Journal of Antimicrobial Chemotherapy最新文献

Background: Coccidioidomycosis (Valley Fever) is a dimorphic fungal infection endemic to the southwest United States, Mexico, Central and South America, which can lead to chronic debilitating illness and death.

Objectives: This qualitative study was conducted to develop a bespoke patient-reported outcome measure for patients with chronic disseminated coccidioidomycosis to assess health-related quality of life (HRQoL) impacts.

Patients and methods: Online, first-person narratives of patient experiences of disseminated coccidioidomycosis were used to create a patient-centred conceptual model of symptoms and impacts of the condition. Interviews were conducted with expert clinicians, followed by concept elicitation interviews with patients, to generate key symptom and impact concepts from which an initial patient-reported outcome measure was developed. The draft measure was reviewed with clinicians for clinical relevance and further assessed in cognitive debriefing interviews with patients to refine the measure and establish content validity.

Results: A total of 25 patients were interviewed, which identified impacts relating to physical function, activities of daily living, cognitive function, social/role function and emotional function of disseminated coccidioidomycosis. Twenty items were developed simultaneously in English and Spanish to capture the main impacts across these 5 areas. In general, items were clear and well understood by patients, and clinicians found the measure clinically relevant and appropriate for assessing the burden of disseminated coccidioidomycosis on HRQoL.

Conclusions: Once fully validated, the Valley Fever-Patient Reported Outcome measure may be used in interventional studies to assess HRQoL outcomes, and in clinical practice to monitor patients' HRQoL.

Objectives: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is compromising gonorrhoea treatment, and enhanced N. gonorrhoeae AMR and genome-based epidemiological surveillance is imperative. Molecular tests are replacing N. gonorrhoeae culture internationally, excluding possibilities to perform WGS. We describe and evaluate a novel approach using a custom SureSelectXTHS Target-Enrichment probe panel automated on the Magnis NGS Prep System and Illumina sequencing to generate accurate N. gonorrhoeae genomes directly from clinical urogenital and extragenital specimens.

Methods: One hundred thirteen clinical N. gonorrhoeae-positive APTIMA Combo 2 (AC2) specimens (with 89 linked N. gonorrhoeae isolates) were included. DNA was extracted using QIAsymphony DSP Virus/Pathogen kit. Amplisens multiplex RT-PCR assay (AM-PCR) identified 105 (92.9%) of the AC2 specimens as N. gonorrhoeae positive, which were further examined. Sequence libraries for AC2 specimens were prepared on the Magnis NGS Prep System using the Magnis SureSelectXTHS Reagent kit for Illumina paired-end platforms. Paired-end sequencing was performed on Illumina platforms.

Results: Seventy-four of the 105 (70.5%) AC2 samples remained N. gonorrhoeae positive with a cycle threshold <20 in the AM-PCR and subjected to SureSelectXTHS target enrichment and subsequently Illumina WGS. Seventy-two (97.3%) of all target-enriched specimens were successfully genome-sequenced. All linked AC2 specimens and N. gonorrhoeae isolates from the same anatomical site had identical AMR determinants and molecular epidemiological sequence types.

Conclusions: We show that custom SureSelectXTHS target enrichment automated on the Magnis NGS Prep System, followed by Illumina sequencing, enables culture-independent genome-based surveillance of N. gonorrhoeae AMR and molecular epidemiology. This novel methodological advancement provides an efficient and accurate WGS of N. gonorrhoeae directly from clinical urogenital and extragenital NAAT specimens.

Objectives: To study the population structure and genomic characteristics, including antimicrobial resistance genes, plasmid types and surface polysaccharide type, of the globally distributed Acinetobacter baumannii belonging to ST32 (Institut Pasteur scheme).

Methods: Antibiotic resistance phenotype for 19 antibiotics was determined using Vitek 2. Whole-genome sequencing was performed using the Illumina MiSeq platform. Genomes were assembled using Newbler. Phylogenetic analysis was done by determining the core-genome alignments using Panaroo v1.3, analysed in IQ-Tree2 v2.2.0.3 to construct Maximum Likelihood trees using the RaxML software. Resistance genes and IS were identified using the Abricate programme, and ISFinder databases.

Results: One hundred and thirty-three (n = 133) ST32 A. baumannii isolates were analysed in this study. These genomes originated mainly from US military treatment facilities (n = 113), but also included additional publicly available genomes in GenBank (n = 20) recovered from a broad geographic distribution extending to Asia and South America. Phylogenetic analysis of all 133 genomes revealed at least four clades, with over 80 genomes forming a tightly clustered branch, suggesting they are likely to represent outbreak strains. Analysis of the ampC region showed that ST32 strains played a significant role in the formation of the widely distributed ampC transposon, Tn6168, and supplying DNA segments containing an ISAba1-ampC from ST32s via homologous recombination.

Conclusions: ST32 strains played a significant role in the evolution of antibiotic resistance in several widely distributed sequence types including ST1 (global clone 1) and ST3.

Background: Subcutaneous (SC) administration of antibiotics is a practical alternative to IV administration. Cefazolin is widely used for skin and soft tissue infections and other complex infections by IV administration.

Methods: In this prospective, cross-over self-controlled study, a single dose of SC cefazolin was administered to 15 stable inpatients established on IV cefazolin as part of their management plan. The equivalent dose of cefazolin was diluted in 50 mL of normal saline via gravity feed over 30 min. Venous blood samples were collected at baseline and 0.5, 1, 2, 4 and 8 h following both the SC and IV doses. Antibiotic concentrations were measured using UPLC-MS/MS. Pharmacokinetic data were analysed using a non-linear mixed-effects modelling approach. Pain scores and infusion site reactions (oedema/erythema) were evaluated.

Results: SC cefazolin was well tolerated. The bioavailability of SC administration was 74.8% (95% CI 66.7%-81.7%). Slower absorption from SC tissue was associated with a BMI of ≥30. Lower peak, and higher trough concentrations were observed with SC administration. Although lower bioavailability was observed with SC administration, the PTA for unbound drug concentrations greater than the MIC for more than 90% of the time between doses was higher for SC compared with IV administration at MICs between 0.25 and 4 mg/L. Simulated SC doses of 3 g twice daily had similar PTA to standard IV dosing of 2 g three times daily. A simulated 6 g continuous 24 h infusion of SC cefazolin had a favourable pharmacokinetic profile.

Conclusion: SC cefazolin appears to be well tolerated, with an improved pharmacokinetic profile compared with IV administration. Either 3 g twice daily, or 6 g as a 24 h SC infusion could be considered for future evaluation.

Background: Nacubactam (NAC), a new diazabicyclooctane β-lactamase inhibitor, is being developed for use together with aztreonam (AZT) and cefepime (CFPM). However, the effective clinical dosages of AZT/NAC and CFPM/NAC have not yet been established. We have previously shown that free time above instantaneous MIC (fT > MICi) is a valuable pharmacokinetic (PK)/pharmacodynamic parameter for β-lactam (BL)/NAC in a mouse thigh infection model.

Objectives: This study simulated the fT > MICi (%) for AZT/NAC and CFPM/NAC against carbapenemase-producing Enterobacterales (CPE) with different MIC in humans to estimate the clinical efficacy at practically achievable combination doses of AZT/NAC and CFPM/NAC.

Methods: Using previously reported PK parameters of each drug in humans and chequerboard MIC data, we calculated the fT > MICi (%) for AZT/NAC and CFPM/NAC in 10 000 simulated patients to predict the percentages of target attainment of bacteriostatic and bactericidal efficacies at various combined doses.

Results: The results predicted that both BL/NAC combinations could achieve 100% 2 log10-kill against CPE strains at the lowest combination dose (0.5 g/0.5 g q8h). Additionally, in MIC studies examining BLs/NAC at a 1:1 ratio, the dosage regimen for strains with MICcomb ≤ 1 mg/L was expected to offer 100% bactericidal efficacy (2 log10-kill) at 0.5 g/0.5 g q8h or higher doses. For strains with 1 mg/L < MICcomb ≤ 16 mg/L, BLs/NAC at a 2 g/2 g q8h was predicted to produce bactericidal efficacy (1 log10-kill). At MICcomb = 32 mg/L, some bacteriostatic effect was expected at high BL doses.

Conclusions: AZT/NAC and CFPM/NAC are bactericidal against CPE at practically achievable dosages.

Background: Antibiotic resistance complicates treatment of urinary infections, particularly when these ascend above the bladder, with few oral options remaining. New oral β-lactamase inhibitor combinations present a potential answer, with ceftibuten/avibactam-now undergoing clinical trials-widely active against strains with ESBLs and serine carbapenemases. To inform its development we undertook mutant selection studies.

Methods: Single-step mutants were sought from Enterobacterales (n = 24) with AmpC, ESBL, OXA-48 and KPC β-lactamases. MICs were determined by CLSI agar dilution. Illumina WGS of selected mutants (n = 50) was performed.

Results: Even at low MIC multiples, mutant frequencies were mostly only c. 10-8. β-Lactamase structural mutants were obtained only from KPC and AmpC enzymes. The KPC mutants had Trp105Arg or Ser130Thr substitutions, causing only small MIC shifts; the AmpC mutant had an Asn346Trp replacement, as previously selected with other avibactam combinations. No ESBL mutants were obtained. Rather, from Escherichia coli, we predominantly selected mutants with modifications to ftsI, encoding penicillin-binding protein (PBP) 3. From Klebsiella pneumoniae and Enterobacter cloacae we predominantly obtained variants with modification of uptake and efflux components or their regulators. ftsI mutants lacked cross-resistance to other avibactam combinations; uptake mutants had broader MIC rises. A few putative mutants had other lesion(s) of uncertain significance, or grew as small, stressed colonies lacking detectable lesions.

Conclusions: There seems little risk of ESBLs mutating to confer ceftibuten/avibactam resistance, though some risk may apply for KPC and AmpC enzymes. The propensity to select E. coli ftsI/PBP3 mutants is notable and was not seen with other avibactam combinations.

Background: Enterobacter hormaechei is an important pathogen in humans and animals, which, in addition to its intrinsic AmpC, can acquire a wide variety of genes conferring resistances to extended-spectrum cephalosporins (ESCs) and carbapenems (CPs). In France, human clinical outbreaks of E. hormaechei resistant to ESC or carbapenem were reported.

Objectives: To study E. hormaechei isolates from cats and dogs (=59) as well as from horses (n = 55) presenting a non-susceptible phenotype to beta-lactams in order to determine which clones, resistance genes and plasmids are circulating in France.

Material and methods: E. hormaechei isolates (n = 114) were short-read sequenced and five isolates were long-read sequenced to better characterize the plasmids carrying ESC- and CP-resistance determinants. Phenotypes were characterized by antibiograms using the disc diffusion method.

Results: A clear divergence in the molecular epidemiology was observed depending on the host. In cats and dogs, most of the isolates presented an overexpressed ampC gene or the blaCTX-M-15 gene carried by an IncHI2 plasmid, and eight isolates (8/59, 13.6%) presented the blaOXA-48 carbapenemase gene. Thirty-two isolates (32/59, 54.2%) belonged to the human high-risk clones ST78, ST114 and ST171. Contrarily, in horses, ESC resistance was mostly due to the blaSHV-12 and blaCTX-M-15 genes carried by an IncHI2 plasmid, and high-risk clones were rarely identified (5/55, 9.0%).

Discussion: Potential selection by antibiotic use (which is on an increasing trend in France for cats, dogs and horses), the dissemination capacities of both conjugative IncHI2 plasmids and high-risk clones, and possible transfers of resistant bacteria between humans and animals strongly indicate that E. hormaechei should be closely monitored.

Background: The lack of research on the dose-response relationship of adjuvants in reversing colistin resistance will lead to a lack of scientific theoretical basis for determining the dosage of adjuvants in clinical combination therapy plans or their compound formulations.

Objectives: This study investigates the dose-response relationship of the deworming drug closantel (CST) on the reversal of colistin resistance in mcr-1-positive Escherichia coli (E. coli).

Methods: Firstly, the reversal effect of different concentrations of CST on colistin resistance in mcr-1-positive E. coli was analysed using broth microdilution method, checkerboard method and time-killing curves. Then, the inhibitory effect of CST on the development of colistin resistance, as well as the haemolytic and cytotoxic properties of CST, was analysed. Finally, the in vivo efficacy of the combination of CST and colistin was evaluated.

Results: Both the checkerboard assays and the time-killing curves indicate that there is a special dose-response relationship between CST and its reversal effect on colistin resistance, which is not concentration-dependent. High reversal efficiency can be achieved within a low concentration range. However, as the CST concentration increases, the ability to reverse colistin resistance remains unchanged or decreases, which resulted in a gradual decrease in reversal efficiency. Additionally, CST can inhibit the development of colistin resistance and reduce the cytotoxicity of colistin. Importantly, in a mouse model of E. coli infection, the combination of CST and colistin showed a significant therapeutic effect.

Conclusions: This study indicates a special dose-response relationship between CST and its reversal effect on colistin resistance, which was not concentration-dependent.