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1.
PLoS One ; 17(5): e0265720, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35503768

RESUMO

BACKGROUND: Repeated rotation of empiric antibiotic treatment strategies is hypothesized to reduce antibiotic resistance. Clinical rotation studies failed to change unit-wide prevalence of antibiotic resistant bacteria (ARB) carriage, including an international cluster-randomized crossover study. Unit-wide effects may differ from individual effects due to "ecological fallacy". This post-hoc analysis of a cluster-randomized crossover study assesses differences between cycling and mixing rotation strategies in acquisition of carriage with Gram-negative ARB in individual patients. METHODS: This was a controlled cluster-randomized crossover study in 7 ICUs in 5 European countries. Clinical cultures taken as routine care were used for endpoint assessment. Patients with a first negative culture and at least one culture collected in total were included. Community acquisitions (2 days of admission or less) were excluded. Primary outcome was ICU-acquisition of Enterobacterales species with reduced susceptibility to: third- or fourth generation cephalosporins or piperacillin-tazobactam, and Acinetobacter species and Pseudomonas aeruginosa with reduced susceptibility for piperacillin-tazobactam or carbapenems. Cycling (altering first-line empiric therapy for Gram-negative bacteria, every other 6-weeks), to mixing (changing antibiotic type every empiric antibiotic course). Rotated antibiotics were third- or fourth generation cephalosporins, piperacillin-tazobactam and carbapenems. RESULTS: For this analysis 1,613 admissions were eligible (855 and 758 during cycling and mixing, respectively), with 16,437 microbiological cultures obtained. Incidences of acquisition with ARB during ICU-stay were 7.3% (n = 62) and 5.1% (n = 39) during cycling and mixing, respectively (p-value 0.13), after a mean of 17.7 (median 15) and 20.8 (median 13) days. Adjusted odds ratio for acquisition of ARB carriage during mixing was 0.62 (95% CI 0.38 to 1.00). Acquired carriage with ARB were Enterobacterales species (n = 61), Pseudomonas aeruginosa (n = 38) and Acinetobacter species (n = 20), with no statistically significant differences between interventions. CONCLUSIONS: There was no statistically significant difference in individual patients' risk of acquiring carriage with Gram-negative ARB during cycling and mixing. These findings substantiate the absence of difference between cycling and mixing on the epidemiology of Gram-negative ARB in ICU. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, registered 10 January 2011, NCT01293071.


Assuntos
Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Carbapenêmicos/farmacologia , Cefalosporinas/farmacologia , Estudos Cross-Over , Bactérias Gram-Negativas , Humanos , Unidades de Terapia Intensiva , Piperacilina/farmacologia , Estudos Prospectivos , Pseudomonas aeruginosa , Tazobactam/farmacologia
2.
Int J Mol Sci ; 23(7)2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35409082

RESUMO

Model informed drug development is a valuable tool for drug development and clinical application due to its ability to integrate variability and uncertainty of data. This study aimed to determine an optimal dosage of ceftiofur against P. multocida by ex vivo pharmacokinetic/pharmacodynamic (PK/PD) model and validate the dosage regimens by Physiological based Pharmacokinetic-Pharmacodynamic (PBPK/PD) model. The pharmacokinetic profiles of ceftiofur both in plasma and bronchoalveolar lavage fluid (BALF) are determined. PD performance of ceftiofur against P. multocida was investigated. By establishing PK/PD model, PK/PD parameters and doses were determined. PBPK model and PBPK/PD model were developed to validate the dosage efficacy. The PK/PD parameters, AUC0-24 h/MIC, for bacteriostatic action, bactericidal action and elimination were determined as 44.02, 89.40, and 119.90 h and the corresponding dosages were determined as 0.22, 0.46, and 0.64 mg/kg, respectively. AUC24 h/MIC and AUC 72 h/MIC are simulated by PBPK model, compared with the PK/PD parameters, the therapeutic effect can reach probability of target attainment (PTA) of 90%. The time-courses of bacterial growth were predicted by the PBPK/PD model, which indicated the dosage of 0.46 mg/kg body weight could inhibit the bacterial growth and perform good bactericidal effect.


Assuntos
Pasteurella multocida , Animais , Antibacterianos/uso terapêutico , Cefalosporinas/farmacologia , Testes de Sensibilidade Microbiana , Suínos
3.
Microb Genom ; 8(4)2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35404783

RESUMO

Resistance to piperacillin/tazobactam (TZP) in Escherichia coli has predominantly been associated with mechanisms that confer resistance to third-generation cephalosporins. Recent reports have identified E. coli strains with phenotypic resistance to piperacillin/tazobactam but susceptibility to third-generation cephalosporins (TZP-R/3GC-S). In this study we sought to determine the genetic diversity of this phenotype in E. coli (n=58) isolated between 2014-2017 at a single tertiary hospital in Liverpool, UK, as well as the associated resistance mechanisms. We compare our findings to a UK-wide collection of invasive E. coli isolates (n=1509) with publicly available phenotypic and genotypic data. These data sets included the TZP-R/3GC-S phenotype (n=68), and piperacillin/tazobactam and third-generation cephalosporin-susceptible (TZP-S/3GC-S, n=1271) phenotypes. The TZP-R/3GC-S phenotype was displayed in a broad range of sequence types, which was mirrored in the same phenotype from the UK-wide collection, and the overall diversity of invasive E. coli isolates. The TZP-R/3GC-S isolates contained a diverse range of plasmids, indicating multiple acquisition events of TZP resistance mechanisms rather than clonal expansion of a particular plasmid or sequence type. The putative resistance mechanisms were equally diverse, including hyperproduction of TEM-1, either via strong promoters or gene amplification, carriage of inhibitor-resistant ß-lactamases, and an S133G bla CTX-M-15 mutation detected for the first time in clinical isolates. Several of these mechanisms were present at a lower abundance in the TZP-S/3GC-S isolates from the UK-wide collection, but without the associated phenotypic resistance to TZP. Eleven (19%) of the isolates had no putative mechanism identified from the genomic data. Our findings highlight the complexity of this cryptic phenotype and the need for continued phenotypic monitoring, as well as further investigation to improve detection and prediction of the TZP-R/3GC-S phenotype from genomic data.


Assuntos
Infecções por Escherichia coli , Sepse , Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Escherichia coli/genética , Infecções por Escherichia coli/epidemiologia , Humanos , Combinação Piperacilina e Tazobactam
4.
J Med Microbiol ; 71(4)2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35451945

RESUMO

Introduction. Ceftolozane/tazobactam was approved by the Drug Office, Department of Health, Government of the Hong Kong Special Administrative Region in 2017.Hypothesis/Gap Statement. Currently the in vitro activity of ceftolozane/tazobactam against Gram-negative pathogens isolated from patients in Hong Kong is undocumented. It would be prudent to document the activity of ceftolozane/tazobactam against Pseudomonas aeruginosa and Enterobacterales isolated from hospitalized patients in Hong Kong.Aim. To describe the in vitro susceptibility of recent clinical isolates of P. aeruginosa and the two most common Enterobacterales species (Klebsiella pneumoniae, Escherichia coli) cultured from respiratory tract, intra-abdominal, urinary tract and bloodstream infection samples to ceftolozane/tazobactam and other commonly used antimicrobial agents.Methodology. CLSI-defined broth microdilution MICs were determined and interpreted for Gram-negative isolates collected in Hong Kong from 2017 to 2019 by the SMART surveillance programme.Results. For P. aeruginosa, 96.7 % of isolates (n=210) were susceptible to ceftolozane/tazobactam, while susceptibility rates were ≥14 % lower to meropenem (82.9 % susceptible), cefepime (82.4 %), ceftazidime (81.4 %), piperacillin/tazobactam (76.7 %) and levofloxacin (79.5 %). Ceftolozane/tazobactam inhibited 85.7 % of piperacillin/tazobactam-nonsusceptible isolates, 80.6-82.1 % of cefepime-, ceftazidime- or meropenem-nonsusceptible isolates, and 75.9 % of multidrug-resistant (MDR) isolates of P. aeruginosa. For K. pneumoniae, 96.1 % of isolates (n=308) were susceptible to ceftolozane/tazobactam compared with meropenem (99.0 % susceptible), piperacillin/tazobactam (93.8 %), cefepime (85.7 %) and ceftazidime (85.4 %). The majority (88.3 %) of ESBL (extended-spectrum ß-lactamase) non-CRE (carbapenem-resistant Enterobacterales) phenotype isolates of K. pneumoniae were susceptible to ceftolozane/tazobactam, comparable to piperacillin/tazobactam (85.0 %) but lower than meropenem (100 %). For E. coli, 98.5 % of isolates (n=609) were susceptible to ceftolozane/tazobactam compared to meropenem (99.3 % susceptible), piperacillin/tazobactam (96.7 %), ceftazidime (82.3 %) and cefepime (76.5 %). The majority (96.7 %) of ESBL non-CRE phenotype isolates of E. coli were susceptible to ceftolozane/tazobactam, similar to both meropenem (100 %) and piperacillin/tazobactam (94.5 %).Conclusions. Overall, >96 % of clinical isolates of P. aeruginosa, K. pneumoniae and E. coli collected in Hong Kong in 2017-2019 were susceptible to ceftolozane/tazobactam, while the activity of several commonly prescribed ß-lactams was reduced, especially for P. aeruginosa. Continued surveillance of ceftolozane/tazobactam and other agents is warranted.


Assuntos
Ceftazidima , Infecções por Pseudomonas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefepima , Ceftazidima/farmacologia , Cefalosporinas/farmacologia , Escherichia coli , Hong Kong/epidemiologia , Humanos , Klebsiella pneumoniae , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Combinação Piperacilina e Tazobactam , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/epidemiologia , Pseudomonas aeruginosa , Tazobactam/farmacologia
5.
Sci Rep ; 12(1): 4455, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35292686

RESUMO

Resistant strains of Pseudomonas aeruginosa are common pathogens in the intensive care unit (ICU), limiting available therapeutic options. We aimed to compare ceftolozane/tazobactam (C/T) with colistimethate sodium (CMS) in the treatment of ventilator-associated pneumonia (VAP) due to extensively drug-resistant (XDR) Pseudomonas aeruginosa. A retrospective, observational study was performed at a tertiary care ICU. Clinical and microbiological success rate, 28-day all-cause mortality, and adverse events were compared in patients who received C/T with those treated with systemic CMS. A total of 51 patients were included (18 in the C/T and 33 in the CMS group). Clinical success rates in the C/T and CMS groups were 13 (72.2%) and 10 (30.3%), respectively. On multivariate regression analysis, treatment with C/T was independently associated with clinical success (odds ratio 4.47, 95% CI 1.17-17.08). There was no difference in 28-day all-cause mortality (27.8% and 33.3% in the C/T and CMS group, p = 0.76). Acute kidney injury was more common in patients who received CMS (48.5% vs 11.1%, p = 0.01). In our study, ceftolozane/tazobactam was more efficacious in the treatment of XDR Pseudomonas aeruginosa VAP and showed a better safety profile compared to CMS.


Assuntos
Pneumonia Associada à Ventilação Mecânica , Infecções por Pseudomonas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , Colistina/efeitos adversos , Farmacorresistência Bacteriana Múltipla , Humanos , Testes de Sensibilidade Microbiana , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa , Estudos Retrospectivos , Tazobactam/farmacologia , Tazobactam/uso terapêutico
6.
Klin Lab Diagn ; 67(3): 158-162, 2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35320631

RESUMO

Long-term antibiotic therapy, as well as inappropriate use of drugs in the treatment of osteomyelitis, can lead to the appearance of pan-resistant strains. The existing antibiotic prophylaxis regimens for purulent-septic complications are outdated and need to be adjusted. In this regard, it is necessary to monitor the resistance of microorganisms in order to identify ineffective antibacterial drugs. To analyze the resistance profiles of Enterobacteriaceae isolated from patients with chronic osteomyelitis to cephalosporin drugs over a three-year period. The resistance profiles of 912 clinical strains of Enterobacteriaceae were analyzed: Klebsiella pneumoniae (n=349), Proteus sp. (n=208), Escherichia coli (n=176), Enterobacter cloacae (n=179) for the period from 2018-2020 to cephalosporin drugs. In 2018, 66.2% of Enterobacteriaceace were resistant to the 1st generation cephalosporins, in 2019 - 78.7%, in 2020 - 79.5%. Generation II cephalosporins were most active against Proteus sp. bacteria, but a decrease in clinical effect was observed by 2020. Among the third generation cephalosporins in 2018, cefotaxime was most active, but in 2020 the number of resistant strains doubled and amounted to 86.3%. Ceftazidime was active against 47.1% of Enterobacteriaceae isolates in 2018, in 2019 - 45% of strains, in 2020 - 37.2% of bacterial strains. High activity of ceftriaxone was noted only in 2018 against Proteus sp. Preparations of the IV generation in 2018 showed the highest activity against bacteria of the genus Proteus, the least - against bacteria K. pneumoniae. In the period from 2019-2020, a significant decrease in the effectiveness of cefepime was observed.The monitoring of the resistance profiles to antibiotics of the cephalosporin series revealed their low efficacy against Enterobacteriaceae isolated from wounds and fistulas of patients with chronic osteomyelitis, which shows the inexpediency of their empirical use.


Assuntos
Cefalosporinas , Osteomielite , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , Enterobacteriaceae/genética , Humanos , Testes de Sensibilidade Microbiana , Osteomielite/tratamento farmacológico
7.
Microbiol Spectr ; 10(2): e0008422, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35323031

RESUMO

Cefiderocol is a novel siderophore cephalosporin exhibiting potent antimicrobial activities. Although cefiderocol has not been approved in China, resistance is emerging. A multicenter study was performed to evaluate the cefiderocol resistance in carbapenem-resistant Klebsiella pneumoniae (CRKP) strains from bloodstream infections in patients with hematologic malignancies in China. Clinical data analysis and whole-genome sequencing were conducted for collected cefiderocol-resistant CRKP strains. CRISPR-Cas9 system was employed to construct site-specific mutagenesis for gene cirA. Plasmid curing and cloning were performed to assess the effect of ß-lactamases on cefiderocol resistance. Total 86 CRKP strains were collected. The MICs of cefiderocol ranged from 0.06 to >256 mg/L. Among four cefiderocol-nonsusceptible strains (4/86, 4.7%), two cefiderocol-resistant strains AR8538 (MIC = 32 mg/L) and AR8416 (MIC > 256 mg/L) were isolated from two patients with acute lymphocytic leukemia (frequency of resistance, 2/86, 2.3%). Metallo- and serine-ß-lactamase inhibitors addition would decrease the MIC of cefiderocol from 32 to 1 mg/L in AR8538, which harbors blaSHV-12, blaDHA-1, and two copies of blaNDM-1 in different plasmids. Avibactam did not impact cefiderocol susceptibility of AR8416, which produces NDM-5. However, we found a deficient CirA in AR8416. Using the same K serotype strain D3, we proved CirA deficiency or carrying NDM individually reduced cefiderocol susceptibility, but their simultaneously existence rendered a high-level cefiderocol resistance. In summary, the resistance of CRKP against cefiderocol is mediated by multiple factors, including the deficiency of CirA, metallo- or serine-ß-lactamases, while a high-level cefiderocol resistance could be rendered by the combined effect of NDM expression and CirA deficiency. IMPORTANCE Cefiderocol-resistant CRKP strains are emerging in bloodstream infections in Chinese patients with hematologic malignancies, although cefiderocol has not been approved for clinical use in China. Our study proved that the resistance of CRKP against cefiderocol is mediated by multiple factors, including the deficiency of CirA, metallo- or serine-ß-lactamases, while a high-level cefiderocol resistance could be rendered by the combined effect of NDM expression and CirA deficiency. As NDM production is one of the most critical mechanisms resulting in carbapenem resistance, it would pose great challenges on the clinical efficacy of cefiderocol in future.


Assuntos
Neoplasias Hematológicas , Infecções por Klebsiella , Sepse , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Carbapenêmicos , Cefalosporinas/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Neoplasias Hematológicas/complicações , Humanos , Klebsiella pneumoniae/genética , Testes de Sensibilidade Microbiana , Serina/farmacologia , beta-Lactamases/genética
8.
Drugs ; 82(5): 533-557, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35294769

RESUMO

Sulopenem (formerly known as CP-70,429, and CP-65,207 when a component of a racemic mixture with its R isomer) is an intravenous and oral penem that possesses in vitro activity against fluoroquinolone-resistant, extended spectrum ß-lactamases (ESBL)-producing, multidrug-resistant (MDR) Enterobacterales. Sulopenem is being developed to treat patients with uncomplicated and complicated urinary tract infections (UTIs) as well as intra-abdominal infections. This review will focus mainly on its use in UTIs. The chemical structure of sulopenem shares properties of penicillins, cephalosporins, and carbapenems. Sulopenem is available as an oral prodrug formulation, sulopenem etzadroxil, which is hydrolyzed by intestinal esterases, resulting in active sulopenem. In early studies, the S isomer of CP-65,207, later developed as sulopenem, demonstrated greater absorption, higher drug concentrations in the urine, and increased stability against the renal enzyme dehydropeptidase-1 compared with the R isomer, which set the stage for its further development as a UTI antimicrobial. Sulopenem is active against both Gram-negative and Gram-positive microorganisms. Sulopenem's ß-lactam ring alkylates the serine residues of penicillin-binding protein (PBP), which inhibits peptidoglycan cross-linking. Due to its ionization and low molecular weight, sulopenem passes through outer membrane proteins to reach PBPs of Gram-negative bacteria. While sulopenem activity is unaffected by many ß-lactamases, resistance arises from alterations in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), expression of carbapenemases (e.g., carbapenemase-producing Enterobacterales and in Stenotrophomonas maltophilia), reduction in the expression of outer membrane proteins (e.g., some Klebsiella spp.), and the presence of efflux pumps (e.g., MexAB-OprM in Pseudomonas aeruginosa), or a combination of these mechanisms. In vitro studies have reported that sulopenem demonstrates greater activity than meropenem and ertapenem against Enterococcus faecalis, Listeria monocytogenes, methicillin-susceptible S. aureus (MSSA), and Staphylococcus epidermidis, as well as similar activity to carbapenems against Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. With some exceptions, sulopenem activity against Gram-negative aerobes was less than ertapenem and meropenem but greater than imipenem. Sulopenem activity against Escherichia coli carrying ESBL, CTX-M, or Amp-C enzymes, or demonstrating MDR phenotypes, as well as against ESBL-producing Klebsiella pneumoniae, was nearly identical to ertapenem and meropenem and greater than imipenem. Sulopenem exhibited identical or slightly greater activity than imipenem against many Gram-positive and Gram-negative anaerobes, including Bacteroides fragilis. The pharmacokinetics of intravenous sulopenem appear similar to carbapenems such as imipenem-cilastatin, meropenem, and doripenem. In healthy subjects, reported volumes of distribution (Vd) ranged from 15.8 to 27.6 L, total drug clearances (CLT) of 18.9-24.9 L/h, protein binding of approximately 10%, and elimination half-lives (t½) of 0.88-1.03 h. The estimated renal clearance (CLR) of sulopenem is 8.0-10.6 L/h, with 35.5% ± 6.7% of a 1000 mg dose recovered unchanged in the urine. An ester prodrug, sulopenem etzadroxil, has been developed for oral administration. Initial investigations reported a variable oral bioavailability of 20-34% under fasted conditions, however subsequent work showed that bioavailability is significantly improved by administering sulopenem with food to increase its oral absorption or with probenecid to reduce its renal tubular secretion. Food consumption increases the area under the curve (AUC) of oral sulopenem (500 mg twice daily) by 23.6% when administered alone and 62% when administered with 500 mg of probenecid. Like carbapenems, sulopenem demonstrates bactericidal activity that is associated with the percentage of time that free concentrations exceed the MIC (%f T > MIC). In animal models, bacteriostasis was associated with %f T > MICs ranging from 8.6 to 17%, whereas 2-log10 kill was seen at values ranging from 12 to 28%. No pharmacodynamic targets have been documented for suppression of resistance. Sulopenem concentrations in urine are variable, ranging from 21.8 to 420.0 mg/L (median 84.4 mg/L) in fasted subjects and 28.8 to 609.0 mg/L (median 87.3 mg/L) in those who were fed. Sulopenem has been compared with carbapenems and cephalosporins in guinea pig and murine systemic and lung infection animal models. Studied pathogens included Acinetobacter calcoaceticus, B. fragilis, Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, Proteus vulgaris, and Serratia marcescens. These studies reported that overall, sulopenem was non-inferior to carbapenems but appeared to be superior to cephalosporins. A phase III clinical trial (SURE-1) reported that sulopenem was not non-inferior to ciprofloxacin in women infected with fluoroquinolone-susceptible pathogens, due to a higher rate of asymptomatic bacteriuria in sulopenem-treated patients at the test-of-cure visit. However, the researchers reported superiority of sulopenem etzadroxil/probenecid over ciprofloxacin for the treatment of uncomplicated UTIs in women infected with fluoroquinolone/non-susceptible pathogens, and non-inferiority in all patients with a positive urine culture. A phase III clinical trial (SURE-2) compared intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid with ertapenem in the treatment of complicated UTIs. No difference in overall success was noted at the end of therapy. However, intravenous sulopenem followed by oral sulopenem etzadroxil was not non-inferior to ertapenem followed by oral stepdown therapy in overall success at test-of-cure due to a higher rate of asymptomatic bacteriuria in the sulopenem arm. After a meeting with the US FDA, Iterum stated that they are currently evaluating the optimal design for an additional phase III uncomplicated UTI study to be conducted prior to the potential resubmission of the New Drug Application (NDA). It is unclear at this time whether Iterum intends to apply for EMA or Japanese regulatory approval. The safety and tolerability of sulopenem has been reported in various phase I pharmacokinetic studies and phase III clinical trials. Sulopenem (intravenous and oral) appears to be well tolerated in healthy subjects, with and without the coadministration of probenecid, with few serious drug-related treatment-emergent adverse events (TEAEs) reported to date. Reported TEAEs affecting ≥1% of patients were (from most to least common) diarrhea, nausea, headache, vomiting and dizziness. Discontinuation rates were low and were not different than comparator agents. Sulopenem administered orally and/or intravenously represents a potentially well tolerated and effective option for treating uncomplicated and complicated UTIs, especially in patients with documented or highly suspected antimicrobial pathogens to commonly used agents (e.g. fluoroquinolone-resistant E. coli), and in patients with documented microbiological or clinical failure or patients who demonstrate intolerance/adverse effects to first-line agents. This agent will likely be used orally in the outpatient setting, and intravenously followed by oral stepdown in the hospital setting. Sulopenem also allows for oral stepdown therapy in the hospital setting from intravenous non-sulopenem therapy. More clinical data are required to fully assess the clinical efficacy and safety of sulopenem, especially in patients with complicated UTIs caused by resistant pathogens such as ESBL-producing, Amp-C, MDR E. coli. Antimicrobial stewardship programs will need to create guidelines for when this oral and intravenous penem should be used.


Assuntos
Bacteriúria , Staphylococcus aureus Resistente à Meticilina , Pró-Fármacos , Infecções Urinárias , Monofosfato de Adenosina/farmacologia , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bacteriúria/induzido quimicamente , Bacteriúria/tratamento farmacológico , Carbapenêmicos/farmacologia , Cefalosporinas/farmacologia , Ciprofloxacina/farmacologia , Ertapenem , Escherichia coli , Feminino , Fluoroquinolonas/farmacologia , Bactérias Gram-Negativas , Cobaias , Humanos , Imipenem/farmacologia , Lactamas , Masculino , Proteínas de Membrana/farmacologia , Meropeném/farmacologia , Camundongos , Probenecid/farmacologia , Pró-Fármacos/farmacologia , Staphylococcus aureus , Infecções Urinárias/tratamento farmacológico , beta-Lactamases/farmacologia
9.
J Bacteriol ; 204(4): e0060221, 2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-35258319

RESUMO

Cephalosporins are commonly prescribed antibiotics that impair cross-linking of the bacterial cell wall. The Gram-positive opportunistic pathogen, Enterococcus faecalis, is intrinsically resistant to these antibiotics and proliferates substantially during cephalosporin therapy. As a result, the usage of cephalosporins has the potential to lead to life-threatening enterococcal infections. Yet, the molecular mechanisms that drive cephalosporin resistance (CR) are incompletely understood. Previously, we demonstrated that MurAA, an enzyme that catalyzes the first committed step in peptidoglycan (PG) synthesis, is required for CR. However, the mechanism by which MurAA contributes to CR remained unknown. Here, we tested the hypothesis that MurAA drives CR by controlling metabolic flux through the PG synthesis pathway. To do so, we developed and exploited an inducible gene expression system for E. faecalis based on an interspecies chimeric receptor that responds to exogenous nitrate for control of expression from a NisR-regulated promoter (PnisA). We used this tool to demonstrate synthetic lethality of MurAA with its homolog MurAB, to titrate expression of MurAA, and to conditionally deplete multiple PG synthesis enzymes downstream of MurAA that are predicted to be essential. These genetic manipulations, in addition to pharmacological inhibition of the PG synthesis pathway, all led to reductions in PG synthesis that correlated with reductions in CR. Our findings are consistent with a model in which control of metabolic flux through the PG synthesis pathway is a major driver of CR. IMPORTANCE Enterococci are dangerous opportunistic pathogens with the potential to cause life-threatening infections due in part to their intrinsic resistance to cephalosporin antibiotics. Elucidating the molecular mechanisms that provide this resistance is critical for the development of strategies to both prevent and treat enterococcal infections. Here, we report that the cell wall synthesis enzyme, MurAA, drives cephalosporin resistance at least in part by controlling metabolic flux through the peptidoglycan synthesis pathway. To demonstrate this, we designed and validated an inducible gene expression system based on a chimeric receptor that is functional in multiple lineages of E. faecalis. In doing so, we provided a new tool for inducible gene expression with broad applications beyond our studies, including studies of essential genes.


Assuntos
Resistência às Cefalosporinas , Enterococcus faecalis , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Resistência às Cefalosporinas/genética , Cefalosporinas/metabolismo , Cefalosporinas/farmacologia , Enterococcus faecalis/metabolismo , Expressão Gênica , Peptidoglicano/metabolismo
10.
Diagn Microbiol Infect Dis ; 103(1): 115660, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35306445

RESUMO

Third generation cephalosporins (3GC)-resistant Neisseria flavescens could cause difficult-to-treat infections. This study aimed to investigate the genetic determinants of 3GC resistance using whole genome sequence comparisons of three N. flavescens; one of which was 3GC-resistant, while two were susceptible. Mutations in penA, ponA, and porB might be associated with the 3GC-resistance.


Assuntos
Gonorreia , Neisseria gonorrhoeae , Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Humanos , Líbano , Testes de Sensibilidade Microbiana , Neisseria , Neisseria gonorrhoeae/genética
11.
Diagn Microbiol Infect Dis ; 103(1): 115651, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35228130

RESUMO

Cefiderocol, a siderophore-containing cephalosporin with broad-spectrum antimicrobial activity against many ß-lactam-resistant Gram-negative bacteria, was tested by broth microdilution against 104 carbapenem-non-susceptible Enterobacterales clinical isolates from 2011 to 2018. Carbapenemase identification was determined using PCR followed by targeted gene sequencing or whole genome sequencing (WGS). All isolates were multidrug-resistant, 89.4% (93/104) and produced a serine (KPC or SME) carbapenemase, with as many as four ß-lactamases present. A VIM-1 or NDM-1 metallo-ß-lactamase was confirmed in 6.7% of the isolates (N = 5 and 2, respectively). All isolates were susceptible to cefiderocol, unlike the comparator agents. Susceptibility for comparators ranged from 24.0% for meropenem to 91.3%, 92.3% and 96.1% for imipenem-relebactam, ceftazidime-avibactam and meropenem-vaborbactam, respectively; 48.1%, 75.2% and 79.8% of the isolates were susceptible to omadacycline, colistin and eravacycline, respectively. Two isolates with cefiderocol MICs of 2 mg/L had mutations or deletions of the iron transport genes fhuA/E or fepA, as determined by WGS.


Assuntos
Carbapenêmicos , Cefalosporinas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos , Carbapenêmicos/farmacologia , Cefalosporinas/farmacologia , Combinação de Medicamentos , Humanos , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , beta-Lactamases/genética
12.
Appl Environ Microbiol ; 88(7): e0227621, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35254097

RESUMO

Extended-spectrum cephalosporin-resistant (ESC-R) Escherichia coli have disseminated in food-producing animals globally, attributed to horizontal transmission of blaCTX-M variants, as seen in the InCI1-blaCTX-M-1 plasmid. This ease of transmission, coupled with its demonstrated long-term persistence, presents a significant One Health antimicrobial resistance (AMR) risk. Bacteriophage (phage) therapy is a potential strategy in eliminating ESC-R E. coli in food-producing animals; however, it is hindered by the development of phage-resistant bacteria and phage biosafety concerns. Another alternative to antimicrobials is probiotics, with this study demonstrating that AMR-free commensal E. coli, termed competitive exclusion clones (CECs), can be used to competitively exclude ESC-R E. coli. This study isolated and characterized phages that lysed E. coli clones harboring the InCI1-blaCTX-M-1 plasmid, before investigation of the effect and synergy of phage therapy and competitive exclusion as a novel strategy for decolonizing ESC-resistant E. coli. In vitro testing demonstrated superiority in the combined therapy, reducing and possibly eliminating ESC-R E. coli through phage-mediated lysis coupled with simultaneous prevention of regrowth of phage-resistant mutants due to competitive exclusion with the CEC. Further investigation into this combined therapy in vivo is warranted, with on-farm application possibly reducing ESC-R prevalence, while constricting newly emergent ESC-R E. coli outbreaks prior to their dissemination throughout food-producing animals or humans. IMPORTANCE The emergence and global dissemination of resistance toward critically important antimicrobials, including extended-spectrum cephalosporins in the livestock sector, deepens the One Health threat of antimicrobial resistance. This resistance has the potential to disseminate to humans, directly or indirectly, nullifying these last lines of defense in life-threatening human infections. This study explores a novel strategy, the coadministration of bacteriophages (phages) and a competitive exclusion clone (antimicrobial-susceptible commensal E. coli), to revert an antimicrobial-resistant population to a susceptible population. While phage therapy is vulnerable to the emergence of phage-resistant bacteria, no phage-resistant bacteria emerged when a competitive exclusion clone was used in combination with the phage. Novel strategies that reduce the prevalence and slow the dissemination of extended-spectrum cephalosporin-resistant E. coli in food-producing animals have the potential to extend the time frame in which antimicrobials remain available for effective use in animal and human health.


Assuntos
Bacteriófagos , Infecções por Escherichia coli , Terapia por Fagos , Animais , Antibacterianos/farmacologia , Bacteriófagos/genética , Cefalosporinas/farmacologia , Escherichia coli/genética , Infecções por Escherichia coli/epidemiologia , Infecções por Escherichia coli/prevenção & controle , beta-Lactamases
13.
Microbiol Spectr ; 10(2): e0271221, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35262394

RESUMO

Cefiderocol is a siderophore-conjugated cephalosporin with broad activity against Gram-negative (GN) bacteria, including carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia. Cefiderocol was approved by the FDA for treatment of complicated urinary tract infection, hospital-acquired bacterial pneumonia, and ventilator-associated bacterial pneumonia and by the European Medicines Agency (EMA) for aerobic GN infections in adults with few treatment options. In this study, we analyzed the susceptibility of cefiderocol against GN clinical isolates that were collected from hospitalized patients in the United States and Europe in 2020 as part of the SENTRY Antimicrobial Surveillance Program. GN isolates, including 8,047 Enterobacterales, 2,282 P. aeruginosa, 650 Acinetobacter species, and 338 S. maltophilia isolates, were consecutively collected from patients in 66 hospitals in 19 countries. Susceptibility testing was performed using the CLSI broth microdilution method, and cefiderocol was tested in iron-depleted cation-adjusted Mueller-Hinton broth. Cefiderocol activity against resistant isolates, including CRE and extensively drug-resistant (XDR) isolates, was determined. Enterobacterales susceptibility to cefiderocol was 99.8% (CLSI), and CRE susceptibility was 98.2%. Cefiderocol was the most active antimicrobial against all P. aeruginosa isolates with MIC50/90 values of 0.12/0.5 mg/L, respectively (99.6% susceptible). A total of 256 P. aeruginosa isolates were XDR, 97.3% were susceptible to cefiderocol, and 7.4% were susceptible to meropenem. Acinetobacter susceptibility to cefiderocol was 97.7%. S. maltophilia susceptibility to cefiderocol was 100.0% (CLSI, 2021) and 97.9% (CLSI, 2022). These in vitro data suggest that cefiderocol is an important therapeutic option for the treatment of infections caused by Gram-negative pathogens, including isolates resistant to carbapenems with few therapeutic options. IMPORTANCE Cefiderocol is the first siderophore-conjugated cephalosporin approved for use in the treatment of human bacterial infections. Cefiderocol has broad-spectrum Gram-negative activity against difficult-to-treat bacterial pathogens that can cause serious infections. Our study examines the activity of cefiderocol against a large global collection of Gram-negative clinical isolates collected from hospitalized patients in 2020. In addition, we compare the activities of cefiderocol and recently approved ß-lactam-ß-lactamase inhibitor combinations against various antimicrobial-resistant pathogen groups including carbapenem-resistant Enterobacterales, meropenem-resistant Pseudomonas aeruginosa, and meropenem-resistant Acinetobacter spp. as well as isolates resistant to most classes of antimicrobial drugs. Cefiderocol was the most active antimicrobial tested against the isolates in this study. Our in vitro data suggest that cefiderocol may be useful for treatment of serious infections caused by drug-resistant Gram-negative organisms for patients with limited treatment options.


Assuntos
Acinetobacter , Pneumonia Bacteriana , Antibacterianos/farmacologia , Carbapenêmicos , Cefalosporinas/farmacologia , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas , Humanos , Meropeném , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa , Sideróforos/farmacologia , Estados Unidos
15.
Antimicrob Agents Chemother ; 66(4): e0229421, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35345891

RESUMO

The emergence of multidrug resistance in Neisseria gonorrhoeae is concerning, especially the cooccurrence of azithromycin resistance and decreased susceptibility to extended-spectrum cephalosporin. This study aimed to confirm the antibiotic resistance trends and provide a solution for N. gonorrhoeae treatment in Guangdong, China. A total of 5,808 strains were collected for assessment of antibiotic MICs. High resistance to penicillin (53.80 to 82%), tetracycline (88.30 to 100%), ciprofloxacin (96 to 99.8%), cefixime (6.81 to 46%), and azithromycin (8.60 to 20.03%) was observed. Remarkably, spectinomycin and ceftriaxone seemed to be the effective choices, with resistance rates of 0 to 7.63% and 2.00 to 16.18%, respectively. Moreover, the rates of azithromycin resistance combined with decreased susceptibility to ceftriaxone and cefixime reached 9.28% and 8.64%, respectively. Furthermore, genotyping identified NG-STAR-ST501, NG-MAST-ST2268, and MLST-ST7363 as the sequence types among representative multidrug-resistant isolates. Evolutionary analysis showed that FC428-related clones have spread to Guangdong, China, which might be a cause of the rapid increase in extended-spectrum cephalosporin resistance currently. Among these strains, the prevalence of N. gonorrhoeae was extremely high, and single-dose ceftriaxone treatment might be a challenge in the future. To partially relieve the treatment pressure, a susceptibility test for susceptibility to azithromycin plus extended-spectrum cephalosporin dual therapy was performed. The results showed that all the representative isolates could be effectively killed with the coadministration of less than 1 mg/liter azithromycin and 0.125 mg/liter extended-spectrum cephalosporin, with a synergistic effect according to a fractional inhibitory concentration (FIC) of <0.5. In conclusion, dual therapy might be a powerful measure to treat refractory N. gonorrhoeae in the context of increasing antibiotic resistance in Guangdong, China.


Assuntos
Gonorreia , Neisseria gonorrhoeae , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Azitromicina/farmacologia , Azitromicina/uso terapêutico , Cefixima/farmacologia , Ceftriaxona/farmacologia , Ceftriaxona/uso terapêutico , Resistência às Cefalosporinas , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , China/epidemiologia , Farmacorresistência Bacteriana , Gonorreia/tratamento farmacológico , Gonorreia/epidemiologia , Humanos , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus
16.
J Antimicrob Chemother ; 77(5): 1282-1285, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35134942

RESUMO

OBJECTIVES: Cefiderocol maintains activity against most MDR Gram-negative pathogens including Pseudomonas aeruginosa. In laboratory-derived isolates, down-regulation of TonB-dependent siderophore receptors have been implicated in resistance to cefiderocol. METHODS: In this report, the expression of seven TonB-dependent siderophore receptors was examined in 10 clinical isolates with cefiderocol MICs ranging from ≤0.03-8 mg/L. In addition, genetic sequences of the siderophore receptors were analysed to identify potentially disruptive mutations. RESULTS: There was no clear association between expression of the receptors with cefiderocol susceptibility, including the receptors piuA/piuD and pirA previously implicated in cefiderocol uptake. In addition, there were no disabling mutations identified in the receptors. Acquired ß-lactamase activity also could not explain the range in cefiderocol susceptibility. CONCLUSIONS: The aetiology of reduced susceptibility to cefiderocol in clinical isolates of P. aeruginosa remains an enigma and worthy of further investigation.


Assuntos
Farmacorresistência Bacteriana Múltipla , Pseudomonas aeruginosa , Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Bactérias Gram-Negativas , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/genética
17.
J Antimicrob Chemother ; 77(5): 1306-1312, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35137096

RESUMO

BACKGROUND: There is surprisingly little comparative published data on the bactericidal action of different sub-classes of ß-lactams against aerobic Gram-negative rods, and the assumption is that all behave in the same way. OBJECTIVES: To describe a systematic investigation of a representative penicillin, cephalosporin, monobactam and carbapenem against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. METHODS: Concentration-time-kill curves (TKC) were determined for three strains each of E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. All strains were susceptible to the agents used. The antibiotics were piperacillin/tazobactam, ceftazidime, aztreonam and meropenem. The initial inoculum was 106 cfu/mL and TKC were determined over 48 h. The area-under-the-bacterial-kill curve to 24 h (AUBKC 24 log cfu·h/mL) and 48 h (AUBKC 48) were used to measure antibacterial effect (ABE). Population profiles before and after antibiotic exposure were recorded. RESULTS: Against E. coli and K. pneumoniae meropenem had a maximal ABE at ≥MIC × 1 concentrations while piperacillin/tazobactam and ceftazidime had maximal effect at ≥MIC × 4 and aztreonam at ≥MIC × 8 concentrations. Ceftazidime, aztreonam and meropenem had less ABE against K. pneumoniae than E. coli. Against P. aeruginosa, meropenem was most bactericidal, with a maximum ABE at 8×/16 × MIC. Other ß-lactams had notably less ABE. In contrast, against A. baumannii, ceftazidime and meropenem had the greatest ABE, with a maximal effect at ≥MIC × 4, concentration changes in population profiles were least apparent with E. coli. CONCLUSIONS: ß-Lactam sub-classes (penicillins, cephalosporins, monobactams and carbapenems) have different antibacterial effects against E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. Extrapolation of in vitro pharmacodynamic findings from one species to another or one sub-class of ß-lactam to another is not justified.


Assuntos
Acinetobacter baumannii , Antibacterianos/farmacologia , Aztreonam/farmacologia , Carbapenêmicos , Ceftazidima/farmacologia , Cefalosporinas/farmacologia , Escherichia coli , Klebsiella pneumoniae , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Monobactamas , Piperacilina/farmacologia , Pseudomonas aeruginosa , Tazobactam , beta-Lactamas/farmacologia
18.
J Infect Public Health ; 15(4): 486-490, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35221238

RESUMO

BACKGROUND: Antimicrobial resistance is continuously increasing. Adding tazobactam to ceftolozane improves the latter's activity spectrum against resistant strains. We aimed to determine the susceptibility of recently collected bacterial isolates to ceftolozane/tazobactam (C/T) and other antibiotics. METHODS: This was a prospective cohort study conducted between March 2017 and March 2018. The in-vitro activities of C/T and 14 other antibiotics were assessed against 192 gram-negative bacterial (GNB) isolates (P. aeruginosa, K. pneumonia, E. coli, and other Enterobacterales) prospectively collected from two hospitals in Saudi arabia; in the laboratories of the International Health Management Associates Inc. Samples were obtained from intensive care units (ICUs) and non-ICU locations. The minimum inhibitory concentrations (MICs) of the antibiotics were determined by broth microdilution. Isolates were obtained from different infection sites [urine (31.8%), urinary bladder samples (15.1%), abscess/pus (20.3%), endotracheal aspirates (18.8%)]. RESULTS: Our sample showed substantial drug resistance; 66.1% of the collected isolates showed either multiple or extensive drug resistance. Susceptibility rates of P. aeruginosa (n = 50), E.coli (n = 40), K. pneumoniae (n = 64) and other Enterobacterales (n = 38) to C/T were 74%, 87.5%, 48.4% and 71.1%, respectively. According to MIC50 values (1 µg/mL for both P. aeruginosa and other Enterobacterales, 0.5 µg/mL for E.coli, and 4 µg/mL for K. pneumoniae), C/T was among the most potent antibiotics against these isolates. CONCLUSIONS: C/T displayed high potency against all examined bacterial isolates. It was mainly active against E.coli followed by P.aeruginosa and other Enterobacterales and its lowest susceptibility rate was reported against K. pneumoniae.


Assuntos
Escherichia coli , Infecções por Pseudomonas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefalosporinas/farmacologia , Farmacorresistência Bacteriana Múltipla , Hospitais , Humanos , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Estudos Prospectivos , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa , Arábia Saudita , Tazobactam/farmacologia
19.
Diagn Microbiol Infect Dis ; 103(1): 115654, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35219970

RESUMO

In 2016, our laboratory adopted the 2010 CLSI extended-spectrum cephalosporins (ESC) breakpoint criteria in Enterobacterales. ESBL testing had continued in Blood cultures but discontinued in General Cultures. The aims of this study were to examine the effect of this transition on (1) the resistance rates to ESC; (2) the consumption of parenteral ß-lactam antimicrobials, and (3) the therapeutic use of ESC and the outcome of patients infected by ESBL-producing Enterobacterales. In K. pneumoniae and E. coli, the ESC resistance rates had increased, declined or remained unchanged in Urine, General and Blood cultures, respectively. In P. mirabilis, the resistance rates declined for ceftazidime but remained unchanged for ceftriaxone. Carbapenem consumption had not replaced ESC, but the consumption of piperacillin-tazobactam had increased. The use of ESC in suspected ESBL infections had increased slightly, without effect on clinical outcome.


Assuntos
Cefalosporinas , Escherichia coli , Antibacterianos/farmacologia , Ceftazidima/farmacologia , Cefalosporinas/farmacologia , Humanos , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Proteus mirabilis , beta-Lactamases/farmacologia
20.
Eur J Med Chem ; 232: 114174, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35152091

RESUMO

Antibiotic resistance caused by ß-lactamases, particularly metallo-ß-lactamases, has been a major threat to public health globally. New Delhi metallo-ß-lactamase-1 (NDM-1) represents one of the most important metallo-ß-lactamases; the production of NDM-1 in bacterial pathogen significantly reduces the efficacy of ß-lactam antibiotics, including life-saving carbapenems. Herein, we have demonstrated stereochemically altered cephalosporins as potent inhibitors against NDM-1, as well as mutants of NDM. The structure and activity relationship (SAR) study on over twenty cephalosporin analogues discloses the stereochemistry and the substituents on 7-position and 3'-position of cephalosporin are critical to suppress the activity of NDM-1 and the optimal compound 1u exhibited an IC50 of 0.13 µM. Furthermore, a crystal complex of NDM-1 and 1u has been obtained, suggesting this cephalosporin derivative inhibits enzyme activity by the formation of a relatively stable hydrolytic product-NDM-1 intermediate. The discovery in this study may pave the way to turn cephalosporin, a natural substrate of ß-lactamase, into an effective NDM-1 inhibitor to combat antibiotic resistance.


Assuntos
Antibacterianos , Cefalosporinas , Inibidores de beta-Lactamases , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Cefalosporinas/química , Cefalosporinas/farmacologia , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/química
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