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Infection and Drug Resistance 2019Monte Carlo simulation (MCS) was used to evaluate optimal dosage for cefepime (FEP), moxalactam (MOX), and cefperazone/sulbactam (CFZ/SBT) against extended-spectrum...
Monte Carlo simulation (MCS) was used to evaluate optimal dosage for cefepime (FEP), moxalactam (MOX), and cefperazone/sulbactam (CFZ/SBT) against extended-spectrum β-lactamase (ESBL) producers isolated from the Blood Bacterial Resistant Investigation Collaborative System. : Minimum inhibitory concentration (MIC) was tested by agar dilution, and ESBL producers were identified by modified Clinical and Laboratory Standards Institute tests. Pharmacokinetic parameters were derived from data on healthy individuals, and probability of target attainment (PTA) and cumulative fraction of response (CFR) %fT >MIC values were estimated by MCS. A total of 2032 (875 ESBL-producing) and (157 ESBL-producing) strains, and 371 other strains, were isolated from patients with bloodstream infections (BSIs). MIC values for FEP, MOX, and CFZ/SBT against ESBL-producing and were 64/64 mg/L, 2/32 mg/L, and 64/128 mg/L, respectively. Conventional MOX and CFZ/SBT doses failed to reach 90% PTA against isolates with MICs ≥8 mg/L and ≥4 mg/L, respectively. Against ESBL producers, neither FEP nor CFZ/SBT achieved ≥90% CFR, while CFRs for MOX (1 g iv q6h, 2 g iv q12h, and 2 g iv q8h) exceeded 90% against ESBL-producing . Simulated CFRs for FEP and MOX were similar (>90%) against non-ESBL-producing , and higher than CFRs for CFZ/SBT. ESBL producers from BSIs were highly susceptible to MOX, and PTA values were generally higher for MOX than FEP or CFZ/SBT for conventional dosing regimens. This large MCS analysis shows that MOX but not FEP or CFZ/SBT can be used empirically to treat BSIs caused by ESBL-producing strains.
PubMed: 31190908
DOI: 10.2147/IDR.S193712 -
Infection and Drug Resistance 2018
PubMed: 29608189
DOI: 10.2147/IDR.S163186 -
Journal of Food Protection Apr 2018There is no recommended protocol for detecting and isolating Clostridium difficile present in food samples. Here, we have evaluated the recovery of C. difficile in meat...
There is no recommended protocol for detecting and isolating Clostridium difficile present in food samples. Here, we have evaluated the recovery of C. difficile in meat samples after incubating them in various enrichment broths. The media were as follows: cycloserine-cefoxitin fructose broth supplemented with taurocholic acid, d-cycloserine, cefoxitin, and lysozyme; cycloserine-cefoxitin mannitol broth with taurocholate and lysozyme; and cycloserine-cefoxitin fructose broth supplemented with taurocholic acid, C. difficile moxalactam norfloxacin selective supplement, and lysozyme. Samples were inoculated with various strains and quantities of C. difficile and then enriched in the different broths for 1, 4, and 7 days. C. difficile was isolated on agar plates and detected with quantitative real-time PCR (qPCR). The procedure using enrichment in cycloserine-cefoxitin fructose broth supplemented with taurocholic acid, d-cycloserine, cefoxitin, and lysozyme and incubation for 4 days for qPCR detection and 7 days for isolation (plating on C. difficile agar base with added C. difficile selective supplement and 7% [v/v] defibrinated horse blood after alcoholic shock and centrifugation) was validated. Samples of different kinds of meat and meat preparation were contaminated and used for validation of the chosen protocol. The sensitivity of detection with qPCR was 100%, and the sensitivity of the isolation method was 96%.
Topics: Animals; Clostridioides difficile; Horses; Meat; Microbiological Techniques; Real-Time Polymerase Chain Reaction
PubMed: 29517350
DOI: 10.4315/0362-028X.JFP-17-354 -
Infection and Drug Resistance 2018The aim of this study was to evaluate the bactericidal effects of moxalactam (MOX), cefotaxime (CTX), and cefoperazone/sulbactam (CFZ/SBT) against extended-spectrum...
OBJECTIVES
The aim of this study was to evaluate the bactericidal effects of moxalactam (MOX), cefotaxime (CTX), and cefoperazone/sulbactam (CFZ/SBT) against extended-spectrum β-lactamase (ESBL) producing and , using an in vitro pharmacokinetics (PK)/pharmacodynamics model.
METHODS
Two clinical ESBL-producing strains ( positive 3376 and positive 2689) and American Type Culture Collection (ATCC)25922 were used in the study. The PK Auto Simulation System 400 was used to simulate the human PK procedures after intravenous administration of different doses of MOX, CTX, and CFZ/SBT. Bacterial growth recovery time (RT) and the area between the control growth curve and bactericidal curves (IE) were employed to assess the antibacterial efficacies of all the agents.
RESULTS
The minimum inhibitory concentrations of MOX, CTX, and CFZ/SBT against ATCC25922, 3376, and 2689 strains were 0.5, 0.5, 0.25; 0.06, >256, 256; and 0.5/0.5, 16/16, 32/32 mg/L. All the agents demonstrated outstanding bactericidal effects against ATCC25922 (RT >24 h and IE >120 log CFU/mL·h) with simulating PK procedures, especially in the multiple dose administration models. Against ESBL producers, CTX and CFZ/SBT displayed only weak bactericidal effects, and subsequent regrowth was evident. MOX exhibited potent antibacterial activity against all the strains tested. The values of effective parameters of MOX were much higher than those of CTX and CFZ/SBT (the bacterial RTs with the 3 agents were >24, <4, and <13 h, and the IEs were >110, <10, and <60 log CFU/mL·h, respectively).
CONCLUSION
MOX demonstrated excellent bactericidal effect, which is worthy of further exploration to serve as an alternative therapeutic agent against ESBL-producing Enterobacteriaceae
PubMed: 29391816
DOI: 10.2147/IDR.S150431 -
Chinese Medical Journal Sep 2017Antimicrobial resistance is a serious problem that compromises the empirical treatment of infections, resulting in a lack of effective antibiotics and high medical...
BACKGROUND
Antimicrobial resistance is a serious problem that compromises the empirical treatment of infections, resulting in a lack of effective antibiotics and high medical expenses. Here, we aimed to monitor the trends in antimicrobial resistance among Enterobacteriaceae isolated from blood samples in mainland China.
METHODS
A total of 2240 Enterobacteriaceae isolates from blood were collected from hospitalized patients at 19 tertiary hospitals between October 2004 and June 2014. The minimum inhibitory concentrations of all isolates were determined using the agar dilution method according to the Clinical and Laboratory Standards Institute 2016 guidelines.
RESULTS
The most commonly isolated bacteria were Escherichia coli, compromising 47.0% (1053/2240) of the total isolates, followed by Klebsiella spp. (26.3%), Salmonella spp. (10.4%), and Enterobacter spp. (9.2%). The detection rates of extended-spectrum β-lactamases (ESBLs) among E. coli were 68.9% (2004-2005), 73.2% (2007-2008), 67.9% (2009-2010), 72.6% (2011-2012), and 58.4% (2013-2014), whereas those in ESBL-producing Klebsiella pneumoniae were slightly decreased (75.9%, 50.0%, 41.4%, 40.2%, and 43.0%, respectively). Carbapenems were the most potent agents against the Enterobacteriaceae isolates, followed by moxalactam, tigecycline, and amikacin. However, there was a decrease in the susceptibility rates for carbapenems in all species, particularly K. pneumoniae(decreased by 10.6% for imipenem) and Enterobacter aerogenes (decreased by 21.1% for imipenem). Reviving antibiotics (tigecycline and polymyxins) showed good in vitro activity against Enterobacteriaceae.
CONCLUSIONS
The activity of antibiotics against Enterobacteriaceae isolated from blood was decreased overall. Large proportions of ESBL-producing isolates were identified among E. coli and Klebsiella spp. Carbapenem-resistant isolates have become a major challenge in the treatment of infections.
Topics: Amikacin; Anti-Bacterial Agents; Carbapenems; China; Drug Resistance, Bacterial; Enterobacteriaceae; Escherichia coli; Humans; Imipenem; Microbial Sensitivity Tests; Minocycline; Tigecycline
PubMed: 28836547
DOI: 10.4103/0366-6999.213407 -
Scientific Reports Aug 2017The early postnatal period is the most dynamic and vulnerable stage in the assembly of intestinal microbiota. Antibiotics are commonly prescribed to newborn preterm...
The early postnatal period is the most dynamic and vulnerable stage in the assembly of intestinal microbiota. Antibiotics are commonly prescribed to newborn preterm babies and are frequently used for a prolonged duration in China. We hypothesized that the prolonged antibiotic therapy would affect the early development of intestinal microbiota and their metabolites. To test this hypothesis, we analyzed the stool microbiota and metabolites in 36 preterm babies with or without antibiotic treatment. These babies were divided into three groups, including two groups treated with the combination of penicillin and moxalactam or piperacillin-tazobactam for 7 days, and the other group was free of antibiotics. Compared to the antibiotic-free group, both antibiotic-treated groups had distinct gut microbial communities and metabolites, including a reduction of bacterial diversity and an enrichment of harmful bacteria such as Streptococcus and Pseudomonas. In addition, there was a significant difference in the composition of gut microbiota and their metabolites between the two antibiotic-treated groups, where the piperacillin-tazobactam treatment group showed an overgrowth of Enterococcus. These findings suggest that prolonged antibiotic therapy affects the early development of gut microbiota in preterm infants, which should be considered when prescribing antibiotics for this population.
Topics: Case-Control Studies; Female; Gastrointestinal Microbiome; Humans; Infant, Newborn; Infant, Premature; Intestinal Mucosa; Male; beta-Lactamase Inhibitors
PubMed: 28808302
DOI: 10.1038/s41598-017-08530-9 -
Journal of Clinical Microbiology Jul 2017
Topics: Anti-Bacterial Agents; Bacterial Proteins; Carbapenem-Resistant Enterobacteriaceae; Humans; Microbial Sensitivity Tests; Moxalactam; beta-Lactamases
PubMed: 28468855
DOI: 10.1128/JCM.00606-17 -
Antimicrobial Agents and Chemotherapy Dec 2016BEL-1 is an acquired class A extended-spectrum β-lactamase (ESBL) found in Pseudomonas aeruginosa clinical isolates from Belgium which is divergent from other ESBLs...
BEL-1 is an acquired class A extended-spectrum β-lactamase (ESBL) found in Pseudomonas aeruginosa clinical isolates from Belgium which is divergent from other ESBLs (maximum identity of 54% with GES-type enzymes). This enzyme is efficiently inhibited by clavulanate, imipenem, and moxalactam. Crystals of BEL-1 were obtained at pH 5.6, and the structure of native BEL-1 was determined from orthorhombic and monoclinic crystal forms at 1.60-Å and 1.48-Å resolution, respectively. By soaking native BEL-1 crystals, complexes with imipenem (monoclinic form, 1.79-Å resolution) and moxalactam (orthorhombic form, 1.85-Å resolution) were also obtained. In the acyl-enzyme complexes, imipenem and moxalactam differ by the position of the α-substituent and of the carbonyl oxygen (in or out of the oxyanion hole). More surprisingly, the Ω-loop, which includes the catalytically relevant residue Glu166, was found in different conformations in the various subunits, resulting in the Glu166 side chain being rotated out of the active site or even in displacement of its Cα atom up to approximately 10 Å. A BEL-1 variant showing the single Leu162Phe substitution (BEL-2) confers a higher level of resistance to CAZ, CTX, and FEP and shows significantly lower K values than BEL-1, especially with oxyiminocephalosporins. BEL-1 Leu162 is located at the beginning of the Ω-loop and is surrounded by Phe72, Leu139, and Leu148 (contact distances, 3.5 to 3.9 Å). This small hydrophobic cavity could not reasonably accommodate the bulkier Phe162 found in BEL-2 without altering neighboring residues or the Ω-loop itself, thus likely causing an important alteration of the enzyme kinetic properties.
Topics: Anti-Bacterial Agents; Catalytic Domain; Citric Acid; Crystallography, X-Ray; Disulfides; Imipenem; Moxalactam; beta-Lactamases
PubMed: 27671060
DOI: 10.1128/AAC.00936-16 -
Journal of Clinical Microbiology Dec 2016Disk diffusion testing is widely used to detect methicillin resistance in staphylococci, and cefoxitin is currently considered the best marker for mecA-mediated...
Disk diffusion testing is widely used to detect methicillin resistance in staphylococci, and cefoxitin is currently considered the best marker for mecA-mediated methicillin resistance. In low-inoculum diffusion testing (colony suspension at 10 CFU/ml), the addition of moxalactam in combination with cefoxitin has been reported to improve on cefoxitin alone for the detection of methicillin-heteroresistant staphylococci. However, moxalactam is absent from EUCAST and CLSI guidelines, which use high-inoculum diffusion testing (colony suspension at 10 CFU/ml), calling into question the potential interest of including moxalactam in their recommendations. The inhibition zone diameters of cefoxitin and moxalactam, alone and in combination, were evaluated for concordance with mecA and mecC positivity in a large collection of clinical Staphylococcus isolates (611 Staphylococcus aureus, Staphylococcus lugdunensis, and Staphylococcus saprophyticus isolates and 307 coagulase-negative staphylococci other than S. lugdunensis and S. saprophyticus isolates, of which 22% and 53% were mecA-positive, respectively) and in 25 mecC-positive S. aureus isolates using high-inoculum diffusion testing. Receiver operating characteristic, sensitivity, and specificity analyses indicated that the detection of mecA- and mecC-positive and negative isolates did not improve with moxalactam, either alone or in combination with cefoxitin, compared to cefoxitin alone. These findings were similar in both the S. aureus/S. lugdunensis/S. saprophyticus group and in the coagulase-negative staphylococci group. Our results do not support the use of moxalactam as an additional marker of methicillin resistance when testing with high-inoculum disk diffusion.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Cefoxitin; Disk Diffusion Antimicrobial Tests; Humans; Methicillin-Resistant Staphylococcus aureus; Moxalactam; Penicillin-Binding Proteins; Staphylococcus lugdunensis; Staphylococcus saprophyticus
PubMed: 27629897
DOI: 10.1128/JCM.01195-16 -
Antimicrobial Agents and Chemotherapy Feb 2016Class C β-lactamases poorly hydrolyze cephamycins (e.g., cefoxitin, cefotetan, and moxalactam). In the past 2 decades, a new family of plasmid-based AmpC β-lactamases...
Class C β-lactamases poorly hydrolyze cephamycins (e.g., cefoxitin, cefotetan, and moxalactam). In the past 2 decades, a new family of plasmid-based AmpC β-lactamases conferring resistance to cefoxitin, the FOX family, has grown to include nine unique members descended from the Aeromonas caviae chromosomal AmpC. To understand the basis for the unique cephamycinase activity in the FOX family, we determined the first X-ray crystal structures of FOX-4, apo enzyme and the acyl-enzyme with its namesake compound, cefoxitin, using the Y150F deacylation-deficient variant. Notably, recombinant expression of N-terminally tagged FOX-4 also yielded an inactive adenylylated enzyme form not previously observed in β-lactamases. The posttranslational modification (PTM), which occurs on the active site Ser64, would not seem to provide a selective advantage, yet might present an opportunity for the design of novel antibacterial drugs. Substantial ligand-induced changes in the enzyme are seen in the acyl-enzyme complex, particularly the R2 loop and helix H10 (P289 to N297), with movement of F293 by 10.3 Å. Taken together, this study provides the first picture of this highly proficient class C cephamycinase, uncovers a novel PTM, and suggests a possible cephamycin resistance mechanism involving repositioning of the substrate due to the presence of S153P, N289P, and N346I substitutions in the ligand binding pocket.
Topics: Aeromonas caviae; Amino Acid Sequence; Anti-Bacterial Agents; Bacterial Proteins; Cefoxitin; Crystallography, X-Ray; Drug Resistance, Multiple, Bacterial; Escherichia coli Proteins; Microbial Sensitivity Tests; Models, Molecular; Molecular Sequence Data; Protein Isoforms; Protein Processing, Post-Translational; Sequence Alignment; Tandem Mass Spectrometry; beta-Lactamases
PubMed: 26525784
DOI: 10.1128/AAC.01887-15