Journal of Antimicrobial Chemotherapy最新文献

Klebsiella pneumoniae (KP) is a Gram-negative, opportunistic pathogen known for causing hospital/community-acquired infections, with carbapenem-resistant Klebsiella pneumoniae (CRKP) being a major global health threat due to its resistance to last-resort antibiotics. Tigecycline is one of the most commonly used and accessible agents for CRKP treatment. However, the rapid spread of resistance genes via mobile genetic elements has led to an increase in bacterial resistance, thereby undermining the clinical efficacy. Additionally, controversy remains regarding the MIC breakpoint of tigecycline for KP, with either overestimation or underestimation of resistance rates, which complicates evaluation and selection of appropriate treatment regimens for clinicians. This review aims to elucidate the mechanisms of tigecycline resistance in KP strains, including the newly discovered mutants or resistance mechanisms mediated by efflux pumps and two-component regulatory systems. Subsequently, a global epidemiology of CRKP isolates with different tigecycline MIC values is conducted, finding that the resistance rates in Asia are higher than that in Europe and America. Furthermore, the latest clinical progresses of tigecycline in terms of dosage, combination regimen and adverse events are analysed.

Background: The ototoxic potential of aminoglycosides has limited their use. Although their effects on adult hearing have been extensively studied, there is limited research on their potential effects on newborns following intrauterine exposure. However, aminoglycosides are commonly used to treat urinary tract infections during pregnancy.

Objectives and methods: Evaluate the incidence of sensorineural hearing loss (SNHL) in neonates who were exposed to aminoglycosides in utero. A cohort of children born between 2018 and 2024 at a single urban hospital was analysed; all underwent universal hearing screening and, if necessary, a complete diagnostic audiological evaluation. Hearing test results of newborns whose mothers were exposed to aminoglycosides in utero were compared with those of unexposed newborns.

Results: A total of 39 237 newborns were included in the study. Of these, 85 were exposed in utero to aminoglycosides: gentamicin (13, 34 and 33 in first, second and third trimesters, respectively) or amikacin (3 and 4 in second and third trimesters, respectively), for a mean of three doses. Exposed children had significantly higher rates of other risk factors for hearing loss, including prolonged ICU stay, low birth weight and a family history of hearing loss. However, no exposed newborns developed SNHL, compared to 100 unexposed newborns.

Discussion: Among 85 children exposed to aminoglycosides in utero, mostly to gentamicin, no cases of congenital SNHL were observed, despite the higher prevalence of other risk factors. Although limited by a relatively small number of aminoglycoside exposures, these findings suggest that short courses of aminoglycosides during pregnancy are not likely to be associated with increased risk of congenital SNHL.

Background: Gender shapes health behaviours, access, and outcomes, thereby influencing antibiotic use. Intersecting socio-economic factors, such as education, labour force participation, and political representation, further mediate gender differences in the risk of antimicrobial resistance (AMR). However, evidence linking gender inequalities to antibiotic consumption remains limited.

Methods: This study is an observational, country-level analysis using IQVIA MIDAS® data on yearly antibiotic consumption (defined daily doses/DDDs) from 70 countries (2000-22). We used four gender equality indicators: proportion of females with secondary or higher education, female-to-male labour force participation (FMLFP) ratio, proportion of women in parliament, and share of female population. Using country and year fixed-effects regression models, the study estimated within-country associations between these indicators and overall antibiotic consumption, as well as by antibiotic class, controlling for income, education, healthcare access, and health spending, and demographics. Sensitivity was assessed through an alternative model specification, stratified analyses by income groups and by time periods.

Results: Antibiotic consumption varied widely across countries with an average of 19.13 DDDs per day per 1000 population. Our main findings are that higher female education (P < 0.05) and FMLFP ratio (P < 0.01) were significantly associated with lower antibiotic consumption, while a higher share of females in the population was significantly associated with slightly higher consumption (P < 0.01). Women's parliamentary representation showed no significant association. These associations remained directionally consistent across alternative model specifications and income groups.

Conclusions: Gender inequalities influence antibiotic consumption patterns. The study underscores the need for a community-based approach in tackling AMR, specifically, investments in gender-responsive AMR strategies.

Background: Salmonella enterica serovar Typhi results in >160 000 deaths annually. In endemic regions, infections disproportionately affect infants and children. Current diagnostics rely on culture-based approaches that lack sensitivity and require infrastructure and skills that are not always possible in developing regions.

Objectives: We developed a suite of rapid, sensitive and specific molecular diagnostic tools to detect S. Typhi, and markers of extensive antimicrobial resistance (AMR), with the capacity to be used in low- and middle-income countries (LMIC).

Methods: Singleplex and multiplex PCR assays, recombinase polymerase amplification with lateral flow detection (RPA-LF) assays and loop-mediated isothermal amplification (LAMP) assays were developed, targeting markers consistent with Salmonella Typhi and makers of extensive AMR (blaCTX-M-15 and qnrS1). Assays were tested across four banks of samples (n = 115 total) to assess sensitivity, specificity and limit of detection.

Results: Singleplex and multiplex PCR assays demonstrated excellent sensitivity (100%) and specificity (96%-100%) for detection of XDR S. Typhi and extensive AMR, particularly the H58 clade deletion and STY4669 genes of S. Typhi. Similarly, sensitivity and specificity were also observed for RPA-LF assays (100% sensitivity, 96%-100% specificity) and LAMP assays (100% sensitivity, 87.5%-100% specificity) for all targets.

Conclusions: These tools are timely, providing a range of options for targeted detection of XDR S. Typhi in the laboratory or nearer to the point of care. These assays have the potential to improve resistance-guided therapy for S. Typhi, which is important given the increasing prevalence of XDR S. Typhi in endemic regions of Pakistan, and increasing case reports globally.

Objectives: To develop a population pharmacokinetic (popPK) model to understand factors affecting the broadly neutralizing HIV antibody (bNAb) VR07-523LS disposition and infant predicted serum neutralization 80% inhibitory dilution titre ratio (PT80) and its potential relationship to antiviral effects.

Methods: PK data from two studies were used: infants exposed to HIV initiating therapy ≤5 days of age (IMPAACT P1112, n = 21) and healthy adults (VRC605, n = 25). The infant study implemented fixed subcutaneous (s.c.) dosing whereas the adult study implemented weight-based dosing, via both intravenous (i.v.) and s.c. routes. Monte Carlo simulation assessed two doses (80 mg followed by 100 mg at 12 weeks) to determine the maintenance of levels >10 µg/mL in virtual infants. The broadly neutralizing antibodies (bNAbs) concentration/IC80 ratio (PT80) was calculated on the basis of simulated concentrations from the popPK model and VRC07-523LS HIV-1 sensitivity (IC80) distribution.

Results: This model predicts typical infant CL/F and t1/2 of 159 mL/day/70 kg and 39 days. Comparatively, predicted adult typical CL/F and t1/2 were 269 mL/day/70 kg and 31 days. Concentrations were >10 µg/mL in >87% of virtual infants at 12 weeks following one dose and >98% at 24 weeks following two doses. Median (90% predictive interval) PT80 was 163 (71-383), 116 (51-274) and 61 (26-144) at 6, 8 and 12 weeks, respectively. Significant model covariates included age (infant versus adult) and multiple dosing.

Conclusions: Age and repeat dosing influence VRC07-523LS PK. An 80-mg dose followed by 100 mg at 12 weeks rapidly achieves and maintains concentrations >10 µg/mL for >24 weeks. This dosing strategy is expected to result in antiviral effects in patients with sensitive viruses and supports further evaluation of VRC07-523LS.

Background: Macrolide resistance in Mycoplasma pneumoniae is an increasing concern worldwide.

Objectives: To investigate the prevalence of macrolide resistance in M. pneumoniae in The Netherlands.

Methods: All non-duplicate consecutive specimens with a positive M. pneumoniae PCR were prospectively collected by four hospital laboratories during the outbreak of M. pneumoniae infection in 2023/2024 in The Netherlands. The two most common mutations in the 23S rRNA gene that are known to cause macrolide resistance, A2063G and A2064G, were detected by PCR with melting curve analysis.

Results: PCR-positive specimens were identified in 268 patients. Of the 268 PCR-positive specimens, 238 were available for analysis of which 235 could be amplified for mutational analysis. Mutations were detected in 7 of 235 specimens (3%).

Conclusions: The low resistance rate of 3% still supports the use of macrolides for empirical treatment of M. pneumoniae infections in The Netherlands, but macrolide non-responsive infections should lead to the suspicion of resistant M. pneumoniae. Regular surveillance studies are important as clonal spread may cause rapid changes in resistance rates.

Background: Infections caused by XDR Pseudomonas aeruginosa significantly limit treatment options. Although ceftolozane/tazobactam and ceftazidime/avibactam have emerged as promising alternatives, increasing resistance has been reported. This study describes three critically ill patients with ventilator-associated pneumonia caused by OXA-producing XDR P. aeruginosa that developed resistance to both agents during therapy.

Methods: Antibiotic exposure and resistance were monitored clinically and in a hollow-fibre infection model (HFIM) to evaluate different ceftazidime/avibactam and ceftolozane/tazobactam regimens. Drug concentrations, bacterial burden and resistant mutants were assessed. Whole-genome sequencing and resistance profiling were performed on both clinical and HFIM-derived isolates.

Results: Initial patient isolates were susceptible to both antibiotics. One belonged to ST179 (OXA-10 producer), while two were ST235 (OXA-2 or OXA-2 + OXA-10 producers). Resistance emerged during therapy in all cases. In the HFIM, continuous infusion of ceftolozane/tazobactam plus meropenem achieved bacterial eradication for ST179 within 8 h. For ST235 isolates, high-exposure ceftazidime/avibactam regimens (4-h or continuous infusion) achieved bacterial eradication and prevented regrowth. In contrast, low-exposure 2-h infusions allowed bacterial rebound and resistance selection. Mechanisms of resistance were similar across clinical and HFIM isolates, involving overexpression or structural modification of OXA enzymes, except in one ST235 HFIM derived-isolate, in which resistance development was caused by an AmpC Ω-loop mutation. Pharmacokinetic validation confirmed accurate drug exposure in the model.

Conclusions: These findings underscore the importance of optimized dosing strategies, particularly high-concentration and prolonged infusions, in eradicating and preventing resistance development in OXA-producing P. aeruginosa infections.

Bacillus cereus is a common foodborne pathogen closely related to various foodborne diseases. The diarrhoea-type enterotoxins and vomiting-type enterotoxins it produces can lead to local or systemic infections. In recent years, resistance in B. cereus has been increasing, and multidrug-resistant bacteria have emerged. Therefore, understanding the drug resistance mechanism of B. cereus has become a matter of considerable concern in scientific research. In addition, this review explores the main resistance mechanisms of B. cereus to antibacterial drugs and discusses the detection and control strategies for the drug resistance of this bacterium. In addition, the purpose of this article is to deeply explore the drug resistance mechanism of B. cereus, with the aim of providing scientific basis and practical guidance for rational clinical drug use. Meanwhile, this article also provides innovative ideas for exploring new research approaches and screening safe and efficient antibacterial candidate drugs, with the aim of providing practical assistance for improving the current clinical cure rate.