Antimicrobial Agents and Chemotherapy最新文献

Candida albicans (C. albicans) is a commensal, drug-resistant opportunistic pathogen, and the eradication of invasive candidiasis represents a significant clinical challenge. This study investigated the inhibitory effect of isobavachalcone (IBC) on C. albicans growth and elucidated its mechanism. The antifungal activity of IBC was evaluated using minimum inhibitory concentration 90% (MIC₉₀) and minimum fungicidal concentration (MFC), combined with murine vaginitis and oral thrush models to assess in vivo efficacy. An MTT assay was used to assess drug safety. Mechanistic investigations included cell membrane/wall damage assessments, virulence factor inhibition, oxidative stress evaluation, ATP metabolism analysis, protein expression profiling, and target identification (including RT-qPCR, inhibitor intervention experiments, and related methodologies). The antifungal potency of IBC against C. albicans was demonstrated with a MIC₉₀ of 2 µg/mL and an MFC of 8 μg/mL. Against strain S393, IBC exhibited potent efficacy with median effective and effective concentrations of 1.301 µg/mL and 1.449 µg/mL, respectively. In vivo, IBC significantly alleviated vulvovaginal candidiasis and oropharyngeal thrush, outperforming fluconazole in therapeutic efficacy and mucosal protection. Mechanistic studies revealed that IBC prevented fungal invasion by inhibiting C. albicans adhesion and colonization on mucosal surfaces, mitigated inflammation through suppression of proinflammatory cytokine release, and downregulated the expression of ADE13, TPI1, and ADK1 genes, with ADK1 demonstrating the most significant suppression. Furthermore, IBC specifically bound to ADK1, inhibiting ATP synthesis and disrupting cellular energy metabolism in C. albicans. IBC represents a promising antifungal drug that acts by downregulating the ADE13, TPI1, and ADK1 genes. Its downregulation of ADK1 leads to impaired ATP synthesis, induced DNA damage, and suppressed fungal proliferation.

Retained hardware/prosthetic infections frequently require antimicrobial suppression therapy. Treatment options are often limited by resistance, allergies, and dosing frequencies. Dalbavancin (DAL) is a potentially attractive option for suppression of gram-positive infections given its potential for infrequent dosing. However, optimal DAL suppression dosing is unknown. An in silico pharmacokinetic/pharmacodynamic simulation was performed to assess the predicted dalbavancin concentration resulting from suppressive regimens. Serum levels were deemed adequate if the fAUC₂₄/MIC was above the PK target of 27.1. Patients at a U.S. medical center receiving DAL as suppressive therapy were reviewed. PK simulation of DAL dosed 1,500 mg monthly resulted in free serum concentrations above the PK target. Because many clinicians opt to initiate these regimens with two doses given 1 week apart, the next modeled regimen included this load, before initiating 1,500 mg monthly. This initial load did not significantly alter total drug exposure. The final simulated regimen was 1,000 mg monthly. With this simulation, the lower 95% CI fAUC₂₄/MIC fell just below the PK target for an isolate at the breakpoint. Nine patients who received dalbavancin 1,500 mg monthly as suppressive therapy were reviewed. All had retained hardware and received DAL for a median 591 days, with 7 patients still receiving treatment and no reported suppressive therapy failure. Monthly 1500 mg dalbavancin dosing for suppressive therapy is supported by this case series and PK simulation data. An initial weekly loading dose appears unnecessary. Reducing the monthly dose to 1000 mg may also be appropriate for certain patients, though clinical data is needed to support this practice.

Antibacterial drug mechanisms have traditionally been examined through a drug-pathogen lens, with limited attention to host influences on drug activity. However, growing evidence suggests that the host environment is crucial for antibacterial efficacy. Pyrazinamide (PZA), a key component of modern tuberculosis therapy, exemplifies this complexity, exhibiting potent in vivo activity despite its inability to reduce Mycobacterium tuberculosis viability in standard in vitro culture. Here, using macrophage and murine infection models, we identify a critical role for CD4⁺ T cell-dependent cell-mediated immunity in PZA's antitubercular action. Using MHC class II knockout mice, we demonstrate that CD4 T-cell help is essential for PZA efficacy. While interferon gamma (IFN-γ) is required for PZA-mediated clearance of M. tuberculosis at extrapulmonary sites, bacterial reduction in the lungs occurs, independent of IFN-γ signaling. We show that PZA leverages cell-mediated immunity in part through activation of the oxidative burst. Our findings underscore the need to incorporate host factors into antibacterial drug evaluation and highlight potential avenues for host-directed therapies and adjunctive antibiotics in first- and second-line tuberculosis treatment.

Klebsiella pneumoniae is a leading cause of both hospital- and community-acquired pneumonia. Nanomaterials have the potential to deliver antibiotics directly to sites of infection with improved pharmacokinetics and to avoid development of antimicrobial resistance. We previously demonstrated the use of alveolar macrophage (AM)-targeted polymeric prodrugs to prevent pneumonia in murine models caused by the facultative intracellular pathogens Francisella novicida and Burkholderia pseudomallei. These fully synthetic mannose-tagged polymers engage with AM mannose receptors, permitting uptake and triggering intracellular ciprofloxacin release. Here we show that the AMs can also serve as a reservoir for releasing antibiotics to treat infections caused by a primarily extracellular bacterium. Aerosolized ciprofloxacin polymeric prodrugs significantly improved survival in a murine model of K. pneumoniae pneumonia, reduced lung bacterial burden, lessened extent of lung injury, and prevented excessive neutrophilic inflammation.

While caspofungin is increasingly used to treat invasive fungal infections in pediatric intensive care unit (PICU) patients, its pharmacokinetic profile in this population remains poorly understood, and current dosing regimens are not firmly supported by scientific evidence. This study aimed to characterize the population pharmacokinetics of caspofungin in critically ill children and to identify dosing strategies for optimal exposure. The prospective clinical study was conducted among pediatrics in PICU. Population pharmacokinetic analysis and Monte Carlo simulations were performed. A total of 138 plasma samples collected from 29 pediatric patients (0.33-16 years) were included in the final analysis. The two-compartment model with allometric scaling on body surface area (BSA, exponential 1 for volume of distribution and 0.66 for clearance) accurately described time courses of caspofungin. Extracorporeal membrane oxygenation (ECMO) significantly increased the central volume of distribution (effect coefficient 18.2). There was no significant difference in area under the concentration curve (AUC) between patients with and without ECMO support. Simulations demonstrated that tAUC_ss,24h/MIC-based PTA results showed no significant differences between ECMO and non-ECMO groups and supported the current dosing regimen. A fixed maintenance dose (MD) is appropriate for patients with BSA ≥ 1.4 m², while the standard BSA-based MD remains preferable for those with BSA <1.4 m². Our study confirmed the recommended caspofungin dosing regimen in Chinese critically ill PICU patients. Although the number of patients receiving ECMO in this study was limited, future studies with a larger ECMO population are warranted to further validate these findings.This study is registered with ClinicalTrials.gov as NCT04961593.

HRS-8427, a development-stage siderophore cephalosporin antibiotic, is being investigated for the treatment of aerobic Gram-negative bacterial infections, encompassing urinary tract infections and pulmonary infections. Participants with these indications frequently exhibit concomitant renal impairment (RI). Data from clinical studies suggest that ~60% to ~70% of unchanged HRS-8427 is excreted renally. A phase 1, multicenter, open-label study evaluated the effects of RI on the pharmacokinetics and safety of HRS-8427. In sub-study 1, 21 participants with mild to severe RI who were not on dialysis and six participants with normal renal function received single doses of 1,000 mg HRS-8427. In sub-study 2, six participants with end-stage renal disease (ESRD) requiring hemodialysis (HD) received single doses of the 1,000 mg HRS-8427 under dialysis and non-dialysis conditions, respectively. Plasma HRS-8427 area under the concentration-time curve from zero to infinity (AUC_0-∞) was ~1.2-fold, ~1.4-fold, 2.0-fold, and ~2.0-fold higher, respectively, in participants with mild, moderate, severe RI, and ESRD (without HD) relative to healthy controls. In dialysis-dependent subjects, the systemic exposure of HRS-8427 when dosed before HD was equivalent to 50.6% of that when dosed after HD. Adverse events (AEs) were mostly mild, and RI did not appear to be associated with an increased risk of AEs.CLINICAL TRIALSThis study is registered with http://www.chinadrugtrials.org.cn/ as CTR20230658.

Conventional in vitro susceptibility testing methods may underestimate the bactericidal activity of antibiotics that are chemically unstable in aqueous media, thereby limiting their clinical translatability. Tigecycline is considered a representative example of such compounds, exhibiting notable therapeutic efficacy against a broad range of pathogens despite poor in vitro susceptibility profiles, as reflected by elevated MIC values. This discrepancy is likely attributable, at least in part, to the chemical instability of TGC under standard MIC assay conditions. In this manuscript, we propose a mechanism-based PK/PD modeling approach as a framework to overcome the limitations of traditional MIC assessments and to address potential discrepancies between intrinsic and experimentally measured apparent antibacterial activity. Dynamic time-kill curves for single and multiple dose scenarios of TGC against Mycobacterium abscessus (Mab) were experimentally simulated in 24-well plates, leveraging the chemical instability of TGC. Based on the resulting in vitro data, a mechanism-based model was developed to perform simulations for characterizing intrinsic efficacy and potency of TGC. While the in vitro MIC of TGC determined under standard conditions was determined as 3.125 mg/L, an intrinsic MIC simulated based on model predicted bacterial time-time kill curves was 0.5 mg/L. Model-based analysis also revealed that MIC under standard conditions was stemming from drug instability and bacterial growth rate in the utilized media. In conclusion, the PK/PD modeling and simulation-based MIC determination indicated that clinically achievable exposure levels of TGC are sufficient to kill Mab, underlining the therapeutic potential of TGC against Mab infections.

The role of TetA variants in mediating tigecycline and eravacycline resistance in Klebsiella pneumoniae remains a critical area of investigation. However, there has been a lack of systematic characterization of the epidemiology, resistance phenotypes, and fitness costs of TetA variants. Here, we identified 28 TetA variants in K. pneumoniae from the National Center for Biotechnology Information database from 824 isolates, categorizing them into three phylogenetically distinct clades. Among these, four variants were shown to mediate eravacycline resistance, with concurrent but variable effects on tigecycline susceptibility. Notably, these resistance-conferring variants exhibited limited dissemination across clinical and environmental strains. Analyses revealed that their expression imposes a significant fitness cost, markedly reducing bacterial tolerance to the clinical disinfectant H₂O₂ and an environmental heavy metal cadmium-a trait critical for survival under ecological stress. This trade-off likely explains the limited prevalence of these variants despite their resistance phenotypes. Our findings highlight the evolutionary constraints affecting the spread of TetA-mediated antibiotic resistance and underscore the need for One Health-driven surveillance to monitor variants with potential risk in human, animal, and environmental reservoirs. This work provides novel insights into the interplay between resistance determinants and bacterial adaptability, offering a framework for predicting resistance dynamics in K. pneumoniae within the context of interconnected ecological and clinical ecosystems.

MK-7602 is a first-in-class dual-plasmepsin inhibitor being developed to treat malaria. Safety, tolerability, and pharmacokinetics (PK) of MK-7602 following single and multiple doses were evaluated in two phase 1 studies (7602-001; 7602-002). Study 7602-001 included two parts: part 1, a randomized, single-ascending-dose (10-400 mg), placebo-controlled, double-blind study (n = 24); and part 2, a non-randomized, fixed-sequence, open-label study (n = 12) to assess the effect of itraconazole (200 mg), a cytochrome P450 3A and P-glycoprotein inhibitor, on the PK of MK-7602 (25 mg). Study 7602-002 was a randomized, placebo-controlled, multiple-ascending-dose study (n = 40); participants received MK-7602 (50-300 mg) or placebo for 7 days. Single and multiple doses of MK-7602 were generally well tolerated. Headaches were the most common adverse event (7602-001 part 1: 54.5%; 7602-002: 36.7%). MK-7602 median time to maximal concentration (T_max) was 1.5-3.0 h, with dose-proportional increases in maximum concentration (C_max) and the area under the curve over the dosing interval (AUC_0-tau) at single and multiple doses of ≥50 mg. Terminal half-life was 31.3-41.4 h following multiple dosing, the accumulation ratio for daily dosing was 1.03-2.20, and steady-state concentrations were reached by day 3. Coadministration with itraconazole resulted in a 6- and 12-fold increase in C_max and area under the concentration-time curve to infinity, respectively. The primary hypothesis that a well-tolerated dose of MK-7602 would achieve a trough concentration of ≥0.017 μM was met in both studies. Safety and PK characteristics support continued development of MK-7602.

Multidrug-resistantant (MDR) Pseudomonas aeruginosa is a major public health concern necessitating new antimicrobials. There are new antimicrobials available with activity against MDR-P. aeruginosa, but there is a lack of robust evidence synthesis to guide clinical decision-making for patients with infections caused by MDR-P. aeruginosa. This study, which was supported by Merck & Co., Inc., aimed to evaluate the real-world effectiveness of ceftolozane/tazobactam (C/T) compared to other commonly used therapies (aminoglycosides/polymyxins and ceftazidime/avibactam [CZA]) among adults with MDR-P. aeruginosa infections. A systematic literature review was conducted to identify real-world clinical and healthcare-resource utilization outcomes for C/T versus comparators. A feasibility assessment excluded comparators that were not aminoglycosides/polymyxins or CZA due to insufficient data for comparisons. A meta-analysis and network meta-analysis (NMA) were conducted on the included studies. Heterogeneity between the studies was calculated using I² statistic. The NMA displayed statistically significant results for clinical cure (odds ratio [OR] = 0.308, 95% CI = 0.168-0.515) and all-cause mortality (OR = 1.651, 95% CI = 1.114-2.501) for C/T versus aminoglycosides/polymyxins, while microbiological cure and length of stay did not display statistical significance. However, comparisons for C/T versus CZA demonstrated no statistical significance for any of the outcomes explored. These findings suggest that C/T is more likely to achieve clinical cure and less likely to result in all-cause mortality compared to aminoglycosides/polymyxins. In the absence of head-to-head trials, this real-world evidence indicates potential advantages of using C/T over aminoglycosides/polymyxins for MDR-P. aeruginosa infections. Larger prospective studies with standardized outcome measures are needed to further inform clinical decision-making.