Antimicrobial Agents and Chemotherapy最新文献

Antimicrobial resistance in Neisseria gonorrhoeae (Ng) has severely reduced treatment options, including azithromycin (AZM), which had previously been recommended as dual therapy with ceftriaxone. This study characterizes the emergence of high-level resistance to AZM (HLR-AZM) Ng in Baltimore, Maryland, USA, and describes the global evolution of HLR-AZM Ng. Whole genome sequencing (WGS) of 30 Ng isolates with and without HLR-AZM from Baltimore was used to identify clonality and resistance determinants. Publicly available WGS data from global HLR-AZM Ng (n = 286) and the Baltimore HLR-AZM Ng (n = 3) were used to assess the distribution, clonality, and diversity of HLR-AZM Ng. The HLR-AZM Ng isolates from Baltimore identified as multi-locus sequencing typing sequence type (ST) 9363 and likely emerged from circulating strains. ST9363 was the most widely disseminated ST globally represented in eight countries and was associated with sustained transmission events. The number of global HLR-AZM Ng, countries reporting these isolates, and strain diversity increased in the last decade. The majority (89.9%) of global HLR-AZM Ng harbored the A2059G mutation in all four alleles of the 23S rRNA gene, but isolates with two or three A2059G alleles, and alternative HLR-AZM mechanisms were also identified. In conclusion, HLR-AZM in Ng has increased in the last few years, with ST9363 emerging as an important gonococcal lineage globally. The 23S rRNA A2059G mutation is the most common resistance mechanism, but alternative mechanisms are emerging. Continued surveillance of HLR-AZM Ng, especially ST9363, and extensively drug-resistant Ng is warranted.

Cabotegravir intramuscular gluteal injection is approved for HIV treatment (with rilpivirine) and prevention. Thigh muscle is a potential alternative injection site. We aim to characterize cabotegravir pharmacokinetics and its association with demographics following intramuscular thigh injection in comparison with gluteal injection using population pharmacokinetic (PPK) analysis. Fourteen HIV-negative participants received 600 mg single thigh injection in phase 1 study 208832 and 118 participants with HIV received thigh injections 400 mg monthly 4× or 600 mg once-every-2-months 2× after ≥3 years of gluteal injections in phase 3b study ATLAS-2M provided 1,249 cabotegravir concentrations from 366 thigh injections and 1,998 concentrations from 1,618 gluteal injections. The established gluteal PPK model was modified by adding thigh injection compartment and fit to pharmacokinetic data following both gluteal and thigh injections, enabling within-person comparison in ATLAS-2M. Gluteal parameters were fixed. Similar to the gluteal absorption rate constant (KA_gluteal), the thigh absorption rate constant (KA_thigh) was slower in females than males and in participants with higher BMI. KA_thigh was strongly correlated with KA_gluteal (correlation coefficient 0.766), best described by the additive linear relationship KA_thigh = KA_gluteal + 0.0002527 h^-1. Terminal half-life of thigh injection was 26% (male) and 39% (female) shorter than gluteal injection. Relative bioavailability of thigh to gluteal was estimated to be 89.9%. The impact of covariates on cabotegravir exposure following thigh injections was ≤35%. In conclusion, cabotegravir absorption following thigh injection was correlated with, faster than, and 10% less bioavailable than gluteal injection, and correlated with sex and BMI. The cabotegravir thigh PPK model can inform dosing strategies and future study design.

Carbapenem-resistant Enterobacteriaceae have become widely prevalent globally because of antibiotic misuse and the spread of drug-resistant plasmids, where carbapenem-resistant Escherichia coli (CREC) is one of the most common and prevalent pathogens. Furthermore, E. coli has been identified as a member of normal gut flora and does not cause disease under normal circumstances. However, certain strains of E. coli, due to the expression of virulence genes, can cause severe intestinal and extra-intestinal infections. Therefore, clinically, drug resistance and pathogenic E. coli strains are significantly challenging to treat. In this study, a novel CREC strain DC8855 was isolated from the ascites of a patient with intestinal perforation, identified as a novel sequence type 12531 (ST12531) and an unreported serotype O8:H7. It was revealed that the resistance of ST12531 CREC was predominantly conferred by an IncFII(K) plasmid carrying bla_NDM-4. Furthermore, phylogenetic analysis indicated that this is the first discovery of such plasmids in China and the first identification in E. coli. Moreover, regarding virulence, the swimming assays, qRT-PCR, and in vitro intestinal barrier model indicated that DC8855 had significantly higher motility, flagella gene expression, and intestinal epithelial cell barrier migration ability than the other sequence types CREC strains (ST167 and ST410). In conclusion, this study identified novel CREC which was multidrug resistant as well as enteropathogenic and therefore requires continuous monitoring.

The global epidemic of drug-resistant Candida auris continues unabated. The initial report on pan-drug resistant (PDR) C. auris strains in a hospitalized patient in New York was unprecedented. PDR C. auris showed both known and unique mutations in the prominent gene targets of azoles, amphotericin B, echinocandins, and flucytosine. However, the factors that allow C. auris to acquire pan-drug resistance are not known. Therefore, we conducted a genomic, transcriptomic, and phenomic analysis to better understand PDR C. auris. Among 1,570 genetic variants in drug-resistant C. auris, 299 were unique to PDR strains. The whole-genome sequencing results suggested perturbations in genes associated with nucleotide biosynthesis, mRNA processing, and nuclear export of mRNA. Whole transcriptome sequencing of PDR C. auris revealed two genes to be significantly differentially expressed-a DNA repair protein and DNA replication-dependent chromatin assembly factor 1. Of 59 novel transcripts, 12 transcripts had no known homology. We observed no fitness defects among multi-drug resistant (MDR) and PDR C. auris strains grown in nutrient-deficient or -enriched media at different temperatures. Phenotypic profiling revealed wider adaptability to nitrogenous nutrients and increased utilization of substrates critical in upper glycolysis and tricarboxylic acid cycle. Structural modeling of a 33-amino acid deletion in the gene for uracil phosphoribosyl transferase suggested an alternate route in C. auris to generate uracil monophosphate that does not accommodate 5-fluorouracil as a substrate. Overall, we find evidence of metabolic adaptations in MDR and PDR C. auris in response to antifungal drug lethality without deleterious fitness costs.

The emergence of plasmid-mediated resistance threatens the efficacy of polymyxins as the last line of defense against pan-drug-resistant infections. However, we have found that using Mueller-Hinton II (MHII), the standard minimum inhibitory concentration (MIC) medium, results in MIC data that are disconnected from in vivo treatment outcomes. We found that culturing putative colistin-resistant Acinetobacter baumannii clinical isolates, as defined by MICs of >2 mg/L in standard MHII testing conditions, in bicarbonate-containing media reduced MICs to the susceptible range by preventing colistin resistance-conferring lipopolysaccharide modifications from occurring. Furthermore, the lower MICs in bicarbonate-containing media accurately predicted in vivo efficacy of a human-simulated dosing strategy of colistin and polymyxin B in a lethal murine infection model for some polymyxin-resistant A. baumannii strains. Thus, current polymyxin susceptibility testing methods overestimate the contribution of polymyxin resistance-conferring mutations and incorrectly predict antibiotic activity in vivo. Polymyxins may remain a viable therapeutic option against Acinetobacter baumannii strains heretofore determined to be "pan-resistant."

Topical antifungals may be considered to treat onychomycosis with minimal risk of systemic side effects. In this study, we assess the safety, tolerability, systemic exposure, and pharmacokinetic characteristics of topical terbinafine hydrochloride 10% solution (MOB015B) in adults with moderate-to-severe onychomycosis. Clinically and mycologically confirmed patients with toenail onychomycosis (N = 20) were enrolled in this single-center, open-label study . Each patient had ≥50% involvement of both great toenails and at least four additional toenails affected. MOB015B was applied once daily to all toenails for 28 days. Blood was drawn on days 1, 14, and 28. Plasma concentrations of MOB015B after the first dose were quantifiable in all subjects by 24 h. Steady-state levels in plasma were reached by day 28. The mean systemic exposure on day 28 of 0.72 ng/mL for maximum plasma concentration (C_max) was approximately 2,000 times lower than the mean plasma level of 1.39 µg/mL seen after oral administration of 250 mg terbinafine for 28 days. Adverse events (five patients), such as headache (n = 3), seasonal allergy (n = 1), and neck pain (n = 1), were considered unrelated to MOB015B; no application site reactions or study discontinuations due to an adverse event were observed. MOB015B applied to all affected toenails under maximal usage conditions for 28 days demonstrated very low levels of terbinafine in plasma (C_max <1 ng/mL after 28 days), consistent with a favorable safety and tolerability profile.

Clinical trials: This study is registered with ClinicalTrials.gov as NCT03244280.

Protein arginine methyltransferases (PRMTs) play critical roles in Plasmodium falciparum, a protozoan causing the deadliest form of malaria, making them potential targets for novel antimalarial drugs. Here, we screened 11 novel PRMT inhibitors against P. falciparum asexual growth and found that onametostat, an inhibitor for type II PRMTs, exhibited strong antimalarial activity with a half-maximal inhibitory concentration (IC₅₀) value of 1.69 ± 0.04 µM. In vitro methyltransferase activities of purified PfPRMT5 were inhibited by onametostat, and a shift of IC₅₀ to onametostat was found in the PfPRTM5 disruptant parasite line, indicating that PfPRTM5 is the primary target of onametostat. Consistent with the function of PfPRMT5 in mediating symmetric dimethylation of histone H3R2 (H3R2me2s) and in regulating invasion-related genes, onametostat treatment led to the reduction of H3R2me2s level in P. falciparum and caused the defects on the parasite's invasion of red blood cells. This study provides a starting point for identifying specific PRMT inhibitors with the potential to serve as novel antimalarial drugs.

Osteomyelitis caused by Staphylococcus aureus can involve the persistent infection of osteocytes. We sought to determine if current clinically utilized antibiotics were capable of clearing an intracellular osteocyte S. aureus infection. Rifampicin, vancomycin, levofloxacin, ofloxacin, amoxicillin, oxacillin, doxycycline, linezolid, gentamicin, and tigecycline were assessed for their minimum inhibitory concentration (MIC) and minimum bactericidal concentrations against 12 S. aureus strains, at pH 5.0 and 7.2 to mimic lysosomal and cytoplasmic environments, respectively. Those antibiotics whose bone estimated achievable concentration was commonly above their respective MIC for the strains tested were further assayed in a human osteocyte infection model under acute and chronic conditions. Osteocyte-like cells were treated at 1×, 4×, and 10× the MIC for 1 and 7 days following infection (acute model), or at 15 and 21 days of infection (chronic model). The intracellular effectivity of each antibiotic was measured in terms of CFU reduction, small colony variant formation, and bacterial mRNA expression change. Only rifampicin, levofloxacin, and linezolid reduced intracellular CFU numbers significantly in the acute model. Consistent with the transition to a non-culturable state, few if any CFU could be recovered from the chronic model. However, no treatment in either model reduced the quantity of bacterial mRNA or prevented non-culturable bacteria from returning to a culturable state. These findings indicate that S. aureus adapts phenotypically during intracellular infection of osteocytes, adopting a reversible quiescent state that is protected against antibiotics, even at 10× their MIC. Thus, new therapeutic approaches are necessary to cure S. aureus intracellular infections in osteomyelitis.

TBAJ-876, a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile compared with bedaquiline, is under development for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). A phase 1, first-in-human study of TBAJ-876, comprising a single-ascending dose (SAD) part including a food effect cohort, a multiple-ascending dose (MAD) part, and a relative bioavailability part of tablets versus oral suspension, was conducted on 137 healthy adults. A drug-drug interaction study was conducted on 28 healthy adults to evaluate the effects of TBAJ-876 on a cytochrome P450 3A4 substrate (midazolam) and a P-glycoprotein substrate (digoxin). TBAJ-876 was well-tolerated at single doses up to 800 mg and multiple doses up to 200 mg for 14 days. No deaths or serious adverse events occurred. No episodes of clinically significant prolongation of the QTc interval were observed. TBAJ-876 exposures were dose proportional in the SAD and MAD studies. TBAJ-876 exhibited multicompartmental pharmacokinetics (PK) with a long terminal half-life yielding quantifiable concentrations up to the longest follow-up of 10 weeks after a single dose and resulting in accumulation with multiple dosing. In the fed state, TBAJ-876 exposures approximately doubled with the tablet formulation, whereas M3 metabolite exposures decreased by approximately 20%. The relative bioavailability of TBAJ-876 was similar between tablets and the oral suspension at 100-mg doses. With co-administration of TBAJ-876, the AUC_0-inf of midazolam was unchanged and the C_max was reduced by 14%; the AUC_0-last of digoxin was increased by 51%, and the C_max was increased by 18%. These results support further investigation of TBAJ-876 for the treatment of tuberculosis.

We evaluated the efficacy of ensitrelvir for the treatment of cough due to coronavirus disease 2019 Omicron variant in medical healthcare workers. A total of 633 patients were registered in this study: 206 patients chose ensitrelvir and 427 patients chose symptomatic treatment. Difference in score changes using the Leicester Cough Questionnaire between groups was 3.17 on day 4, 3.24 on day 7, and 2.46 on day 14. The analysis demonstrated a significant difference at all time points.