Marta Ulldemolins

In 2023, international consensus recommendations suggested the use of prolonged‐infusion beta‐lactam antibiotics over short‐infusion dosing in severely ill adult patients to improve mortality or clinical cure, although the certainty of evidence was very low. With the availability of several new randomized controlled trials (RCTs), this focused update re‐evaluates the efficacy of prolonged versus short infusion among severely ill adult patients. The original Population, Intervention, Comparator, and Outcome (PICO) question VII was separated into two questions addressing mortality (VIIa) and clinical cure (VIIb). Methods used for study identification, screening, and evidence grading were consistent with the original guideline, with the addition of Bayesian meta‐analyses. A total of 28 RCTs evaluating mortality in severely ill adults were analyzed, with pooled estimates favoring prolonged infusion (RR 0.91; 95% confidence interval 0.85 to 0.97), supported by Bayesian analyses demonstrating a 98.76% posterior probability of benefit. Across 21 RCTs evaluating clinical cure, prolonged infusion improved outcomes compared with short infusion (RR 1.11; 95% confidence interval 1.06 to 1.17), supported by Bayesian analyses demonstrating a 99.97% posterior probability of benefit. Certainty of evidence was strengthened to moderate for mortality and low for clinical cure. Consistent with the original recommendation (PICO X), subgroup analyses evaluating loading doses suggested improved outcomes when a loading dose is used before continuous infusion. Overall, the cumulative evidence reinforces and strengthens the recommendation for use of prolonged‐infusion beta‐lactam therapy in severely ill adult patients to improve survival and clinical cure. Continued use of loading doses when initiating continuous‐infusion therapy is suggested. Future research should identify subpopulations most likely to benefit, clarify optimal prolonged‐infusion strategies, and define the role of therapeutic drug monitoring.

Background Critically ill patients exhibit acute physiological changes leading to marked antibiotic exposure variability and an increased probability of either subtherapeutic or potentially toxic exposures. Beta-lactam antibiotics are often affected by these physiological changes, leading to variable and often subtherapeutic exposures. Furthermore, although this medication class is associated with minimal concentration-related adverse effects, recent evidence suggests that beta-lactams may be associated with neurotoxicity and nephrotoxicity. Therefore, methods to increase the probability of a therapeutic exposure may be beneficial for critically ill patients. Model Informed Precision Dosing (MIPD) is an emerging strategy using advanced computer models to individualise dosing in this vulnerable population with or without therapeutic drug monitoring (TDM). By tailoring therapy to the individual patient scenario, MIPD aims to improve clinical outcomes by enhancing the likelihood of effective and safe therapy. Summary MIPD-guided beta-lactam antibiotic dosing may improve the probability of attaining target therapeutic exposures and clinical cure rates compared to standard fixed dosing in critically ill patients. Moreover, MIPD allows clinicians to target higher beta-lactam antibiotic exposures whilst minimising the risk of toxicity, when the goal of treatment is both improving clinical cure rates and suppressing the probability of antibiotic resistance emergence. No differences in mortality and adverse event reduction compared to standard dosing has been currently identified in the literature. However, the exact potential of MIPD has yet to be determined given the significant limitations in the current evidence base, including heterogeneous study designs, small sample sizes, inconsistent implementation strategies and variable outcome definitions. Clinical practice and future research should optimise MIPD performance by selecting appropriate and innovative beta-lactam antibiotic exposure models, as well as identify methods to instigate early MIPD dosing and timely TDM dose adjustments. This may further improve clinical and economic outcomes for critically ill patients.

Hematological patients with febrile neutropenia receiving piperacillin-tazobactam may experience pharmacokinetic alterations that compromise drug exposure. We aimed to characterize the population pharmacokinetics of piperacillin in plasma and provide optimized dosing recommendations for this patient population. A population pharmacokinetic analysis was conducted in patients who received piperacillin-tazobactam as part of the BEATLE study, which compared the efficacy, safety, and pharmacokinetic/pharmacodynamic target attainment of β-lactams administered in extended infusion versus short 30 min infusion in adult hematological patients with febrile neutropenia. Monte Carlo simulations were performed to evaluate, for each dosing regimen, the probability of attaining (i) an efficacy target of unbound piperacillin concentrations above the minimum inhibitory concentration (MIC) of the bacteria for the entire dosing interval (100% ƒ T _>MIC ), and (ii) a toxicity threshold of ≥160 mg/L. A total of 44 patients and 221 plasma concentrations were included. A one-compartment model best described piperacillin plasma pharmacokinetics, with Cockcroft-Gault creatinine clearance (CrCL) significantly influencing drug clearance. Dosing simulations showed that extended and continuous infusions were superior to short 30 min infusions in the attainment of 100% ƒ T _>MIC , even for bacteria with low to intermediate MIC (≤2–4 mg/L). In patients with higher CrCL (>90 mL/min) or infections caused by less susceptible Gram-negative bacilli (MIC: 8–16 mg/L), only continuous infusions of 12–16 g/day were likely to achieve 100% ƒ T _>MIC . These findings support the use of extended or continuous infusions of piperacillin in the initial management of patients with febrile neutropenia, particularly in patients with higher CrCL or when infections caused by less susceptible pathogens, such as Pseudomonas aeruginosa , are suspected.

Patients undergoing elective pelvic exenteration surgery who receive piperacillin/tazobactam as surgical prophylaxis are at risk of suboptimal intraoperative antibiotic exposure. With this work, we aimed to study the plasma pharmacokinetics of piperacillin and tazobactam in this population to provide dosing recommendations that optimize antibiotic exposure. We developed a prospective, observational, pharmacokinetic study of piperacillin/tazobactam in patients undergoing pelvic exenteration. Population pharmacokinetic analysis and Monte Carlo simulations were performed with Monolix and Simulx software. Probabilities of target attainment of different dosing regimens against the minimum inhibitory concentration (MIC) breakpoints (8 and 16 mg/L) were calculated. Twelve patients were included in the study, with a median age of 50.0 years [interquartile interval (45.3–57.5)] and a median weight of 79.0 kg (61.3–88.3). Median surgical time was 10.5 h (9.8–11.7). A two-compartment linear model best fitted piperacillin and tazobactam data (190 plasma samples). Monte Carlo simulations showed that a lower dose of 2 g/0.25 g loading dose followed by 4 g/0.5 g q8h by continuous infusion provided ≥90% probability of target attainment for MIC = 16 mg/L for most of the patients. For non-continuous infusion regimens, only the 2-hourly bolus re-dosing achieved intraoperative concentrations of piperacillin ≥16 mg/L. Patients with weights ≥ 100 kg and glomerular filtration rates ≥ 120 mL/min required 4 g/0.5 g q6h by continuous infusion after a loading dose. In conclusion, continuous infusion of lower doses of piperacillin/tazobactam is as adequate as the 2-hourly re-dosing recommended by the current guidelines for surgical prophylaxis in pelvic exenteration. Patients with higher weights and glomerular filtration rates are at greater risk of inadequate exposure.

Infection after spinal instrumentation (IASI) by Cutibacterium spp. is being more frequently reported. The aim of this study was to analyse the incidence, risk factors, clinical characteristics, and outcome of a Cutibacterium spp. IASI (CG) compared with non-Cutibacterium IASI (NCG) infections, with an additional focus on the role of rifampin in the treatment. All patients from a multicentre, retrospective, observational study with a confirmed IASI between January 2010 and December 2016 were divided into two groups: (CG and NCG) IASI. Baseline, medical, surgical, infection treatment, and follow-up data were compared for both groups. In total, 411 patients were included: 27 CG and 384 NCG. The CG patients were significantly younger. They had a longer median time to diagnosis (23 vs. 13 days) (p = 0.025), although 55.6% debuted within the first month after surgery. Cutibacterium patients were more likely to have the implant removed (29.6% vs. 12.8%; p = 0.014) and received shorter antibiotic regimens (p = 0.014). In 33% of Cutibacterium cases, rifampin was added to the baseline therapy. None of the 27 infections resulted in treatment failure during follow-up regardless of rifampin use. Cutibacterium spp. is associated with a younger age and may cause both early and late IASIs. In our experience, the use of rifampin to improve the outcome in the treatment of a Cutibacterium spp. IASI is not relevant since, in our series, none of the cases had therapeutic failure regardless of the use of rifampin.

Background: Daptomycin-induced eosinophilic pneumonia (DEP) is a rare but severe adverse effect and the risk factors are unknown. The aim of this study was to determine risk factors for DEP. Methods: A retrospective cohort study was performed at the Bone and Joint Infection Unit of the Hospital Universitari Bellvitge (January 2014–December 2018). To identify risk factors for DEP, cases were divided into two groups: those who developed DEP and those without DEP. Results: Among the whole cohort (n = 229) we identified 11 DEP cases (4.8%) and this percentage almost doubled in the subgroup of patients ≥70 years (8.1%). The risk factors for DEP were age ≥70 years (HR 10.19, 95%CI 1.28–80.93), therapy >14 days (7.71, 1.98–30.09) and total cumulative dose of daptomycin ≥10 g (5.30, 1.14–24.66). Conclusions: Clinicians should monitor cumulative daptomycin dosage to minimize DEP risk, and be cautious particularly in older patients when the total dose of daptomycin exceeds 10 g.