Physicochemical compatibility of mixtures of dornase alfa and tobramycin containing nebulizer solutions

Patients suffering from cystic fibrosis (CF) often need to inhale multiple doses of different nebulizable drugs per day. Patients attempt to shorten the time consuming administration procedure by mixing drug solutions/suspensions for simultaneous inhalation. The objective of this experimental study was to determine whether mixtures of the nebulizer solution dornase alfa (Pulmozyme®) with tobramycin nebulizer solutions (TOBI® and GERNEBCIN® 80 mg) are physico‐chemically compatible. Drug combinations were prepared by mixing the content of one respule Pulmozyme® with either one respule TOBI® or one ampoule GERNEBCIN® 80 mg. Test solutions were stored at room temperature and exposed to light. Dornase alfa activity and tobramycin concentrations were determined by using a kinetic colorimetric DNase activity assay and a fluorescence immunoassay, respectively. Physical compatibility was determined by visual inspection and measurements of pH and osmolality. Tobramycin concentration was not affected by mixing the drug products. In spite of the high variability of the dornase alfa potency assay, it is obvious that activity is especially affected by sodium metabisulfite, used as excipient in GERNEBCIN®. Patients should be advised, not to mix Pulmozyme® with GERNEBCIN® because of the incompatibility reaction. Further analytical studies are needed in order to determine the integrity and activity of dornase alfa in mixtures of Pulmozyme® with TOBI®. Finally clinical studies are necessary in order to demonstrate equivalent efficacy and safety of simultaneous inhalation in comparison to consecutive inhalation of both drugs. Pediatr Pulmonol. 2009; 44:134–141. © 2008 Wiley‐Liss, Inc.     

Susceptibility of Malassezia pachydermatis to aminoglycosides

Previous studies have evaluated the action of gentamicin against Malassezia pachydermatis. The aim of this study was to evaluate in vitro susceptibility of M. pachydermatis to the aminoglycosides— gentamicin, tobramycin, netilmicin and framycetin. The minimum inhibitory concentration (MIC) of gentamicin was determined following methods M27‐A3 microdilution and Etest^®. The Etest^® was used to determine the minimum inhibitory concentration (MIC) of the tobramycin and netilmicin. The Kirby‐Bauer test was used to determine the antibiotic susceptibility to the framycetin. The MIC50 and MIC90 were 8.12 μg/mL and 32.5 μg/mL by microdilution method for gentamicin. The MIC50, determined by the Etest^®, was 8 μg/mL for gentamicin and netilmicin and 64 μg/mL for tobramycin. The MIC90 was 16 and 32 μg/mL for gentamicin and netilmicin respectively. The MIC90 was outside of the detectable limits for tobramycin. To framycetin, 28 strains (40%) of the 70 M. pachydermatis isolates tested showed a diameter of 22 mm, 22 strains (31.42%) showed a diameter of 20 mm, 16 strains showed a diameter of ≤ 18 mm, and only 5.71% of the isolates showed a diameter of ≥ 22 mm. This study provides evidence of high in vitro activity of the aminoglycosides—gentamicin, tobramycin, netilmicin and framycetin against M. pachydermatis. For gentamicin Etest^® showed similar values of MIC50 y MIC90 that the obtained by microdilution method. We considered Etest^® method could be a good method for these calculations with aminoglycosides.     

EFFECTS OF GENTAMICIN, NEOMYCIN AND TOBRAMYCIN ON RENAL CALCIUM AND MAGNESIUM HANDLING IN TWO RAT STRAINS

1. Standard renal clearance techniques were used to compare the acute effects of gentamicin, neomycin and tobramycin on renal calcium and magnesium handling in Sprague-Dawley and Fischer 344 rats. 2. Significant hypercalciuric and hypermagnesiuric responses to all three drugs (P<0.01) were apparent within 30 min of the onset of drug infusion. 3. The magnitude of the acute hypercalciuric and hypermagnesiuric response to the three aminoglycosides was comparable. This contrasts with their nephrotoxic action where neomycin >> gentamicin > tobramycin. The magnitude of the acute physiological responses to these drugs do not therefore reflect their nephrotoxic potential. 4. Sprague-Dawley rats were at least as responsive as Fischer rats in their acute renal responses to gentamicin. If Fischer rats are more sensitive to aminoglycoside nephrotoxicity than Sprague-Dawley rats, this is not reflected in their acute responses to gentamicin.     

Influence of age on amikacin pharmacokinetics in patients without renal disease. Comparison with gentamicin and tobramycin

Summary The influence of age on amikacin pharmacokinetics was examined in 87 patients with normal renal function. All patients had a gram negative infection, were febrile, weighed within 20% of their ideal body weight, did not receive penicillin antibiotics concurrently, had normal hematocrits and had a measured 24 h creatinine clearance greater than 80 ml/min/1.73 m². 31 patients were 20–39 years old, 27 patients were between the ages of 40–59 years, and 29 patients were 60–79 years old. These patients were compared to patients in similar previous studies who received gentamicin or tobramycin. No significant differences in clearance, volume of distribution or half-life were found due to age within a single drug group (amikacin, gentamicin, or tobramycin) or among the 3 drug groups. However, a substantial amount of intersubject variability existed in the calculated pharmacokinetic parameters. Patients over 40 years old tended to be underdosed with amikacin and the other 2 aminoglycosides. The average amikacin dose needed to achieve the desired steady-state concentrations was 18.9 mg/kg/day. 52% of the amikacin patients required doses greater than the recommended maximum (15 mg/kg/day). Since aminoglycoside pharmacokinetics do not change as age increases, doses do not need to be arbitrarily changed in older patients with normal renal function.     

Acute renal failure in cystic fibrosis: association with inhaled tobramycin therapy

We describe a 20-year-old patient with cystic fibrosis who developed acute nonoliguric renal failure associated with inhaled tobramycin. Clinical evaluation and renal biopsy findings were consistent with aminoglycoside-induced changes. Renal failure due to inhaled aminoglycosides has not been previously reported. The incidence may rise, however, with the increased use of this treatment modality. Measurable tobramycin levels due to inhalational therapy with conventional dosing in the reported patient indicate that the drug can be systemically absorbed, and renal tubular toxicity may occur.     

Treatment with tobramycin solution for inhalation reduces hospitalizations in young CF subjects with mild lung disease

Our objective was to study the effect of tobramycin solution for inhalation (TSI; TOBI, Chiron Corp.) on lung function decline rate in 400 young persons with cystic fibrosis (CF) and mild lung disease. Effects on hospitalization, antibiotic use, school days missed, and nutritional status also were determined. This was an open-label, randomized (stratified by sex and age group, i.e., 6-10 and 11-15 years), parallel-group, multicenter study. Routine subject management (control group) was compared to routine management plus 28 days of twice-daily TSI inhalation, followed by 28 days off the drug (TSI group) for 56 weeks. Primary efficacy endpoints included rate of lung function decline (as measured by forced expiratory volume in 1 sec; FEV(1)), hospitalization, and concomitant antibiotic use. Safety was assessed by analysis of treatment-emergent adverse events. Only 184 of 400 planned subjects were recruited and randomized (93 to the TSI group, and 91 to the control group). Enrollment was ended after 2 years because of difficult recruitment. An interim safety review showed a 2.42-fold risk of respiratory hospitalization for control group subjects (P = 0.020), and the study was terminated. Sixty-three subjects (34.2%) completed the entire study (30 in the TSI group, or 32.3%; and 33 in the control group, or 36.3%). Significantly fewer TSI subjects were hospitalized for worsening of respiratory symptoms (11.0% vs. 25.6%; P = 0.011), and fewer TSI subjects were hospitalized overall (16.5% vs. 27.8%; P = 0.065). Fewer TSI subjects received antibiotics other than the study drug (78.0% vs. 95.6%), and significantly fewer received oral antibiotics (76.9% vs. 91.1%; P = 0.009). No other safety or adverse event differences were observed. In conclusion, significant reductions in respiratory hospitalizations, concomitant antibiotic use, and a trend towards improvement in percent predicted forced expiratory flow (FEF(25-75)) provide evidence of a clinical benefit of TSI use in young persons with CF and mild lung disease. An effect on lung function decline rate could not be evaluated as planned, due to inadequate enrollment and early study termination.     

强化妥布霉素滴眼液治疗绿脓杆菌性角膜溃疡的临床观察

目的 探讨1．34％强化妥布霉素滴眼液治疗绿脓杆菌性角膜溃疡的方法和疗效。方法 26例（26眼）随机分成两组．每组13例（13眼）。强化浓度组（A组）：1.34％妥布霉素滴眼液滴眼；对照组（B组）0．3％妥布霉素滴眼液滴眼。两组均接受全身加局部同种和相同剂量的抗生素及激素治疗。分别观察两组角膜溃疡局限、前房积脓吸收、角膜水肿消退平均时间、病原菌培养结果和治愈后1个月最佳矫正视力，统计学处理采用t检验。结果 两组病例角膜溃疡均得到控制，所有病例均得以保留眼球，视力得到不同程度改善。强化治疗组角膜溃疡局限、前房积脓吸收时间短于对照组，经统计学分析差异有显著性。两组病原菌培养结果和治愈后1个月最佳矫正视力分布差异经统计学分析差异无显著性。结论 妥布霉素滴眼液为治疗绿脓杆菌性角膜溃疡的一线药物，强化妥布霉素频繁点眼可以快速达到较高组织浓度，加快角膜溃疡愈合过程，是有效而且安全的治疗方法。     

Aminoglycosides in cystic fibrosis: a descriptive study of current practice in Australia

Aim: To determine the diversity of clinical practice with respect to aminoglycosides in cystic fibrosis (CF) units within Australia. Method: In April 1999, a questionnaire on the use of aminoglycosides was sent to 30 CF units across Australia. Information was collected about drug selection, dosing, monitoring and toxicity with intravenous administration. Results: Completed surveys were received from 26 of the 30 units (response rate = 86%) and all units with > 40 patients. Tobramycin was the drug of choice in all but two centres where there was equivalent use of gentamicin and tobramycin. The survey demonstrated a trend in recent years to reduce the number of doses per day with 54% of centres prescribing once daily, 23% twice daily and 23% thrice daily regimens. Initial dosing was generally based on mg/kg per day (mean 8.8, range 7.5–10 mg/kg per day). Dosing by infusion occurred in 11 of 14 units using once‐daily dosing and there was equivalent use of bolus and infusion methods for multiple‐daily regimens. Drug monitoring depended on dosing regimen. Units using multiple daily regimens monitored using trough ± peak levels, whereas 50% of units using once‐daily dosing used two postdose levels to alter dose. Actual toxicity, in particular nephrotoxicity, ototoxicity and vestibular toxicity was reported by 19, 27 and 12% of units, respectively. Conclusion: The prescribing, dosing and monitoring of aminoglycosides in CF across Australia varies greatly. This is likely to be due to a lack of definitive evidence as to the optimum use in this patient group. (Intern Med J 2001; 31: 23–26)