem, such as imipenem and meropenem. The least active substances were ciprofloxacin (20.7%), Levofloxacin (22.7%), Trimethoprim-sulfamethoxazole (34.3%), and ampicillin-clavulanate (42.9 %). Overall, 243/277 (87.7%) of the isolates tested were susceptible to fosfomycin tromethamine. Higher fosfomycin sensitivity in E. coli (94.9%) were observed compared to Klebsiella (61.7%) (p1⁄40.001). ESBL-positive isolates from urological (68 isolates) and nonurological patients (209 isolates) showed similar susceptibility profiles. Except for carbapenem, CA-UTI showed higher sensitivity to fosfomycin (100%) and nitrofurantoin (93.1%), HCA-UTI showed higher sensitivity to amikacin (94.1%) and HA-UTI showed an overall poor sensitivity to antibiotics. CONCLUSIONS: Fosfomycin could be an alternative treatment option for UTIs related to ESBL-producing E. coli spp. and CA-UTI, but not for ESBL-producing Klebsiella spp. Antimicrobial susceptibilities in ESBL producing UTI was different to UTI classification. Fosfomycin showed decreased sensitivity in HCA-UTI and HA-UTI.

Multi-spectroscopic investigation of the binding interaction of fosfomycin with bovine serum albumin

The interaction between fosfomycin (FOS) and bovine serum albumin (BSA) has been investigated effectively by multi-spectroscopic techniques under physiological pH 7.4. FOS quenched the intrinsic fluorescence of BSA via static quenching. The number of binding sites n and observed binding constant KA were measured by the fluorescence quenching method. The thermodynamic parameters ΔG0, ΔH0 and ΔS0 were calculated at different temperatures according to the van’t Hoff equation. The site of binding of FOS in the protein was proposed to be Sudlow’s site I based on displacement experiments using site markers viz. warfarin, ibuprofen and digitoxin. The distance r between the donor (BSA) and acceptor (FOS) molecules was obtained according to the Förster theory. The effect of FOS on the conformation of BSA was analyzed using synchronous fluorescence spectra (SFS), circular dichroism (CD) and 3D fluorescence spectra. A molecular modeling study further confirmed the binding mode obtained by the experimental studies.

Antibacterial Susceptibility of &lt;i&gt;Enterobacteriaceae&lt;/i&gt; Isolated from Raw Horsemeat Intended for Human Consumption (&lt;i&gt;Basashi&lt;/i&gt;)

Drug susceptibility testing was carried out using 14 antibiotics in order to identify trends in the antibiotic tolerance of 142 strains of Enterobacteriaceae isolated from horsemeat commercially available for raw consumption (basashi). A comparison of the sensitivity to the 14 antibiotics using the 90% MIC (minimum inhibitory concentration) values (MIC90) showed the strongest tolerance to ampicillin (ABPC) at a concentration of > 128 μg/mL, followed by that to fosfomycin (FOM) at a concentration of 128 μg/mL. When the sensitivity to these antibiotics was examined for each individual genus of tested bacteria, Hafnia spp. exhibited relative tolerance to ceftazidime (CAZ) and ceftriaxone (CTRX) at a concentration of 4 μg/mL and 2 μg/mL, respectively, which was high in comparison to that observed for the other strains. Furthermore, Raoultella spp. and Serratia spp. were found to be highly resistant to tetracycline (TC) at a concentration of 128 μg/mL and 64 μg/mL, respectively. Of the 142 strains of test bacteria, 140 (98.6%) demonstrated resistance to ABPC, with the exception of Hafnia alvei and Klebsiella pneumonia. In addition, a total of eight strains (5.6%), seven Serratia marcescens strains and one Raoultella terrigena strain, were found to be resistant to TC. Furthermore, one strain of Citrobacter freundii exhibited resistance to nalidixic acid (NA), while another displayed resistance to ofloxacin (OFLX) (0.7% each), and one strain (0.7%) each of Enterobacter cloacae, Serratia marcescens and Citrobacter youngae demonstrated resistance to fosfomycin (FOM), streptomycin (SM) and kanamycin (KM), respectively. A single strain of C. freundii was found to be resistant to three antibiotics, ABPC, NA and OFLX. Resistance to two antibiotics was confirmed in 11 strains, including seven strains of S. marcescens and one strain of R. terrigena (a total of eight strains) resistant to ABPC and TC, and one strain each of C. youngae, S. marcescens and E. cloacae resistant to ABPC and KM, ABPC and SM, and ABPC and FOM, respectively. In addition, 128 strains were resistant to the single antibiotic of ABPC alone. Of the 140 strains demonstrating antibiotic resistance, 137 (97.9%) retained the conjugative R-plasmid transfer factor, excluding three strains of S. marcescens. All transfer factors were ABPC and retained by a high proportion of the bacterial groups, with one strain (100%) being resistant to three antibiotics, nine (81.8%) of the 11 strains being resistant to two antibiotics, and 127 (99.2%) of the 128 strains being resistant to a single antibiotic. In addition, we examined ESBL productivity in the 140 strains of bacteria demonstrating drug tolerance; however, no strains exhibited this characteristic. Therefore, further observation is required to ascertain trends in antibiotic-tolerant bacteria.

Fosfomycin tromethamine. Antibiotic of choice in the female patient: A multicenter study.

IntroductionThe aim of this study was to evaluate oral single/multiple doses of Fosfomycin Trometamol with clinical and microbiological efficacy in:Asymptomatic bacteriuria in pregnancy.Endourological procedures.Lower urinary tract infections. Material and methodsThis prospective, uncontrolled, open label study was conducted in two tertiary hospitals over a period of three years. A total of 400 patients were included in the study. Group A (200 patients) with asymptomatic bacteriuria in pregnancy and Group B (200 Patients) with symptomatic lower urinary tract infections and with any day care endourological procedures were enrolled in our study. Efficacy end points like post- antibiotic urinalysis, microbiological efficacy and clinical improvement with adverse effects of the drug were evaluated.ResultsOf the 400 patients studied, 98% returned for follow-up. Out of the 304 urinary isolates in Table 2 (ASB and symptomatic LUTS) grown on urinary culture, majority of the isolates were Gram-negative Enterobacteriacae family. After oral single/multiple doses of fosfomycin, bacterial eradication, bacterial persistence, bacterial reinfection were 96.3%, 3.9%, 3.9% respectively (Figure 2). No isolates were grown in 8 cases (Table 2). However, on administration of the drug 23.5% patients noticed diarrhea (loose stools) followed by itching (19.7%) in genital area (Figure 1).ConclusionsFosfomycin Trometamol is a bactericidal antibiotic with a broad spectrum activity against Gram-positive also Gram-negative bacteriae. It has an advantage of oral single /multiple doses, higher eradication rate of bacteria after 48 hours, excellent tolerability and safety in pregnancy and other female age groups. We recommend Fosfomycin Trometamol as the drug of choice particularly in patients with poor drug compliance and for minor day care endourological procedures.

Intravenous fosfomycin therapy in critically ill patients infected with colistin-resistant enterobacteriacae

Carbapenem-resistant enterobacteriacae emerged in recent years as one of the most challenging groups of antibiotic-resistant pathogens. Polymyxins are considered as the last resort for the treatment of infections with carbapenem-resistant Gram-negative bacilli (GNB). Inadequate or extensive use of colistin leads to emergence of colistin resistance in GNB, jeopardizing treatment options in ICUs, potentially increasing mortality and morbidity and necessitating prudent use of alternative antibiotics. Fosfomycin, a phosponic acid derivative which acts primarily by disrupting bacterial cell wall synthesis, is a broad-spectrum antibiotic. Fosfomycin tromethamine is an oral formulation approved for the treatment of uncomplicated urinary tract infection caused by multidrug-resistant (MDR) bacteria. Recently fosfomycin is also available as a sodium/disodium formulation for intravenous use, which is showing promising result against MDR/ potentially drug-resistant pathogens.

Efficacy of combined vancomycin and fosfomycin against methicillin-resistant Staphylococcus aureus in biofilms in vivo.

Infection by methicillin-resistant Staphylococcus aureus (MRSA) is a life-threatening condition, and formation of biofilms can lead to treatment failure in a clinical setting. The aim of this study was to demonstrate the in vivo bactericidal effects of a combination of vancomycin (VAN) and fosfomycin (FOS) against MRSA in a rat carboxymethyl cellulose-pouch biofilm model. The results of the time-kill assay showed that the combination therapy was capable of killing at low minimal inhibitory concentrations (MIC) (½× MIC VAN +1× MIC FOS and 1× MIC VAN + 1× MIC FOS). In the in vivo study, a synergistically bactericidal effect was observed when using the combination therapy on MRSA embedded in the mature biofilm model. In comparison with the untreated control group and the groups receiving either VAN or FOS alone, the rats treated with combination therapy had lower MRSA colony counts in exudates from the pouch, lower white blood cell and neutrophil counts, and C-reactive protein (CRP) in peripheral blood. Furthermore, histological analysis of the pouch wall indicated combination therapy resulted in disappearance of biofilm-like structures, marked decrease in necrosis, and formation of granular tissue. In conclusion, the combination of VAN with FOS had a synergistic bactericidal effect on chronic MRSA infection embedded in biofilm, providing an alternative approach to treating this condition.

In vitro activity of fosfomycin alone and in combination with ceftriaxone or azithromycin against clinical Neisseria gonorrhoeae isolates.

New therapeutic strategies are needed to combat the emergence of infections due to multidrug-resistant Neisseria gonorrhoeae. In this study, fosfomycin (FOS) was tested against 89 N. gonorrhoeae isolates using the Etest method, showing MIC50/MIC90s of only 8/16 μg/ml (range, ≤1 to 32 μg/ml). FOS in combination with ceftriaxone (CRO) or azithromycin (AZT) was then evaluated using the checkerboard method for eight strains, including N. gonorrhoeae F89 (CRO-resistant) and AZT-HLR (high-level AZT-resistant). All combinations that included FOS gave indifferent effects (fractional inhibitory concentration [FIC] index values, 1.2 to 2.3 for FOS plus CRO, 1.8 to 3.2 for FOS plus AZT). Time-kill experiments for FOS, CRO, AZT, and their combinations (at 0.5×, 1×, 2×, and 4× the MIC) were performed against N. gonorrhoeae strain ATCC 49226, one N. gonorrhoeae multiantigen sequence typing (NG-MAST) sequence type 1407 (ST1407) strain, F89, and AZT-HLR. For all strains, at 24 h, the results indicated that (i) FOS was bactericidal at 2× the MIC, but after >24 h, there was regrowth of bacteria; (ii) CRO was bactericidal at 0.5× the MIC; (iii) AZT was bactericidal at 4× the MIC; (iv) CRO plus AZT was less bactericidal than was CRO alone; (v) FOS plus AZT was bactericidal at 2× the MIC; and (vi) CRO plus AZT and FOS plus CRO were both bactericidal at 0.5× the MIC, but FOS plus CRO had more rapid effects. FOS is appealing for use in the management of N. gonorrhoeae infections because of its single and oral formulation. However, our results suggest it be used in combination with CRO. After the appropriate clinical trials are conducted, this strategy could be implemented for the treatment of infections due to isolates possessing resistance to CRO and/or AZT.

In vitro activity of fosfomycin tromethamine against extended spectrum beta-lactamase producing urinary tract bacteria.

To determine the in vitro activity of Fosfomycin tromethamine against extended spectrum beta-lactamase producing uropathogens. Experimental study. Department of Microbiology, Armed Forces Institute of Pathology, Rawalpindi, from October 2011 to October 2012. A total of 381 culture positive ESBL producing isolates from 2400 urine samples submitted over a period of one year were included in this study. Identification of isolates was done by standard biochemical profile of the organisms. The antimicrobial susceptibility of culture positive isolates was performed by disk diffusion method as recommended by Clinical Laboratory Standard Institute guidelines (CLSI). The antimicrobial activity of Fosfomycin to various isolates revealed that 93% of E. coli, 64% Klebsiella spp. 50% Proteus spp. 75% Enterobacter cloacae, 100% Citrobacter freundii, 100% Burkholderia spp. 100% Serratia spp. and 50% Stenotrophomonas maltophilia were susceptible to this chemical compound. Fosfomycin showed excellent effectiveness to most of the common ESBL producing bacteria such as E. coli, Klebsiella and Proteus spp.

Neue Aspekte zur Diagnose und Therapie der unkomplizierten Zystitis

Acute uncomplicated cystitis in women is one of the most frequently diagnosed bacterial infections. A clinically symptomatic urinary tract infection must be differentiated from asymptomatic bacteriuria, which is not considered an infection but more a colonization which as a rule should not be treated. Acute cystitis can also be caused by a low number of uropathogenic bacteria, especially Escherichia coli, which is often overlooked during routine bacteriological diagnostics. According to the guidelines the old oral antibiotics (e.g. fosfomycin tromethamine, nitrofurantoin and pivmecillinam) should be prescribed for antimicrobial therapy which are still effective against Escherichia coli in over 90% of cases. With new therapeutic concepts the elimination of bacteria is no longer the main aim but treatment of the inflammatory (over) reaction of the host. To establish the significance of these therapeutic options as compared to the standard antibiotic therapy, the results of the ongoing and planned phase 3 studies need to be awaited. Thus, reliable clinical measurement parameters for diagnostics and outcome are needed. The acute cystitis symptom score (ACSS) has now also been developed and validated in the German language. Because of its high reliability, validity and predictive value it can be used not only in daily practice but also for clinical studies for the diagnosis of acute uncomplicated cystitis in women.

Evaluation of antimicrobial combinations against colistin-resistant carbapenemase (KPC)-producing Klebsiella pneumoniae

Carbapenemase (KPC)-producing Klebsiella pneumoniae have been disseminating worldwide during the last decade, and currently, are recognized as the leading causes of severe nosocomial infections mainly in intensive care unit (ICU) patients. 1 Widespread hospital outbreaks due to KPC-producing K. pneumoniae (KPC-Kp) have been reported in the United States, Israel, and Greece. 2–4 The blaKPC genes encoding KPC enzymes reside on transferable plasmids and are often linked with other resistance determinants conferring resistance not only to carbapenems but also to all beta-lactam antibiotics, including beta-lactam/beta-lactamase inhibitor combinations, extended-spectrum cephalosporins, monobactams, and also to fluoroquinolones and some aminoglycosides. 5 Antibiotic treatment options for the management of the infections caused by these multidrug-resistant Enterobacteriaceae are often limited to colistin (COL), tigecycline (TIG), gentamicin (GM), amikacin, fosfomycin (FOS), and polymyxin B. 6 However, these agents when used as monotherapy in critically ill patients with severe infections due to KPCKp resulted in clinical failures with high mortality rates. 7 In contrast, combination antibiotic regimens have been proven more effective and are associated with improved survival rates in patients with bloodstream infections. 8,9 In this study, we investigated the in vitro activities of imipenem (IMI), meropenem (MER), doripenem (DORI), COL, TIG, FOS, rifampicin (RIF), and GM alone and in combination, against COL-resistant (CST-R) KPC-Kp isolated in our institution. The strains tested comprised 30 non-duplicate

Mutations in the primary sigma factor σA and termination factor rho that reduce susceptibility to cell wall antibiotics.

Combinations of glycopeptides and β-lactams exert synergistic antibacterial activity, but the evolutionary mechanisms driving resistance to both antibiotics remain largely unexplored. By repeated subculturing with increasing vancomycin (VAN) and cefuroxime (CEF) concentrations, we isolated an evolved strain of the model bacterium Bacillus subtilis with reduced susceptibility to both antibiotics. Whole-genome sequencing revealed point mutations in genes encoding the major σ factor of RNA polymerase (sigA), a cell shape-determining protein (mreB), and the ρ termination factor (rho). Genetic-reconstruction experiments demonstrated that the G-to-C substitution at position 336 encoded by sigA (sigA(G336C)), in the domain that recognizes the -35 promoter region, is sufficient to reduce susceptibility to VAN and works cooperatively with the rho(G56C) substitution to increase CEF resistance. Transcriptome analyses revealed that the sigA(G336C) substitution has wide-ranging effects, including elevated expression of the general stress σ factor (σ(B)) regulon, which is required for CEF resistance, and decreased expression of the glpTQ genes, which leads to fosfomycin (FOS) resistance. Our findings suggest that mutations in the core transcriptional machinery may facilitate the evolution of resistance to multiple cell wall antibiotics.

Efficacy and safety of oral fosfomycin for urinary tract infections (UTIs) in hospitalized patients

Efficacy and safety of oral fosfomycin for urinary tract infections (UTIs) in hospitalized patients

Fosfomycin for the treatment of resistant gram-negative bacterial infections. Insights from the Society of Infectious Diseases Pharmacists.

The antimicrobial agent fosfomycin was discovered in 1969, at a time when bacteria had not yet developed extended-spectrum β-lactamases or carbapenemases. Decades later, it is not uncommon for gram-negative organisms to be multidrug-resistant and even pan-resistant to available antibiotic regimens, leaving clinicians with few therapeutic alternatives. Because fosfomycin has been shown to retain activity against these virulent pathogens, there is renewed interest in its use as a therapeutic agent. Fosfomycin formulations including fosfomycin disodium and the newer tromethamine salt are less toxic than other alternatives and are attractive options for resistant gram-negative and gram-positive infections. Oral fosfomycin tromethamine is approved for urinary tract infections in the United States, and an intravenous formulation is also available outside of the United States for systemic disease. The bactericidal action of fosfomycin occurs at an earlier step in cell wall synthesis than that of β-lactam antibiotics. From an in vitro standpoint, fosfomycin generally has high activity against ESBL- and carbapenemase-producing Enterobacteriaceae; multidrug-resistant Pseudomonas aeruginosa susceptibility appears to be more dependent on the local antibiogram. Fosfomycin formulations have a large volume of distribution, penetrate biofilms, and concentrate in the urine. Both oral and intravenous fosfomycin formulations are effective for a wide range of gram-negative infections and disease severities; however, clinical studies are limited. Fosfomycin formulations are well-tolerated, and mild gastrointestinal distress is the most common adverse effect. The primary limitations of fosfomycin are the lack of established regimens for complicated infections and the lack of availability of the intravenous formulation in the United States. Further study of this promising agent seems warranted in the current climate of antibiotic resistance.

Trends and Antimicrobial Susceptibilities of Clinical Methicillin-Resistant &lt;i&gt;Staphylococcus aureus&lt;/i&gt; Isolates in Fukuoka University Chikushi Hospital 2008-2012

The aim of this study was to investigate the trends and antimicrobial susceptibilities of methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates from outpatients and inpatients from April 2008 to March 2013 at Fukuoka University Chikushi Hospital. The proportion of MRSA among the S. aureus isolates from outpatients was stable over the study period, however, that from inpatients gradually decreased (p=0.026). There was no difference in the susceptibility to anti-MRSA agents between MRSA isolates from outpatients and inpatients, however, the susceptibilities to fosfomycin (FOM), minocycline (MINO), levofloxacin, erythromycin and clindamycin were higher in MRSA isolates from outpatients than from inpatients (48.6% vs. 35.6%, 56.1% vs. 40.1%, 38.2% vs. 4.9%, 16.2% vs. 3.9% and 18.5% vs. 4.5%, respectively, p<0.01). The susceptibility to FOM improved in MRSA from both outpatients and inpatients over time (p<0.05). In MRSA isolates from inpatients, the susceptibility to FOM and gentamicin increased significantly over the study period (p=0.023 and p=0.010, respectively), while, the susceptibility to MINO tended to decrease (p=0.094). The rate of MRSA isolates which were susceptible to more than two non-β-lactam antibiotics was significantly higher in outpatients than in inpatients (24.5% vs. 47.4%, p<0.01), however, this rate increased significantly during the study period only in inpatients, with a rate of 12.2% in 2008 and 53.1% in 2012 (p<0.01). In conclusion, our findings indicate a changing antimicrobial susceptibility of MRSA isolates, especially to non-β-lactam antibiotics. The determination of the prevalence and antimicrobial susceptibilities of MRSA clinical isolates will help physicians to select the initial empirical treatment.