A retrospective, comparative evaluation of dysglycemias in hospitalized patients receiving gatifloxacin, levofloxacin, ciprofloxacin, or ceftriaxone

STUDY OBJECTIVES: To compare rates of blood glucose abnormalities in hospitalized patients receiving fluoroquinolones or ceftriaxone, and to describe the characteristics of patients who develop blood glucose abnormalities while receiving these agents. DESIGN: Retrospective chart review. SETTING: Two community-based hospitals in the Houston, Texas, region. PATIENTS: Seventeen thousand one hundred eight patients who received fluoroquinolones or ceftriaxone; of those, 101 received levofloxacin, gatifloxacin, or ceftriaxone and also had serum glucose concentrations above 200 or below 50 mg/dl within 72 hours of receiving the drug. MEASUREMENTS AND MAIN RESULTS: Baseline demographics of patients with glucose abnormalities while receiving gatifloxacin, levofloxacin, or ceftriaxone were similar. Mean +/- SD patient age, weight, and estimated creatinine clearance were 67 +/- 17 years, 79 +/- 21 kg, and 52 +/- 32 ml/minute, respectively. Dysglycemia rates relative to treatment were as follows: gatifloxacin 76 (1.01%) of 7540 patients, levofloxacin 11 (0.93%) of 1179, ceftriaxone 14 (0.18%) of 7844, ciprofloxacin 0 (0%) of 545, and any fluoroquinolone 87 (0.94%) of 9264. Dysglycemia was more likely to occur in patients receiving any fluoroquinolone than in those receiving ceftriaxone (relative risk [RR] 3.32, 95% confidence interval (CI) 2.31-4.78, p < 0.05). The rate of dysglycemia did not differ with gatifloxacin and levofloxacin (RR 1.07, 95% CI 0.62-1.86, p = 0.8). Of the 101 patients with dysglycemias, hypoglycemia occurred in nine (9%) and hyperglycemia in 92 (91%). In a multivariate analysis of patients receiving fluoroquinolones, only concomitant sulfonylurea therapy was identified as an independent risk factor for development of hypoglycemia compared with patients who experienced hyperglycemia. CONCLUSION: In the 17,108 patients receiving a fluoroquinolone or ceftriaxone, the rate of dysglycemia was greater in those receiving levofloxacin or gatifloxacin than in those receiving ceftriaxone. However, no difference was noted in the rate of glucose abnormalities with levofloxacin versus gatifloxacin. Clinicians should be aware of dysglycemic events that may occur in patients receiving fluoroquinolones, especially in those with diabetes mellitus or those receiving sulfonylureas.     

Effects of gatifloxacin and levofloxacin on rates of hypoglycemia and hyperglycemia among elderly hospitalized patients

STUDY OBJECTIVES: To compare rates of hypoglycemia and hyperglycemia among elderly hospitalized patients with normal blood glucose concentrations at baseline who were receiving either gatifloxacin or levofloxacin, and to determine if appropriateness of their doses, according to their package inserts, was associated with hypoglycemia or hyperglycemia. DESIGN: Retrospective cohort study. SETTING: Integrated Veterans Administration (VA) health care system. PATIENTS: Nine hundred thirty-seven elderly (>or= 65 yrs) patients with documented blood glucose levels of 65-140 mg/dl before receiving a fluoroquinolone. MEASUREMENTS AND MAIN RESULTS: Between January 2003 and April 2004, 405 patients receiving levofloxacin met study criteria. In April 2004, gatifloxacin was substituted for levofloxacin on the formulary of this VA system. Thus, between April 2004 and December 2004, 532 patients received gatifloxacin. All blood glucose concentrations during hospitalization that were measured during fluoroquinolone therapy or within 72 hours of completion of therapy were reviewed. Demographic characteristics, comorbidities, insulin and oral hypoglycemic therapies, disease severity, blood glucose levels, and outcomes were recorded and compared between groups. The two groups were similar at baseline for all characteristics examined except previous hospitalization. In the logistic regression, gatifloxacin was independently associated with both hypoglycemia (adjusted odds ratio [AOR] 2.5, 95% confidence interval [CI] 1.2-5.7, p=0.04) and hyperglycemia (AOR 2.4, 95% CI 1.5-3.6, p<0.001). Improper dosage adjustment based on renal function was not associated with higher rates of hypoglycemia and hyperglycemia for either drug. Of the 532 patients receiving gatifloxacin, 465 (87.4%) received appropriate doses, yet gatifloxacin was associated with higher rates of hypoglycemia and hyperglycemia compared with patients receiving levofloxacin. CONCLUSIONS: Higher rates of both hypoglycemia and hyperglycemia were noted among elderly hospitalized patients who received gatifloxacin compared with those receiving levofloxacin, irrespective of dosing.     

喹诺酮类药物引起血糖异常不良反应的对比研究

目的:研究糖尿病和非糖尿病患者使用氟喹诺酮类药物(左氧氟沙星、环丙沙星、莫西沙星)对血糖的影响(低血糖或高血糖).方法:采用回顾性分析的方法,筛选我院医院信息系统(HIS)在2014年6月—2016年6月接受静脉氟喹诺酮类药物治疗的744例住院患者纳入研究,其中糖尿病患者134例,应用Logistic分析方法评估其糖代...     

An evaluation of the effects of gatifloxacin on glucose homeostasis

Introduction The United States labeling for gatifloxacin has been updated to include contradictions related to its reported association with dysglycemia. However, adequately controlled studies in acute care settings assessing the magnitude and clinical determinants of dysglycemia are lacking. Objectives To compare the hypoglycemic and hyperglycemic effects of gatifloxacin with ceftriaxone in hospitalized patients. Methods A retrospective cohort study of hospitalized adult (≥18 years) patients admitted with Community Acquired Pneumonia (CAP) or Acute Exacerbation of Chronic Bronchitis (AECB) in a US tertiary care hospital between 7/1/01 and 12/31/04 treated with gatifloxacin or ceftriaxone during hospital admission. Outcomes of interests were incidence of hypoglycemia (blood glucose levels <46 mg/dL) or hyperglycemia (>200 mg/dL) during up to 5 days of drug exposure. Risks for gatifloxacin and ceftriaxone were compared adjusting for variables previously reported to be independent predictors of hypoglycemia or hyperglycemia. Results 1504 patients met the study inclusion criteria. Compared to ceftriaxone, gatifloxacin was associated with an increased risk of hypoglycemia: (adjusted odds ratio (OR) 2.34, 95% confidence interval (CI) 1.4–4.0). The increased risk of hypoglycemia during exposure to gatifloxacin was similar in patients with and without a diagnosis of diabetes mellitus. Gatifloxacin was not associated with an increased risk for hyperglycemia (adjusted OR: 1.06 95% CI 0.8–1.4) considering the whole study cohort. However, stratification by diagnosis of diabetes, gatifloxacin treated patients appeared to have a reduced risk of hyperglycemia (adjusted OR: 0.4 95% CI 0.2–0.4) while non-diabetic gatifloxacin treated patients appeared to have an increased risk of hyperglycemia (adjusted OR: 1.64 95% CI 1.1–2.4). Conclusion The risk of dysglycemia with gatifloxacin in this population of hospitalized patients was not as high as previously reported in ambulatory patients. Although these results suggest gatifloxacin use is safer in acute care settings, we recommend that clinicians monitor blood glucose levels carefully or consider alternatives to gatifloxacin therapy whenever possible.     

Incidence of allergic reactions associated with antibacterial use in a large, managed care organisation.

BACKGROUND: Data on the incidence of serious allergic reactions to fluoroquinolone antibacterials are mainly derived from spontaneous reports that cannot be used to accurately estimate incidence. METHODS: This study estimated the drug-specific incidence of serious allergic reactions after fluoroquinolone, cephalosporin and phenoxymethylpenicillin potassium exposure, using claims for healthcare services with confirmation through medical record abstraction within a large health insurer database. Cohorts exposed to each antibacterial of interest (moxifloxacin, levofloxacin, ciprofloxacin, gatifloxacin, cephalosporins and penicillin) were identified, and followed for 14 days for anaphylaxis (9th revision of the International Classification of Diseases [ICD-9] code 995.0), other allergic drug reactions (ICD-9 995.2, 995.3) or cardiopulmonary resuscitation. RESULTS: The incidence per 10,000 first dispensings of any allergic diagnosis made in the hospital or emergency department was similar for moxifloxacin (4.3; 95% CI 3.5, 5.3), penicillin (4.7; 95% CI 3.8, 5.7) and ciprofloxacin (5.4; 95% CI 4.4, 6.5). The incidence for moxifloxacin was lower than that for levofloxacin (8.7; 95% CI 7.4, 10.0), gatifloxacin (6.7; 95% CI 5.6, 7.9) and the cephalosporins (7.5; 95% CI 6.3, 8.8). The incidence of anaphylaxis/anaphylactoid reactions after first dispensings was similar for the fluoroquinolones: 0.1 (95% CI 0.0, 0.3) for ciprofloxacin, 0.3 (95% CI 0.1, 0.5) for moxifloxacin, 0.3 (95% CI 0.1, 0.6) for gatifloxacin and 0.5 (95% CI 0.3, 0.9) for levofloxacin; and comparable with that of the cephalosporins (0.2; 95% CI 0.0, 0.4) and penicillin (0.1; 95% CI 0.0, 0.3). CONCLUSIONS: Anaphylactic reactions were rare and their incidence did not differ substantially among the drug groups studied. By determining the occurrence of reactions following defined exposures, these results provide a context for the interpretation of spontaneous reports of allergic reactions.     

Hypoglycemia in inpatients after gatifloxacin or levofloxacin therapy: nested case-control study

STUDY OBJECTIVES: To compare the incidence of hypoglycemic events in patients exposed to gatifloxacin or levofloxacin, and to measure the odds of experiencing a hypoglycemic event after receiving gatifloxacin versus levofloxacin while adjusting for confounders. DESIGN: Nested case-control study within a historical cohort. SETTING: A tertiary care, 730-bed, teaching hospital in central Illinois. PATIENTS: Seven thousand two hundred eighty-seven hospitalized patients who received gatifloxacin or levofloxacin therapy. MEASUREMENTS AND MAIN RESULTS: A total of 113 patients (case patients) had blood glucose levels below 51 mg/dl; 113 control patients, matched for age and sex, had no hypoglycemia. Matched conditional logistic regression models adjusted the odds of having hypoglycemia for significant covariates. The 12-month incidence of hypoglycemia was 11/1000 patients after levofloxacin administration and 21/1000 patients after gatifloxacin (absolute risk increase 10/1000 patients, 95% confidence interval [CI] 4-16/1000). Renal failure, sepsis syndrome, and concomitant hypoglycemic drug therapy significantly predicted hypoglycemia. After adjustment for significant predictors, the odds of having hypoglycemia were 2.81 (95% CI 1.02-7.70) times higher after gatifloxacin than levofloxacin therapy. CONCLUSION: Among inpatients, the incidence of hypoglycemic events is greater after treatment with gatifloxacin than levofloxacin. The odds of experiencing hypoglycemic events are greater with gatifloxacin even after adjusting for other hypoglycemia risk factors, such as concomitant hypoglycemic drugs, renal failure, and sepsis syndrome.     

Levofloxacin: an updated review of its use in the treatment of bacterial infections

Levofloxacin is the L-form of the fluoroquinolone antibacterial agent, ofloxacin. In in vitro studies, levofloxacin demonstrated a broad range of activity against Gram-positive and -negative organisms and anaerobes. The drug is more active against Gram-positive organisms than ciprofloxacin, but less active than newer fluoroquinolones such as gatifloxacin. Its activity against Streptococcus pneumoniae is unaffected by the presence of penicillin resistance. In several randomised controlled trails, 5 to 14 days' treatment with intravenous and/or oral levofloxacin proved an effective therapy for upper and lower respiratory tract infections. In patients with mild to severe community-acquired pneumonia (CAP), intravenous and/or oral levofloxacin 500mg once or twice daily was as effective as intravenous and/or oral gatifloxacin, clarithromycin, azithromycin or amoxicillin/clavulanic acid. Overall, clinical response rates with levofloxacin ranged from 86 to 95% versus 88 to 96% with comparator agents; bacteriological response rates were 88 to 95% and 86 to 98%, respectively. Sequential (intravenous +/- oral switch) therapy with levofloxacin 750mg once daily was as effective as intravenous imipenem/cilastatin (+/- oral switch to ciprofloxacin) in patients with severe nosocomial pneumonia. Generally, oral levofloxacin 250 or 500mg once daily was at least as effective as oral cefaclor, cefuroxime axetil, clarithromycin or moxifloxacin in patients with acute exacerbations of chronic bronchitis as assessed by either clinical or bacteriological response rates. This approach also provided similar efficacy to amoxicillin/ clavulanic acid or clarithromycin in patients with acute sinusitis. Sequential therapy with levofloxacin 500mg twice daily for 7 to 14 days' was as effective as intravenous imipenem/cilastatin in patients with suspected bacteraemia. Oral levofloxacin 500mg once daily for 7 to 10 days was also an effective treatment in patients with uncomplicated skin and skin structure infections, and in those with complicated urinary tract infections. A higher dosage of sequential levofloxacin 750mg once daily proved as effective as intravenous ticarcillin/clavulanic acid (+/- oral switch to amoxicillin/clavulanic acid) in the treatment of complicated skin and skin structure infections. Pharmacoeconomic studies suggest that levofloxacin may be cost-saving in comparison to conventional therapies. CONCLUSIONS: Levofloxacin continues to demonstrate good clinical efficacy in the treatment of a range of infections, including those in which S. pneumoniae is a potential pathogen. Importantly, it has efficacy in CAP similar to that of gatifloxacin and at least as good as that of the third generation cephalosporins. Extensive clinical data confirm the good tolerability profile of this agent without the phototoxicity, hepatic and cardiac events evident with some of the other newer fluoroquinolone agents. Levofloxacin therefore offers a unique combination of documented efficacy and tolerability, and provides an important option for the treatment of bacterial infections.     

Single-dose azithromycin versus erythromycin or amoxicillin for Chlamydia trachomatis infection during pregnancy: a meta-analysis of randomised controlled trials

This review aimed to compare data regarding the effectiveness and safety of azithromycin with alternative regimens in the treatment of pregnant women with Chlamydia trachomatis infection. PubMed and Scopus databases were searched to identify relevant randomised controlled trials (RCTs). The main analysis focused on comparison of azithromycin with erythromycin. In a secondary analysis, azithromycin was compared with erythromycin or amoxicillin. Eight RCTs studying 587 pregnant women with microbiologically documented C. trachomatis infection were included in the meta-analysis. Overall, there was no difference between azithromycin and erythromycin regarding treatment success in intention-to-treat patients (pooled odds ratio (OR)=2.66, 95% confidence interval (CI) 0.69-10.29) or in clinically evaluated patients (OR=1.46, 95% CI 0.56-3.78). Furthermore, azithromycin was associated with fewer gastrointestinal adverse events (OR=0.11, 95% CI 0.07-0.18), fewer total adverse events (OR=0.11, 95% CI 0.07-0.18), a smaller proportion of patients who withdrew from the study (OR=0.12, 95% CI 0.04-0.37) and better compliance (OR=23.7, 95% CI 9.34-60.14) than erythromycin. The results of the secondary analysis comparing azithromycin with erythromycin or amoxicillin were similar to those of the main analysis. In conclusion, azithromycin was associated with similar effectiveness but less adverse events compared with erythromycin or amoxicillin in the treatment of pregnant women with C. trachomatis infection.     

Anticoagulation-related outcomes in patients receiving warfarin after starting levofloxacin or gatifloxacin

STUDY OBJECTIVE: To compare anticoagulation-related outcomes in patients receiving stable dosages of warfarin who started levofloxacin or gatifloxacin therapy. DESIGN: Retrospective medical record review. SETTING: Veterans Affairs medical center. PATIENTS: Of 92 patients receiving the same dosages of warfarin for at least 4 weeks before starting antibiotic therapy, 54 received levofloxacin between January and September 2003, and 38 received gatifloxacin between January and September 2004. MEASUREMENTS AND MAIN RESULTS: Data were obtained through the hospital's pharmacy, laboratory, and general patient databases and through electronic medical records. The INRs evaluated were prefluoroquinolone use, defined as the last INR measured before the start of antibiotic therapy (up to 4 wks earlier), and postfluoroquinolone use, defined as any INR measured during antibiotic therapy through 1 week after discontinuation of the antibiotic. Analyzed outcomes included the percentage of patients with postfluoroquinolone INRs that were above 4, that exceeded the therapeutic goal, or that exceeded the goal by more than 1 point; INR changes of more than 0.5, 1, or 1.5 points above the INR before fluoroquinolone use; major or minor bleeding events; requirement for vitamin K administration; warfarin dosage reduction or withholding doses; and warfarin-related hospital, emergency, or urgent care admissions or visits. No significant differences were noted in baseline characteristics with regard to age, sex, prefluoroquinolone INR, or anticoagulation indications between the two groups. The percentage of patients with a postfluoroquinolone INR above 4 was 2% (1 of 54 patients) in the levofloxacin group versus 21% (8 of 38 patients) in the gatifloxacin group (p=0.003). The percentage of patients receiving vitamin K in the levofloxacin and gatifloxacin groups was 0% (0 of 54 patients) and 11% (4 of 38, p=0.026), respectively. For the other anticoagulation-related outcomes, no significant differences were noted between the groups. CONCLUSION: Patients receiving warfarin who take gatifloxacin may be at higher risk for an INR above 4 compared with those taking levofloxacin. Close monitoring of warfarin therapy while concomitantly receiving gatifloxacin is warranted.     

Azithromycin for the secondary prevention of coronary artery disease: a meta-analysis.

PURPOSE: A meta-analysis of randomized, controlled trials that evaluated the effect of the macrolide antibiotic, azithromycin, on clinical outcomes in patients with coronary artery disease (CAD) was conducted. METHODS: A systematic literature search of MEDLINE, EMBASE, Web of Science, and the Cochrane Database of Systematic Reviews was conducted using specific search terms. Randomized, controlled trials comparing azithromycin or placebo in secondary CAD patients with adequately reported data on mortality and clinical cardiac endpoints were included. A random-effects model was used. RESULTS: Six studies (n=13,778) met the inclusion criteria. The trials varied in their design. On meta-analysis, azithromycin resulted in a nonsignificant reduction in mortality versus placebo (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.77-1.09; p=0.31). Four trials reported the rate of nonfatal myocardial infarction (MI). Azithromycin did not have an effect on the rate of nonfatal MI versus placebo (OR, 0.95; 95% CI, 0.80-1.13; p=0.57). Five trials reported rates of hospitalization in which no significant difference was seen with azithromycin versus placebo (OR, 0.97; 95% CI, 0.80-1.17; p=0.76). Six trials were used to evaluate the composite cardiovascular endpoint. Again, no significant benefit was seen with azithromycin versus placebo (OR, 0.93; 95% CI, 0.84-1.03; p=0.218). CONCLUSION: Meta-analysis showed that azithromycin does not appear to reduce the frequency of recurrent cardiac events in patients with CAD. Results from ongoing trials may clarify the role of azithromycin in the secondary prevention of coronary events.     

Achilles tendon rupture and its association with fluoroquinolone antibiotics and other potential risk factors in a managed care population

BACKGROUND: Case reports and observational studies have implicated fluoroquinolone antibiotic exposure as a risk factor for Achilles tendon rupture (ATR), an uncommon condition for which there are few formal studies. We sought to quantify the strength of association between exposure to fluoroquinolone antibiotics and the occurrence of ATR, accounting for other risk factors. METHODS: This was a case-control study nested within a health insurer cohort. Cases of ATR were identified and confirmed using patterns of health insurance claims that were validated through sampled medical record review. Information on risk factors, including fluoroquinolone exposure, came from health insurance claims. RESULTS: There were 947 cases of ATR and 18 940 controls. A dispensing of a fluoroquinolone antibiotic in the past 6 months was more common among ATR cases than controls, although not significantly so (odds ratio (OR) = 1.2; 95% confidence interval (CI) = 0.9-1.7), and exposure to a higher cumulative fluoroquinolone dose was more strongly associated (OR = 1.5, 95%CI = 1.0-2.3). Other risk factors for ATR were trauma (OR = 17.2, 95%CI = 14.0-20.2), male sex (OR = 3.0, 95%CI = 2.6-3.5), injected corticosteroid administration (OR = 2.2, 95%CI = 1.6-2.9), obesity (OR = 2.0, 95%CI = 1.2-3.1), rheumatoid arthritis (OR = 1.9, 95%CI = 1.0-3.7), skin or soft tissue infections (OR = 1.5, 95%CI = 0.9-2.3), oral corticosteroids (OR = 1.4, 95%CI = 1.0-1.8), and non-fluoroquinolone antibiotics (OR = 1.2, 95%CI = 1.1-1.5). CONCLUSIONS: The elevation in ATR risk associated with fluoroquinolones was similar in magnitude to that associated with oral corticosteroids or non-fluoroquinolone antibiotics. Trauma and male sex were more strongly associated with ATR, as were obesity and injected corticosteroids.     

加替沙星与左氧氟沙星治疗泌尿系感染的Meta分析

目的 评价加替沙星与左氧氟沙星治疗泌尿系统感染的临床安全性、有效性,及疗效与成本。方法 检索1998年1月-2016年4月在PubMed、Cochrane图书馆、中国期刊全文数据库（CNKI）、万方数据库、中文科技期刊全文数据库（VIP）、中国生物医学文献数据库（CBM）发表的有关加替沙星与左氧氟沙星治疗泌尿系统感染的文献,按照Cochrane系统评价方法,运用Rev Man 4.2.10软件进行Meta分析。结果 纳入文献17篇,共1 348例;加替沙星治疗泌尿系统感染的有效性明显高于左氧氟沙星[RR=2.01,95% CI（1.44、2.79）],疗程与不良反应无差异[RR=0.76,95% CI（0.50、1.17）,P=0.22],但加替沙星治疗泌尿系统感染的成本-效果明显低于左氧氟沙星。结论 目前泌尿系统感染的治疗方案中,尽管左氧氟沙星的疗效稍逊色于加替沙星,但左氧氟沙星更具成本-效果优势。     

Blood pressure control and factors predicting control in a treatment-compliant male veteran population

STUDY OBJECTIVE: To estimate blood pressure control and identify treatment variables predicting control in treatment-compliant, hypertensive, male veterans. SETTING: Outpatient clinic of a Veterans Affairs medical center. DESIGN: Retrospective review of computerized patient records over a 12-month period for demographics, comorbidities, patient-specific blood pressure goals, blood pressure history, antihypertensive therapy, and refill history. PATIENTS: Two hundred fifty hypertensive men aged 39-90 years whose antihypertensive regimen remained unchanged over 12 months. MEASUREMENTS AND MAIN RESULTS: The proportion of patients with blood pressures below 160/90 mm Hg was 86%; only 34.8% had pressures below 140/90 mm Hg. Blood pressure control was less common with advancing age (42.1%, 33.7%, and 29.4% for patients aged < 60, 60-75, and > 75 yrs, respectively, p = 0.057 for trend). Treatment intensity was highest in obese men, those aged 60-75 years, and those with a history of chronic heart failure or angina, and lowest in men older than 75 years or with a history of stroke. Blood pressure control was independently associated with therapy with beta-blockers (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.5-10.2, p = 0.005), loop diuretics (OR 4.3, 95% CI 1.6-12.1, p = 0.005), angiotensin-converting enzyme inhibitors (OR 3.1, 95% CI 1.2-8.2, p = 0.025), and long-term simvastatin therapy (OR 3.7, 95% CI 1.9-7.4, p = 0.0001), and with a diagnosis of coronary artery disease (OR 3.2, 95% CI 1.35-7.69, p = 0.009). The relationship between simvastatin therapy and blood pressure control persisted after controlling for the higher treatment intensity in patients taking the drug. Factors predicting poor control included a history of stroke (OR for control 0.36, 95% CI 0.19-0.69, p = 0.002), age over 75 years (OR 0.43, 95% CI 0.18-0.98, p = 0.046), highest low-density lipoprotein tertile (OR 0.37, 95% CI 0.17-0.80, p = 0.013), highest body mass index tertile (OR 0.46, 95% CI 0.21-1.00, p = 0.05), and therapy with two or fewer antihypertensives (OR 0.14, 95% CI 0.04-0.61, p = 0.009). CONCLUSION: In a compliant veteran population, control of blood pressure appeared inadequate but was significantly more likely in those receiving at least three antihypertensive agents. Long-term therapy with simvastatin was independently associated with increased odds of control.     

Nonadherence as a predictor of antidiabetic drug therapy intensification (augmentation)

PURPOSE: To determine if nonadherence with antidiabetic drug therapy is predictive of subsequent antidiabetic drug therapy intensification. METHODS: We conducted a retrospective cohort study examining retail pharmacy dispensings of sulfonylureas or metformin to 1067 patients having diabetes. Patients that did not receive a sufficient quantity of medication to cover at least 80% of days during the evaluation period were classified as nonadherent. Outcomes identified were increase in the dose of antidiabetic medication utilized, the addition of a second antidiabetic agent to the regimen or either. RESULTS: Among users of sulfonylurea monotherapy, those classified as nonadherent were 45% more likely to intensify therapy in subsequent months as compared with those classified as adherent (age-adjusted odds ratio (OR) 1.45; 95% confidence interval (CI) 1.06-2.00). This finding was largely driven by observed increases in dosage, which were more likely among patients classified as nonadherent (age-adjusted OR 1.48, 95%CI 1.07-2.05). Nonadherence was not found to be predictive of the subsequent addition of a second antidiabetic agent (OR 1.02; 95%CI 0.64-1.63). Overall findings were similar for the smaller sample of patients receiving metformin monotherapy, though observed differences did not achieve statistical significance. CONCLUSIONS: Patients who were poorly adherent to oral antidiabetic drug therapy more frequently experienced an increase in the dose of medication prescribed, as compared to patients that were classified as adherent. This finding underscores the need for prescribers to consider nonadherence as a root cause when patients fail to achieve therapeutic goals.     

Exposure-toxicity relationships for tipifarnib in cancer patients

AIMS: To explore the potential relationship between systemic exposure to tipifarnib and the incidence of toxicity in cancer patients. METHODS: Data from 673 subjects (540 receiving tipifarnib and 133 receiving placebo) were included in the analysis. Tipifarnib was administered in doses ranging from 100 mg to 850 mg twice daily under fed conditions for 21 days in a 28 day cycle. Univariate and multivariate logistic regression models were used to evaluate the relationships between tipifarnib exposure and haematological (neutropenia and thrombocytopenia) and nonhaematological toxicities. Tipifarnib exposure was quantified as the area under the curve during the first cycle of chemotherapy (AUC), the maximum plasma concentration (C(max)), the time above plasma tipifarnib concentrations of 400 (T400) and 600 ng ml(-1) (T600), the cumulative area under the curve (AUC(T)), and the area under the curve density (AUC(D)), defined as the ratio AUC(T) to the duration of treatment. The nonhaematological toxicities measured were elevation of AST, ALT, bilirubin and serum creatinine, the occurrence of a skin rash, CNS or peripheral neuropathy, nausea and vomiting, diarrhoea and inflammation of the gastrointestinal tract. Odds ratios (OR) associated with drug exposure were used to measure the effect of the drug. RESULTS: Tipifarnib AUC exhibited a positive and significant association with neutropenia grade > or =3 (OR 1.69, 95% CI 1.47, 1.95) and thrombocytopenia grade > or =3 (OR 1.41, 95% CI 1.21, 1.63) in patients with solid tumours, but not in refractory or relapsed AML patients. The incidence of exposure-related nonhaematological toxicity is small regardless of tumour type. No association was found between tipifarnib AUC and the elevation of AST, ALT and total bilirubin, and nausea and vomiting. There was a weak relationship between tipifarnib AUC and serum creatinine elevation (OR 1.18, 95% CI 1.11, 1.26), CNS (OR 1.05, 95% CI 1.01, 1.10) and peripheral neurotoxicity (OR 1.10, 95% CI 1.03, 1.18), diarrhoea (OR 1.14, 95% CI 1.08, 1.21), gastrointestinal tract inflammation (OR 1.13, 95% CI 1.07, 1.19), and skin rash (OR 1.10, 95% CI 1.04, 1.17). CONCLUSIONS: In those patients who develop severe toxicity, dose reduction may improve the tolerability of tipifarnib. However, an exposure-guided approach to dosage adjustment to limit haematological and nonhaematological toxicity is not warranted.