Determinants of potential drug–drug interaction associated dispensing in community pharmacies in the Netherlands

Objective: There are many drug–drug interactions (D–DI) of which some may cause severe adverse patient outcomes. Dispensing interacting drug combinations should be avoided when the risks are higher than the benefits. The objective of this study was to identify determinants of dispensing undesirable interacting drug combinations by community pharmacies in the Netherlands. Methods: A total of 256 Dutch community pharmacies were selected, based on the dispensing of 11 undesirable interacting drug combinations between January 1st, 2001 and October 31st, 2002. These pharmacies were sent a questionnaire by the Inspectorate for Health Care (IHC) concerning their process and structure characteristics. Main outcome measure: The number of times the 11 undesirable interacting drug combinations were dispensed. Results: Two hundred and forty-six questionnaires (response rate 96.1%) were completed. Dispensing determinants were only found for the D–DI between macrolide antibiotics and digoxin but not for the other 10 D–DIs. Pharmacies using different medication surveillance systems differed in the dispensing of this interacting drug combination, and pharmacies, which were part of a health care centre dispensed this interacting drug combination more often. Conclusion: Medication surveillance in Dutch community pharmacies seems to be effective. Although for most D–DIs no determinants were found, process and structure characteristics may have consequences for the dispensing of undesirable interacting drug combinations.     

Coumarin anticoagulants and co-trimoxazole: avoid the combination rather than manage the interaction

Objective The objective of our study was to examine the management of the interaction between acenocoumarol or phenprocoumon and several antibiotics by anticoagulation clinics and to compare the consequences of this interaction on users of co-trimoxazole with those for users of other antibiotics. Methods A follow-up study was conducted at four anticoagulation clinics in The Netherlands. Data on measurements of the International Normalised Ratio (INR), application of a preventive dose reduction (PDR) of the coumarin anticoagulant, fever and time within or outside the therapeutic INR range were collected. Results The study cohort consisted of 326 subjects. A PDR was given more often to users of co-trimoxazole PDR than to users of other antibiotics. The PDR in co-trimoxazole users resulted in a significantly reduced risk of both moderate overanticoagulation (INR >4.5) and severe overanticoagulation (INR >6.0) compared with no PDR, with odds ratios (ORs) of 0.06 [95% confidence interval (CI): 0.01–0.51] and 0.09 (95% CI: 0.01–0.92), respectively. In co-trimoxazole users without PDR, the risk of overanticoagulation was significantly increased compared with users of other antibiotics. All co-trimoxazole users spent significantly more time under the therapeutic INR range during the first 6 weeks after the course than users of other antibiotics. Conclusion PDR is effective in preventing overanticoagulation in co-trimoxazole users, but results in a significantly prolonged period of underanticoagulation after the course. Avoidance of concomitant use of co-trimoxazole with acenocoumarol or phenprocoumon seems to be a safer approach than management of the interaction between these drugs.     

Evaluation of drug–drug interactions with fesoterodine

Purpose  To assess drug–drug interactions of fesoterodine with cytochrome P450 (CYP) 3A4 inhibitor (ketoconazole), inducer (rifampicin), and substrates (ethinylestradiol and levonorgestrel). Methods  Effects of ketoconazole 200 mg twice daily and rifampicin 600 mg twice daily on fesoterodine 8 mg once daily were investigated in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) based on 5-hydroxymethyl tolterodine (5-HMT) pharmacokinetics (principal active fesoterodine metabolite and CYP3A4 substrate). Effects of fesoterodine 8 mg versus placebo once daily on ethinylestradiol and levonorgestrel were investigated based on oral contraceptive pharmacokinetics and on pharmacodynamic effects on progesterone, luteinizing hormone, follicle-stimulating hormone, and estradiol plasma levels. Results  Compared with fesoterodine alone, coadministration of fesoterodine with ketoconazole resulted in increases in mean 5-HMT maximum concentration in plasma (C_max; from 3.0 to 6.0 ng/mL in EMs and from 6.4 to 13.4 ng/mL in PMs) and mean area under the plasma concentration time curve (AUC; from 38.2 to 88.3 ng h/mL in EMs and 88.3 to 217.2 ng h/mL in PMs). Coadministration of festerodine with rifampicin resulted in decreases in mean 5-HMT C_max (from 5.2 to 1.5 ng/mL in EMs and from 6.8 to 1.9 ng/mL in PMs) and mean AUC (from 62.4 to 14.4 ng h/mL in EMs and from 87.8 to 19.6 ng h/mL in PMs). Fesoterodine did not affect oral contraceptive pharmacokinetics or pharmacodynamics or the suppression of ovulation. Conclusions  Fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors. Coadministration of CYP3A4 inducers with fesoterodine may produce subtherapeutic 5-HMT exposures. No dose adjustment is necessary for concomitant use of fesoterodine with oral contraceptives. Funding for this study was provided by Schwarz Biosciences GmbH, and Pfizer Inc.     

某医院2009-2012年金黄色葡萄球菌的分离及耐药性变迁分析

目的 回顾性分析金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌(MRSA)的耐药性变迁情况,为预防控制措施的制定提供依据.方法 对2009-2012年临床分离的576株金黄色葡萄球菌进行分析,细菌鉴定和药敏试验采用VITEK 2 Compact全自动细菌培养鉴定仪.结果 2009-2012年MRSA的分离率为59.5％,但每年的分离率呈逐年递减趋势.MRSA对万古霉素、利奈唑胺、奎奴普丁/达福普汀、替考拉宁、呋喃妥因的抗菌活性较好(耐药率＜2.4％);对替加环素的耐药率和敏感率均为0.0％,中介率为100.0％;对庆大霉素、环丙沙星、莫西沙星、克林霉素、四环素和红霉素的耐药性呈逐年递减趋势.2010-2012年对复方磺胺甲噁唑耐药性明显降低,由2010年的65.3％降至2011年和2012年的28.2％和4.7％(P＜0.05).结论 MRSA的分离和耐药性逐年递减,应继续加强抗菌药物管理,合理科学使用抗菌药物,降低多重耐药细菌的发生率和耐药性.     

产ESBLs大肠埃希菌耐药性与抗菌药物使用量的相关性分析

目的:了解6种抗菌药年用量变化与产超广谱β-内酰胺酶(ESBLs)大肠埃希菌耐药性的相关性,为临床合理用药提供依据。方法:分别统计我院2004-2010年6种抗菌药的年用量(用药频度(DDDs))及产ESBLs大肠埃希菌平均耐药率。采用SPSS13.0软件Spearman相关分析法对产ESBLs大肠埃希菌耐药率与6种药物的DDDs进行相关性分析。结果:阿米卡星的用量与大肠埃希菌对阿米卡星、氨曲南、头孢哌酮/舒巴坦、头孢他啶耐药率的变化呈显著正相关(r分别为0.821、0.821、0.857、0.893,P<0.05);大肠埃希菌对阿米卡星耐药率与大肠埃希菌对氨曲南、头孢哌酮/舒巴坦、头孢他啶耐药率呈显著正相关(r分别为0.786、0.946、0.929,P<0.05);大肠埃希菌对头孢他啶耐药率与大肠埃希菌对氨曲南、头孢哌酮/舒巴坦耐药率呈显著正相关(r分别为0.929、0.857,P<0.05)。结论:抗菌药物用量增加会导致产ESBLs菌株增加,使细菌对多种抗菌药物耐药,甚至是多重耐药。提示临床应注意控制抗菌药物的使用频度,防止产生了ESBLs耐药菌株。     

2017-2019年某院住院儿童肠杆菌科细菌分布及耐药分析

摘要：目的 了解某院住院儿童肠杆菌科细菌的检出和耐药情况,指导临床抗菌药物合理应用。方法 收集某院2017年1月1日至2019年12月31日住院儿童标本分离出的肠杆菌科细菌资料,对病原菌分布、标本来源、耐药情况以及ESBLs阳性和CRE菌株检出情况进行分析。结果 共分离得到儿童肠杆菌科细菌558株,其中新生儿96株,非新生儿462株。呼吸道标本占74.9%,分泌物标本8.06%,无菌体液5.91%,尿液和肠道标本均为5.56%。儿童株肠杆菌科细菌检出率前3位的是大肠埃希菌、肺炎克雷伯菌和阴沟肠杆菌。大肠埃希菌和肺炎克雷伯菌对头孢他啶之外的第一代至第三代头孢菌素耐药率均高于40%。阴沟肠杆菌对第三代头孢菌素耐药率均低于30%,但是对于碳青霉烯类抗菌药物亦有11%~14%的耐药率。未发现对替加环素耐药的肠杆菌科细菌。ESBLs阳性肠杆菌科细菌比例为19.5%,CRE比例为8.4%。结论 儿童肠杆菌科细菌分布广泛,耐药形式严峻,新生儿肺炎克雷伯菌耐药率高于非新生儿,新生儿菌株ESBLs阳性率及CRE检出率亦较非新生儿高,应高度重视肠杆菌科细菌及其耐药性的监测,合理应用抗菌药物。     

Changes in the use of antibacterial drugs in the countries of central and eastern Europe

Use of systemic antibacterial drugs in the countries of central and eastern Europe (CCEE) has been studied using the defined daily doses (DDD) methodology. For the comparison, national wholesale data from Bulgaria, the Czech Republic, Estonia, Hungary, Lithuania, Slovakia, Slovenia and Romania for the years 1989 and 1992 were used, i.e. for the years before and after the rapid sociopolitical changes in these countries. Substantial differences in the patterns of antibacterial drug use between countries as geographically and economically similar as the CCEE were observed. The general sales of antibiotics varied almost twofold among the CCEE and had decreased in most of the CCEE during the study period. The proportion of tetracyclines in the sales of 1992 ranged from 10% in Slovenia to 49% in Estonia, and that of broad-spectrum penicillins from 6% in Estonia to 40% in Slovenia. The use of narrow-spectrum penicillins varied within the range of 4% in Bulgaria to 38% in Slovakia, and had decreased during the study years in all countries. Aminoglycosides accounted for 5–12% of all antibacterials in Bulgaria, Estonia, Lithuania, Romania and Slovakia in the study period, and these countries, with the exception of Slovakia, also had a high consumption of chloramphenicol. In 1992, by far the most popular antiinfectives in the CCEE were doxycycline, ampicillin and co-trimoxazole, which ranked among the top ten drugs in all countries studied. All countries had their specific preferences in the top ten lists, but the rationality of these traditions can be questioned: tetracycline + oleandomycin in Bulgaria; penamecillin in the Czech Republic and Hungary; sulphonamides in Estonia and Lithuania; and benzathine penicillin and streptomycin in Slovakia. The international differences in antibiotic utilization are suggested to be related to the respective health care systems (e.g. drug reimbursement) and prescribing preferences (e.g. therapeutic traditions), quite apart from possible differences in drug efficacy, drug tolerance and the prevalence and severity of various infections.     

Use and costs of anti-secretory and cardiovascular co-medication in osteoarthritis patients treated with selective or non-selective NSAIDS

Objective This study aims to compare use and costs of anti-secretory and cardiovascular co-medication in osteoarthritis patients treated with selective or non-selective NSAIDs.Method A retrospective study examined Belgian patients aged 65 years or more who suffer from osteoarthritis and are chronic users of selective NSAIDs (n = 1,376) or non-selective NSAIDs (n = 8,482). A before-and-after analysis compared drug use and costs between period 1 (first 6 months of 2002) and period 2 (several 1-year periods stretching over 2003–2004). A cohort analysis contrasted patients taking selective NSAIDs with patients taking non-selective NSAIDs.Main outcome measures Anti-secretory co-medication included histamine H2-receptor antagonists and proton pump inhibitors. Cardiovascular co-medication referred to cardiac glycosides, anti-arrhythmics, anti-thrombotics, anti-angina drugs, anti-hypertensive drugs and serum-lipid-reducing drugs. Volume of drug use was expressed as number of packages and costs were computed in Euro.Results The volume of anti-secretory co-medication increased by 36% with selective NSAIDs and by 55% with non-selective NSAIDs between periods 1 and 2. Cardiovascular co-medication rose by 18% with selective NSAIDs and by 12% for non-selective NSAIDs. Focusing on patients who did not take anti-secretory co-medication in period 1, patients taking selective NSAIDs were just as likely to start anti-secretory co-medication in period 2 as patients taking non-selective NSAIDs (odds ratio: 1.05; 95% confidence interval: 0.90–1.23). Patients taking selective NSAIDs were just as likely to start cardiovascular co-medication as patients taking non-selective NSAIDs (odds ratio: 1.03; 95% confidence interval: 0.78–1.36). Annual costs of treating osteoarthritis in ambulatory care amounted to 756 € with selective NSAIDs and 416 € with non-selective NSAIDs. This originated from higher acquisition costs (278 € vs. 24 €) and higher costs of co-medication (477 € vs. 392 €) with selective NSAIDs.Conclusions The use of selective and non-selective NSAIDs is accompanied by a higher use of co-medication over time. The increase in anti-secretory co-medication was more prominent with non-selective NSAIDs. The rise in cardiovascular co-medication was more pronounced with selective NSAIDs. Treatment of osteoarthritis with selective NSAIDs is more expensive than with non-selective NSAIDs in terms of acquisition costs and costs of co-medication.     

Effect of aliskiren,an oral direct renin inhibitor,on the pharmacokinetics and pharmacodynamics of a single dose of acenocoumarol in healthy volunteers

ABSTRACT

Objective: Aliskiren is a direct renin inhibitor approved for the treatment of hypertension. This study investigated the effects of aliskiren on the pharmacokinetics and pharmacodynamics of a single dose of acenocoumarol in healthy volunteers.

Methods: This two-sequence, two-period, randomized, double-blind crossover study recruited 18 healthy subjects (ages 18–45) to receive either aliskiren 300?mg or placebo once daily on days 1–10 of each treatment period and a single dose of acenocoumarol 10?mg on day 8. Treatment periods were separated by a 10-day washout. Blood samples were taken frequently for determination of steady-state plasma concentrations of aliskiren (LC-MS/MS) and of R (+)- and S (?)-acenocoumarol (HPLC-UV), prothrombin time (PT) and international normalized ratio (INR).

Results: Co-administration with aliskiren had no effect on exposure to R (+)-acenocoumarol. Geometric mean ratios (GMR; aliskiren:placebo co-administration) for R (+)-acenocoumarol AUC_0?t and C_max were 1.08 and 1.04, respectively, with 90% CI within the range 0.80–1.25. Co-administration of aliskiren resulted in a 19% increase in S (?)-acenocoumarol AUC_0?t (GMR 1.19; 90% CI 0.92, 1.54) and a 9% increase in C_max (GMR 1.09; 90% CI 0.88, 1.34). The anticoagulant effect of acenocoumarol was not affected by co-administration of aliskiren. Geometric mean ratios were 1.01 for all pharmacodynamic parameters (AUC_PT, PT_max, AUC_INR and INR_max), with 90% CI within the range 0.97–1.05.

Conclusion: Aliskiren has no clinically relevant effect on the pharmacokinetics or pharmacodynamic effects of a single dose of acenocoumarol in healthy volunteers, hence no dosage adjustment of acenocoumarol is likely to be required during co-administration with aliskiren.     

Ⅰ类切口围手术期抗菌药物应用调查

目的：调查分析医院Ⅰ类切口围手术期应用抗菌药物的情况。方法回顾性分析2013年1~12月600份Ⅰ类切口手术病例围手术期应用抗菌药物情况,并评价其合理性。结果Ⅰ类切口手术预防使用抗菌药物175例,比率为29.2%;预防使用抗菌药物≤24h的有46例,比率为26.3%;平均预防用药时间3.8 d,疗程不合理129例,占73.7%;无预防指征用药2例;抗菌药物选择不合理的1例;给药时机选择不合理的13例;单次剂量不合理6例;给药次数不合理10例。结论医院Ⅰ类切口围手术期抗菌药物使用基本规范,但仍有预防用药持续时间过长、抗菌药物种类选择不合理等问题,需继续加强围手术期预防用药的监督和管理。     

A comparison of the relative sensitivities of factor VII and prothrombin time measurements in detecting drug interactions with warfarin

Summary We have studied the comparative abilities of the prothrombin time and factor VII clotting activity, measured using a chromogenic assay, to detect drug interactions with warfarin. Pharmacokinetic and pharmacodynamic data were collected from studies involving the single administration of 25 mg of warfarin in the absence and presence of fengabin, cimetidine, ranitidine, and enoxacin. Fengabin caused changes in both the pharmacokinetics and pharmacodynamics of warfarin, whereas cimetidine and enoxacin only caused changes in its pharmacokinetics. Ranitidine had no effect on either the pharmacokinetics or pharmacodynamics of warfarin. In general, factor VII clotting activity showed greater sensitivity but also greater variability than the prothrombin time to changes in clotting activity. Consequently, factor VII clotting activity did not have greater discriminatory power than the prothrombin time in detecting drug interactions involving warfarin.     

Assessment of drug–drug interactions between moxonidine and antiepileptic drugs in the maximal electroshock seizure test in mice

Hypertension is a common comorbid condition with epilepsy, and drug interactions between antihypertensive and antiepileptic drugs (AEDs) are likely in patients. Experimental studies showed that centrally active imidazoline compounds belonging to antihypertensive drugs can affect seizure susceptibility. The purpose of this study was to assess the effect of moxonidine, an I₁-imidazoline receptor agonist, on the anticonvulsant efficacy of numerous AEDs (carbamazepine, phenobarbital, valproate, phenytoin, oxcarbazepine, topiramate and lamotrigine) in the mouse model of maximal electroshock. Besides, the combinations of moxonidine and AEDs were investigated for adverse effects in the passive avoidance task and the chimney test. Drugs were administered intraperitoneally (ip). Moxonidine at doses of 1 and 2 mg/kg ip did not affect the convulsive threshold. Among tested AEDs, moxonidine (2 mg/kg) potentiated the protective effect of valproate against maximal electroshock. This interaction could be pharmacodynamic because the brain concentration of valproate was not significantly changed by moxonidine. The antihypertensive drug did not cause adverse effects when combined with AEDs. This study shows that moxonidine may have a neutral or positive effect on the anticonvulsant activity of AEDs in patients with epilepsy. The enhancement of the anticonvulsant action of valproate by moxonidine needs further investigations to elucidate potential mechanisms involved.     

Lamotrigine in children and adolescents: the impact of age on its serum concentrations and on the extent of drug interactions

Objective To investigate the impact of age and co-treatment with other drugs on the serum concentrations of lamotrigine in children and adolescents. Methods A review of routine serum concentration measurements of lamotrigine performed in our laboratory yielded a total of 744 serum samples from 296 subjects (110 males, 186 females, age: 2–19 years) suitable for statistical analysis. The primary outcome variable was the dose-corrected lamotrigine serum concentration, expressed as the lamotrigine concentration/dose (C/D) ratio. A linear mixed model that allowed multiple observations from the same patient was used to identify and quantify the effect of factors influencing the lamotrigine C/D ratio. Results According to the model, the lamotrigine C/D ratio decreases by 6% per year of age. Valproate and levetiracetam were found to raise the lamotrigine C/D ratio, whereas the following co-medications reduced it: carbamazepine, clobazam, fluoxetine, clonazepam and ethinyl estradiol. The effect of carbamazepine decreased with increasing age. No gender difference was detected. Conclusions Age is an important factor with respect to the pharmacokinetics and the extent of drug interactions of lamotrigine in children and adolescents. In this population, older individuals will need higher doses than younger ones in order to achieve the same serum concentrations.     

Treatment stabilization in children and adolescents with attention-deficit/hyperactivity disorder: data from the Netherlands

Abstract

Objective:

To evaluate the number of patients reaching stable treatment with a stimulant (methylphenidate or dexamphetamine) or non-stimulant (atomoxetine) attention-deficit/hyperactivity disorder (ADHD) medication approved for use in the Netherlands, and the time to treatment stabilization among children and adolescents aged 6–17 years.     

泌尿系结石患者感染病原体分布及耐药趋势分析

目的 分析1053例泌尿系结石合并尿路感染患者尿培养结果及耐药趋势变化,为临床应用抗菌药物提供依据,指导合理使用抗生素.方法 分析本院2012年6月至2015年6月收治的1053例泌尿系结石合并细菌感染患者中段尿培养及药敏试验结果.结果 1 053例患者中共检出致病菌199株,其中革兰氏阴性菌131株,占65.83％,以大肠埃希菌、奇异变形杆菌、肺炎克雷伯菌、铜绿假单胞菌为主;革兰氏阳性菌65株,占32.7％,以粪肠球菌、表皮葡萄球菌为主;真菌3株,占1.5％.肠杆菌科细菌对亚胺培南、美罗培南、哌拉西林/他唑巴坦、头孢哌酮/舒巴坦、头孢吡肟、阿米卡星的敏感率均大于70％.对哌拉西林、左旋氧氟沙星的耐药率均＞60％.非发酵菌除左旋氧氟沙星外,对其余抗菌药物均保持较高的敏感率.肠球菌及表皮葡萄球菌对万古霉素、利奈唑胺、替考拉宁为全敏感.结论 泌尿系结石合并感染的致病菌以大肠埃希菌及粪肠球菌为主,多重耐药菌检出率较低,患者早期行中段尿培养对减少耐药菌的产生、合理应用抗生素有重要意义.