Fosfomycin Resistance Rate Research Articles

Healthcare-associated Staphylococcus aureus infections in children in Turkey: A six-year retrospective, single-center study

Objective: To describe clinical and epidemiological characteristics, antimicrobial susceptibility and mortality-associated factors of healthcare-associated infections (HCAIs) caused by Staphylococcus (S.) aureus in children. Methods: We conducted a retrospective, single-centre study of pediatric HCAIs caused by S. aureus from a tertiary care hospital in Turkey between February 2014 and December 2019. The clinical and epidemiological characteristics and antimicrobial susceptibility of the methicillin-susceptible and methicillin-resistant S. aureus (MSSA and MRSA) isolates was evaluated. Results: A total of 310 pediatric patients were examined. Overall, 225 (72.6%) isolates were MSSA and 85 (27.4%) were MRSA. All S. aureus isolates were susceptible to teicoplanin, vancomycin, linezolid, tigecycline, mupirocin, and daptomycin. Penicillin resistance rates were high (89.0%), while fosfomycin, gentamicin, and clindamycin resistance rates were low (1.3%, 1.0%, and 2.3%, respectively). Except susceptibility to fosfomycin, which was significantly lower in 2014 compared to 2018 and 2019, no significant difference was found in the antimicrobial susceptibility of S. aureus isolates between the years. Baseline characteristics and mortality rate were similar comparing MRSA and MSSA causing HCAIs. The mortality rate of HCAIs caused by S. aureus was 6.5% (20 patients). Malignancy was an independent risk factor associated with mortality in the multivariate analysis (OR 5.446, 95% CI 1.573-18.849). Conclusions: Our findings demonstrate that MSSA remained the most causative agent of HCAIs caused by S. aureus. The mortality rate was 6.5%, the antibiotic resistance rate was quite high for penicillin and diagnosis of malignancy was the main risk factor for increasing mortality in children. These findings could help improve the management of HCAIs caused by S. aureus in children.

Investigation of O25b-ST131 Clone Frequency and Presence of Carbapenem and Fosfomycin Resistance Genes in Escherichia coli Isolates: First Detection of fosA3 from Escherichia coli O25bSTf131 Clone from Türkiye

Escherichia coli ST131 clone was first reported in 2008 and defined as a 'high-risk pandemic clone'. This clone plays a critical role in the spread of antimicrobial resistance worldwide. It was reported in many studies that the E.coli ST131 clone is widespread worldwide and can carry virulence and antibiotic resistance genes. E.coli ST131 clone is associated with a fluoroquinolone and broad-spectrum cephalosporin resistance. The agents used in the treatment of infections caused by the E.coli ST131 clone are limited. For this reason, monitoring the resistance status of these limited agents is crucial. In this study, we aimed to investigate the prevalence of the O25b-ST131 clone, and the presence of carbapenem and fosfomycin resistance genes in fluoroquinolone-resistant E.coli isolates isolated from mid-stream urine samples. For the detection of the O25b-ST131 clone in fluoroquinolone-resistant E.coli isolates, amplification was performed with primers O25pabBspe-F and O25pabBspe-R. For the determination of resistance genes, carbapenem resistance genes blaNDM, blaVIM, blaKPC, blaIMP, and blaOXA-48 in carbapenem resistant isolates and plasmid-mediated fosfomycin resistance genes fosA3 and fosC2 in fosfomycin resistant isolates were investigated by multiplex PCR method. According to PCR results, the prevalence of E.coli O25b-ST131 isolates was 51.2%. Carbapenem resistance rate was 3.41%, and fosfomycin resistance rate was 3.41% in fluoroquinolone-resistant E.coli isolates. Carbapenem and fosfomycin resistance rates in E.coli O25bST131 isolates were determined as 0.83% and 2.5%, respectively. At least one of the carbapenem-resistance genes (blaNDM and/or blaOXA-48) was detected in six of the eight carbapenem-resistant isolates. Fosfomycin resistance gene fosA3 was seen in four of eight fosfomycin-resistant isolates. fosC2 gene was not detected in any of the isolates. In addition, the plasmid-mediated fosfomycin resistance gene fosA3 was detected in an E.coli O25b-ST131 isolate, and this result was confirmed by sequence analysis. To the best of our knowledge, this is the second report about fosA3 positivity in E.coli ST131 isolates from the world and the first reported from Europe and Türkiye. As a result, approximately half of the fluoroquinolone-resistant E.coli isolates were identified as E.coli ST131 clones. Despite the high rate of this clone, the carbapenem and fosfomycin resistance rates are still relatively low, which is pleasing for the future of treatment. However, it should not be forgotten that resistance rates and the prevalence of resistance genes should be constantly monitored.

Up-regulation of resident chromosomal fosB gene expression: a novel mechanism of acquired fosfomycin resistance in MRSA.

This study investigated fosfomycin susceptibility and mechanisms of resistance in a collection of 99 Staphylococcus aureus isolated from cases of hospital-acquired pneumonia, previously collected from a multicentre survey carried out in Italy. Fosfomycin susceptibility was tested by reference agar dilution. Bioinformatic and gene expression analysis, mutant selection experiments and WGS were executed to characterize fosfomycin resistance mechanisms. Fosfomycin resistance rates were 0% (0 of 35) among MSSA and 22% (14 of 64) among MRSA, with no evidence of clonal expansion. Resistance mechanisms were putatively identified in 8 of the 14 resistant strains, including: (i) chromosomal mutations causing loss of function of the UhpT transporter; (ii) overexpression of the gene encoding the Tet38 efflux pump; and (iii) overexpression of a fosB gene encoding a fosfomycin-inactivating enzyme, which was found to be resident in the chromosome of several S. aureus lineages but not always associated with fosfomycin resistance. The latter mechanism, which had not been previously described and was confirmed by results of in vitro mutant selection experiments, was associated in two cases with transposition of an IS1182 element upstream of the chromosomal fosB gene, apparently providing an additional promoter. This study showed that some S. aureus clonal lineages carry a resident chromosomal fosB gene and can evolve to fosfomycin resistance by overexpression of this gene.

Prevalence and genetic characteristics of fosB-positive Staphylococcus aureus in duck farms in Guangdong, China in 2020.

To investigate the epidemiology of fosB-positive Staphylococcus aureus in waterfowl farms in the Pearl River tributaries in Guangdong Province, China in 2020. A total of 63 S. aureus were recovered from 315 samples collected from six duck farms and one goose farm. PFGE, WGS and analysis were performed on 19 fosB-positive S. aureus. The fosfomycin resistance rate of the strains was as high as 52.4% (33/63), and 30.1% (19/63) of the strains carried fosB. Resistance gene prediction results showed that duck farm environment-derived strains contained the oxazolidinone drug resistance gene optrA. All fosB-positive S. aureus were MRSA and most of them were MDR, mainly ST9-t899 and ST164-t899. PFGE showed that fosB-positive S. aureus from humans and ducks could be clustered into the same clade. In addition, core-genome SNP analysis showed that clonal transmission of S. aureus occurred between humans and water. Pan-genome analysis showed that S. aureus had an open pangenome. The fosB gene was located on 2610-2615 bp plasmids, which all contained a broad host-range plasmid replication protein family 13. Small plasmids carrying the fosB gene could be found in different multilocus STs of S. aureus. This study indicated that duck farms in Guangdong, China could be an important reservoir of fosB-positive S. aureus. The spread of drug-resistant bacteria in waterfowl farms requires further monitoring.

Prevalence of Fosfomycin Resistance Among Enterobacterales Isolates in A Tertiary Care Hospital from Turkey.

Urinary tract infections are one of the most common causes of morbidity around the world. Fosfomycin is a specific broad-spectrum antibiotic used to treat these infections. However, in recent years, many studies have reported increased fosfomycin resistance in Enterobacterales isolates. Therefore, this study aimed to evaluate the distribution of pathogens isolated from urine samples and find the fosfomycin resistance rates over nine years (2012-2020). A total of 18,884 uropathogenic Enterobacterales isolates were included in the study between 2012 and 2020. The isolates were identified by VITEK® 2 Compact (bioMérieux, Marcy l'Etoile, France), and the antimicrobial susceptibilities of the isolates were also evaluated using the VITEK® MS automated system (bioMérieux, Marcy l'Etoile, France). Escherichia coli (64.04%) was the most common bacteria among Enterobacterales. Fosfomycin resistance rates were 1.98%, 21.64%, and 10.36% in E. coli, Klebsiella pneumoniae, and all bacteria, respectively. The 34.97% of isolates were extended-spectrum β-lactamase (ESBL)-producing Enterobacterales, and the fosfomycin resistance rate was 13.08% in these isolates. In addition, fosfomycin resistance rates were found as 3.06% and 23.84% in ESBL-producing E. coli and ESBL-producing K. pneumoniae, respectively. Fosfomycin seems a good option for effectively treating UTIs caused by E. coli. On the other hand, we found that fosfomycin resistance tends to increase over the years. Therefore, we recommend further studies to evaluate fosfomycin resistance.

Characteristics of fosA-carrying plasmids in E. coli and Klebsiella spp. isolates originating from food and environmental samples.

Fosfomycin is an important antibiotic for the treatment of MDR Enterobacteriaceae infections. High susceptibility rates are, however, threatened by the spread of plasmids encoding fosfomycin-modifying enzymes. In this study, we sought to characterize the genetic context of fosA in plasmids from Escherichia coli and Klebsiella spp. isolates recovered from food, wastewater and surface water in Switzerland. E. coli and Klebsiella spp. isolates collected between 2012 and 2019 in Switzerland were screened for fosfomycin resistance. Presence of fosA was verified by PCR and sodium phosphonoformate (PPF) disc potentiation testing, and transferability was tested using conjugation assays. Whole-genome sequences including complete fosA-containing plasmids were determined using long- and short-read sequencing. In 11 E. coli and two Klebsiella spp. isolates, high-level fosfomycin resistance was mediated by plasmids containing fosA3 (n = 12) or fosA8 (n = 1). Four isolates harboured a near-identical 45 kb IncN plasmid with fosA3, while replicon types varied in the remaining plasmids. The fosA genes were typically embedded in IS26-bounded transposition units and frequently located in the proximity of blaCTX-M transposition units. Although fosfomycin resistance rates are currently low, the presence of fosA-encoding plasmids circulating in the Enterobacteriaceae population suggests that fosfomycin resistance may rapidly spread upon increased selection pressure. Transposition mobility of fosA and co-location on plasmids with other resistance genes may further promote its dissemination.

In vitro fosfomycin study on concordance of susceptibility testing methods against ESBL and carbapenem-resistant Enterobacteriaceae

ObjectivesThe increasing emergence and diffusion of multidrug-resistant (MDR) pathogenic bacteria, both in hospital and community settings, is inducing clinicians to reconsider old antibiotics, such as fosfomycin, to overcome the difficulties posed by these microorganisms. Recent studies have reported good in vitro activity of fosfomycin against extended spectrum ß-lactamases (ESBL) and carbapenem-resistant Enterobacteriaceae. The aim of this study was to assess thein vitro activity of fosfomycin by different methods against 120 clinical MDR isolates. MethodsFosfomycin minimum inhibitory concentrations were determined using the agar dilution reference method (AD), gradient test (GT), broth microdilution method (BMD), according to CLSI recommendations, and automated systems (VITEK 2 and BD Phoenix) against 85 carbapenem-resistant Klebsiella pneumoniae and 35 ESBL-producing Escherichia coli. Agreement and discrepancies between the evaluated methods and the reference method were calculated. ResultsFosfomycin showed very good activity against ESBL-producing E. coli (88.6%). Excellent agreement (100%) between the three (AD, BMD and GT) susceptibility methods was found for E. coli. No major errors were observed. The fosfomycin resistance rate ranged from 24% (KPC-producing) to 100% (NDM-OXA-48 co-producing) K. pneumoniae. For all carbapenem-resistant K. pneumoniae strains, categorical agreement was >90% for all methods except for VITEK 2, which was 84%. ConclusionsWhen ESBL E. coli isolates are found to be susceptible to fosfomycin with automated systems, it is not necessary to verify these results with the AD reference method; while for resistant strains, the GT can be used. In cases of KPC K. pneumoniae resistant to fosfomycin, the AD method is the only reference method.

Prevalence of fosfomycin resistance and gene mutations in clinical isolates of methicillin-resistant Staphylococcus aureus

BackgroundFosfomycin exhibits excellent in vitro activity against multidrug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Increasing fosfomycin resistance among clinical MRSA isolates was reported previously, but little is known about the relative abundance of Fosfomycin resistance genes in MRSA isolates circulating in Taiwan.MethodsAll MRSA isolates, collected in 2002 and 2012 by the Taiwan Surveillance of Antimicrobial Resistance (TSAR) program, were used in this study. Susceptibility to various antimicrobial agents, including fosfomycin, was determined by broth microdilution. Genetic determinants of fosfomycin resistance, including fosB carriage and murA, glpT and uhpT mutations, were investigated using PCR and sequencing of amplicons. Staphylococcal protein A (spa) typing was also performed to determine the genetic relatedness of MRSA isolates.ResultsA total of 969 MRSA strains, 495 in the year 2002 and 474 in the year 2012, were analyzed. The overall in vitro susceptibility was 8.2% to erythromycin, 18.0% to clindamycin, 29.0% to tetracycline, 44.6% to ciprofloxacin, 57.5% to trimethoprim/sulfamethoxazole, 86.9% to rifampicin, 92.9% to fosfomycin and 100% to linezolid and vancomycin. A significant increase in the fosfomycin resistance rate was observed from 3.4% in 2002 to 11.0% in 2012. Of 68 fosfomycin-resistant MRSA isolates, several genetic backgrounds probably contributing to fosfomycin resistance were identified. Twelve isolates harbored the fosB gene, and various mutations in murA, uhpT, and glpT genes were noted in 11, 59, and 66 isolates, respectively. The most prevalent gene mutations were found in the combination of uhpT and glpT genes (58 isolates). The vast majority of the fosfomycin-resistant MRSA isolates belonged to spa type t002.ConclusionsAn increased fosfomycin resistance rate of MRSA isolates was observed in our present study, mostly due to mutations in the glpT and uhpT genes. Clonal spread probably contributed to the increased fosfomycin resistance.

Fosfomycin Resistance in Escherichia coli Isolates from South Korea and in vitro Activity of Fosfomycin Alone and in Combination with Other Antibiotics.

We investigated fosfomycin susceptibility in Escherichia coli clinical isolates from South Korea, including community-onset, hospital-onset, and long-term care facility (LTCF)-onset isolates. The resistance mechanisms and genotypes of fosfomycin-resistant isolates were also identified. Finally, the in vitro efficacy of combinations of fosfomycin with other antibiotics were examined in susceptible or extended spectrum β-lactamase (ESBL)-producing E. coli isolates. The fosfomycin resistance rate was 6.7% and was significantly higher in LTCF-onset isolates than community-onset and hospital-onset isolates. Twenty-one sequence types (STs) were identified among 19 fosfomycin-resistant E. coli isolates, showing diverse genotypes. fosA3 was found in only two isolates, and diverse genetic variations were identified in three genes associated with fosfomycin resistance, namely, GlpT, UhpT, and MurA. Some fosfomycin-resistant E. coli isolates carried no mutations. In vitro time-kill assays showed that fosfomycin alone did not exhibit an excellent killing activity, compared with ciprofloxacin in susceptible isolates and with ertapenem in ESBL producers. However, combining fosfomycin with cefixime or piperacillin-tazobactam eradicated susceptible or ESBL-producing isolates, respectively, even with 0.5× minimum inhibitory concentrations. Overall, we found a relatively high fosfomycin resistance rate in E. coli isolates from South Korea. Based on their genotypes and resistance mechanisms, most of the fosfomycin-resistant E. coli isolates might occur independently. Antibiotic combinations with fosfomycin could be a suitable therapeutic option for infections caused by E. coli isolates.

Sensitivity of extended spectrum of β-lactamase producing Escherichia coli and Klebsiella species to Fosfomycin.

To investigate extended spectrum β-lactamase production and Fosfomycin resistance rates of Escherichia coli and Klebsiella species isolates from patients' urine culture. Chromogenic agar was used to identify Escherichia coli and Klebsiella species strains. All antibiogram processing was carried out on a fully automated VITEK 2 identification and antibiogram system. The results obtained between January 2015 and December 2018 were retrospectively screened. Escherichia coli and Klebsiella species were isolated from total 2868 urine cultures. Thus, 844 (34.9%) of 2418 Escherichia coli and 305 (67.8%) of 450 Klebsiella species producted ESBL. Sensitivity rate of ESBL producing Escherichia coli to Fosfomycin was 96.5%, and 98.8% for ESBL negative Escherichia coli. Sensitivity rate of ESBL producing Klebsiella pneumoniae to Fosfomycin was 70.5%, and 53.1% for ESBL negative Klebsiella pneumoniae. None of the three ESBL producing Klebsiella oxytoca strains were found to be resistant to Fosfomycin, though five of 15 ESBL negative strains were found to be resistant to Fosfomycin. Taking into consideration the advantages of low resistant rate, it is concluded that Fosfomycin may be a good alternative for first step empirical treatment in urinary tract infections, especially in Escherichia coli positive cases. However, the rate of resistance identified in Klebsiella strains informs the onset of resistance problems in Fosfomycin.

611. Fosfomycin Resistance of Multidrug-Resistant Escherichia coli and Mechanisms of Fosfomycin Resistance

BackgroundFosfomycin is one of the antibiotics that may be a candidate for the next-generation antimicrobial agents againt multidrug-resistant bacteria. To date, it is known that the resistance rate is not high for Escherichia coli. However, it is necessary to update the fosfomycin resistance rates in E. coli according to the studies that extended spectrum β-lactamase (ESBL) producing E. coli strains are highly resistance to fosfomycin. We evaluated the resistance rate of fosfomycin, the resistant mechanism of fosfomycin in E. coli, and the activity of fosfomycin against susceptible and resistant strains of E. coli.MethodsA total of 283 clinical isolates was collected from patients with Escherichia coli species during the period of January 2018 to June 2018, in three tertiary hospitals of Republic of Korea. In vitro antimicrobial susceptibility tests were performed in all E. coli isolates using the broth microdilution method according to the Clinical and Laboratory Standard Institute (CLSI). Multilocus sequence typing (MLST) of the Oxford scheme was conducted to determine the genotypes of E. coli isolated. Fosfomycin genes were investigated for all fosfomycin-resistant E. coli strains.ResultsThe overall resistance rate to fosfomycin was 10.2%, compared with 53.4%, 46.3%, 41.3%, 31.1%, 10.6%, 2.5%, and 2.1% for ciprofloxacin, cefixime, cefepime, piperacillin/tazobactam, colistin, ertapenem, and amikacin, respectively. The 29 fosfomycin-resistant isolates did not show a clonal pattern on the phylogenetic tree. MurA and glp genes were identified in all strains. FosA3 were identified in two strains and uhp gene were identified in 4 strains. In time-kill curve studies, fosfomycin was more bactericidal than cefixime against all sensitive E. coli strain. Morever, fosfomycin was more bactericidal than piperacillin/tazobactam against ESBL-producing E. coli strain.ConclusionThe resistant rate of fosfomycin to E. coli is still low. Fosfomycin was active against E. coli including ESBL producing strains.Disclosures All authors: No reported disclosures.

2396. Fosfomycin Resistance Among Carbapenem-Resistant Enterobacteriaceae Clinical Isolates in Connecticut, 2017

BackgroundFosfomycin is among the limited treatment options for carbapenem-resistant Enterobacteriaceae (CRE) infections. Despite its use, prevalence of fosfomycin resistance among CRE in the United States is largely unknown. In 2017, submission of Enterobacteriaceae isolates resistant to ≥1 carbapenem became mandated in Connecticut (CT), allowing further characterization at the state public health laboratory (SPHL). We analyzed fosfomycin resistance among CRE isolates in CT during 2017, and explored demographic and molecular factors potentially associated with resistance.MethodsAfter confirming carbapenem resistance, SPHL tests fosfomycin susceptibility using disk diffusion. For each CRE patient, the isolate most resistant to fosfomycin was included in this analysis. We used the Clinical and Laboratory Standards Institute (CLSI) fosfomycin breakpoint for Escherichia coli (nonsusceptible <16 mm) to evaluate associations among fosfomycin resistance and demographic factors, carbapenemase activity (modified carbapenem inactivation method, mCIM) and carbapenemase genes tested at SPHL. We report fosfomycin resistance rate by European Committee on Antimicrobial Susceptibility Testing (EUCAST, resistance <24 mm for E. coli) criteria for comparison.ResultsAmong 138 CRE isolates, 39 (28.3%) were fosfomycin nonsusceptible by CLSI criteria. Most nonsusceptible isolates were Enterobacter cloacae (18; 46.2%) or Klebsiella pneumoniae (17; 43.6%). Isolates from patients aged ≥65 years were more likely to be fosfomycin nonsusceptible than isolates from patients aged <65 years (χ2 = 3.8; P = 0.050). No other demographic characteristics were statistically significant. Of fosfomycin nonsusceptible isolates, 12 (30.8%) produced a carbapenemase (mCIM-positive), and 9 (23.1%) had the blaKPC gene. By EUCAST criteria, 96 (69.6%) CRE isolates were fosfomycin resistant.ConclusionA substantial proportion of CRE in CT during 2017 were fosfomycin nonsusceptible, and nonsusceptibility was associated with older patient age. Fosfomycin resistance risk factors and molecular mechanisms need further exploration. The substantial proportion of isolates with results falling between CLSI and EUCAST breakpoints warrants evaluation.Disclosures All authors: No reported disclosures.

Prevalence of Fosfomycin Resistance in Methicillin-Resistant Staphylococcus aureus Isolated from Patients in a University Hospital in China from 2013 to 2015.

In this study, we investigated the fosfomycin susceptibility rates among different methicillin-resistant Staphylococcus aureus (MRSA) clones. A total of 293 MRSA isolates obtained from Sir Run Run Shaw hospital during 2013-2015 were tested for fosfomycin susceptibility. The overall fosfomycin resistance rate among these MRSA isolates was 53.2%. Although 91.9% of the ST5 MRSA isolates (MIC50>1,024 mg/L) were resistant to fosfomycin, no fosfomycin-resistant isolate was found among the 69 ST59 MRSA isolates (MIC50/90, 0.5/4 mg/L). The fosfomycin resistance rate among the MRSA isolates recovered from skin and soft tissue infections was 19.1%, which was lower than the rates detected among MRSA isolates from other types of invasive infections. The fosfomycin resistance rate in community-onset MRSA was 30.2%, which was lower than that detected in healthcare-associated MRSA of 70.7%. One MRSA isolate had the fosB7 gene, whereas most (127/156) of the fosfomycin-resistant MRSA isolates had deletions in glpT genes. These findings highlight the importance of monitoring the fosfomycin susceptibility in MRSA isolates for epidemiological purposes.

Complete Sequence of a Novel IncR-F33:A–:B– Plasmid, pKP1034, Harboring fosA3 , bla KPC-2 , bla CTX-M-65 , bla SHV-12 , and rmtB from an Epidemic Klebsiella pneumoniae Sequence Type 11 Strain in China

A high fosfomycin resistance rate was observed in Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-KP) in our previous study, but little is known about its mechanisms. In this study, we explored the prevalence of plasmid-mediated fosfomycin resistance determinants among fosfomycin-resistant KPC-KP strains from a Chinese university hospital and determined the complete sequence of a novel fosA3-carrying plasmid isolated from an epidemic K. pneumoniae sequence type (ST) 11 strain. A total of 97 KPC-KP strains were studied, of which 57 (58.8%) were resistant to fosfomycin, including 44 (45.4%) harboring fosA3 and 1 harboring fosA. All fosA3-positive strains belonged to the dominant ST11-pulse type (PT) A clone according to multilocus sequence typing and pulsed-field gel electrophoresis, suggesting clonal dissemination. The fosA-positive isolate belonged to ST11-PTE. The fosA3-carrying plasmid pKP1034 is 136,848 bp in length and is not self-transmissible. It is a multireplicon plasmid belonging to IncR-F33:A-: B-. Besides fosA3, a variety of other resistance determinants, including blaKPC-2, rmtB, blaCTX-M-65, and blaSHV-12, are identified in pKP1034, which would allow for coselection of fosA3 by most β-lactams and/or aminoglycosides and facilitate its dissemination despite limited use of fosfomycin in China. Detailed comparisons with related plasmids revealed that pKP1034 is highly mosaic and might have evolved from alarming recombination of the blaKPC-2-carrying plasmid pKPC-LK30 from Taiwan and the epidemic fosA3-carrying plasmid pHN7A8 from mainland China.

Dissemination of a clone carrying a fosA3-harbouring plasmid mediates high fosfomycin resistance rate of KPC-producing Klebsiella pneumoniae in China

Fosfomycin has been proposed as an adjunct to other active agents for treating KPC-producing Klebsiella pneumoniae infections. This study aimed to investigate the prevalence of fosfomycin resistance and plasmid-mediated resistance determinants among KPC-producing K. pneumoniae isolates from clinical samples in China. In total, 278 KPC-producing and 80 extended-spectrum β-lactamase (ESBL)-producing (non-KPC-producing) clinical K. pneumoniae isolates were collected in 12 hospitals from 2010 to 2013. Fosfomycin susceptibility testing was carried out using the agar dilution method. Phylogenetic clonal patterns were revealed by pulsed-field gel electrophoresis (PFGE). Isolates were screened for plasmid-mediated fosfomycin resistance genes (fosA, fosA3 and fosC2) by PCR amplification. A plasmid was completely sequenced by next-generation sequencing. The fosfomycin resistance rate in KPC-producers (60.8%; 169/278) was significantly higher than in ESBL-producers (12.5%; 10/80). In addition, 94 KPC-producing isolates were positive for fosA3 and most of them were clonally related. A 23939-bp plasmid (pFOS18) co-harbouring fosA3 and blaKPC-2 was completely sequenced, revealing that the fosA3 gene was flanked by two copies of IS26; however, blaKPC-2 was located on a Tn3–Tn4401 integration structure. Although the fosA3 and blaKPC-2 genes are located on different transposon systems, they are able to spread together worldwide through plasmid transfer. Dissemination of the clone carrying the fosA3-harbouring plasmid mediates the high fosfomycin resistance rate of KPC-producing K. pneumoniae in China. Fosfomycin as an alternative option for treating infections caused by KPC-producing K. pneumoniae should not be recommended in hospitals in which fosfomycin-resistant clonal dissemination is emerging.

Helicobacter pylori susceptibility to fosfomycin, rifampin, and 5 usual antibiotics for H. pylori eradication

The aim of the study was to assess Helicobacter pylori resistance to fosfomycin, rifampin, and 5 other antibiotics. Susceptibility of 50 consecutive H. pylori strains was tested by E test and breakpoint susceptibility testing method. Overall and primary resistance rates were amoxicillin 2.0 and 0%, metronidazole 34.0 and 31.2%, tetracycline 2.0 and 2.1%, levofloxacin 18.0 and 16.7%, rifampin 12.0 and 10.4%, and fosfomycin 8.3 and 6.5%, respectively. Clarithromycin resistance was >20.0% in all patients (22.0%) and in untreated subjects (20.8%). Rifampin resistance was higher than those usually reported. Quinolone resistance rose from 2005–2007 (8.7%) to 2012–2013 (18.0%). High double/multidrug resistance rates (overall 22.0% and 20.0% in untreated adults), including a 5-fold resistance, were found. In conclusion, fosfomycin and rifampin resistance rates were much lower than that of metronidazole and slightly lower than those of clarithromycin and levofloxacin. MICs90 of both fosfomycin and rifampin were lower than those of clarithromycin and metronidazole. Thus, in countries of high/increasing H. pylori resistance and multidrug resistance, both rifamycins and fosfomycin could be helpful in rescue regimens.

Evaluation of the in vitro activity of fosfomycin tromethamine against Gram-negative bacterial strains recovered from community- and hospital-acquired urinary tract infections in Turkey

The aim of this study was to evaluate the in vitro activities of antimicrobial agents including fosfomycin tromethamine against Gram-negative isolates recovered from urine samples. A total of 2334 strains (1562 Escherichia coli, 509 Klebsiella spp, 85 Proteus spp, 75 Pseudomonas spp, 45 Enterobacter spp, 37 Acinetobacter baumannii, 8 Citrobacter spp, 7 Morganella morganii, and 6 Serratia spp) were identified by VITEK 2 during the study period, November 2008 to June 2012. Antimicrobial susceptibilities of the strains were also evaluated using the Kirby-Bauer disk diffusion method, in accordance with the Clinical and Laboratory Standards Institute guidelines. Overall, 2160 (92.5%) of the isolates tested were susceptible to fosfomycin tromethamine. Higher resistance rates were observed among inpatients compared to outpatients. Resistance rates by strain were: 2.0% for E. coli, 4.4% for Enterobacter spp, 6.9% for Klebsiella spp, 9.4% for Proteus spp, 48.6% for A. baumannii, 56.0% for Pseudomonas spp, and 100% for Morganella morganii. All Serratia spp and Citrobacter spp strains were susceptible. Extended-spectrum beta-lactamase (ESBL)-producing isolates displayed higher fosfomycin resistance rates than negative strains (19.2% vs. 2.9%). The highest in vitro activity was detected for amikacin, piperacillin-tazobactam, and imipenem for all strains including ESBL-producers. Regardless of ESBL production, the excellent activity of fosfomycin against E. coli, Enterobacter spp, Serratia spp, and Citrobacter spp, indicates that the drug is a valuable therapeutic option for urinary tract infections, even those with co-trimoxazole- and ciprofloxacin-resistant isolates, but not in ESBL-producing Klebsiella spp, Pseudomonas spp, A. baumannii, and Proteus spp. Further studies should be carried out to determine the in vivo drug activity among Enterobacteriaceae other than E. coli.

Introducing Fosfomycin for Surgical Prophylaxis-Emergence of Resistance in Aerobic Faecal Gram-negative Bacteria of In-patients, but Not Among Strains Causing Infection after Elective Colorectal Procedures

Fosfomycin was introduced for prophylaxis of surgical infection at 6 centres in a randomized study of elective colorectal operations (fosfomycin/metronidazole, n = 251 vs doxycycline/metronidazole, n = 237). Preoperative faecal specimens from the patients showed a relatively high prevalence rate of doxycycline-resistant bacteria (aerobic Gram-negative isolates 38%, enterococci 24%, overall 35%) with constant rates over time during the 15-month study period. The resistance rates for fosfomycin were lower (overall 12%), and remained constant for enterococci (average 10%), but increased for aerobic Gram-negative isolates from 9% during the initial part to 17% during the final part of the study (p = 0.007). Most aerobic strains in wound secretions from infected patients (20/26) could not be recovered from a preoperative faecal swab of the same patient. Isolates from infection after doxycycline prophylaxis had twice as high doxycycline resistance rates (overall 63%, 82% for Gram-negative isolates) as wound isolates from infection after fosfomycin prophylaxis (30%) and preoperative faecal flora isolates (35%, p = 0.02), indicating that bacterial resistance contributed to failure of doxycycline prophylaxis. In contrast, no increase in fosfomycin resistance rates was found among aerobic isolates from infection after fosfomycin prophylaxis (10%). This suggested that the emerging fosfomycin resistance was associated with reduced bacterial virulence and thus was of less clinical significance than doxycycline resistance.