Journal of Antimicrobial Chemotherapy最新文献

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.

Background: Antibiotic consumption is considered an important risk factor for Clostridioides difficile infection (CDI). This ecological analysis investigates the influence of outpatient antibiotic prescriptions in statutory health insurance (SHI) on the admission prevalence of CDI in German hospitals participating in voluntary CDI surveillance through the hospital infection surveillance system (Krankenhaus-Infektions-Surveillance-System; KISS).

Methods: The annual CDI admission prevalence of a hospital at the federal state level was associated with the outpatient antibiotic consumption of the corresponding federal state. The quantification of outpatient antibiotic prescriptions was determined as the average DDD per 1000 insured persons per day. The risk factors for CDI on hospital admission included the annual consumption of the eight substance groups aminopenicillin combinations/staphylococcal penicillins, basic penicillins, cephalosporins, quinolones, lincosamides/macrolides, nitrofurantoin/fosfomycin/nitroxoline, sulphonamides/trimethoprim and tetracyclines, the type of care provided by the hospital, and the calendar year, and were examined using multivariable regression analyses (generalized estimating equations models).

Results: Between 2011 and 2019, the number of outpatient antibiotic prescriptions decreased from 13.9 to 10.4 DDD per 1000 insured persons per day (-25%), and the CDI admission prevalence decreased from 0.22 to 0.12 per 100 patients (-45%). Basic penicillins and cephalosporins were identified as risk factors for increased CDI admission prevalence, while nitrofurantoin/fosfomycin/nitroxoline and sulphonamides/trimethoprim were associated with decreased CDI admission prevalence.

Conclusions: A decrease in outpatient antibiotic prescriptions with known risk of developing CDI was associated with a decrease in hospital CDI admission prevalence. Our ecological analysis indicates that rational and restrained antibiotic use in the outpatient setting may reduce the incidence of CDI in the population requiring inpatient treatment.