International Journal of Antimicrobial Agents最新文献

The emerging resistance to cephalosporins and carbapenems in gram-negative pathogens poses significant health challenges and increased treatment failures. The development and evaluation of novel therapeutic options are needed urgently. This study aimed to assess the in vitro activity of ceftolozane/tazobactam (C/T), a new cephalosporin and β-lactamase inhibitor combination, against isolates of Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae from different infection sources in two general hospitals in Singapore. Susceptibility testing revealed that C/T has good activity against 600 tested gram-negative pathogens, showing a 94.8% susceptibility rate across different species and infection types. Additionally, emergence of C/T resistance was also observed and characterized with whole genome sequencing (WGS) analysis. WGS analysis indicated that C/T resistance was predominantly associated with harbouring broad-spectrum β-lactamases such as carbapenemases, ESBLs, AmpC and others. Novel mutations in penicillin-binding-protein 3 (PBP3), the target of ceftolozane, and variants associated with hyper ampC expression (ampD, ampR, and dacB), were also found in C/T-resistant isolates, potentially contributing to C/T resistance. The finding of this study provides valuable local data on C/T susceptibility, which is important for guiding the proper clinical use of C/T and promoting antimicrobial stewardship in managing gram-negative infections.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the authors. The authors have requested the retraction of the article due to unexpected identification of contaminated bacterial strains in their laboratory, including six strains used in this study. This issue was identified during a routine internal quality control procedure shortly after publication and has compromised the validity of the results in this study. The article's original Handling Editor and the journal's Editor in Chief have both agreed with the authors to retract the article to preserve the integrity of the scientific record. The authors deeply regret this incident and sincerely apologize for any inconvenience it may have caused. They remain committed to improving their internal review processes to avoid similar issues in the future.

The increasing prevalence of infections due to metallo-β-lactamase (MBL)-producing Enterobacterales poses a serious concern given the limited treatment options available. This systematic literature review (SLR) describes the molecular epidemiology, geographical distribution, and clinical outcomes of such infections. Systematic searches of literature published between January 2013 and May 2023 were performed, and 39 studies with an MBL sample size of ≥25 isolates and ≥2 well-defined outcomes were eligible. Most of the studies were from Asia (21/39) followed by Europe (11/39) and evaluated more than two species (24/39). Overall, the percentage of MBL-producing isolates ranged from 6.8%-100.0%. Among 6620 MBL-producers, the majority were from Europe (3837/6620; 58.0%), followed by Asia (2079/6620; 31.4%). New Delhi MBL (NDM)-producers (5668/6620; 85.6%) were the most frequent across all regions, with NDM-1 as the common variant. The majority of IMP-producing isolates (586/592; 99.0%) came from Asia, while the majority of VIM-producing isolates were found in Europe (322/371; 86.8%). Studies focused on MBL-specific outcomes (n=28) reported reduced susceptibility (<80.0%) to most antimicrobials except for colistin and tigecycline. Six studies reported significantly longer hospital and/or ICU stay due to MBL-Enterobacterales compared to other infection groups. Common mortality measures reported were overall mortality (18.8%-57.0%; 9 studies), in-hospital mortality (11.1%-55.3%; 6 studies), and 30-day mortality (0%-36.4%; 7 studies). Previous antibiotic use (9 studies) and hospital and/or ICU stay (8 studies) were common risk factors for colonization/infection and mortality. Reporting of MBL prevalence across regions will provide a better understanding of the infection burden and prevent further spread. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023450571.

Global demand for food has driven expansion and intensification of livestock production, particularly in developing nations where antibiotic use is often routine. Waste from poultry production, including manure, is commonly utilized as fertilizers in agroecosystems, risking environmental contamination with potentially zoonotic bacteria and antimicrobial resistance genes (ARGs). Here, 33 bacterial isolates were recovered from broiler (n=17) and layer (n=16) chicken manure by aerobic culture using Luria Bertani agar. Antimicrobial susceptibility testing (AST) by disc diffusion revealed all isolates were resistant to a minimum of three antibiotics, with resistance to ampicillin, co-trimoxazole, fluoroquinolones, tetracyclines, streptomycin, rifampicin and/or chloramphenicol detected. MALDI-ToF and 16S rRNA sequencing were used to identify and compare a subset of antibiotic-resistant isolates (n=13). Stutzerimonas sp. and Acinetobacter sp. were the common genera observed in this study. Genome sequencing of each selected isolate revealed carriage of multiple ARGs capable of conferring resistance to many antimicrobials commonly employed in poultry production and human medicine, including tetracyclines, quinolones, macrolides, sulfonamide and cephalosporins. Comparison of whole genome sequence assemblies and phenotypic assays were used to assess capacity for biofilm formation, heavy metal tolerance and virulence. The high occurrence of ARGs in studied bacterial isolates confirms that poultry manure could act as a source of genetic material that could be transferred to commensal microbiota and opportunistic pathogens of humans. Understanding the complex resistome interplay between humans, animals, and the environment requires a One Health approach, with implications for agricultural settings and public health.

Ceftobiprole, an advanced-generation cephalosporin with broad bactericidal activity, is approved for community-acquired and hospital-acquired pneumonia (excluding ventilator-associated pneumonia). We aimed to evaluate, in a real-world setting, the safety profile of ceftobiprole in patients with risk conditions (severe renal impairment, hepatic impairment, and immunocompromised status), groups excluded from clinical trials. In this retrospective study (NCT04170309), 396 consecutive charts of patients treated with ceftobiprole during 2016-2022 in 15 centers in France, Italy, and Spain were analyzed: 62 had severe renal impairment, 51 had hepatic impairment, 120 were immunocompromised, and 203 had no predefined risk condition (controls). Ceftobiprole was used for off-label indications in 110/396 (27.8%) patients; 46/396 (11.6%) patients received a higher-than-recommended dose. Treatment-emergent adverse events (TEAEs) considered as ceftobiprole-related occurred in 44 patients, more frequently in the risk groups compared to controls (severe renal impairment: 8/62 [12.9%]; hepatic impairment: 7/51 [13.7%]; immunocompromised: 19/120 [15.8%]; controls: 15/203, [7.4%]); in 7/44 patients, these events were serious. Compared to controls, liver-related AEs occurred more frequently in the impaired hepatic function (17/51 [33.3%] vs 22/203 [10.8%], odds ratio [OR:]: 4.11; 95% confidence interval [CI]: 1.98-8.55) and immunocompromised (30/120 [25.0%] vs 22/203 [10.8%], OR: 2.74; 95%CI: 1.50-5.02) groups. Hyponatremia was also more frequent in immunocompromised patients than controls (14/120 [11.7%] vs 9/203 [4.4%], OR: 2.85; 95%CI: 1.19-6.80). Underlying disease, concomitant medications and the poor health status of the patients likely affected these imbalances. Overall, no new safety concerns related to ceftobiprole use in real-world patients with severe renal impairment, hepatic impairment or immunocompromised status were identified.

The prevalence of herpes simplex virus type 1 (HSV-1) infection and the emergence of drug-resistant HSV-1 strains posts a significant global health challenge, necessitating the urgent development of effective anti-HSV-1 drugs. As one of the most prevalent molecular chaperones, heat shock protein 90 α (Hsp90α) has been extensively demonstrated to regulate a range of viral infections, thus representing a promising antiviral target. In this study, we identified JD-13 as a novel Hsp90α inhibitor and explored its capability in inhibiting HSV-1 infection. The inhibitory effect of JD-13 on Hsp90α activity was confirmed by molecular docking, molecular dynamic stimulations, fluorescence quench titration and cellular thermal shift assay. Furthermore, we found that JD-13 significantly inhibits the infection of both normal and acyclovir-resistant HSV-1 strains. In addition, JD-13 alleviated skin damage in guinea pigs caused by cutaneous HSV-1 infection. Further studies revealed that JD-13 impaired HSV-1 early infection and suppressed the Akt/β-catenin signaling pathway by promoting Akt degradation. Consequently, the inhibition of the Akt/β-catenin signaling pathway restricted HSV-1 infection. In conclusion, these results suggest JD-13 as a novel HSP90α inhibitor with the potential to be developed as an antiviral agent for the treatment of HSV-1-related diseases.

Objectives: Carbapenem-resistant Klebsiella pneumoniae (CRKP) has become a global concern owing to its difficult treatment. This study aimed to determine the impact of colistin resistance on susceptibility to cefiderocol.

Methods: The colistin-susceptible clinical strain CRKP12-130 (colistin minimum inhibitory concentration [MIC] 0.5 mg/L) was cultured in medium containing 4× and 8× the MIC of colistin. Eight colistin-resistant derivatives were randomly selected for susceptibility testing of cefiderocol and zeta potential changes. To compare the impact of colistin resistance on bacterial uptake of iron, growth curve experiments were conducted in cation-adjusted Mueller-Hinton broth (CAMHB) and iron-depleted CAMHB (ID-CAMHB). Resistant strains and the original strain CRKP12-130 were subjected to next-generation sequencing.

Results: Colistin MICs ranged from 16 to 128 mg/L for the eight colistin-resistant derivatives. The key genetic variants identified in colistin-resistant strains involved insertions and deletions in mgrB, and missense mutations in pmrB and phoQ. The colistin-resistant derivatives also exhibited reduced susceptibility to cefiderocol, with MICs increasing from 1 mg/L to 2-8 mg/L. Additionally, colistin-resistant strains demonstrated higher zeta potentials, ranging from -45.2 mV to levels between -32.8 mV and -14.2 mV. Resistant strains showed a more significant decrease in growth rate when cultivated in ID-CAMHB medium.

Conclusion: This study investigated the phenomenon of co-resistance to colistin and cefiderocol in CRKP under pressure of colistin. The simultaneous decrease in susceptibility poses a potential threat to the efficacy of clinical treatment of CRKP infections.

Objectives: Both vancomycin (VAN) and teicoplanin (TEI) augment the risk of acute kidney injury (AKI) when combined with piperacillin-tazobactam (TZP). We aimed to compare the risk of AKI among patients receiving TZP-VAN versus TZP-TEI.

Methods: This was a prospective, multinational, multicentre cohort study conducted in 12 centres from Turkiye, Italy and Spain between June 1, 2022, and December 31, 2023. The primary outcome was the occurrence of acute kidney injury (AKI) between the first day of antibiotic treatment and the third day after completing therapy, according to the Kidney Disease Improving Global Outcomes criteria. Multivariable logistic regression and propensity-score match analyses were employed to adjust for confounding variables. Stratified Kaplan-Meier analysis was used to assess the time-to-AKI between the comparison groups.

Results: Of 187 patients (TZP-TEI, n=102; TZP-VAN, n=85), the AKI occurred in 21 patients (24.7%) who received TZP-VAN and in 15 patients (14.7%) with TZP-TEI (unadjusted odds ratio [OR], 1.90; 95% CI: 0.91-3.97; P= 0.087). After adjusting for confounding variables with multivariable analysis, TZP-VAN was not associated with increased odds of AKI compared with TZP-TEI; with an adjusted OR of 2.24 (95% CI: 0.78-6.42; P= 0.133). In propensity-score matched analysis (n= 49 pairs), the AKI risk was similar between the two groups (OR, 2.10; 95% CI: 0.67-6.50; P= 0.199). The stratified Kaplan-Meier analysis indicated no difference between the treatment groups in terms of time-to-AKI (log-rank test, P=0.107).

Conclusions: The risk of AKI in TZP-VAN was similar to that in TZP-TEI. These results should be confirmed in randomized controlled trials.

Objectives: To expand a translational pharmacokinetic-pharmacodynamic (PKPD) modelling approach for assessing the combined effect of polymyxin B and minocycline against Klebsiella pneumoniae.

Methods: A PKPD model developed based on in vitro static time-kill experiments of one strain (ARU613) was first translated to characterize that of a more susceptible strain (ARU705), and thereafter to dynamic time-kill experiments (both strains) and to a murine thigh infection model (ARU705 only). The PKPD model was updated stepwise using accumulated data.

Results: The same model structure could be used in each translational step, with parameters being re-estimated. Dynamic data were well predicted by static-data-based models. The in vitro - in vivo differences were primarily quantified as a change in polymyxin B effect: a lower killing rate constant in vivo compared to in vitro (concentration of 3 mg/L corresponds to 0.05 /h and 57 /h, respectively), and a slower adaptive resistance rate (the constant in vivo was 2.5% of that in vitro). There was no significant difference in polymyxin B - minocycline interaction functions. Predictions based on both in vitro and in vivo parameters indicated that the combination has a greater-than-monotherapy antibacterial effect in humans, forecasting a reduction of approximately 5 and 2 log₁₀ CFU/mL at 24 hours, respectively, under combined therapy, while in monotherapy the maximum bacterial load was reached.

Conclusions: The study demonstrated the utility of the PKPD modelling approach to understand translation of antibiotic effects across experimental systems and showed a promising antibacterial effect of polymyxin B and minocycline in combination against K. pneumoniae.

Development of neutralizing monoclonal antibody (nAb) is a strategy for treatment of infections caused by SARS-CoV-2. This study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of HFB30132A, a fully human nAb targeting SARS-CoV-2 spike protein receptor binding domain, in healthy subjects. Randomized, double-blind, placebo-controlled phase I trial was performed in healthy Chinese and US subjects, respectively. The subjects (n=44) received a single ascending dose (400, 1000, 2000 mg) or placebo. Safety and PK data were analysed. PD was evaluated by pseudovirus neutralization test in vitro using serum samples of Chinese subjects. Population PK/PD model was developed using non-linear mixed effects modeling. Effect of covariates was evaluated via covariate screening, Monte Carlo simulation, and randomisation test. The PK profile was consistent with three-compartment model. The clearance (CL) and V₁ were 0.38 mL/h and 2.9 L, respectively. Ethnicity and body weight (BW) were factors affecting PK. Compared to the subjects who are not Hispanic or Latino, AUC_0-∞ increased by 64% in the healthy subjects of Han nationality. The PD was consistent with effect-compartment model when ND₅₀ titre (reciprocal of 50% neutralization dilution) was used as PD index. E_max reduced along with time, consistent with exponential model. The EC₅₀ was 4590 mg/L. Half-life for reduction of E_max was 133 days. Albumin, lymphocytes, neutrophils or monocytes were covariates on PD. There was ethnic difference in PK, and tolerance in PD of HFB30132A. Population PK/PD model characterized dose-exposure-response relationship of HFB30132A in healthy subjects. These findings are useful for drug development in the future. Clinical trial registration: ClinicalTrial.gov NCT04590430, NCT05275660.