International Journal of Antimicrobial Agents

In a vast majority of bacteria, protozoa and plants, the methylerythritol phosphate (MEP) pathway is utilized for the synthesis of isopentenyl diphosphate (IDP) and dimethylallyl diphosphate (DMADP), which are precursors for isoprenoids. Isoprenoids, such as cholesterol and coenzyme Q, play a variety of crucial roles in physiological activities, including cell-membrane formation, protein degradation, cell apoptosis, and transcription regulation. In contrast, humans employ the mevalonate (MVA) pathway for the production of IDP and DMADP, rendering proteins in the MEP pathway appealing targets for antimicrobial agents...

Due to intramolecular ring structures, the ribosomally produced and post-translationally modified peptide mersacidin shows antimicrobial properties comparable to those of vancomycin without exhibiting cross-resistance. Although the principles of mersacidin biosynthesis are known, there is no information on the molecular control processes for the initial stimulation of mersacidin bioproduction. By using Bacillus subtilis for heterologous biosynthesis, a considerable amount of mersacidin could be produced without the mersacidin-specific immune system and the mersacidin-activating secretory protease...

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OBJECTIVES: To analyze the impact of the most clinically relevant β-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/xeruborbactam and meropenem/nacubactam against recombinant E. coli strains. METHODS: We constructed 82 Escherichia coli laboratory transformants expressing the main β-lactamases circulating in Enterobacterales (70 expressing single β-lactamase and 12 producing double carbapenemase) under high (E...

INTRODUCTION: Ceftazidime-avibactam (CAZ-AVI) is a new option to treat KPC- and OXA-48 carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. However, clinical evidence is limited regarding its use in treating CRKP infections, especially in solid organ transplantation (SOT) recipients. In this study, we assessed the efficacy of CAZ-AVI in treating CRKP infections in both the general population and the SOT recipients in comparison with other antibiotic regimens. METHODS: This is a single-center retrospective cohort study of patients admitted between January 1, 2018 and June 30, 2021 with the diagnosis of CRKP infections receiving either CAZ-AVI or other regimens ≥ 72 hours and clinical outcomes were analyzed...

BACKGROUND: American guidelines recommend trimethoprim-sulfamethoxazole (TMP-SMX) for preventing Pneumocystis jirovecii pneumonia (PJP) in pediatric patients at doses of 5-10 mg/kg/day of the TMP component, administered either daily, three times weekly, or twice weekly. However, limited studies describe the effectiveness and safety of these prophylactic regimens. Our study aimed to assess the clinical effectiveness and incidence of adverse events associated with each TMP-SMX regimen in pediatric patients, and to identify risk factors for adverse events...

The emergence and prevalence of carbapenem-resistant Enterobacterales on a global scale has posed a serious challenge to global public health security. Clinical research has rarely reported the co-infection of multidrug-resistant Serratia marcescens and Klebsiella pneumoniae. In this study, we describe the case of a hospitalized patient infected with carbapenem-resistant S. marcescens and K. pneumoniae. The evolution and transmission of blaKPC-2 occurred during the treatment with ceftazidime-avibactam and trimethoprim-sulfamethoxazole...

BACKGROUND: Blood brain barrier impairment is frequent in people living with HIV (PLWH), affecting the penetration of target cells and antiretrovirals into the central nervous system, through transporters (e.g. ABCB1), leading to neuroinflammation. OBJECTIVES: The aim of this study was to identify variants of genes encoding transporters able to predict neuroinflammation biomarker levels. MATERIALS AND METHODS: Cerebrospinal fluid (CSF) and plasma samples were obtained from PLWH...

OBJECTIVE: Predictions of antimicrobial effects typically rely on plasma-based pharmacokinetic-pharmacodynamic (PK-PD) targets, ignoring target-site concentrations and potential differences in tissue penetration between antibiotics. In this study, we applied PK-PD modelling to compare target site-specific effects of antibiotics by integrating clinical microdialysis data, in vitro time-kill curves, and antimicrobial susceptibility distributions. As a case study, we compared the effect of lefamulin and ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA) at soft-tissue concentrations...

Daptomycin is one of the few last-line antimicrobials available for the treatment of multidrug-resistant Staphylococcus aureus infections. An increasing number of daptomycin non-susceptible S. aureus infections has been reported worldwide, including Australia. Resistance to daptomycin is multifactorial and involves chromosomal mutations in genes encoding proteins involved in cell membrane and cell wall synthesis. In this study, we performed broth microdilution (BMD) to determine the daptomycin minimum inhibitory concentration (MIC) of 66 clinical isolates of S...

Extracellular vesicles (EVs) have become the focus of research as an emerging method of horizontal gene transfer. In recent years, studies on the association between EVs and the spread of bacterial resistance have emerged, but there is a lack of research on the role of EVs secreted by ESBL-producing E. coli in the spread of β-lactam resistance. Therefore, in this study, the role of EVs secreted by ESBL-E. coli in the transmission of β-lactam resistance in E. coli was evaluated. The results showed that ESBL-EVs were protective against β-lactam antibiotic-susceptible bacteria, and this protective effect was dependent on the integrity of the EVs and showed dose- and time-dependent effects...

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OBJECTIVES: The rapid dissemination of the mcr-1 gene via plasmid-mediated transfer has raised concerns regarding the efficacy of colistin as a last-resort treatment for multidrug-resistant Gram-negative bacterial infections. Current mcr-1 gene detection methods mainly focus on cultured bacterial which suffer from complexity, time-consuming process, and skilled personnel requirements, making them unsuitable for field analysis. METHODS: A rapid detection technique combining recombinase polymerase amplification (RPA) with lateral flow dipstick (LFD) targeting on uncultured clinical samples was developed...

Intracellular human pathogens are the deadliest infectious diseases and pose great difficulty to effectively treat due to their protection inside the host cell and the development of antimicrobial resistance (AMR). An emerging approach to combat these intracellular pathogens is host-directed therapies (HDT), which harnesses the innate immunity of host cells. HDT relies on small molecules to promote host protection mechanisms that ultimately leads to pathogen clearance. These therapies are hypothesized to 1) possess indirect yet broad, cross species antimicrobial activity, 2) effectively target drug-resistant pathogens, 3) carry a reduced susceptibility to the development of AMR, and 4) have synergistic action with conventional antimicrobials...

OBJECTIVES: This study aimed to investigate the clinical impact of the Intelligent Antimicrobial System (iAMS) on patients with bacteraemia due to methicillin-resistant (MRSA) and methicillin-susceptible Staphylococcus aureus (MSSA). METHODS: A total of 1,008 patients with suspected SA infection were enrolled before and after the implementation of iAMS. Among them, 252 with bacteraemia caused by SA, including 118 in the iAMS and 134 in the non-iAMS groups, were evaluated...

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INTRODUCTION: Peritonitis remains the major infectious complication in the setting of peritoneal dialysis (PD). Despite known only moderate pathogenicity, the most frequently detected pathogens in PD-related peritonitis are surprisingly coagulase-negative staphylococci. However, this could be explained, at least in part, by Staphylococcus aureus small colony variants (SCVs) induced by PD fluids (PDFs) and misidentified by routinely used microbiological methods. MATERIAL AND METHODS: Bacteria were exposed to commonly used PDFs in various regimens designed to simulate daily use as closely as possible...

BACKGROUND: We aim to investigate the efficacy of intravenous (IV) Fosfomycin as combination therapy for treatment of difficult-to-treat (DTT) multidrug-resistant (MDR) gram negative bacteria (GNB) acute and subacute infections and risk factors associated with 90-day mortality. METHODS: A retrospective, observational, monocentric study enrolled patients treated with IV Fosfomycin in combination regimens (>/= 72 h) for proven DTT-MDR-GNB based infection . Multivariate regression analysis identified independent risk factors for 90-day mortality...

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