fosfomycin and Klebsiella-Infections

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamases; Ceftazidime; Drug Combinations; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Urinary Tract Infections

Klebsiella pneumoniae producing KPC-type carbapenemase causes severe nosocomial infection at a high mortality rate. Nosocomial pneumonia in particular is associated with high mortality, likely due to the unfavorable pulmonary pharmacokinetics of the antibiotics used against this agent. Therefore, early and accurate microbiological identification and susceptibility evaluation are crucial in order to optimize antibiotic therapy. We report a case of ventilator-associated pneumonia caused by colistin-resistant K. pneumoniae producing KPC-type carbapenemase treated using a carbapenem-sparing therapy and tailored according to the serum procalcitonin concentration in order to limit the duration of antibiotic therapy.

Topics: Adult; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Calcitonin; Calcitonin Gene-Related Peptide; Colistin; Cross Infection; Drug Resistance, Bacterial; Drug Therapy, Combination; Equipment Contamination; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Minocycline; Pneumonia, Bacterial; Protein Precursors; Tigecycline; Treatment Outcome; Ventilators, Mechanical

The increasing incidence of carbapenem-resistant Klebsiella pneumoniae (CR-KP) fundamentally alters the management of patients at risk to be colonized or infected by such microorganisms. Owing to the limitation in efficacy and potential for toxicity of the alternative agents, many experts recommend using combination therapy instead of monotherapy in CR-KP-infected patients. However, in the absence of well-designed comparative studies, the best combination for each infection type, the continued role for carbapenems in combination therapy and when combination therapy should be started remain open questions. Herein, the authors revise current microbiological and clinical evidences supporting combination therapy for CR-KP infections to address some of these issues.

Topics: Aminoglycosides; Anti-Bacterial Agents; Carbapenems; Colistin; Drug Therapy, Combination; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Minocycline; Rifampin; Risk Factors; Tigecycline

Intensive care unit (ICU)-acquired infections as a result of multidrug-resistant Gram-negative pathogens remain a serious problem in critically ill patients. Adult ICU patients who received intravenous fosfomycin were prospectively examined to assess its safety and effectiveness as an adjunct to the antimicrobial therapy of life-threatening infections caused by carbapenem-resistant Klebsiella pneumoniae. Fosfomycin was administered intravenously in 11 patients for treatment of hospital-acquired infections caused by carbapenem-resistant K. pneumoniae. Fosfomycin (2-4 g every 6 h) was administered in combination with other antibiotics. The mean +/- SD duration of treatment was 14 +/- 5.6 days. All patients had good bacteriological and clinical outcome of infection. All-cause hospital mortality was two out of 11 (18.2%) patients. No patient experienced adverse events related to the administration of fosfomycin. Intravenous fosfomycin may be a beneficial and safe adjunctive treatment in the management of life-threatening ICU-acquired infections caused by carbapenem-resistant K. pneumoniae.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactam Resistance; Carbapenems; Critical Illness; Cross Infection; Female; Fosfomycin; Humans; Infusions, Intravenous; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Prospective Studies; Treatment Outcome

The aim of the study was to evaluate clinical and microbiological efficacy and safety of intravenous fosfomycin for the treatment of carbapenem-resistant

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Pneumonia; Urinary Tract Infections

Optimal treatment of carbapenemase-producing Enterobacterales (CPE) bone infections is poorly defined. This study evaluated the efficacy of the novel beta-lactam-beta-lactamase inhibitor-ceftazidime-avibactam (CAZ-AVI)-with different antibiotic combinations in an experimental model of CPE osteomyelitis.. KPC-99YC is a clinical strain of Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae with intermediate susceptibility to meropenem (MIC 4 mg/L), gentamicin (MIC 0.25 mg/L), colistin (MIC 0.25 mg/L), fosfomycin (MIC 4 mg/L) and ceftazidime-avibactam (MIC 1 mg/L). Time-kill curves were performed at 4x MIC. Osteomyelitis was induced in rabbits by tibial injection of 2×10. In vitro, CAZ-AVI plus colistin or gentamicin were rapidly bactericidal in contrast with CAZ-AVI plus fosfomycin. In vivo, compared with controls, colistin alone (P = 0.045) and CAZ-AVI alone or in combination significantly lowered bone bacterial counts (P < 0.001). Bone sterilisation was achieved in 67% and 100% of animals with combinations of CAZ-AVI plus colistin or gentamicin (P = 0.001 and P < 0.001, respectively) whereas other treatments were no different from controls. CAZ-AVI plus gentamicin provided greater bone bacterial reduction than CAZ-AVI plus colistin (P = 0.033). No CAZ-AVI-resistant strains emerged in treated rabbits, regardless of combination.. CAZ-AVI plus gentamicin was the best effective combination therapy. Combinations with CAZ-AVI appear to be a promising treatment of KPC-producing Klebsiella pneumoniae osteomyelitis.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Ceftazidime; Colistin; Drug Combinations; Fosfomycin; Gentamicins; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Osteomyelitis; Rabbits

With the emergence of multi-drug resistant strains among Klebsiella isolates, the use of old drugs such as fosfomycin has been considered. In this context, we investigated the effect of fosfomycin on biofilm-producing Klebsiella pneumoniae and Klebsiella oxytoca strains isolated from ICU patients. A total of 90 isolates of Klebsiella pneumoniae and 30 isolates of Klebsiella oxytoca were collected from the ICU ward. All isolates were confirmed by biochemical and genotypic methods. Antibiotic susceptibility testing was performed by disc diffusion method and for fosfomycin and colistin, minimum inhibitory concentration (MIC) was done using micro broth dilution. The presence of the beta-lactamase encoding genes, biofilm-related genes, and fosfomycin resistance-related genes was detected by PCR. Finally, for fosfomycin-resistant isolates, we determined the sequence type by the MLST method. Sensitivity rate to fosfomycin in Klebsiella pneumoniae and Klebsiella oxytoca isolates was 92.2% and 100%, respectively. Fosfomycin was the most active antimicrobial agent with 96% sensitivity among all tested antibiotics. All tested isolates could produce biofilm. The frequency of biofilm-related genes for Klebsiella pneumoniae was as follows: 95.5% fimH, 86.6% mrkD, 77.7% mrkA, and 50% wcaG. The frequency of these genes for Klebsiella oxytoca was as follows: 56.6% fimA, 46.6% mrkA, 93.3% matB, and 90% pilQ. Only 4.4% of Klebsiella pneumoniae isolates showed resistance to fosfomycin, and the fosA gene was detected in all of them. Our results showed that fosfomycin effectively inhibits multidrug-resistant (MDR) strains of Klebsiella pneumoniae and Klebsiella oxytoca.

Topics: Anti-Bacterial Agents; beta-Lactamases; Fosfomycin; Humans; Klebsiella Infections; Klebsiella oxytoca; Klebsiella pneumoniae; Microbial Sensitivity Tests; Multilocus Sequence Typing; Urinary Tract Infections

Little is known regarding outcomes and optimal therapeutic regimens of infections caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) resistant to ceftazidime/avibactam (CZA) and susceptible to meropenem (MEM). Although susceptible to MEM in vitro, the possibility of developing MEM resistance overtime is a concern. We describe the clinical characteristics of patients with colonization/infection due to KPC variants with a focus on the in vitro activity of fosfomycin (FOS)-containing combinations.. Patients with colonization/infection due to a KPC variant were included. Fosfomycin susceptibility was performed by agar dilution method. Synergistic activity of FOS-based combinations was evaluated by gradient strip-agar diffusion method. The emergence of in vitro MEM resistance was also tested.. Eleven patients were included: eight with infection [four with ventilator-associated pneumonia and four with bloodstream infections] and three with colonization. Previous therapy with CZA was administered to all patients (with a mean cumulative duration of 23 days). All subjects with infection received meropenem, in monotherapy (n = 4) or with amikacin (n = 2) or fosfomycin (n = 2), and achieved clinical cure. A new CZA-susceptible and MEM-resistant KPC-Kp strain was subsequently isolated in three patients (27.3%). Meropenem/vaborbactam (MVB) showed high in vitro activity, while FOS+MEM combination was synergistic in 40% of cases. In vitro resistance to MEM was observed with maintenance of CZA resistance.. Detection of KPC variants may occur within the same patient, especially if CZA has been previously administered. Although clinical success has been obtained with carbapenems, the emergence of MEM resistance is a concern. Fosfomycin plus meropenem is synergistic and may be a valuable combination option for KPC variants, while MVB may be considered in monotherapy. The detection of KPC variants in an endemic setting for KPC-Kp represents a worryingly emerging condition. The optimal therapeutic approach is still unknown and the development of meropenem resistance is of concern, which may lead to therapeutic failure in clinical practice. In these cases, the addition of fosfomycin to meropenem, or a more potent antibiotic, such as meropenem/vaborbactam, may be valuable therapeutic options.

Topics: Agar; Ceftazidime; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Meropenem

The incidence of infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) is increasing worldwide, and very limited number of effective antibiotics are available for therapy. In our study, the in vitro efficacy of meropenem/polymyxin B and meropenem/fosfomycin combinations against CRKP strains was investigated. The efficiency of meropenem/polymyxin B and meropenem/fosfomycin combinations was tested by checkerboard microdilution and checkerboard agar dilution methods, respectively, against 21 CRKP strains containing major carbapenem resistant genes (7 blaKPC, 7 blaOXA-48 gene, and 7 blaOXA-48+ blaNDM), and seven additional CRKP strains without carbapenemase genes.Among the 28 CRKP strains, the meropenem/polymyxin B combination was synergistic in ten (35.7%), partially synergistic in 12 (42.8%), and indifferent in six (21.4%) isolates. The meropenem/fosfomycin combination was found to be synergistic in three isolates (10.7%), partially synergistic in 20 (71.4%), and indifferent in five (17.8%). In 21 strains containing carbapenem resistance genes, meropenem/polymyxin B and meropenem/fosfomycin combinations exhibited synergistic/partial synergistic effects in 15 (71.4%) and 16 (76.2%) strains, respectively, compared to 100% synergistic/partial synergistic efficiency in both combinations in seven strains free of carbapenemase genes. No antagonistic effect was detected in either combination.Regardless of presence or absence of carbapenem resistance genes, meropenem/polymyxin B and meropenem/fosfomycin combinations both demonstrated high synergistic and partial synergistic activity against 78.4% and 82.1% of CRKP strains, respectively. Also, they have no antagonistic effects and can be used successfully to prevent therapeutic failure with monotherapy, according to our in vitro studies.

Topics: Anti-Bacterial Agents; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Polymyxin B

The aim of this study was to evaluate the combination treatments with intravenous fosfomycin for carbapenem-resistant Klebsiella pneumoniae infections in a tertiary-care center.. Between December 24, 2018 and November 21, 2022, adult patients diagnosed with bloodstream infection or ventilator-associated pneumonia due to culture-confirmed carbapenem-resistant Klebsiella pneumoniae in the anesthesiology and reanimation intensive care units were investigated retrospectively.. There were a total of 62 patients fulfilling the study inclusion criteria. No significant difference was recorded in 14- and 30-day mortality among different types of combination regimens such as fosfomycin plus one or two antibiotic combinations. Hypokalemia (OR:5.651, 95%CI 1.019-31.330, p=0.048) was found to be a significant risk factor for 14-day mortality, whereas SOFA score at the time of diagnosis (OR:1.497, 95%CI 1.103-2.032, p=0.010) and CVVHF treatment (OR:6.409, 95%CI 1.395-29.433, p=0.017) were associated with 30-day mortality in multivariate analysis.. In our study, high mortality rates were found in patients with bloodstream infection or ventilator-associated pneumonia due to carbapenem-resistant Klebsiella pneumoniae, and no significant difference was recorded in 14- and 30-day mortality among different types of combination regimens such as fosfomycin plus one or two antibiotic combinations.

Topics: Adult; Anti-Bacterial Agents; Carbapenems; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Pneumonia, Ventilator-Associated; Retrospective Studies; Sepsis

The aim of this study was to determine the in vitro efficacy of intravenous (IV) fosfomycin against extensively drug-resistant Enterobacterales strains and the effect of glucose 6-phosphate (G6-P) on sensitivity results.. Thirty-two extensively drug-resistant Klebsiella pneumonia strains were included in the study. Detection of the carbapenemase genes was performed using the Gene-Xpert® System Carba R® kit. Susceptibility of IV fosfomycin was assessed using the agar dilution method. The agar dilution method was repeated using Muller-Hinton Agar medium without G6-P to assess the effect of G6-P on sensitivity results.. All strains in the study produced carbapenemases and were resistant to all drugs tested, including carbapenems, piperacillin-tazobactam, ceftriaxone, and ceftazidime. Fosfomycin resistance was detected in 3 (9.3%) strains. When the sensitivity test was repeated without G6-P, fosfomycin resistance was detected in 82.7% of the fosfomycin-susceptible strains. The Gene-Xpert® System showed NDM-1 in 46.8%, OXA-48 in 18.7%, KPC in 3.1%, and NDM-1 + OXA-48 in 21.8% of the strains. OXA-48 was detected in one of the resistant strains, and none of the viable genes were detected in two of the resistant strains.. This study shows that IV fosfomycin is a potentially important treatment alternative for infections caused by common resistant strains. Accurate results may not be obtained unless G6-P is used in the agar dilution method for in vitro susceptibility studies of fosfomycin.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Fosfomycin; Genetic Variation; Genotype; Glucose-6-Phosphate; Humans; Klebsiella Infections; Klebsiella pneumoniae

The use of oral fosfomycin for urinary tract infections (UTIs) caused by non-Escherichia coli uropathogens is uncertain, including Klebsiella pneumoniae, the second most common uropathogen.. A multicompartment bladder infection in vitro model was used with standard media and synthetic human urine (SHU) to simulate urinary fosfomycin exposure after a single 3 g oral dose (fAUC0-72 16884 mg·h/L, t½ 5.5 h) against 15 K. pneumoniae isolates including ATCC 13883 (MIC 2 to >1024 mg/L) with a constant media inflow (20 mL/h) and 4-hourly voiding of each bladder. The impact of the media (CAMHB + G6P versus SHU) on fosfomycin MIC measurements, drug-free growth kinetics and regrowth after fosfomycin administration was assessed. A low and high starting inoculum (5.5 versus 7.5 log10 cfu/mL) was assessed in the bladder infection model.. Compared with CAMHB, isolates in SHU had a slower growth rate doubling time (37.7 versus 24.1 min) and reduced growth capacity (9.0 ± 0.3 versus 9.4 ± 0.3 log10 cfu/mL), which was further restricted with increased inflow rate (40 mL/h) and more frequent voids (2-hourly). Regrowth was commonly observed in both media with emergence of fosfomycin resistance promoted by a high starting inoculum in CAMHB (MIC rise to ≥1024 mg/L in 13/14 isolates). Resistance was rarely detected in SHU, even with a high starting inoculum (MIC rise to ≥1024 mg/L in 2/14 isolates).. Simulated in an in vitro UTI model, the regrowth of K. pneumoniae urinary isolates was inadequately suppressed following oral fosfomycin therapy. Efficacy was further reduced by a high starting inoculum.

Topics: Anti-Bacterial Agents; Culture Media; Cystitis; Escherichia coli; Female; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Urinary Bladder; Urinary Tract Infections

Determining the role of the immune response in preventing antimicrobial resistance and optimising antibiotic regimens against carbapenemase-producing Klebsiella pneumoniae is a research gap that exists and needs to be further explored. The objective of this study was to determine the pharmacodynamic and immunomodulatory effects of fosfomycin alone and in combination with polymyxin B against KPC-2-producing K. pneumoniae clinical isolates. Six K. pneumoniae isolates were selected (polymyxin B MIC, 0.5-64 mg/L; fosfomycin MIC, 16-128 mg/L) to evaluate the pharmacodynamics of monotherapy and combination therapies in static time-kill studies. A mechanism-based model was used to characterise the joint activity of polymyxin B and fosfomycin. A549 human airway epithelial cells were infected with four isolates to evaluate the immunomodulatory effects of treatment. Our mechanism-based model indicated greater bacterial killing efficacy of fosfomycin with polymyxin B compared with monotherapy. In combination, polymyxin B was assumed to exert an outer membrane effect that resulted in an increase in the ability of fosfomycin to reach its target site. The mechanism-based model described the data well across all six strains, with R

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Fosfomycin; Humans; Immunity; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Polymyxin B

The aim of this study was to describe the prevalence and epidemiology distribution of K. pneumoniae isolated at University Hospital of Campania "Luigi Vanvitelli," including the susceptibility evolution profile. Data on resistant phenotype strains, such as extended-spectrum-β-lactamase (ESBL) producers and carbapenem-resistant K. pneumoniae (CRE) isolates, were also reported. K. pneumoniae strains were collected at the Complex Operative Unit (UOC) of Virology and Microbiology from different colonization and infection sites from January 2016 to December 2020. The highest rates of isolation were in urinary samples and in respiratory and wound swabs. Antibiotics susceptibility patterns showed more than 50% of the isolates resistant to cephalosporins, fluoroquinolones and penicillin. On the other hand, from 20% to 40% of K. pneumoniae strains were resistant to carbapenems and aminoglycosides. Based on our analysis, fosfomycin, ceftazidime/avibactam and ceftolozane/tazobactam are still therapeutic alternatives. Data analysis on carbapenem class evolution in 2016-2020 showed a significant increase in resistance rates (p<0.05). Increased rates in CRE and ESBL producing K. pneumoniae since 2017 were reported. Providing information on clinical characteristics and epidemiology data on contemporary K. pneumoniae evolution could help mitigate the spread of these isolates in our hospital and avert the endemic levels that have been observed in Southern Italy and in other European countries.

Topics: Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Drug Resistance, Bacterial; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests

The threat of antibiotic resistance has increased dramatically in recent years. Fosfomycin, an old antibiotic agent, has been re-introduced to fight infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP). However, the trend of fosfomycin resistance among KPC-KP strains is increasing. In this study, 80 KPC-KP clinical isolates were collected from three teaching hospitals during 2014-2017 in China and were subjected to whole-genome sequencing (WGS). The fosfomycin resistance phenotype and resistance mechanisms were investigated by antimicrobial susceptibility testing and carbon source growth test, respectively. Among all KPC-KP strains, 80.0% (64/80) were resistant to fosfomycin and 36.3% (29/80) were positive for the mobile fosfomycin resistance gene fosA3. Among the 63 strains that were unable to grow in M9 basic medium with glycerol-3-phosphate (G3P) as the sole carbon source (mediated by mutation of the target gene glpT), there was no significant difference regarding the MIC distribution of fosfomycin between fosA3-positive and fosA3-negative strains (P = 0.577). Among the 50 strains that were negative for fosA3 but positive for fosA, the fosfomycin MICs of strains unable to grow in M9 basic medium with G3P as the sole carbon source were significantly higher (P < 0.001) than in strains that were able to grow in M9 basic medium with G3P as the sole carbon source. Our findings indicate that fosfomycin resistance among KPC-KP in China is an emerging problem and the two major mechanisms of resistance identified were plasmid-mediated fosfomycin resistance gene fosA3 and mutation of the target gene glpT.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; China; DNA, Bacterial; Drug Resistance, Bacterial; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Mutation; Plasmids; Prevalence

Carbapenem-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.. A 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.. Twenty-one of 35 K. pneumoniae isolates were classified as CRKP. Most of CRKP isolates carried bla. These findings suggested that the fosfomycin and gentamicin combination might be useful as a possible treatment option for CRKP infection.

Topics: Anti-Bacterial Agents; beta-Lactamases; Fosfomycin; Hospitals; Humans; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Thailand

Limited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function.. The simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75-91%).. The use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Colistin; Critical Illness; Female; Fosfomycin; Humans; Kidney; Kidney Function Tests; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Tigecycline

Fosfomycin has been proven to be a vital choice to treat infection caused by multidrug resistance bacteria, especially carbapenem-resistant Klebsiella pneumoniae (CRKP). However, fosfomycin resistant cases has been reported gradually. In this study, we reported the fosfomycin-resistant rate in CRKP strains and further revealed the molecular mechanisms in resistance gene dissemination.. A total of 294 non-duplicated CRKP strains were collected. And 55 fosfomyin-resistant strains were detected, 94.5% of which were clustered to sequence type (ST) 11 by PCR followed up sequencing. PFGE further revealed two major groups and four singletons. The positive rates of genes responsible to fosfomycin and carbapenem resistance were 81.8% (fosA3), 12.7% (fosA5) and 94.5% (bla. Although the resistant rate of CRKP to fosfomycin is relatively low in our area, considering its gene is located on transferrable plasmid and inserted in IS structure, continuous monitoring is still needed.

Topics: Carbapenem-Resistant Enterobacteriaceae; China; Drug Resistance, Bacterial; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Molecular Epidemiology; Tertiary Care Centers

This study evaluates whether the rapid fosfomycin resistance (fosfomycin NP) method can be used for detecting fosfomycin resistance in routine laboratory work. Results from the disk diffusion and rapid fosfomycin NP methods were compared with the reference agar dilution method for Escherichia coli and Klebsiella spp. strains isolated from urinary tract infections. The study included 57 E. coli and 48 Klebsiella spp. isolates from urinary tract infections. The reference agar dilution and disk diffusion methods were performed in accordance with EUCAST recommendations, and the results were evaluated according to EUCAST V.10.0. The method developed by Nordmann et al. was used for rapid detection of fosfomycin resistance (Nordmann, P., Poirel, L., Mueller, L., 2019. Rapid Detection of Fosfomycin Resistance in Escherichia coli. J Clin Microbiol. 57(1), e01531-18. doi:https://doi.org/10.1128/JCM.01531-18). The acceptable categorical agreement (CA ≥ 90%) and the rates of major error (ME <3%) and very major error (VME < 3%) of the two methods were compared with the reference method according to the criteria of ISO 20776-1. Fosfomycin resistance was detected in 15.8% of E. coli and 75% of Klebsiella spp. isolates using the reference method. Disk diffusion method showed CA 89.5%, ME 12.5% in E. coli isolates, and CA 75%, ME 100% in Klebsiella spp. isolates. No VME was detected in both methods. The rapid fosfomycin NP method resulted in CA 96.4%, ME 0.0%, VME 22.2% in E. coli isolates, and CA 77.3%, ME 81.8%, and VME 3% in Klebsiella spp. isolates. We believe the results from both of disk diffusion assay and rapid fosfomycin NP for the E. coli and Klebsiella spp. isolates are incompatible with the reference method and should not be used as an alternative to the agar dilution method.

Topics: Agar; Anti-Bacterial Agents; Diagnostic Tests, Routine; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Fosfomycin; Humans; Klebsiella; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Urinary Tract Infections

Topics: Bacteremia; beta-Lactamases; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Meropenem

Treatment of infections caused by carbapenemase-producing Klebsiella pneumoniae (CPKP) frequently involves combination therapy with various antimicrobial agents in the hope of achieving synergistic effects. Routine laboratory antimicrobial synergy testing is a service that is currently unavailable owing to the laborious nature of the reference time-kill assay (TKA) as well as the widely used chequerboard method. In this study, we explored whether easier methods, based on the Etest technique, might offer a suitable alternative.. In vitro interactions of tigecycline combination with colistin, gentamicin, fosfomycin or meropenem against 26 CPKP isolates were evaluated employing the TKA, chequerboard method and three Etest methodologies (the MIC/MIC ratio, the cross formation and the agar/Etest method). Rates of consequent synergy and concordance of the studied methods were determined.. All antimicrobial combinations demonstrated some degree of synergy against the CPKP isolates tested. No antagonism was observed for any of the combinations. All methods showed poor synergy concordance with the TKA, producing non-significant kappa (κ) results. Etest methods (MIC/MIC ratio and agar/Etest) exhibited fair agreement (κ=0.29 and 0.38, respectively) with the chequerboard method.. There is a poor correlation between synergy testing methods of tigecycline combinations, which may be associated with their different endpoints. To elucidate method comparability and reliability, their correlation with clinical outcomes appears important.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Drug Synergism; Drug Therapy, Combination; Fosfomycin; Gentamicins; Humans; In Vitro Techniques; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Tigecycline

To assess the antibacterial effects of a single 3 g oral fosfomycin dose on Escherichia coli and Klebsiella pneumoniae clinical isolates within a dynamic bladder infection model.. An in vitro model simulating dynamic urinary fosfomycin concentrations was used. Target fosfomycin exposure (Cmax = 1984 mg/L and Tmax = 7.5 h) was validated by LC-MS/MS. Pharmacodynamic responses of 24 E. coli and 20 K. pneumoniae clinical isolates were examined (fosfomycin MIC ≤0.25-128 mg/L). Mutant prevention concentration (MPC), fosfomycin heteroresistance, fosfomycin resistance genes and fosA expression were examined. Pathogen kill and emergence of high-level resistance (HLR; MIC >1024 mg/L) were quantified.. Following fosfomycin exposure, 20 of 24 E. coli exhibited reductions in bacterial counts below the lower limit of quantification without regrowth, despite baseline fosfomycin MICs up to 128 mg/L. Four E. coli regrew (MIC = 4-32 mg/L) with HLR population replacement. At baseline, these isolates had detectable HLR subpopulations and MPC >1024 mg/L. All E. coli isolates were fosA negative. In contrast, 17 of 20 K. pneumoniae regrew post exposure, 6 with emergence of HLR (proportion = 0.01%-100%). The three isolates without regrowth did not have a detectable HLR subpopulation after dynamic drug-free incubation. All K. pneumoniae had MPC >1024 mg/L and were fosA positive. WGS analysis and fosA expression failed to predict fosfomycin efficacy.. E. coli and K. pneumoniae isolates demonstrate discrepant responses to a single fosfomycin dose in a dynamic bladder infection in vitro model. Treatment failure against E. coli was related to an HLR subpopulation, not identified by standard MIC testing. Activity against K. pneumoniae appeared limited, regardless of MIC testing, due to universal baseline heteroresistance.

Topics: Anti-Bacterial Agents; Chromatography, Liquid; Escherichia coli; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Tandem Mass Spectrometry; Urinary Tract Infections

Topics: Anti-Bacterial Agents; Escherichia coli; Escherichia coli Infections; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Urinary Tract Infections

Wide-spectrum antibiotics have been favored to treat acute uncomplicated cystitis (AUC) for a long time, leading to the emergence of multi-drug resistant bacteria. We hypothesize that narrow-spectrum antibiotics might mitigate the issue and aim to investigate the clinical efficacy of cefaclor in patients with AUC.. We retrospectively reviewed the clinical data of female outpatients with AUC treated with cefaclor and evaluated the safety and clinical efficacy. Clinical cure was defined as the elimination of clinical symptom under 4 white blood cells (WBCs) per high power field on microscopy.. Overall, 223 women with AUC were enrolled. Escherichia coli was the dominant pathogen (n = 160; 68.6%), followed by Klebsiella species and E. coli-extended spectrum β-lactamase (ESBL) (n = 19; 8.1% and n = 18; 7.7%). Overall success rate was 94.0% (n = 219) and susceptibility rate of cefazolin was 84.1%, which was close to that of levofloxacin (82.9%). Ampicillin showed the lowest rate of 63.7% with a significantly greater resistance rate of 35.3% among all antibiotics (P < 0.001). In the subgroup analysis, the success rate in patients with resistance to levofloxacin or cefazolin was 100% (n = 24) or 93.3% (n = 14). The rate in patients with resistance to both antibiotics was 60.0% (n = 9), and the pathogens in the other 40.0% (n = 6) of patients with treatment failure were E. coli-ESBL.. Cefaclor showed excellent efficacy in AUC patients, even in those with in vitro resistance to cefazolin or levofloxacin. Cefaclor may be considered as a first-line option in patients with AUC and a second-line option for those with levofloxacin treatment failure.

Topics: Adult; Aged; Aged, 80 and over; Amikacin; Ampicillin; Anti-Bacterial Agents; beta-Lactam Resistance; Cefaclor; Cefazolin; Cystitis; Drug Resistance, Multiple, Bacterial; Escherichia coli Infections; Female; Fosfomycin; Humans; Klebsiella Infections; Levofloxacin; Microbial Sensitivity Tests; Middle Aged; Proteus Infections; Retrospective Studies; Staphylococcal Infections; Treatment Failure; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections; Young Adult

Co-existence of both virulence and multidrug-resistant (MDR) determinants on a self-transmissible plasmid facilitates simultaneous transfer of virulence and resistance in a single event and rapid emergence of virulent and MDR Klebsiella pneumoniae clones.. This study identified extensively drug-resistant ST15 strains, KP17-15 and KP17-16, from clinical cases with microbiological and genomical approaches.. The chromosomes of KP17-15 and KP17-16 were highly homologous with 12 SNP differences, indicating that the two strains were derived from the same clone. Multiple plasmids existed in the isolates, including novel virulence plasmids p17-15-vir (479 kb) and p17-16-vir (290 kb) for KP17-15 and KP17-16, respectively. Notably, the plasmid p17-15-vir (479 kb) was a hybrid plasmid that might be formed by recombination of two homologous regions encoding group II intron reverse transcriptase and mobile element ISShes11 shared by p17-16-vir (290 kb) and a conjugative MDR plasmid p17-16-CTX (188 kb). p17-15-vir was readily transferable to ST11 Klebsiella pneumoniae by conjugation. Moreover, p17-16-vir, a non-conjugative virulence plasmid lacking the transfer (tra) operon, was also transferable by conjugation under the help of p17-16-CTX or p17-16-KPC. Fusion of p17-16-vir with p17-16-CTX into a p17-15-vir-like plasmid was also observed in the transconjugant.. The findings uncover the evolutionary pathway of a novel hybrid virulence MDR plasmid and transfer mechanism of a non-conjugative virulence plasmid. Systematic surveillance of such hybrid virulence MDR plasmids in clinical Klebsiella pneumoniae should be performed.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; China; Conjugation, Genetic; Drug Resistance, Multiple, Bacterial; Fosfomycin; Genome, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Multilocus Sequence Typing; Phylogeny; Plasmids; Virulence

Infections caused by Carbapenemase-producing Enterobacterales (CPE) are an important public health issue. Intravenous fosfomycin can be considered as an alternative for the treatment of serious infections caused by CPE. In this study, in vitro activity of fosfomycin was investigated among CPE isolates.. Overall, 158 clinically relevant isolates obtained from 18 hospitals of 13 cities in Turkey with predetermined carbapenemase types were evaluated in the study, including Escherichia coli (n = 19) and Klebsiella spp. (n = 139). In vitro activity of fosfomycin was determined with agar dilution method. Among Klebsiella spp., 104 harbored blaOXA-48, 15 isolates carried both blaOXA-48 and blaNDM; three had both blaOXA-48 and blaVIM and nine isolates had blaNDM alone. Four isolates carried only blaVIM and two isolates harbored blaIMP alone. One isolate co-harbored blaVIM and blaNDM. Among E. coli isolates, blaOXA-48 and blaNDM were carried by 18 and one isolates, respectively.. Resistance to fosfomycin was detected in 43.7% of the isolates. Among Klebsiella spp. and E. coli, these rates were 46.8% and 21.1%, respectively. In Klebsiella spp. resistance to fosfomycin was 49.5% in blaOXA-48 carriers; 26.7% in isolates co-harbouring blaOXA-48 and blaNDM and 66.7% in blaNDM carriers. In E. coli, fosfomycin resistance was detected among 16.7% of the blaOXA-48 carriers.. High level of fosfomycin resistance in these isolates may be attributable to the fact that these isolates are multidrug resistant. The genetic background of resistance should also be investigated in order to understand the co-occurrence and transfer of resistance among the CPE.

Topics: beta-Lactamases; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Turkey

KPC-producing Klebsiella pneumonia (KPC-Kp) represents a major therapeutic challenge in critically ill patients. Ceftazidime-avibactam (CAZ-AVI) is a new effective drug against KPC-Kp but, due to emerging resistant strains during monotherapy, the association with a second antibiotic has been advocated. Therefore, intravenous fosfomycin may be a possible choice for combination therapy. The aim of this study was to evaluate the in vitro susceptibility of CAZ-AVI alone and in combination with fosfomycin and carbapenems against KPC-Kp clinical isolates by E-test method. The combination of CAZ-AVI with carbapenems showed synergistic activity, whereas with fosfomycin showed addictive activity, suggesting that fosfomycin may be a carbapenem-sparing strategy in antimicrobial stewardship programs.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Carbapenems; Ceftazidime; Drug Combinations; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests

The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a looming threat to human health. Although there are numerous studies regarding porin alteration in association with the production of ESBLs and/or AmpC β-lactamase, a systematic study on the treatment-emergence of porins alteration in antibiotic resistance does not yet exist. The aim of this study was to investigate the underlying mechanism of resistance of K. pneumoniae during carbapenem treatment.. Here, we report three strains (FK-2624, FK-2723 and FK-2820) isolated from one patient before and after imipenem treatment during hospitalization. Antibiotic susceptibility testing indicated that that the first isolate, FK-2624, was susceptible to almost all tested antimicrobials, being resistant only to fosfomycin. The subsequent isolates FK-2723 and FK-2820 were multidrug resistant (MDR). After imipenem therapy, FK-2820 was found to be carbapenem-resistant. PCR and Genome Sequencing analysis indicated that oqxA, and fosA5, were identified in all three strains. In addition, FK-2624 also harbored bla. This study in China highlight that the alteration of outer membrane porins due to the 14-day use of imipenem play a potential role in leading to clinical presentation of carbapenem-resistance. This is the first description of increased resistance developing from a carbapenem-susceptible K. pneumoniae with imipenem treatment driven by outer membrane remodeling.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Carbapenems; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Fosfomycin; Humans; Imipenem; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Multilocus Sequence Typing; Phylogeny; Plasmids; Virulence Factors; Whole Genome Sequencing

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.

Topics: Anti-Bacterial Agents; beta-Lactamases; Escherichia coli; Escherichia coli Infections; Fosfomycin; Humans; Klebsiella; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Retrospective Studies

The effective treatment of carbapenemase-producing Klebsiella pneumoniae infection has been limited and required novel potential agents. Due to the novel drug development crisis, using old antimicrobial agents and combination therapy have been highlighted. This study focused on fosfomycin which inhibits cell wall synthesis and has potential activity on Enterobacteriaceae. We evaluated fosfomycin activity against carbapenemase-producing K. pneumoniae and characterized fosfomycin resistance mechanisms. Fosfomycin revealed effective activity against only 31.8% of carbapenemase-producing K. pneumoniae isolates. The major resistance mechanism was FosA3 production. The co-occurrence of FosA3 overexpression with the mutation of glpT (or loss of glpT) and/or uhpT was mediated high-level resistance (MIC>256 mg/L) to fosfomycin. Moreover, fosA3 silenced in sixteen fosfomycin-susceptible isolates and the plasmid carrying fosA3 of these isolates increased 32- to 64-fold of fosfomycin MICs in Escherichia coli DH5α transformants. The in vitro activity of fosfomycin combination with amikacin by checkerboard assay showed synergism and no interaction in six (16.2%) and sixteen isolates (43.3%), respectively. No antagonism of fosfomycin and amikacin was observed. Notably, the silence of aac (6)'-Ib and aphA6 was observed in amikacin-susceptible isolates. Our study suggests that the combination of fosfomycin and amikacin may be insufficient for the treatment of carbapenemase-producing K. pneumoniae isolates.

Topics: Amikacin; Amino Acid Substitution; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Drug Resistance, Bacterial; Escherichia coli; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Membrane Transport Proteins; Microbial Sensitivity Tests; Plasmids; RNA, Messenger

The Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae has become a serious problem because the species is wide ranging and there are few treatment options. Fosfomycin has attracted renewed interest in combination therapy for infections caused by KPC-producing K. pneumoniae isolates. Because of the increasing use of fosfomycin, resistant isolates have been continually reported in carbapenem-resistant K. pneumoniae (CRKP). At present, multiple mechanisms can result in fosfomycin resistance. However, there is limited knowledge with respect to plasmid-mediated fosfomycin resistance gene (fosA3) determinants in KPC-producing K. pneumoniae isolates. In this study, a total of 101 CRKP strains were collected from four hospitals in Zhejiang province from January 2013 to August 2014; 28.7% (29/101) of CRKP isolates were resistant to fosfomycin. Gene fosA3 was detected in 29 fosfomycin-resistant KPC-producing K. pneumoniae isolates, whereas genes fosA, fosB, fosB2, fosC, fosC2, and fosX were all negative among the resistant isolates. In addition, among 29 fosfomycin-resistant KPC-producing K. pneumoniae isolates, pulsed-field gel electrophoresis (PFGE) analysis revealed five pulsotypes. S1-PFGE and Southern blot showed that the fosA3 gene was located on an approximately 140-kb plasmid in all isolates. Eight of the 29 isolates (27.6%) tested could successfully transfer their fosfomycin-resistant phenotype to Escherichia coli strain J53. All fosA3-positive isolates were determined to have an identical genetic background, IS26-tetR-cadC-orf1-fosA3-IS26, which is the same as that of the fosA3-positive plasmid pFOS18 in China. The primary resistance mechanism to fosfomycin was caused by a plasmid-mediated fosA3. Furthermore, it is noteworthy that the plasmid genetically carrying a combination of the fosA3 and bla

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; China; Conjugation, Genetic; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Fosfomycin; Genotype; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Molecular Epidemiology; Plasmids; Polymerase Chain Reaction

Fosfomycin susceptibility testing with Sensititre, Vitek2, Etest, Mic Strip Test and disk diffusion methodologies was compared versus reference agar dilution method (AD) with 78 clinical isolates of KPC-producing Klebsiella pneumoniae. All methodologies showed a Categorical Agreement and Essential Agreement of ≤69% and ≤72%, respectively, revealing a very low concordance with AD.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Diagnostic Errors; Drug Resistance, Bacterial; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Reagent Kits, Diagnostic

The emergence of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) infections requires re-assessment of therapeutic choices. Here we report the efficacy of cefoxitin-based antibiotic therapy for ESBL-E prostatitis. A prospective study including patients with ESBL-E prostatitis resistant to trimethoprim/sulfamethoxazole and fluoroquinolones from January 2014 to March 2016 was conducted. Cefoxitin was administered by continuous infusion for 3 weeks in the case of acute bacterial prostatitis or 6 weeks in the case of chronic bacterial prostatitis (CBP), with intravenous fosfomycin for the first 5 days. Urological investigations were performed to diagnose underlying urinary tract pathology. Clinical and microbiological efficacy were evaluated 3 months (M3) and 6 months (M6) after the end of therapy. A total of 23 patients were included in the study. The median patient age was 74 years (range 48-88 years). Of the 23 infections, 14 (61%) were CBP and 12 (52%) were healthcare-associated infections. The bacteria involved were Escherichia coli in 11 cases, Klebsiella pneumoniae in 10 cases and Klebsiella oxytoca in 2 cases. Clinical cure was observed in 19/23 patients (83%) at M3 and in 17/22 patients (77%) at M6. Urocultures were sterile in 13/23 patients (57%) at M3 and in 9/19 patients (47%) and M6. Urinary colonisation was observed in 6/19 patients (32%) with clinical cure at M3 and 5/14 patients (36%) with clinical cure at M6. No resistance to cefoxitin was detected. Surgical treatment was required for 7/23 patients (30%). In conclusion, cefoxitin-based antibiotic therapy is suitable for difficult-to-treat ESBL-E infections such as prostatitis.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactamases; Cefoxitin; Cross Infection; Escherichia coli; Escherichia coli Infections; Fluoroquinolones; Fosfomycin; Humans; Klebsiella Infections; Klebsiella oxytoca; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Pilot Projects; Prospective Studies; Prostatitis; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections

The spread of carbapenem-resistant Klebsiella pneumoniae (CR-KPN) is a major concern, but data on CR-KPN infection/colonization in paediatric populations are limited.. To analyse epidemiologic and clinical characteristics, and therapeutic options for CR-KPN infections in neonates in China.. A retrospective study was performed at the Children's Hospital of Fudan University, including 88 neonates with CR-KPN admitted between November 2015 and October 2016. Forty-seven CR-KPN isolates were chosen at random for further study, including antimicrobial susceptibility testing, potential β-lactamase screening and homology analysis.. Most of the CR-KPN isolated from neonates produced New Delhi metallo-beta-lactamase-1 and were highly homologous. Fosfomycin-containing regimens and meropenem-/panipenem-containing combination therapy were efficient for CR-KPN infection in neonates.

Topics: Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Carrier State; China; Drug Therapy, Combination; Female; Fosfomycin; Hospitals, Pediatric; Humans; Infant; Infant, Newborn; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Retrospective Studies; Treatment Outcome

Fosfomycin susceptibility testing is complicated and prone to error. Before using fosfomycin widely in patients with serious infections, acquisition of WT distribution data and reliable susceptibility testing methods are crucial. In this study, the performance of five methods for fosfomycin testing in the routine laboratory against the reference method was evaluated.. Ten laboratories collected up to 100 ESBL-producing isolates each (80 Escherichia coli and 20 Klebsiella pneumoniae). Isolates were tested using Etest, MIC test strip (MTS), Vitek2, Phoenix and disc diffusion. Agar dilution was performed as the reference method in a central laboratory. Epidemiological cut-off values (ECOFFs) were determined for each species and susceptibility and error rates were calculated.. In total, 775 E. coli and 201 K. pneumoniae isolates were tested by agar dilution. The ECOFF was 2 mg/L for E. coli and 64 mg/L for K. pneumoniae. Susceptibility rates based on the EUCAST breakpoint of ≤32 mg/L were 95.9% for E. coli and 87.6% for K. pneumoniae. Despite high categorical agreement rates for all methods, notably in E. coli, none of the alternative antimicrobial susceptibility testing methods performed satisfactorily. Due to poor detection of resistant isolates, very high error rates of 23.3% (Etest), 18.5% (MTS), 18.8% (Vitek2), 12.5% (Phoenix) and 12.9% (disc diffusion) for E. coli and 22.7% (Etest and MTS), 16.0% (Vitek2) and 12% (Phoenix) for K. pneumoniae were found. None of the methods adequately differentiated between WT and non-WT populations.. Overall, it was concluded that none of the test methods is suitable as an alternative to agar dilution in the routine laboratory.

Topics: Anti-Bacterial Agents; Diagnostic Errors; Escherichia coli; Escherichia coli Infections; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Netherlands; Reproducibility of Results

Nine Klebsiella pneumoniae isolates coproducing NDM-1 and OXA-232 carbapenemases were successively isolated from a single patient. Although they were isolated simultaneously and were isogenic, they presented different colony phenotypes (matt and mucoid). All nine isolates were resistant to most antibiotics except colistin and fosfomycin. In addition, matt-type isolates were resistant to tigecycline. No differences were detected in the cps cluster sequences, except for the insertion of IS5 in the wzb gene of two matt-type isolates. In vitro virulence assays based on production of capsular polysaccharide, biofilm formation, and resistance to human serum indicated that the mucoid-type isolates were significantly more virulent than the matt-type. In addition, mucoid-type isolates showed higher survival rates than the matt-type ones in infection experiments in the fruit fly, suggesting a higher virulence of K. pneumoniae isolates with a mucoid phenotype. To our knowledge, this is the first report of K. pneumoniae colonies with different phenotypes being isolated from the same sample. In addition, we show that virulence varies with colony phenotype. Dissemination of K. pneumoniae isolates expressing both antibiotic resistance and high virulence would constitute a great threat.

Topics: Animals; Anti-Bacterial Agents; Bacterial Capsules; Bacterial Proteins; beta-Lactamases; Biofilms; Colistin; Drosophila melanogaster; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gene Expression Regulation, Bacterial; Genes, Bacterial; Genotype; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Phenotype; Serotyping; Survival Rate; Tigecycline; Virulence; Virulence Factors

KPC-producing Klebsiella pneumoniae are an emerging public health problem around the globe. We defined the combinatorial pharmacodynamics and ability to suppress resistance of two 'old' antibiotics, fosfomycin and colistin, in time-kill experiments and hollow-fibre infection models (HFIM).. Two KPC-2-producing K. pneumoniae isolates were used: one susceptible to both colistin and fosfomycin (KPC 9A: MIC colistin 0.25 mg/L and MIC fosfomycin ≤8 mg/L) and the other resistant to colistin and susceptible to fosfomycin (KPC 5A: MIC colistin 64 mg/L and MIC fosfomycin 32 mg/L). Time-kill experiments assessed an array of colistin and fosfomycin concentrations against both isolates. Colistin and fosfomycin pharmacokinetics from critically ill patients were simulated in the HFIM to define the pharmacodynamic activity of humanized regimens over 5 days against KPC 9A.. In time-kill experiments, synergy was demonstrated for all colistin/fosfomycin combinations containing >8 mg/L fosfomycin against the double-susceptible KPC strain, 9A. Synergy versus KPC strain 5A was only achieved at the highest concentrations of colistin (4 mg/L) and fosfomycin (512 mg/L) at 48 h. In the HFIM, colistin or fosfomycin monotherapies resulted in rapid proliferation of resistant subpopulations; KPC 9A regrew by 24 h. In contrast to the monotherapies, the colistin/fosfomycin combination resulted in a rapid 6.15 log 10  cfu/mL reduction of KPC 9A by 6 h and complete suppression of resistant subpopulations until 120 h.. Colistin and fosfomycin may represent an important treatment option for KPC-producing K. pneumoniae otherwise resistant to traditional antibiotics.

Topics: Adult; Aged; Anti-Bacterial Agents; beta-Lactamases; Colistin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Female; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Models, Biological

To investigate the synergistic and bactericidal effects of antimicrobial combinations of any two of colistin, fosfomycin and tigecycline against the nine extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae (KP) clinical isolates, including 4 carbapenem-susceptible strains and five imipenem and/or meropenem-resistant strains.. The most active combination group was colistin plus tigecycline, showing synergy in 8 isolates and bactericidal activities in 6 isolates by using concentrations of 1/2× MIC and 1/4× MIC, respectively. The least active combination was tigecycline plus fosfomycin, which showed synergy in only 4 isolates and no bactericidal activities by using concentrations of 1/2× MIC and 1/4× MIC, respectively.. The combination of tigecycline and colistin may be considered as a last-resort approach to the ESBL-producing KP infections, especially those isolates with carbapenem resistance.

Topics: Anti-Bacterial Agents; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Colistin; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Tigecycline

Topics: Adult; Anti-Bacterial Agents; Antibiotic Prophylaxis; Carbapenems; Drug Resistance, Multiple, Bacterial; Ertapenem; Female; Fosfomycin; Humans; Intestines; Kidney Transplantation; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Postoperative Complications; Precision Medicine

Urinary tract infections (UTIs) are a common reason for empirical treatment with broad-spectrum antibiotics worldwide. However, population-based antimicrobial resistance (AMR) prevalence data to inform empirical treatment choice are lacking in many regions, because of limited surveillance capacity. We aimed to assess the prevalence of AMR to commonly used antimicrobial drugs in Escherichia coli and Klebsiella pneumoniae isolated from patients with community- or healthcare-associated UTIs on two islands of Indonesia.. We performed a cross-sectional patient-based study in public and private hospitals and clinics between April 2014 and May 2015. We screened patients for symptoms of UTIs and through urine dipstick analysis. Urine culture and susceptibility testing were supported by telemicrobiology and interactive virtual laboratory rounds. Surveillance data were entered in forms on mobile phones.. Of 3424 eligible patients, 3380 (98.7%) were included in the final analysis, and yielded 840 positive cultures and antimicrobial susceptibility data for 657 E. coli and K. pneumoniae isolates. Fosfomycin was the single oral treatment option with resistance prevalence <20% in both E. coli and K. pneumoniae in community settings. Tigecycline and fosfomycin were the only options for treatment of catheter-associated UTIs with resistance prevalence <20%, whilst the prevalence of resistance to meropenem was 21.3% in K. pneumoniae .. Patient-based surveillance of AMR in E. coli and K. pneumoniae causing UTIs indicates that resistance to the commonly available empirical treatment options is high in Indonesia. Smart AMR surveillance strategies are needed to inform policy makers and to guide interventions.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Catheter-Related Infections; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Epidemiological Monitoring; Escherichia coli; Escherichia coli Infections; Female; Fosfomycin; Humans; Indonesia; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Middle Aged; Minocycline; Population Surveillance; Tertiary Care Centers; Thienamycins; Tigecycline; Urinary Tract Infections; Young Adult

We characterized NDM-1-producing

Topics: Amikacin; Anti-Bacterial Agents; Bacterial Typing Techniques; beta-Lactamases; Brazil; Clone Cells; DNA Transposable Elements; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Fosfomycin; Gene Expression; Genotype; Humans; Klebsiella Infections; Klebsiella pneumoniae; Minocycline; Multilocus Sequence Typing; Phylogeny; Plasmids; Polymyxin B; Tigecycline

Bolivia is among the lowest-resourced South American countries, with very few data available on antibiotic resistance in bacterial pathogens. The phenotypic and molecular characterization of bacterial isolates responsible for urinary tract infections (UTIs) in the Bolivian Chaco are reported here.. All clinical isolates from UTIs collected in the Hospital Basico Villa Montes between June 2010 and January 2014 were analyzed (N=213). Characterization included susceptibility testing, extended-spectrum beta-lactamase (ESBL) detection, identification of relevant resistance determinants (e.g., CTX-M-type ESBLs, 16S rRNA methyltransferases, glutathione S-transferases), and genotyping of CTX-M producers.. Very high resistance rates were observed. Overall, the lowest susceptibility was observed for trimethoprim-sulphamethoxazole, tetracycline, nalidixic acid, amoxicillin-clavulanic acid, ciprofloxacin, and gentamicin. Of E. coli and K. pneumoniae, 11.6% were ESBL producers. Resistance to nitrofurantoin, amikacin, and fosfomycin remained low, and susceptibility to carbapenems was fully preserved. CTX-M-15 was the dominant CTX-M variant. Four E. coli ST131 (two being H30-Rx) were identified. Of note, isolates harbouring rmtB and fosA3 were detected.. Bolivia is not an exception to the very high resistance burden affecting many South American countries. Optimization of alternative approaches to monitor local antibiotic resistance trends in resource-limited settings is strongly encouraged to support the implementation of effective empiric treatment guidelines.

Topics: Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; beta-Lactamases; Bolivia; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Fosfomycin; Genotype; Humans; Klebsiella Infections; Klebsiella pneumoniae; Methyltransferases; RNA, Ribosomal, 16S; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections

Topics: Anti-Bacterial Agents; beta-Lactamases; Blood; Critical Illness; Drug Resistance, Bacterial; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Urine

Antibiotic resistance is an emerging phenomenon in kidney transplantation (KT).. We compared species distribution and antimicrobial susceptibility patterns in 1052 isolates from urine cultures obtained in 2 different cohorts of kidney transplant recipients in a single center (Cohort A: 189 patients undergoing KT between January 2002 and December 2004 [336 isolates]; Cohort B: 115 patients undergoing KT between January 2011 and December 2013 [716 isolates]).. Asymptomatic bacteriuria accounted for most of the isolates (86.9% in Cohort A and 92.3% in Cohort B). Klebsiella pneumoniae (9.5% vs. 15.6%), Pseudomonas aeruginosa (1.8% vs. 7.9%), and Enterobacter cloacae (0.6% vs. 3.1%) were significantly more common in Cohort B. The isolation of K. pneumoniae in Cohort B was associated with the occurrence of acute pyelonephritis (9.8% of all K. pneumoniae isolates vs. 2.8% of the remaining uropathogens; P = 0.001). Non-susceptibility rates among Enterobacteriaceae in Cohort B were higher for every class of antibiotics (P ≤ 0.003) with the exception of fosfomycin. Compared to Cohort A, significant increases were seen in isolates from Cohort B for multidrug-resistant (MDR) (43.9% vs. 67.8%, respectively; P = 0.001), extended-spectrum beta-lactamase (ESBL)-producing (6.6% vs. 26.1%; P = 0.001), and carbapenemase-producing Enterobacteriaceae strains (0.0% vs. 5.0%; P = 0.001). Such differences were mostly attributable to K. pneumoniae (as 54.5% and 13.4% of isolates in Cohort B were ESBL-producing and carbapenemase-producing, respectively). MDR isolates were responsible for 69.1% of episodes of symptomatic urinary tract infection in Cohort B.. The increase in resistance rates among Enterobacteriaceae uropathogens is significant and may have an effect on KT programs.

Topics: Adult; Aged; Anti-Bacterial Agents; Asymptomatic Infections; Bacterial Proteins; beta-Lactamases; Drug Resistance, Bacterial; Enterobacter cloacae; Enterobacteriaceae Infections; Female; Fosfomycin; Humans; Kidney Transplantation; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Randomized Controlled Trials as Topic; Retrospective Studies; Urinary Tract Infections

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

Topics: Amdinocillin; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Cefpodoxime; Ceftibuten; Ceftizoxime; Cephalosporins; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Fosfomycin; Genotype; Humans; In Vitro Techniques; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Multiplex Polymerase Chain Reaction; Penicillins; Singapore; Trimethoprim; Urinary Tract Infections

Donor-derived infections with multidrug-resistant gram-negative bacteria are associated with poor outcomes, in part because of limited treatment options. Here, we describe a case of donor-derived, disseminated infection with colistin-resistant, carbapenemase-producing Klebsiella pneumoniae in a liver transplant recipient that was cured with addition of intravenous fosfomycin to a multidrug regimen, in conjunction with aggressive surgical source control. Intravenous fosfomycin represents a promising adjunctive agent for use in treatment of extensively drug-resistant infections in immunocompromised hosts.

Topics: Aged; Allografts; Anti-Bacterial Agents; Antibiotic Prophylaxis; Bacterial Proteins; beta-Lactamases; Colistin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Fibrosis; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Liver Transplantation; Microbial Sensitivity Tests; Minocycline; Tigecycline

Klebsiella pneumoniae New Delhi metallo-beta-lactamase-1 (NDM-1) strains have recently become a new threat in kidney transplant recipients due to the strains' resistance to almost all antibiotics, including carbapenems.. We present a case series of 3 patients with urinary tract infections (UTIs) caused by multiresistant K pneumoniae NDM-1 strains who were treated with the same protocol. Genotyping sequencing with pulsed-field gel electrophoresis was performed in all cases.. All patients were male and had undergone kidney transplantation 4, 7, and 8 months, respectively, before the admission. Combined antibiotic therapy consisting of imipenem/cilastatin in maximal doses, gentamicin and/or colistin for 21 to 27 days, followed by oral fosfomycin, was used in all cases. There were no further UTI episodes in 2 patients at the 12-month visit. Three months after initial treatment, the third patient presented with leukocyturia with no clinical symptoms and a urine culture positive for K pneumonia NDM-1 strain. Interestingly, the strain was susceptible to trimethoprim/sulfamethoxazole despite resistance in previous urine culture samples. The patient was successfully treated with trimethoprim/sulfamethoxazole 2 × 960 mg/d for 3 weeks followed by 480 mg/d and 3 doses of fosfomycin. Genotyping sequencing revealed identical DNA restriction fragments in bacterial strains from 2 patients. In the third case, although a difference in 2 restriction fragments was observed, the strain was considered related to the others.. In cases of UTI caused by K pneumoniae NDM-1 strains, prolong combined treatment followed by oral fosfomycin prophylaxis can be successful. Strain genotyping should be performed to optimize further treatment protocols in such cases.

Topics: Anti-Bacterial Agents; beta-Lactamases; Cilastatin; Cilastatin, Imipenem Drug Combination; Colistin; Drug Combinations; Drug Resistance, Microbial; Electrophoresis, Gel, Pulsed-Field; Fosfomycin; Genotype; Gentamicins; Humans; Imipenem; Kidney Transplantation; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Transplant Recipients; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections

Fosfomycin is increasingly called upon for the treatment of multi drug-resistant (MDR) organisms causing urinary tract infection (UTI). We reviewed oral fosfomycin use for UTI treatment in a large UK hospital. The primary goal was to audit our clinical practice against current national guidelines. Secondary aims were to identify factors associated with treatment failure, and to investigate the potential for using fosfomycin in patients with co-morbidities.. We retrospectively studied 75 adult patients with UTI who received 151 episodes of treatment with fosfomycin from March 2013 to June 2015. We collected clinical data from our electronic patient record, and microbiology data pre- and post- fosfomycin treatment. We recorded additional data for patients receiving prolonged courses in order to make a preliminary assessment of safety and efficacy. We also reviewed >18,000 urinary tract isolates of Escherichia coli and Klebsiella spp. processed by our laboratory over the final year of our study period to determine the prevalence of fosfomycin resistance.. There was a significant increase in fosfomycin treatment episodes over the course of the study period. Co-morbidities were present in 71 % of patients. The majority had E. coli infection (69 %), of which 59 % were extended spectrum beta-lactamase (ESBL)-producers. Klebsiella infections were more likely than E. coli to fail treatment, and more likely to be reported as fosfomycin resistant in cases of relapse following treatment. There were no adverse events in five patients treated with prolonged fosfomycin. Among all urinary isolates collected over a year, fosfomycin resistance was documented in 1 % of E. coli vs. 19 % of Klebsiella spp. (p < 0.0001).. We report an important role for oral fosfomycin for MDR UTI treatment in a UK hospital population, and based on the findings from this study, we present our own local guidelines for its use. We present preliminary data suggesting that fosfomycin is safe and effective for use in patients with complex comorbidities and over prolonged time periods, but may be less effective against Klebsiella than E. coli.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Female; Fosfomycin; Humans; Klebsiella; Klebsiella Infections; Male; Microbial Sensitivity Tests; Middle Aged; Retrospective Studies; Treatment Outcome; Urinary Tract Infections; Young Adult

Although fosfomycin is a treatment option for infections caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, fosfomycin resistance has been documented. To our knowledge, fosfomycin resistance mechanisms in Klebsiella pneumoniae have not been systematically investigated. A total of 108 ESBL-producing K. pneumoniae isolates collected from Kaohsiung Medical University Hospital, Taiwan, from August 2012 to May 2013 were analysed in this study. Pulsed-field gel electrophoresis (PFGE) revealed 64 pulsotypes and six non-typeable isolates, indicating high genetic diversity. Moreover, pulsotypes V (n = 6), VII (n = 11) and LI (n = 4) belonging to ST11 were major types. Among 30 (27.8%) fosfomycin-non-susceptible isolates, 21 (70%) had a MurA amino acid substitution, and seven new variations increased the fosfomycin minimum inhibitory concentration (MIC) by 8- to 16-fold compared with wild-type MurA in Escherichia coli DH5α.strain. Functionless transporters (GlpT and UhpT) with various mutations were found in 29 isolates (97%). No known fosfomycin-modifying enzymes were detected in this study. The major resistance mechanisms to fosfomycin in K. pneumoniae were amino acid variations in the drug target and transporters.

Topics: Alkyl and Aryl Transferases; Amino Acid Substitution; Anti-Bacterial Agents; beta-Lactamases; Electrophoresis, Gel, Pulsed-Field; Escherichia coli; Fosfomycin; Gene Expression; Genetic Variation; Humans; Klebsiella Infections; Klebsiella pneumoniae; Membrane Transport Proteins; Microbial Sensitivity Tests; Molecular Epidemiology; Molecular Typing; Taiwan

Topics: Aged; Amikacin; Anti-Bacterial Agents; Bacteremia; beta-Lactamases; Coinfection; Fosfomycin; Humans; Klebsiella Infections; Klebsiella oxytoca; Male; Methicillin Resistance; Staphylococcal Infections; Staphylococcus epidermidis; Treatment Outcome; Vancomycin

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 bla(KPC-2) was completely sequenced, revealing that the fosA3 gene was flanked by two copies of IS26; however, bla(KPC-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.

Topics: Anti-Bacterial Agents; beta-Lactamases; China; DNA, Bacterial; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Fosfomycin; Genotype; Hospitals; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Molecular Epidemiology; Molecular Sequence Data; Plasmids; Polymerase Chain Reaction; Sequence Analysis, DNA

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; beta-Lactamases; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male

The appearance of extended-spectrum beta-lactamase (ESBL)-producing gram-negative bacteria in urinary tract infection (UTI) constitutes an important therapeutic challenge. The aim of this study was to describe drug susceptibility profiles of ESBL-producing bacteria isolated from urine samples. We also determined the antimicrobial co-resistance to several agents, including fosfomycin.. The computerized database was used to identify ESBL-positive urine samples. We analyzed E. coli and Klebsiella isolates obtained from urine cultures, and duplicate isolates and isolates not tested against fosfomycin were excluded. The cases were further categorized according to UTI definition [community-acquired (CoA) UTI, community-onset health care-associated (HCA) UTI, and hospital-acquired (HA) UTI]. ESBL isolates were stratified according to their origin into two groups: urology and non-urology isolates.. Antimicrobial susceptibilities of the strains to fosfomycin were tested in 277 ESBL-positive strains, 217 ESBL-EC strains, and 60 ESBL-KP strains. The most effective agents were carbapenems, 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 out of the 277 (87.7 %) isolates tested were susceptible to fosfomycin. Higher fosfomycin sensitivity was observed in E. coli (94.9 %) compared to Klebsiella (61.7 %) (p = 0.001). ESBL-positive isolates from urological (68 isolates) and non-urological patients (209 isolates) showed similar susceptibility profiles. Other than carbapenems, isolates from CoA-UTI showed higher sensitivity to fosfomycin (100 %) and nitrofurantoin (93.1 %), isolates from HCA-UTI showed higher sensitivity to amikacin (94.1 %), and isolates from HA-UTI showed overall poor sensitivity to antibiotics.. Fosfomycin could be an alternative treatment option for UTIs related to ESBL-producing E. coli spp. and CoA-UTI, but not for UTIs related to ESBL-producing Klebsiella spp. Antimicrobial susceptibilities of ESBL-producing strains were different according to the UTI classification. Fosfomycin showed decreased activity against isolates from HCA-UTI and HA-UTI. However, further clinical verification is required to assess the clinical efficacy of fosfomycin for the treatment of UTIs caused by ESBL-producing E. coli isolates.

Topics: Adolescent; Adult; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactamases; Cross Infection; Escherichia coli; Escherichia coli Infections; Female; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Outcome Assessment, Health Care; Republic of Korea; Retrospective Studies; Urinary Tract Infections

Topics: Administration, Intravenous; Anti-Bacterial Agents; Bacteremia; Fatal Outcome; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Liver Transplantation; Middle Aged; United States

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.

Topics: Bacterial Proteins; Base Sequence; beta-Lactamases; China; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Epidemics; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Multilocus Sequence Typing; Plasmids

Fosfomycin is active in vitro against extensively drug-resistant (XDR) and pandrug-resistant (PDR) Pseudomonas aeruginosa and Klebsiella pneumoniae carbapenemase-producing strains; however, the in vivo effectiveness against such pathogens is almost unknown. A multicentre, observational, prospective case-series study was performed in 11 ICUs. All consecutive fosfomycin-treated patients suffering from XDR or PDR fosfomycin-susceptible, microbiologically documented infections were recorded. Clinical and microbiological outcomes were assessed. A safety analysis was performed. In total, 68 patients received fosfomycin during the study period, 48 of whom were considered suitable for effectiveness analysis based on predefined criteria. Bacteraemia and ventilator-associated pneumonia were the main infections. Carbapenemase-producing K. pneumoniae and P. aeruginosa were isolated in 41 and 17 cases, respectively. All isolates exhibited an XDR or PDR profile, being fosfomycin-susceptible by definition. Fosfomycin was administered intravenously at a median dose of 24g/day for a median of 14 days, mainly in combination with colistin or tigecycline. Clinical outcome at Day 14 was successful in 54.2% of patients, whilst failure, indeterminate outcome and superinfection were documented in 33.3%, 6.3% and 6.3%, respectively. All-cause mortality at Day 28 was 37.5%. Bacterial eradication was observed in 56.3% of cases. Fosfomycin resistance developed in three cases. The main adverse event was reversible hypokalaemia. In conclusion, fosfomycin could have a place in the armamentarium against XDR and PDR Gram-negative infections in the critically ill. Resistance development during therapy, which has been a matter of concern in previous studies, did not occur frequently. The necessity of combination with other antibiotics requires further investigation.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Fosfomycin; Humans; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Tigecycline; Treatment Outcome

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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactamases; Child; Child, Preschool; Drug Resistance, Bacterial; Escherichia coli Infections; Female; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Infant; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Urinary Tract; Urinary Tract Infections; Uropathogenic Escherichia coli; Young Adult

In recent years, the rising rates of resistance to antimicrobial drugs among pathogens have caused great difficulty for clinicians treating infectious diseases. The aim of the study was to assess the curative effect of fosfomycin in treating urinary tract infections (UTIs) in China.. We collected clinical isolates of UTIs to determine their susceptibility to fosfomycin by the agar dilution method and to analyze extended-spectrum β-lactamase (ESBL)-producing isolates by the double-disc method on Mueller-Hinton agar. Fosfomycin-modifying enzyme analysis was conducted by PCR. Differences between the different groups were determined by the χ(2) test.. We collected 433 UTI isolates, and the result showed that the susceptibility rates of clinical isolates were all above 80%. Only Klebsiella pneumoniae was fosA positive, with a positive rate of 26.7%. No correlation was found for the resistance between the antibiotic drugs tested and fosfomycin in the other bacteria, except for cefepime, levofloxacin and ciprofloxacin in Enterobacter cloacae and imipenem in K. pneumoniae.. Our data suggest that fosfomycin may be a suitable antimicrobial agent for UTI isolates and ESBL-producing bacteria in our hospital.

Topics: Anti-Bacterial Agents; beta-Lactamases; Enterobacter cloacae; Enterobacteriaceae Infections; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Urinary Tract Infections

Topics: Anti-Bacterial Agents; Bacteremia; Bacteriuria; Brazil; Drug Resistance, Bacterial; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Linear Models; Meropenem; Microbial Sensitivity Tests; Rectum; Thienamycins

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.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; Colistin; Disk Diffusion Antimicrobial Tests; Drug Synergism; Fosfomycin; Humans; Imipenem; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Minocycline; Molecular Typing; Real-Time Polymerase Chain Reaction; Thienamycins; Tigecycline

A woman aged 56 years of age had a community-acquired left neck abscess and internal jugular vein thrombosis with septicemia due to extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae. Even though she was treated with intravenous meropenem, the bacteremia persisted. She was complicated with multiple brain abscesses, seizure, and leucopenia. After a combination of intravenous fosfomycin and meropenem, her clinical condition became stable. Combination treatment was continued for 2 months and she recovered. In individual cases of Lemierre syndrome with brain abscess caused by ESBL-producing Enterobacteriaceae, fosfomycin combination therapy may be the alternative choice.

Topics: Anti-Bacterial Agents; beta-Lactamases; Brain; Brain Abscess; Community-Acquired Infections; Drug Therapy, Combination; Female; Fosfomycin; Humans; Infusions, Intravenous; Klebsiella Infections; Klebsiella pneumoniae; Lemierre Syndrome; Meropenem; Middle Aged; Sepsis; Thienamycins; Tomography, X-Ray Computed; Treatment Outcome

Topics: Anti-Bacterial Agents; Bacteremia; Drug Resistance, Bacterial; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests

To investigate the prevalence of plasmid-mediated fosfomycin resistance determinants among extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae and their genetic environments.. A total of 347 non-duplicate ESBL-producing E. coli (165) and K. pneumoniae (182) were collected. The fosfomycin MICs were determined by the agar dilution method according to CLSI guidelines. PCR was used to detect the plasmid-encoded fosfomycin resistance genes (fosA, fosA3, fosB and fosC2). For isolates harbouring plasmid-encoded fosfomycin resistance genes, sequence types (STs) were determined. The transformation experiment was performed using E. coli TOPO10 (Invitrogen, USA) as a recipient strain. With the plasmids from the transformants, plasmid replicon typing was performed and the nucleotide sequences adjacent to fosA3 were determined.. The susceptibility to fosfomycin was 92.9% in E. coli and 95.2% in K. pneumoniae. Of the 21 isolates non-susceptible to fosfomycin (8 E. coli and 13 K. pneumoniae), 7 (5 E. coli and 2 K. pneumoniae) isolates harboured fosA3 and all of them co-harboured bla(CTX-M-1group) or bla(CTX-M-9group). The STs of the isolates harbouring fosA3 were diverse (E. coli: ST1, ST1, ST533, ST2 and ST86; K. pneumoniae: ST11 and ST101). The plasmid replicon types of transformants co-harbouring bla(CTX-M-1group) and bla(CTX-M-9group) were IncF and IncN, respectively. By sequence analysis, we found the common feature that the fosA3 gene, connected to bla(CTX-M) via insertion sequences, was located between two IS26 elements oriented in the opposite direction, composing an IS26-composite transposon.. An IS26-composite transposon appears to be the main vehicle for dissemination of fosA3 in E. coli and K. pneumoniae of diverse clones.

Topics: Anti-Bacterial Agents; beta-Lactamases; DNA Transposable Elements; DNA, Bacterial; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Fosfomycin; Genotype; Humans; Klebsiella Infections; Klebsiella pneumoniae; Korea; Microbial Sensitivity Tests; Molecular Sequence Data; Plasmids; Polymerase Chain Reaction; Prevalence; Sequence Analysis, DNA; Transformation, Bacterial

Guideline recommendations on therapy in urinary tract infections are based on antibiotic resistance rates. Due to a lack of surveillance data, little is known about resistance rates in uncomplicated urinary tract infection (UTI) in general practice in Germany. In a prospective observational study, urine cultures of all women presenting with urinary tract infections in general practice were analysed. Resistance rates against antibiotics recommended in German guidelines on UTI are presented.. In a prospective, multi-center observational study general practitioner included all female patients ≥ 18 years with clinically suspected urinary tract infection. Only patients receiving an antibiotic therapy within the last two weeks were excluded.. 40 practices recruited 191 female patients (mean age 52 years; range 18-96) with urinary tract infections. Main causative agent was Escherichia coli (79%) followed by Enterococcus faecalis (14%) and Klebsiella pneumoniae (7.3%).Susceptibility of E.coli as the main causative agent was highest against fosfomycin and nitrofurantoin, with low resistance rates of 4,5%; 2,2%. In 17,5%, E.coli was resistant to trimethoprim and in 8,5% to ciprofloxacin.. Resistance rates of uropathogens from unselected patients in general practice differ from routinely collected laboratory data. These results can have an impact on antibiotic prescribing and treatment recommendations.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Infective Agents; Ciprofloxacin; Drug Resistance, Bacterial; Escherichia coli Infections; Female; Fosfomycin; General Practice; Germany; Gram-Positive Bacterial Infections; Humans; Klebsiella Infections; Microbial Sensitivity Tests; Middle Aged; Nitrofurantoin; Prospective Studies; Trimethoprim; Urinary Tract Infections; Young Adult

Seven carbapenem-resistant NDM-1-positive Klebsiella pneumoniae isolates were recovered from patients hospitalized between 2007 and 2009 in different wards at a referral and tertiary care center in Nairobi. Most of the isolates were obtained from urine. All isolates carried the bla(NDM-1) carbapenemase gene previously reported from India, Pakistan, and the United Kingdom. These isolates were clonally related and expressed many other resistance determinants, including β-lactamases CTX-M-15, OXA-1, OXA-9, CMY-6, and aminoglycoside resistance methylase RmtC. This work corresponds to the first report of NDM-1 producers in Africa.

Topics: Adult; Aged; Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Cross Infection; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Female; Humans; Kenya; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Polymerase Chain Reaction

We have collected cases of iatrogenic meningitis managed in the Children's Hospital of Tunis, between January 1998 and December 2006. Clinical information about each patient were collected, all bacterial samples were investigated in the microbiology laboratory of the hospital. Bacterial isolates were identified according to conventional criteria. In the interval under study, we recorded three cases of iatrogenic meningitis after lumbar puncture. Two cases occurred in newborn admitted for suspicion of neonatal infection and one in a 2-month-old infant admitted for exploration of hyperpyretic convulsion. In all patients, the initial cerebrospinal fluid was normal. All patients developed symptoms of acute meningitis within 72 hours after lumbar puncture; the second cerebrospinal fluid was, then, typical for purulent meningitis. The causal agents isolated in the three cases were Klebsiella pneumoniae, Enterobacter cloacae, and Serratia marcescens, all resistant to beta-lactams by extended spectrum beta-lactamase production. The use of quinolones was required in all cases. Different complications were recorded: hydrocephalus and brain abscess in one case, respiratory and hemodynamic failure managed in the intensive care unit in the second, and brain hygroma in the third case. This study shows high morbidity of iatrogenic meningitis. Simple aseptic precautions undertaken before the procedure of lumbar puncture can prevent such cases. The urgent need for increasing the awareness among medical personnel in hospitals of developing countries cannot be overemphasized.

Topics: beta-Lactam Resistance; Brain Abscess; Brain Damage, Chronic; Ciprofloxacin; Drug Therapy, Combination; Enterobacter cloacae; Enterobacteriaceae Infections; Female; Fosfomycin; Humans; Hydrocephalus; Iatrogenic Disease; Imipenem; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Klebsiella Infections; Klebsiella pneumoniae; Male; Meningitis, Bacterial; Muscle Hypotonia; Seizures; Serratia Infections; Serratia marcescens; Spinal Puncture; Subdural Effusion; Tunisia

Urinary tract infections (UTIs) caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae have become clinical problems because of limited therapeutic options. The role of fosfomycin in the era of growing bacteria resistance has been widely discussed recently. In this study, we aimed to know the local antimicrobial susceptibilities, fosfomycin susceptibility in particular, of urinary ESBL-producing E coli and K pneumoniae isolates in Taiwan.. We collected 200 urine isolates, including 134 ESBL-producing E coli (ESBL-EC) and 66 ESBL-producing K pneumoniae (ESBL-KP) isolates from July 2008 to December 2009 in a university-affiliated teaching hospital in Taiwan. We used disk diffusion method to determine susceptibility to fosfomycin. Fosfomycin may have lower susceptibility when using disk diffusion method compared with agar dilution method. Broth microdilution test was also used to determine minimal inhibitory concentrations (MICs) and susceptibilities to other antimicrobial agents.. Imipenem was active against ESBL-EC and ESBL-KP. Fosfomycin had good susceptibility to ESBL-EC (95.5%), including in hospital-acquired isolates, but lower antimicrobial activity against ESBL-KP (57.6%). Trimethoprim-sulfamethoxazole had the highest resistance rate to ESBL-EC and ESBL-KP. Comparing with non-hospital-acquired isolates, hospital-acquired ESBL-KP was associated with significantly lower susceptibility of gentamicin (13.3% vs. 66.7%), trimethoprim-sulfamethoxazole (8.9% vs. 38.1%), ciprofloxacin (26.7% vs. 61.9%), and amikacin (46.1% vs. 81.0%) (p<0.05). The resistance of some strains to ciprofloxacin was significantly associated with lower susceptibilities of gentamicin (32.6% in ESBL-EC), nitrofurantoin (2.4% in ESBL-KP) and trimethoprim-sulfamethoxazole (9.8% in ESBL-KP) (p<0.05) but not accompanied with decreasing susceptibility of fosfomycin.. Fosfomycin had the excellent activity against ESBL-EC but not ESBL-KP in this study. Based on the study findings, we suggest that fosfomycin can be a therapeutic option for UTIs with ESBL-EC. Nitrofuranoin was actively against ESBL-EC. Nitrofurantoin may be an alternative option for uncomplicated UTIs with ESBL-EC in Taiwan.

Topics: Anti-Bacterial Agents; beta-Lactamases; Escherichia coli; Escherichia coli Infections; Fosfomycin; Hospitals, Teaching; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Nitrofurantoin; Taiwan; Urinary Tract Infections

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Middle Aged; Polymyxin B; Treatment Failure; Urinary Tract Infections

In vitro activity of fosfomycin was evaluated against 68 bla(KPC)-possessing Klebsiella pneumoniae (KpKPC) isolates, including 23 tigecycline- and/or colistin-nonsusceptible strains. By agar dilution, 93% of the overall KpKPC were susceptible (MIC(50/90) of 16/64 microg/ml, respectively). The subgroup of 23 tigecycline- and/or colistin-nonsusceptible strains showed susceptibility rates of 87% (MIC(50/90) of 32/128 microg/ml, respectively). Notably, 5 out of 6 extremely drug-resistant (tigecycline and colistin nonsusceptible) KpKPC were susceptible to fosfomycin. Compared to agar dilution, disk diffusion was more accurate than Etest.

Topics: Anti-Bacterial Agents; beta-Lactamases; Colistin; Drug Resistance, Bacterial; Fosfomycin; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Phenotype; Tigecycline

Topics: Anti-Bacterial Agents; Carbapenems; Drug Resistance, Bacterial; Drug Synergism; Escherichia coli; Escherichia coli Infections; Fosfomycin; Hospitals; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; Escherichia coli Infections; Fosfomycin; Humans; Klebsiella Infections; Nitrofurantoin

The agar dilution, broth microdilution, and disk diffusion methods were compared to determine the in vitro susceptibility of 428 extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae to fosfomycin. Fosfomycin showed very high activity against all ESBL-producing strains. Excellent agreement between the three susceptibility methods was found for E. coli, whereas marked discrepancies were observed for K. pneumoniae.

Topics: Anti-Bacterial Agents; Escherichia coli; Escherichia coli Infections; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests

Infection due to extended-spectrum beta-lactamase (ESBL)-producing microorganisms is an emerging problem in the community; a high proportion of these microorganisms have been isolated from urine samples of women with uncomplicated urinary tract infections (UTI). The options for oral treatment of uncomplicated UTI are limited because of the multiple drug resistance typical of ESBL-producing strains.. The in vitro activity of fosfomycin (FOS) was determined against 428 ESBL-producing strains, including 290 (68%) E. coli and 138 (32%) K. pneumoniae. Activity of fosfomycin was compared with that of amoxicillin-clavulanate (AMC), ciprofloxacin (CIP) and cotrimoxazole (SxT). MICs of AMC, CIP, and SxT, and detection of ESBL production were tested by the broth microdilution method, whereas FOS MICs were determined by the agar dilution method. ESBLs were characterized by isoelectric focusing, polymerase chain reaction (PCR) and direct sequencing of encoding genes. The genetic relationship among the isolates was determined by REP-PCR.. Among the 428 ESBL-producing isolates studied, 417 (97.4%) were susceptible to FOS (MIC < or = 64 microg/mL). The resistance rate of E. coli to FOS was 0.3%, and was lower than resistance to AMC (11.7%), whereas the resistance rate of K. pneumoniae was 7.2% and was equal to resistance to AMC. SxT and CIP were the least active antibiotic agents against ESBL-producing isolates (sensitivity < 50%). There were no differences in fosfomycin activity against strains expressing different types of ESBLs.. Fosfomycin showed maintained activity against ESBL-producing strains and did not present co-resistance with other antimicrobial groups.

Topics: Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; Ciprofloxacin; Cross Infection; Escherichia coli; Escherichia coli Infections; Fosfomycin; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Multicenter Studies as Topic; Substrate Specificity; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections

The authors studied the activity of fosfomycin (FOS) and/or gentamicin (GEN) against a Klebsiella pneumoniae strain resistant to all beta-lactams--except cephamycins and imipenem--by production of a plasmid mediated extended broad-spectrum beta-lactamase-TEM-3, to all aminoglycosides--except gentamicin--by production of a plasmid mediated 6' aminoglycoside acetyltransferase IV, to sulfonamides and to tetracyclines. In vitro, the combination FOS (MIC = MBC = 32 mg/l) + GEN (MIC = MBC = 2) appeared indifferent (FIC = 0.75; FBC = 1). In vivo, on experimental endocarditis in rabbits, FOS alone was ineffective, GEN alone was active but only at high dose regimen, FOS - GEN combination was active as compared with controls. Fosfomycin - gentamicin combination may be an alternative in the therapy of severe infections due to multiresistant Enterobacteriacae.

Topics: Animals; beta-Lactamases; Drug Resistance, Microbial; Drug Therapy, Combination; Endocarditis, Bacterial; Female; Fosfomycin; Gentamicins; In Vitro Techniques; Klebsiella Infections; Klebsiella pneumoniae; Rabbits

Topics: Animals; Cystitis; Drug Combinations; Drug Evaluation, Preclinical; Escherichia coli Infections; Fosfomycin; Klebsiella Infections; Norfloxacin; Pipemidic Acid; Proteus Infections; Rats; Rats, Inbred Strains; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Amniotic Fluid; Ampicillin; Animals; Anti-Bacterial Agents; Bile; Cefaclor; Cephalexin; Escherichia coli Infections; Fosfomycin; Gentamicins; Humans; In Vitro Techniques; Kanamycin; Klebsiella Infections; Microbial Sensitivity Tests; Urine

Topics: Anti-Bacterial Agents; Binding, Competitive; Cephalexin; Drug Combinations; Drug Synergism; Drug Therapy; Enzyme Inhibitors; Escherichia coli Infections; Fosfomycin; Humans; Klebsiella Infections; Proteus Infections; Salmonella Infections; Staphylococcal Infections; Streptococcal Infections

In chemotherapy of otherwise fatally infected mice (intraperitoneally) the effective dose50 (ED50) of fosfomycin (2 single doses, subcutaneous application 1 and 6 h post infect.) was decreased significantly by supplementing the antibiotic solution with 100 mg glucose-6-phosphate (G-6-P) per kg animal and per injection if also the MIC of the infecting strain (Klebsiella oxytoca and K. aerogenes II) was lowered by addition of G-6-P (25 mg/l) to the nutrient medium (Table 1 and 2). With strains not exhibiting any influence on the MIC no such effect was observed (Table 1). From this it is concluded that the enhancement of antimicrobial activity of fosfomycin in vivo is based on the same mechanism as in vitro. This mechanism is the initiation of a second route of transportation into the bacterial cell (7), the hexose-6-phosphate transport system that apparently is inducible not only in vitro but also in vivo. Blood levels of G-6-P sufficient or above to induce this system in vitro (5 mg/l) were being held with doses of 100 mg/kg body weight in dogs during 70 to 120 min (Fig. 3) and 45 to 70 min (Fig. 4) when applied subcutaneously or intravenously respectively. These periods of contact area adequate to induce a considerable decrease of the MIC. With the strain used (K. oxytoca) the MIC of 128 mg/l was lowered by contact with G-6-P during 60 or 120 min to 16 or 8 mg/l respectively (Fig. 5). For full induction of the hexose-6-phosphate system resulting in a MIC of 2 mg/l however, 8 h were necessary. From the above findings it is concluded that clinical studies are necessary. As G-6-P is a (short-lived) physiological product of cell metabolism and nontoxic such studies are justifiable in cases where therapeutic use of fosfomycin can be regarded as an indication.

Topics: Animals; Anti-Bacterial Agents; Biological Transport; Dogs; Drug Synergism; Fosfomycin; Glucose-6-Phosphate; Glucosephosphates; Hexosephosphates; Klebsiella; Klebsiella Infections; Klebsiella pneumoniae; Male; Mice; Proteus Infections; Proteus mirabilis

We have examined the antibacterial activity of the new antibiotic, fosfomycin (FOM) in vitro and in vivo. The following results were obtained. 1. FOM showed a broad antibacterial spectrum. 2. The antibacterial activity of FOM was enhanced in the medium at pH 6 and pH 7, and was also influenced by the addition of rabbit serum, calf serum, glucose-6-phosphate or defibrilated sheep blood to the growth medium, and by the size of inoculum. 3 FOM showed especially strong bactericidal action upon the bacteria at the logarithmic phase. 4. FOM showed remarkable therapeutic effect against most strains of gram-positive and gram-negative bacteria tested in experimental infections of mice. 5. The therapeutic effect of FOM was especially remarkable for infection with Salmonella. 6. The therapeutic effect of FOM was more potent than the other drugs tested against infection of Pseudomonas aeruginosa. 7. It seems that FOM is more active in vivo than in vitro with respect to antibacterial activity.

Topics: Animals; Anti-Bacterial Agents; Drug Evaluation, Preclinical; Escherichia coli; Escherichia coli Infections; Fosfomycin; Haemophilus influenzae; Klebsiella Infections; Male; Mice; Microbial Sensitivity Tests; Proteus; Proteus Infections; Pseudomonas aeruginosa; Pseudomonas Infections; Salmonella; Salmonella Infections, Animal; Serratia marcescens; Staphylococcal Infections; Staphylococcus