Model-based assessment of neutrophil-mediated phagocytosis and digestion of bacteria across in vitro and in vivo studies.

Neutrophil granulocytes are key components of the host response against pathogens, and severe neutropenia, with neutrophil counts below 0.5 × 106 cells/mL, renders patients increasingly vulnerable to infections. Published in vitro (n = 7) and in vivo (n = 5) studies with time-course information on bacterial and neutrophil counts were digitized to characterize the kinetics of neutrophil-mediated bacterial killing and inform on the immune systems' contribution to the clearance of bacterial infections. A mathematical model for the in vitro dynamics of bacteria and the kinetics of neutrophil-mediated phagocytosis and digestion was developed, which was extended to in vivo studies in immune-competent and immune-compromised mice. Neutrophil-mediated bacterial killing was described by two first-order processes-phagocytosis and digestion-scaled by neutrophil concentration, where 50% of the maximum was achieved at neutrophil counts of 1.19 × 106 cells/mL (phagocytosis) and 6.55 × 106 cells/mL (digestion). The process efficiencies diminished as the phagocytosed bacteria to total neutrophils ratio increased (with 50% reduction at a ratio of 3.41). Neutrophil in vivo dynamics were captured through the characterization of myelosuppressive drug effects and postinoculation neutrophil influx into lungs and by system differences (27% bacterial growth and 9.3% maximum capacity, compared with in vitro estimates). Predictions showed how the therapeutically induced reduction of neutrophil counts enabled bacterial growth, especially when falling below 0.5 × 106 cells/mL, whereas control individuals could deal with all tested bacterial burdens (up to 109 colony forming units/g lung). The model-based characterization of neutrophil-mediated bacterial killing simultaneously predicted data across in vitro and in vivo studies and may be used to inform the capacity of host-response at the individual level.

Intervention fidelity and process outcomes of medication reviews including post-discharge follow-up in older hospitalized patients: Process evaluation of the MedBridge trial.

WHAT IS KNOWN AND OBJECTIVE: Drug-related problems (DRPs) are a growing healthcare burden worldwide. In an ongoing cluster-randomized controlled trial in Sweden (MedBridge), comprehensive medication reviews (CMRs) including post-discharge follow-up have been conducted in older hospitalized patients to prevent and solve DRPs. As part of a process evaluation of the MedBridge trial, this study aimed to assess the intervention fidelity and process outcomes of the trial's interventions. METHODS: For intervention delivery, the percentage of patients that received intervention components was calculated per study group. Process outcomes, measured in about one-third of all intervention patients, included the following: the number of identified medication discrepancies, DRPs and recommendations to solve DRPs, correction rate of discrepancies, and implementation rate of recommendations. RESULTS AND DISCUSSION: The MedBridge trial included 2637 patients (mean age: 81 years). The percentage of intervention patients (n = 1745) that received the intended intervention components was 94%-98% during admission, and 40%-81% upon and after discharge. The percentage of control patients (n = 892) that received at least one unintended intervention component was 15%. On average, 1.1 discrepancies and 2.0 DRPs were identified in 652 intervention patients. The correction and implementation rates were 79% and 73%, respectively. Stop medication was the most frequently implemented recommendation (n = 293) and 77% of the patients had at least one corrected discrepancy or implemented recommendation. WHAT IS NEW AND CONCLUSION: The intervention fidelity within the MedBridge trial was high for CMRs during hospital stay and lower for intervention components upon and after discharge. The high prevalence of corrected discrepancies and implemented recommendations may explain potential effects of CMRs in the MedBridge trial.

Piperacillin pharmacokinetics and target attainment in children with cancer and fever: Can we optimize our dosing strategy?

BACKGROUND: Data on piperacillin-tazobactam pharmacokinetics and optimal dosing in children with cancer and fever are limited. Our objective was to investigate piperacillin pharmacokinetics and the probability of target attainment (PTA) with standard intermittent administration (IA), and to simulate PTA in other dosing regimens. PROCEDURE: This prospective pharmacokinetic study was conducted from April 2016 to January 2018. Children with cancer receiving empiric piperacillin-tazobactam to treat infections were included. Piperacillin-tazobactam 100 mg/kg was infused over 5 min every 8 hours (IA). An optimized sample schedule provided six blood samples per subject for piperacillin concentration determination. The evaluated targets included: (1) 100% time of free piperacillin concentration above the minimum inhibitory concentration (fT > MIC) and (2) 50% fT > 4× MIC. MIC50 and MIC90 were defined based on an intrainstitutional MIC range. RESULTS: A total of 482 piperacillin concentrations were obtained from 43 children (aged 1-18 years) during 89 fever episodes. Standard IA resulted in insufficient target attainment, with significant differences in piperacillin pharmacokinetics for different body weights. Median fT > MIC was 61.2%, 53.5%, and 36.3% for MIC50 (2.0 mg/L), MIC90 (4.0 mg/L), and breakpoint for Pseudomonas aeruginosa (16.0 mg/L), respectively. Correspondingly, the median fT > 4× MIC was 43%, 36.3%, and 20.1%. Simulations showed that only continuous infusion reached a PTA of 95% for MIC = 16.0 mg/L, while extended infusion lasting half of the dosing interval reached a PTA of 95% for MIC ≤ 8 mg/L. CONCLUSIONS: Our data revealed insufficient PTA with standard IA of piperacillin-tazobactam in children with cancer and fever. Alternative dosing strategies, preferably continuous infusion, are required to ensure adequate PTA.

Medication Reviews Bridging Healthcare (MedBridge): Study protocol for a pragmatic cluster-randomised crossover trial.

BACKGROUND: Mismanaged prescribing and use of medication among elderly puts major pressure on current healthcare systems. Performing a medication review, a structured critical examination of a patient's medications, during hospital stay with active follow-up into primary care could optimise treatment benefit and minimise harm. However, a lack of high quality evidence inhibits widespread implementation. This manuscript describes the rationale and design of a pragmatic cluster-randomised, crossover trial to fulfil this need for evidence. AIM: To study the effects of hospital-initiated comprehensive medication reviews, including active follow-up, on elderly patients' healthcare utilisation compared to 1) usual care and 2) solely hospital based reviews. DESIGN: Multicentre, three-treatment, replicated, cluster-randomised, crossover trial. SETTING: 8 wards with a multidisciplinary team within 4 hospitals in 3 Swedish counties. PARTICIPANTS: Patients aged 65years or older, admitted to one of the study wards. EXCLUSION CRITERIA: Palliative stage; residing in other than the hospital's county; medication review within the last 30days; one-day admission. INTERVENTIONS: 1, comprehensive medication review during hospital stay; 2, same as 1 with the addition of active follow-up into primary care; 3, usual care. PRIMARY OUTCOME MEASURE: Incidence of unplanned hospital visits during a 12-month follow-up period. DATA COLLECTION AND ANALYSES: Extraction and collection from the counties' medical record system into a GCP compliant electronic data capture system. Intention-to-treat-analyses using hierarchical models. RELEVANCE: This study has a high potential to show a reduction in elderly patients' morbidity, contributing to more sustainable healthcare in the long run.

Evaluation of automated time-lapse microscopy for assessment of in vitro activity of antibiotics.

This study aimed to evaluate the potential of a new time-lapse microscopy based method (oCelloScope) to efficiently assess the in vitro antibacterial effects of antibiotics. Two E. coli and one P. aeruginosa strain were exposed to ciprofloxacin, colistin, ertapenem and meropenem in 24-h experiments. Background corrected absorption (BCA) derived from the oCelloScope was used to detect bacterial growth. The data obtained with the oCelloScope were compared with those of the automated Bioscreen C method and standard time-kill experiments and a good agreement in results was observed during 6-24h of experiments. Viable counts obtained at 1, 4, 6 and 24h during oCelloScope and Bioscreen C experiments were well correlated with the corresponding BCA and optical density (OD) data. Initial antibacterial effects during the first 6h of experiments were difficult to detect with the automated methods due to their high detection limits (approximately 105CFU/mL for oCelloScope and 107CFU/mL for Bioscreen C), the inability to distinguish between live and dead bacteria and early morphological changes of bacteria during exposure to ciprofloxacin, ertapenem and meropenem. Regrowth was more frequently detected in time-kill experiments, possibly related to the larger working volume with an increased risk of pre-existing or emerging resistance. In comparison with Bioscreen C, the oCelloScope provided additional information on bacterial growth dynamics in the range of 105 to 107CFU/mL and morphological features. In conclusion, the oCelloScope would be suitable for detection of in vitro effects of antibiotics, especially when a large number of regimens need to be tested.

Semimechanistic pharmacokinetic/pharmacodynamic model for assessment of activity of antibacterial agents from time-kill curve experiments.

Dosing of antibacterial agents is generally based on point estimates of the effect, even though bacteria exposed to antibiotics show complex kinetic behaviors. The use of the whole time course of the observed effects would be more advantageous. The aim of the present study was to develop a semimechanistic pharmacokinetic (PK)/pharmacodynamic (PD) model characterizing the events seen in a bacterial system when it is exposed to antibacterial agents with different mechanisms of action. Time-kill curve experiments were performed with a strain of Streptococcus pyogenes exposed to a wide range of concentrations of the following antibiotics: benzylpenicillin, cefuroxime, erythromycin, moxifloxacin, and vancomycin. Bacterial counts were monitored with frequent sampling during the experiment. A simultaneous fit of all data was accomplished. The degradation of the drugs was monitored and corrected for in the model, and a link model was used to account for an effect delay. In the final PK/PD model, the total bacterial population was divided into two subpopulations: one growing drug-susceptible population and one resting insusceptible population. The drug effect was included as an increase of the killing rate of bacteria in the susceptible state, according to a maximum-effect (E(max)) model. An internal model validation showed that the model was robust and had good predictability. In conclusion, for all drugs, the final PK/PD model successfully described bacterial growth and killing kinetics when the bacteria were exposed to different antibiotic concentrations. The semimechanistic model that was developed might, after further refinement, serve as a tool for the development of optimal dosing strategies for antibacterial agents.