International Journal of Antimicrobial Agents最新文献

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.

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.

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.