Trends in fluoroquinolone prescribing in UK primary and secondary care between 2019 and 2023.

Introduction: Fluoroquinolones are important antibiotics but have associations with a number of adverse outcomes. A recent (January 2024) decision by the UK drug regulator, the Medicines and Health Regulatory Authority (MHRA), restricted systemic use of these antibiotics to when 'absolutely necessary'. One stated reason for the ban was the failure of previous guidance (2019, 2023) to reduce prescribing, with the MHRA stating there had been 'no change in prescribing' of fluoroquinolones in relation to guidance.

Pharmacodynamics of taniborbactam in combination with cefepime studied in an in vitro model of infection.

Objectives: To define the in vitro pharmacodynamics of taniborbactam against Enterobacterales with CTXM-15, KPC, AmpC, and OXA-48 β-lactamases.

Methods: An in vitro pharmacokinetic model was used to simulate serum concentrations associated with cefepime 2G by 1 h infusion 8 h. Taniborbactam was given in exposure ranging and fractionation simulations.

Antibiotic pharmacokinetics in infected pleural effusions.

Pleural infection is usually treated with empirical broad-spectrum antibiotics, but limited data exist on their penetrance into the infected pleural space. We performed a pharmacokinetic study analysing the concentration of five intravenous antibiotics across 146 separate time points in 35 patients (amoxicillin, metronidazole, piperacillin-tazobactam, clindamycin and cotrimoxazole). All antibiotics tested, apart from co-trimoxazole, reach pleural fluid levels equivalent to levels within the blood and well above the relevant minimum inhibitory concentrations.

Exposure of Escherichia coli to antibiotic-efflux pump inhibitor combinations in a pharmacokinetic model: impact on bacterial clearance and drug resistance.

Background: Efflux pump inhibitors (EPIs) offer an attractive therapeutic option when combined with existing classes. However, their optimal dosing strategies are unknown.

Methods: MICs of ciprofloxacin (CIP)+/-chlorpromazine, phenylalanine-arginine β naphthylamide (PAβN) and a developmental molecule MBX-4191 were determined and the pharmacodynamics (PD) was studied in an in vitro model employing Escherichia coli MG1655 and its isogenic MarR mutant (I1147).

Prevalence, drivers and surveillance of antibiotic resistance and antibiotic use in rural China: Interdisciplinary study.

This study aimed to characterise antibiotic prescribing and dispensing patterns in rural health facilities in China and determine the community prevalence of antibiotic resistance. We investigated patterns and drivers of antibiotic use for common respiratory and urinary tract infections (RTI/UTI) in community settings, examined relationships between presenting symptoms, clinical diagnosis and microbiological results in rural outpatient clinics, and assessed potential for using patient records to monitor antibiotic use. This interdisciplinary mixed methods study included: (i) Observations and exit interviews in eight village clinics and township health centres and 15 retail pharmacies; (ii) Urine, throat swab and sputum samples from patients to identify potential pathogens and test susceptibility; (iii) 103 semi-structured interviews with doctors, patients, pharmacy workers and antibiotic-purchasing customers; (iv) Assessment of completeness and accuracy of electronic patient records through comparison with observational data.

Antibacterial effect of seven days exposure to ceftolozane-tazobactam as monotherapy and in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa with ceftolozane-tazobactam MICs at or above 4 mg/l in an in vitro pharmacokinetic model.

Objectives: To use a pre-clinical pharmacokinetic infection model to assess the antibacterial effect of ceftolozane/tazobactam alone or in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa strains with MICs at or higher than the clinical breakpoint (MIC ≥ 4 mg/L).

Methods: An in vitro model was used to assess changes in bacterial load and population profiles after exposure to mean human serum concentrations of ceftolozane/tazobactam associated with doses of 2 g/1 g q8h, fosfomycin concentrations associated with doses of 8 g q8h or tobramycin at doses of 7 mg/kg q24 h over 168 h.

Results: Simulations of ceftolozane/tazobactam at 2 g/1 g q8h alone produced 3.

The relationship between minimum inhibitory concentration and 28 day mortality in patients with a Gram-negative bloodstream infection: an analysis of data from a cohort study (BSI-FOO).

Objectives: To explore the association between MIC/EUCAST breakpoint ratio and 28 day mortality in patients with a Gram-negative bloodstream infection (BSI).

Methods: Using data from the Bloodstream Infection-Focus on Outcomes (BSI-FOO) observational study, we defined an average MIC/EUCAST breakpoint ratio that was updated daily to reflect changes in treatment in the first 7 days after blood culture. Cox regression analysis was performed to estimate the association between MIC/EUCAST breakpoint ratio and mortality, adjusting for organism and a risk score calculated using potential confounding variables.

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study.

Background: Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis.

Oral minocycline plus rifampicin versus oral linezolid for complicated skin and skin structure infections caused by methicillin-resistant : The AIDA open label, randomized, controlled Phase 4 trial.

Background: The need for oral, cost-effective treatment for complicated skin and skin structure infections (cSSSIs) due to methicillin-resistant (MRSA) was addressed by the non-inferiority comparisons of oral minocycline plus rifampicin with linezolid.

Methods: In the AIDA multicenter, open label, randomized, controlled clinical trial, hospitalized adults with cSSSI and documented MRSA were randomly assigned at a 2:1 ratio to either oral 600 mg rifampicin qd plus 100 mg minocycline bid or oral 600 mg linezolid bid for 10 days. The primary endpoint was the clinical cure rate in the clinically evaluable (CE) population at the test-of-cure visit (14 days).

Outcomes of octogenarians and nonagenarians with Pseudomonas aeruginosa bacteremia: a multicenter retrospective study.

Background: P. aeruginosa bacteremia is a common and severe infection carrying high mortality in older adults. We aimed to evaluate outcomes of P.

The effect of duration of therapy for treatment of Staphylococcus aureus blood stream infection: an application of cloning to deal with immortal-time bias in an analysis of data from a cohort study (BSI-FOO).

Objective: To estimate the effect of treatment duration on in-hospital mortality in patients with Staphylococcus aureus blood stream infection and demonstrate the biases that can arise when immortal-time bias is ignored.

Exposure: We compared three treatment strategies: short therapy (<10 days), intermediate (10-18 days) and long (>18 days).

Main Outcome Measures: Twenty-eight-day all-cause in-hospital mortality.

Clinical and cost effectiveness of single stage compared with two stage revision for hip prosthetic joint infection (INFORM): pragmatic, parallel group, open label, randomised controlled trial.

Objectives: To determine whether patient reported outcomes improve after single stage versus two stage revision surgery for prosthetic joint infection of the hip, and to determine the cost effectiveness of these procedures.

Design: Pragmatic, parallel group, open label, randomised controlled trial.

Setting: High volume tertiary referral centres or orthopaedic units in the UK (n=12) and in Sweden (n=3), recruiting from 1 March 2015 to 19 December 2018.

Exploring Cluster-Dependent Antibacterial Activities and Resistance Pathways of NOSO-502 and Colistin against Enterobacter cloacae Complex Species.

The Enterobacter cloacae complex (ECC) is a group of diverse environmental and clinically relevant bacterial species associated with a variety of infections in humans. ECC have emerged as one of the leading causes of nosocomial infections worldwide. The purpose of this paper is to evaluate the activity of NOSO-502 and colistin (CST) against a panel of ECC clinical isolates, including different Hoffmann's clusters strains, and to investigate the associated resistance mechanisms.

Patients with transplantation have reduced mortality in bacteraemia: Analysis of data from a randomised trial.

Objectives: Infection remains a major complication of organ transplantation. Paradoxically, epidemiological studies suggest better survival from serious infection. We analysed the relationship between organ transplantation and short -term mortality of patients with bloodstream infection.

Emulating the MERINO randomised control trial using data from an observational cohort and trial of rapid diagnostic (BSI-FOO).

Objective: The aim of this study was to emulate the MERINO trial of piperacillin-tazobactam vs meropenem for the definitive treatment of bloodstream infection (BSI) caused by ceftriaxone-nonsusceptible E coli or Klebsiella spp.

Methods: Data from an observational study of BSI and a randomised controlled trial of a rapid diagnostic in BSI were used to emulate the MERINO trial. The primary outcome of the emulated trial was 28-day mortality after blood culture.

Comparative bactericidal activity of representative β-lactams against Enterobacterales, Acinetobacter baumannii and Pseudomonas aeruginosa.

Background: There is surprisingly little comparative published data on the bactericidal action of different sub-classes of β-lactams against aerobic Gram-negative rods, and the assumption is that all behave in the same way.

Objectives: To describe a systematic investigation of a representative penicillin, cephalosporin, monobactam and carbapenem against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa.

Methods: Concentration-time-kill curves (TKC) were determined for three strains each of E.