OBJECTIVE: To investigate the molecular mechanism underlying inherent fosfomycin resistance of Klebsiella pneumoniae (K. pneumoniae). METHODS: The draft genomic sequences of 14 clinical hypervirulent/hypermucoviscous K. pneumoniae (HvKP/ HmKP) isolates were obtained using the next-generation sequencing technology. The genomic sequences were analyzed using the Resistance Gene Identifier (RGI) software for predicting the resistome based on homology and SNP models in the Comprehensive Antibiotic Resistance Database (CARD) and for identification of the presence of phosphomycin resistancerelated genes uhpt and fosA and their mutations in the bacterial genomes. The results were verified by analyzing a total of 521 full-length genomic sequences of K. pneumonia strains obtained from GenBank. RESULTS: All the 14 clinical isolates of HvKP/ HmKP carried hexose phosphate transporter (UhpT) gene mutation, in which the glutamic acid was mutated to glutamine at 350aa (UhpT^E350Q mutation); the presence of fosA6 gene was detected in 12 (85.71%) of the isolates and fosA5 gene was detected in the other 2 (14.29%) isolates. Analysis of the genomic sequences of 521 K. pneumonia strains from GenBank showed that 508 (97.50%) strains carried UhpT^E350Q mutation, 439 (84.26%) strains harbored fosA6, and 80 (15.36%) strains harbored fosA5; 507 (97.31%) strains were found to have both UhpT^E350Q mutation and fosA6/5 genes in the genome. Only 12 (2.30%) strains carried fosA6/5 genes without UhpT^E350Q mutation; 1 (0.19%) strain had only UhpT^E350Q mutation without fosA6/5 genes, and another strain contained neither UhpT^E350Q mutation nor fosA6/5 genes. CONCLUSION UhpT^E350Q mutation with the presence of fosA6/5 genes are ubiquitous in K. pneumonia genomes, indicating a possible intrinsic mechanism of fosfomycin resistance in the bacterium to limit the use of fosfomycin against infections caused by K. pneumoniae, especially the multi-resistant HvKP/HmKP strains.
Fosfomycin ; Klebsiella pneumoniae ; Mutation ; Databases, Factual ; High-Throughput Nucleotide Sequencing

ObjectiveTo investigate the effects of fosfomycin tromethamine (FT) on the expressions of tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), and interleukin-6 (IL-6) in the prostate tissue of the rats with chronic bacterial prostatitis (CBP).

METHODSWe randomly divided 70 male SD rats into 7 groups of equal number: blank control, CBP model control, positive control, 14 d low-dose FT, 7 d low-dose FT, 14 d high-dose FT, and 7 d high-dose FT. The CBP model rats in the latter five groups were treated intragastrically with levofloxacin at 100 mg/kg/d for 30 days and FT at 200 mg/kg/d for 14 and 7 days and at 300 mg/kg/d for 14 and 7 days, respectively. Then we collected the prostate tissue from the animals for determination of the levels of TNF-α, IL-8 and IL-6 by ELISA.

RESULTSCompared with the blank controls, the CBP model rats showed significantly increased levels of TNF-α (［19.83 ± 6.1］ vs ［32.93 ± 6.21］ ng/g prot, P <0.01), IL-8 (［8.26 ± 0.52］ vs ［16.2 ± 2.84］ ng/g prot, P <0.01) and IL-6 (［1.55 ± 0.11］ vs ［2.51 ± 1.06］ ng/g prot, P <0.05) in the prostate tissue. In comparison with the CBP model controls, the levels of TNF-α and IL-8 were remarkably decreased in the groups of positive control (［20.54 ± 5.78］ ng/g prot, P <0.01; ［12.43 ± 4.02］ ng/g prot, P <0.05), 14 d low-dose FT (［21.95 ± 6.48］ ng/g prot, P <0.01; ［11.11 ± 2.86］ ng/g prot, P <0.01), 7 d low-dose FT (［23.8 ± 6.93］ ng/g prot, P <0.05; ［12.43 ± 4.02］ ng/g prot, P <0.05), 14 d high-dose FT (［19.97 ± 2.58］ ng/g prot, P <0.01; ［8.83 ± 1.32］ ng/g prot, P <0.01), and 7 d high-dose FT (［21.97 ± 3.38］ ng/g prot, P <0.01; ［12.68±1.97］ ng/g prot, P <0.05). No statistically significant differences were observed between the positive control and FT groups in the contents of TNF-α, IL-8 or IL-6 (P >0.05). The expression of IL-6 was markedly reduced in the 14 d high-dose FT group as compared with the model controls (［1.76 ± 0.46］ vs ［2.51 ± 1.06］ ng/g prot, P<0.05) but exhibited no significant difference between the CBP model control and the other groups (P >0.05).

CONCLUSIONSFosfomycin tromethamine inhibits the expressions of TNF-α, IL-8 and IL-6 in the prostate tissue, suppresses its inflammatory reaction, promotes the repair of damaged prostatic structure, and thus contributes to the treatment of chronic bacterial prostatitis in rats.

Animals ; Anti-Bacterial Agents ; pharmacology ; Bacterial Infections ; drug therapy ; microbiology ; Fosfomycin ; pharmacology ; Interleukin-6 ; metabolism ; Interleukin-8 ; metabolism ; Levofloxacin ; pharmacology ; Male ; Prostate ; drug effects ; metabolism ; Prostatitis ; drug therapy ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; metabolism

Carbapenem-resistant Enterobacteriaceae (CRE) are now spread worldwide. In Korea, the number of CRE isolation is rapidly increasing, and impending endemicity is a concern. To cope well with CRE, thorough infection control, such as active surveillance, early detection, strict contact precaution, cleaning the environment, and antibiotic stewardship is very important. Therapeutic options include polymyxin, tigecycline, fosfomycin or the combination of them with carbapenem, which is currently the mainstay of treatment. In addition, various combination regimens with new carbapenemase inhibitors such as avibactam, vaborbactam, or relebactam, and other classes of antimicrobials such as plazomicin and siderophore cephalosporin are in the process of evaluation.
Carbapenems ; Enterobacteriaceae* ; Fosfomycin ; Infection Control ; Korea ; Polymyxins

Carbapenem-resistance emerging in Gram-negative pathogens, such as Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, has become a major human health problem globally. The therapeutic options available for carbapenem-resistant pathogens are very limited. Antibiotics such as colistin, tigecycline, fosfomycin, and aminoglycosides are often the only ones that can be used to treat carbapenem-resistant pathogens. Carbapenem may still be an option in certain circumstances. The administration of combination therapy for carbapenem-resistant pathogens is controversial. This review presents the current knowledge of available antimicrobial therapeutic options for infections due to carbapenem-resistant pathogens in Korea.
Acinetobacter baumannii ; Aminoglycosides ; Anti-Bacterial Agents ; Colistin ; Drug Resistance ; Fosfomycin ; Gram-Negative Bacteria* ; Humans ; Klebsiella pneumoniae ; Korea ; Pseudomonas aeruginosa ; Treatment Outcome

The emergence of carbapenem-resistant Enterobacteriaceae (CRE) has become a major problem within the field of healthcare-associated infections worldwide in the last decade. The treatment of infections caused by CRE is challenging, and a consensus strategy has not been established. This article reviews old and new antibiotics for the treatment of CRE, and summarizes the overall mechanisms of resistance, epidemiology, diagnosis, and infection control of CRE. For CRE treatment, combination therapies may be preferred. Carbapenem still plays an important role in CRE treatment. Other existing treatment options against CRE include colistin, tigecycline, fosfomycin, and aminoglycosides. New therapeutic options include ceftazidime-avibactam, aztreonam-avibactam, plazomicin, eravacycline, meropenem-vaborbactam, and imipenem-cilastatin-relebactam. Few randomized controlled trials have been conducted, so more studies of new agents against CRE are needed. Because there are relatively few therapeutic options for CRE, adequate infection prevention measures and antimicrobial stewardship are required. Moreover, both personal and national preventive efforts are needed.
Aminoglycosides ; Anti-Bacterial Agents ; Colistin ; Consensus ; Diagnosis ; Enterobacteriaceae ; Epidemiology ; Fosfomycin ; Humans ; Infection Control ; Korea

BACKGROUND: The emergence of fosfomycin resistance and extended-spectrum β-lactamase (ESBL) genes is a serious threat to public health and a new challenge in shigellosis treatment. The purpose of this study was to identify fosfomycin resistance and characterize β-lactamase genes in fos-carrying isolates of Shigella flexneri from patients in China. METHODS: A total of 263 S. flexneri isolates were collected from 34 hospitals in the Anhui Province of China during September 2012-September 2015 and screened for fosA3, fosA, and fosC2 by PCR amplification and sequencing. The fos-carrying isolates were then screened for β-lactamase genes. The clonal relationships between fosA3-carrying isolates, the transmissibility of fosfomycin resistance, replicon types of plasmids carrying fosfomycin resistance genes and other associated resistance genes were investigated. RESULTS: Twenty-five of the 263 isolates (9.5%) showed resistance to fosfomycin, and 18 (6.8%) were positive for fosA3. None of the isolates was positive for fosA or fosC2. Seventeen of the isolates carrying fosA3 (94%) were CTX-M producers (seven CTX-M-55, five CTX-M-14, and five CTX-M-123), while three (16.7%) were TEM producers (TEM-1).Sixteen (88.9%) fosA3-carrying isolates exhibited multi-drug resistance. The replicon types of the 13 fosA3-carrying plasmids were IncF (n=13), IncHI2 (n=3), IncIl-Ir (n=2), and IncN (n=1). CONCLUSIONS: Our results indicated that fosA3 could spread through plasmids in S. flexneri isolates, along with the bla(CTX-M) and bla(TEM), which facilitate its quick dispersal. To the best of our knowledge, this is the first report of CTX-M-123-type ESBLs in S. flexneri isolates from patients in China.
China* ; Drug Resistance, Multiple ; Dysentery, Bacillary ; Fosfomycin* ; Humans ; Plasmids ; Polymerase Chain Reaction ; Public Health ; Replicon ; Shigella flexneri* ; Shigella*

BACKGROUND: Over the past two decades, enterococci have emerged as an important agent responsible for hospital acquired infection. Several virulence factors contribute to the adherence, colonization, evasion of the host immune response, and pathogenicity and severity of the infection. Enterococcus faecalis is the most common and virulent species causing infections in hospitalized patients. The aim of the present study was to examine the prevalence of genes encoding virulence factors and antimicrobial resistance patterns of E. faecalis strains isolated from hospitalized patients in Shiraz, south west of Iran. MATERIALS AND METHODS: A total of 51 E. faecalis isolates from the urine, blood, pleural fluid, peritoneal fluid, eye discharge, endotracheal tube (ETT) and transjugular intrahepatic portosystemic shunt (TIPS) specimens of patients were identified by phenotypic and genotypic methods. Antimicrobial sensitivity tests and detection of virulence factors were performed using standard methods. RESULTS: The efa and asa1 were the most frequently detected gene (100%) among the isolates, followed by esp (94.1%), ace (90.2%), gelE (80.4%), cylA (64.7%), and hyl (51%). More than half of the isolates (52.9%) were high level gentamicin resistant (HLGR). Vancomycin resistance was observed among 23 (45.1%) isolates. The lowest antimicrobial activity was related to erythromycin (3.9%), tetracycline (5.9%) and ciprofloxacin (9.8%). No isolate was found resistant to fosfomycin and linezolid. CONCLUSION: Our data indicated a high incidence of virulence factors among E. faecalis strains isolated from clinical samples. Colonization of drug resistant virulent isolates in hospital environment may lead to life threatening infection in hospitalized patients. Therefore, infection control procedures should be performed.
Ascitic Fluid ; Ciprofloxacin ; Colon ; Enterococcus faecalis* ; Enterococcus* ; Erythromycin ; Fosfomycin ; Gentamicins ; Humans ; Incidence* ; Infection Control ; Iran* ; Linezolid ; Portasystemic Shunt, Surgical ; Prevalence ; Tetracycline ; Vancomycin Resistance ; Virulence Factors* ; Virulence*

Objectives: The goal to prevent increasing antibiotic resistance in urologic procedures has a significant impact on the choice of preoperative antibiotic prophylaxis. The efficacy of an old-new antibioticfosfomycin in TRUS-guided prostate biopsy was also evaluated. Methods: Included were patients who underwent TRUS-guided prostate biopsy from August 1, 2015- July 31, 2016. Patients who satisfied the inclusion criteria were included. Patients were asked to take a single dose of 3g oral fosfomycin 1-3 hours prior to the procedure. Urinalysis was taken pre biopsy and post biopsy (at least 7-10 days). Occurrence of afebrile and febrile UTI were noted. Patients were informed of the signs and symptoms that need to be reported to the investigators. Results: There were 74 patients enrolled in the study. The mean average age of patients was 66.5(±7). Majority of patients were having moderate lower urinary tract symptoms (40.5%) followed by patients with indwelling foley catheter (31.1%). Seventeen percent of patients had concomitant diseases like diabetes mellitus, cystolithiasis, nephrolithiasis, hypertension, etc. Pre biopsy, 51.4% of patients had asymptomatic urinary tract infection and 35% of these patients showed resolution of UTI post biopsy. The incidence of febrile UTI was 4%, 3.8% of patients with UTI pre biopsy and 50% of patients without UTI pre biopsy. Finally, the presence of afebrile and febrile UTI pre and post biopsy was statistically significant at 5% level of significance. Conclusion Single dose oral fosfomycin as prophylactic antibiotic in TRUS- guided prostate biopsy can be an alternative to reduce the rate of fluoroquinolone- resistant infections.
Fosfomycin ; Urinary Tract Infections

INTRODUCTIONIncreasing resistance in Escherichia coli and Klebsiella pneumoniae to firstline antibiotics makes therapeutic options for urinary tract infections (UTIs) challenging. This study investigated the in vitro efficacies of 6 antibiotics against multidrug resistant (MDR) uropathogens.

MATERIALS AND METHODSMinimum inhibitory concentrations to ceftibuten, cefpodoxime, fosfomycin, mecillinam, temocillin, and trimethoprim were determined against 155 MDR-isolates of E. coli and K. pneumoniae. The presence of extended-spectrum beta-lactamases (ESBL) and plasmid-borne AmpC enzymes was determined by phenotypic testing with genotyping performed by multiplex polymerase chain reaction.

RESULTSTemocillin demonstrated highest susceptibility rates for both E. coli (95%) and K. pneumoniae (95%) when breakpoints for uncomplicated UTIs were applied; however, temocillin susceptibility was substantially lower when "systemic infection" breakpoints were used. Fosfomycin demonstrated the best in vitro efficacy of the orally available agents, with 78% and 69% of E. coli and K. pneumoniae isolates susceptible, respectively. The next most effective antibiotics were ceftibuten (45%) and mecillinam (32%). ESBL and ampC genes were present in 47 (30%) and 59 (38%) isolates.

CONCLUSIONThis study demonstrated few oral therapeutic options for MDR-uropathogens, with fosfomycin demonstrating the best in vitro activity.

Amdinocillin ; pharmacology ; Anti-Bacterial Agents ; pharmacology ; Bacterial Proteins ; genetics ; Ceftizoxime ; analogs & derivatives ; pharmacology ; Cephalosporins ; pharmacology ; Drug Resistance, Multiple, Bacterial ; genetics ; Escherichia coli ; drug effects ; genetics ; Escherichia coli Infections ; microbiology ; Fosfomycin ; pharmacology ; Genotype ; Humans ; In Vitro Techniques ; Klebsiella Infections ; microbiology ; Klebsiella pneumoniae ; drug effects ; genetics ; Microbial Sensitivity Tests ; Multiplex Polymerase Chain Reaction ; Penicillins ; pharmacology ; Singapore ; Trimethoprim ; pharmacology ; Urinary Tract Infections ; microbiology ; beta-Lactamases ; genetics

Fosfomycin (FOM) is an antibiotic with a small relative molecular weight (138.1) and a long half-life, and has a unique chemical structure and antibacterial mechanisms. It exerts a bactericidal activity by inhibiting the early synthesis of bacterial cell walls. It is also a broad-spectrum antibiotic with a good drug tolerance and compliance and a low pressure to bacterial resistance, but no cross-resistance with other antibiotics. Recent studies show the effectiveness of FOM in the treatment of acute uncomplicated urinary tract infections and urogenital tract infections as well, such as prostatitis and epididymitis. This review focuses on the clinical application of FOM in the treatment of infectious diseases of the urogenital tract.
Anti-Bacterial Agents ; therapeutic use ; Epididymitis ; drug therapy ; Fosfomycin ; therapeutic use ; Humans ; Male ; Male Urogenital Diseases ; drug therapy ; Prostatitis ; drug therapy ; Urinary Tract Infections ; drug therapy