Judy Williams-Warren

Intermittent Administration of Inhaled Tobramycin in Patients with Cystic Fibrosis

BACKGROUND AND METHODS We conducted two multicenter, double-blind, placebo-controlled trials of intermittent administration of inhaled tobramycin in patients with cystic fibrosis and Pseudomonas aeruginosa infection. A total of 520 patients (mean age, 21 years) were randomly assigned to receive either 300 mg of inhaled tobramycin or placebo twice daily for four weeks, followed by four weeks with no study drug. Patients received treatment or placebo in three on-off cycles for a total of 24 weeks. The end points included pulmonary function, the density of P. aeruginosa in sputum, and hospitalization. RESULTS The patients treated with inhaled tobramycin had an average increase in forced expiratory volume in one second (FEV1) of 10 percent at week 20 as compared with week 0, whereas the patients receiving placebo had a 2 percent decline in FEV1 (P<0.001). In the tobramycin group, the density of P. aeruginosa decreased by an average of 0.8 log10 colony-forming units (CFU) per gram of expectorated sputum from week 0 to week 20, as compared with an increase of 0.3 log10 CFU per gram in the placebo group (P<0.001). The patients in the tobramycin group were 26 percent (95 percent confidence interval, 2 to 43 percent) less likely to be hospitalized than those in the placebo group. Inhaled tobramycin was not associated with detectable ototoxic or nephrotoxic effects or with accumulation of the drug in serum. The proportion of patients with P. aeruginosa isolates for which the minimal inhibitory concentration of tobramycin was 8 microg per milliliter or higher increased from 25 percent at week 0 to 32 percent at week 24 in the tobramycin group, as compared with a decrease from 20 percent at week 0 to 17 percent at week 24 in the placebo group. CONCLUSIONS In a 24-week study of patients with cystic fibrosis, intermittent administration of inhaled tobramycin was well tolerated and improved pulmonary function, decreased the density of P. aeruginosa in sputum, and decreased the risk of hospitalization.

Sputum changes associated with therapy for endobronchial exacerbation in cystic fibrosis

We sought to define objective indicators of the resolution of Pseudomonas aeruginosa endobronchial infection in patients with cystic fibrosis. We prospectively studied 75 patients admitted for treatment of a pulmonary exacerbation and quantitated sputum bacterial density, DNA content, and the concentration of albumin and total protein in sputum, and compared these values with clinical evaluation. Eleven of the 75 patients had systemic signs, fever, and leukocytosis, which we arbitrarily defined as due to endobronchial infection. At the end of hospitalization, these 11 patients were afebrile, had peripheral leukocyte counts in the normal range, and were judged improved. Sputum P. aeruginosa density, DNA content, and total protein content on admission were similar in the two illness groups. Hospitalization and parenteral antibiotic administration for an average of 14.6 days were associated with improved pulmonary function in all 75 subjects (P values for forced vital capacity, forced expiratory volume at 1 second, and peak expiratory flow rate were all less than 0.001). With improvement, there was a decrease in sputum P. aeruginosa density (mean of both groups decreased from 10(7.80) CFU/g on admission to 10(5.96) CFU/g; P less than 0.001), and a decreased DNA concentration (overall mean 4.73 +/- 4.75 on admission to 2.76 +/- 2.49 mg/g; P less than 0.002). The decrease in sputum total protein concentration for both groups was not significant (overall mean 60.5 +/- 48.4 to 43.9 +/- 38.2 mg/g; P = 0.06). Sputum albumin concentrations did not change in either group. We conclude that in cystic fibrosis subjects with a pulmonary exacerbation, bacterial density, sputum DNA and protein content decrease with hospitalization and parenteral antibiotic therapy. At the end of treatment, these indices of sputum infection and inflammation correlate with improved pulmonary function and clinical improvement. These changes are independent of the presence or absence of fever on admission.

Disposition of tobramycin in patients with cystic fibrosis: A prospective controlled study†

The pharmacokinetics of tobramycin in adolescents or young adults with cystic fibrosis and in age-matched controls were prospectively compared. Patients with CF had a higher tobramycin total body clearance (121.2 +/- 14.2 ml/min/1.73 m2) than did controls (102.2 +/- 18.9 ml/min/1.73 m2, P less than 0.05). This was not associated with a higher glomerular filtration rate (iothalamate total body clearance 147.5 +/- 29.2 ml/min/1.73 m2 in patients vs 142.9 +/- 33.3 ml/min/1.73 m2 in controls) or a lower binding of gentamicin to serum proteins (14.3% +/- 2.6% in patients vs 17.4% +/- 3.8% in controls). Tobramycin renal clearance was not significantly different in the two groups (89.5 +/- 17.9 ml/min/1.73 m2 in patients vs 81.0 +/- 15.8 ml/min/1.73 m2 in controls). In the control group, tobramycin total body and renal clearances were highly correlated with iothalamate total body clearance (r = +0.95 and +0.88, P less than 0.01). In patients with cystic fibrosis, the correlation was not significant (r = +0.56, P greater than 0.05 for total body clearance, and r = 0.32, P greater than 0.1 for renal clearance). There was no significant difference in volume of distribution normalized to body surface area or in half-life of elimination. The higher tobramycin total body clearance without an increase in renal clearance, and the lower correlation with glomerular filtration rate indicate that an extrarenal clearance pathway might play a significant role in the elimination of tobramycin from the serum of patients with cystic fibrosis.

Comparison of a β-lactam alone versus β-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis

We determined whether a β-lactam and an aminoglycoside have efficacy greater than a β-lactam alone in the management of a pulmonary exacerbation in patients with cystic fibrosis. Study design: Azlocillin and placebo or azlocillin and tobramycin were administered to 76 patients with a pulmonary exacerbation caused by Pseudomonas aeruginosa in a randomized double-blind, third-party monitored protocol. Improvement was assessed by standardized clinical evaluation, pulmonary function testing, sputum bacterial density, sputum DNA content, and time to the next pulmonary exacerbation requiring hospitalization. Results: No significant difference was seen between the 2 treatment groups in clinical evaluation, sputum DNA concentration, forced vital capacity, forced expiratory volume in second 1, or peak expiratory flow rate at the end of treatment (33 receiving azlocillin alone and 43 both antibiotics); adverse reactions were equivalent in each group. Sputum P. aeruginosa density decreased more with combination therapy (P = .034). On follow-up evaluation, an average of 26 days after the end of treatment, all outcome indicators had worsened in both groups. Time to readmission for a new pulmonary exacerbation was significantly longer in the group receiving azlocillin plus tobramycin (P < .001). Treatment-emergent tobramycin resistance occurred in both groups and was more frequent with combination therapy. Conclusion: We conclude that the combination of a β-lactam and an aminoglycoside produces a longer clinical remission than a β-lactam alone and slightly better initial improvement. (J Pediatr 1999;134:413-21)

Effect of nebulizer type and antibiotic concentration on device performance

We compared the performance of selected ultrasonic and jet nebulizers when aerosolizing several antibiotic formulations to determine optimum combinations for delivery of a respirable antibiotic aerosol. Three ultrasonic devices were tested: the UltraNeb 99/100®, the UltraAIR® and the Aerosonic®. The reusable jet nebulizers were the Dura ProNeb®, Pari‐LL® and the Sidestream®. The six disposable jet nebulizers were Marquest Acorn II®, Hudson T Updraft® II, Baxter MistyNeb®, Pari‐LC®, Pari IS‐2®, and a disposable Sidestream®. Each jet was tested with four compressors: a DeVilbiss AP‐50®, a Pulmo‐Aide®, a DuraNeb® and a PariMaster®. All nebulizing systems were initially tested with normal saline. From the initial data, six jet nebulizers and one ultrasonic device were tested with varying concentrations of tobramycin, gentamicin, ceftazidime, ciprofloxacin and colistin. Output was assessed by measuring volume (milliliters per minute), and amount of drug (milligrams per minute) nebulized. We then measured mean particle size of the antibiotic aerosol with seven jet nebulizers and two different compressors, Pulmo‐Aide® and PariMaster®, and two ultrasonic devices. The rate of nebulization of saline and antibiotic solutions (milliliters per minute) was greater with the ultrasonic device(s) than all jet nebulizer systems tested. Increasing the reservoir antibiotic concentration increased the drug output (milligrams per minute) with the jet nebulizers to a maximum, followed by decreasing output. When antibiotic concentrations were increased the output decreased more precipitously with the ultrasonic devices than with the jet nebulizers. At the highest antibiotic concentrations tested, the ultrasonic devices had the lowest output. Particle size distribution was most dependent on the specific jet device, with particle size distribution less affected by a specific antibiotic or its concentration. Higher reservoir concentrations can be utilized for increasing output of respirable antibiotic aerosols by jet nebulizers. We conclude that antibiotic output is dependent upon both the nebulizing system and the reservoir concentration of antibiotic. Pediatr Pulmonol. 1997; 23:249–260.

Disposition of drugs in cystic fibrosis. IV. Mechanisms for enhanced renal clearance of ticarcillin

To investigate the hypothesis that renal secretion of penicillins is enhanced in cystic fibrosis the maximal tubular secretion rate (Tmax) of ticarcillin and the serum concentration of ticarcillin at half‐maximal secretion rate (TC50) were determined in patients with cystic fibrosis (n= 6) and control subjects (n= 6). Each subject received three consecutive constant‐rate intravenous infusions of ticarcillin (4, 13, and 70 mg/kg/hr; 21/2 hours each) simultaneously with a constant‐rate (30 mg/kg/hr) infusion of inulin. Urine samples were collected at 1/2‐hour intervals and serum samples at the midpoint of the urine collections. Ticarcillin and inulin concentrations in serum and urine were determined by high‐performance liquid chromatographic and a spectrophotometric method, respectively. Ticarcillin serum protein binding was determined by ultrafiltration. Steady‐state ticarcillin serum concentrations were achieved at all three infusion rates. The TC50 was significantly lower (p < 0.05) in patients with cystic fibrosis (33.7 ± 12.2 μg/ml) compared with that in control subjects (77.6 ± 38.4 μg/ml). In contrast, the Tmax was similar (cystic fibrosis, 0.25 ± 0.12 mg/min/kg; control, 0.22 ± 0.14 mg/min/kg; p> 0.05). These data indicate that renal clearance of penicillins is enhanced in cystic fibrosis because of greater affinity of the renal secretory system for these drugs.

Pharmacokinetics of rifampin in children. II. Oral bioavailability.

The absolute bioavailability of oral rifampin was determined in 20 pediatric patients. Intravenous doses of rifampin (mean 287 mg/m2) were compared with p.o. doses (mean 324 mg/m2). Serum concentrations of rifampin, 25-O-desacetylrifampicin, and 3-formylrifamycin SV were determined by high performance liquid chromatography. Following a 1/2-h intravenous infusion, serum rifampin concentrations declined in a monoexponential fashion. Pharmacokinetic analysis of the rifampin serum concentration data indicated that only 50 +/- 22% of a freshly prepared p.o. suspension was absorbed. The rifampin elimination half-life following i.v. administration (2.25 +/- 0.64 h) was not different from that observed following p.o. dose administration (2.61 +/- 1.35 h). Peak rifampin concentrations were significantly higher following i.v. administration when corrected to a 300 mg/m2 dose (27.4 vs. 9.1 micrograms/ml, respectively, p less than 0.0001) than after p.o. administration. The peak concentration following a p.o. dose occurred at 2.0 +/- 0.9 h. The ratio of desacetylrifampicin to rifampin areas under the curves were similar for i.v. and p.o. routes of administration (0.23 vs. 0.19), suggesting linear metabolism of rifampin to this metabolite. 3-formylrifamycin SV concentrations were lower than those of desacetylrifampicin and were detectable in less than half of the patients. The results of this study indicate the need for larger p.o. doses when serum concentrations similar to those obtained following intravenous doses are desired.

Tobramycin Serum Concentrations After Aerosol and Oral Administration in Cystic Fibrosis.

We sought to describe tobramycin absorption after aerosol administration to cystic fibrosis (CF) subjects. Serum tobramycin concentrations were determined by modification of the radioimmunoassay (R1A) technique, lowering the limit of detection from 1.0 μg ml−1 to 0.05 μg ml−1. In 37 studies, after aerosol delivery of 666 ± 195 mg to the airway of 24 patients, in which 222 samples were assayed, only 1 serum sample contained tobramycin at a concentration greater than 1.0 μgml 1. Twenty-six of the 37 studies permitted estimation of pharmacokinetic parameters of tobramycin. The serum clearance of tobramycin following aerosol administration is 39.13 ± 0.393 L h 1 (mean ± standard error of the mean), with an elimination half-life of 3.072 ± 0.194 h. The half-fife was significantly longer than that found after intravenous administration. The elimination rate constant (Ke) was calculated to be 0.234 ± 0.002 h−1. Estimated total-body clearance in which systemic absorption was determined from sputum and urinary recovery of tobramycin was 0.094 ± 0.002 l hr−1kg−1. We also studied tobramycin absorption in six CF subjects after ingestion of a 80-mg m−2 dose, to gain insight into the tobramycin levels observed after swallowing an aerosol. Four out of the six subjects had measurable serum tobramycin concentration after ingestion. The serum concentration-time curve mirrored what was seen after aerosol administration. We concluded that tobramycin has poor systemic absorption in CF subjects after aerosol administration. Tobramycin in serum after aerosol administration is in part due to the gastrointestinal absorption of swallowed drug, as well as absorption from lower respiratory tract.

Utilization of salivary concentrations of ciprofloxacin in subjects with cystic fibrosis

SummaryCiprofloxacin, an orally-absorbed fluoroquinolone is effective against multiply resistantPseudomonas aeruginosa in cystic fibrosis patients. It is the only practicable agent against extraintestinal salmonellosis and shigellosis in developing countries. However, concern with the risk of arthropathy in young children has restricted its use in pediatrics. Pharmacokinetic studies with ciprofloxacin are limited in the pediatric population. As a result, the dose and frequency of administration are not established in children. In this study the possibility of using salivary concentrations as surrogate measure of serum concentrations was investigated. A pediatric formulation of the drug (125 mg per capsule) was prepared and compared to 250 mg tablets. Relative bioavailability was 105% (tablet/capsule). The time to peak salivary concentration and elimination rate from saliva were significantly different from serum (p<0.01 and p<0.05 respectively). The linear regression analysis of post-peak concentrations in serum and saliva yielded a slope of 1.25 and correlation coefficient of 0.83. It was also found that salivary concentrations may be contaminated from drug retained in the oral cavity. The conclusion was drawn that salivary concentrations could not be reliably used as a surrogate measure of serum levels for therapeutic drug monitoring.

Pharmacokinetics of rifampin in children. I. Multiple dose intravenous infusion.

The pharmacokinetics of intravenous rifampin (280 +/- 78 mg/m2) were investigated during multiple dose administration in 12 pediatric patients aged 3 months to 12.8 years. Serum rifampin concentration data were fit to a linear one-compartment model. There was a significant effect of duration of therapy on rifampin clearance (Cl) and half-life (t1/2) (p = 0.027 and p = 0.048, respectively). A mean increase of 52.0% in Cl (3.10-4.72 L/h/m2) and a mean decrease of 27.0% in t1/2 (2.38-1.73 h) were observed when data collected during the first 2 days of therapy were compared with data collected following 8 or more days of therapy. Peak concentrations extrapolated to the end of infusion were 27.0 +/- 8.2 micrograms/ml, and concentrations at 8 h after the dose were only 1.9 +/- 1.5 micrograms/ml. There was no significant effect of duration of therapy on these concentration values. There was no correlation between Cl and age or administered dose. Intrapatient variation in Cl was great, as evidence by the lack of correlation of initial Cl values with subsequent values in individual patients (r = 0.259). It would appear that dosage intervals may need to be shortened from 12 to 8 h during continuous therapy, and that periodic measurement of rifampin concentration may be required.