Prevalence of and risk factors for dysglycemia in patients receiving gatifloxacin and levofloxacin in an outpatient setting

STUDY OBJECTIVES: To assess the prevalence of dysglycemia (hypoglycemia or hyperglycemia) associated with oral levofloxacin and gatifloxacin therapy in an outpatient setting, and to determine the characteristics of patients who developed dysglycemia while receiving either fluoroquinolone. DESIGN: Retrospective medical record review. SETTING: Outpatient clinic of a Veterans Affairs teaching hospital. PATIENTS: A total of 1573 patients who received oral levofloxacin (343 patients), gatifloxacin (589 patients), or azithromycin (as a control, 641 patients) between June 1, 2004, and May 31, 2006. MEASUREMENTS AND MAIN RESULTS: Dysglycemia occurred in 33 patients: 13 (2.2%), 9 (2.6%), and 11 (1.7%), respectively, of those in the gatifloxacin, levofloxacin, and azithromycin groups. Of 13 patients who experienced a hyperglycemic event, 11 (84.6%) had diabetes mellitus. After adjustment for confounding factors, neither levofloxacin nor gatifloxacin were associated with increased odds of developing a dysglycemic event compared with azithromycin. Multivariate analysis demonstrated that lack of downward dosage adjustment based on creatinine clearance (odds ratio [OR] 10.3, 95% confidence interval [CI] 3.8-27.6), presence of diabetes (OR 17.1, 95% CI 3.1-94.9), or treatment with insulin (OR 5.3, 95% CI 1.8-15.7) or sulfonylureas (OR 3.6, 95% CI 1.3-10.4) independently increased dysglycemia risk. Obesity (body mass index > or = 30 kg/m(2)) was independently protective (OR 0.22, 95% CI 0.09-0.55) against dysglycemic events. CONCLUSION: Levofloxacin and gatifloxacin were not significantly associated with increased dysglycemic events compared with azithromycin. Lack of downward fluoroquinolone dosage adjustment for renal function, presence of diabetes, and treatment with insulin or sulfonylureas each independently increased the risk of dysglycemia. Obesity was independently protective against dysglycemia. More data are needed on the contributing effects of diabetes, fluoroquinolone dosage, and concomitant drug therapy so that an appropriate risk-management strategy can be developed.     

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.     

加替沙星相关血糖异常临床病例分析

目的:了解加替沙星对住院患者血糖水平的影响。方法:通过计算机管理系统进行回顾性研究,对2005年6月1日至2006年6月1日732例应用加替沙星患者及32例应用红霉素患者的血糖数据进行分析与比较,并采用排除法结合病例分析对加替沙星致血糖异常的因果关系与危险因素进行评估。结果:加替沙星引起血糖异常35例,其中高血糖27例(3.69%),低血糖8例(1.09%)。此外,35例中,非糖尿病患者为24例(68.57%),老年患者(>60岁)为27例(77.14%)。所有患者在停药及相应治疗后均恢复正常。32例应用红霉素患者未出现血糖异常。结论:加替沙星可引起血糖异常,尤其是老年患者。临床医师应了解该不良反应的风险,对使用加替沙星的患者进行血糖监测以保障患者安全。     

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.     

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...     

Gatifloxacin-induced dysglycemia.

PURPOSE: The development of gatifloxacin-induced dysglycemia in 13 patients is described; the details of the 3 most severe cases are presented. SUMMARY: Three elderly patients developed dysglycemia after initiation of gatifloxacin therapy. Both patients who developed hypoglycemia were receiving concomitant insulin or oral antidiabetic agents. Repeated doses of dextrose were required for management. The Naranjo et al. probability rating scale revealed that gatifloxacin was the probable cause in the majority of the 13 cases, primarily because of the temporal relationship with gatifloxacin and, in some instances, resolution of dysglycemia after drug discontinuation. Although the mechanism of gatifloxacin-induced hyperglycemia is not known, in vitro studies have found that certain quinolone antimicrobials can lower serum glucose levels by blocking adenosine 5'-triphosphate-dependent potassium channels in the pancreatic beta-cell, stimulating insulin release. It is difficult to unequivocally implicate gatifloxacin as the only cause of dysglycemia in the cases presented, as there are many explanations for poor glycemic control in hospitalized patients, such as stress, infection, decreased renal function, and concomitant drug therapies. However, the patients' medication regimens appeared to be stable before gatifloxacin administration. CONCLUSION: Thirteen patients developed dysglycemia after receiving gatifloxacin. Gatifloxacin was found to be the probable cause in the majority of cases.     

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.     

Effects of fluoroquinolones on insulin secretion and beta-cell ATP-sensitive K+ channels

Although fluoroquinolones are used widely in the treatment of various infectious diseases, some of the drugs are known to cause hypoglycemia as a side-effect. We have investigated the effects of three fluoroquinolone derivatives, levofloxacin, gatifloxacin, and temafloxacin, on insulin secretion and pancreatic beta-cell ATP-sensitive K(+) channel (K(ATP) channel) activity. While levofloxacin had only a small effect on insulin secretion and K(ATP) currents, gatifloxacin and temafloxacin stimulated insulin secretion and inhibited K(ATP) channel currents in a dose-dependent manner. We also determined the site of action of gatifloxacin and temafloxacin on the K(ATP) channel. In a reconstituted system, gatifloxacin and temafloxacin inhibited Kir6.2 Delta C26 channels, which function in the absence of the SUR subunit, indicating direct action of the drugs on the Kir6.2 subunits. These results suggest that stimulation of insulin secretion by inhibition of pancreatic beta-cell K(ATP) channels underlies the hypoglycemia caused by certain fluoroquinolones.     

Pharmacodynamic analysis of ceftriaxone, gatifloxacin,and levofloxacin against Streptococcus pneumoniae with the use of Monte Carlo simulation

STUDY OBJECTIVE: To evaluate the pharmacodynamics of four intravenous antimicrobial regimens-ceftriaxone 1 g, gatifloxacin 400 mg, levofloxacin 500 mg, and levofloxacin 750 mg, each every 24 hours-against recent Streptococcus pneumoniae isolates. DESIGN: Pharmacodynamic analysis using Monte Carlo simulation. DATA SOURCE: The Surveillance Network (TSN) 2002 database. MEASUREMENTS AND MAIN RESULTS: Streptococcus pneumoniae isolates (7866 isolates) were stratified according to penicillin susceptibilities as follows: susceptible (4593), intermediate (1986), and resistant (1287). Risk analysis software was used to simulate 10,000 patients by integrating published pharmacokinetic parameters, their variability, and minimum inhibitory concentration (MIC) distributions from the TSN database. Probability of target attainment was determined for percentage of time above the MIC (%T > MIC) from 0-100% for ceftriaxone and area under the concentration-time curve (AUC):MIC ratio from 0-150 for the fluoroquinolones. For ceftriaxone, probability of target attainment remained 90% or greater against the three isolate groups until a %T > MIC of 70% or greater, and it remained 90% or greater against susceptible and intermediate isolates over the entire interval (%T > MIC 0-100%). For levofloxacin 500 mg, probability of target attainment was 90% at an AUC:MIC < or = 30, but the curve declined sharply with further increases in pharmacodynamic target. Levofloxacin 750 mg achieved a probability of target attainment of 99% at an AUC:MIC ratio < or = 30; the probability remained approximately 90% until a target of 70 or greater, when it declined steeply. Gatifloxacin demonstrated a high probability (99%) of target attainment at an AUC:MIC ratio < or = 30, and it remained above 90% until a target of 70. CONCLUSION: Ceftriaxone maintained high probability of target attainment over a broad range of pharmacodynamic targets regardless of penicillin susceptibility (%T > MIC 0-60%). Levofloxacin 500 mg maintained high probability of target attainment for AUC:MIC ratios 0-30; whereas, levofloxacin 750 mg and gatifloxacin maintained high probability of target attainment for AUC:MIC ratios 0-60. Rate of decline in the pharmacodynamic curve was most pronounced for the two levofloxacin regimens and more gradual for gatifloxacin and ceftriaxone.     

Gatifloxacin: a review of its use in the management of bacterial infections.

Gatifloxacin is an 8-methoxy fluoroquinolone antibacterial agent. The drug has a broader spectrum of antibacterial activity than the older fluoroquinolones (e.g. ciprofloxacin) and shows good activity against many Gram-positive and Gram-negative pathogens, atypical organisms and some anaerobes. Notably, gatifloxacin is highly active against both penicillin-susceptible and -resistant strains of Streptococcus pneumoniae, a common causative pathogen in community-acquired pneumonia (CAP), acute sinusitis and acute bacterial exacerbations of bronchitis. Gatifloxacin is absorbed well from the gastrointestinal tract (oral bioavailability is almost 100%). Therefore, patients can be switched from intravenous to oral therapy without an adjustment in dosage. High concentrations of gatifloxacin are achieved in plasma and target tissues/fluids. Gatifloxacin has a long plasma elimination half-life, thus allowing once-daily administration. Few clinically significant interactions between gatifloxacin and other drugs have been reported. In patients with CAP, clinical response rates in recipients of intravenous/oral gatifloxacin 400 mg/day ranged from 86.8 to 98.0% and rates of bacterial eradication ranged from 83.1 to 100% (up to 28 days post-treatment). Gatifloxacin showed efficacy similar to that of amoxicillin/clavulanic acid, ceftriaxone (with or without erythromycin) with or without stepdown to clarithromycin, levofloxacin or clarithromycin. Gatifloxacin was as effective as clarithromycin or amoxicillin/clavulanic acid, and was significantly more effective (in terms of clinical response; p < 0.035) than 7 to 10 days' treatment with cefuroxime axetil in the treatment of acute exacerbations of chronic bronchitis. In acute sinusitis, gatifloxacin showed clinical efficacy similar to that of clarithromycin, trovafloxacin or amoxicillin/clavulanic acid. Genitourinary infections were also successfully treated with gatifloxacin. Gatifloxacin is generally well tolerated. Its tolerability profile was broadly similar to those of comparator agents in comparative trials. The most common adverse events are gastrointestinal symptoms (oral formulation) and injection site reactions. CONCLUSIONS: Gatifloxacin has an extended spectrum of antibacterial activity and provides better coverage of Gram-positive organisms (e.g. S. pneumoniae) than some older fluoroquinolones. The drug has favourable pharmacokinetic properties, is administered once daily and is at least as well tolerated as other fluoroquinolones. Gatifloxacin is a useful addition to the fluoroquinolones currently available for use in the clinical setting and has an important role in the management of adult patients with various bacterial infections. As with other fluoroquinolones, careful control of gatifloxacin usage in the community is important in order to prevent the emergence of bacterial resistance and thus preserve the clinical value of this agent.     

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.     

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.     

加替沙星与糖代谢紊乱

加替沙星是第四代喹诺酮类抗菌药。在临床应用中,人们发现该药可导致糖代谢紊乱,引发低血糖或高血糖。本文综述了国内外相关研究报道,提示临床医生在加替沙星用药过程中应密切监测血糖,一旦发生血糖紊乱,应立即停药并纠正血糖紊乱。     

Severe and resistant hypoglycemia associated with concomitant gatifloxacin and glyburide therapy

Severe and resistant hypoglycemia occurred in two patients with diabetes mellitus who were receiving concomitant gatifloxacin and glyburide. An 84-year-old woman treated with glyburide for type 2 diabetes mellitus experienced, for the first time, a severe episode of hypoglycemia after 2 days of gatifloxacin 400 mg/day for nonproductive cough. Her blood glucose level on hospital admission was 28 mg/dl. Gatifloxacin and glyburide were discontinued, and the patient was treated with intravenous dextrose infused over 36 hours. Glyburide was restarted before her discharge, with no recurrence of hypoglycemia. A 79-year-old man with type 2 diabetes mellitus treated with glyburide was prescribed gatifloxacin 400 mg/day for pneumonia. After 1 day of therapy, the patient was admitted to the emergency department in a coma. His blood glucose level was 18 mg/dl. Despite discontinuation of gatifloxacin and oral hypoglycemic therapy, hypoglycemia was reversed only after administration of multiple boluses of intravenous dextrose, followed by intravenous dextrose infused over 48 hours. On hospital day 7, gliclazide and levofloxacin were started; the patient experienced no recurrence of hypoglycemia and was discharged on day 10. Several cases of severe and resistant hypoglycemia associated with gatifloxacin therapy have been reported in the recent literature. Although the exact mechanism is not fully understood, it may be linked to a gatifloxacin-induced closing of the adenosine 5'-triphosphate-sensitive potassium channels in the pancreatic beta cells, leading to insulin secretion. The onset of hypoglycemia in relation to the start of gatifloxacin suggests that the drug precipitated this adverse event. Patients receiving oral hypoglycemic agents are at greater risk of experiencing gatifloxacin-induced hypoglycemia than patients not receiving these agents. Clinicians should be aware of this potentially life-threatening adverse event and monitor blood glucose levels in all patients receiving concomitant oral hypoglycemic agents and gatifloxacin.     

Urinary concentrations and bactericidal activities of newer fluoroquinolones in healthy volunteers

Eleven healthy male subjects participated in a crossover study to compare the urine concentrations and bactericidal activities of newer fluoroquinolones against common uropathogens. Each volunteer received a single oral dose of gatifloxacin (400 mg), levofloxacin (250 mg), moxifloxacin (400 mg) and trovafloxacin (200 mg), and a urine sample was obtained at 2, 6, 12 and 24 h after the dose. Urine concentrations were highest with gatifloxacin and levofloxacin and lowest with trovafloxacin. Each drug concentration was studied against a levofloxacin susceptible and moderately-susceptible strain of Escherichia coli (minimal inhibitory concentration, MICs: 0.125 and 4 mg/l), K. pneumoniae (MICs: 0.125 and 4 mg/l), Pseudomonas aeruginosa (MICs: 0.5 and 4 mg/l) and Enterococcus faecalis (MICs: 0.25 and 4 mg/l). The duration of urine bactericidal activity (UBA) was based upon the median bactericidal titre at each time period. Both gatifloxacin and levofloxacin exhibited prolonged (> or = 6 h) UBA against all of the study isolates. Moxifloxacin exhibited prolonged UBA against both isolates of E. coli, K. pneumoniae and E. faecalis but not against either strain of P. aeruginosa. Prolonged UBA was not observed for trovafloxacin against the moderately-susceptible strains with the exception of E. faecalis. Furthermore, UBA was not observed for trovafloxacin against the susceptible strain of P. aeruginosa. Although these newer fluoroquinolones exhibited similar in vitro activity against these uropathogens, only those compounds with the highest urinary concentrations (gatifloxacin and levofloxacin) produced prolonged UBA against both strains of P. aeruginosa. The findings from this study suggest that both microbiological activity and urinary concentrations are important parameters to consider when choosing a fluoroquinolone for empirical treatment of urinary tract infections (UTIs).     

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.     

Susceptibility to fluoroquinolones among commonly isolated Gram-negative bacilli in 2000: TRUST and TSN data for the United States. Tracking Resistance in the United States Today. The Surveillance Network

From January to May 2000, as part of the Tracking Resistance in the United States Today (TRUST) surveillance initiative, clinical isolates of Enterobacteriaceae (n=2519) and non-fermentative Gram-negatives (n=580) were prospectively collected from 26 hospital laboratories across the United States. Isolates were tested for susceptibility to three fluoroquinolones (ciprofloxacin, levofloxacin, gatifloxacin) and seven other agents. In addition, data for the same period were collected from The Surveillance Network (TSN) Database-USA, an electronic surveillance network that receives data from more than 200 laboratories in the US. Both surveillance methods produced similar results. Against isolates of Enterobacteriaceae, imipenem was the most active agent, followed by the fluoroquinolones; > or = 86.7% of isolates of all species of Enterobacteriaceae except Providencia spp. were susceptible to fluoroquinolones by TRUST and TSN surveillance. TRUST identified differences in susceptibility to the three fluoroquinolones of > or = 2% for Citrobacter spp., Enterobacter cloacae, Proteus mirabilis and Serratia marcescens. Isolates of P. mirabilis were considerably more susceptible to levofloxacin (94.0%) than to ciprofloxacin (87.7%) and gatifloxacin (87.7%). Other results from TRUST included Pseudomonas aeruginosa being slightly more susceptible to ciprofloxacin (73.5%) and levofloxacin (73.0%) than gatifloxacin (71.0%). Imipenem was the only compound with significant activity (95.1% susceptible, TRUST; 87.4% susceptible, TSN) against Acinetobacter baumannii, but it was inactive against Stenotrophomonas maltophilia. S. maltophilia isolates were more susceptible to levofloxacin and gatifloxacin (77.7-79.8%) than ciprofloxacin (29.7-33.0%). Against 513 urinary isolates of Escherichia coli in TRUST, levofloxacin, gatifloxacin and ciprofloxacin were equipotent. Age and gender had no clear effect on the activity of levofloxacin, ciprofloxacin or gatifloxacin. Similar results for all three fluoroquinolones were seen in outpatients and inpatients. TRUST and TSN data indicated that resistance rates had not changed appreciably for any compound studied since a similar study conducted in 1999. TRUST centralized in vitro and electronic (TSN) surveillance methods provided an effective strategy for monitoring trends in resistance.     

Moxifloxacin and glucose homeostasis: a pooled-analysis of the evidence from clinical and postmarketing studies.

BACKGROUND: Recently, clinical data has emerged suggesting that the fluoroquinolone, gatifloxacin, can affect glucose homeostosis through an unknown mechanism. In order to explore the potential effects of moxifloxacin on glucose metabolism in humans, a pooled analysis of phase II/III clinical trials and postmarketing studies was performed and compared with results from an investigation in laboratory animals. METHODS: A pooled analysis of 30 (26 controlled, 4 uncontrolled) oral and two intravenous/oral prospective, controlled phase II/III moxifloxacin studies was performed to evaluate the frequency of hyper- and hypoglycaemic episodes and glucose-related adverse events and adverse reactions (i.e. those considered to be drug related) versus comparator antimicrobials (penicillins, cephalosporins, macrolides, doxycycline, fluoroquinolones). Similar evaluations were conducted on data pooled from five postmarketing surveillance studies. In addition, potential effects of supratherapeutic doses of moxifloxacin on blood glucose and plasma insulin levels in fed and fasted rats were assessed in comparison with those of gatifloxacin, levofloxacin and glibenclamide (glyburide). RESULTS: The phase II/III database was comprised of 14,731 patients (8474 moxifloxacin, 6257 comparator antimicrobial).There were no drug-related hypoglycaemic adverse events reported for moxifloxacin in either the oral or intravenous/oral database. Two drug-related hypoglycaemic adverse events were reported in the oral comparator group, both following administration of levofloxacin and both of mild severity; one drug-related hypoglycaemic adverse event was reported in the intravenous/oral comparator group after trovafloxacin administration. Drug-related hyperglycaemic adverse events were reported in seven (<0.1%) moxifloxacin and 1 (<0.1%) comparator-treated patients in the oral study database, none of these cases were considered serious and six of the seven moxifloxacin cases were graded as mild and required no countermeasures. There were no cases of drug-related hyperglycaemic events in any patient enrolled in the intravenous/oral studies. Coadministration of oral antidiabetic drugs with moxifloxacin or comparator antimicrobials did not change the rate of blood glucose increases or decreases in diabetic patients. Data from five moxifloxacin postmarketing studies (46 130 subjects) reported no episodes of hypoglycaemia and two non-drug-related hyperglycaemic episodes. Data from animal studies revealed that supratherapeutic doses of moxifloxacin and levofloxacin did not affect blood glucose or plasma insulin levels in both fed and fasted rats, whereas gatifloxacin decreased both blood glucose and plasma insulin in a dose-dependent manner in fed rats only. The reference compound glibenclamide increased insulin and decreased glucose levels as expected. CONCLUSIONS: Hyperglycaemic or hypoglycaemic adverse reactions were reported rarely in studies with oral or sequential intravenous/oral moxifloxacin, and incidence was comparable in moxifloxacin and comparator groups. Changes in glucose metabolism were also similar in diabetic patients treated with moxifloxacin compared with those patients without diabetes mellitus. This comprehensive analysis of the datapool for moxifloxacin phase II/III clinical trials and postmarketing studies suggests that moxifloxacin administration has no clinically relevant effect on blood glucose homeostasis.     

A novel method of estimating cost of therapy by using patient population characteristics: analysis of fluoroquinolones in various populations with different distributions of renal function

INTRODUCTION: Formulary decisions regarding a given drug class are often made in the absence of patient outcome and/or sophisticated pharmacoeconomic data. Analyses that consider factors beyond simple acquisition costs may be useful in such situations. For example, the cost implications of using manufacturers' recommendations for dosing in patients with renal dysfunction may be important, depending on the distribution of various levels of renal function within a patient population. METHODS: Using four 1000-patient populations representing different renal function distributions and a fifth population of our medical center's distribution, we determined the costs of therapy for intravenous and oral levofloxacin, gatifloxacin, and moxifloxacin for a 10-day course of therapy for community-acquired pneumonia. Costs considered were average wholesale prices (AWPs), 50% of AWP, or same daily price, plus intravenous dose preparation and administration costs when applicable. Costs for each renal function distribution were examined for significant differences with an analysis-of-variance test. Also, costs of failing to adjust dosing regimens for decreased renal function were determined. RESULTS: Differences in fluoroquinolone costs (AWP, 50% AWP, or when matched as the same daily price) among the populations were found. When considering same daily prices, differences among populations ranged from about 35,000 dollars with intravenous gatifloxacin to more than 51,000 dollars for intravenous levofloxacin (all fluoroquinolones, p>0.05). Within a population, differences in costs among the intravenous fluoroquinolones ranged from 47,000-99,000 dollars. Rank orders of the drugs and population costs of therapy were affected by the pricing structure used and varied by the specific population and drug. Differences among the fluoroquinolones or populations were much smaller (<2100 dollars) when considering oral regimens. Costs potentially incurred by failing to adjust dosing for renal function were substantial. CONCLUSION: Formulary decisions can be facilitated by considering factors such as patient characteristics and related dosing in addition to simple acquisition costs. In our example, consideration of the distribution of renal function within a given patient population and related dosing for these fluoroquinolones revealed potentially important differences within the class.