Journal of Antimicrobial Chemotherapy最新文献

Background: AUC-based dosing with validated Bayesian software is recommended as a good approach to guide bedside vancomycin dosing.

Objectives: To compare treatment and vancomycin-associated acute kidney injury (AKI) costs between Bayesian AUC-based dosing and conventional therapeutic drug monitoring (TDM) using steady-state plasma concentrations of vancomycin administered as continuous infusion in hospitalized non-critically ill patients with severe Gram-positive infection.

Methods: A cost-benefit analysis presented as a return on investment (ROI) analysis from a hospital perspective was conducted using a decision tree model (TDM versus AUC-based dosing) to simulate treatment cost (personnel, serum sampling and drug cost), vancomycin-associated AKI risk and cost up to 14 days. ROI was calculated against AUC-based software cost. One-way and probabilistic sensitivity analyses (respectively OWSA and PSA) were performed to check for robustness.

Results: In base case, an overall cost per patient of €621.0 with TDM and €543.6 with AUC-based dosing resulted in a treatment saving of €77.4 per patient when applying AUC-based dosing. This saving against the software cost (€26.9/patient) generated an ROI per patient of €1.9 per invested € in software [€1.9 (95% CI 1.6-2.2) in PSA]. Enrolling 900 AUC-based dosed patients annually translated to a net saving of €45 469. Software break-even was reached after 313 patients. In OWSA, a higher AKI risk with TDM strongly contributed to a positive ROI.

Conclusions: AUC-based dosing appeared a cost-saving strategy compared with conventional TDM when applying base-case settings of vancomycin-associated AKI risk, treatment and AKI costs.

Objectives: International guidelines recommend integrase strand-transfer inhibitor (INSTI)-based regimens as initial and switch therapy in people with HIV. As novel INSTIs become available, understanding how emergence of resistance at virological failures and seroconversions affects subsequent treatment options is needed. For the latest approved INSTI, cabotegravir, resistance patterns comprising Q148K/R, N155H, R263K, G118R, E138A/K and G140A/S (alone or in combination) have been documented in virological failures and seroconversions. Here, the effect of these substitutions on antiviral activity of commercially approved INSTIs, bictegravir and elvitegravir, was assessed.

Methods: Antiviral testing was performed using person-derived clinical isolates (n = 52) with viral profiles similar to cabotegravir INSTI resistance patterns; susceptibility to cabotegravir, bictegravir and elvitegravir was measured using a phenotypic assay. Substitution patterns from isolates included triple [Q148K/H/R + E138A/K + G140A/C/S (n = 16)], double [Q148R + E138K (n = 3); Q148H/R + G140A/S (n = 24)] and single [N155H (n = 6); Q148R (n = 3)] resistance-associated mutations (RAMs).

Results: IC50 fold changes (FCs) for triple RAMs were the highest, at 47.0, 7.59 and >144 for cabotegravir, bictegravir and elvitegravir, respectively. For cabotegravir, bictegravir and elvitegravir, respectively, mean IC50 FCs were 9.5, 2.5 and >144 for double RAMs; and 3.3, 1.4 and >65 for single RAMs. When considering clinical/biological assay cut-offs, 54% (28/52) of isolates were susceptible to bictegravir, 40% (21/52) were partially susceptible and 6% (3/52) were resistant; for elvitegravir, 100% of isolates were resistant. Cabotegravir cut-offs were not available at the time of reporting.

Conclusions: Overall, clinical isolates with RAM patterns similar to clinically observed cabotegravir INSTI resistance showed meaningful increases in IC50 FCs, suggesting that cabotegravir-associated resistance may negatively affect efficacy of bictegravir- and elvitegravir-based regimens.

Introduction: The specificity of HIV-1 DNA genotypic resistance tests (GRTs) is hampered by the detection of the APOBEC-context drug resistance mutations (AC DRMs), usually harboured by replication-incompetent proviruses. We sought factors associated with defective sequences in the HIV-1 pol region. In addition, AC DRMs and their link with defective sequences were investigated.

Methods: We included ART-treated patients with viral suppression or plasma viral load (VL) lower than 200 copies/mL, who underwent HIV-1 DNA genotyping, with successful sequencing of protease (PR), reverse transcriptase (RT) and integrase (IN) regions. Sequencing was performed using either the Sanger method or the Sentosa® NGS approach with a 20% cut-off. All hypermutated sequences and/or those containing at least one stop codon were considered defective.

Results: A total of 613 HIV-1 DNA GRTs were analysed. Defective sequences were identified for 186 samples (30.3%) including 65 PR sequences, 92 RT sequences and 65 IN sequences. No association, including HIV-1 DNA levels, was found with the detection of defective pol sequences. A total of 226 AC DRMs were recorded in all sequences. Most of these mutations (78%) were harboured by defective sequences. AC DRMs did not emerge in the plasma viral population, and likely do not impact the virological response to ART.

Conclusions: Defectives pol sequences were not associated with HIV-1 DNA levels and harboured most of the AC DRMs. Such mutations likely have no clinical impact, and should not be reported in routine practice. Consensus guidelines for reporting HIV-1 DNA GRTs are needed, especially for the assessment and management of AC DRMs.

Background: Vancomycin-resistant Enterococcus (VRE) are present across the One Health continuum and pose a considerable risk for transmission along the food chain. This systematic review and meta-analysis estimates the prevalence of VRE colonization in livestock, food of animal origin, and in human populations.

Methods: Embase, MEDLINE and CAB Abstracts were searched for eligible literature. A total of 54 manuscripts passed inclusion criteria by providing prevalence estimates of VRE in a human population and at least one of either livestock or food. Random effects meta-analysis was conducted to determine prevalence estimates, and risk of bias in pooled estimates was assessed using funnel plots and Egger regression.

Results: Global pooled prevalence of VRE colonization was highest in poultry and poultry meat at 16% (95% CI: 6%-28%) and 15% (95% CI: 1%-39%), respectively. Human-associated VRE colonization was highest in livestock workers, with a pooled prevalence of 11% (95% CI: 2%-25%), and lowest in the general public at 2% (95% CI: 0%-3%). Meta-regression demonstrated that human VRE prevalence increased at a rate of 0.75% (95% CI: 0.46%-1.04%; P < 0.001) per 1% increase in livestock VRE colonization.

Conclusions: This meta-analysis established a clear link of VRE across One Health sectors. VRE colonization is likely elevated for those in contact with colonized animals or contaminated food products. Quality of evidence in pooled prevalence estimates was limited by publication bias and heterogeneity. The results of this study enhance calls for a One Health approach for mitigating the global burden of priority antimicrobial resistance pathogens.

Objectives: Teicoplanin is a commonly used antibiotic in critically ill children. However, teicoplanin dosing is often inaccurate, especially in children undergoing continuous kidney replacement therapy (CKRT). This study aims to develop a population pharmacokinetic (PK) model to optimize teicoplanin dosing in critically ill children, including those on CKRT.

Methods: Data from 26 critically ill children (12 with CKRT) receiving the standard dosing regimen were analysed. In total, 172 teicoplanin concentration measurements from plasma, pre- and post-filter ports were modelled simultaneously using NONMEM 7.4. Simulations were conducted to assess the target attainment (Cmin = 10 mg/L and AUC24/MIC > 800 h) of the current standard dosing regimen and of different alternative dosing regimens.

Results: A two-compartment model was selected. Weight significantly affected renal clearance and volume of distribution of the central compartment, while filter surface area affected haemofilter clearance. Only 16 patients (59%) achieved a Cmin of >10 mg/L with the standard dosing regimen, and only 1 achieved the target AUC/MIC. Based on simulation results, 3 × 15 mg/kg q12h + 10 mg/kg q24h (CKRT) and 3 × 15 mg/kg q12h + 15 mg/kg q24h (no CKRT) could be better alternative regimens.

Conclusions: This population model is a good proof of concept to develop modelling approaches that could help in an individualized dosing approach that needs to be adopted in critically ill paediatric patients. The standard paediatric dosage for teicoplanin could be insufficient for optimal exposure, and higher doses may benefit both CKRT and non-CKRT patients.

Objectives: This study aimed to predict the impact of different infusion strategies on pharmacokinetic/pharmacodynamic (PK/PD) target attainment and the potential risk for toxicity in an ICU cohort treated with β-lactams.

Method: Using collected patient data from 137 adult ICU patients, and applying population PK models, individual PK parameters were estimated and used to predict concentrations and target attainment following cefotaxime 2 g q8h, piperacillin/tazobactam 4.5 g q6h and meropenem 1 g q8h, applying 15 min short infusions (SI), 3 h extended infusions (EI) and 24 h continuous infusion (CI). The MIC level of the most common primary pathogens, and the worst-case scenario (WCS) pathogen, were used in analyses.

Results: For primary pathogens, target was reached in 94% (129/137) using SI. For WCS pathogens treated with piperacillin/tazobactam and meropenem, 78% (65/83) and 92% (76/83) reached target using SI and EI, respectively. However, target attainment was lower for cefotaxime [SI: 31% (17/54), EI: 44% (24/54)]. Overall, the number of individuals with potentially toxic concentrations was low, both in EI (n = 7) and SI (n = 5). For CI and WCS, target was reached in 50% (27/54), 96% (54/56) and 93% (25/27) for cefotaxime, piperacillin/tazobactam and meropenem, respectively.

Conclusions: In a Swedish ICU cohort target attainment rates for primary pathogens were high regardless of infusion strategy. In WCS pathogens, SI was insufficient, suggesting the benefit of routine use of EI or CI. However, for cefotaxime, target attainment remained low also with EI and CI. The use of CI might lead to unnecessarily high concentrations, but well-established toxicity levels are lacking and future studies are warranted.

Background: Since 2006, artemisinin-based combination therapies (ACTs) have been introduced in Senegal in response to chloroquine resistance (CQ-R) and have shown high efficacy against Plasmodium falciparum. However, the detection of the PfKelch13R515K mutation in Kaolack, which confers artemisinin resistance in vitro, highlights the urgency of strengthening antimalarial drug surveillance to achieve malaria elimination by 2030.

Objective: To assess the proportion of P. falciparum parasites carrying molecular signatures associated with antimalarial resistance (PfKelch13, Pfmdr1, Pfcrt, dhfr and dhps) in isolates collected at Kédougou using multiplex amplicon deep sequencing.

Methods: Venous blood samples were collected from patients diagnosed with P. falciparum infection over a 3-year period (2021, 2022 and 2023). Parasite DNA was extracted, and multiplex amplicon sequencing was used to investigate gene polymorphisms.

Results: Analysis of PfKelch13 did not reveal any non-synonymous mutations. Pfcrt mutations were present in 45% of the samples, mainly K76T (44%) and I356T (36%). The dominant Pfmdr-1 allele was Y184F (62%). The sextuple mutant 51I/59R/108N + 436A/437G/613S dhfr/dhps was observed in 10% of the samples.

Conclusion: The absence of PfKelch13 mutants suggests that ACT efficacy remains uncompromised, although clinical outcome studies are required to confirm this. Analysis of Pfcrt and Pfmdr-1 shows that CQ-R alleles, probably from previous CQ use, are slowly decreasing. Likewise, the detection of the dhfr/dhps sextuple mutant highlights the need to monitor sulfadoxine-pyrimethamine resistance and the emergence of 581G. There is therefore a need for continued antimalarial resistance surveillance in Senegal.

Objectives: This study aimed to evaluate the prevalence and characteristics of drug resistance mutations (DRMs) in patients with low-level viremia (LLV) in Southwestern China, as it has become a growing challenge in AIDS clinical practice.

Methods: This cross-sectional study was performed in Yunnan Province, Southwestern China. LLV was defined as 50-999 copies/mL of plasma viral load with antiretroviral therapy (ART) for at least 6 months. HIV-1 DRM detection used validated in-house protocol.

Results: A total of 470 sequences were obtained, and 13 HIV-1 genotypes were identified, among which CRF08_BC (47.5%), CRF07_BC (22.3%) and CRF01_AE (10.0%) subtypes were the most prevalent. The overall prevalence of DRMs was 45.7% (215/470), and the prevalence of DRMs to non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) was 39.4% (185/470), 20.6% (97/470) and 5.3% (25/470), respectively. The most common NNRTI-associated mutations were K103N (16.0%), E138A (6.6%), V179D (6.6%) and P225H (4.9%), and those in NRTIs were M184V (17.0%), D67N (3.4%) and K65R (3.0%). PI-associated mutations were infrequent, occurring in less than 1.8% of cases. The prevalence of NNRTI-associated mutations (K101E and Y188C) was found to be statistically significant among various LLV groups. Additionally, significant variations were observed in the prevalence of NNRTI-associated mutations (V106I, V106M, E138A and P225H), NRTI-associated mutation (K65R) and PI-associated mutations (L33F and Q58E) across different subtypes.

Conclusions: The prevalence of DRMs in ART-experienced patients with LLV was high, and HIV-1 genotypes exhibited diversity in Yunnan Province. These findings indicate that regular DRM monitoring during LLV episodes was essential for effective clinical treatment and management in this region.

Objectives: Yellow fever-associated viscerotropic disease (YEL-AVD) is a rare but serious complication arising from administration of live-attenuated yellow fever vaccine to individuals with risk factors such as thymectomy. At present there is no evidence-based treatment, and case fatality rates are high. Sofosbuvir, an NS5B nucleotide inhibitor, has activity against yellow fever virus in vitro and in vivo.

Patient and methods: Here we describe clinical and virological response to use of off-licence sofosbuvir as post-exposure prophylaxis for a patient inadvertently given yellow fever vaccine despite previous thymectomy.

Results: A 14-day course of oral sofosbuvir was administered in an outpatient setting with regular clinical and biochemical monitoring. The patient remained well without developing clinical features of YEL-AVD and did not experience adverse effects from the treatment.

Conclusions: This supports the use of sofosbuvir as post-exposure prophylaxis in patients at high risk of developing YEL-AVD. Ongoing trials of efficacy of sofosbuvir in yellow fever infection may result in stronger support for this approach in the future.