Antimicrobial Agents and Chemotherapy最新文献

The combination of aztreonam and ceftazidime-avibactam (ATM-CZA) is a last resort regimen against recalcitrant infections caused by metallo-β-lactamase (MBL)-producing organisms. Susceptibility testing is warranted due to emerging resistance to the combination, but there are no widely implemented methods for use in clinical laboratories. Here, we used a cohort of 100 Enterobacterales, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia strains, including 68 MBL producers, to evaluate the performance of two ETEST strip-based synergy testing methods: the side-by-side (SS) method with an ATM ETEST placed next to a CZA ETEST (10 mm apart) and the strip cross (SX) method with a CZA ETEST placed perpendicularly on top of the ATM ETEST (at the 8 µg/mL mark). By reference broth microdilution (BMD), 89.1% (41/46) of the Enterobacterales, 15% (3/20) of the P. aeruginosa, and 97.1% (33/34) of the S. maltophilia isolates tested susceptible to the ATM-CZA combination. The SS method yielded 72% categorical agreement with BMD and 28 major errors (ME, 36.4%). Initial testing with the SX method yielded three ME , of which one was resolved upon repeat testing, yielding a final categorical agreement of 98% with BMD with two ME (2.6%). The SX method also yielded 100% reproducibility across three brands of Mueller Hinton agar (BD, Hardy, Remel). Our study demonstrates that the SX method is accurate, precise, and feasible for clinical laboratories to perform ATM-CZA susceptibility testing to guide use of the combination for treatment of multidrug-resistant gram-negative pathogens.

Molnupiravir, a prodrug of β-D-N⁴-hydroxycytidine (NHC), is administered orally as four 200 mg capsules twice daily for 5 days to treat COVID-19. This randomized, open-label, four-treatment sequence, three-period crossover study (NCT06615869) evaluated the bioequivalence of a new single 400 mg oral dose of the molnupiravir tablet Formulation 1 (F1) to a 400 mg oral dose of the currently authorized molnupiravir capsule formulation (administered as two 200 mg capsules) by comparing the plasma pharmacokinetics of NHC following administration to healthy participants. The effect of food on the plasma NHC pharmacokinetics following the administration of the molnupiravir F1 tablet, safety and tolerability of a single oral 400 mg dose of molnupiravir, and pharmacokinetics of a separate molnupiravir tablet Formulation 2 (F2) with a slower in vitro dissolution rate were also evaluated. The geometric mean ratio and 90% confidence intervals ([1 × 400-mg F1 tablet]/[2 × 200 mg reference capsules]) for plasma NHC area under the concentration-time curve (AUC) from time 0-infinity, AUC from time 0-last measurable time point, and maximum plasma concentration were 1.00 (0.97, 1.03), 1.00 (0.97, 1.03), and 0.98 (0.93, 1.03), respectively. All estimates were within prespecified limits (0.80, 1.25), demonstrating bioequivalence of the molnupiravir F1 tablet and reference capsules. Administration of the F1 tablet with a high-fat meal did not meaningfully impact the rate or extent of absorption. The pharmacokinetics of the F2 tablet were similar to the reference capsules. Administered in either formulation, molnupiravir was generally safe and well tolerated. In conclusion, a single 400 mg tablet of molnupiravir is bioequivalent to the reference capsule formulation in healthy adults.CLINICAL TRIALSThis study was registered at ClinicalTrials.gov as NCT06615869.

Last resort antibiotics, like ceftazidime-avibactam (CZA), were used to treat urinary tract infections caused by multidrug-resistant bacteria. However, no data on tissue distribution were available. Our aim was to describe the in vivo kidney distribution of CZA in healthy rats and pigs using a physiologically based pharmacokinetic model (PBPK). Microdialysis probes were inserted into the blood, muscle, and kidney of both species. The experiment started with a retrodialysis by drug period. An i.v. single dose of CZA was administered. Samples were collected for 3 h in rats and 7 h in pigs. A PBPK model was developed to describe tissue and blood CZA pharmacokinetics in animals and to predict human concentrations. The PBPK model adequately described CZA rat and pig data in each tissue and blood. In both species, the concentration profiles of CZA in muscle and blood were almost superimposed, with muscle-to-plasma area under the curve (AUC) ratios close to one. However, kidney CZA concentrations were higher than those in blood, as indicated by kidney-to-plasma AUC ratios exceeding one (respectively 2.27 in rats and 2.63 in pigs for ceftazidime [CAZ]; 2.7 in rats and 4.5 in pigs for avibacam [AVI]). Prediction of human concentrations led to same observations. This study demonstrated an excellent penetration of CZA into the renal parenchyma of rats and pigs. Our PBPK model adequately described the data, and AUCs were higher in the renal cortex interstitium compared with unbound plasma. Our data suggested that the joint PK/PD target for CZA in humans could be attained with reduced CZA doses.

Piperacillin/tazobactam (PTZ) is frequently prescribed during the perioperative period as prophylaxis in critically ill patients. Current international guidelines recommend that the pediatric intraoperative dosing regimen for PTZ be 90-112.5 mg/kg (80-100 mg/kg as piperacillin [PIP]) administered every 2 hours (Q2H). Concerns have been raised not only about the risk of nephrotoxicity due to elevated PIP exposure but also regarding the practicality of adhering to a 2-h dosing interval in clinical settings. To address these concerns, we employed population pharmacokinetic (PK) modeling and simulation approaches to optimize PTZ dosing regimens in pediatric intraoperative patients. PIP plasma concentration data were obtained from 34 patients using an opportunistic sampling strategy. A two-compartment model was found to adequately describe the PK data. Creatinine clearance was identified as a significant covariate on clearance. The inclusion of inter-occasion variability significantly improved model fit. Simulations across body weights of 10-70 kg and creatinine clearance of 20-130 mL/min/1.73 m² demonstrated that 6-15 mg/kg Q2H, or a 10 mg/kg loading dose followed by 1.0-2.75 mg/kg/h continuous infusion would achieve free PIP concentrations being above the minimum inhibitory concentration (MIC) for 100% of the dosing interval (100% fT >1× MIC). For achieving 100% fT >4× MIC, 25-55 mg/kg Q2H or a 20 mg/kg loading dose followed by 3.25-9.25 mg/kg/h continuous infusion was derived. The model-informed simulations indicated that both lower Q2H doses and continuous infusion methods are clinically viable options and potentially resolve current clinical challenges during intraoperative dosing.

Rapid molecular diagnostic tests improve antimicrobial stewardship (AMS) by facilitating earlier refinement of antimicrobial therapy. The INHALE trial tested the application of the BioFire FilmArray Pneumonia Panel (Pneumonia Panel) for antibiotic prescribing for hospital-acquired and ventilator-associated pneumonias (HAP/VAP) in UK intensive care units (ICUs). We report a behavioral study embedded within the INHALE trial examining clinicians' perceptions of using these tests. Semi-structured interviews were conducted with 20 ICU clinicians after using the Pneumonia Panel to manage suspected HAP/VAP. Thematic analysis identified factors reinforcing perceptions of the necessity to modify antibiotic prescribing in accordance with test results and doubts/concerns about doing so. While most acknowledged the importance of AMS, the test's impact on prescribing decisions was limited. Concerns about potential consequences of undertreatment to the patient and prescriber were often more salient than AMS, sometimes leading to "just-in-case" antibiotic prescriptions. Test results indicating a broad-spectrum antibiotic were unnecessary often failed to influence clinicians to avoid an initial prescription or de-escalate antibiotics early as they considered their use to be necessary to protect the patient and themselves, "erring on the side of caution." Some clinicians described cases where antibiotics would be prescribed for a sick patient regardless of test results because, in their opinion, it fits with the clinical picture-"treating the patient, not the result." Our findings illustrate a tension between prescribing guidelines and clinicians' "mindlines," characterized by previous experiences. This highlights the need for a "technology plus" approach, recognizing the challenges clinicians face when applying technological solutions to patient care.IMPORTANCERapid molecular diagnostic tests for pathogens and resistance genes may improve antibiotic-prescribing decisions and stewardship. However, clinicians' desire to protect their patients with antibiotics often overrides more distal concerns about possible resistance selection, limiting the application of these tests in practice. Findings underscore the challenge of changing prescribing decisions based on technical results or guidelines, highlighting factors such as clinicians' previous experience and "knowledge in practice" as more proximal drivers of these decisions. Implementation strategies for technological solutions to antimicrobial resistance must be "behaviorally intelligent," recognizing the challenges facing clinicians when making "life or death" prescribing decisions.CLINICAL TRIALSThis study is registered with ISRCTN as ISRCTN16483855.

Chronic hepatitis B (CHB) patients receiving entecavir (ETV) treatment might develop low-level viremia (LLV), which is proven to be associated with worse clinical outcomes, such as risk of drug-related mutations, progression to cirrhosis, and even hepatocellular carcinoma. This real-world prospective study evaluated the efficacy and safety of switching from ETV to tenofovir alafenamide fumarate (TAF) in CHB patients with LLV. From August 2020 to August 2023, 351 ETV-experienced CHB patients with LLV were enrolled from eight hospitals. Patients either continued ETV or switched to TAF. The primary efficacy endpoint was the complete virological response (CVR) at week 48; the safety endpoint was the first occurrence of any clinical adverse event during the treatment; and the renal safety and change in blood lipids were also assessed. Inverse probability treatment weighting (IPTW) generated 350.9 cases in the ETV group and 351.4 cases in the TAF group. After the 48-week treatment, the CVR and ALT normalization rates in the TAF group were 75.3% and 67.8%, which were significantly higher than 11.4% and 17.1% in the ETV group (P < 0.001). The two strategies showed comparable impact on renal function and lipid profiles, regarding low-density lipoprotein (LDL) cholesterol and the total cholesterol to high-density lipoprotein (TC/HDL) ratio. Therefore, for ETV-treated patients with LLV, switching to TAF is superior compared with continuing ETV treatment in terms of virological and biochemical response, with non-inferior renal safety and lipid profiles.CLINICAL TRIALSThis study is registered with the Chinese Clinial Trial Registry as ChiCTR2400089257.

Artemisinin resistance, which poses a serious threat to malaria control efforts, is monitored in the field by delayed parasite clearance in patients, elevated parasite survival rate in the ring-stage survival assay, and mutations in the Plasmodium falciparum kelch13 gene. However, sporadic cases of artemisinin-resistant malaria do not meet all of these criteria, highlighting that our understanding of artemisinin resistance is still incomplete. Here, we selected for artemisinin resistance in vitro in nine P. falciparum field isolates from Africa, Asia, and South America. Artemisinin pressure selected highly resistant parasites in all lineages, but only one acquired a validated pfkelch13 mutation. Phenotypic tests evidenced an unconventional response of selected parasites that can be artemisinin-resistant only at an advanced ring age, making them undetectable by the standard "0-3 h" test used to monitor resistance. These results highlight the need for broader approaches to artemisinin resistance monitoring.

Acquisition of multiple carbapenemase genes by Klebsiella pneumoniae (Kp) is an emerging public health threat. Here, we aim to elucidate the population structure of Kp blood isolates carrying two different carbapenemase genes and identify the mechanism facilitating their dissemination. The study was conducted in a tertiary healthcare center between 2014 and 2022. Twenty-four patients with bacteremia caused by Kp carrying two different carbapenemase genes were identified. All 24 blood isolates were analyzed by short-read genome sequences supplemented by long reads in a selected number of isolates. All isolates carried bla_KPC (23 bla_KPC-2, 1 bla_KPC-3) and bla_VIM-1 genes, along with a variety of antimicrobial resistance determinants. The isolates were clustered in six clonal lineages (ST39, ST147, ST323, ST258, ST3035, and ST340). Long-read genome sequences demonstrated that each carbapenemase gene was located in a separate group of plasmids: the bla_KPC-2 on a fusion of IncFIB(pQil) and IncFII(K) plasmids, the bla_KPC-3 on IncX3, the bla_VIM-1 on IncC, or a fusion of the IncFIB(pNDM-Mar) and IncHI1B(pNDM-MAR) plasmids. Comparison of plasmid content of eight isolates carrying a single carbapenemase gene from a previous study with eight isolates carrying two carbapenemase genes from the present study, matched by clonal lineages, revealed that the second carbapenemase gene was acquired by addition of another plasmid. Identical plasmids were found within the same lineage and across lineages. These findings suggest that dissemination of carbapenemase genes in our hospital setting was driven by multiple plasmids across a variety of highly efficient clones.

Coronavirus disease 2019, which leads to pneumonia, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RAY1216 is a 3C-like protease inhibitor that targets SARS-CoV-2. The aim of our study was to assess the pharmacokinetics (PK) and safety of RAY1216 in healthy volunteers. This was a randomized, placebo-controlled, double-blind study consisting of four components: a single ascending dose study, a drug-drug interaction study, a multiple ascending dose study, and a food-effect study. All participants were randomly assigned to receive either a single dose or multiple doses of RAY1216 or placebo. A total of 88 healthy adult participants (male-to-female ratio of 1:1) aged 18-50 years were enrolled. A total of 37 participants (42%) experienced at least one adverse event (AE). All AEs were mild or moderate and were resolved without additional treatment. The most commonly reported adverse drug reactions were hypertriglyceridemia, hyperuricemia, and elevated serum creatinine levels. RAY1216 was well-absorbed after administration with exposure increasing in a dose-dependent manner. Food appeared to increase exposure and delay the absorption of RAY1216. Ritonavir significantly inhibited drug metabolism, and increased drug exposure increased the associated safety risks. RAY1216 was found to be well tolerated and safe in healthy participants. On the basis of preclinical results, PK characteristics, and the safety profile of RAY1216, a dosage of 400 mg three times daily was selected, thereby establishing a foundation for future research and for the clinical application of RAY1216.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05829551.

Novel drugs and improved diagnostics for Mycobacterium tuberculosis (MTB) are urgently needed and go hand in hand. We evaluated the in vitro activity of two benzothiazinone drug candidates (MCZ, PBTZ169; BTZ043) and their main metabolites against MTB using advanced nanomotion technology. The results demonstrated significant reductions in MTB viability within 7 h, indicating the potential for rapid, precise antibiotic susceptibility testing based on a phenotypic read-out in real time. PBTZ169 and H₂-PBTZ169 achieved 100% separation between the susceptible H37Rv and a resistant dprE1 mutant strain NTB1. These findings support nanomotion technology's potential for faster antibiotic susceptibility testing of novel MTB drug candidates targeting the DprE1 enzyme that could reduce empirical treatment duration and antibiotic resistance selection pressure due to inaccurate treatments.