SciCombinator

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Concept: Ceftazidime

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Ceftolozane is a new cephalosporin with potent activity against Pseudomonas aeruginosa and Enterobacteriaceae. The neutropenic murine thigh-infection was used to determine which pharmacokinetic/pharmacodynamic index and magnitude drives efficacy of ceftolozane with gram-negative bacilli, compare the rate of in-vivo killing of ceftolozane with ceftazidime against P. aeruginosa, and determine the impact of different ratios of ceftolozane plus tazobactam on Enterobacteriaceae containing extended-spectrum-β-lactamases (ESBLs). Neutropenic mice had 10(6.2-7.1) cfu/thigh when treated with ceftolozane for 24 h with [1] varying doses (3.12 to 1600 mg/kg) and dosage intervals (3, 6, 12 and 24 h) against 2 Enterobacteriaceae, [2] 0.39-800 mg/kg every 6 h for 4 Enterobacteriaceae and 4 P. aeruginosa, and [3] 400 or 800 mg/kg with 2:1. 4:1, and 8:1 ratios of tazobactam against 5 Enterobacteriaceae with ESBLs. Pharmacokinetics of ceftolozane at 25, 100, and 400 mg/kg was linear with peak/dose values of 1.0-1.4 and half-lives of 12-14 min. T>MIC was the primary index driving efficacy. For stasis (1 log kill), T>MIC was 26.3% ± 2.1 (31.6% ± 1.6) for wild-type Enterobacteriaceae, 31.1% ± 4.9 (34.8% ±4.4) for Enterobacteriaceae with ESBLs, and 24.0% ± 3.3 (31.5% ± 3.9) for P. aeruginosa. At 200 mg/kg every 3 h, the rate of in-vivo killing of P. aeruginosa was faster with ceftolozane than with ceftazidime (-0.34 to -0.41 versus -0.21 to -0.24 log(10) cfu/thigh/h). The 2:1 ratio of ceftolozane with tazobactam was the most potent combination studied. T>MIC required for ceftolozane is less than with other cephalosporins and may be due to more rapid killing.

Concepts: Escherichia coli, Pseudomonas aeruginosa, Pseudomonas, Gram negative bacteria, Beta-lactamase, Pseudomonadales, Cephalosporin, Ceftazidime

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Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin conjugated with a catechol moiety at the 3(rd)-position side chain. The in vitro activity of cefiderocol against Pseudomonas aeruginosa was enhanced in the iron-depleted condition where that of ceftazidime was not affected. The monitoring of [Thiazole-(14)C]-cefiderocol revealed the increased intracellular accumulation of cefiderocol in the P. aeruginosa cells incubated under iron-depleted condition compared with those incubated under iron-sufficient condition. Cefiderocol was shown to have potent chelating activity with ferric iron, and extracellular iron was efficiently transported into P. aeruginosa cells in the presence of cefiderocol as well as siderophores, while enhanced transport of extracellular ferric iron was not observed when one of the hydroxyl groups of catechol moiety of cefiderocol was substituted with a methoxy group. We conclude that cefiderocol forms a chelating complex with iron, which is actively transported into P. aeruginosa cells via iron transporters, resulting in potent antibacterial activity of cefiderocol against P. aeruginosa.

Concepts: Alcohol, Bacteria, Pseudomonas aeruginosa, Pseudomonas, Transport, Hydroxyl, Cephalosporin, Ceftazidime

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The United States Clinical and Laboratory Standards Institute recently elected not to revise ceftazidime and cefepime Pseudomonas aeruginosa minimum inhibitory concentration (MIC) susceptibility breakpoints but rather recommended specific dosage regimens to correspond to breakpoints. This study’s objective was to examine mortality of low and high MIC P. aeruginosa isolates in bacteremic patients treated with cefepime or ceftazidime. Data were gathered through a Veterans Health Administration national administrative database for veterans with P. aeruginosa blood cultures who received cefepime or ceftazidime. Seventy-four patients in the low MIC (≤2 μg/mL) group and 29 patients in the high (4-8 μg/mL) MIC group were included. Independent baseline variables associated with 30-day all-cause mortality were determined through multivariate analysis to calculate propensity scores and perform matching. All-cause 30-day mortality was not statistically significant between the 2 resultant propensity score-matched groups (17.2% mortality in the low MIC group versus 27.6% in the high MIC group; P=0.34). Data suggested that P. aeruginosa bacteremia episodes where the cephalosporin MIC = 8 μg/mL may have higher mortality, however this may be reflective of higher propensity scores. Our study suggests that it is reasonable to designate a cefepime or ceftazidime MIC ≤8 μg/mL as susceptible for P. aeruginosa bacteremia infections, but potential suboptimal outcomes in episodes for which the P. aeruginosa MIC is 8 μg/mL may need further investigation.

Concepts: Bacteria, Pseudomonas aeruginosa, Pseudomonas, Pseudomonadales, Bacteremia, Cephalosporin, Ceftazidime, Cefepime

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The activity of ceftazidime-avibactam was compared with that of ceftazidime alone and meropenem against a collection of 190 P. aeruginosa clinical isolates recovered from a multicenter study of bloodstream infections. The addition of avibactam increased ceftazidime susceptibility in the complete collection of strains (64.7% to 91.1%) and particularly among subsets of isolates showing AmpC hyperproduction (10.9% to 76.1%) or MDR profiles (27% to 77.8%). MICs of ceftazidime-avibactam, in contrast with those of ceftazidime or meropenem, remained ≤4 μg/mL for a panel of 16 PAO1 isogenic mutants, expressing multiple combinations of the most relevant β-lactam resistance mechanisms.

Concepts: Immune system, Bacteria, Antibiotic resistance, Pseudomonas aeruginosa, Pseudomonas, Pseudomonadales, Ertapenem, Ceftazidime

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Broth microdilution antimicrobial susceptibility testing was performed for ceftazidime-avibactam and comparator agents against 7,062 clinical isolates of Pseudomonas aeruginosa collected during 2012 - 2014 in four geographic regions (Europe, Asia/South Pacific, Latin America, Middle East/Africa) as part of the INFORM global surveillance program. The majority of isolates were susceptible to ceftazidime-avibactam with the proportion susceptible varying marginally across the four regions (MIC90, 8-16 μg/ml; 88.7-93.2% susceptible), in contrast to lower susceptibilities to comparator β-lactam agents: ceftazidime (MIC90, 32-64 μg/ml; 71.5-80.8% susceptible), meropenem (MIC90, >8 μg/ml; 64.9-77.4% susceptible) and piperacillin-tazobactam (MIC90, >128 μg/ml; 62.3-71.3% susceptible). Compared to the overall population, susceptibility to ceftazidime-avibactam of isolates non-susceptible to ceftazidime (n=1,627) was reduced to between 56.8% (Middle East/Africa; MIC90, 64 μg/ml) and 68.9% (Asia/South Pacific; MIC90, 128 μg/ml), but these percentages were higher than susceptibilities to other β-lactam agents (0-44% susceptible, depending on region and agent; meropenem MIC90, >8 μg/ml; 26.5-43.9% susceptible). Amikacin (MIC90, >32 μg/ml; 53.2-80.0% susceptible) and colistin (MIC90, 1 μg/ml; 98.5-99.5% susceptible) showed comparable or higher susceptibility among this subset of isolates. A similar observation was made with isolates non-susceptible to meropenem (n=1,926), with susceptibility to ceftazidime-avibactam between 67.8% (Middle East/Africa; MIC90, 64 μg/ml) and 74.2% (Europe; MIC90, 32 μg/ml) accompanied again by reduced susceptibility to comparators except for amikacin (MIC90, >32 μg/ml; 56.8-78.7% susceptible) and colistin (MIC90, 1 μg/ml; 98.9-99.3% susceptible). Of the 8% of isolates not susceptible to ceftazidime-avibactam, half could be explained by their possession of genes encoding metallo-β-lactamases. The data reported here are consistent with results from other country-specific and regional surveillance studies and show that ceftazidime-avibactam demonstrates in vitro activity against globally collected clinical isolates of P. aeruginosa, including isolates resistant to ceftazidime and meropenem.

Concepts: Bacteria, Antibiotic resistance, Pseudomonas aeruginosa, Pseudomonas, Pseudomonadales, Ertapenem, Colistin, Ceftazidime

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Ceftazidime is one of the few cephalosporins with activity againstPseudomonas aeruginosa Using whole genome comparative analysis, we set out to determine the prevalent mechanism(s) of resistance to ceftazidime using a set of 181 clinical isolates. These isolates represented various multi-locus sequence types that consisted of both ceftazidime susceptible and resistant populations. A presumptive resistance mechanism against ceftazidime was identified in 88% of the non-susceptible isolates using this approach.

Concepts: Bacteria, Antibiotic resistance, Pseudomonas aeruginosa, Sequence, Cephalosporin, Ceftazidime

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We compared ceftazidime-avibactam, ceftolozane-tazobactam, ceftazidime, cefepime and piperacillin-tazobactam minimum inhibitory concentrations (MICs) against 38 meropenem-resistant P. aeruginosa. No isolates harbored carbapenemases; 74% were OprD mutants. Ceftazidime-avibactam and ceftolozane-tazobactam were active against 92%, including 80% that were resistant to all three β-lactams. Forty-three percent of ceftazidime-avibactam and 6% of ceftolozane-tazobactam-susceptible isolates exhibited MICs at respective breakpoints. Ceftolozane-tazobactam and ceftazidime-avibactam are therapeutic options against meropenem-resistant P. aeruginosa infections, which should be used judiciously to preserve activity.

Concepts: Bacteria, Antibiotic resistance, Pseudomonas aeruginosa, Phage therapy, Pseudomonas, Pseudomonadales, Cephalosporin, Ceftazidime

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The in vitro antibacterial activity of ceftazidime-avibactam and comparator agents was evaluated by reference broth microdilution methods against a collection of 1,743 Pseudomonas aeruginosa isolates collected from sixty-nine medical centers in the United States during 2014 representing each of the nine Census regions. Ceftazidime-avibactam demonstrated potent activity against P. aeruginosa, including many isolates non-susceptible to ceftazidime, meropenem, and piperacillin-tazobactam. In each of the nine Census regions, ceftazidime-avibactam demonstrated the highest percentage of susceptible isolates.

Concepts: Immune system, Bacteria, United States, Pseudomonas aeruginosa, Pseudomonas, Pseudomonadales, Ertapenem, Ceftazidime

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Mutation-dependent overproduction of intrinsic ß-lactamase AmpC is considered as the main cause of resistance of clinical strains of Pseudomonas aeruginosa to antipseudomonal penicillins and cephalosporins. Analysis of 31 AmpC-overproducing clinical isolates exhibiting a greater resistance to ceftazidime than to piperacillin-tazobactam revealed the presence of 17 mutations in the ß-lactamase, combined to various polymorphic amino acid substitutions. When overexpressed in AmpC-deficient P. aeruginosa 4098, the genes coding for 20/23 of these AmpC variants were found to confer a higher (2- to >64-fold) resistance to ceftazidime and ceftolozane-tazobactam than did the gene from reference strain PAO1. The mutations had variable effects on the minimal inhibitory concentrations (MICs) of ticarcillin, piperacillin-tazobactam, aztreonam, and cefepime. Depending on their location in the AmpC structure and their impact on ß-lactam MICs, they could be assigned to 4 distinct groups. Most of the mutations affecting the omega loop, the R2 domain and the C-terminal end of the protein were shared with ESACs (Extended-Spectrum AmpCs) from other Gram-negative species. Interestingly, two new mutations (F121L, P154L) were predicted to enlarge the substrate binding pocket by disrupting the stacking between residues F121 and P154. We also found that the reported ESACs emerged locally in a variety of clones some of which are epidemic, and did not require hypermutability. Taken together, our results show that P. aeruginosa is able adapt to efficacious ß-lactams including the newer cephalosporin ceftolozane through a variety of mutations affecting its intrinsic ß-lactamase, AmpC. Data suggest that the rates of ESAC-producing mutants are ≥ 1.5% in the clinical setting.

Concepts: Protein, Gene, Bacteria, Antibiotic resistance, Pseudomonas aeruginosa, Beta-lactamase, Cephalosporin, Ceftazidime

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We previously described extended-spectrum oxacillinase OXA-145 from Pseudomonas aeruginosa, which differs from narrow-spectrum OXA-35 by loss of Leu-155. The deletion results in loss of benzylpenicillin hydrolysis and acquisition of activity against ceftazidime. We report the crystal structure of OXA-145 and provide the basis of its switch in substrate specificity.

Concepts: Enzyme, Crystal, Pseudomonas aeruginosa, Solid, Crystallographic database, Cephalosporin, Ceftazidime