Defining a pulmonary exacerbation in cystic fibrosis.

OBJECTIVES: Despite the central importance of pulmonary exacerbations (PExs) as an outcome measure in cystic fibrosis clinical trials, no standardized definition of PEx exists. We conducted a prospective, multicenter study to establish a standardized PEx definition and score for use in clinical trials, based on clinical status rather than on treatment decisions. STUDY DESIGN: Subjects were 246 patients enrolled in the placebo arm of a randomized, controlled trial of tobramycin for inhalation. Physician-investigators completed PEx questionnaires on all subjects at scheduled intervals during the 6-month study, indicating new or worsening symptoms, physical examination findings, and impression of PEx status (presence or absence and severity). Logistic regression was used to assess the relative importance of each of the characteristics in predicting a PEx. RESULTS: We developed 2 PEx scores that use easily ascertained symptoms and chest examination findings; one also includes change in forced expiratory volume in 1 second over the preceding month. Both scores were sensitive and specific for predicting the presence of a PEx (sensitivity, 86%; specificity, 86%). The scores were validated in subjects in the intervention arm of the trial. CONCLUSION: We hope that the proposed PEx score might serve as a standardized outcome measure for future clinical trials in cystic fibrosis, allowing meaningful comparisons of study results.

Safety of aerosolized INS 365 in patients with mild to moderate cystic fibrosis: results of a phase I multi-center study.

Cystic fibrosis (CF) is characterized by defective cystic fibrosis transmembrane regulator (CFTR) expression and function, associated with abnormal ion transport and mucociliary clearance, and clinical lung disease. Triphosphate nucleotides such as uridine-5'-triphosphate (UTP) and INS 365, may be useful for CF through actions, mediated via P2Y(2) extracellular receptors, on chloride and liquid secretion, and ciliary beat frequency. INS 365 may offer chemical stability advantages over UTP. In a randomized, double-blind, multicenter phase I study, we studied the safety and maximally tolerated dose of escalating, single doses of aerosolized INS 365, in adult and pediatric patients with mild to moderate CF lung disease (FEV(1) > or = 45% predicted). In four successive dose cohorts of adult patients (n = 12 per cohort, age > or = 18 years) and four successive pediatric dose cohorts (n = 12 per cohort, age 5-12 years), patients were randomized 3:1 active/placebo (0.9% saline) to evaluate doses of 20, 40, 80, and 100 mg INS 365 delivered by nebulizer (Pari Star ). Sputum was collected pre- and post-dosing to obtain preliminary results on clinical efficacy. After each dose cohort, a Data Safety Monitoring Committee (DSMC) reviewed the data. Forty-eight adult and 36 pediatric patients completed the protocol (up to 100 mg for adults, 80 mg for pediatric patients). The predominant adverse events were cough, wheezing, chest tightness, and a decrease in FEV(1) (occurring in 8/48 adults, and 5/36 pediatric patients), which occurred predominantly in the 80-mg and 100-mg dose cohorts. Though a few adult patients had a tendency to increase sputum production, there was little consistent effect noted on sputum production in this acute, single-dose study. The data suggest that aerosolized INS 365 is safe when delivered at single doses of up to 40 mg in adults and children with CF, but that higher doses are unlikely to be tolerated.

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

UNLABELLED: We determined whether a beta-lactam and an aminoglycoside have efficacy greater than a beta-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 beta-lactam and an aminoglycoside produces a longer clinical remission than a beta-lactam alone and slightly better initial improvement.

Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group.

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.

Effects of repetitive use and cleaning techniques of disposable jet nebulizers on aerosol generation.

STUDY OBJECTIVE: Patients with cystic fibrosis use disposable jet nebulizers for the self-administration of antibiotics, DNase, and bronchodilators several times per day. Most patients elect to reuse their disposable nebulizers. The purpose of this study was to determine if significant changes in particle size distribution or output (mL/min) occurred with reuse. DESIGN: In vitro studies were performed using four disposable models and one durable jet nebulizer for up to 100 runs; measurements of particle size and output were obtained at 10 run intervals, using saline solution alone, tobramycin, gentamicin, or a mixture of albuterol and cromolyn. Particle size determinations were made with a laser diffraction analyzer. RESULTS: There was no significant difference between the baseline performance of the four disposable models and the durable Pari LC, when measuring particle size distribution of the aerosol; the Pari LC had an output rate two to three times higher than the four disposable models. For each of the four solutes tested, there was no clinically significant change in performance for up to 100 cycles, when the nebulizers were properly cleaned between uses. Unwashed units containing tobramycin started to fail by 40 runs. CONCLUSIONS: When properly maintained, there was no trend of deterioration of performance with repeated use of disposable nebulizers. Microbial contamination was not addressed in this study and must be considered prior to recommendations for the reuse of disposable nebulizers.

Home nebulizer use among patients with cystic fibrosis.

OBJECTIVE: To describe current patterns of home nebulizer use among patients with cystic fibrosis. STUDY DESIGN: A population-based survey of home nebulizer practices among 227 patients with cystic fibrosis using nebulizers from 1993 to 1994 (Objective 1), and a prospective study of "typical" home use, including testing of performance and bacterial cultures in nebulizers after use, completed by 36 subjects (Objective 2). RESULTS: Objective 1: 85% of subjects reported using jet and 8% ultrasonic nebulizers (categories not mutually exclusive); 15% used unknown brands. Most jet nebulizers were disposable models, which were used for > 14 days by more than half the subjects. Mixing of medications in a single treatment (other than cromolyn and a bronchodilator) was reported by 28% of patients. Objective 2: no apparent deterioration in aerosol particle size or output rate of returned nebulizers compared with new units was observed. Staphylococcus aureus was cultured from 55% and Pseudomonas aeruginosa from 35% of returned nebulizers. Concordance between nebulizer and sputum cultures was poor. CONCLUSIONS: Although not generally tested for reusability, disposable nebulizers are generally used by patients for long periods. Medication mixing is common, although its effects on aerosol properties are unknown. Cystic fibrosis respiratory pathogens are frequently isolated from used nebulizers. Patient guidelines for home nebulizer use need to be established.

A comparison of peak sputum tobramycin concentration in patients with cystic fibrosis using jet and ultrasonic nebulizer systems. Aerosolized Tobramycin Study Group.

STUDY OBJECTIVE: To determine whether adequate concentrations of a new formulation of tobramycin could be delivered to the lower respiratory tract of patients with cystic fibrosis (CF) using a jet nebulizer delivery system. DESIGN: A multicenter, open-label, randomized, crossover study. SETTING: Ten tertiary care, university-affiliated, teaching hospitals in the United States. PATIENTS AND CONTROL SUBJECTS: Sixty-eight patients recruited from 10 CF Foundation centers and who were at least 8 years of age, had a diagnosis of CF, and expectorated daily sputum. No control subjects enrolled. INTERVENTIONS: Each patient received one administration of aerosolized tobramycin from each of the three nebulizer systems in random order. Each administration was separated by a minimum of 48 h. The two jet nebulizer systems tested were the Sidestream (Medic-Aid; Sussex, UK), and the Pari LC (Pari Respiratory Equipment; Richmond, Va), with a DeVilbiss Pulmoaide compressor (DeVilbiss Health Care; Somerset, Pa), both administering 300 mg tobramycin in 5 mL of 1/4 normal saline solution (NS). Patients were also administered 600 mg tobramycin in 30 mL of 1/2 NS with the UltraNeb 99/100 (DeVilbiss). MEASUREMENTS: Sputum and serum tobramycin concentration and pulmonary function were monitored. An adequate peak sputum tobramycin concentration was defined as > 128 microg/g sputum at any of three time points (10, 60, or 120 min) after completion of treatments. RESULTS: The peak tobramycin concentrations in expectorated sputum were 687+/-663 microg/g (mean+/-SD) with the Pari LC and 489+/-402 microg/g with the Sidestream. Adequate peak sputum tobramycin concentration was achieved in 93% of the patients with the Sidestream, and in 87% of the patients with the Pari LC. Peak sputum concentrations were found to be substantially higher when patients received tobramycin administered with the UltraNeb 99/100, 1,498+/-1,331 microg/g with 30% of patients having levels exceeding 2,000 microg/g. Serum tobramycin concentrations were < or = 4 microg/mL for all patients following administration with each nebulizer. CONCLUSIONS: Adequately high sputum tobramycin concentrations were documented in sputum in > 85% of patients following the administration of 300 mg/5 mL formulation of tobramycin aerosolized by the two jet nebulizer delivery systems, Sidestream and Pari LC. The single tobramycin administration delivered by these two systems is well-tolerated.

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.

Utilization of salivary concentrations of ciprofloxacin in subjects with cystic fibrosis.

Ciprofloxacin, an orally-absorbed fluoroquinolone is effective against multiply resistant Pseudomonas 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.

Nebulizer delivery of tobramycin to the lower respiratory tract.

We characterized a tobramycin aerosol generated by five nebulizers: Micron One, Pulmosonic, Pulmo-Aide, DeVilbiss Model 65, and UltraNeb 100 by particle size and drug concentration. The Micron One nebulizer did not produce a recoverable aerosol, while the Pulmosonic had a minimal output; therefore three machines were examined for their ability to deliver tobramycin to the lower respiratory tract of patients with cystic fibrosis (CF). The DeVilbiss 65 had the greatest output: with air as the carrier gas it produced an aerosol with > 60% of the particles having a mean mass aerodynamic diameter (MMAD) of > 5.5 microns. Using helox shifted the MMAD so that > 65% of the particles were < 5.5 microns. Increasing the power in the DeVilbiss 65 increased the output of particles > 9.2 microns, without a change in the particles < 3.3 microns. With air as the carrier gas the Pulmo-Aide and the UltraNeb 100 produced an aerosol with > 60% particles, < 3.3 microns MMAD. Using helox the UltraNeb 100 increased the amount of aerosol with a < 3.3 microns MMAD to 98%. Tobramycin delivery to the lower respiratory tract with the Pulmo-Aide and UltraNeb 100 was compared using air or helox by measuring sputum drug concentration. Pulmo-Aide failed to produce detectable tobramycin in sputum in 2 out of 9 patients with CF. With the UltraNeb 100, all patients had measurable sputum tobramycin immediately after administration (range, 16.2-3385 micrograms/g), but no statistically significant difference was found when using either compressed air, helox, or ambient air.(ABSTRACT TRUNCATED AT 250 WORDS)

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; 2 1/2 hours each) simultaneously with a constant-rate (30 mg/kg/hr) infusion of insulin. 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 micrograms/ml) compared with that in control subjects (77.6 +/- 38.4 micrograms/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.

Disposition of drugs in cystic fibrosis. II. Hepatic blood flow.

To determine whether the increased clearance of high extraction-ratio drugs in cystic fibrosis is caused by an increase in hepatic blood flow, the blood flow in main branches of the hepatic vein and portal vein was measured by use of noninvasive duplex ultrasound scanning in 10 adult subjects with cystic fibrosis and in 10 healthy age-, gender-, and height-matched control subjects. No statistically significant differences between subjects with cystic fibrosis and control subjects were detected in either the hepatic vein (217 +/- 103 ml/min for subjects with cystic fibrosis versus 211 +/- 135 ml/min for control subjects) or the portal vein (205 +/- 114 ml/min for subjects with cystic fibrosis versus 190 +/- 101 ml/min for control subjects) blood flows. These data indicate that a large (greater than or equal to 100%) increase in the clearance of high extraction-ratio drugs in patients with cystic fibrosis is unlikely to be primarily caused by an increase in hepatic blood flow. It is probable that alternative mechanisms such as enhanced secretory or metabolic pathways account in large part for increases in clearance of high extraction-ratio drugs.

Predictive value of oropharyngeal cultures for identifying lower airway bacteria in cystic fibrosis patients.

Identifying lower respiratory pathogens in young, non expectorating cystic fibrosis (CF) patients has been problematic. Bronchial secretions are difficult to obtain, and little is known about lower airway flora in these patients. We collected simultaneous bronchial and oropharyngeal specimens in 43 CF patients in optimal respiratory status, including both expectorating (17) and nonexpectorating (26) patients, to determine the predictive value of oropharyngeal cultures for identifying lower airway pathogens. An additional goal was to characterize the lower respiratory flora of these patients. Predictive values were defined as the proportion of oropharyngeal culture results that accurately reflected the results of bronchial cultures. Predictive values of positive oropharyngeal cultures in nonexpectorating patients were 83% (95% confidence interval 36 to 100%) for Pseudomonas aeruginosa and 91% (59 to 100%) for Staphylococcus aureus. Predictive values of negative oropharyngeal cultures were lower: 70% (48 to 86%) for R aeruginosa and 80% (52 to 96%) for S. aureus. A relatively high proportion of nonexpectorating CF patients less than 10 yr old had R aerusginosa (11 of 24, 46%) or Klebsiella species (5 of 24, 21%) in their lower airways. The isolation of Klebsiella was associated with younger age (p = 0.03) and recent administration of antistaphylococcal antibiotics (p = 0.05). Our results suggest that oropharyngeal cultures yielding R aeruginosa or S. aureus are highly predictive, but such cultures lacking these organisms do not rule out the presence of these pathogens in the lower airways of CF patients.

Probenecid pharmacokinetics in cystic fibrosis.

Probenecid pharmacokinetics were studied in 5 cystic fibrosis (CF) subjects and 5 control subjects at oral dosages of 5, 15, and 30 mg/kg. Serum and urine samples were collected for 8 h after administration and assayed by reverse phase high performance liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. All parameters were compared by 2-tailed analysis of variance with two major groupings: patient and dose. Both CF subjects and controls demonstrated dose-dependent kinetics, i.e., decreased elimination constant and decreased total body clearance with increasing dosage. The volume of distribution and time to peak were the only parameters that were not significantly dose dependent. At all dosages studied, we found no significant difference in total body clearance by CF subjects. Urinary recovery in an 8-hour period was not significantly different between CF subjects and controls nor was the percentage of dose recovered in the urine at each dosage level. Time to peak concentration varied widely between 0.5 and 4 h in both CF subjects and controls. We conclude, that CF patients have normal probenecid clearance, and that the standard dose for a CF patient is sufficient to attain a serum area under the curve equivalent to that of controls.

The impact of Haemophilus influenzae type b meningitis on nutritional status.

We investigated the immediate impact and long-term effects of Haemophilus influenzae type b meningitis on nutritional status and growth in 111 children. Mean weight change during 10 d of hospitalization was a loss of less than 1%. Follow-up median weight-for-height percentiles increased after admission (p less than 0.01). Percentile values were as follows: admission, 45th; 1 mo, 60th; 3 mo, 60th; and 6 mo, 68th. Forty-three percent of the cases were greater than 75th percentile of weight-for-height at 6 mo after disease. An additional follow-up assessment of weight-for-height indicated that 43% of a representative sample subset of 49 were still obese 1.17-5.5 y after disease. Significant differences in median concentrations of serum prealbumin were found between days 1 (128 mg/L) and 5 (199 mg/L, p less than 0.0001) and days 5 and 10 (214 mg/L, p less than 0.02). Median erythrocyte glutathione reductase activity coefficients increased between days 1 (1.16) and 5 (1.20, p less than 0.01). The mean free erythrocyte protoporphyrin-heme ratio increased between days 5 (10.78 X 10(-6)) and 10 (14.22 X 10(-6), p less than 0.01). We conclude that there were transient adverse changes in nutritional status. Obesity appears to occur after disease.

Safety of aerosol tobramycin administration for 3 months to patients with cystic fibrosis.

To determine the potential toxicity of prolonged aerosol tobramycin administration, 22 patients with cystic fibrosis were monitored while receiving inhaled tobramycin three times a day for 12 weeks. Prior to, four times during administration and approximately 6 weeks after discontinuation of treatment, we assessed pulmonary function, weight, height, body temperature, eighth cranial nerve function, serum creatinine, blood urea nitrogen, urinary creatinine clearance, plasma iothalamate clearance, urinary beta-2 microglobulin concentration, and Pseudomonas aeruginosa density in sputum. There was no detectable laboratory evidence of nephrotoxicity. Neither a decrease in auditory acuity (range 250-20,000 Hz) nor vestibular dysfunction was detected. Pulmonary function tests significantly improved during the first month in all subjects (P less than 0.05) but returned to enrollment values by the end of the 12th week of administration of tobramycin aerosol. Sputum P. aeruginosa density initially decreased from a mean of 10(7) cfu/gm to a mean of 10(4) cfu/gm after 2 weeks of aerosol tobramycin administration and remained significantly below the enrollment value throughout. Coincident with the reduced bacterial density, a reduction in cough frequency and sputum production, as well as a weight gain was observed. Seventy-three percent of the patients with sputum P. aeruginosa isolates susceptible to tobramycin on enrollment yielded resistant organisms during aerosol administration. However, 1 year later all sputum P. aeruginosa isolates obtained from patients were susceptible to tobramycin. We conclude that thrice daily aerosol tobramycin administration for 3 months is not associated with detectable eighth cranial nerve or renal toxicity. Transient emergence of tobramycin resistant P. aeruginosa may occur.

Pharmacokinetics of ciprofloxacin in cystic fibrosis.

We studied the pharmacokinetics of ciprofloxacin in 12 adult males with and 12 adult males without cystic fibrosis (CF). In a randomized crossover sequence, the subjects received 200 mg intravenously or 750 mg orally. With intravenous dosing, subjects also received 651 mg of iothalamate, a marker of glomerular filtration, and 700 mg of antipyrine, an indicator of hepatic oxidative drug metabolism. Pharmacokinetic parameters were determined by model independent methods. In the CF subjects, the ciprofloxacin concentration in serum during the first hour after intravenous administration was higher, and the oral absorption rate was slower. Other parameters did not differ between the groups. Mean concentrations in serum 5 min postinfusion were 3.08 and 2.14 micrograms/ml, and mean peak concentrations after oral dosing were 3.24 and 3.34 micrograms/ml in subjects with and without CF, respectively. Mean values for elimination half-life in all subjects were 4.8 and 5.0 h after intravenous and oral administration, respectively. The mean renal clearances in all subjects after intravenous and oral administration were 19.4 and 14.5 liters/h and accounted for 64 and 47% of the total clearance, respectively. These values were significantly greater than renal iothalamate clearance, indicating that tubular secretion contributed to the renal clearance of ciprofloxacin. A total of 69 and 35.4% of the administered ciprofloxacin was recovered from the urine within 48 h after intravenous and oral administration, respectively. The mean bioavailability was 71.2% and did not differ between the groups. We conclude that similar dosing regimens can be used to treat patients with CF and their normal counterparts.

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.

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.

Pharmacokinetics of high-dose azlocillin sodium in patients with cystic fibrosis.

The pharmacokinetics of high-dose azlocillin sodium was studied in 18 patients with cystic fibrosis. Nine male and nine female patients with a mean age of 14.7 years (range 3 to 29 years) participated in the study. They received azlocillin 450 mg/kg/day (as the sodium salt) in six divided doses. During a steady-state dosing interval, a dose of azlocillin was coadministered with a 10-mg/kg dose of iothalamate sodium as a 30-minute infusion. Serum concentrations of azlocillin and iothalamate were determined by high-pressure liquid chromatography assay. The data were analyzed using model-independent methods. The mean elimination rate constant for azlocillin was 0.64 +/- 0.22 hr-1 and the mean serum half-life was 1.22 +/- 0.39 hr. Total clearance of azlocillin, calculated by noncompartmental analysis, was 77.2 +/- 26.4 mL/min/sq m. Glomerular filtration rate, as estimated by measuring iothalamate clearance, was 79.6 +/- 21.9 mL/min/sq m. The total clearance of azlocillin correlated with iothalamate clearance. Patients with cystic fibrosis appear to eliminate azlocillin more rapidly than healthy individuals. This rapid elimination warrants the use of high doses to maintain high serum concentrations.