Levofloxacin based non-rifampicin anti-tuberculous therapy: An effective alternative in renal transplant recipients in resource limited setting.

INTRODUCTION: Rifampicin is one of the most effective components of anti-tuberculous therapy (ATT). Since rifampicin is a hepatic enzyme (CYP3A4) inducer, in a post-renal transplant recipient, the dose of calcineurin inhibitors needs to be up-regulated and frequently monitored. In resource-limited (low- and lower-middle-income countries) setting this is not always feasible. Therefore, we evaluated a non-rifampicin-based ATT using levofloxacin in kidney transplant recipients. METHODS: We retrospectively studied the medical records of renal transplant recipients diagnosed with tuberculosis in our institute between 2014 and 2017. After a brief discussion with patients regarding the nature and course of ATT, those who opted for a non-rifampicin based therapy due to financial constraints were included in the study and followed for a minimum of 6 months period after the completion of ATT. RESULTS: Out of the 550 renal transplant recipients, 67 (12.2%) developed tuberculosis after a median period of 24 (1-228) months following transplantation, of them, 64 patients opted for non-rifampicin-based ATT. The mean age was 37.6 years. Only 25% were given anti-thymocyte globulin based induction, while the majority (56; 87.5%) of them were on tacrolimus-based triple-drug maintenance therapy. Extrapulmonary tuberculosis was noted in 33% of cases, while 12 (18.7%) had disseminated disease. The median duration of treatment was 12 months and the cure rate of 93.7% (n = 60) was achieved at the end of therapy. CONCLUSION: Levofloxacin based ATT appears to be a safe and effective alternative of rifampicin in kidney transplant recipients who cannot afford heightened tacrolimus dosage.

Assessment of the risk of musculoskeletal adverse events associated with fluoroquinolone use in children: A meta-analysis.

BACKGROUND: The use of fluoroquinolone antibiotics has been restricted in children because of their potential to cause adverse musculoskeletal events. This study was performed to systematically evaluate whether there is a difference between fluoroquinolone and non-fluoroquinolone antibiotics in terms of their associated risk of adverse musculoskeletal events in children. METHODS: Cochrane Library, Embase, and PubMed databases were used to retrieve studies related to fluoroquinolone and non-fluoroquinolone-induced musculoskeletal adverse events in children. A meta-analysis was performed using Stata 11. RESULTS: A total of 10 studies were included in the analysis. The combined results showed that there was no statistical difference between fluoroquinolone and non-fluoroquinolone groups in terms of musculoskeletal adverse events in children (risk ratio = 1.145, 95% confidence interval = 0.974 - 1.345, P = .101). Subgroup analysis was performed using a random-effects model. Here, the effects on the trovafloxacin and levofloxacin groups were significantly different from that of the control group. However, musculoskeletal adverse events due to either drug was not reported after long-term follow-up. CONCLUSIONS: The results showed that fluoroquinolone and non-fluoroquinolone antibiotics were not different in terms of their ability to cause musculoskeletal adverse events in children. For this reason, fluoroquinolone antibiotics can be used in children as appropriate. PROSPERO REGISTRATION NUMBER: CRD42019133900.

Levofloxacin versus placebo for the prevention of tuberculosis disease in child contacts of multidrug-resistant tuberculosis: study protocol for a phase III cluster randomised controlled trial (TB-CHAMP).

BACKGROUND: Multidrug-resistant (MDR) tuberculosis (TB) presents a challenge for global TB control. Treating individuals with MDR-TB infection to prevent progression to disease could be an effective public health strategy. Young children are at high risk of developing TB disease following infection and are commonly infected by an adult in their household. Identifying young children with household exposure to MDR-TB and providing them with MDR-TB preventive therapy could reduce the risk of disease progression. To date, no trials of MDR-TB preventive therapy have been completed and World Health Organization guidelines suggest close observation with no active treatment. METHODS: The tuberculosis child multidrug-resistant preventive therapy (TB-CHAMP) trial is a phase III cluster randomised placebo-controlled trial to assess the efficacy of levofloxacin in young child contacts of MDR-TB cases. The trial is taking place at three sites in South Africa where adults with MDR-TB are identified. If a child aged < 5 years lives in their household, we assess the adult index case, screen all household members for TB disease and evaluate any child aged < 5 years for trial eligibility. Eligible children are randomised by household to receive daily levofloxacin (15-20 mg/kg) or matching placebo for six months. Children are closely monitored for disease development, drug tolerability and adverse events. The primary endpoint is incident TB disease or TB death by one year after recruitment. We will enrol 1556 children from approximately 778 households with an average of two eligible children per household. Recruitment will run for 18-24 months with all children followed for 18 months after treatment. Qualitative and health economic evaluations are embedded in the trial. DISCUSSION: If the TB-CHAMP trial demonstrates that levofloxacin is effective in preventing TB disease in young children who have been exposed to MDR-TB and that it is safe, well tolerated, acceptable and cost-effective, we would expect that that this intervention would rapidly transfer into policy. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN92634082 . Registered on 31 March 2016.

Quadruple, sequential, and concomitant first-line therapies for H. pylori eradication: a prospective, randomized study.

BACKGROUND: Current Italian guidelines recommend 10-day bismuth-based or bismuth-free (sequential and concomitant) regimens for first-line H. pylori eradication. However, comparison among these regimens is lacking in our country. AIM: To perform a 'head-to-head' comparison among these three therapies as first-line treatment for H. pylori eradication in clinical practice. METHODS: This was a prospective, open-label randomized study enrolling consecutive patients diagnosed with H. pylori infection never previously treated. Patients were randomized to receive one of the following 10-day therapies: (a) Bismuth-based therapy: esomeprazole 20mg b.i.d and Pylera 3 tablets q.i.d; (b) Concomitant therapy: esomeprazole 20mg plus amoxicyllin 1,000mg, clarithromycin 500mg and tinidazole 500mg (all b.i.d.), and (c) Sequential therapy: esomeprazole 20mg plus amoxicyllin 1,000mg for 5days followed by esomeprazole 20mg plus clarithromycin 500mg and tinidazole 500mg for 5days (all b.i.d). H. pylori eradication was assessed by using UBT 4-6 weeks after the end of therapy. RESULTS: Overall, 187 patients were enrolled. The eradication rates achieved with Pylera, concomitant and sequential were 85.2%, 95.2%, and 93.6%, respectively, at intention to treat, and 94.5%, 96.7%, and 95.1% at per protocol analyses, without a statistically significant difference. The incidence of severe side-effects was higher with the bismuth-based therapy than with the two bismuth-free regimens (9.8% vs 1.6%; p=0.046). CONCLUSIONS: Bismuth-based and bismuth-free therapies are equally effective for first-line H. pylori eradication. However, bismuth therapy was more frequently interrupted for side-effects than bismuth-free therapies.

Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas.

IMPORTANCE: Certain antimicrobial drugs interact with sulfonylureas to increase the risk of hypoglycemia. OBJECTIVE: To determine the risk of hypoglycemia and associated costs in older patients prescribed glipizide or glyburide who fill a prescription for an antimicrobial drug. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study of Texas Medicare claims from 2006 to 2009 for patients 66 years or older who were prescribed glipizide or glyburide and who also filled a prescription for 1 of the 16 antimicrobials most commonly prescribed for this population. METHODS: We assessed hypoglycemia events and associated Medicare costs in patients prescribed 1 of 7 antimicrobial agents thought to interact with sulfonylureas, using noninteracting antimicrobials as a comparison. We used a repeated measure logistic regression, controlling for age, sex, ethnicity, Medicaid eligibility, comorbidity, prior emergency department visits for hypoglycemia, prior hospitalizations for any cause, nursing home residence, and indication for the antimicrobial. We estimated odds of hypoglycemia, number needed to harm, deaths during hospitalization for hypoglycemia, and Medicare costs for hypoglycemia treatment. MAIN OUTCOMES AND MEASURES: Any hospitalization or emergency department visit owing to hypoglycemia within 14 days of antimicrobial exposure. RESULTS: In multivariable analyses controlling for patient characteristics and indication for antimicrobial drug use, clarithromycin (odds ratio [OR], 3.96 [95% CI, 2.42-6.49]), levofloxacin (OR, 2.60 [95% CI, 2.18-3.10]), sulfamethoxazole-trimethoprim (OR, 2.56 [95% CI, 2.12-3.10]), metronidazole (OR, 2.11 [95% CI, 1.28-3.47]), and ciprofloxacin (OR, 1.62 [95% CI, 1.33-1.97]) were associated with higher rates of hypoglycemia compared with a panel of noninteracting antimicrobials. The number needed to harm ranged from 71 for clarithromycin to 334 for ciprofloxacin. Patient factors associated with hypoglycemia included older age, female sex, black or Hispanic race/ethnicity, higher comorbidity, and prior hypoglycemic episode. In 2009, 28.3% of patients prescribed a sulfonylurea filled a prescription for 1 of these 5 antimicrobials, which were associated with 13.2% of all hypoglycemia events in patients taking sulfonylureas. The treatment of subsequent hypoglycemia adds $30.54 in additional Medicare costs to each prescription of 1 of those 5 antimicrobials given to patients taking sulfonylureas. CONCLUSIONS AND RELEVANCE: Prescription of interacting antimicrobial drugs to patients on sulfonylureas is very common, and is associated with substantial morbidity and increased costs.

Levofloxacin dosing regimen in severely morbidly obese patients (BMI ≥40 kg/m(2)) should be guided by creatinine clearance estimates based on ideal body weight and optimized by therapeutic drug monitoring.

BACKGROUND: Levofloxacin is a commonly prescribed antimicrobial where recommendations exist to reduce doses for renal impairment but not to increase doses for augmented renal function. Morbidly obese patients are increasing in prevalence, and represent a population that can have augmented renal function requiring higher-than-standard doses. OBJECTIVE: The current investigation was performed to characterize the pharmacokinetics (PK) and evaluate the influence of alternate body size descriptors and renal function as predictors of levofloxacin clearance (CL) and the area under the curve over 24 h (AUC24). METHODS: A database of patients undergoing levofloxacin therapeutic drug monitoring (TDM) were queried to identify patients ≥18 years of age with a body mass index ≥40 kg/m(2). A maximum a posteriori probability Bayesian approach using a two-compartment linear PK model was used to estimate individual PK parameters and AUC24. RESULTS: A total of 394 concentration-time data points (peaks and trough) from 68 patients between 98 and 250 kg were evaluated. The median (5th, 95th percentile) daily dose and AUC24 was 1,000 (250, 1,500) mg and 90.7 (44.4, 228) mg·h/L, respectively. Levofloxacin CL was significantly (p < 0.05) related to height but not weight. As a result, levofloxacin CL was best related (R (2) = 0.57) to creatinine CL (CLcr) estimated by the Cockcroft-Gault (CG) equation and ideal body weight (IBW) because IBW is a height transformation. An empiric four-category daily-dose regimen (500, 750, 1,000, 1,250 mg) stratified by CLcr (CG-IBW) is expected to have >90 % probability of achieving an AUC24 of 50-150 mg·h/L in morbidly obese patients. Subsequent application of TDM and integration with pathogen-specific information could then be applied to tailor the levofloxacin regimen. CONCLUSIONS: The proposed approach serves as a relevant alternative to the current fixed-dosing paradigm of levofloxacin in the morbidly obese.

Economic evaluation of adjustments of levofloxacin dosage by dispensing pharmacists for patients with renal dysfunction.

Since April 2011, a dosage adjustment program has been implemented at Gifu Municipal Hospital. In this program, upon receiving a prescription for renally eliminated drugs, pharmacists verify patients' serum creatinine concentrations by using a computerized medical record system to evaluate the patient's kidney function and suggest the appropriate dosage to doctors, if necessary. In our study, we used questionnaires that were administered to pharmacists and doctors at the hospital to investigate their respective working times and the cost of the program, in order to comprehensively analyze the clinical resource costs of the hospital and evaluate the economic burden of the program for levofloxacin. In addition, we studied the pharmacists' and doctors' attitudes toward the program and the circumstances of prescriptions for patients with renal dysfunction. The questionnaire comprised items such as time required for the program; attitude toward the program, including satisfaction; and attitude toward the circumstances of prescriptions for patients with renal dysfunction. The pharmacists' and doctors' working times and cost of the program were obtained from the questionnaire responses. For cost estimation, we used data from this study as well as those of our previous study that suggested that the levofloxacin program was economically beneficial. Furthermore, their attitudes toward the program and circumstances of prescriptions for patients with renal dysfunction were clarified. Regarding the pharmacists' tasks and interventions, we need to not only investigate attitudes toward them but also perform a cost analysis by the method of the economic evaluation of the medical techniques used in our study.

[Antibiotic therapy regimens for mild community-acquired pneumonia in patients with risk factors for ineffective treatment: clinical and economic comparisons].

AIM: To evaluate the clinical efficiency, tolerance, and pharmacoeconomic parameters of treatment for mild community-acquired pneumonia (CAP) in patients with risk factors for ineffective treatment with levofloxacin (Glevo) versus original levofloxacin and standard pharmacotherapy regimens for mild pneumonia (real practice). SUBJECTS AND METHODS: An open-label comparative randomized trial was conducted in parallel groups of 147 patients aged > or = 18 years with mild CAP and risk factors for ineffective treatment. Group 1 included 61 patients (59 men and 2 women; mean age 23.3 +/- 11.2 years) receiving levofloxacin (Glevo) 500 mg/day; Group 2 comprised 41 patients (39 men and 1 woman; mean age 26.4 +/- 13.4 years) treated with original levofloxacin 500 mg/day; Group 3 consisted of 45 patients (all men; mean age 23.7 +/- 9.9 years) on standard therapy. The trial was performed in 3 pulmonology centers. RESULTS: The use of the respiratory fluoroquinolone levofloxacinto treat mild CAP in the patients with risk factors for failure for its therapy demonstrated a higher efficiency than the antibiotic regimens used in real clinical practice. This suggests that physicians underestimate risk factors and do not always make a rational choice of an antimicrobial agent in the given clinical situation. CONCLUSION: The generic form of levofloxacin (Glevo) is as clinically effective as its original drug in the treatment of CAP and characterized by its optimal pharmacoeconomic parameters.

Impact of levofloxacin dose adjustments by dispensing pharmacists on adverse reactions and costs in the treatment of elderly patients.

Ensuring an appropriate dosage of renally eliminated drugs for patients with renal insufficiency is important for preventing adverse drug reactions. We investigated the effectiveness of interventions by pharmacists in a hospital pharmaceutical department. The comparative study was performed at Gifu Municipal Hospital in Japan from March to August 2011, and included an intervention (142 patients) and a control group (98 patients). Upon receiving a prescription of levofloxacin for patients aged > or = 75 years, pharmacists evaluated the patients' kidney function and adjusted the appropriate dosage at the time of dispensation. In the intervention and control groups, levofloxacin-induced adverse reactions developed in 6 of 142 (4.2%) and 13 of 98 (13.3%) patients, respectively (p < 0.05). The cost of reducing levofloxacin per patient was yen 191.1 and yen 0 in the intervention and control groups, respectively. The cost per patient for adverse reaction treatments and examinations was yen 15.5 and yen 290.0 in the intervention and control groups, respectively. The intergroup difference in the total cost per patient was yen 465.6. Dose adjustment of levofloxacin at the time of dispensation by the pharmacist for patients aged > or = 75 years resulted in a decrease in the incidence of adverse reactions and cost. These findings can be applied not only to hospitals, but also to community pharmacies, because the intervention, which is a manual system, is simply performed when pharmacists are dispensing drugs.