Parametric and Nonparametric Population Pharmacokinetic Models to Assess Probability of Target Attainment of Imipenem Concentrations in Critically Ill Patients.

Population pharmacokinetic modeling and simulation (M&S) are used to improve antibiotic dosing. Little is known about the differences in parametric and nonparametric M&S. Our objectives were to compare (1) the external validation of parametric and nonparametric models of imipenem in critically ill patients and (2) the probability of target attainment (PTA) calculations using simulations of both models. The M&S software used was NONMEM 7.2 (parametric) and Pmetrics 1.5.2 (nonparametric). The external predictive performance of both models was adequate for eGFRs ≥ 78 mL/min but insufficient for lower eGFRs, indicating that the models (developed using a population with eGFR ≥ 60 mL/min) could not be extrapolated to lower eGFRs. Simulations were performed for three dosing regimens and three eGFRs (90, 120, 150 mL/min). Fifty percent of the PTA results were similar for both models, while for the other 50% the nonparametric model resulted in lower MICs. This was explained by a higher estimated between-subject variability of the nonparametric model. Simulations indicated that 1000 mg q6h is suitable to reach MICs of 2 mg/L for eGFRs of 90-120 mL/min. For MICs of 4 mg/L and for higher eGFRs, dosing recommendations are missing due to largely different PTA values per model. The consequences of the different modeling approaches in clinical practice should be further investigated.

Exploratory drilling: how to set up, carry out, and evaluate a seroprevalence study.

Seroprevalence studies represent a very important tool to find out what fraction of population has already met with the new type of coronavirus (e.g. SARS-CoV-2). Without these data, it is almost impossible for the state authorities to manage the epidemic and adopt rational measures. This article brings the results of a medium-sized seroprevalence study which was carried out in the spring of 2020 in South Bohemia. In the Strakonice and Písek regions, the ELISA method was used to test the prevalence of IgA and IgG antibodies in 2011 subjects, volunteers from general public and selected professions working in areas with a higher exposure to the infection. The study showed that already in May 2020, 2.9% of inhabitants of the Strakonice region and 1.9% of inhabitants of the Písek region had antibodies against the coronavirus. These numbers imply that for each PCR positive person, there were at least fifty others who had probably already undergone the infection. The article points out three types of problems that might occur in such a study. First, the study must be planned correctly, and possible outcomes must be pre-assessed. Second, an appropriate test must be selected with known parameters. This enables us to correctly estimate the share of false positive and false negative results. Third, the data must be evaluated in a reasonable way and correct inference must be performed. We offer a set of recommendations how to manage these issues and how to solve problems that inevitably arise in such a large-scale testing.

Gut microbiota metabolizes nabumetone in vitro: Consequences for its bioavailability in vivo in the rodents with altered gut microbiome.

1. The underlying microbial metabolic activity toward xenobiotics is among the least explored factors contributing to the inter-individual variability in drug response. 2. Here, we analyzed the effect of microbiota on a non-steroidal anti-inflammatory drug nabumetone. 3. First, we cultivated the drug with the selected gut commensal and probiotic bacteria under both aerobic and anaerobic conditions and analyzed its metabolites by high-performance liquid chromatography (HPLC) with UV detection. To analyze the effect of microbiota on nabumetone pharmacokinetics in vivo, we administered a single oral dose of nabumetone to rodents with intentionally altered gut microbiome - either rats treated for three days with the antibiotic imipenem or to germ-free mice. Plasma levels of its main active metabolite 6 methoxy-2-naphthylacetic acid (6-MNA) were analyzed at pre-specified time intervals using HPLC with UV/fluorescence detection. 4. We found that nabumetone is metabolized by bacteria to its non-active metabolites and that this effect is stronger under anaerobic conditions. Although in vivo, none of the pharmacokinetic parameters of 6-MNA was significantly altered, there was a clear trend towards an increase of the AUC, Cmax and t1/2 in rats with reduced microbiota and germ-free mice.

A patient called Medical Research.

We report the case of a patient called Medical Research who presents with multiple life threatening symptoms, including a plethora of false positive results. This paper describes the course of the disease, discusses possible etiologies and offers options for future management to ensure the survival of the patient and that of our civilization.

Is continuous infusion of imipenem always the best choice?

Monte Carlo simulations allow prediction and comparison of concentration-time profiles arising from different dosing regimens in a defined population, provided a population pharmacokinetic model has been established. The aims of this study were to evaluate the population pharmacokinetics of imipenem in critically ill patients with hospital-acquired pneumonia (HAP) and to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) using EUCAST data. A two-compartment model based on a data set of 19 subjects was employed. Various dosage regimens at 0.5-h and 3-h infusion rates and as continuous infusion were evaluated against the pharmacodynamic targets of 20%fT>MIC, 40%fT>MIC and 100%fT>MIC. For the target of 40%fT>MIC, all 0.5-h infusion regimens achieved optimal exposures (CFR ≥ 90%) against Escherichia coli and Staphylococcus aureus, with nearly optimal exposure against Klebsiella pneumoniae (CFR ≥ 89.4%). The 3-h infusions and continuous infusion exceeded 97% CFR against all pathogens with the exception of Pseudomonas aeruginosa and Acinetobacter spp., where the maximum CFRs were 85.5% and 88.4%, respectively. For the 100%fT>MIC target, only continuous infusion was associated with nearly optimal exposures. Higher PTAs for the targets of 40%fT>MIC and 100%fT>MIC were achieved with 3-h infusions and continuous infusion in comparison with 0.5-h infusions; however, continuous infusion carries a risk of not reaching the MIC of less susceptible pathogens in a higher proportion of patients. In critically ill patients with HAP with risk factors for Gram-negative non-fermenting bacteria, maximum doses administered as extended infusions may be necessary.

Effect of Lactobacillus casei on the Pharmacokinetics of Amiodarone in Male Wistar Rats.

BACKGROUND AND OBJECTIVES: The probiotic bacterium Escherichia coli strain Nissle 1917 has previously been shown to alter the pharmacokinetics of amiodarone. The aim of this study was to determine whether the probiotic bacterium Lactobacillus casei produces similar alterations in amiodarone disposition. METHODS: A suspension of live probiotic bacteria L. casei strain DN-114 001 (1.5 × 109 CFU/dose; probiotic pre-treated group) or a saline solution (control group) was administered directly into the stomach of male Wistar rats (N = 30 in each group) by oral gavage daily for 7 consecutive days. On the eighth day, all rats (N = 60) were given a single oral dose of an amiodarone hydrochloride suspension (model drug; 50 mg/kg). The concentrations of amiodarone and of its main metabolite N-desethylamiodarone were determined in rat plasma by high-performance liquid chromatography. RESULTS: Comparison of the pharmacokinetics of amiodarone in the control group and probiotic pre-treated group revealed that the peak plasma concentration of amiodarone was delayed by >2 h in the probiotic pre-treated group. The plasma level of N-desethylamiodarone was unchanged in the probiotic pre-medicated group and its pharmacokinetic parameters were not altered. CONCLUSIONS: The slower absorption of amiodarone in the probiotic pre-treated rats compared to the control ones and the unchanged pharmacokinetics of its main metabolite suggest that the probiotic strain of L. casei DN-114 001 has probably no clinical consequences as the difference was not statistically significant.

A road toward better education in personalized medicine at universities and beyond.

Personalized medicine is likely to become a future direction of medicine. There is increased knowledge about gene functions in human health and disease and a rapid advance of biotechnologies. Personal genetic testing is available outside the medical room, as direct-to-consumer testing. There is concern about genetic literacy of general public and healthcare professionals which are to handle genetic results and their clinical interpretation. Education and training in personalized medicine and genetic/genomics/pharmacogenomics issues at different levels (high school, university, continuing medical education) is needed. Examples of innovated educational tools and curricula over the world are presented. The educational initiatives in the field of personalized medicine in the Czech Republic are followed from the very beginning.

Pharmacokinetics of imipenem in critically ill patients during empirical treatment of nosocomial pneumonia: a comparison of 0.5-h and 3-h infusions.

In critically ill patients, pathophysiological changes alter the pharmacokinetics of antibiotics. Imipenem exhibits primarily time-dependent killing. Its administration by prolonged infusion may increase the time for which its plasma concentration exceeds the minimum inhibitory concentrations (MICs) of suspected pathogens. The objectives of this study were to compare the pharmacokinetic parameters of imipenem administered by standard short infusion (1g imipenem/1g cilastatin over 30min three times daily) and by extended infusion with a reduced total dose (0.5g imipenem/0.5g cilastatin over 3h four times daily) and to compare the target pharmacokinetic/pharmacodynamic indices, namely percentage of the dosing interval for which the free plasma concentration of imipenem exceeds the MIC and 4× MIC (%fT>MIC and %fT>4×MIC) of 0.5, 1, 2 and 4mg/L, for these two regimens in critically ill adult patients with nosocomial pneumonia on Day 2 of empirical antibiotic therapy. The study included 22 patients. Whilst no significant differences were found between both groups for %fT>MIC, %fT>4×MIC was 87.4±12.19%, 68.6±15.08%, 47.31±6.64% and 27.81±9.52% of the 8-h interval in the short infusion group for MICs of 0.5, 1, 2 and 4mg/L, respectively, and 85.15±17.57%, 53.14±27.27%, 13.55±24.47% and 0±0% of the 6-h interval for the extended infusion group. In conclusion, administration of 0.5g of imipenem by a 3-h infusion every 6h does not provide sufficient drug concentrations to treat infections caused by pathogens with a MIC of ≥2mg/L.

Fenofibrate-induced decrease of expression of CYP2C11 and CYP2C6 in rat.

This short communication is aimed to investigate whether the widely used hypolipidemic drug fenofibrate affects CYP2C11 and CYP2C6 in rats, both counterparts of human CYP2C9, known to metabolise many drugs including S-warfarin and largely used non-steroidal antiinflammatory drugs such as ibuprofen, diclofenac and others. The effects of fenofibrate on the expression of rat liver CYP2C11 and CYP2C6 were studied in both healthy Wistar rats and hereditary hypertriglyceridemic rats. Both strains of rats were fed on diet containing fenofibrate (0.1% w/w) for 20 days. Fenofibrate highly significantly suppressed the expression of mRNA of CYP2C11 and less that of CYP2C6 in liver microsomes of both rat strains; this effect was associated with a corresponding decrease in protein levels. The results indicate that the combination of fenofibrate with drugs metabolised by CYP2C9 in humans should be taken with caution as it may lead, for example, to the potentiation of warfarin effects. This type of drug interaction has been observed previously and the results presented here could contribute to the explanation of their mechanism.

Early diagnosis of DIC development into the overt phase.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a syndrome characterized by over-activation of intravascular coagulation, accompanied by consumption of coagulation factors. It is a pathologic systemic inflammatory response accompanied by release of coagulatory substances into the circulation. AIM: The aim of this paper is to emphasize the importance of early the early diagnosis of DIC and to present a case report of a successful early diagnosis and treatment. METHOD: A case report giving a detailed account of clinical and laboratory presentation of a case of DIC in a patient with sepsis. Relevant laboratory results and other tests are presented, treatment is described in detail. CONCLUSIONS: DIC remains an important and potentially life-threatening complication of severe disease and states. Early diagnosis is vital for the success of treatment, and in severely ill patients, the possibility of DIC should always be kept in mind in order to detect early signs and initiate treatment as soon as possible.

Utilization of fluoroquinolones and Escherichia coli resistance in urinary tract infection: inpatients and outpatients.

OBJECTIVES: The aim of this study was to evaluate the dependence of Escherichia coli resistance to fluoroquinolones on their use in the outpatients and inpatients in the Olomouc region of the Czech Republic. METHODS: Data on inpatient antibiotic use were obtained from the database of the Department of Pharmacology and expressed as defined daily dose per 100 bed-days (DBD). Data on outpatient prescriptions were obtained from the database of General Health Insurance Company and expressed in defined daily doses per 1000 clients per day (DID). Escherichia coli strains were isolated from samples of urine of both community and hospitalized patients suffering from acute bacterial urinary tract infection, examined using aerobic cultivation, and determined by standard biochemical procedures. RESULTS: The utilization of fluoroquinolones in inpatients has significantly (p < 0.01) increased from 2.52 DBD in 1997 to 4.29 DBD in 2002. In outpatients, fluoroquinolone utilization has also increased significantly from 0.14 to 0.95 DID (p < 0.01). In the same period, 9192 E. coli strains were isolated from inpatients and outpatients suffering by urinary tract infections and tested for the susceptibility to fluoroquinolones. Resistance increased significantly (p < 0.01) both in the hospital (from 2 to 9%) and in the community (from 1 to 10%). The development of E. coli resistance to fluoroquinolones correlates significantly with their utilization both in the hospital (r = 0.944, p = 0.005) and in the community (r = 0.859, p = 0.029). CONCLUSIONS: Results of this study shows the impact of fluoroquinolone utilization on E. coli resistance and support the need of controlled use of these effective antibiotics.

Pharmacotherapeutical approaches to decreasing hematocrit and increasing claudication distance in diabetic patients with peripheral vascular disease.

The paper deals with pharmacotherapeutical approaches to decreasing hematocrit in order to improve macro and microcirculation in arteries of lower limbs of type 2 diabetes patients. The study included 37 patients with diabetic angiopathy, all of whom had inoperable changes to arteries. In order to decrease hematocrit and cause haemodilution, we used 10 % solution of hydroxyethyl starch. Indications for inclusion in the study were carried out in close cooperation with a vascular surgeon. We applied hydroxyethyl starch according to a predetermined scheme. Using normovolemic and hypervolemic haemodilution, we decreased hematocrit to 0.41-0.42. Patients underwent a treadmill examination at the beginning of the study and then repeatedly during the course of study, when we measured the claudication distance to quantify, the effects of decreased hematocrit. The results show that the effect is most pronounced after 6 weeks, when hematocrit fell from a baseline of 0.435 to 0.421 (p < 0.01) and claudication distance increased to 51% (also significant). On average the claudication distance rose from 55.7 m to 84.6 m (p < 0.01). In the following weeks (after the sixth week of the study), the studied parameters changed only insignificantly (p > 0.05).