Patterns in anticoagulant utilization in the Czech Republic during 2007-2017.

Direct oral anticoagulants (DOACs) have gradually entered the Czech market as alternatives to vitamin K antagonists and parenteral anticoagulants since 2008. Considering the eventual changes, the aim was to evaluate drug use and expenditure patterns on anticoagulants in the Czech Republic. A retrospective utilization study was conducted retrieving data from the State Institute for Drug Control database, including reports on drug supplies from distributors with anatomical therapeutic chemical classification (ATC) codes B01AA, B01AB, B01AE, B01AF, and B01AX. The utilization on national level was expressed as the ratio of the number of defined daily doses per 1000 inhabitants per day (DDD/TID). Expenditures on all anticoagulants were also assessed. Data was analyzed using PASW (version 18.0). Between January 2007 and December 2017, the national anticoagulant utilization rate increased continuously from 14.15 to 27.67 DDD/TID. The use of DOACs was 0.002 DDD/TID in 2008, increased to 6.04 DDD/TID in 2017. Warfarin utilization, after a small decrease in 2008, has shown nearly stable levels in the recent years (70.9% of all anticoagulants; mean 11.55 DDD/TID over the last 5 years), while its increase was halted by the spread of DOACs utilization (p < 0.05). In 2017, over half of the expenditures (51.1%) were due to oral anticoagulants, whereof 47.6% was related to DOACs. The results reflected a growing utilization and increasing costs of all anticoagulants, especially in DOACs at the expense of warfarin. Still, additional information regarding patient persistence and prescribing patterns is needed for a better understanding of oral anticoagulant utilization.

Study connective capabilities of solid residues from the waste incineration.

Currently there is increasingly closer interaction between the importance of environmental protection and efficient promoting of scientific and technological progress in the field of waste incineration. Waste is not only undesirable source of pollution, but if it is effectively used it also has great economic importance. In the Czech Republic 34.5 million tonnes of all wastes was produced in 2017, of which 5.7 million tonnes of municipal waste. 50% of the produced municipal waste was used, 38% of which was used for the material and 12% for energy utilization. 45% of municipal waste was deposited in the landfills. The method of waste incineration is among the major tools to reduce the landfill waste. The use or processing of the product which the process of incineration of municipal and hazardous waste generated can be considered as an obstacle to the favorable reception of this process. Apart from flammable components, waste also contains certain amount of dangerous particles. This is especially the sulfur chlorides, fluorine, PCBs and other heavy decomposable organic substances and heavy metals. This fact puts high demands on the gas cleaning processes followed by neutralization of other products that the incinerator leaves, in which these substances can be contained in higher concentrations than in the original waste. For this reason subsequent stabilization of these toxic substances is necessary to ensure new environmental burdens are avoided when not used properly. The major part of the waste combustion process is made up of ash and slag. One of the most common ways of dealing with these solid residues is disposing them to avoid creating new hazardous waste landfills. Other filtering waste also passes hazardous waste stabilization process before landfilling. Currently there is intensive search for new possibilities for utilization of solid residues from incineration. Nowadays there is emphasis on process control of their pretreatment for the production of draft procedure with its management. Appropriate procedures may minimize the instances of improper use.

Analysis and management of drug related problems on a nephrology ward from a pharmacist's point of view.

The main goal of the study was to determine the incidence and the character of drug related problems (DRPs) identified in chronic kidney disease patients by the clinical pharmacist at the nephrology department. As secondary objective, the aim was to identify the frequency and character of DRPs of selected high risk drugs in medication reviews. The clinical pharmacist reviewed patients' medication records and made drug therapy-related recommendations to physicians. The clinical pharmacists' interventions were categorized using an adaptation of the Pharmaceutical Care Network Europe. During the study period (January 2016 - June 2018) the clinical pharmacist performed 1192 interventions in 1870 adult patients admitted to the Nephrology Department. The most frequent DRP was untreated indication 324 (27.18%) of all interventions, and incorrect dose 248 (20.81%). Anti-infectives were identified as the drug category with the highest frequency of interventions. Almost 93% of all interventions were accepted by the attending physicians. Still within the second objectives, underdosing was observed as the most frequent problem for renally excreted drugs. It was found that an incorrect dose is a very frequent issue at the nephrology department. Surprisingly, the main problem was underdosing. In the category of renally excreted drugs, underdosing was observed in antithrombotics and antivirals. The above- mentioned results prove the need of a clinical pharmacist, preferably in sense of maximizing of the treatment effect and improving the care of patients.

Patients' intention to consume prescribed and non-prescribed medicines: A study based on the theory of planned behaviour in selected European countries.

WHAT IS KNOWN AND OBJECTIVE: Polypharmacy has a significant impact on patients' health with overall expenditure on over-the-counter (OTC) medicines representing a substantial burden in terms of cost of treatment. The aim of this study, which was conducted within the framework of a European Project funded by the European Union under the Seventh Framework Programme and was entitled OTC-SOCIOMED, was to report on possible determinants of patient behaviour regarding the consumption of medicines, and particularly OTCs, in the context of primary care. METHODS: A multicentre, cross-sectional study was designed and implemented in well-defined primary healthcare settings in Cyprus, the Czech Republic, France, Greece, Malta and Turkey. Patients completed a questionnaire constructed on the basis of the theory of planned behaviour (TPB), which was administered via face-to-face interviews. RESULTS AND DISCUSSION: The percentage of patients who had consumed prescribed medicines over a 6-month period was consistently high, ranging from 79% in the Czech Republic and 82% in Turkey to 97% in Malta and 100% in Cyprus. Reported non-prescribed medicine consumption ranged from 33% in Turkey to 92% in the Czech Republic and 97% in Cyprus. TPB behavioural antecedents explained 43% of the variability of patients' intention to consume medicines in Malta and 24% in Greece, but only 3% in Turkey. Subjective norm was a significant predictor of the intention to consume medicines in all three countries (Greece, Malta and Turkey), whereas attitude towards consumption was a significant predictor of the expectation to consume medicines, if needed. WHAT IS NEW AND CONCLUSION: This study shows that parameters such as patients' beliefs and influence from family and friends could be determining factors in explaining the high rates of medicine consumption. Factors that affect patients' behavioural intention towards medicine consumption may assist in the formulation of evidence-based policy proposals and inform initiatives and interventions aimed at increasing the appropriate use of medicines.

[Drug interactions in the elderly with diabetes mellitus]. / Lékové interakce u starsích diabetiku

The elderly with diabetes mellitus are usually treated with many types of drugs. This, together with pharmacokinetic and pharmacodynamic changes connected with aging, can lead to an occurrence of drug interactions. They are often manifested as hypoglycaemia, decompensation of diabetes or an increase of frequency of adverse effects of drugs used together. It is important to pay an attention especially to hypoglycaemia, which brings many risks in the elderly. An article is focused on probable drug interactions when combination of various antidiabetics, antidiabetics with antihypertensives or hypolipidemics is used. Despite ACE-inhibitors and beta-blockers can influence the compensation of diabetics, their use is not contraindicated in these patients, because of their huge benefit in the prevention of cardiovascular events. An article brings an overview of antidiabetics metabolised by means of the system of cytochrome P 450 and resulting drug interactions with inhibitors and inductors of these enzymes. These drug interactions are not usually important in clinical practice and it is possible to prevent them with careful monitoring of glycaemia, instruction of patients and alternatively modification of the doses of hypoglycaemic medication after a termination of the treatment of responsible inductor or inhibitor.

[Interactions between glucocorticoids and warfarin in chronic inflammatory (autoimmune) diseases]. / Interakce glukokortikoidu s warfarinem u chronických zánetlivých (autoimunitních) chorob.

Glucocorticosteroids are still very important part of the treatment of chronic inflammatory disorders. Their use is often accompanied by unpleasant adverse effects, problems associated with withdrawal during their long-term use and interactions with concomitantly administered drugs. One of the important interactions that may often occur in clinical practice is interaction with warfarin. Despite the fact that as glucocorticosteroids so warfarin are used for many years and seem to be completely known, their co-administration is still accompanied by uncertainties. The interaction may have pharmacodynamic or pharmacokinetic character and both types result in increased risk of bleeding. The pharmacodynamic interaction can be expected to increase a risk of gastrointestinal bleeding to which a gastrotoxicity of glucocorticosteroids contributes. A pharmacokinetic interaction is considered to influence a hepatic metabolism of warfarin and to increase its availability. The exact mechanism is still not fully understood. Manifestations of both types of interactions are taken up with a delay. Co-administration requires increased attention and close monitoring of international normalized ratio. At higher doses of glucocorticosteroids proton pump inhibitors are also effective in prevention of gastrotoxicity.

[Drug compliance - a pitfall of therapy of rheumatoid arthritis?]. / Léková compliance - úskalí terapie revmatoidní artritidy?

Drug compliance is one of the conditions for effective treatment of various chronic diseases, including rheumatoid arthritis as well. This disease is characterized by a variable course, remissions and relapses, and also by specific treatment. The character of this illness and used medications may represent a risk in terms of non-compliance. As in other chronic diseases, scientists engage in identifying of the compliance rate for many years and the aim of this work is to summarize the state of knowledge in the field of drug compliance in rheumatoid arthritis.

[An overview of so far published analyses comparating the effectiveness of the treatment with insulin pump and multiple daily injections in type 1 diabetes mellitus]. / Prehled dosud publikovaných analýz srovnávajících efektivitu lécby inzulinovou pumpou a rezimu nekolika injekcí inzulinu denne u diabetiku 1. typu.

The paper brings an overview of published systematic reviews and meta-analyses concerning the evaluation of the effectiveness of the treatment with insulin pump (CSII) in comparison with multiple daily injections (MDI) in type 1 diabetes mellitus. According to found works CSII leads to slightly lower levels of glycosylated hemoglobin (HbA1c) in patients with type 1 diabetes mellitus against MDI. The levels of HbA1c and the variability of glycaemia during the day on MDI before an initiation of CSII should serve for the prediction of an effect of CSII in particular patient. Type 1 diabetics on CSII have less often hypoglycaemia, higher flexibility of their daily regime and thus higher satisfaction with their treatment against MDI. The daily doses of insulin decrease. The weight of patients is the same or slightly higher after the initiation of CSII. There were not enough information for the assesment of the frequency of adverse reactions. It is necessary to educate each patient not only how to manipulate the particular insulin pump, but also about general recommendations for the treatment of diabetes and the application of insulin.

Association of FcRn expression with lung abnormalities and IVIG catabolism in patients with common variable immunodeficiency.

The neonatal Fc receptor (FcRn) acts as a key regulator of IgG homeostasis and is an important sensor of luminal infection. We analyzed the influence of FcRn expression on disease phenotype and the catabolism of therapeutically administered intravenous immunoglobulins (IVIG) in 28 patients with common variable immunodeficiency (CVID). Patients with generalized bronchiectasis and fibrosis had lower levels of FCRN mRNA compared to patients without these complications (P=0.027 and P=0.041, respectively). Moreover, FCRN mRNA levels correlated negatively with the extent of bronchiectasis and the rate of IgG decline after infusion of IVIG (P=0.027 and P=0.045, respectively). No relationship of FCRN expression with age at disease onset, age at diagnosis, diagnostic delay, IgG levels or frequency of infections before or during replacement immunoglobulin treatment, the presence of lung functional abnormalities, chronic diarrhea, granulomas, lymphadenopathy, splenomegaly or autoimmune phenomena was observed. Our results showed that FcRn might play a role in the development of lung structural abnormalities and in the catabolism of IVIG in patients with CVID.

Can intranasal corticosteroids cause migraine-like headache?

Intranasal corticosteroids (INCs) act predominantly locally and are considered to exert minimal systemic effects. On reviewing the international data collected in the World Health Organization's global pharmacovigilance programme an unexpected cluster was found of 38 case reports of migraine in suspected connection with INCs. These reports came from five countries (May 2007) and concerned six different drugs. In all reports the INC was the sole suspect drug. In nine cases re-exposure to the drug had taken place, leading to the recurrence of the event in eight of these patients. However, INCs are mainly used for rhinitis, and there is a known connection between rhinitis and migraine. Although representing only 0.6% of the total of case reports, international pharmacovigilance data suggest that the use of INCs may cause or trigger migraine or migraine-like headache. Further study is needed to determine if the reported association is true or not and, if so, what the possible mechanism is.

[Pharmaceutical care of patients with diabetes mellitus and its relationship to clinical pharmacy]. / Farmaceutická péce a pacienta s diabetes mellitus a vztah ke klinické farmacii.

INTRODUCTION: Pharmaceutical care develops both at universities in the Czech Republic and in daily practice, and is focused on drug-related issues as a pharmacist has the broadest knowledge of the drug and offers such knowledge to other persons involved in patient care. Pharmaceutical care is part of health care and although the pharmacist is considered to be a health service officer by legislation, health insurance companies--probably due to the fact the pharmacist is paid based on the margin obtained in business activities from the purchase and sale of prescribed drugs--do not see the pharmacist as such and they need to be convinced that such activity is necessary for the patient and is positive within the medical team. The aim of the article is to define what pharmaceutical care is, where it can be provided, why it is necessary within medical and nursing care, and to point out drug-related issues occurring in diabetic patients as well as the method for identifying and resolving them. METHOD: The method is the answer to the following questions: Where to class pharmaceutical care and how to define the knowledge preconditions for such activity? Where is pharmaceutical care provided and what is its objective? How and where is pharmaceutical care taught? How can pharmaceutical care be applied in diabetology? The answers to the questions raised are based on literature and the authors' own teaching experience and activities performed in the position of clinical pharmacist at the 2nd Department of Internal Medicine of the University Hospital in Hradec Králové. Another method was the analysis of the incidence of drug issues related to the prescription of antidiabetics identified by 66 pharmacists over 2 months of active recording of drug-related issues and detected in hospitalized patients of the 2nd Department of Internal Medicine, both in outpatient and inpatient care. Another method was the monitoring of physicians' opinions about the doctor-pharmacist cooperation in the form of an interactive lecture at the spring congress of physicians in Prague in 2008. RESULTS: The basic method of pharmaceutical care is the maximization of benefits (instructions, how to use the drug correctly, how to support the patient's compliance, change in lifestyle) and the minimization of risks (to look for risk signals and to help resolve them; to resolve them directly with the OTC drug). Pharmacists can do this, in particular, if they are educated in clinical pharmacy and have sufficient training in pharmaceutical care--which nowadays is not an inaccessible activity. Pharmacists have identified, within the analysis of drug-related mistakes, 38 drug issues related to antidiabetics--which represent approximately 3 percent of all detected drug-related issues. The following problems were identified in diabetic patients at the 2nd Department of Internal Medicine: high doses of hydrochlorothiazide administered to diabetic patients, the administration of beta-blockers to diabetic patients with hypoglycemic attacks, the administration of metformin to a patient with malfunctioning kidneys, the reduction of corticoids without sufficient diabetes control. Most of the interviewed physicians (approx. 200) supported active cooperation with pharmacists not only in economic but also in professional issues. CONCLUSION: A pharmacist is able, within pharmaceutical care, to identify the first signs of the disease and to recommend the patient for a medical examination. He can detect drug-related issues thus minimising risks. He can maximise the effect by supporting drug compliance, repeating instructions for use of the drug and recommending a change in lifestyle; he can also help detect and minimise the impact of various risk factors. All these activities (in the strategic alliance of doctor-patient-pharmacist) can reduce the incidence of complications, which are expensive for the payers and reduce the quality of the patient's life.

Microstructure evolution in amorphous Hf-B-Si-C-N high temperature resistant coatings after annealing to 1500 °C in air.

Recently, amorphous Hf-B-Si-C-N coatings found to demonstrate superior high-temperature oxidation resistance. The microstructure evolution of two coatings, Hf7B23Si22C6N40 and Hf6B21Si19C4N47, annealed to 1500 °C in air is investigated to understand their high oxidation resistance. The annealed coatings develop a two-layered structure comprising of the original as-deposited film followed by an oxidized layer. In both films, the oxidized layer possesses the same microstructure with HfO2 nanoparticles dispersed in an amorphous SiOx-based matrix. The bottom layer in the Hf6B21Si19C4N47 coating remains amorphous after annealing while Hf7B23Si22C6N40 recrystallized partially showing a nanocrystalline structure of HfB2 and HfN nanoparticles separated by h-Si3N4 and h-BN boundaries. The HfB2 and HfN nanostructures form a sandwich structure with a HfB2 strip being atomically coherent to HfN skins via (111)-Hf monolayers. In spite of the different bottom layer structure, the oxidized/bottom layer interface of both films was found to exhibit a similar microstructure with a fine distribution of HfO2 nanoparticles surrounded by SiO2 quartz boundaries. The high-temperature oxidation resistance of both films is attributed to the particular evolving microstructure consisting of HfO2 nanoparticles within a dense SiOx-based matrix and quartz SiO2 in front of the oxidized/bottom layer interface acting as a barrier for oxygen and thermal diffusion.

Is computer-assisted aminoglycoside dosing managed by a pharmacist a safety tool of pharmacotherapy?

This pilot prospective study verified the hypothesis that use of computer-assisted therapeutic drug monitoring of aminoglycosides by pharmacists leads to better safety therapeutic outcomes and cost avoidance than only concentration measurement and dose adjustments based on a physician's experience. Two groups of patients were enrolled according to the technique of monitoring. Patients (Group 1, n=52) underwent monitoring by a pharmacist using pharmacokinetic software. In a control group (Group 2, n=11), plasma levels were measured but not interpreted by the pharmacist, only by physicians. No statistically significant differences were found between the groups in factors influenced by therapy. However, the results are not statistically significant but a comparison of the groups showed a clear trend towards safety and cost avoidance, thus supporting therapeutic drug monitoring. Safety limits were achieved in 76 % and 63 % of cases in Groups 1 and 2, respectively. More patients achieved both concentrations (peak and trough) with falling eGFR in Group 1. In present pilot study, the pharmacist improved the care of patients on aminoglycoside therapy. A larger study is needed to demonstrate statistically significantly improved safety and cost avoidance of aminoglycoside therapy monitoring by the pharmacist using pharmacokinetic software.

Mannose-binding lectin gene polymorphic variants predispose to the development of bronchopulmonary complications but have no influence on other clinical and laboratory symptoms or signs of common variable immunodeficiency.

Mannose-binding lectin (MBL), activating protein of the lectin pathway of the complement system, is an important component of the non-specific immune response. MBL2 gene polymorphisms, both in the coding and promoter regions, lead to low or deficient serum MBL levels. Low serum MBL levels were shown to be associated with serious infectious complications, mainly in patients in whom other non-specific immune system barriers were disturbed (granulocytopenia, cystic fibrosis). We have analysed two promoter (-550 and -221) and three exon (codons 52, 54 and 57) MBL2 polymorphisms in a total of 94 patients with common variable immunodeficiency (CVID) from two immunodeficiency centres. Low-producing genotypes were associated with the presence of bronchiectasis (P = 0.009), lung fibrosis (P = 0.037) and also with respiratory insufficiency (P = 0.029). We could not demonstrate any association of MBL deficiency with age at onset of clinical symptoms, age at diagnosis, the number of pneumonias before diagnosis or serum immunoglobulin (Ig)G, IgA and IgM levels before initiation of Ig treatment. No association with emphysema development was observed, such as with lung function test abnormalities. No effect of MBL2 genotypes on the presence of diarrhoea, granuloma formation, lymphadenopathy, splenomegaly, frequency of respiratory tract infection or the number of antibiotic courses of the patients was observed. Our study suggests that low MBL-producing genotypes predispose to bronchiectasis formation, and also fibrosis and respiratory insufficiency development, but have no effect on other complications in CVID patients.

Improvements in antibiotic prescribing by community paediatricians in the Czech Republic.

Repeated surveys among primary care paediatricians were performed annually from 1998 to 2002 in the Czech Republic. The task was to assess the prescription of antibiotics in treatment of respiratory infections in children. The results were evaluated in the light of existing guidelines and conclusions were used in a number of interventions aimed at reducing the inadequate use of antibiotics and hence preventing the potential increase of the antibiotic resistant bacteria. In addition, data on overall consumption of antibiotics in outpatient care and trends in the prevalence of resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes are discussed.

The spectrum and types of adverse side effects to biological immune modulators: a proposal for new classification.

In recent years, a growing number of biological agents such as cytokines, monoclonal antibodies and fusion proteins have become available for the treatment of various autoimmune, neoplastic, cardiovascular, infectious, allergic, and other conditions. Their introduction has resulted in marked clinical improvements for many patients. Nevertheless, a variety of adverse side effects have been observed with these agents. Based on the special features of biological agents a new classification of these side effects of biological agents is proposed--related but clearly distinct from the classification of side effects observed with chemicals and drugs. This classification differentiates five distinct types, namely clinical reactions due to high cytokine levels (type alpha), hypersensitivity due to an immune reaction against the biological agents (type beta), immune or cytokine imbalance syndromes (type gamma), symptoms due to cross-reactivity (type delta), and symptoms not directly affecting the immune system (type epsilon). This classification could help to better deal with the clinical features of these side effects, to identify possible individual and general risk factors and to direct research in this novel area of medicine.

[Risk of drug interactions and their possible solutions in the population of patients with inflammatory bowel disease]. / Riziko lékových interakcí a jejich mozná resení v populaci pacientu s idiopatickým strevním zánetem.

Concurrent use of several medicinal preparations is connected with an increased risk of the occurrence of drug interactions. This study analyzes the complete pharmacotherapy of 573 patients diagnosed with inflammatory bowell disease. An analysis of the medication of the cohort of patients tested identified potential drug interactions of all degrees of gravity. All drug interactions in the study were considered to be only potential, and therefore they are not known to cause any complications for the patient. An important factor in the process of revealing drug interaction may be the pharmacist during dispensation in a pharmacy. Pharmacist's expertise of the problems of drug interactions is a component of his/her professional competence and should be continuously intensively increased in postgraduate education. This study is not limited to simply stating the occurrence of potential drug interactions. It is also focused on the management of drug interactions from the party of the physician and the pharmacist and attempts to outline the way of encountering this problem.

[Consumption of old and new antiepileptic drugs in the Czech Republic in 1999-2004]. / Sledování spotreby starsích a nových antiepileptik v Ceské republice v období 1999-2004.

Trends in antiepileptic drug (AEDs) consumption in the period from 1999 to 2004 in the Czech Republic were assessed in this study. The data from extramurally prescribed, reimbursed AEDs were obtained from the Czech Health Insurance Company Skoda Mladá Boleslav. The AEDs utilization was assessed according to ATC/DDD methodology on the fourth and fifth level of the ATC classification and expressed as the number of defined daily doses per 1000 insured per day (DDD/TID). During the study period, the AEDs consumption increased by 130%; 76% of which consisted of new AEDs. The most frequently prescribed drugs were carbamazepine and valproate. It correlates well with recent guidelines, where carbamazepine and valproate are licensed as the first line therapy in the treatment of epilepsy. The utilization of barbiturates and hydantoines is decreasing. Gabapentin, lamotrigine and topiramate were the most frequently prescribed new AEDs. The total cost of AEDs increased three times, 84.5% of this increase accounted for new AEDs. The outcomes are in agreement with current recommendations. The AEDs consumption follows trends similar to those in other countries with a fast shift to new antiepileptic drugs.

Deep vein thromboembolism in malignant diseases.

Tumourous diseases are associated with haemorrhagic as well as thrombotic complications. Trousseau described in 1865 a mutual association between tumourous diseases and venous thromboembolism. As many as 15-20% patients with venous thromboembolism have an undetected malignity, which equals a prevalence of 2-3% in the population. From this ensues the relative risk of a newly diagnosed malignity which is higher during the first year after venous thromboembolism. Migrating thrombophlebitis is a relatively specific sign in tumours, in particular in pancreatic tumours. In the pathogenesis of venous thromboembolisms in tumourous diseases, the following factors play a significant part: elevated coagulation parameters, reduced fibrinolysis, frequent immobilization, surgical operations in the case history, chemotherapy, hormonal therapy and central venous catheters. Conventional long term management of VTE involves the use of vitamin K antagonists, such as warfarin, to reduce the risk of recurrence. Recent evidence-based approach in long term management of VTE in patients with tumorous disease shows that the use of LMWH offers an effective alternative to VKAs with higher efficacy, without a significantly increased risk of bleeding, and without the need for regular laboratory monitoring.

Netilmicin in the neonate: population pharmacokinetic analysis and dosing recommendations.

Netilmicin pharmacokinetics were studied in neonates of 27 to 42 weeks' gestational age and 0.8 to 5.0 kg body weight in their first 2 weeks of life by the population pharmacokinetic approach. The data were best described by a two-compartment model. Clearance depends on body weight, gestational age, and postnatal age. Volume of distribution of the central and peripheral compartments was also related to body weight. Including these patient characteristics in the population pharmacokinetic regression model resulted in a marked reduction of the unexplained interindividual variability. This enabled us to derive dosage recommendations that result in peak and average concentrations within the desired range for 95% of the neonates with gestational age above 31 weeks, thus avoiding the need for individual drug-level monitoring in a well-defined large group of patients. Only for infants with gestational age less than 31 weeks who are less than 6 days old is individual dose adjustment based on serum concentration measurements required.