Cutaneous reactions to drugs. An analysis of spontaneous reports in four Italian regions

AIMS: Cutaneous manifestations are frequently reported in association with drug use. The aim of this study was to analyse the skin reactions reported to the spontaneous surveillance systems of four Italian regions (Friuli Venezia Giulia, Lombardy, Sicily and the Veneto), and correlate the reports with estimated drug consumption during the same period, paying particular attention to the reactions to antimicrobial agents and nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: All of the adverse drug reactions (ADRs) reported spontaneously between January 1996 and December 1997 to the surveillance systems of four Italian regions (a total population of about 20 million people) were analysed by a panel of experts including dermatologists. On the basis of the Critical Term List of the World Health Organization (WHO), the reactions were classified as either serious or nonserious events. Drug consumption was expressed as a daily defined dose (DDD)/1000 inhabitants/day. RESULTS: A total of 2224 adverse skin reaction reports (44.7% of all of the reported ADRs) were identified, making a reporting rate of about 5.5 per 100 000 inhabitants/year. The female/male ratio was 1.58, and the reporting rate progressively increased with age. The drug categories with the highest number of cutaneous reactions were antimicrobials, followed by NSAIDs, analgesics and radiology contrast media. There was a total of 372 (16.9%) serious reaction reports, the most frequent being angioedema (171 cases), erythema multiforme (68 cases) and photosensitivity (37 cases). Co-trimoxazole, followed by the cephalosporins and fluoroquinolones, were associated with the highest consumption-related reporting rate among the antimicrobials, and aspirin and dipyrone among the NSAIDs and analgesics. CONCLUSIONS: Spontaneous reports from four Italian regions revealed that the skin was the organ most frequently affected by ADRs. The paper shows the validity of a regional decentralized system in Italy.     

Adverse reactions induced by NSAIDs and antibacterials: analysis of spontaneous reports from the Sicilian regional database.

OBJECTIVES: To (i) evaluate the suspected adverse drug reactions (ADRs) related to NSAIDs and antibacterials that were reported to Sicilian local health officers by healthcare professionals; and (ii) to detect new or serious potential signals of alarm related to these two widely used drug categories. METHODS: We selected all the spontaneous reports of ADRs sent between January 1998 and June 2004 and analysed those attributed to NSAIDs and systemic antibacterials, applying proportional reporting ratio (PRR) methodology. PRRs >2, chi(2) >4 and >3 ADRs were regarded as signals. RESULTS: During the period considered, 1585 reports of ADRs were received overall (42.6% serious), with an annual reporting rate of approximately 49.1 reports per million inhabitants on average; 351 referred to systemic antibacterials, and 179 to NSAIDs. There were 174 (49.6%) reports of serious ADRs associated with antimicrobials and 108 (60.3%) associated with NSAIDs. Disproportionality was observed, in particular for anaphylactic shock induced by ceftriaxone (all reports were associated with off-label use of the drug), photosensitivity reaction induced by lomefloxacin (administered in the summer), hepatitis induced by nimesulide (three cases leading to liver transplantation) and vasculitis induced by nimesulide. CONCLUSION: Our analysis highlighted several signals of alarm deserving further investigation or measures to influence prescribing. This study underlines the value of a regional centre in identifying local factors (such as prescribing patterns) that may increase the prevalence of serious ADRs.     

Influence of fluoroquinolone purchasing patterns on antimicrobial expenditures and Pseudomonas aeruginosa susceptibility.

The influence of using ofloxacin in place of ciprofloxacin on hospital fluoroquinolone expenditures, total antimicrobial expenditures, and susceptibility of Pseudomonas aeruginosa to fluoroquinolones was studied. Hospitals with fluoroquinolone expenditures of at least $1 per occupied bed per year were administered annual surveys covering the years 1993 through 1996. The two most recent consecutive years of data were compared among hospitals that used ciprofloxacin as their primary fluoroquinolone during both years (group 1), hospitals whose ofloxacin purchases increased from accounting for < or =25% of total fluoroquinolone expenditures during year 1 to accounting for >25% during year 2 (group 2), and hospitals whose ofloxacin purchases accounted for at least 25% of total fluoroquinolone expenditures for both years (group 3). A total of 109 hospitals were included in the study. Most hospitals spent more on fluoroquinolones and total antimicrobials in year 2 than year 1. Group 3 hospitals had a significant increase in expenditures for fluoroquinolones and non-fluoroquinolone antipseudomonal antimicrobials. Group 2 hospitals did not realize antimicrobial cost savings and had higher rates of Pseudomonas aeruginosa resistance than hospitals that used ciprofloxacin. Whether a hospital changed its pattern of ciprofloxacin and ofloxacin purchasing was not significantly associated with expenditures for fluoroquinolones, nonfluoroquinolone antimicrobial agents, or all antimicrobials. Susceptibility of P. aeruginosa to ciprofloxacin was lower in hospitals with greater proportions of ofloxacin use. Individual hospital, ciprofloxacin expenditures, and study year were found to be predictive of P. aeruginosa susceptibility to ciprofloxacin among all pooled hospitals.     

Adverse effects of neuromuscular blocking agents based on yellow card reporting in the U.K.: are there differences between males and females?

BACKGROUND: Adverse drug reactions (ADRs) are known to occur during anaesthesia; in the U.K. such ADRs may be reported through the Yellow Card Scheme (YCS). Our aim was to determine the demographics of ADRs to neuromuscular blocking drugs without formal causality assessment. METHODS: A retrospective analysis of ADRs to seven neuromuscular blocking drugs reported via the YCS during a greater than 30-year period was performed. Sex and age were analysed in order to identify at risk groups. RESULTS: Of 998 reports, 969 included gender. Non-allergic suspected reactions occurred with almost the same frequency as those with an allergic component. The majority occurred in females 676 (70%), and significant sex differences were measured between drugs. Males were more likely to have suffered an ADR to atracurium (p = 0.01) whilst females experienced more ADRs to suxamethonium (p = 0.01). ADRs proved fatal in 81 (9%) of the 950 reports for single drugs. Mortality following suxamethonium was significantly higher in males at 22% compared with 9% females (p < 0.001). More women than men were reported to have allergic reactions, 73% (362/499) compared with 27% (137/499) respectively. The female:male ratio for ADRs was reversed for subjects < 10 years compared with peak ADR reports during the decade from 31-40 years. CONCLUSIONS: Sex differences in mortality exist in this analysis. The unexpected high frequency of non-allergic ADRs suggests that morbidity and mortality from reactions to established drugs is twice that expected from allergic reactions alone. Standards and guidance for the reporting of ADRs warrant urgent development.     

Activity of nine fluoroquinolones against strains of Bordetella bronchiseptica

Thirty-two strains of Bordetella bronchiseptica were tested for their antimicrobial susceptibilities to nine fluoroquinolones. The most active agents were fleroxacin, temafloxacin, ciprofloxacin (MIC₉₀ 1 μg/ml), ofloxacin, lomefloxacin and enoxacin (MIC₉₀ 2 μg/ml). Pefloxacin and norfloxacin were active only against 59.3 and 83.1%, respectively, of the strains tested, whereas rufloxacin lacked activity against all the strains of B. bronchiseptica tested.     

氟喹诺酮类药物不良反应分析

目的探讨氟喹诺酮类药物的合理使用。方法对我院2010年1月～2011年12月间126例氟喹诺酮类药物不良反应报告进行回顾性分析,对不良反应的发生情况进行分类汇总,并对所采取救治措施进行总结。结果氟喹诺酮类药物不良反应中左氧氟沙星和氟罗沙星所占比例最高,给药方式中静脉滴注给药所占比例最高,各种不良反应中以过敏反应最为多见。结论应密切关注氟喹诺酮类药物使用过程中可能出现的不良反应,采取必要的防治措施,确保用药的安全性和有效性。     

Nurses are increasingly involved in pharmacovigilance in Sweden

INTRODUCTION: In Sweden, voluntary adverse drug reaction (ADR) reporting started over 40 years ago to detect rare, serious, unexpected adverse, mainly type B, reactions. During the period 1965-2004, 92,000 reports were assessed. Since certain nurses are licensed to prescribe a limited number of drugs, nurses also form part of the reporting team. AIM: To analyse the ADR reporting by nurses in Sweden. METHODS: All reports by nurses and other health-care personnel entered into the Swedish ADRs database SWEDIS (Swedish Drug Information System) were retrieved for the 10-year period 1995-2004 (Swedish population: 9 million). The intention was to analyse the nurses' reports from a quantitative and qualitative point of view. RESULTS: The total number of ADR reports has gradually increased during the past 10 years from 3000 to over 4000 in 2004 (465 per million inhabitants), an increase by 28%. All ADR reports originate from health care personnel. The nurses' contribution to the ADR reporting increased from 2-3% in the mid-90s to 12% in 2004. The most common drugs involved in the nurses' reporting were various kinds of vaccines. Skin reactions dominated among the nurses' ADR reports. The ADRs reported by nurses were, as a consequence of many vaccine reports, compared to all reports, not so often classified as serious, but were on the other hand more often assessed with a causal relationship. CONCLUSIONS: Nurses, in their position as drug administrators who record signs and symptoms of the patients, play an increasingly important role for detection of suspected ADRs and are now contributing to a significant amount of the ADR reporting in Sweden.     

氟喹诺酮类抗菌药物致药物不良反应205例调查分析

目的分析氟喹诺酮类抗菌药物(FQNS)药物不良反应(ADR)的特点,为临床合理用药提供依据。方法对2001-2010年某院门、急诊及住院部应用FQNS致ADR患者205例进行回顾性统计、分析。结果男性ADR发生率高于女性,31～40岁年龄段ADR发生率最高(31.2%);引起ADR的主要给药途径为静脉注射,共105例(51.2%);共涉及10种FQNS,不良反应主要表现在神经、循环、皮肤、泌尿、消化、呼吸、血液等系统,其中以神经系统、皮肤及消化系统症状较突出。结论 FQNS致ADR因素较多,临床使用时应注意ADR的监测,合理用药,以提高用药的安全性,减少ADR的发生。     

Fluoroquinolone-associated anaphylaxis in spontaneous adverse drug reaction reports in Germany: differences in reporting rates between individual fluoroquinolones and occurrence after first-ever use.

BACKGROUND: The frequency of fluoroquinolone-associated anaphylaxis has been estimated to be 1.8-23 per 10 million days of treatment based on spontaneous reports. It is unknown whether there are differences between the reporting rates of anaphylaxis with individual fluoroquinolones. According to pathophysiology, anaphylaxis may be immune mediated (anaphylactic) or not (anaphylactoid). The latter may occur after first-ever intake since no sensitisation phase is necessary. OBJECTIVE: To analyse spontaneous reports of fluoroquinolone-associated anaphylaxis contained in the spontaneous adverse drug reaction database of the Federal Institute for Drugs and Medical Devices in Germany with regard to differences in reporting rates between various fluoroquinolones, the previous intake and the time to onset of the reaction. METHODS: All fluoroquinolone-associated cases of anaphylaxis, anaphylactic shock, and anaphylactic/anaphylactoid reaction spontaneously reported to the Federal Institute for Drugs and Medical Devices between 1 January 1993 and 31 December 2004 were identified and assessed with regard to the correctness of the diagnosis of anaphylaxis, the causal relationship with the drug, the previous intake of fluoroquinolones and the time to onset of the reaction. RESULTS: In 166 of 204 cases identified, the diagnosis of anaphylaxis and a causal relationship with the drug were considered at least possible. Moxifloxacin, levofloxacin, ciprofloxacin and ofloxacin accounted for 90 (54%), 25 (15%), 21 (13%) and 16 (10%) of the 166 cases, respectively. The corresponding reporting rates per 1 million defined daily doses based on crude estimates of exposure were 3.3, 0.6, 0.2 and 0.2 for moxifloxacin, levofloxacin, ciprofloxacin and ofloxacin, respectively. The occurrence of anaphylaxis after the first dose or within the first three days was reported in 71 of 166 (43%) cases, but no information on prior exposure with this or any other fluoroquinolone was provided with these reports. In 21 of 166 (13%) cases, the reaction occurred within the first 3 days and it was stated that the particular fluoroquinolone had never been taken before. CONCLUSIONS: Anaphylaxis appears to be associated with the fluoroquinolone class of antibacterials. Observed differences in reporting rates should be further investigated. Fluoroquinolone-associated anaphylaxis may occur after first-ever intake of the agent.     

Ten years of pharmacovigilance in Italy: the experience of Emilia-Romagna region in the monitoring of drug’s safety profile

Objective: To describe the evolution of adverse drug reactions (ADRs) spontaneously reporting in the Emilia-Romagna region (ERR) in the period 2001 – 2010 through qualitative and quantitative indicators following local educational and editorial initiatives.

Methods: Data of regional spontaneous reporting from 1 January 2001 to 31 December 2010 were obtained from the Pharmacovigilance National Network of the Italian Medicines Agency. Drugs were classified according to the Anatomical Therapeutic Chemical classification. ADRs were coded using the Medical Dictionary for Regulatory Activities Terminology.

Results: The overall contribution of the ERR was 9.7% of the total national number of reports (9631 out of 99,319) with a rate of 8 reports per 100 physicians and 230 per million inhabitants. Reports concerned more females and more patients aged 0 – 2 and 60 – 80 years. Differences between the individual local health authorities were identified in rate of ADR reporting. Hospital doctors were the main source of reports followed by general physicians. Out of 2555 serious reports, 124 cases were lethal (4.9% of serious ADRs and 1.3% of all regional reports).

Conclusion: The results represent a useful trend analysis of the post-marketing surveillance and suggest that, although the pharmacovigilance system has succeeded in reaching a stable and lasting flow of information in ERR, there is considerable place for improvement.     

Immune Checkpoint Inhibitors and Cardiotoxicity: An Analysis of Spontaneous Reports in Eudravigilance

Introduction

Immune checkpoint inhibitors (ICIs) are widely used in the treatment of many cancers as they improve clinical outcomes. However, ICIs have also been associated with the development of immune-related adverse drug reactions (ADRs). Among immune-related ADRs, cardiac immune-related ADRs are rare, but also associated with high mortality rates.

Objective

The objective of this study was to evaluate the occurrence of cardiac ADRs reported with ICIs in the European spontaneous reporting system.

Methods

We retrieved individual case safety reports on ICI-induced cardiac ADRs from the website of suspected ADR (www.adrreports.eu) of the European pharmacovigilance database (Eudravigilance). Data were retrieved from the date of marketing authorization of each ICI (ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab) to 14 March, 2020. The reporting odds ratio and its 95% confidence interval were computed to assess the reporting frequency of cardiac ADRs for each ICI compared to all other ICIs.

Results

A total of 2478 individual case safety reports with at least one ICI as the suspected drug were retrieved from Eudravigilance, of which 249 (10%) reported more than one ICI. The three most reported ICIs were nivolumab (43.2%), pembrolizumab (32.5%), and the association of nivolumab/ipilimumab (9.4%). A total of 3388 cardiac ADRs were identified. Cardiac ADRs were serious (99.4%) and had a fatal outcome (30.1%). The most reported cardiac events were myocarditis, cardiac failure, atrial fibrillation, pericardial effusion, and myocardial infarction. Nivolumab was reported with a small increased reporting frequency of individual case safety reports with cardiac ADRs compared to all other ICIs (reporting odds ratio 1.09, 95% confidence interval 1.01–1.18).

Conclusions

Immune checkpoint inhibitor-induced cardiac ADRs were serious and had unfavorable outcomes. In our study, nivolumab was the only ICI with a small increased reporting frequency of individual case safety reports with cardiac ADRs compared to all other ICIs. In this regard, further head-to-head studies are needed.

     

Spontaneous reporting of adverse drug reactions in an Italian region: Six years of analysis and observations

Pharmacovigilance started in Italy in 1965, and from 1987 reporting of ADRs has been mandatory. Doctors have to send the filled forms on suspected ADRs to the Local Health Districts which transmit biannually all the reports to the Health Department. In a Northern Italian Region (Veneto) spontaneous reporting of adverse drug reactions (ADRs) has been studied during the period 1988–1993. This Region contributes a substantial percentage of the total Italian reports. The total number of reports was 3700, most of these (54 per cent) coming from GPs. A great variability in the reporting rate among the 36 districts of Veneto Region (range: 0–8.8 per 10,000 inhabitants per year) and an important under-reporting have been evident. Underreporting is also emphasized by the fact that in 1993 the Veneto doctors who sent at least one report were only 2.7 per cent. On the whole about 35 per cent of reports concerned minor reactions caused by drugs which have a well known toxicological profile. Comparison between reports coming from Veneto and the UK in some cases show a similar safety profile (omeprazole and simvastatin), whereas in other cases (e.g. terfenadine, glafenine, fluoxetine) no correspondence can be found. This article reveals the limits of the actual spontaneous reporting in Italy and suggests some possible measures for improving it.     

Different mechanisms for the photoinduced production of oxidative DNA damage by fluoroquinolones differing in photostability.

Several fluoroquinolone antibacterial agents exhibit an adverse phototoxic effect in humans and are photo-cocarcinogenic in mice. The UV-induced production of reactive oxygen species plays a role in the toxicity and may be involved in carcinogenicity. Four fluoroquinolones were examined for the ability to photochemically produce oxidative damage in naked DNA. The major structural difference in the fluoroquinolones that would have an effect on their photostability is the functionality at the 8-position. At this position, 1-cyclopropyl-7-(2,8-diazbicyclo[4.3.0]non-8-yl)-6, 8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (BAY y3118) contains a chlorine atom, lomefloxacin a fluorine atom, ciprofloxacin a proton, and moxifloxacin a methoxy group. The formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) in calf thymus DNA was assessed by HPLC with electrochemical detection, and strand breaks were measured in pBR322 with agarose gel electrophoresis. The relative photolability of the fluoroquinolones correlated to the extent of production of 8-oxodGuo and strand breaks, with both UVA and UVB irradiation, in the following order: BAY y3118 approximately lomefloxacin > ciprofloxacin > moxifloxacin. Experiments were performed to determine whether the mechanism of damage was due to a type I (radical) or type II (singlet oxygen) pathway. Nitrogen depletion of oxygen resulted in a decrease in the extent of formation of 8-oxodGuo, suggesting that oxygen was involved. The use of selective radical or singlet oxygen inhibitors was inconclusive with respect to which pathway was involved. The use of D(2)O as a solvent, which would extend the lifetime of singlet oxygen, suggested that this species is involved in the formation of 8-oxodGuo by moxifloxacin and ciprofloxacin, but not by lomefloxacin and BAY y3118. Similarly, it was found that singlet oxygen was not involved in strand break formation. Thus, the evidence suggests that fluoroquinolones can photochemically produce DNA damage by both type I and type II mechanisms.     

Musculoskeletal adverse drug reactions: a review of literature and data from ADR spontaneous reporting databases

The musculoskeletal system can be a target organ for adverse drug reactions (ADRs). Drug-induced muscle, bone or connective tissue injuries may be due to, i), primary direct drug action, or, ii), undirected consequence of generalized drug-induced disease. Musculoskeletal ADRs may be only temporarily disabling, such as muscle cramps, as well as in other cases may be serious and life-threatening, such as rhabdomyolysis. In the last few years there has been an increasing awareness of musculoskeletal ADRs. Some recent drug safety issues dealt with serious or uncommon musculoskeletal reactions like rhabdomyolysis associated to statins and tendon rupture associated to fluoroquinolones. In this review, we firstly selected those drug classes having a significantly high percentage of musculoskeletal disorder reports in the WHO adverse drug reaction database, maintained by the Uppsala Monitoring Centre. Secondly, the different musculoskeletal ADRs were closely analyzed through the data obtained from an Italian interregional ADRs spontaneous reporting database. The findings on drugs associated to different musculoskeletal disorders, have been integrated with a review of the epidemiological data available in the literature. For the most involved drugs (HMG-CoA reductase inhibitors, fluoroquinolones, corticosteroids, bisphosphonates, retinoids) the underlying musculoskeletal ADR mechanisms were also reviewed and discussed.     

Binding characteristics of fluoroquinolones to synthetic levodopa melanin

To define the binding characteristics of fluoroquinolones to synthetic levodopa melanin, the binding of various drugs, including levofloxacin and ofloxacin, and positive controls (timolol and chloroquine), was investigated in-vitro. The affinity and capacity of the drug binding were calculated by Langmuir's adsorption isotherm. The affinity constant (K) and the binding capacity (r(max)) of levofloxacin were similar to those of timolol and much lower than those of chloroquine. Racemic ofloxacin and its enantiomers showed similar K and r(max), suggesting that the binding lacked stereoselectivity. The binding experiment with levofloxacin derivatives indicated that the basic nitrogen atom at position 7 of the quinolone ring, but not carboxyl group at position 3, would play a critical role in the interaction of fluoroquinolones with melanin. The melanin-drug complexes of levofloxacin and chloroquine were washed with neutral phosphate buffer, ethanol and 1 M HCl solution to explain the nature of the interaction of melanin with the drugs. Electrostatic forces mainly participate in the formation of the chloroquine-melanin complex, whereas van der Waals' and hydrophobic interactions are involved in the levofloxacin-melanin complex in addition to electrostatic forces. The interactions of various fluoroquinolones such as norfloxacin, enoxacin, sparfloxacin, ciprofloxacin and lomefloxacin with melanin were also studied. The results showed that the relative K value was: chloroquine approximately ciprofloxacin, sparfloxacin >/= lomefloxacin > timolol, levofloxacin approximately enoxacin, norfloxacin, and that the relative r(max) value was: norfloxacin, enoxacin >/= chloroquine, sparfloxacin > levofloxacin, ciprofloxacin, timolol, lomefloxacin. The fluoroquinolones vary in their affinity and capacity to bind with melanin, and ciprofloxacin and sparfloxacin showed a stronger interaction with melanin than the other fluoroquinolones studied.     

Neuropsychiatric reactions to drugs: an analysis of spontaneous reports from general practitioners in Italy.

Limited information is available on drug-induced neuropsychiatric disorders in general practice. The spontaneous reports of both neurological and psychiatric adverse drug reactions (ADRs) collected during a 2-year period in PharmaSearch database, an Italian database recording reports of ADRs from general practitioners (GPs), were examined. Between January 2002 and December 2003, 171 general practitioners sent to PharmaSearch a total of 1131 reports corresponding to 1892 ADRs. Of overall reports, 310 (27.4%) involved the central nervous system resulting in 440 neuropsychiatric reactions (specifically, 241 neurological and 199 psychiatric). In our survey, 40 reports were excluded because they were incomplete or contradictory and thus classified as 'unlikely' or 'unclassifiable'. Therefore, the present analysis was carried out on 270 reports with 391 neuropsychiatric reactions (213 neurological and 178 psychiatric, respectively). Vertigo (16.4%), confusion (10.7%) and headache (10.0%) were the reactions more commonly reported. Drugs indicated for the treatment of nervous system disorders (ATC 1 code=N) accounted only for 38.4% of neuropsychiatric reactions, while most of these reactions were related to drugs indicated for other than nervous system diseases. Non-steroidal anti-inflammatory drugs (NSAIDs), fluoroquinolones, antidepressant drugs, opioids, and drugs for peptic ulcer were the categories most frequently suspected for neuropsychiatric reactions. Of 391 neuropsychiatric reactions, 78 (19.9%) were unlabeled and 41 (10.5%) were serious. In conclusion, the present study carried out in general practice underlines the importance of neuropsychiatric ADRs and reminds GPs to pay attention to this kind of toxicity when they prescribe pharmacological agents to their patients.     

Effect of fluoroquinolone expenditures on susceptibility of Pseudomonas aeruginosa to ciprofloxacin in U.S. hospitals.

The effect of fluoroquinolone use on the susceptibility of Pseudomonas aeruginosa to fluoroquinolones in U.S. hospitals was studied. Benchmarking surveys were sent annually to pharmacists practicing in U.S. hospitals from 1993 to 1999. Data collected included hospital characteristics, antimicrobial expenditures and use, antimicrobial stewardship activities, and bacterial susceptibilities. Antimicrobial expenditures were normalized for the number of occupied beds (OBs) per year. General linear modeling and repeated-measures mixed-effects modeling were used to determine factors predictive of P. aeruginosa susceptibility to fluoroquinolones. A total of 174 hospitals provided data for fluoroquinolone expenditures and susceptibility of P. aeruginosa; the median number of years of data was 3 (range, 1-6), representing 416 hospital years. Community hospitals contributed a majority of the data. Median fluoroquinolone expenditures increased gradually from $230 per OB in 1993 to $400 per OB in 1998. A 55% increase to $620 per OB occurred in 1999, largely because of increased spending on levofloxacin. Susceptibility to ciprofloxacin was commonly used to assess fluoroquinolone susceptibility. The median susceptibility of P. aeruginosa to ciprofloxacin decreased from 84% to 71%. Increasing expenditures for ofloxacin and levofloxacin, but not ciprofloxacin, were associated with decreasing P. aeruginosa susceptibility to ciprofloxacin. In the final multivariable model, each study year after 1993 and every increase in ofloxacin expenditure of $100 per OB were associated with decreases in P. aeruginosa susceptibility. Data from a benchmarking survey of U.S. hospitals for 1993-1999 revealed increases in levofloxacin expenditures, total fluoroquinolone expenditures, expenditures for nonfluoroquinolone antipseudomonal antimicrobials, and total antimicrobial expenditures in 1999. Increases in expenditures for levofloxacin and ofloxacin were associated with a significant decrease in P. aeruginosa susceptibility to ciprofloxacin.     

住院患者药物不良反应监测方法的探索

目的比较自动化实验室检验信号途径(ALS)与自愿呈报系统(SRS)收集药物不良反应(ADRs)的特点,完善目前医院内ADRs监测系统.方法在某医院通过SRS和ALS两种方式收集从2000年3月至2001年2月发生的ADRs.结果通过激励机制改进后的SRS提高了ADRs的呈报率;使用ALS后,进一步增加了ADRs的呈报率,ADRs报告表增加了53.52%,且ALS与SRS所呈报的ADRs在严重程度构成上有显著性差异.结论ALS弥补了SRS漏报率高和资料偏差的缺点,进一步完善了目前医院内ADRs监测系统.     

Intrinsic fluoroquinolone resistance in Orientia tsutsugamushi

Scrub typhus is a public health concern for a population of over a billion humans, with an estimated incidence of one million cases/year in endemic areas. Although doxycycline remains the standard therapy, fluoroquinolones have been used successfully in a few patients. However, there is also clinical evidence that fluoroquinolones are ineffective in the treatment of scrub typhus. To clarify this matter, we determined the in vitro susceptibility of Orientia tsutsugamushi strain Kato to ciprofloxacin and ofloxacin and sequenced the quinolone resistance-determining region (QRDR) of the gyrA gene, the target of fluoroquinolones, of 18 fresh isolates from the Lao PDR. Orientia tsutsugamushi strain Kato was resistant to ciprofloxacin and ofloxacin in vitro (minimum inhibitory concentration = 8 μg/mL). All sequences obtained, including those from the two available genomes of O. tsutsugamushi (strains Boryong and Ikeda), had a Ser83Leu mutation in their QRDR domain that is known to be associated with fluoroquinolone resistance. These findings re-emphasise the usefulness of in silico analysis for the prediction of antibiotic resistance and suggest that fluoroquinolones should not be used in the treatment of scrub typhus.     

Use and safety profile of antiepileptic drugs in Italy

Objective To analyse and discuss the use and the safety profile of individual antiepileptic drugs (AEDs) in Italy. Methods The AED safety data referred to the period January 1988–June 2005 and were obtained from the database of the Italian Interregional Group of Pharmacovigilance (GIF). This database collects all spontaneous reports of suspected adverse drug reactions (ADRs) from six Italian regions which are the main contributors to the Italian spontaneous reporting system. Individual AED consumption data (defined daily dose/1,000 inhabitants per day) in the GIF area and in the whole of Italy referred to the period January 2003-June 2005 and were derived from drug sales data (Institute for Medical Statistics Health). Results Phenobarbital was the most frequently used AED in the GIF area (4.26 DDD/1,000 inhabitants per day) followed by carbamazepine (1.97), valproic acid (1.33) and gabapentin (1.10). AED consumption in the whole of Italy showed a similar pattern. Gabapentin was the most frequently used AED among newer AEDs. In the GIF database 37,906 reports (up to June 2005) were present; 666 of them (1.76%) were associated with at least one AED (Anatomical Therapeutic Chemical code N03A). The AED with the highest number of reports was carbamazepine (208 reports) followed by phenobarbital (98), gabapentin (80), phenytoin (56), valproic acid (55), lamotrigine (51), oxcarbazepine (43) and vigabatrin (35). Use and toxicity profile were evaluated only for AEDs associated with at least 30 reports. Skin reactions were the most frequently reported ADRs, followed by haematological, general condition, hepatic, neurological and gastrointestinal adverse reactions. Phenobarbital, lamotrigine, carbamazepine and phenytoin had the highest percentage of skin reactions (69, 67, 60 and 54%, respectively). Many haematological reactions were reported for each AED; the highest percentage was related to valproic acid (25%). Vigabatrin was associated with the highest percentage of reactions related to hearing, vision and other senses (97%). Phenytoin and valproic acid had the highest percentage of hepatic reactions (30 and 20%), whereas gabapentin of nervous system, psychiatric, gastrointestinal and urinary reactions (26, 21, 21 and 14%, respectively) and phenobarbital of musculoskeletal reactions (13%). Conclusions In Italy antiepileptic drug therapy appears to be still dominated by traditional drugs. Our analysis showed a different safety profile related to each AED. Some of the drug-adverse reaction associations discussed are not included in the Italian drug leaflets or have not been reported before in the literature.