Drug–drug interactions (DDIs) pose an important concern in elderly and multimorbid patients receiving complex pharmacotherapy. The addition of antimicrobial therapy can increase DDI risk, potentially reducing therapeutic efficacy or increasing toxicity. This review evaluates pharmacokinetic DDIs associated with antibacterial agents approved between 2012 and 2024 in the European Union (EU) and UK. To this end, all studies published on recently introduced antibiotics were consulted, with a focus on cytochrome P450 (CYP450) modulation, renal transporter interactions, and their clinical implications, excluding the papers concerning pharmacodynamics and spectrum of action. A systematic search of the PubMed database and summary of product characteristics (SmPCs) was conducted using key terms such as “drug–drug interaction,” “DDI,” “antibiotic,” and “CYP450,” combined with the name of the respective antibacterial agent. Human data were prioritized, although in vitro studies were included when clinical data were unavailable. Among the evaluated agents, cefiderocol, oritavancin, and meropenem/vaborbactam showed capacity for CYP450-mediated interactions. Although most examined antibiotics carry minimal risk of CYP-mediated DDIs, interactions with renal transporters may still pose clinical concerns, particularly when coadministered with nephrotoxic drugs. In conclusion, most recently approved antibiotics have a low potential for interaction, but certain agents may carry clinically significant risks, especially in vulnerable patient populations. Oritavancin poses notable clinical concern owing to its higher degree of CYP450‑mediated interactions. Further clinical studies are warranted to validate in vitro findings to better characterize the relevance of DDIs involving these novel agents.

OBJECTIVES:The objective of the study was to explore the distribution of gepotidacin into prostate tissue by ex vivo microdialysis (MD) after a single oral dose of gepotidacin. METHODS:We developed and validated an ex vivo MD technique to quantify unbound gepotidacin concentrations in the interstitial fluid of human prostate tissue after a single oral dose of 1500 mg. Adult male patients scheduled for radical prostatectomy received gepotidacin at different timepoints before surgery. MD probes were inserted into prostate tissue immediately after surgical removal for sampling of tissue concentrations. Plasma samples were collected in parallel. Population pharmacokinetic (popPK) modelling was used to analyse the concentration data. RESULTS:Thirty participants were recruited, of whom 24 had at least one prostate MD sample with concentrations above the limit of quantification. A popPK model was successfully developed that described plasma and prostate gepotidacin concentration well. The model-predicted geometric mean of unbound area under the concentration-time curve from zero to infinity was 15 500 h∗ng/mL (geometric coefficient of variation (GCV): 15.7%) in both prostate and plasma (prostate penetration ratio = 1). The model-predicted geometric mean of the unbound peak concentration (Cmax) of 1340 ng/mL (GCV: 38.7%) was reached after 4.25 hours (range: 3.25-12.2 hours) in prostate tissue. The model-predicted geometric mean of unbound plasma Cmax of 2090 (GCV 48.2%) ng/mL was reached after 1.75 hours (range: 0.75-8.25 hours). Model-estimated median total apparent plasma clearance and terminal apparent volume of distribution were 65.0 L/h (GCV 15.7%) and 1310 L (GCV 11.2%), respectively. CONCLUSIONS:Ex vivo MD proved feasible for quantifying gepotidacin in human prostate tissue, interstitial fluid showing exposures comparable with plasma. However, defining pharmacokinetic/pharmacodynamic targets against relevant pathogens for bacterial prostatitis remains essential for predicting drug efficacy for treatment of this disease.

Immune dysregulation is central in bacterial sepsis with lipopolysaccharide (LPS) of gram-negative bacteria acting as a key component in innate immune activation. Modulation of the host response by potential immunomodulatory agents may confer benefits. This ex vivo study compared cytokine responses induced by E. coli and P. aeruginosa LPS and evaluated the impact of cefiderocol on LPS-induced immune activation in human whole blood. Whole blood from ten healthy volunteers was stimulated ex vivo with E. coli or P. aeruginosa LPS in the presence or absence of cefiderocol and incubated for 4 h at 37 °C. Plasma concentrations of TNF-α, IL-1β, IL-6, IL-10, IFN-α, IFN-γ, and IL-8 were quantified at 0 h, 2 h, and 4 h using a multiplex immunoassay. Cytokine release was significantly higher after E. coli LPS stimulation than with P. aeruginosa LPS across all analytes. Mean TNF-α area under the curve (AUC₀–₄) was 2379 pg*h/mL with cefiderocol vs 1936 pg*h/mL without (percent difference 18.2

Background:The impact of high-dose versus standard-dose meropenem on outcomes in critically ill patients remains uncertain. Methods:We conducted an observational cohort study in Vienna, Austria, including critically ill patients treated with meropenem from March 2014 to March 2024. Eligible patients had an intensive care unit (ICU) stay of ≥3 days and received either high-dose (6 g/day) or standard-dose (3 g/day) meropenem via intermittent infusion (or equivalent doses in patients with impaired renal function). We applied 2:1 propensity score matching with covariate adjustment to adjust for confounding by indication. The primary outcome was 90-day all-cause mortality. Secondary outcomes included 30-day mortality, emergence of antimicrobial resistance, initiation of extracorporeal membrane oxygenation (ECMO), new onset of acute respiratory distress syndrome (ARDS) and length of ICU and hospital stay. Occurrence of acute kidney injury (AKI) was evaluated as a safety endpoint. Results:Of 4,210 critically ill patients who received meropenem, we matched 1144 treated with high-dose intermittent infusions with 572 patients who received standard-dose therapy. The 90-day all-cause mortality was significantly lower in the high-dose meropenem group (adjusted risk, 31.5%; 95% CI, 28.5-34.5) compared to the standard-dose group (adjusted risk, 40.9%; 95% CI, 36.7-45.1), with an adjusted risk difference of 9.4% (95% CI, 4.8-14.1; p < 0.001). Secondary outcomes did not differ between groups, with adjusted risks for 30-day mortality (high-dose vs. standard-dose: adjusted risks, 20.0% vs. 22.2%), resistance emergence (5.0% vs. 6.2%), ECMO initiation (6.1% vs. 7.3%), and new-onset ARDS (20.8% vs. 24.9%) showing no significant differences. Adjusted mean ICU and hospital length of stay were comparable (21.5 vs. 21.4 days and 44.3 vs. 41.7 days, respectively). High-dose therapy was associated with a lower adjusted risk of AKI (60.6% vs. 68.2%). Conclusions:High-dose intermittent meropenem was independently associated with lower 90-day all-cause mortality compared with standard-dose therapy in critically ill patients.

OBJECTIVES:COVID-19 vaccines are periodically updated to address SARS-CoV-2 evolution. Whether minor antigen changes provide immunological or even clinical benefit remains unclear. This study compared neutralizing antibody responses following vaccination with the JN.1-based or KP.2-based 2024/25 Pfizer-BioNTech mRNA vaccine. METHODS:Adults aged 18-64 years who received the JN.1 vaccine in Austria, or the KP.2 vaccine in the United States were enrolled. A single blood sample was obtained within 120 days post-vaccination. Pseudovirus neutralization assays against SARS-CoV-2 variants XBB.1.5, JN.1, KP.2, KP3.1.1, XEC and LP.8.1 were performed. Geometric mean titre (GMT) ratios were analysed using t-tests and multivariable regression adjusted for age, sex, vaccination intervals, and prior infection. RESULTS:Among 191 participants (78 JN.1, 113 KP.2), GMTs (95% CI) for XBB.1.5 variant were higher in the JN.1 cohort (3498 [2535-4826]) than in the KP.2 cohort (1901 [1386-2607]), GMT ratio 1.84 (1.16-2.92). For the JN.1 variant, GMTs were 1122 (819-1538) in the JN.1 cohort and 695 (510-948) in the KP.2 cohort (GMT ratio: 1.61 [1.03-2.54]). GMTs for other variants did not differ significantly. After adjustment, only the XBB.1.5 difference remained significant (p = 0.04). CONCLUSIONS:Comparable neutralizing responses across JN.1 lineage variants suggest that annual COVID-19 strain updates targeting variants with small differences within the same antigenic cluster may have limited impact on vaccine-induced protection. These findings may inform future public health policy and regulatory decision-making for COVID-19 vaccines.

BACKGROUND:This research was motivated by the widespread use of oral antivirals during the Covid-19 pandemic and the remaining uncertainty regarding their effects on viral kinetics, which have rarely been studied in real-world population cohorts of this size. METHODS:We analysed 291,340 SARS-CoV-2 cycle threshold (CT) values from 113,399 non-hospitalized adult patients in Vienna (01/2022-05/2023), including 30,451 from 12,166 nirmatrelvir-ritonavir recipients, 27,959 from 10,752 molnupiravir recipients, and 232,930 from 90,481 untreated controls. RESULTS:Both antivirals initially caused a rapid increase in mean CT values. After completion of the 5-day treatment course, CT values declined in both antiviral groups, which was not observed in untreated individuals. CONCLUSIONS:These findings provide population-level evidence on post-treatment viral kinetics of oral antivirals during the Omicron wave.

Subcutaneous antibiotic administration is increasingly recognized as a valuable alternative to intravenous therapy in selected clinical contexts. It is particularly advantageous for patients with poor venous access, frail or cachectic individuals, and in outpatient or palliative care settings, when oral options are not feasible. Subcutaneous delivery of antibiotics with predominantly time-dependent activity, particularly β-lactams (eg ceftriaxone, ertapenem) and glycopeptides (teicoplanin), allows attainment of therapeutic pharmacokinetic/pharmacodynamic (PK/PD) targets comparable to intravenous administration, while maintaining stable concentrations and reducing catheter-related complications. By contrast, PK/PD benefits are limited for agents with more concentration-dependent activity, such as aminoglycosides and fluoroquinolones due to reduced peak levels and local toxicity, whereas daptomycin shows favorable exposure and target attainment with acceptable tolerability. Available evidence suggests good tolerability, although regulatory frameworks remain limited. This multidisciplinary review, authored by infectious disease specialists, clinical pharmacologists, and nurses, summarizes current clinical experience, PK/PD data, and technical aspects of subcutaneous infusion.

PurposeDopamine D2/3 receptors are expressed throughout the human brain, but synchronous receptor quantification in subcortical and cortical brain areas remains difficult to achieve with a single radioligand. Here, we assessed the suitability of a bolus plus constant infusion (B/I) paradigm for brain-wide dopamine D2/3 receptor imaging with the agonist radioligand [11C]-(+)-PHNO.MethodsFive healthy male volunteers underwent two B/I [11C]-(+)-PHNO positron emission tomography (PET) scans combined with a mid-scan intravenous amphetamine challenge. Non-displaceable binding potentials (BPND) were calculated using the equilibrium ratio method and an algorithmically constrained cerebellum as the reference region.ResultsReproducible baseline BPND values were obtained for the majority of regions examined, with intraclass correlation coefficients ranging from 0.5 to 0.93, and test-retest variability remaining below 10%. Moreover, amphetamine-induced decreases in receptor binding were observed in both scans in cortical and a number of subcortical regions. In the globus pallidus and ventral striatum, however, equilibrium had not been reached prior to amphetamine injection, suggesting that further optimization of the protocol might be needed to quantify amphetamine effects in D3 receptor-rich regions.ConclusionsThese results indicate that, within certain limitations, synchronous cortical and subcortical measurements of D2/3 receptors at baseline and under challenge conditions can be achieved using the B/I approach and [11C]-(+)-PHNO PET.

BACKGROUND:ABO blood group has been associated with SARS-CoV-2 susceptibility. Little data exist regarding the impact of ABO and Rhesus (Rh[D]) type on breakthrough infections and antibody responses following SARS-CoV-2 booster vaccination. METHODS:This multicenter, population-based cohort study includes individuals ≥ 18 years who received a booster vaccination against SARS-CoV-2. Antibody levels against SARS-CoV-2 receptor binding domain (RBD) and neutralizing antibodies against wild-type (WT) virus and Omicron variant were assessed at baseline, after 4 weeks and after 6 months. At 6 months follow-up, self-reported ABO and Rh(D) type, time to, and severity of breakthrough infections were collected. RESULTS:In total, 3066 participants (mean age 49 [35-59], 62% female) were included in multivariable regression models, showing no association of anti-RBD and neutralizing antibodies against wild-type and Omicron variant with ABO or Rh(D) 4 weeks after booster vaccination. Time-dependent Cox regression analysis showed significantly lower rates of breakthrough infections in patients with AB (hazard ratio [HR] 0.67 [0.50-0.90]; p = 0.008) compared to O, even after adjustment for relevant covariates and a trend for blood group B (HR 0.82 [0.66-1.01]; p = 0.06) compared to O; there were no associations between Rh(D) and breakthrough infection rates or between observed (asymptomatic to moderate) COVID-19 symptom severity and ABO or Rh(D) blood group. CONCLUSIONS:ABO or Rh(D) blood group was not associated with COVID-19 severity or antibody responses following SARS-CoV-2 vaccination. Breakthrough infections were least common in blood groups AB and B. Although our data do not support previously discussed protective effects of anti-A/B/Rh(D) agglutinins, differences in ABO group appear relevant for Omicron transmission.

Biofilm-associated infections represent a major therapeutic challenge due to reduced antimicrobial susceptibility and the limited predictive value of conventional pharmacokinetic/pharmacodynamic (PK/PD) indices with clinical outcome. A wide spectrum of experimental models has been developed to study biofilms, ranging from simple in vitro assays to ex vivo tissue-derived systems and in vivo infection models. Each category provides distinct advantages: in vitro platforms enable high-throughput compound screening and measurement of biofilm-specific indices such as MBIC and MBEC; ex vivo models preserve host tissue architecture and allow investigation of topical therapies and therapeutic windows; and in vivo systems are indispensable for analysing host-pathogen interactions and systemic PK/PD relationships. No single model is sufficient to replicate clinical biofilm complexity, but combined use and progressive standardization can improve translational value. This review provides a structured overview of available models, their PK/PD readouts and their strengths and limitations, aiming to guide model selection in preclinical biofilm research and antimicrobial development.

Adenosine triphosphate-binding cassette (ABC) transporters are expressed throughout the lung epithelium, where they may influence the pulmonary disposition of inhaled therapeutics and contribute to transporter-mediated drug-drug interactions. Imaging approaches using radiolabeled transporter-specific probe substrates potentially offer a means to assess drug-transporter interactions directly in the lung. [99mTc]Tc-sestamibi, a widely used myocardial perfusion tracer, is a known substrate of P-glycoprotein (P-gp/ABCB1) and multidrug resistance-associated protein 1 (MRP1/ABCC1). Here, we evaluated the suitability of [99mTc]Tc-sestamibi for imaging transporter activity in the lungs. We measured pulmonary elimination kinetics by dynamic planar gamma scintigraphy following intratracheal aerosolization of [99mTc]Tc-sestamibi in wild-type and MRP1-deficient (hABCC1(-/-)) mice, with and without co-administration of the P-gp inhibitor tariquidar. P-gp inhibition significantly reduced the pulmonary elimination rate constant (kE) of [99mTc]Tc-sestamibi (1.14 ± 0.32 h-1 in wild-type mice versus 0.56 ± 0.36 h-1 in tariquidar-treated wild-type mice; P = 0.0056). In contrast, MRP1 deficiency did not alter pulmonary elimination of [99mTc]Tc-sestamibi (0.93 ± 0.23 h-1), and combined MRP1 deficiency with P-gp inhibition (0.61 ± 0.24 h-1) produced no additional effect beyond P-gp inhibition alone. These findings indicate that pulmonary disposition of [99mTc]Tc-sestamibi is primarily governed by P-gp, with minimal contribution from MRP1 in mice, supporting its potential use as an imaging probe of pulmonary P-gp activity. Nevertheless, given possible species differences in transporter abundance, cellular localization, or function, clinical studies are required to evaluate the translatability of these results to humans.

Surgical site infections remain significant complications after cardiac surgery and perioperative antibiotic exposure may be altered by cardiopulmonary bypass and patient characteristics. Ceftaroline fosamil is active against methicillin resistant Staphylococcus aureus (MRSA) and may be a potential alternative for patients with risk factors for MRSA. However, parasternal subcutaneous tissue exposure during cardiac surgery has not been studied. This prospective, randomized pharmacokinetic study investigated plasma and parasternal subcutaneous concentrations in patients undergoing cardiac surgery with cardiopulmonary bypass. Fourteen patients were randomized to receive a total dose of 1,800 mg of ceftaroline fosamil administered either intermittently or by continuous infusion following a loading dose. Plasma and subcutaneous tissue concentrations were measured for 24 h using arterial blood sampling and in vivo microdialysis. Pharmacokinetic parameters and pharmacodynamic target attainment were assessed for both dosing regimens. In plasma, free drug concentrations remained above the MIC of 1 mg/L for nearly the entire dosing interval in both groups (mean fT>MIC ∼99-100%). Subcutaneous parasternal tissue concentrations were lower in both groups and showed marked interindividual variability. At an MIC of 1 mg/L, mean tissue fT>MIC ranged from 93% to 99% with intermittent and 75%-86% during continuous administration. These findings demonstrate that ceftaroline penetration into subcutaneous parasternal tissue is highly variable in cardiac surgery patients and may limit tissue exposure under perioperative conditions despite favorable plasma concentrations. While continuous infusion improves plasma exposure, this does not necessarily translate into superior tissue exposure. Therefore, measurement of tissue concentrations is important when evaluating antibiotic dosing strategies in the perioperative setting.

Invasive fungal infections are a major cause of morbidity and mortality in immunocompromised and critically ill patients. While plasma pharmacokinetics (PK) commonly guide antifungal dosing, they may not reliably reflect drug exposure at infection sites, particularly in compartments that are difficult to reach. Tissue PK is increasingly recognised as an important determinant of optimal dosing and therapeutic success. This review summarises available clinical data on tissue PK of approved antifungal agents, including triazoles, echinocandins, amphotericin B formulations, and flucytosine. Studies were identified via a PubMed search through July 2025, focusing on prospective human trials reporting both plasma and tissue concentrations. Our findings revealed marked variability in tissue penetration across drugs and compartments. These findings underscore the limitations of relying solely on plasma concentrations to estimate tissue exposure and emphasise the importance of considering tissue penetration when selecting and dosing antifungal therapy.

Organic anion-transporting polypeptide 2B1 (OATP2B1/SLCO2B1) is an uptake transporter expressed in the liver and in several extrahepatic tissues, including skeletal muscle. Muscular OATP2B1 is thought to facilitate intracellular accumulation of statins, potentially contributing to statin-induced myotoxicity. To investigate functional OATP2B1 activity in vivo in human skeletal muscle, we performed positron emission tomography (PET) with the radiolabelled OATP2B1 substrate [11C]erlotinib. Nine healthy male volunteers (age: 31 ± 9 years) underwent two dynamic 60-min PET scans of the head with concurrent arterial blood sampling following intravenous injection of a microdose of [11C]erlotinib (< 10 µg). The first scan was performed without any pharmacological pre-treatment (baseline scan), whereas the second scan was performed after pre-treatment with a single oral dose of unlabelled erlotinib (650 mg), administered 3.0 ± 0.1 h before the start of the PET scan. Volumes of interest (VOIs) were manually delineated for the right and left temporal muscle surrounding the skull on co-registered PET/magnetic resonance imaging (MRI) data and averaged to generate a global temporal muscle VOI. Time-activity curves for temporal muscle and arterial plasma were analysed using a 1-tissue-2-rate constant (1T2K) compartment model and Logan graphical analysis to estimate the total volume of distribution (VT) of [11C]erlotinib (reflecting the steady-state muscle-to-plasma concentration ratio), as well as the rate constants for transfer of [11C]erlotinib from plasma to muscle (K1) and from muscle to plasma (k2). Both Logan analysis and the 1T2K model demonstrated a significant reduction in VT after erlotinib pre-treatment compared with baseline (VT Logan: baseline: 0.85 ± 0.11 mL/cm3, erlotinib: 0.70 ± 0.08 mL/cm3, -18 ± 8%, p = 0.00047; VT 1T2K: baseline: 0.83 ± 0.11 mL/cm3, erlotinib: 0.67 ± 0.07 mL/cm3, -18 ± 7%, p = 0.00033). K1 showed a trend toward reduction after erlotinib pre-treatment without reaching statistical significance, whereas k2 remained unchanged. Our findings demonstrate saturable distribution of [¹¹C]erlotinib to human skeletal muscle, consistent with functional OATP2B1 activity. These results support a mechanistic role for muscular OATP2B1 in statin-induced myotoxicity and highlight its potential broader relevance for the safety and pharmacology of other OATP2B1 substrate drugs.

BACKGROUND:This study aimed to investigate pharmacokinetic (PK)/pharmacodynamic (PD) target attainment, tissue and plasma PK and PK interactions of ampicillin/sulbactam. METHODS:Thirty healthy volunteers received a single intravenous 30-min infusion of ampicillin 2000 mg (n = 10), sulbactam 1000 mg (n = 10) or ampicillin 2000 mg/sulbactam 1000 mg (n = 10). Drug concentrations were determined in the interstitial fluid of subcutis and muscle using microdialysis and in plasma over 8 h. A non-compartmental analysis and an adjustment to the plasma protein binding determined by ultrafiltration were performed to calculate PK parameters and the proportion of participants achieving PK/PD targets. The PK/PD targets selected for ampicillin were fT>MIC >50% and fT>MIC >70%, reflecting established efficacy thresholds for β-lactam antibiotics across varying degrees of disease severity. RESULTS:Fewer than 90% of participants reached the PK/PD target of ampicillin fT>MIC > 50% at MICs ≥4 mg/L and the target of fT>MIC > 70% at MICs ≥0.5 mg/L in plasma, muscle and subcutis, assuming three times daily dosing. In the pooled analysis, the mean fAUC0-8 of ampicillin was 80 (S.D. 25), 84 (S.D. 29) and 80 (S.D. 20) mg/L × h in subcutis, muscle and plasma. The mean fAUC0-8 of sulbactam was 49 (S.D. 13), 54 (S.D. 15) and 60 (S.D. 17) mg/L × h in subcutis, muscle and plasma. While ampicillin concentrations were similar between the groups, sulbactam showed higher concentrations in the combined group than in the sulbactam alone group, including an increased plasma fAUC0-8 (68 [S.D. 12] vs. 51 [S.D. 18] mg/L × h, P = 0.027). CONCLUSION:Although tissue concentrations almost reached plasma levels, the target attainment of ampicillin may be suboptimal when administered three times daily. Sulbactam tissue and plasma levels were slightly higher after combined administration with ampicillin than after administration of sulbactam alone.

OBJECTIVE:Cardiopulmonary bypass (CPB) alters the pharmacokinetics (PK) of antibiotics administered as surgical prophylaxis (SAP) due to haemodilution, circuit interactions, protein binding and inflammation. This study investigated plasma and interstitial fluid (ISF) concentrations of cefuroxime in patients undergoing on- versus off-pump coronary artery bypass graft (CABG) surgery. METHODS:Patients undergoing on- or off-pump CABG received SAP with cefuroxime, consisting of a bolus of 3 g before skin incision and a second dose of 1.5 g at CPB weaning or at sternal closure, respectively. ISF concentrations were measured by two microdialysis catheters in the subcutaneous tissue of both upper arms. Plasma and ISF concentrations were determined up to 8 hours after the first dose. Pharmacokinetic analysis was performed by non-compartmental analysis. RESULTS:Fifteen patients were enrolled per group. Baseline characteristics and cardiovascular risk profile were comparable between groups. Median [minimum; maximum] surgical duration was 4.3 h [3.1 h; 6.1 h] in the on-pump and 3.4 h [1.8 h; 4.0 h] in the off-pump group, with a median bypass time of 1.7 h [0.8 h; 2.5 h]. The ƒAUC0-8h in plasma (on-pump versus off-pump group; mean ± SD: 417 ± 124 versus 542 ± 238 h·mg/L, P = 0.081) and in ISF (488 ± 212 versus 508 ± 209 h·mg/L, P = 0.835) did not differ significantly. Based on an extrapolation of the first dose, plasma concentrations remained above a minimum inhibitory concentration of 8 mg/L for up to 4.5 h in the on-pump and 4.8 h in the off-pump group. CONCLUSION:For a median bypass time of 1.7 h and considering all factors cumulatively, no significant impact of CPB on cefuroxime plasma and ISF concentrations was observed. A dose of 3 g cefuroxime administered intravenously 30-60 min before skin incision with a second repetitive dose of 1.5 g administered after CPB weaning in the on-pump group or after sternal closure in the off-pump group, resulted in adequate plasma and ISF concentrations in patients undergoing cardiac bypass surgery.

RATIONALE:The impact of fluid resuscitation strategies on patient-centered outcomes of sepsis survivors is unknown. OBJECTIVES:To assess the effect of an early restrictive or liberal fluid resuscitation strategy on long-term functional outcomes in patients with sepsis-induced hypotension. METHODS:SHAMROC (Sepsis-induced Hypotension: Assessing effect of Method of Resuscitation On Patient-centered Outcomes) prospectively assessed the impact of random assignment to a restrictive or liberal fluid resuscitation strategy for sepsis-induced hypotension outcomes at 6 and 12 months after randomization in the NIH NHLBI PETAL Network's CLOVERS trial (NCT03434028). The pre-specified analyses used trimmed means at 50% to prevent informative censoring of deceased patients. MEASUREMENTS AND MAIN RESULTS:Of the 1563 participants included in the CLOVERS trial, 898 (57%) were included in the SHAMROC trial. As 196 were lost to follow-up, 702 participants were analyzed at 6 months (431 survivors and 271 non-survivors). Baseline characteristics were similar between the groups. At 6 months, no group differences were observed in cognitive function (restrictive versus liberal; trimmed mean difference in Montreal Cognitive Assessment-Blind Score, 0.11, 95% CI -1.44-1.70), executive function (trimmed mean difference in Hayling Sentence Completion Test, 0.38, 95% CI -0.97-1.76), disability status (trimmed mean difference in Activity of Daily Living Score, 0.03, 95% CI -0.84-0.90), mobility (trimmed mean difference in PROMIS Mobility Score, 0.72, 95% CI -2.20-3.64), and health-related quality of life (trimmed mean difference in EQ-5D-5L, -0.01, 95% CI -0.07-0.06). Outcomes also did not differ at 12 months. CONCLUSIONS:In this long-term follow-up of a randomized controlled trial of patients with sepsis-induced hypotension, the restrictive fluid strategy used in this study resulted in similar cognitive and physical function at 6 and 12 months, compared to a liberal fluid strategy.

OBJECTIVES:Amiodarone or lidocaine are recommended for the treatment of shockable out-of-hospital cardiac arrest (OHCA). Previous comparisons between the two antiarrhythmic drugs were inconclusive. DESIGN:This analysis included data from the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry 3 (2011-2015). A target trial framework was used to overcome confounding inherent in observational comparisons. SETTING:Data from patients with OHCA were prospectively collected by emergency medical services (EMS) at multiple North American sites. PATIENTS:Adults with nontraumatic OHCA and an initial shockable rhythm who received at least three defibrillation attempts were included. Time zero was defined as first antiarrhythmic drug administration, at which eligibility criteria had to be met. INTERVENTIONS:Two antiarrhythmic treatment strategies were compared: lidocaine vs. amiodarone. MEASUREMENTS AND MAIN RESULTS:The primary outcome was survival to hospital discharge. The key secondary outcome was favorable neurologic outcome at discharge (modified Rankin scale score of 3 or less). Group differences were adjusted using inverse probability weighting (key covariates: age, sex, location of OHCA, witness status, bystander resuscitation, automated external defibrillator shock, elapsed time from call to advanced life support arrival/first EMS shock/advanced airway, intraosseous access) and a multiple logistic regression model. Of 2451 patients included, 987 received lidocaine and 1464 received amiodarone. The adjusted percentage point difference in survival to hospital discharge was 2.8% favoring lidocaine (95% CI, -0.6 to 6.2); the estimated survival probabilities were 26.2% (275/987) with lidocaine and 23.5% (329/1464) with amiodarone. No difference was observed in the estimated probability of favorable neurologic outcome at discharge between the lidocaine group (17.7%) and the amiodarone group (16.2%) (adjusted difference, 1.5%; 95% CI, -1.5 to 4.5). CONCLUSIONS:No statistically significant difference in survival or favorable neurologic outcome was observed between lidocaine and amiodarone; however, the wide CIs cannot exclude a clinically meaningful benefit for lidocaine. These findings are consistent with randomized controlled trials, but residual confounding cannot be excluded.

BACKGROUND:Peritoneal dialysis (PD) enables intraperitoneal antibiotic delivery, but the efficacy of ceftazidime/avibactam (CAZ/AVI) in PD fluid (PDF) is not well-characterized. OBJECTIVES:To assess the in vitro activity of ceftazidime/avibactam against Pseudomonas aeruginosa in fresh PDF and patient-derived dialysate at isolate-specific MIC levels and at a clinically measured intraperitoneal peak concentration (Cmax). METHODS:MICs were determined for P. aeruginosa ATCC 27583 and nine clinical isolates using broth microdilution in CAMHB. Two isolates (123/19, 174/19) underwent time-kill experiments at MIC (8-16 µg/mL) and maximum peritoneal concentration (Cmax 64 µg/mL), with avibactam fixed at 4 µg/mL. Bacterial counts were evaluated over 24 h in CAMHB, icodextrin-containing PDF, and patient-derived dialysate (n = 4). RESULTS:Isolates showed variable growth. Ceftazidime/avibactam was bactericidal in CAMHB but only bacteriostatic in PDF and patient-derived dialysate (±1 log10 cfu/mL reduction at 8 h). No further reduction occurred at 24 h, even at Cmax. CONCLUSIONS:Reduced bacterial growth in PDF is associated with diminished ceftazidime/avibactam activity, yielding primarily bacteriostatic effects. Single-dose intraperitoneal administration may be insufficient to eradicate P. aeruginosa, as Cmax concentrations failed to achieve ≥3 log10 cfu/mL reduction in vitro. These findings highlight potential limitations of ceftazidime/avibactam in PD-related infections and might guide future dosing strategies research.