Jing Zhang

Borderline oxacillin-resistant Staphylococcus aureus (BORSA) represents a mecA / mecC -negative phenotype characterized by oxacillin minimum inhibitory concentrations (MICs) of 1–8 mg/L. The molecular basis of this resistance, particularly regarding lineage-associated differences in induction profiles, remains incompletely understood. In this study, 11 clinical BORSA isolates from pneumonia and bloodstream infections were identified among 374 clinical S. aureus isolates. Resistance-associated features were investigated using phenotypic profiling, whole-genome sequencing (WGS), RT-qPCR of blaZ expression, and time-kill assays. All BORSA isolates were cefoxitin-susceptible, β-lactamase-positive, and distributed across six clonal backgrounds, with ST25 and ST7 each represented by three isolates. WGS identified a shared GdpP N105D substitution in all isolates, together with lineage-associated variations in pbp1 and pbp4 . Following oxacillin exposure, blaZ was significantly upregulated in all three ST25 isolates (all P < 0.001), accompanied by accelerated nitrocefin hydrolysis, whereas the remaining isolates showed weaker or more heterogeneous responses. While oxacillin monotherapy (1× MIC) failed to prevent bacterial regrowth, oxacillin/sulbactam combinations produced sustained synergistic killing. This effect was most consistently observed among the ST25 isolates, whereas the ST7 isolates showed greater phenotypic variation. These findings suggest that the BORSA phenotype in this cohort may involve a multifactorial resistance profile, including candidate gdpP variation, inducible β-lactamase activity, and alterations in penicillin-binding proteins (PBPs). The cefoxitin susceptibility of these isolates presents a diagnostic challenge that may lead to therapeutic misclassification and subsequent inappropriate therapy. β-lactam/β-lactamase inhibitor combinations demonstrated promising in vitro activity and warrants further investigation for BORSA isolates exhibiting strong inducible β-lactamase activity. IMPORTANCE: Borderline oxacillin-resistant Staphylococcus aureus (BORSA) is difficult to detect because it lacks mecA / mecC and remains susceptible to cefoxitin, increasing the risk of misclassification and inappropriate β-lactam therapy. This study suggests that BORSA resistance in this cohort is multifactorial, involving candidate gdpP variation, lineage-associated variations in penicillin-binding proteins, and inducible β-lactamase activity. Importantly, the ST25 isolates in this cohort exhibited rapid blaZ induction and stronger responses to oxacillin/sulbactam than to oxacillin alone. These findings improve understanding of BORSA biology, highlight a significant diagnostic blind spot in routine susceptibility testing, and support further evaluation of β-lactam/β-lactamase inhibitor combinations as a promising treatment strategy for BORSA isolates exhibiting strong inducible β-lactamase activity.

Background: Meropenem-vaborbactam is a fixed-dose β-lactam/β-lactamase inhibitor combination active against carbapenem-resistant Enterobacterales (CRE), especially Klebsiella pneumoniae carbapenemase (KPC)-producing CRE. This study evaluated its pharmacokinetics (PK), safety, and tolerability in Chinese participants, and performed population pharmacokinetics/pharmacodynamics (PK/PD) analysis using in vitro data to assess the suitability of the standard dosing regimen for treating CRE infections in China. Methods: This single-center, open-label study included 20 healthy participants divided into two groups receiving meropenem-vaborbactam (1:1) at 1 g/1 g or 2 g/2 g via 3-h infusion. Plasma and urine concentrations of meropenem, its open-ring metabolite, and vaborbactam were analyzed using a validated liquid chromatography-tandem mass spectrometry method. PK analysis was conducted using WinNonlin. Monte Carlo simulations were used to evaluate the 1 g/1 g and 2 g/2 g regimens administered every 8 h as 3-h intravenous infusions. For the standard 2 g/2 g regimen, the impact of extending the infusion duration from 3 to 4 h was further evaluated based on the FDA-recommended PK/PD target. Results: Plasma concentrations of meropenem, its open-ring metabolite, and vaborbactam peaked immediately after infusion, with rapid distribution and elimination. Exposure increased proportionally with dose, and almost no accumulation was observed after repeated 8-hourly dosing. Most meropenem (68.5%–77.0%) and nearly all vaborbactam were excreted unchanged in urine. Both single and multiple doses were well tolerated, with no severe or serious adverse events. In addition, PK/PD analysis showed that, for CRE isolates, the standard 2 g/2 g every 8 h regimen with a 3-h intravenous infusion achieved ≥90% probability of target attainment for meropenem (45% f T > MIC) at MIC values up to 8 mg/L. The corresponding cumulative fraction of response ranged from 98.67 to 100% across ESBL-producing and KPC-producing Enterobacterales , including bla _KPC variants resistant to ceftazidime-avibactam. Conclusion: The standard meropenem-vaborbactam regimen (2 g/2 g every 8 h, 3-h intravenous infusion) demonstrated favorable PK and safety profiles, with PK/PD analyses supporting the appropriateness of the standard regimen in Chinese participants, consistent with global findings. These results provide PK/PD support for the standard regimen and warrant further evaluation in Chinese patients with CRE infections.

Vancomycin, the guideline-recommended first-line treatment for severe methicillin-resistant Staphylococcus aureus (MRSA) infections, exerts its potent bactericidal activity by targeting the D-alany...

Aim: This Phase Ib/II study aimed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of Firsekibart in the treatment of gout flares. Methods: Phase Ib part utilized an open‐label, single‐dose, dose‐escalation design. Patients were enrolled and received a single subcutaneous injection of Firsekibart at a dose of 50, 100, or 195 mg. Phase II part was a multicenter, randomized, double‐blind, parallel, positive‐controlled study. Patients were assigned to receive either Firsekibart (100 or 195 mg) or Diprospan. Results: As of June 9, 2022, a total of 120 patients (Phase Ib N = 29, Phase II N = 91) received the study drugs. In Phase Ib, Firsekibart demonstrated dose‐dependent efficacy. Firsekibart 50 mg treatment provided less pain relief compared to the 100 mg and 195 mg. In Phase II, the visual analogue scale (VAS) score decreased by 5.51 ± 1.56, 4.72 ± 1.56 and 4.94 ± 2.44 cm after 72 h in Firsekibart 195 mg, 100 mg and Diprospan groups, respectively. Firsekibart 195 mg treatment showed a more effective pain relief trend. The pharmacokinetic (PK) profile of serum Firsekibart exhibits typical characteristics of monoclonal antibodies, featuring slow absorption (median T _max approximately 5.9–6.9 days), limited distribution (distributed volume approximately 8.0–12.1 L) and slow elimination (clearance approximately 9.2–11.5 mL/h). Safety of Firsekibart was favorable and comparable across doses and relative to Diprospan. Conclusion: A single subcutaneous injection of Firsekibart is safe and well tolerated in the treatment of gout flares. It provides dose‐dependent pain relief with favorable pharmacokinetic properties and potential for reducing the risk of gout flare recurrence. Trail Registration: Trial Registration: ClinicalTrials.gov NCT05328531

Chronic kidney disease (CKD) is a global public health challenge, affecting 10% to 15% of the world’s adult population, with an estimated 130 million patients in China [1,2]. A major and progressiv...

Background: Vancomycin, primarily excreted through the urine, is used for complicated urinary tract infections (cUTIs) caused by Gram-positive bacteria. Although serum therapeutic drug monitoring (TDM) is usually performed in vancomycin therapy, its benefits and risk factors in patients with cUTIs remain unclear. Methods: Adults with Gram-positive bacterial cUTIs receiving serum vancomycin TDM were enrolled from three prospective, multicenter trials. Minimal inhibitory concentration (MIC) was measured by agar dilution for pathogens collected from all patients. Clinical characteristics and pharmacokinetic/pharmacodynamic (PK/PD) indices were analyzed between the vancomycin treatment success and failure groups. Results: A total of 74 adult patients with cUTIs were enrolled. Median initial daily dose of vancomycin was 1.0 g (interquartile range [IQR], 1.0–2.0 g), given in divided doses every 12 h or as a once-daily regimen. Most concomitant antibiotics targeted Gram-negative bacteria or fungi, with very limited anti-Gram-positive co-therapy. The median serum trough concentration (C _min ) of vancomycin was 9.22 mg/L (IQR, 4.36–14.33 mg/L) and 24-h area under the concentration-time curve to MIC (AUC ₂₄ /MIC) was 455 (IQR, 268–627). Despite low attainment of the AUC ₂₄ /MIC 400–600 target (27/74, 36.5%), the treatment success rate was 86.5% (64/74) and the nephrotoxicity rate was 4.1% (3/74). Urinary pathogens isolated included Enterococcus spp (55/74), Streptococcus spp (10/74), and Staphylococcus aureus (9/74), including eight methicillin-resistant S . aureus [MRSA]). Both solid tumor and S. aureus infection showed exploratory associations with vancomycin treatment failure. Patients with solid tumor had a lower probability of attaining the target AUC ₂₄ /MIC, likely due to the elevated MIC of the predominant Enterococcus strains in this population. In contrast, patients with S. aureus -induced cUTIs achieved higher AUC ₂₄ /MIC levels. All isolates exhibited low MICs (≤1 mg/L), no heteroresistance was detected, and the predominant molecular type was clone complex 5 (CC5). Conclusion: Vancomycin was effective in Enterococcus -dominant cUTIs and had a modest response in a few MRSA cases, despite low PK/PD target attainment. Serum C _min and AUC ₂₄ /MIC showed limited association with clinical outcomes, whereas solid tumor and S. aureus infection showed exploratory associations with treatment failure. However, TDM remains valuable for safety monitoring and individualized dosing. These findings should be validated in larger cohorts.

Nemonoxacin, a novel non-fluorinated quinolone, is approved for community-acquired pneumonia, but its efficacy against uncomplicated urinary tract infections (uUTIs) caused by Escherichia coli ( E. coli ) is uncertain. We aimed to establish an in vitro uUTIs model simulating urinary concentrations to evaluate dosing regimens. An in vitro model was developed using cation-adjusted Mueller–Hinton broth (CAMHB) and synthetic human urine (SHU) to reproduce urinary exposure. The model was applied to 12 E. coli clinical isolates and ATCC 25922 (MICs 512 mg/L) over 24 h. The effects of medium type on MICs and bacterial growth were assessed. Pharmacokinetics/pharmacodynamics (PK/PD) relationships were described using a sigmoid E _max model, with change in bacterial density (Δlog ₁₀ CFU/mL) and the area under the bacterial kill curve (AUBKC) as efficacy endpoints. Monte Carlo simulation (MCS) estimated the probability of target attainment (PTA) and cumulative fraction of response (CFR) for 500 mg and 750 mg once-daily regimens. Nemonoxacin MICs were higher in SHU, and bacterial growth showed early inhibition. The AUC _0–24 /MIC ratio best correlated with antibacterial effect ( R ² = 0.951 in CAMHB; 0.982 in SHU). For a 1-log CFU reduction, AUC _0–24 /MIC targets were 46.5 in CAMHB and 199 in SHU. The 500 mg regimen achieved ≥90% PTA for isolates with MIC ≤ 16 mg/L (CFR 92.1%) using CAMHB-derived targets but only ≤8 mg/L (CFR 59.4%) in SHU. A 500 mg once-daily regimen of nemonoxacin appears to be a promising therapeutic option for the treatment of uUTIs, although further clinical studies are necessary to validate these findings.