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Background Temocillin is increasingly considered as an alternative to carbapenems. However, there is no consensus on optimal dosing strategies and limited data on temocillin efficacy in systemic infections. Objectives We compared temocillin dosing strategies using pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation based on plasma exposure and in vitro time–kill data. Methods Temocillin effects on four Escherichia coli strains were evaluated using static time–kill experiments and the hollow-fibre infection model, in which unbound plasma concentrations following intermittent and continuous infusion regimens of 4 and 6 g daily were replicated over 72 h. A PK/PD model was developed to describe the time–kill data. The PK/PD model was coupled to a population PK model of temocillin in critically ill patients to predict bacterial killing and resistance development following various dosing regimens. Results Amplification of resistant subpopulations was observed within 24 h for all strains. The PK/PD model described the observed bacterial kill kinetics and resistance development from both experimental systems well. Simulations indicated dose-dependent bacterial killing within and beyond the currently used daily dose range, and a superiority of continuous compared with intermittent infusions. However, regrowth of resistant subpopulations was frequently observed. For two strains, bacteriostasis over 72 h was predicted only with doses that are higher than those currently licensed. Conclusions Continuous infusions and 6 g daily doses of temocillin kill E. coli more effectively than 4 g daily doses and intermittent infusions, and may increase efficacy in the treatment of systemic infections. However, higher daily doses may be required to suppress resistance development. [ABSTRACT FROM AUTHOR]

Introduction: Lipopolysaccharide (LPS) stimulation of human whole blood ex vivo has been widely used to investigate human innate immune responses. However, there are uncertainties regarding the reproducibility and reliability of this assay. Methods: In this prospective, single-center study, cytokine responses (interleukin 8, interferon-α, interferon-γ, interleukin 10, interleukin 1-β, interleukin 6, and tumor necrosis factor-α) to ex vivo whole blood LPS stimulation were assessed in 12 healthy volunteers. Cytokine levels were measured at 0, 2, and 4 h using a multiplex immunoassay (Luminex ®). Stimulation was repeated after six weeks. We examined reproducibility across technical and biological replicates at baseline and between repeated experiments after 6 weeks based on the area under the curve (AUC) of the individual cytokines using Pearson's correlation coefficient and the mean coefficient of variation. Results: The lowest mean coefficients of variation were observed for the technical replicates (5.4 to 9.2%), followed by the biological replicates (8.1 to 24.8%), and the repeated experiments after 6 weeks (17 to 31.2%). Between the baseline and 6-week AUCs, the following Pearson correlation coefficients R were observed: interleukin 10, 0.97; interferon-α, 0.84; interleukin 1-β, 0.83; interleukin 8, 0.79; interleukin 6, 0.73; interferon-γ, 0.73; and tumor necrosis factor-α, 0.63. Discussion: The level of agreement between the baseline and week-6 cytokine response to ex vivo LPS stimulation was high across the seven cytokines analyzed. While interleukin 10 exhibited the lowest level of variability over time, tumor necrosis factor-α showed the highest variability in repeated experiments, which should be considered in the design and interpretation of future studies. [ABSTRACT FROM AUTHOR]

Background Antimicrobial activity of antibiotics can be impacted by pH, enhancing or reducing their bactericidal properties. Cefiderocol, a novel cephalosporin antibiotic that is among others indicated for the treatment of complicated urinary tract infections (cUTIs), lacks data on activity in urine. Methods Pooled human urine (iron levels ∼0.05 mg/L/24 h), CAMHB and iron-depleted CAMHB (ID-CAMHB) at pH 5, 7 and 8 served as media. MIC testing was done according to EUCAST with the broth microdilution method for 17 clinical isolates of Escherichia coli and ATCC 25922 (including isolates with ESBL activity), 17 clinical isolates of Klebsiella pneumoniae and ATCC 700603 (also with ESBL), and 6 clinical isolates of Pseudomonas aeruginosa and ATCC 27853. Time–kill curves (TKCs) were performed for selected strains at pH 5, 7 and 8 in urine. Results MIC values in urine, CAMHB and ID-CAMHB exhibited isolate-specific variations when assessed under identical pH conditions, ranging from a 1-fold dilution to changes of up to 4-fold dilutions in either direction. Median MICs of cefiderocol were up to 50-fold higher in pH 5 than in pH 7 for P. aeruginosa isolates and 32-fold higher in E. coli and K. pneumoniae isolates. TKCs with 650 and 1300 mg/L cefiderocol in urine showed that ATCC strains were efficiently eradicated despite the pH set. Conclusions Acidic pH had a significant negative impact on cefiderocol activity. Yet, after a recommended IV administration of 2 g cefiderocol every 8 h, a concentration of approximately 1300 mg/L can be achieved in urine, suggesting that efficient killing of all tested pathogens could have been possible even under acidic conditions in vivo. [ABSTRACT FROM AUTHOR]

Background: Acidic pH has been shown to impact the antibiotic activity of non-β-lactams in urine.Objectives: To investigate the in vitro activity of ceftolozane/tazobactam compared with meropenem at different pH settings in urine.Methods: We determined the MICs for 30 clinical isolates of Escherichia coli, 25 clinical isolates of Klebsiella pneumoniae and 24 clinical isolates of Proteus mirabilis in pooled human urine and standard growth medium at pH 5 and 7. Time-kill curves were produced for one representative clinical isolate of tested bacterial strains in urine at pH 5, 6 and 7 for both antibiotics at concentrations above and below the MIC. HPLC analysis of the stability of ceftolozane/tazobactam and meropenem was performed at different pH values.Results: The median MICs of both antibiotics were up to 8-fold higher at pH 5 than at pH 7. Bacterial growth of E. coli was not impacted by pH, while for K. pneumoniae and P. mirabilis low pH slightly reduced growth. Compared with pH 7, pH 5 resulted in a significant decrease in antibiotic activity with a delta of up to 3 log10 bacterial counts after 24 h. Impact of acidic pH was lowest for P. mirabilis; however, this strain metabolically increased the pH during experiments. Stability was not impacted by low pH.Conclusions: Acidic pH had a significant negative impact on the activity of ceftolozane/tazobactam and meropenem in urine. Considering concentrations achieved in urine, our results confirm existing breakpoints and do not advocate increasing ceftolozane/tazobactam breakpoints for urinary tract infections. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Clomipramine (CLOMI) has shown effectiveness in treating premature ejaculation but is linked to erectile dysfunction and reduced libido. Yohimbine (YOH), by contrast, is effective in treating erectile dysfunction and may improve libido. Combining CLOMI and YOH could potentially leverage the benefits of both drugs. This study aimed to investigate the interactions between these drugs and to evaluate their safety profile.A prospective, open‐labelled, single‐centre, pharmacokinetic (PK) drug–drug interaction study was performed in 15 healthy male subjects. Single‐dose and steady‐state PK were investigated using noncompartmental analysis after mono‐ and combination therapy of the 2 orally applied drugs. Plasma sampling was performed at baseline, 0.5 (YOH), 1, 1.5 (YOH), 2, 3, 4, 5, 6, 8, 12 and 24 h (CLOMI). Differences in the area under the curve after multiple dosing (MD) were determined using an equivalence boundary of 80–125%.The geometric mean ratio of the area under the curve up to 12 h for MD CLOMI (combination vs. monotherapy) was 112% (90% confidence interval: 104–120%), whereas for MD YOH this ratio was 137% (90% confidence interval: 112–168%). The study drugs were safe and well tolerated as mono‐ and combination therapy, with no major adverse events reported.A PK assessment of clomipramine and yohimbine indicated a clinically significant drug–drug interaction for MD YOH in combination with CLOMI. This might be explained by competitive, CLOMI‐related inhibition of YOH metabolism, probably mediated by cytochrome P450 2D6. However, according to European Medicines Agency guidelines, the effect can be classified as interaction absent (<1,25 fold) or minor (>1.25–<2‐fold). Given the complimentary mechanisms of action and the favourable safety profiles, the findings pave the way for future efficacy studies. [ABSTRACT FROM AUTHOR]

Background: Temocillin is increasingly considered as an alternative to carbapenems. However, there is no consensus on optimal dosing strategies and limited data on temocillin efficacy in systemic infections., Objectives: We compared temocillin dosing strategies using pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation based on plasma exposure and in vitro time-kill data., Methods: Temocillin effects on four Escherichia coli strains were evaluated using static time-kill experiments and the hollow-fibre infection model, in which unbound plasma concentrations following intermittent and continuous infusion regimens of 4 and 6 g daily were replicated over 72 h. A PK/PD model was developed to describe the time-kill data. The PK/PD model was coupled to a population PK model of temocillin in critically ill patients to predict bacterial killing and resistance development following various dosing regimens., Results: Amplification of resistant subpopulations was observed within 24 h for all strains. The PK/PD model described the observed bacterial kill kinetics and resistance development from both experimental systems well. Simulations indicated dose-dependent bacterial killing within and beyond the currently used daily dose range, and a superiority of continuous compared with intermittent infusions. However, regrowth of resistant subpopulations was frequently observed. For two strains, bacteriostasis over 72 h was predicted only with doses that are higher than those currently licensed., Conclusions: Continuous infusions and 6 g daily doses of temocillin kill E. coli more effectively than 4 g daily doses and intermittent infusions, and may increase efficacy in the treatment of systemic infections. However, higher daily doses may be required to suppress resistance development., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)