A pharmacokinetic-pharmacodynamic assessment of oral antibiotics for pyelonephritis.

Antibiotic resistance to oral antibiotics recommended for pyelonephritis is increasing. The objective was to determine if there is a pharmacological basis to consider alternative treatments/novel dosing regimens for the oral treatment of pyelonephritis. A systematic review identified pharmacokinetic models of suitable quality for a selection of antibiotics with activity against Escherichia coli. MIC data was obtained for a population of E. coli isolates derived from patients with pyelonephritis. Pharmacokinetic/pharmacodynamic (PK/PD) simulations determined probability of target attainment (PTA) and cumulative fraction response (CFR) values for sub-populations of the E. coli population at varying doses. There are limited high-quality models available for the agents investigated. Pharmacokinetic models of sufficient quality for simulation were identified for amoxicillin, amoxicillin-clavulanic acid, cephalexin, ciprofloxacin, and fosfomycin trometamol. These antibiotics were predicted to have PTAs ≥ 0.85 at or below standard doses for the tested E. coli population including cephalexin 1500 mg 8 hourly for 22% of the population (MIC ≤ 4 mg/L) and ciprofloxacin 100 mg 12 hourly for 71% of the population (MIC ≤ 0.06 mg/L). For EUCAST-susceptible E. coli isolates, doses achieving CFRs ≥ 0.9 included amoxicillin 2500 mg 8 hourly, cephalexin 4000 mg 6 hourly, ciprofloxacin 200 mg 12 hourly, and 3000 mg of fosfomycin 24 hourly. Limitations in the PK data support carrying out additional PK studies in populations of interest. Oral antibiotics including amoxicillin, amoxicillin-clavulanic acid, and cephalexin have potential to be effective for a proportion of patients with pyelonephritis. Ciprofloxacin may be effective at lower doses than currently prescribed

Modelling of neutrophil dynamics in children receiving busulfan or treosulfan for haematopoietic stem cell transplant conditioning

AIM: Busulfan and treosulfan are cytotoxic agents used in the conditioning regime prior to paediatric hematopoietic stem cell transplantation (HSCT). These agents cause suppression of myeloid cells leaving patients severely immunocompromised in the early post‐HSCT period. The main objectives were: (i) to establish a mechanistic PKPD model for the treatment and engraftment effects on neutrophil counts comparing busulfan and treosulfan‐based conditioning, and (ii) to explore current dosing schedules with respect to time to HSCT. METHODS: data on 126 patients, 72 receiving busulfan (7 months‐18 years, 5.1–47.0 Kg) and 54 treosulfan (4 months–17 years, 3.8–35.8 Kg), were collected. 8,935 neutrophil count observations were recorded during the study period in addition to drug concentrations to develop a mechanistic PKPD model. ANC profiles were modelled semi‐mechanistically accounting for transplant effects and differing set points pre‐ and post‐transplant. RESULTS: Pharmacokinetics were best described by two‐compartment models for both drugs. The Friberg semi‐mechanistic neutropenia model was applied with a linear model for busulfan and an Emax model for treosulfan describing drug effects at various stages of neutrophil maturation. System parameters were consistent across both drugs. The HSCT was represented by an amount of progenitor cells enhancing the neutrophils' proliferation and maturation compartments. Alemtuzumab was found to enhance the proliferative rate under which the ANC begin to grow after HSCT. CONCLUSIONS: A semi‐mechanistic PKPD model linking exposure to either busulfan or treosulfan to the neutrophil reconstitution dynamics was successfully built. Alemtuzumab co‐administration enhanced the neutrophil proliferative rate after HSCT. Treosulfan administration was suggested to be delayed with respect to time to HSCT, leaving less time between the end of the administration and stem cell infusion

Relation between acute and long-term cognitive decline after surgery: Influence of metabolic syndrome.

IntroductionThe relationship between persistent postoperative cognitive decline and the more common acute variety remains unknown; using data acquired in preclinical studies of postoperative cognitive decline we attempted to characterize this relationship.MethodsLow capacity runner (LCR) rats, which have all the features of the metabolic syndrome, were compared postoperatively with high capacity runner (HCR) rats for memory, assessed by trace fear conditioning (TFC) on the 7th postoperative day, and learning and memory (probe trial [PT]) assessed by the Morris water-maze (MWM) at 3 months postoperatively. Rate of learning (AL) data from the MWM test, were estimated by non-linear mixed effects modeling. The individual rat's TFC result at postoperative day (POD) 7 was correlated with its AL and PT from the MWM data sets at postoperative day POD 90.ResultsA single exponential decay model best described AL in the MWM with LCR and surgery (LCR-SURG) being the only significant covariates; first order AL rate constant was 0.07 s(-1) in LCR-SURG and 0.16s(-1) in the remaining groups (p<0.05). TFC was significantly correlated with both AL (R=0.74; p<0.0001) and PT (R=0.49; p<0.01).ConclusionSeverity of memory decline at 1 week after surgery presaged long-lasting deteriorations in learning and memory

Pharmacometrics Markup Language (PharmML): Opening New Perspectives for Model Exchange in Drug Development

The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps