Search Results (7)

Non-tuberculous mycobacteria (NTM) comprise more than 190 species capable of causing severe pulmonary, lymphatic, cutaneous, and disseminated infections, particularly in immunocompromised populations. Over the past two decades, the global incidence of NTM infections has risen steadily, underscoring an urgent unmet medical need. Treatment remains highly challenging due to intrinsic antimicrobial resistance and the requirement for prolonged multidrug regimens that are often poorly tolerated and associated with unsatisfactory outcomes. At the same time, the development of novel therapies has lagged behind other disease areas, hindered by the high costs of antimicrobial drug discovery and the relatively low commercial return compared with treatments for chronic conditions. Over the past decade, discovery and development have diversified across novel small molecules, next-generation analogues of existing classes, and adjunctive or host-directed strategies. While most candidates remain preclinical, several agents have advanced clinically in other infections, including gepotidacin (topoisomerase inhibitor; FDA-approved 2025 for urinary tract infection (UTI)), sulbactam–durlobactam (DBO β-lactamase inhibitor; FDA-approved 2023 for Acinetobacter baumannii complex), and contezolid, supporting repurposing opportunities for NTM. Conversely, SPR720 (gyrase B prodrug) was suspended after not meeting its Phase 2 endpoint in 2024, underscoring translational risk. Overall, the NTM pipeline is expanding, with near-term progress most likely from repurposed agents and optimised combinations, alongside earlier-stage candidates that target biofilms or resistance mechanisms. This review aims to provide a critical and up-to-date overview of emerging antimicrobial strategies against NTM, highlighting recent advances, translational challenges, and opportunities to accelerate the development of effective therapeutics. Full article

Background: Clarithromycin is a commonly used macrolide antibiotic. Infection is a major source of mortality and morbidity in critical care units. Pharmacokinetics may vary during critical illness and suboptimal antimicrobial exposure has been shown to be associated with treatment failure. The pharmacokinetics of intravenous clarithromycin in critical illness have not previously been described. Methods: Pharmacokinetic, clinical and demographic data were collected from critically ill adults receiving intravenous clarithromycin. Drug concentrations were measured using high-performance liquid chromatography/mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM version 7.5.1. Allometric weight scaling was added, and periods of renal replacement therapy were excluded a priori. Simulations of 10,000 patients were performed to assess pharmacokinetic–pharmacodynamic (PKPD) target attainment. Results: The analysis included 121 samples taken from 19 participants. A two-compartment model was found to provide the best fit. The addition of covariates did not improve model fit. There was no evidence of auto-inhibition in this population. Population parameter estimates of clearance and volume of distribution were lower than previously reported, with high interindividual variability. Simulations suggested reasonable pharmacokinetic–pharmacodynamic (PKPD) target attainment with current dosing regimens for most organisms that clarithromycin is used to treat with known clinical breakpoints. Conclusions: To our knowledge, this is the first study to describe the pharmacokinetics of intravenous clarithromycin in humans. Although our simulations suggest reasonable target attainment, further investigation into appropriate PKPD targets and clinical breakpoints for clarithromycin may enable dosing optimisation in this population. Full article

The antimicrobial concentration–time profile in humans affects antimicrobial activity, and as such, it is critical for preclinical infection models to simulate human-like dynamic concentration–time profiles for maximal translatability. This review discusses the setup, principle, and application of various dynamic in vitro PK/PD infection models commonly used in the development and optimisation of antimicrobial treatment regimens. It covers the commonly used dynamic in vitro infection models, including the one-compartment model, hollow fibre infection model, biofilm model, bladder infection model, and aspergillus infection model. It summarises the mathematical methods for the simulation of the pharmacokinetic profile of single or multiple antimicrobials when using the serial or parallel configurations of in vitro systems. Dynamic in vitro models offer reliable pharmacokinetic/pharmacodynamic data to help define the initial dosing regimens of new antimicrobials that can be developed further in clinical trials. They can also help in the optimisation of dosing regimens for existing antimicrobials, especially in the presence of emerging antimicrobial resistance. In conclusion, dynamic in vitro infection models replicate the interactions that occur between microorganisms and dynamic antimicrobial exposures in the human body to generate data highly predictive of the clinical efficacy. They are particularly useful for the development new treatment strategies against antimicrobial-resistant pathogens. Full article

(1) Background: Postoperative infections are major contributors of morbidity and mortality after paediatric liver transplantation (pLTX). Evidence and recommendations regarding the most effective antimicrobial strategy are lacking. (2) Results: Of 39 pLTX centres, 20 responded. Aminopenicillins plus ß-lactamase inhibitors were used by six (30%) and third generation cephalosporins by three (15%), with the remaining centres reporting heterogenous regimens. Broad-spectrum regimens were the standard in 10 (50%) of centres and less frequent in the 16 (80%) centres with an infectious disease specialist. The duration ranged mainly between 24–48 h and 3–5 days in the absence and 3–5 days or 6–10 days in the presence of risk factors. Strategies regarding antifungal, antiviral, adjunctive antimicrobial, and surveillance strategies varied widely. (3) Methods: This international multicentre survey endorsed by the European Liver Transplant Registry queried all European pLTX centres from the registry on their current practice of perioperative antibiotic prophylaxis and antimicrobial strategies via an online questionnaire. (4) Conclusions: This survey found great heterogeneity regarding all aspects of postoperative antimicrobial treatment, surveillance, and prevention of infections in European pLTX centres. Evidence-based recommendations are urgently needed to optimise antimicrobial strategies and reduce the spectrum and duration of antimicrobial exposure. Full article

Adjusting dosing regimens based on measurements of carbapenem levels may improve carbapenem exposure in patients. This systematic review aims to describe the effect carbapenem therapeutic drug monitoring (TDM) has on health outcomes, including the emergence of antimicrobial resistance (AMR). Four databases were searched for studies that reported health outcomes following adjustment to dosing regimens, according to measurements of carbapenem concentration. Bias in the studies was assessed with risk of bias analysis tools. Study characteristics and outcomes were tabulated and a narrative synthesis was performed. In total, 2 randomised controlled trials (RCTs), 17 non-randomised studies, and 19 clinical case studies were included. Significant variation in TDM practice was seen; consequently, a meta-analysis was unsuitable. Few studies assessed impacts on AMR. No significant improvement on health outcomes and no detrimental effects of carbapenem TDM were observed. Five cohort studies showed significant associations between achieving target concentrations and clinical success, including suppression of resistance. Studies in this review showed no obvious improvement in clinical outcomes when TDM is implemented. Optimisation and standardisation of carbapenem TDM practice are needed to improve intervention success and enable study synthesis. Further suitably powered studies of standardised TDM are required to assess the impact of TMD on clinical outcomes and AMR. Full article

Antimicrobial dosing in the intensive care unit (ICU) can be problematic due to various challenges including unique physiological changes observed in critically ill patients and the presence of pathogens with reduced susceptibility. These challenges result in reduced likelihood of standard antimicrobial dosing regimens achieving target exposures associated with optimal patient outcomes. Therefore, the aim of this review is to explore the various methods for optimisation of antimicrobial dosing in ICU patients. Dosing nomograms developed from pharmacokinetic/statistical models and therapeutic drug monitoring are commonly used. However, recent advances in mathematical and statistical modelling have resulted in the development of novel dosing software that utilise Bayesian forecasting and/or artificial intelligence. These programs utilise therapeutic drug monitoring results to further personalise antimicrobial therapy based on each patient’s clinical characteristics. Studies quantifying the clinical and cost benefits associated with dosing software are required before widespread use as a point-of-care system can be justified. Full article

Infectious diseases (ID) specialists advise on complicated infections and are advocates for the interventions of antibiotic stewardship programs (ASP). Early referral to ID specialists has been shown to improve patient outcomes; however, not all referrals to ID specialists are made in a timely fashion. A retrospective cross-sectional study of all referrals to ID specialists in a Singaporean tertiary hospital was conducted from January 2016 to January 2018. The following quality indicators were examined: early referral to ID specialists (within 48 h of admission) and ASP intervention for inappropriate antibiotic usage, even after referral to ID specialists. Chi-square was used for univariate analysis and logistic regression for multivariate analysis. A total of 6490 referrals over the 2-year period were analysed; of those, 36.7% (2384/6490) were from surgical disciplines, 47.0% (3050/6490) were from medical disciplines, 14.2% (922/6490) from haematology/oncology and 2.1% (134/6490) were made to the transplant ID service. Haematology/oncology patients and older patients (aged ≥ 60 years) had lower odds of early referral to ID specialists but higher odds of subsequent ASP intervention for inappropriate antibiotic usage, despite prior referral to an ID specialist. Elderly patients and haematology/oncology patients can be referred to ID specialists earlier and their antimicrobial regimens further optimised, perhaps by fostering closer cooperation between ID specialists and primary physicians. Full article