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.

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.

Lactobacillus acidophilus as a cause of liver abscess in a NOD2/CARD15-positive patient with Crohn's disease.

INTRODUCTION: The development of a fistula and/or an abscess are major complications in patients with Crohn's disease. An abscess can involve any of the major viscera, including the liver and spleen. CASE REPORT: A 27-year-old male patient with a 6-month history of NOD2/CARD15-positive Crohn's disease with stenosis of the terminal ileum, previously treated with corticosteroids, was admitted with fever, chills, diarrhea, fatigue and cachexia. Diagnostic work-up revealed sepsis, an abscess in the right hepatic lobe, multiple abdominal collections and right-sided pleural effusion. It was felt that his poor general condition prevented surgical intervention and complex conservative treatment was initiated. It consisted of total parenteral nutrition, antibiotics, percutaneous drainage of the liver abscess, and thoracocentesis. Pus and blood cultures showed Lactobacillus acidophilus. There was a gradual improvement in the patient's condition and the liver abscess decreased in diameter from 14 to 2 cm. Aminosalicylates and enteral nutrition were gradually introduced. The patient was discharged after 9 weeks in good general condition. CONCLUSION: Although extremely rarely, L. acidophilus can cause hepatic abscess and sepsis. This can be explained by immunologic incompetence due to corticosteroid treatment of Crohn's disease.

Outpatient use of systemic antibiotics in Croatia.

According to the results of the European Surveillance of Antimicrobial Consumption (ESAC), outpatient antibiotic use in Croatia in 2001 (17.6 DDD per 1000 inhabitants per day) was comparable to the median use of 24 European countries, which were able to deliver valid data.

Pregnancy outcomes in women with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

OBJECTIVE: Despite earlier detection, treatment, and surgical advances, fertility prognosis in women with classical 21-hydroxylase deficiency (21-OHD) is still low, especially in the salt-wasting (SW) form. PATIENTS AND METHODS: We analysed the course and outcome of four pregnancies in two simple virilizing (SV) and one SW patient. RESULTS: The evaluation of carrier status indicated that all three fathers had two normal CYP21 genes. During the pregnancy, the dose of prednisolone was increased in one of the SV patients and the SW patient. In the SW patient who developed pre-eclampsia, the dose of fludrocortisone was also increased. Three patients gave birth to a total of four healthy girls who were heterozygotes for 21-OHD with normal genitalia (one by vaginal delivery and three by Caesarean section). Family studies revealed that the mother of the SW patient has nonclassical 21-OHD. CONCLUSION: Improving a low birth rate in females with SW 21-OHD remains a problem and new approaches are required. If the mother has 21-OHD (even nonclassical 21-OHD), pre-conception counselling and paternal genotyping are advisable and prenatal dexamethasone therapy should be considered.

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.

Inadequate use of preventive strategies in patients receiving NSAIDs.

OBJECTIVE: Little is known about the factors that influence the decision to use NSAIDs in combination with gastroprotective drugs. The aims of this observational study were to evaluate the extent to which NSAID users are prescribed concomitant gastroprotective drug regimens ('preventive strategies'), and to determine how patient risk factors for NSAID-associated gastrointestinal toxicity and physician prescribing preferences influenced the decision to prescribe a gastroprotective drug in combination with an NSAID. DESIGN AND PATIENTS: The study was conducted on 29 June 2004 and comprised 109 eligible adult patients hospitalised at the Clinical Hospital Center, Zagreb. Use of NSAIDs and gastroprotective drugs, risk factors for NSAID-associated gastrointestinal toxicity, and physician prescribing preferences were monitored throughout the study. RESULTS: Sixty-six percent of patients receiving proton pump inhibitors or histamine H(2)-receptor antagonists with NSAIDs had no risk factors for gastrointestinal toxicity. Furthermore, 29% of patients who used NSAIDs had risk factors for gastrointestinal toxicity but were not receiving gastroprotective drugs. Even though patients at risk of NSAID-associated gastrointestinal complications had higher odds of receiving preventive strategies (odds ratio 1.25), the absolute rate of utilisation of these therapies in at-risk populations was unacceptably low (69%). However, the strongest independent correlation for gastroprotective drug use was the prescribing physician, with an odds ratio of 6.40. CONCLUSION: This study demonstrates that an individual physician's prescribing style largely determines the odds of receiving preventive strategies with NSAID treatment and is more important than the patient's risk factors for gastrointestinal toxicity.

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.

Duration of clinical symptoms in female patients with acute urethral syndrome caused by Chlamydia trachomatis treated with azithromycin or doxycycline.

One hundred fifty-one female patients with acute urethral syndrome caused by Chlamydia trachomatis were examined. First, patients were divided into two groups, those with clinical symptoms present < 3 weeks before the start of treatment, and those with clinical symptoms > or = 3 weeks prior to the beginning of therapy. Then patients were further divided into groups and randomized to receive azithromycin once daily in a single dose of 1.0 g or 500 mg once daily for 6 days, or to receive doxycycline 100 mg b.i.d. for 14 days or 100 mg b.i.d. for 7 days (8 study groups in all). Clinical and bacteriological efficacy was evaluated 3 weeks after the end of therapy. In the group of patients with disease symptoms lasting for 3 weeks or longer, the eradication and clinical cure rates were significantly higher after administration of azithromycin in a dose of 1x500 mg/6 days than after a single dose of 1.0 g (p<0.01), and after administration of doxycycline 2x100 mg/14 days than by using doxycycline 2x100 mg/7 days (p<0.05).

Oral antibiotic prescription in ambulatory care in 1999--a contribution to the development of methods for drug consumption and prescription surveillance monitoring.

The aim of the study was to estimate the consumption of antibiotic in ambulatory care. Oral antibiotic consumption in 1999 was analyzed in four pharmacies in the Zagreb area. The use of oral antibiotics in comparison with total drug consumption, the share of individual subclasses of oral antibiotics and the respective shares of individual products were also analyzed. The results obtained were expressed in terms of both the defined daily doses (DDD) and US$, and were compared with available national and international data. The study demonstrated a high share of oral antibiotics in the overall drug consumption, especially of newer and more expensive agents within individual subclasses of antibiotics. Further research is required to assess the rationale of such prescribing practices, especially in view of the current financial pressure on the Croatian health care system.

Effects of ondansetron on portal hemodynamics in liver cirrhosis.

OBJECTIVE: The double-blind randomized pilot study was undertaken to compare the effects of a 10-day course of ondansetron 8 mg/day and propranolol 80 mg/day perorally in treating portal hypertension. SUBIECTS AND METHODS: 16 patients with liver disease were enrolled in the study. Measurements of portal vein diameter, portal blood flow velocity and portal blood flow volume were done at days 1, 5 and 10 of treatment using duplex Doppler sonography. RESULTS: The propranolol group demonstrated a decrease in portal venous diameter, while patients treated with ondansetron exhibited reduced portal blood flow velocity values. A decreased portal blood flow volume was found in both groups after 10 days of therapy. CONCLUSION: No statistically significant differences were found between the groups with the exception of portal venous diameter which is significantly lower at the end of the treatment in the case of propranolol.

[A model for monitoring drug prescribing in general practice]. / Model pracenja propisivanja lijekova u opcoj medicini.

When prescribing drugs, general practitioners at the same should satisfy the requirements of medical science and their vocation, being aware of their task of a rational disposal of the limited resources allocated for health care. The aim of the paper was to determine the characteristics of monitoring model for drug prescription in general practice, taking into consideration the characteristics of the population, morbidity, drugs and physicians. A prospective monitoring of prescribing drug during one month was carried out in six doctor's offices of general practice/family medicine at the Dugave-Travno Health Station of the Novi Zagreb Health Center. In processing data on patients, drugs and physicians the following were used: distribution description and analysis, pair's tests and General Factorial Anova. Out of 3397 patients who visited the above mentioned doctor's offices, 2320 (68.3%) patients were prescribed 4796 prescriptions--an average of 2.07 prescriptions per patient (from 2.00 to 2.42). The total cost of drug prescription was 360,117.33 kunas (from 43,632 to 77,910 kunas). The number of prescriptions and the cost of prescribed drugs increased significantly in terms of statistics with the age of patients (Spearman's correlation coefficient 0.2263; p < 0.001). By General Factorial Anova statistically significant difference was determined in the cost variable among the physicians with the impact of covariate age and number of prescriptions. Professionally, the most appropriate and most rational prescribing was observed among physicians who had the highest educational level and the longest experience in practice. In order to analyze and assess the appropriatness of drug prescription in general practice, the first essential step is to collect data on what is being prescribed, for whom it is being prescribed, and to enable access to data for physicians. This paper has indicated some of the characteristics of a monitoring model for drug prescription in general practice. Formulation and implementation of this model would considerably promote the professional appropriateness and rationality in drug prescription in general practice.

How safe are bioequivalence studies in healthy volunteers?

Between 1981 and 1994, 58 bioequivalence studies (b.s.) were performed in 885 healthy volunteers. 93.1 per cent were single-dose, mainly of two way cross-over design. According to ATC groups, 13 were of cardiovascular drugs(C), 11 musculoskeletal (M), nine alimentary (A), seven urogenital (G), seven antimicrobial (J), six haematological (B), three nervous (N) and two respiratory (R). 97.2 per cent of volunteers finished the studies. Out of 25 withdrawals, 14 did it by their own will, seven were excluded because of lack of compliance with the protocol, one because of an adverse drug reaction (ADR) (preputial oedema), one because of intercurrent illness, and two for other objective reasons. In 35 studies the probants have been males, in 23 both sexes. Subjects were between 18 and 40 years. 209 adverse events were reported in 18 studies (31 per cent). From 885 volunteers that came to first session at the time, 115 (13 per cent) had ADRs. The association of the drug and ADRs was defined as probable in 91 ADRs (45.9 per cent), definite in 66 (33.4 per cent) and possible in 41 (20.7 per cent). 73 (63.5 per cent) volunteers had one ADR, 22 (19.1 per cent) had two and 20 (17.4 per cent) more than two ADRs. The majority -117 (56 per cent)-of ADRs were mild, 78 (37.3 per cent) moderate and 14 (6.7 per cent) severe. The most frequent ADR was headache (22.9 per cent), followed by nasal congestion (12.9 per cent), sweating (12.4 per cent), nausea (6.7 per cent), restlessness (6.7 per cent), deafness and tinnitus (6.2 per cent), change of biochemical or haematological parameters (5.3 per cent) and other. An unusual and rare ADR was impotence and preputial oedema (two volunteers on frusemide). All studies of G group (7-100 per cent) had ADRs, followed by C group (5-38 per cent) and A (3-33 per cent). Glipizide (5 mg) had highest number of ADRs (64-30.6 per cent), bromocriptine (10 mg) had 31 (14.8 per cent) and frusemide (500 mg) 22 (10.6 per cent). The largest number of subjects with ADRs were on frusemide (13-72 per cent), glipizide (17-68 per cent) and bromocriptine (15-52 per cent). At a time when generic drugs are of increasing importance, the safety of b.s. is of considerable interest. Our data confirm their safety and indicate that the majority of ADRs are mild.

Determination of bioequivalence of two furosemide preparations; the effect of high doses of furosemide on some pharmacokinetic parameters.

The bioequivalence of two oral preparations of the diuretic furosemide, namely (i) a Croatian pharmaceutical product (test preparation A) and (ii) a reference preparation B, both in a dose of 500 mg was assessed in an open, cross-over, randomized trial in 15 healthy male volunteers, in whom the HPLC method with a fluorescent detector was used to determine its concentrations. The test preparation (A) was found to achieve a considerably higher concentration (17.2 +/- 9.304 mg/l) than the reference preparation (11.1 +/- 6.484 mg/l); the time to peak concentrations was statistically significantly shorter for the test preparation (1.033 +/- 0.743 h) than for the reference preparation (1.656 +/- 0.586), and the areas under the concentration curves were statistically significantly greater for the examined preparation (65.9 mg.h/l) than for the reference preparation (46.845 mg.h/l). The relative bioavailability of the test preparation was 129%, i.e. it was not bioequivalent with the reference preparation. This finding was consistent with the previously performed laboratory quality testing in vitro, where the release of the reference preparation was found to be considerably slower and weaker than that of the test preparation. High doses of furosemide exemplified by 500 mg were found to affect only some of the pharmacokinetic parameters, i.e. they induce an accelerated absorption, an increase in serum concentration, and a prolongation of its half-life.

Pharmacokinetic changes in patients with oedema.

The pharmacokinetics of furosemide (frusemide) in patients with oedema have been relatively well studied, but in many studies it is unclear whether the disease or the oedema per se has the major effect. The rate of absorption of oral furosemide in patients with oedema was decreased, but total bioavailability was almost unchanged. The peak serum concentration (Cmax) and time taken to achieve Cmax were either decreased or unchanged. Binding of furosemide to plasma proteins is lower in patients with congestive heart failure (CHF), decompensated liver cirrhosis (DLC) and nephrotic syndrome, probably as a result of hypoalbuminaemia. The elimination half-life (t1/2) can be unchanged (CHF, DLC) or prolonged (chronic renal failure: CRF). Plasma and renal clearance are reduced in patients with CRF and nephrotic syndrome, but are almost unchanged in CHF and DLC. Disease-induced disorders are mainly responsible for the alterations of furosemide pharmacokinetics in oedematous conditions, while the influence of oedema per se is probably not clinically relevant. The pharmacokinetics of digoxin have been studied in a small number of studies only. In patients with CHF, considerable interindividual differences have been found. Because digoxin has a narrow therapeutic window, this drug should be administered cautiously to oedematous patients. Theophylline has higher bioavailability in patients with oedema, with a significantly higher Cmax in patients with hepatic cirrhosis and CHF than in healthy volunteers (29 and 22%, respectively). Furthermore, clearance decreases and t1/2 increases in these patients. Angiotensin converting enzyme (ACE) inhibitors are often administered as prodrugs, and their pharmacokinetic profile could be influenced by the diseases that accompany oedematous states. However, the effect of oedema is difficult to discriminate from that of the disease. Individual ACE inhibitors are affected differently, but importantly the dosage of perindopril should be reduced in patients with CHF, while for most other ACE inhibitors the changes in pharmacokinetic parameters are clinically irrelevant. In conclusion, studies on pharmacokinetic changes in oedema are limited. Besides affecting absorption (after oral administration) and conversion of the prodrug to the active form, probably as a result of the associated disease, oedema has not been proven to cause any clinically relevant changes in pharmacokinetic parameters for individual drugs. However, further studies of this aspect of pharmacokinetics are needed.

Adverse drug reactions resulting in hospital admission.

A 14-month (1992/3) prospective study was performed in two departments of the University Hospital Centre (UHC) in Zagreb. The aim of the study was to assess the rate of drug-related hospitalizations, drugs that caused adverse drug reactions (ADRs), and all factors which could have been of importance for their appearance. One hundred and thirty (2.5%) of 5,227 patients were admitted to hospital because of ADRs. The most frequently ADR-related drugs were nonsteroidal anti-inflammatory drugs and analgesics (64.6%). They were followed by cardiovascular agents (20.8%) and antimicrobials (3.8%). Acetylsalicylic acid (aspirin) caused 38.5% of hospital admissions, other nonsteroidal anti-inflammatory drugs (NSAIDs) 23.1% and medigoxin 15.4% of hospitalizations. The most frequent ADRs were upper gastro-intestinal tract bleeding (64.6%), cardiac rhythm disturbances (13.9%), blood cell disorders (4.6%) and hypoglycemia (2.3%). Regarding the patients' age, 52.3% of patients was younger and 47.7% older than 65. Sixty-one point five percent of patients was taking more than one drug, older patients (48 patients--77.4%) have been taking a significantly higher number of drugs than the younger (32 patients--47.1%) (p < 0.0001) ones. Drug interactions caused 23.8% of ADRs. Only 11 (8.5%) of patients suspected themselves that the drug might have caused the ADR. Improvement was observed in the majority of patients (65.4%), 25.4% recovered completely, 4 (3.0%) died in the hospital because of ADRs. 3.0% of patients as well died of their underlying diseases, 2.3% were transferred to other departments for their underlying diseases, and one patient left the hospital on his free will.