Avoiding concomitant prescription of drugs with a potential for interaction: mission impossible?

OBJECTIVE: The increased prevalence of multi-drug therapy increases the risk of drug interactions. We conducted a study with the aim of evaluating the prevalence of prescribing potentially interacting drug combinations, their severity, mechanism, and in particular, their clinical relevance, in medical inpatients at two Croatian university hospitals. METHODS: A cross-sectional study was conducted that included all medical inpatients receiving >= 2 drugs. Data were analyzed for 200 predefined drug-drug combinations compiled from the Micromedex data-base and literature. Two rating scales were used, one indicating the severity of a potential drug-drug interaction (pDDI) (minor, moderate, major), and the other assessing its clinical relevance (1: contraindicated; 2: avoidable; 3: consider risk-benefit ratio; 4: hardly avoidable). RESULTS: The prescribing patterns were similar between evaluated hospitals. The prevalence of pDDIs was 46%. The mean number of drugs prescribed per patient was 6.2 (± 95% CI 5.9 - 6.5). Out of 200 predefined pDDIs, 96 were found in our study population with mean 2.8 pDDIs per patient (± 95% CI 2.4 - 3.1). Out of 478 single identified pDDIs, most were of moderate and major severity (56% and 33%, respectively). However, only 9% out of them were considered completely avoidable, 57% were considered hardly avoidable, and for 35% the consideration of risk-benefit ratio was recommended. Most pDDIs were classified as pharmacodynamic by mechanism of interaction (45%). Age and number of prescribed drugs were significant risk factors for prescription of potentially interacting drug combinations (OR 1.01 (± 95% CI 1.001 - 1.03) and OR 1.46 (± 95% CI 1.33 - 1.59), respectively). CONCLUSIONS: Despite the high prevalence of pDDIs, only 1 in 10 was considered avoidable.

Toxic epidermal necrolysis associated with carvedilol treatment.

OBJECTIVE: To report a case of fatal toxic epidermal necrolysis associated with carvedilol treatment. CASE SUMMARY: Two days after the initiation of carvedilol treatment, a 70-year old woman presented with skin eruptions in the form of maculous rash with blisters that rapidly progressed to epidermal necrolysis. Although the suspected drug was withdrawn, the reaction was extremely rapid in its development with fatal outcome. DISCUSSION: Carvedilol is not a drug commonly associated with TEN. To our knowledge there are no cases of carvedilol related TEN reported in the literature. CONCLUSION: Because of the close temporal relationship between the initiation of carvedilol treatment and the appearance of skin eruptions, and because carvedilol was the only new medication the patient had taken, the etiology of TEN was most likely a reaction to this drug. Physicians should be aware of this extremely rare but serious ADR.

Leukocytoclastic vasculitis associated with insulin aspart in a patient with type 2 diabetes.

OBJECTIVE: To report a case of leukocytoclastic vasculitis associated with insulin aspart therapy. CASE SUMMARY: A 56-year-old man was admitted to the Department of Endocrinology because of a poorly controlled Type 2 diabetes. In an attempt to reach a tight blood glucose control, an intensive diabetes management consisting of one evening dose of intermediate-acting NPH insulin and three preprandial doses of short-acting insulin aspart was introduced. Two weeks following insulin aspart introduction the patient developed palpable purpura on distal parts of the upper and lower limbs. Four days after the onset of purpura, a skin biopsy was preformed. Histological examination showed vasculitis with perivascular infiltrates of lymphocytes and erythrocyte extravasation. Direct immunofluorescence was negative. On the day the purpuric eruptions appeared, insulin aspart was substituted with regular human insulin. All skin lesions disappeared spontaneously within 8 days. Insulin aspart was not re-administered. DISCUSSION: Other possible causes of vasculitis in this case were excluded by diagnostic tests. The temporal relationship between the insulin aspart administration and the occurrence of purpura, with no further episodes of skin eruptions after discontinuation of the drug, support the hypothesis of an insulin aspart caused vasculitis. Based on the Naranjo's algorithm, the adverse drug reaction could be considered possible. CONCLUSION: Clinicians should be aware of the possibility of leukocytoclastic vasculitis occurring during insulin aspart treatment.

Views and experiences with regard to antibiotic use of hospitalized patients in five European countries: a qualitative descriptive study.

OBJECTIVES: To explore inpatients experiences and views with regard to antibiotics in five European hospitals. METHODS: Qualitative study where a patient-centred framework was used to explore inpatients' experiences concerning antibiotic treatment. A purposeful sample of inpatients treated with antibiotics in five hospitals participated in interviews (all centres) and focus groups (Switzerland only). RESULTS: A total of 31 interviews (five in Belgium, ten in Croatia, nine in France, five in the Netherlands and two in Switzerland) and three focus groups (in Switzerland, 11 participants) were performed. The median age of participants was 61 years (range 33-86 years). The following main themes emerged: (a) patients trust doctors to take the best decisions for them even though communication concerning different antibiotic-related aspects is often insufficient, (b) patients feel that doctors do not prioritize communication due to time constraints and do not seem to adapt information based on patients' preferences, (c) patients differ in their wish to be informed but overall want to be informed on the main aspects in an understandable way, (d) patients often find reassurance in sharing information about their antibiotic treatment with close family, (e) professionals should explore patients' preferences to be involved or not in shared decision making for antibiotic treatment. CONCLUSION: Inpatients often doubt their ability to understand medical information and trust their physicians to take the best decisions for them. Tailored strategies that inform hospitalized patients, acknowledging their concerns and preferences, may be useful to promote patient involvement and to improve communication regarding antibiotic use.

Patient-related determinants of antibiotic use: a systematic review.

OBJECTIVES: We aimed to assess patient-related determinants potentially influencing antibiotic use. METHODS: Studies published in MEDLINE until 30 September 2015 were searched. We included: qualitative studies describing patients' self-reported determinants of antibiotic use; and quantitative studies on either self-reported or objectively assessed determinants associated with antibiotic use. Whenever possible, reported determinants were categorized as 'barriers' or 'facilitators' of responsible antibiotic use. RESULTS: A total of 87 studies from 33 countries were included. Seventy-five (86.2%) were quantitative and described self-reported (45/75, 60.0%), objectively assessed (20/75, 26.7%) or self-reported and objectively assessed (10/75, 13.3%) patient-related determinants. Twelve (12/87, 13.8%) were qualitative studies or had a qualitative and quantitative component. Eighty-six of the studies (98.8%) concerned the outpatient setting. We identified seven broad categories of determinants having an impact on different aspects of antibiotic use (in descending order of frequency): demographic and socio-economic characteristics, patient-doctor interactions (e.g. counselling), treatment characteristics (e.g. administration frequency), attitudes (e.g. expecting antibiotics), access to treatment (e.g. patients' direct costs), characteristics of the condition for which the antibiotic was prescribed (e.g. duration of symptoms), knowledge (e.g. regarding indications for treatment). Most determinants were classified as 'barriers' to responsible antibiotic use. CONCLUSION: A large variety of patient-related determinants impact antibiotic use. The most easily 'modifiable' determinants concern patient-doctor interactions, treatment characteristics and knowledge. Data from the inpatient setting and low- and middle-income countries were underrepresented. Further studies should develop and test interventions that take these determinants into account with the ultimate aim of improving responsible use of antibiotics.

Benchmarking antimicrobial drug use at university hospitals in five European countries.

A point-prevalence survey of five European university hospitals was performed to benchmark antimicrobial drug use in order to identify potential problem areas in prescribing practice and to aid in establishing appropriate and attainable goals. All inpatients at the university hospitals of Rijeka (Croatia), Tartu (Estonia), Riga (Latvia), Vilnius (Lithuania) and Karolinska-Huddinge (Sweden) were surveyed for antimicrobial drug use during a single day. The frequency of antimicrobial drug use was 24% in Rijeka, 30% in Tartu, 26% in Riga, 14% in Vilnius and 32% in Huddinge. Surgical patients were treated with antimicrobial agents more often than medical patients in Riga (53% vs. 31%), Tartu (39% vs. 26%) and Vilnius (54% vs. 25%). Two-thirds of patients in Rijeka, Tartu, Riga and Vilnius, and fewer than half of the patients in Huddinge, received antimicrobial agents intravenously. Broad-spectrum antimicrobial agents were used most commonly in Rijeka. The prevalence of nosocomial infections treated with antibiotics was 9% at Huddinge, and 3-5% at the other centres. Benchmarking antimicrobial drug use at five university hospitals identified differences and problem areas. The high rates of intravenous administration, poor compliance with guidelines, and prolonged surgical prophylaxis were general problems that deserved specific attention at all centres. A change in prescription practices may reduce unnecessary drug use and decrease antimicrobial resistance.

Antimicrobial use at a university hospital: appropriate or misused? A qualitative study.

OBJECTIVE: To evaluate the quality of antimicrobial drug use in a university hospital medical department (Department of Medicine, University Hospital Rijeka, Croatia) with 279 hospital-beds in wards containing patients from endocrinology, gastroenterology, hematology, clinical immunology, cardiology and coronary care unit, nephrology and pulmonology sections of the hospital. METHODS: The appropriateness of antimicrobial treatment for all in-patients in the Department of Medicine was assessed in a prospective, longitudinal survey carried out during a 21-week period using Kunin's criteria where Categories I and II indicate "appropriate therapy", Categories III and IV indicate major deficiency in the choice or use of antimicrobials. Category V indicates unjustified antimicrobial administration. RESULTS: During the study period, a total of 438 patients were treated with antimicrobials in the Department of Medicine. Of these, 159 (36%) received antimicrobials appropriately (Category I and II), 180 (41%) needed antimicrobials (Category III and IV) but they should have been prescribed differently. The main reason for inappropriate antimicrobial treatment was the wrong choice of antimicrobials (broad-spectrum where a narrow spectrum antibiotic would have been sufficient). In the case of 99 patients (23%) an indication for antimicrobial therapy did not exist (Category V). CONCLUSION: The main reason for suboptimal use of antimicrobials was the over-prescribing of broad-spectrum antimicrobials. This situation should be corrected e.g. by changes in the post-graduate medical teaching program.

European survey on principles of prudent antibiotic prescribing teaching in undergraduate students.

We surveyed European medical schools regarding teaching of prudent antibiotic prescribing in the undergraduate curriculum. We performed a cross-sectional survey in 13 European countries (Belgium, Croatia, Denmark, France, Germany, Italy, Netherlands, Norway, Serbia, Slovenia, Spain, Switzerland, United Kingdom) in 2013. Proportional sampling was used, resulting in the selection of two to four medical schools per country. A standardized questionnaire based on literature review and validated by a panel of experts was sent to lecturers in infectious diseases, medical microbiology and clinical pharmacology. In-depth interviews were conducted with four lecturers. Thirty-five of 37 medical schools were included in the study. Prudent antibiotic use principles were taught in all but one medical school, but only four of 13 countries had a national programme. Interactive teaching formats were used less frequently than passive formats. The teaching was mandatory for 53% of the courses and started before clinical training in 71%. We observed wide variations in exposure of students to important principles of prudent antibiotic use among countries and within the same country. Some major principles were poorly covered (e.g. reassessment and duration of antibiotic therapy, communication skills). Whereas 77% of the respondents fully agreed that the teaching of these principles should be prioritized, lack of time, mainly due to rigid curriculum policies, was the main reported barrier to implementation. Given the study design, these are probably optimistic results. Teaching of prudent antibiotic prescribing principles should be improved. National and European programmes for development of specific learning outcomes or competencies are urgently needed.

Factors influencing antimicrobial utilization at a university hospital during a period of 11 years.

OBJECTIVE: A number of factors may influence antibiotic prescribing. The objective of this study was to identify trends in antimicrobial prescribing during a period of 1 years at the University Hospital Center Rijeka (UHC), Croatia, and to identify possible factors that might have influenced changes in prescribing patterns. This may help in establishing criteria for future intervention. METHODS: Antimicrobial utilization was evaluated retrospectively for the 11-year period from 1990-2000. It was measured in defined daily doses (DDDs) per 100 bed days using the ATC Index with DDDs 2000. RESULTS: During the investigation period, marked differences were noted in total and individual antimicrobial consumption. In the first 4 years of this study, the utilization of all groups of antimicrobials decreased, while in its second part (i.e. from 1995-1997) an increase in utilization of all antimicrobial groups occurred. Changes in utilization of groups of antimicrobials did not coincide completely with the changes in total antimicrobial utilization. The most prominent changes were a decrease in penicillin and cephalosporin utilization, and an increase of macrolides and aminoglycosides utilization from 1997-2000. Ampicillin and cefalexin were mostly prescribed as single antibiotics during a 5-year period (1990-1995) with the exception of 1 year (1994) when a marked decline in antimicrobial utilization was noted. In the following years, amoxicillin and amoxicillin with enzyme inhibitor became the most-used antimicrobials. CONCLUSION: Various factors influenced antimicrobial utilization during the investigation period. There were factors that directly influenced prescribing, e.g. the physicians' prescribing habit, guidelines, policy and formulary. Other factors directly influenced utilization, e.g. availability of a drug through purchasing, dispensing, procurement, pricing etc.

Analysis of antiepileptic drugs use at a university hospital in Croatia.

To analyse the consumption rate of new generation antiepileptic drugs (AEDs) compared with traditional AEDs at a university hospital in Croatia. Antiepileptic drugs use was analysed retrospectively for two consecutive years, 2001 and 2002 at Departments of Neurology, Paediatrics, Psychiatry and Neurosurgery at the University Hospital Centre (UHC) Rijeka. The results obtained are expressed as number of defined daily doses (DDDs) per 100 bed days, as proposed by the WHO. The use of new generation AEDs was represented by 2% in 2001 and 5% in 2002. Majority of AEDs administered was taken by the barbiturates in both years. A wide spectrum of AEDs has been used at the Department of Paediatrics. At the Department of Neurology and Psychiatry use of barbiturates and carbamazepine predominated. The use of new AEDs at UHC has increased during the investigation period but it is still rather low compared with traditional AEDs. The similarity of our results with the result of the leading Croatian university hospitals might represent general routine AED prescription in country. Nationally based guidelines may bring more appropriate and rational approach for usage of modern AED. This task should be supported and promoted by international and national neurology associations.

Antimicrobial drug use in hospitalised paediatric patients: a cross-national comparison between Germany and Croatia.

PURPOSE: To compare the utilisation of systemic antimicrobials at the paediatric units of the university hospitals in Marburg (Germany) and Rijeka (Croatia). METHODS: A prospective, observational analysis of hospital records from 300 incident users of antimicrobials in each study centre that were younger than 19 years. Antimicrobial utilisation was analysed in six gender-specific age groups with respect to drug choice, duration of treatment and hospital stay, indication and route of administration. The extent of antimicrobial drug use was assessed by the number of treatment courses. RESULTS: In each hospital, more than 1/3 of the patients were younger than 1 year. The duration of hospital stay was about two-fold longer in Rijeka (18.5 +/- 5.8 days) than in Marburg (8.6 +/- 3.8 days). Pneumonia and other respiratory tract infections were the most common indications in Marburg (38.6%) and Rijeka (58.7%). The cumulative percentage of patients treated with an equal number of different antimicrobials was lower in Rijeka than in Marburg. The most commonly used antimicrobials were ampicillin (40.3%) and cefuroxim (35.9%) in Marburg, but ceftriaxone (43.3%) and cefotaxim (14.0%) in Rijeka. CONCLUSIONS: A shorter treatment duration, less variation in the prescribing pattern and a greater adherence to the use of recommended antimicrobials argue for a more rational antimicrobial drug use in Marburg than in Rijeka. However, a further identification of drug choice determinants is warranted.

Antibiotic utilization at the university hospital after introducing an antibiotic policy.

OBJECTIVE: Antibiotic formulary restrictions are among the most popular methods to control antibiotic utilization in hospitals. The aim of the present survey was to investigate the influence of "reserve antibiotic" on antimicrobial utilization at the University Hospital Center (UHC) Rijeka. METHODS: At the UHC Rijeka, reserve antibiotic was implemented in July 1997. The antimicrobial drug consumption was monitored 6 months prior to and 6 months after the introduction of the method. Antimicrobial consumption was measured in defined daily doses (DDDs) among the major clinics. RESULTS: Reserve antibiotic has led to a decrease in total antibiotic consumption at the UHC Rijeka (45.9 DDDs/100 bed days vs 32.9 DDDs/100 bed days). Antibiotic utilization decreased in the second semester at most clinics: at the Clinic for Infectious Diseases 41%, at the Anesthesiology and Intensive Care Unit 30%, at the Clinic for Internal Medicine 18% and at the Surgical Clinic 12%. At the Clinic for Gynecology and Obstetrics, the antibiotic utilization remained the same, while at the Pediatric Clinic an increase of 28% in antibiotic utilization was noted. CONCLUSION: Our study indicates that restriction of usage of some antibacterial agents is a successful method to decrease antibiotic consumption and a way to bring cost savings and helps prevent emergence of resistant microorganisms in hospitals. To improve antimicrobial prescribing, additional methods such as education are required.

Antimicrobial utilization and bacterial resistance at three different hospitals.

It has been generally recognized that the prevalence of bacterial resistance among bacteria is an unavoidable consequence of antibiotic use and is positively linked to the overall use of antibacterial drugs. The purpose of this study was to investigate the extent of antimicrobial usage and to evaluate the antimicrobial resistance at three different hospital settings in Croatia: a clinical hospital, a general hospital and a specialized clinic for infectious diseases. In this survey the antimicrobial drug consumption and antimicrobial susceptibility test results were analyzed for the first 6 months of 1997 in three different hospitals in Croatia: the University Hospital Center (UHC), Rijeka, the Clinic for Infectious Diseases 'Dr Fran Mihaljevic', Zagreb and the Dubrovnik General Hospital. The data were collected from corresponding hospital pharmacy records and microbiology laboratories. Antimicrobial drug utilization was expressed in number of defined daily doses (DDDs) per 100 bed days. High antimicrobial utilization and high resistance rates were found in all three hospitals. At the Clinic for Infectious Diseases, the most frequently used antimicrobials where those of narrow spectrum while at the UHC Rijeka and the Dubrovnik General Hospital the broad spectrum antimicrobials were mostly used. The highest antimicrobial consumption was noted at the Susak locality of the UHC, Rijeka, where the highest resistance rates of bacteria to antimicrobials were also found. Results of this observational study indicate that attempts should be made to reduce the influence of factors that may lead to emergent resistance. The most effective approach to the prevention of transmission of multidrug-resistant pathogens is preventing the initial emergence of resistance. A rational and strict antibiotic policy is thus of great importance for the optimal use of these agents.

Antibiotics utilization during the war period: influence of drug donations.

The purpose of the present study was to investigate the antibiotics utilization in the University Hospital Center of Rijeka (UHC), with capacity of 1566 beds, during the period of 4 years (1990-1994). The data concerning the antibiotics utilization were collected from a hospital pharmacy record and calculated as the defined daily dose (DDD) per 100 bed days. Total antibiotics use decreased continually from 1990 through 1994. According to our study, metronidazole became the most frequently prescribed antibiotic. Comparing the 1994 to the 1990 antibiotics utilization, we may notice an outstanding decrease in cotimoxazole, ampicillin and cefalexin utilization and an increase in amoxicillin + clavulanic acid, gentamycin and cefuroxime (there are no tetracyclines among the 10 most frequently prescribed antibiotics). The changes noticed in the use of antibiotics are partly caused by changes in therapeutic principles, but we consider drug donations as the most important factor. Drug donations have retained the treatment quality of our patients in very difficult conditions in Croatia during the war period.

Education in clinical pharmacology at the Rijeka School of Medicine, Croatia.

OBJECTIVE: Irrational drug prescribing is a global problem that exists both in developed and developing countries. Education is the key to improved effectiveness and safety in drug therapy. Development of clinical pharmacology (CP) as an independent discipline at the Rijeka School of Medicine has been slow and unsatisfactory. It was taken only as a part of some postgraduate courses. In the 1995/1996 academic year clinical pharmacology was offered for the first time to sixth year medical students as a non-mandatory subject. The purpose of this study was to emphasize the importance of education in clinical pharmacology at the Rijeka School of Medicine. METHODS: This survey was an uncontrolled study based on responses to questionnaires and a test consisting of written patient problems given to sixth year medical students and to general practitioners who were following a course in clinical pharmacology. RESULTS: The results of the questionnaire showed that both undergraduate and postgraduate students consider that they are not being adequately trained to prescribe drugs rationally and that they believe that clinical pharmacology should become a mandatory subject in the undergraduate medical curriculum. The results of the written patient problem test support this. Both groups of students demonstrated greater skills in solving the diagnostic part than the therapeutic part of the test. A great improvement in the students' ability to solve the therapeutic part was observed after they had completed the CP course. CONCLUSION: The results of this survey underline the necessity of education in clinical pharmacology.