Journal of Antimicrobial Chemotherapy最新文献

Introduction: Risk of transmission of HIV through breastfeeding is minimal in case of maternal viral suppression due to antiretroviral therapy. However, to what extent antiretroviral drugs transfer into breastmilk is not fully understood. Data are especially lacking for relatively newer drugs-such as bictegravir-that only recently was approved to use in pregnancy. Therefore, the aim of this study is to determine infant exposure to bictegravir through breastmilk.

Materials and methods: Concentrations of bictegravir were measured in plasma and breastmilk of healthy, lactating women without HIV after a single dose of bictegravir 50 mg (co-formulated with tenofovir alafenamide 25 mg and emtricitabine 200 mg). Concentrations were measured using validated LC-MS/MS assays and pharmacokinetic parameters were calculated using non-compartmental analysis. Breastmilk to maternal plasma ratio, daily infant dosage and relative infant dose were established to determine infant exposure to bictegravir through breastmilk.

Results: Twelve volunteers participated in the study. The geometric mean (CV%) area under the curve based on the last measured concentration was 52.17 (22.6) mg*h/L in plasma and 0.44 (32.0) mg*h/L in breastmilk, resulting in a geometric mean (CV%) breastmilk to maternal plasma ratio of 0.009 (26.6). The median (IQR) daily infant and relative infant doses with an intake of 150 or 200 mL/kg/day were 0.034 mg/kg/day (0.026-0.060) and 0.046 (0.035-0.080) mg/kg/day and 0.68 (0.53-1.00) % and 0.90% (0.71-1.33), respectively.

Conclusion: Exposure to bictegravir through breastmilk is very low, with a relative infant dose below 1%. Even though metabolizing capacity in newborns is not yet fully developed, it is not expected to cause infant toxicity.

Objectives: Pseudomonas aeruginosa is a common microorganism in chronic infections due to biofilm formation and antibiotic resistance. This study aimed to compare the synergistic effects of antibiotic combinations against carbapenem-resistant P. aeruginosa (CRPA) in planktonic and biofilm-embedded states.

Methods: Twelve CRPA bloodstream isolates from the Asian Bacterial Bank (2016-2018) were analysed. The minimum biofilm eradication concentrations (MBECs) were determined using the peg lid system, and antimicrobial interactions were assessed using biofilm checkerboard assays, testing three double combinations (colistin-rifampin, colistin-imipenem, and rifampin-ceftazidime/avibactam) and two triple combinations (colistin-rifampin-imipenem and colistin-rifampin-ceftazidime/avibactam).

Results: The MBEC values of all four antimicrobial agents (rifampin, colistin, imipenem, and ceftazidime/avibactam) were significantly higher than their corresponding minimum inhibitory concentration values (P < 0.001). Although single agents required markedly elevated concentrations to eradicate CRPA biofilms, approximately half of the double and triple antimicrobial combinations demonstrated synergistic activity. In the biofilm phase, synergism rates were comparable between triple combinations (colistin-rifampin-ceftazidime/avibactam, 50%; colistin-rifampin-imipenem, 66%) and double combinations (colistin-rifampin, 42%; rifampin-ceftazidime/avibactam, 42%; colistin-imipenem, 66%). The triple combinations showed lower FBEC indices (colistin-rifampin-imipenem: median 0.17; colistin-rifampin-ceftazidime/avibactam: 0.34) than the corresponding double combinations (colistin-rifampin: 0.53; colistin-imipenem: 0.20; rifampin-ceftazidime/avibactam: 0.78), although these differences were not statistically significant.

Conclusions: Our study provides experimental evidence that antimicrobial combination therapy may offer advantages over single agents for CRPA biofilm eradication, supporting further investigation into the role of such regimens in biofilm-associated infections.

Introduction: Selection and dosing of surgical antimicrobial prophylaxis (SAP) to prevent surgical site infections (SSIs) is variable and often inappropriate in clinical settings resulting in increased risk of SSI. We therefore developed and implemented a novel computer decision-support tool to improve appropriate SAP selection specific to each patient's procedure and clinical context.

Methods: The intervention, performed at a multi-site tertiary hospital network, was a computer decision-support tool programmed within the hospital's electronic health record (EHR) to provide patient-specific SAP recommendations based on four variables: procedure name, patient's beta-lactam allergy status, MRSA status and weight. Safety of cefazolin prophylaxis among patients with self-reported beta-lactam allergy was established in the pre-operative clinic using a validated simple two-item questionnaire. Before each operation, a best practice SAP recommendation alert was provided to the anaesthesiologist based on the inputs from the four aforementioned variables.

Results: In the post-intervention period of 2 years, a total of ∼110 recommendation alerts were logged. A random sample audit of 408 surgical encounters were selected from the pre- and post-intervention periods. Overall, appropriate antibiotic administration rose from 77% (161/208) to 92.5% (185/200) (χ2 = 18.0, P < 0.001) post-intervention. Significant improvements were made for procedure-specific antibiotic selection (80.5% versus 94.5%; χ2 = 19.3, P < 0.001) and weight-based dosing (92.5% versus 98.4%; χ2 = 7.45, P = 0.006). Using National Surgical Quality Improvement Program (NSQIP) auditing of 21 912 surgeries showed a significant decline in SSIs following the implementation of the intervention in June 2022.

Conclusion: In this first-ever intervention designed to direct SAP prescribing based on patient-specific variables, we significantly improved appropriate SAP selection and reduced SSIs across a comprehensive list of surgical procedures.

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.

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: 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.

Background: Antibiotic resistance and tolerance pose dual challenges to clinical antibiotic therapy, with tolerance potentially accelerating resistance evolution. LYSC98, a candidate drug that has just received clinical approval in China, has been reported to have bactericidal activity against antibiotic-resistant Staphylococcus aureus. However, its mechanism and activity against antibiotic-resistant bacteria in tolerant state remains unexplored.

Objectives: To evaluate the antibacterial activity of LYSC98 against antibiotic-resistant bacteria in different metabolite states, and to elucidate its mechanism of action.

Materials and methods: MIC values of antimicrobial agents were determined using broth microdilution. Time-kill assays were used to evaluate the bactericidal effect. SEM and TEM were conducted to visualize the morphological changes. Membrane permeability was determined by propidium iodide.

Results: LYSC98 showed potent antibacterial activity against Gram-positive pathogens, with MICs ranging from 0.06 to 2 mg/L. It demonstrated a rapid bactericidal effect against antibiotic-resistant pathogens, irrespective of their growth phase or tolerant state, and conferred an extended post-antibiotic effect. Significantly, LYSC98 displayed a low potential for resistance development. It targeted both bacterial cell wall and membrane, with in vitro membrane assays indicating selective damage to these structures and no observed harm to mammalian cells.

Conclusions: LYSC98's rapid bactericidal activity, selective disruption of bacteria without harming mammalian cells and low propensity for resistance development make it a novel promising candidate for combating chronic, clinically recalcitrant infections.

Background: Antimicrobial resistance among Enterobacter cloacae complex and Klebsiella aerogenes is a growing clinical challenge, often driven by AmpC β-lactamase hyperproduction. This phenotype limits therapeutic options to cefepime or carbapenems.

Objectives: To assess the in vitro activity of conventional β-lactams, such as cefepime, piperacillin/tazobactam or carbapenems, and new-generation agents, including ceftazidime/avibactam, cefepime/taniborbactam, imipenem/relebactam, meropenem/vaborbactam, and cefiderocol, against AmpC-hyperproducing E. cloacae complex and K. aerogenes.

Methods: A total of 314 clinical isolates (200 E. cloacae complex and 114 K. aerogenes) recovered between March and December 2024, from eight Spanish centres were tested by broth microdilution (EUCAST). AmpC hyperproduction was confirmed phenotypically and carbapenemase was screened phenotypically/molecularly. WGS was performed for (i) 84 E. cloacae complex isolates, and (ii) six isolates with reduced susceptibility to at least one novel agent.

Results: High resistance rates were observed for piperacillin/tazobactam (up to 82.4%) and cefepime (up to 20.5%), whereas carbapenems showed variable activity. New-generation agents exhibited excellent activity, with susceptibility rates ≥99% in both species. Resistance to at least one new agent was found in only six isolates. In the WGS-analysed E. cloacae complex subset, Enterobacter hormaechei predominated (75%) with high STs and blaACT allele diversity. In the six reduced-susceptibility isolates, no carbapenemase or explanatory acquired β-lactamase was found.

Conclusions: Our findings underscore the need to take this phenotype into account in clinical practice and confirm the limited activity of conventional β-lactams against AmpC-hyperproducing E. cloacae complex and K. aerogenes, and support the use of newer agents as effective alternatives.