Is continuous infusion of beta-lactam antibiotics worthwhile?--efficacy and pharmacokinetic considerations

The most important pharmacodynamic parameter for beta-lactam antibiotics has been shown to be the time above the MIC, which is used as an argument to administer beta-lactam antibiotics by continuous infusion. Studies in vitro and in laboratory animals comparing efficacy of continuous an

Pharmacokinetic-pharmacodynamic modeling of activity of ceftazidime during continuous and intermittent infusion

We developed and applied pharmacokinetic-pharmacodynamic (PK-PD) models to characterize in vitro bacterial rate of killing as a function of ceftazidime concentrations over time. For PK-PD modeling, data obtained during continuous and intermittent infusion of ceftazidime in Pseudomonas aeruginosa killing experiments with an in vitro pharmacokinetic model were used. The basic PK-PD model was a maximum-effect model which described the number of viable bacteria (N) as a function of the growth rate (lambda) and killing rate (epsilon) according to the equation dN/dt = [lambda - epsilon x [Cgamma(EC50gamma + Cgamma)]] N, where gamma is the Hill factor, C is the concentration of antibiotic, and EC50 is the concentration of antibiotic at which 50% of the maximum effect is obtained. Next, four different models with increasing complexity were analyzed by using the EDSIM program (MediWare, Groningen, The Netherlands). These models incorporated either an adaptation rate factor and a maximum number of bacteria (Nmax) factor or combinations of the two parameters. In addition, a two-population model was evaluated. Model discrimination was by Akaike's information criterion. The experimental data were best described by the model which included an Nmax term and a rate term for adaptation for a period up to 36 h. The absolute values for maximal growth rate and killing rate in this model were different from those in the original experiment, but net growth rates were comparable. It is concluded that the derived models can describe bacterial growth and killing in the presence of antibiotic concentrations mimicking human pharmacokinetics. Application of these models will eventually provide us with parameters which can be used for further dosage optimization

Novel therapeutic modalities: the future is now

Pharmacolog

Leopard Panthera pardus density and survival in an ecosystem with depressed abundance of prey and dominant competitors

The leopard Panthera pardus is in range-wide decline, and many populations are highly threatened. Prey depletion is a major cause of global carnivore declines, but the response of leopard survival and density to this threat is unclear: by reducing the density of a dominant competitor (the lion Panthera leo) prey depletion could create both costs and benefits for subordinate competitors. We used capture-recapture models fitted to data from a 7-year camera-trap study in Kafue National Park, Zambia, to obtain baseline estimates of leopard population density and sex-specific apparent survival rates. Kafue is affected by prey depletion, and densities of large herbivores preferred by lions have declined more than the densities of smaller herbivores preferred by leopards. Lion density is consequently low. Estimates of leopard density were comparable to ecosystems with more intensive protection and favourable prey densities. However, our study site is located in an area with good ecological conditions and high levels of protection relative to other portions of the ecosystem, so extrapolating our estimates across the Park or into adjacent Game Management Areas would not be valid. Our results show that leopard density and survival within north-central Kafue remain good despite prey depletion, perhaps because (1) prey depletion has had weaker effects on preferred leopard prey compared to larger prey preferred by lions, and (2) the density of dominant competitors is consequently low. Our results show that the effects of prey depletion can be more complex than uniform decline of all large carnivore species, and warrant further investigation

Manuscript for Drug Metabolism and Disposition Title Developmental changes in hepatic OCT1 protein expression from neonates to children

Abstract Organic cation transporter 1 (OCT1) plays an important role in the disposition of clinicallyimportant drugs, and the capacity of OCT1 activity is presumed to be proportional to the protein expression level in organ tissues. Presently, knowledge of OCT1 protein expression in children is very limited, especially among neonates and small infants. Here, we report on the characterization of OCT1 protein expression in neonatal, infant and pediatric liver samples performed by Immunoblot analysis. OCT1 protein expression was detected in liver samples from neonates as early as postnatal day 1 -2. This youngest group showed significantly lower OCT1 expression normalized by GAPDH (0.03 ±0.02 arbitrary unit (AU), mean ± SD, N=7) compared to samples aged 3 -4 weeks (0.08 ±0.03 AU, N=5, **P< 0.01), 3 -6 months (0.23 ± 0.15 AU, N=7, **P< 0.01), 11 months -1 year (0.42 ± 0.32 AU, N=6, **P< 0.01), and 8 -12 years (1.00 ± 0.44 AU, N=7, **P< 0.01). These data demonstrate an age-dependent increase in OCT1 expression from birth up to 8-12 years of age, and the findings of this study contribute to the understanding of OCT1 functional capacity and their effect of the disposition of OCT1 substrates in neonates and small infants

Alternate-Day Micafungin Antifungal Prophylaxis in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation: A Pharmacokinetic Study

Disseminated fungal infection is a major cause of morbidity and mortality in children undergoing hematopoietic stem cell transplantation (HSCT). Prophylaxis with amphotericin B can be limited by renal toxicity. Oral triazoles can be limited by poor absorption, large interindividual pharmacokinetic (PK) variability, and hepatic toxicity, leading to interruptions in therapy and breakthrough infections. Intravenous (i.v.) micafungin has potential advantages, because of its better safety profile, specifically in terms of hepatic and renal toxicity, and lack of drug-drug interactions with common medications used in the HSCT setting. We hypothesized that higher dose micafungin (3 mg/kg) every other day will provide drug exposure similar to standard dosing (1 mg/kg) given daily, and improve patient compliance in very young children in whom oral medications can be challenging, at reduced administration costs. Both animal and adult patient data support the use of this approach. Fifteen children (M/F = 11/4, aged ≤10 years; mean: 3.9 years, range: 0.6-10 years) with various hematologic, metabolic, and immune deficiency disorders undergoing HSCT received a single dose of micafungin (3 mg/kg) i.v. over 1 hour. Dose selection was based on published PK data in pediatric patients, and exploration of different dosing regimens using Monte Carlo PK/PD simulation. Blood samples were drawn around this dose and PK analysis was conducted using standard noncompartmental methods. Micafungin at 3 mg/kg dose was well tolerated in all patients. Measurable plasma concentrations were present in all cases at 48 hours. Half-life and clearance observed were comparable to previous pediatric PK data, with clearance being higher than adults as expected. Volume of distribution was higher in our patients compared to published pediatric data, likely because of a larger proportion of very young children in our study cohort. After correction for protein binding, concentrations at the end of the dosing interval during maintenance treatment remain above the minimum inhibitory concentration (MIC) of highly susceptible fungal pathogens. These data suggest that alternate day micafungin dosing, as described here, may provide an attractive alternative for antifungal prophylaxis in HSCT patients and merits further evaluation

Population Pharmacokinetic Modeling of Total and Free Ceftriaxone in Critically Ill Children and Young Adults and Monte Carlo Simulations Support Twice Daily Dosing for Target Attainment

Critical illness, including sepsis, causes significant pathophysiologic changes that alter the pharmacokinetics (PK) of antibiotics. Ceftriaxone is one of the most prescribed antibiotics in patients admitted to the pediatric intensive care unit (PICU). We sought to develop population PK models of both total ceftriaxone and free ceftriaxone in children admitted to a single-center PICU using a scavenged opportunistic sampling approach. We tested if the presence of sepsis and phase of illness (before or after 48 h of antibiotic treatment) altered ceftriaxone PK parameters. We performed Monte Carlo simulations to evaluate whether dosing regimens commonly used in PICUs in the United States (50 mg/kg of body weight every 12 h versus 24 h) resulted in adequate antimicrobial coverage. We found that a two-compartment model best described both total and free ceftriaxone concentrations. For free concentrations, the population clearance value is 6.54 L/h/70 kg, central volume is 25.4 L/70 kg, and peripheral volume is 19.6 L/70 kg. For both models, we found that allometric weight scaling, postmenstrual age, creatinine clearance, and daily highest temperature had significant effects on clearance. The presence of sepsis or phase of illness did not have a significant effect on clearance or volume of distribution. Monte Carlo simulations demonstrated that to achieve free concentrations above 1 mu g/ml for 100% of the dosing intervals, a dosing regimen of 50 mg/kg every 12 h is recommended for most patients. A continuous infusion could be considered if the target is to maintain free concentrations four times above the MICs (4 mu g/ml)

Medication administration errors for older people in long-term residential care

Background Older people in long-term residential care are at increased risk of medication errors. The purpose of this study was to evaluate a computerised barcode medication management system designed to improve drug administrations in residential and nursing homes, including comparison of error rates and staff awareness in both settings. Methods All medication administrations were recorded prospectively for 345 older residents in thirteen care homes during a 3-month period using the computerised system. Staff were surveyed to identify their awareness of administration errors prior to system introduction. Overall, 188,249 attempts to administer medication were analysed to determine the prevalence of potential medication administration errors (MAEs). Error classifications included attempts to administer medication at the wrong time, to the wrong person or discontinued medication. Analysis compared data at residential and nursing home level and care and nursing staff groups. Results Typically each resident was exposed to 206 medication administration episodes every month and received nine different drugs. Administration episodes were more numerous (p < 0.01) in nursing homes (226.7 per resident) than in residential homes (198.7). Prior to technology introduction, only 12% of staff administering drugs reported they were aware of administration errors being averted in their care home. Following technology introduction, 2,289 potential MAEs were recorded over three months. The most common MAE was attempting to give medication at the wrong time. On average each resident was exposed to 6.6 potential errors. In total, 90% of residents were exposed to at least one MAE with over half (52%) exposed to serious errors such as attempts to give medication to the wrong resident. MAEs rates were significantly lower (p < 0.01) in residential homes than nursing homes. The level of non-compliance with system alerts was low in both settings (0.075% of administrations) demonstrating virtually complete error avoidance. Conclusion Potentially inappropriate administration of medication is a serious problem in long-term residential care. A computerised barcode system can accurately and automatically detect inappropriate attempts to administer drugs to residents. This tool can reliably be used by care staff as well as nurses to improve quality of care and patient safety

Drug-related problems in home-dwelling older adults: a systematic review

Purpose:The complex combination of medicinesassociated with age-related physiological alterationsleads older adults to experience drug-relatedproblems (DRPs). The goal of this study was toreview the frequency and type of DRPs and DRP riskfactors in home-dwelling older adults.Methods:A MEDLINE PubMed and EMBASEscientific databases search was performed. Articlespublished from January 2000 through December2018 reporting DRPs in home-dwelling older adultswere included.Findings:From 668 articles screened, 13 met theinclusion criteria and were included in this study.Overall, the studies included 8935 home-dwellingpatients. The mean number of DRPs per patientobserved was 4.16 (1.37e10). The main causes ofDRPs were“drug selection”(51.41%),“dose selection”(11.62%), and“patient related”(10.70%) problems.The drug classes more frequently associated withDRPs were“cardiovascular system,”“alimentary tractand metabolism,”and“nervous system,”and theyrepresented 32.1%, 29.4%, and 16.5% of all drugselection problems, respectively. Respiratory systemmedicines accounted for 6.65% of all DRPs, of which“patient related”problems accounted for 97.28%.Implications:Despite the heterogeneity ofmethodology of the included studies and theheterogeneity of tools used to identify DRPs, thisanalysis clearly shows the high prevalence of DRPs inhome-dwelling older adults and highlights the needfor interventions to improve medicine use in thispopulation. This work also provides usefulinformation for the development of strategies toimprove medication use in home-dwelling olderadults.publishe