Journal of Antimicrobial Chemotherapy最新文献

Background: Non-tuberculous mycobacteria (NTM) infection presents a growing global health problem and requires new antibiotics targeting enzymes that are essential for the pathogens under various metabolic conditions, with high target specificity, good solubility and with attractive combinatory potency.

Methods: SQ31f was synthesized by a simplified synthesis protocol, and its effect on growth inhibition of fast- and slow-growing NTM and clinical isolates, whole-cell ATP depletion, ex vivo macrophages and its potency in combination with other antibiotics were evaluated. Molecular docking studies were employed to assess SQ31f's binding mode.

Results: We present- squaramide SQ31f as a novel anti-NTM inhibitor targeting the NTM F1FO-ATP synthase, essential for ATP formation, regulation of ATP homeostasis and proton motive force under multiple growth conditions. The potency of SQ31f in growth inhibition of fast- and slow-growing NTM and clinical isolates correlates with whole-cell ATP depletion, which is not caused by altered oxygen consumption. SQ31f's high aqueous solubility enables binding to the waterfilled cytosolic proton half channel in the subunits a-c interface of the FO domain. As presented for the fast-growing Mycobacterium abscessus, the compound is active against intracellular-residing M. abscessus. Importantly, SQ31f shows an additive effect of the anti-M. abscessus drugs clofazimine, rifabutin or amikacin, and an attractive potentiation of linezolid, clarithromycin, or the oral pair tebipenem and avibactam.

Conclusions: SQ31f represents an attractive inhibitor to tackle the issues associated with NTM drug tolerance and toxicity. Its combinatory potency with anti-M. abscessus drugs holds potential for overcoming resistance, while also reducing intensive compound synthesis and associated costs.

Objectives: Neisseria gonorrhoeae strains associated with the high-level ceftriaxone-resistant FC428 clone or containing its main resistance determinant, penA allele 60.001, have shown global transmission. In Hangzhou, China, 10% of the isolates were associated with the FC428 clone in 2019. Here, we investigated ceftriaxone resistance and the prevalence of FC428-associated strains in Hangzhou in 2020-22.

Methods: A total of 209 gonococcal isolates were investigated for antimicrobial susceptibility to ceftriaxone and other antibiotics by agar dilution method. Sequence types and penA alleles were determined by PCR and sequence analysis.

Results: Resistance to ceftriaxone (MIC > 0.125 mg/L) was observed for 16% (33/209) of the isolates, whereas 6.7% (14/209) of the isolates displayed high-level ceftriaxone resistance (MIC = 1 mg/L). These 14 high-level ceftriaxone-resistant isolates and another isolate displaying an MIC = 0.25 mg/L contained penA allele 60.001, with eight of these isolates, all from 2020 to 2021 belonging to MLST ST1903, the sequence type commonly associated with the original FC428 clone. Importantly, the six penA allele 60.001-containing isolates from 2022 belonged to MLST ST8123, ST7365 and ST7367, which are among the most frequently encountered sequence types found in China. Therefore, these results indicate that endemic lineages in China have acquired penA allele 60.001.

Conclusions: Here, we report continued transmission of gonococcal strains associated with the FC428 clone or containing penA allele 60.001 in Hangzhou. A major concern for public health is the acquisition of penA allele 60.001 by successful endemic lineages, which might enhance the transmission of this high-level ceftriaxone resistance trait.

Background: Ganaplacide, also known as KAF156, is among the new antimalarial drug candidates that have successfully reached Phase III clinical trials, and is proposed in combination with lumefantrine. This combination could replace the current front-line artemisinin-based combination therapies (ACTs) in case of Plasmodium falciparum resistance to both artemisinins and partner drugs. Indeed, the African continent, where the malaria burden is the highest, is currently experiencing worrying multiple emergences and spread of artemisinin resistance, which urges for the exploration of the antiparasitic properties of KAF156 in this context.

Objectives and methods: The objectives of this work were firstly to evaluate the risk of cross-resistance between artemisinins and KAF156 alone, and in combination with lumefantrine, using a panel of artemisinin-resistant strains carrying different pfk13 mutations and markers of other antiplasmodial drug resistances; secondly to explore in vitro the relevance of combining KAF156 and lumefantrine with artemisinins, based on the model of triple ACTs.

Results: Our results highlighted that KAF156 activity was not impaired by mutations in pfk13, pfcrt, pfmdr1, pfmdr2, pfdhps and pfdhfr genes or by pfmdr1 amplification. Moreover, we demonstrated that KAF156 alone and in combination with lumefantrine was active against artemisinin-resistant parasites, including when they are quiescent.

Conclusions: All these in vitro results evidence that multi-drug resistant parasites currently in circulation in the field might not affect KAF156 efficacy, and are encouraging signs for KAF156 use in a triple ACT to preserve the use of artemisinins for as long as possible.

Background: The antiviral efficacy of Evusheld (AZD7442) in patients hospitalized for SARS-CoV-2 is unknown.

Methods: We analysed the evolution of both the nasopharyngeal viral load and the serum neutralization activity against the variant of infection in 199 hospitalized patients (109 treated with Evusheld, 90 treated with placebo) infected with the SARS-CoV-2 virus and included in the randomized, double-blind, trial DisCoVeRy (NCT04315948). Using a mechanistic mathematical model, we reconstructed the trajectories of viral kinetics and how they are modulated by the increase in serum neutralization activity during Evusheld treatment.

Results: Our model identified that the neutralization activity was associated with viral kinetics. Reflecting the variant-dependent neutralization activity of Evusheld, the antiviral activity of Evusheld was larger in patients infected with pre-Omicron or Omicron BA.2 variants than in patients infected with Omicron BA.1 variant. More specifically, the model predicted that Evusheld reduced the median time to viral clearance compared with placebo-treated patients by more than 5 days in patients infected by pre-Omicron (median: 5.9; 80% PI: 2.1-13.6) or Omicron BA.2 (median: 5.4; 80% PI: 2.0-12.4), respectively. The effect was more modest in patients infected by the Omicron BA.1 variant, reducing the median time to viral clearance by 2 days (median: 2.2; 80% PI: 0.4-8.9).

Conclusions: Hospitalized patients treated with Evusheld had a shorter median time to SARS-CoV-2 viral clearance. As Evusheld antiviral activity is mediated by the level of neutralization activity, its impact on viral clearance varies largely according to the variant of infection.

Background: Sepsis and pneumonia in the elderly comprise a significant portion of medical admissions. Chloramphenicol has been used in Israel for treatment of bacterial infections, without evidence regarding its efficacy and safety.

Objectives: We aimed to examine whether chloramphenicol was associated with similar outcomes to ceftriaxone, for treatment of sepsis and pneumonia in the elderly with dementia and functional disability.

Methods: Patients over 75, with dementia and functional disability, admitted to the internal medicine ward at Beilinson Hospital between 2011 and 2021, with community-acquired aspiration pneumonia or sepsis of undetermined source were included. Patients with mild dementia and independent in their activities of daily living were excluded. Primary outcome was 30- and 90-day all-cause mortality. A propensity-weighted multivariable model was constructed using inverse probability of treatment weighting. Results were expressed as OR with 95% CI.

Results: In total, 1558 patients were included: 512 treated with chloramphenicol and 1046 with ceftriaxone. The cohort consisted of elderly patients (mean age 87 ± 6.2 years) with comorbidities; 30- and 90-day all-cause mortality were similar [222/512 (43.3%) versus 439/1046 (41.9%) P = 0.602, and 261/512 (50.9%) versus 556/1046 (53.1%) P = 0.419, respectively]. Propensity-weighted, logistic multivariable analysis for 30- and 90-day all-cause mortality revealed similar mortality rates for chloramphenicol and ceftriaxone (OR 1.049 95% CI 0.217-1.158, OR 0.923 95% CI 0.734-1.112, respectively).

Conclusion: In this retrospective cohort of elderly debilitated patients hospitalized with pneumonia and sepsis, we found no difference in 30- and 90-day mortality between those treated with chloramphenicol or ceftriaxone. Further studies should determine the efficacy and safety of chloramphenicol in this population.

Objectives: Clinical experience in the use of teicoplanin for treating enterococcal infective endocarditis (EIE) is scarce. The aim of this study was to describe the characteristics and outcomes of patients with EIE treated with teicoplanin monotherapy compared to standard therapy with ampicillin plus ceftriaxone.

Methods: All consecutive adult patients diagnosed with EIE between January 2018 and September 2022 at a referral centre were reviewed. Characteristics of individuals treated with teicoplanin for ≥14 days [the treated with teicoplanin (TT) group] were compared with those who received ampicillin plus ceftriaxone (AC group).

Results: Sixty-six patients were included [61 (92%) E. faecalis infective endocarditis (IE) and 5 (8%) E. faecium IE]. Twenty-seven (41%) received teicoplanin: eight as first-line treatment and 19 as continuation therapy.The median duration of teicoplanin treatment was 30 (25-43) days. Surgery was indicated in 14/27 (52%) in the TT group and in 21/39 (54%) in the AC group, but was finally performed in 11/14 (79%) and 13/21 (62%) (P = 0.46), respectively. In-hospital mortality rate was 3/27 (11%) in the TT group and 12/39 (31%) in the AC group (P = 0.06). Patients treated with teicoplanin were more often discharged on outpatient parenteral antibiotic therapy [18/27 (67%) versus 6/39 (15%), P < 0.001] and median hospital stay was shorter [29 days (IQR 20-61) versus 50 days (IQR 43-68), P = 0.006]. One-year cumulative mortality was 8/27 (30%) in the TT group and 13/39 (33%) in the AC group (P = 0.46). There was one relapse in each group.

Conclusion: Teicoplanin seems an effective treatment for selected patients with enterococcal IE, mainly to facilitate discharge.

Objectives: We performed a retrospective analysis of MRSA isolates collected at the university equine clinic including clinical isolates from 2008 to 2021 and screening environmental, equine and personnel isolates from 2016.

Methods: Screening and clinical samples were cultured on Brilliance MRSA 2 and Columbia agar (Oxoid), respectively, with enrichment for environmental samples. Antimicrobial susceptibility was assessed by disc diffusion. All the isolates were characterized by spa typing. Eighteen selected isolates were subjected to WGS with subsequent wgMLST clonal analysis.

Results: Among 75 MRSA isolates, five spa types were identified, the majority (n = 67; 89.33%) was t011. All isolates were resistant to cefoxitin and ampicillin and carried the mecA gene. In addition, the isolates were resistant to tetracycline (n = 74; 98.67%), gentamicin (n = 70; 93.33%), enrofloxacin (n = 54; 72.00%), sulfamethoxazole-trimethoprim (n = 5; 6.67%) and lincomycin (n = 3; 4.00%) with corresponding genetic markers for the resistance detected in the sequenced isolates. All 18 sequenced isolates belonged to ST398, 16 carried SCCmec type IVa and two carried SCCmec type Vc (5C2&5). Further, isolates carried aur, hlgA, hlgB and hlgC virulence genes, and five isolates carried sak and scn genes, which are part of the immune evasion cluster. Close genetic relatedness was found between isolates from the staff of the clinic and clinical samples of horses.

Conclusions: Repeated introduction and long-term persistence of the equine LA-MRSA subclone (ST398-MRSA-IVa/Vc(5C2&5), t011) among the infected horses at the equine clinic with the colonization of personnel, and the environment contamination that might contribute to transmission were observed.

The UK Overseas Territories (UKOTs) are small, often remote territories with historical and territorial links to the UK. They range from densely populated areas (Cayman, Bermuda, Gibraltar) to land with no permanent inhabitants (British Antarctic Territory, South Georgia). However, they are linked by ecosystem instability (the permacrisis) including antimicrobial resistance (AMR), climate change and biodiversity disruption. The Chief Medical Officers of the UKOTs met in June 2024 and were unanimous in their concerns about the threat of global AMR. They have issued this statement on their hopes and expectations for the United Nations' General Assembly High-Level Meeting, in September 2024. These may be summarized by the hope of achieving united and sustained global political will to reduce the threat of AMR by equitable access to treatments, prevention of AMR by sanitation and accurate diagnostics, and education in health care and the public.