Journal of Antimicrobial Chemotherapy最新文献

Objectives: To (1) assess the prevalence and patterns of HIV drug resistance (HIVDR) mutations, (2) identify correlations between different HIVDR mutations within drug classes, and (3) examine the association between resistance mutations and high HIV viral load.

Methods: We conducted a secondary analysis of retrospective data collected through the Population-based HIV Impact Assessment (PHIA) surveys conducted between 2015 and 2019 in 13 African countries. We included participants aged ≥15 years with available HIVDR genotyping. The primary outcomes were (1) prevalence of HIVDR mutations, categorized by drug class into non-nucleoside reverse transcriptase inhibitors (NNRTIs), Nucleoside Reverse Transcriptase Inhibitors (NRTIs), and Protease inhibitors (PIs); (2) high HIV viral load (VL), (HIV RNA ≥1000 copies/mL).

Results: The analysis included 2292 participants, with a median age range between 31 and 41 years. More than one-third of participants were not receiving ART. Of all participants, 1949 (85%) had high VL. Resistance to NNRTIs and NRTIs was the most prevalent in most countries, ranging from 43% to 60%, and 37% to 53%, respectively. Resistance to PI ranges from 0.2% to 5%. Multiple drug resistance mutations across all ART classes were strongly associated with high VL. Among NNRTIs, 16/39 mutations (e.g. K103N, Y181C) and 18/34 NRTI mutations (e.g. M184V, K65R) showed strong associations with high VL in ≥10 countries. For PIs, Q58E and L33F emerged as key mutations strongly associated with high VL across multiple nations.

Conclusions: Strengthening resistance surveillance, optimising ART regimens, and improving adherence are crucial to curb resistance and sustain HIV epidemic control.

Aims: Ciprofloxacin has been demonstrated to prolong QT intervals at higher doses beyond those used in conventional practice. We investigated the effect of ciprofloxacin on the QT interval by examining the difference between mean QT intervals (raw and corrected) at baseline and after theoretical achievement of steady state levels in 88 patients receiving oral ciprofloxacin therapy. The utility of a nomogram to decide the cut point for QT interval prolongation was also examined.

Patients and methods: A retrospective study examined serial surface 12-lead ECGs in a sample of patents prescribed oral ciprofloxacin by physicians in the Department of Ambulatory Care and Hospital in the Home Service at Liverpool Hospital, a tertiary referral hospital in Sydney, Australia. All patients had a baseline ECG and a follow-up ECG after achievement of theoretical steady state.

Results: A total of 88 patients were included. No significant difference in either raw QT or corrected QT using Bazett's formula was observed. Two methods were used to measure the QT interval, one using the median of six observations and one using a single lead. Poor inter-rater reliability for raw measures was observed. A high level of agreement for the cut point for QT prolongation was observed using a nomogram.

Conclusion: QT and QTc prolongation in a standard 12 lead ECG would not be expected after oral administration of ciprofloxacin at conventional doses. We recommend ECG monitoring to be undertaken only with increased clinical risk.

Objectives: Biapenem is used to treat bacterial infections in various populations. However, no dosing recommendations exist for renal impairment and elderly populations. This study aimed to simulate the pharmacokinetics of biapenem in special populations using physiologically based pharmacokinetic (PBPK) modelling and to optimize dosing regimens.

Methods: A whole-body PBPK model for biapenem was developed and evaluated in healthy adults. Then the model was extrapolated to renal impairment and elderly populations. Box-whisker analysis and Monte Carlo simulation were performed to optimize the dosing regimen.

Results: The developed PBPK models incorporating glomerular filtration and hydrolase metabolism accurately characterized biapenem pharmacokinetics in healthy adults and in renal impairment and elderly populations. For moderate, severe and end-stage renal impairment populations, we recommend reducing the biapenem dose to 67%, 50% and 30% of that for healthy adults, respectively, to achieve comparable therapeutic efficacy. No dose adjustment is necessary for individuals with mild renal impairment. The elderly population with renal impairment should follow the same dosage adjustments as those recommended for general renal impairment. Against Escherichia coli and Klebsiella pneumoniae, most simulated dosage regimens achieved cumulative fraction of response (CFR) values exceeding 80% for targets of 40%, 60% and 80% of time that free drug concentrations exceed the minimum inhibitory concentration (%fT > MIC) in healthy adults and in renal impairment and elderly populations. However, none of the simulated regimens produced satisfactory CFR values against Pseudomonas aeruginosa or Acinetobacter baumannii in these populations.

Conclusions: Biapenem PBPK models were successfully developed to optimize dosing regimens for special populations.

Background: Limited data exist on whether the presence of type-2 diabetes mellitus (T2DM) increases the risk of significant liver fibrosis (LF) among people with HIV (PWH) and metabolic dysfunction-associated steatotic liver disease (MASLD). This study examined liver stiffness progression and significant LF risk according to T2DM status in PWH with MALSD (PWH-MASLD) diagnosed via vibration-controlled transient elastography (VCTE).

Methods: PWH who had MASLD and had ≥2 VCTE measurements during the follow-up (median duration 4 years) were included. Change in liver stiffness measurement (LSM) from baseline (ΔLSM) was evaluated using a linear mixed-effects model. Multivariable Poisson regression was used to evaluate association between baseline T2DM and significant LF incidence (LSM ≥7.5 kPa).

Results: Among 345 PWH with MASLD (35% female), 97 (28%) had T2DM at baseline. In adjusted analysis, LSM declined modestly over time [mean -0.15 kPa/year (95% CI -0.28, -0.01)]. The ΔLSM over time was not associated with baseline T2DM (Pinteraction = 0.40). Among 253 PWH-MASLD without LF at baseline, the incidence of LF was 3.89 [95% CI 2.79-5.41]/100 person-years. Participants with baseline T2DM had a >3-fold higher risk of significant LF compared with those without T2DM [adjusted incidence risk ratio (aIRR): 3.35, 95% CI: 1.67-6.75). Time-updated BMI (per kg/m2 increase) was also associated with significant LF (aIRR, 1.10, 95% CI 1.03-1.18).

Conclusions: Despite stable LSM over 4 years of follow-up, PWH with MASLD and T2DM have a significantly higher risk of LF. Prioritizing this population for intensive monitoring and treatments interventions may help mitigate liver disease progression.

Background: Switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) has been associated with reduced transaminase level among people with HIV (PWH), with and without HBV. It is unclear whether the effect is mediated by HBV serostatus.

Methods: We conducted a longitudinal observational study of PWH who switched from TDF to TAF between 2016 and 2023. A mixed-effects model with random intercepts assessed the effect of the switch on transaminases, including an interaction term for HBV status: chronic hepatitis B (HBsAg+), possible occult HBV infection (pOBI; HBsAg-/HBcAb+) and no HBV.

Results: Among 727 individuals, 7% had chronic hepatitis B and 35% had pOBI. Switching to TAF was associated with a significant ALT decrease (β -3.5 UI/mL, 95%CI: -5.2 to -1.9). Compared to HBV-negative individuals, individuals with chronic hepatitis B experienced steeper ALT reduction (β -7.5, 95%CI: -11.8 to -3.2), while pOBI was associated with a non-significant reduction (β -1.9; 95%CI: -4.4-0.6; P = 0.133). These findings persisted after adjusting for other predictors of transaminase levels. TAF was also associated with accelerated weight gain (+0.75 kg/year, 95% CI: 0.63-0.87) and a transient drop in the Hepatic Steatosis Index (-0.22; 95% CI: -0.38 to -0.06) followed by an annual increase thereafter (+0.18/year; 95% CI: 0.10-0.27).

Conclusions: Switching from TDF to TAF is associated with modest but statistically significant ALT reduction in PWH, especially in HBsAg + individuals. Our findings suggest that TAF may represent a favourable option in this subgroup, although potential metabolic consequences warrant close monitoring.

Background: Following a successful pilot study of a three-day-per-week regimen of efavirenz, emtricitabine, and tenofovir disoproxil fumarate, we hypothesized that this strategy would sustain virological efficacy and reduce long-term toxicities.

Methods: After a 24-week randomized phase, participants in the A-TRI-WEEK trial (ClinicalTrials.gov NCT01778413) were offered the three-day-per-week regimen. The extension was approved by the Institutional Review Board, and participants provided informed consent; follow-up continued until further participation no longer offered additional clinical or research value. HIV-RNA, CD4 and CD8 cells, blood and urine chemistries, and bone mineral density (BMD) were assessed every 6 months. Treatment failure was defined a priori as virological failure (HIV RNA >1000 copies/mL once or ≥50 copies/mL confirmed), discontinuation, or loss to follow-up. Secondary outcomes included changes in lipids, estimated glomerular filtration rate (eGFR), urine protein/creatinine, and BMD.

Results: Of 61 participants completing the 24-week phase, 59 (97%) entered the extension. After 7 years, 37 (63%) remained free of treatment failure. Only one participant experienced virological failure, following an unintentional treatment interruption, with no resistance mutations detected. All other failures were due to discontinuations (CNS symptoms, n = 7; BMD decline, n = 7; drug interactions, n = 2; regimen preference, n = 2; cancer, n = 1; death unrelated, n = 1; loss to follow-up, n = 1). Laboratory parameters showed biphasic patterns, with initial stability followed by modest late declines in eGFR and BMD and increases in triglycerides and proteinuria. Most discontinuations occurred in the latter half of follow-up (years 4-7).

Conclusions: A three-day-per-week regimen of efavirenz, emtricitabine, and tenofovir disoproxil fumarate maintained durable long-term viral suppression, while mitigating but not fully preventing toxicities associated with EFV/TDF/FTC. These findings support reduced-exposure antiretroviral therapy and warrant evaluation of similar strategies with modern integrase inhibitor-based regimens.

HIV/AIDS remains a global health challenge with significant disparities in access to prevention strategies, particularly among underserved populations. Pre-exposure prophylaxis (PrEP) has proven to be an effective intervention in reducing HIV transmission, yet its uptake remains suboptimal in Europe. This report examines the current state of PrEP implementation in Spain, identifies key barriers to its access and proposes strategies for overcoming these obstacles, with a focus on equity and innovation. Despite PrEP being available since 2019, challenges such as centralized, hospital-based distribution, stigmatization, rigid eligibility criteria, excess medicalization and insufficient healthcare provider education persist. This study highlights the disproportionate underutilization of PrEP among populations with difficulty accessing prevention programmes, including women, migrants, sex workers, transgender individuals and people who inject drugs. Moreover, the introduction of long-acting injectables (LAI) and their endorsement by WHO represent a promising solution to improve PrEP efficacy, adherence and reduce the burden of frequent clinic visits. Drawing on successful international models, such as the 56 Dean Street clinic in London, this paper advocates for a decentralized, de-medicalized, community-based approach to PrEP delivery alongside policy reforms to simplify eligibility criteria and integrate PrEP into broader healthcare services. These solutions aim to address geographical and socio-cultural barriers, ultimately facilitating more equitable access to HIV prevention across Europe. The findings emphasize the importance of flexibility, community engagement and innovation to ensure that those most at need are ultimately offered PrEP, contributing to global efforts to close the HIV prevention gap.

Objectives: Mutations in the 3'-polypurine tract (3'PPT) of HIV-1 have been observed under pressure with two integrase strand transfer inhibitors, dolutegravir and cabotegravir. In the DOMONO randomized clinical trial, 3'PPT mutations emerged in a participant who experienced treatment failure under dolutegravir monotherapy. To understand the basis for this rare mutational pathway, we examined baseline viral sequences and identified the K156N natural polymorphism. Given the role of K156 in viral DNA binding, the potential relationship between K156N and 3'PPT mutations was further investigated.

Methods: We assessed the impact of K156N on integrase using in silico modelling and biochemical assays with recombinant proteins. Infectivity, replicative capacity, and drug susceptibility of viruses carrying K156N, 3'PPT mutations, or both were measured. Viral evolution was assessed in cell culture.

Results: Structural models indicated that K156N altered viral DNA binding. K156N reduced strand transfer activity through decreased affinity for the LTR but increased 3'-processing. The K156N virus had normal infectivity, whereas the 3'PPT mutations decreased infectiousness sixfold and lowered maximal infectivity. K156N partially compensated for this defect, but maximal infectivity remained diminished. K156N also partially compensated for defects in replicative capacity imposed by 3'PPT mutations. K156N alone did not confer resistance against dolutegravir, nor did it increase the modest (2.5-fold) resistance conferred by the 3'PPT mutations. K156N alone promoted the spontaneous emergence of 3'PPT mutations distinct from those seen in DOMONO.

Conclusions: These findings establish a direct functional relationship between natural variation in HIV-1 integrase and the emergence of 3'PPT mutations. People harbouring a virus with the K156N natural polymorphism may be predisposed to developing 3'PPT mutations upon failure with DTG. However, the clinical relevance of this association remains to be established.

Objectives: To assess the biliary pharmacokinetic/pharmacodynamic (PK/PD) of continuous infusion (CI) ceftazidime-avibactam in a series of critical orthotopic liver transplant (OLT) recipients having pre-emptive therapy during OLT because of carbapenemase-producing Enterobacterales (CPE) rectal colonization or targeted therapy of CPE intra-abdominal (IAIs) and/or biliary tract infections (BTIs).

Methods: We performed an exploratory, hypothesis-generating prospective case series including critical OLT recipients carrying a Kehr's tube and undergoing therapeutic drug monitoring of ceftazidime and avibactam in both bile and plasma simultaneously while receiving CI ceftazidime-avibactam pre-emptive or targeted therapy. Biliary aggressive joint PK/PD target attainment [defined as a free ceftazidime steady-state concentrations fCss/MIC ratio >4 coupled with an avibactam fCss/target concentration (CT = 4 mg/L) ratio >1] was selected as optimal threshold of ceftazidime-avibactam efficacy, given this was previously shown to be independently associated with lower rates of microbiological failure and resistance development. Bile-to-plasma fCss ratios were calculated.

Results: Overall, four critical OLT recipients were included. Aggressive biliary ceftazidime-avibactam joint PK/PD target during treatment with CI 2 g/0.5 g q8 h over 8 h was attained in 2/4 cases (quasi-optimal and suboptimal in one case each). Median (range) fCss bile-to-plasma ratios were 0.28 (0.22-0.38) for ceftazidime and 0.24 (0.11-0.52) for avibactam.

Conclusions: Our limited cases series suggested that both ceftazidime and avibactam showed a moderate and broadly similar biliary penetration. Administration by CI may be helpful in attaining an aggressive biliary joint PK/PD target of ceftazidime-avibactam against pathogens with an MIC up to 8 mg/L.

Objectives: The COVID-19 pandemic impacted healthcare use, with mixed reports regarding impacts on antimicrobial resistance. The aim was to identify changes in healthcare utilisation and antibiotic prescribing related to the COVID-19 pandemic and quantify subsequent impacts on antibiotic resistance in clinical Escherichia coli isolates in Scotland.

Methods: Data involving ∼490 000 people from January 2018 to March 2022 were analysed. Joinpoint regression analyses identified trend changes in healthcare encounters, and antibiotic use in community and hospital settings. Using these joinpoints as an 'intervention' timepoint, interrupted time series analysis quantified associated changes in proportions of E. coli blood and urine culture isolates that were antibiotic resistant and multidrug resistant (MDR).

Results: January 2020 was identified as the intervention point. From 26% resistant (not MDR) and 35% MDR among urine E. coli isolates immediately pre-intervention, there were changes in level of +2.5% (95%CI -0.4% to 5.4%) and trend of +0.3% (95%CI 0.1% to 0.5%) per month for resistant (not MDR), and level change of +0.4% (95%CI -2.0% to 2.8%) but trend change of -0.3% (95%CI -0.5% to -0.1%) per month for MDR. By 9 month post-intervention, compared with predicted levels without intervention, resistant (not MDR) proportions increased while MDR proportions decreased. Similar changes occurred among blood culture isolates, but with less certainty around estimates.

Conclusion: Small but significant reductions in MDR E. coli resulted from COVID-19-related changes in healthcare and antibiotic use. The findings are critical for antimicrobial stewardship and infection control interventions and evaluation.