Alan F. Isles

Pseudomonas cepacia infection in cystic fibrosis: An emerging problem

The prevalence of Pseudomonas cepacia infection increased from 10% in 1971 to 18% by 1981 in a population of approximately 500 patients with cystic fibrosis. Carriage of P. aeruginosa has remained unchanged at 70% to 80% over the same period. Patients infected with P. cepacia have greater impairment of pulmonary function than those with P. aeruginosa. A syndrome characterized by high fever, severe progressive respiratory failure, leukocytosis, and elevated erythrocyte sedimentation rate has occurred in eight patients over the past 3 years, with a 62% fatality rate. Because P. cepacia strains are uniformly resistant to ticarcillin, piperacillin, and aminoglycosides, and because ceftazidime is ineffective despite in vitro activity, treatment of these infections is very difficult. Prevention of acquisition and effective treatment of P. cepacia in patients with cystic fibrosis are now major clinical problems in our clinic.

Efficacy of inhaled tobramycin in the treatment of pulmonary exacerbations in children with cystic fibrosis.

Two forms of treatment of acute pulmonary exacerbations in patients with cystic fibrosis were compared: intravenous ticarcillin (300 mg drug per kg per day) and tobramycin (10 mg drug per kg per day) versus the same intravenous antibiotic therapy plus inhaled tobramycin (80 mg three times per day). The 16 patients in the intravenous plus inhaled tobramycin group were similar to the 12 control patients in age, sex, Schwachman scores, pulmonary function and pretreatment colony counts of Pseudomonas aeruginosa in sputum. Treatment resulted in significant improvement in clinical status and pulmonary function without any apparent differences in the two groups. However, intravenous plus inhaled tobramycin resulted in temporary eradication of P. aeruginosa in 63% of the patients compared to 25% in the intravenous only group (P = 0.03). Suppression of P. aeruginosa in sputum cultures did not correlate with clinical response to treatment. No renal toxicity or elevations of serum tobramycin were observed in the intravenous plus inhaled tobramycin group.

Ceftazidime disposition in acute and stable cystic fibrosis

Ceftazidime disposition after an intravenous dose of 50 mg/kg infused over 20 min was followed in 10 subjects with cystic fibrosis (CF) hospitalized with acute pulmonary exacerbations and in 10 healthy subjects. Serum ceftazidime elimination t½ decreased from 105.3 ± 12.4 min (X̄ ± SD) in controls to 90.0 ± 11.1 min in subjects with CF. Calculated distribution volumes were both larger in subjects with CF. When normalized for body surface area, total body clearance (Cl) was 41.9% greater in the CF group (142.4 ± 16.9 and 100.5 ± 10.3 ml/min/1.73 m2). Normalization for body weight revealed 64.8% greater Cl in subjects with CF. Fraction of dose recovered in urine was of the same order for each group, while renal clearance (ClR) was 40.9% greater in the subjects with CF (130.1 ± 11.4 and 92.7 ± 11.6 ml/min/1.73 m2). Five subjects with CF were restudied while infection‐free 119 to 219 days after the original study day. With the exception of a 10% increase in the volume of distribution at steady state while infection‐free, kinetic parameters were much the same. No changes in Cl or ClR were evident from one study day to the next. Acute pulmonary infection does not appear to alter ceftazidime clearance in CF. The mechanism underlying increased ceftazidime Cl and ClR in CF is not apparent from the present data.

Sustained-release theophylline: A significant advance in the treatment of childhood asthma

7. Reeves DS, and Bywater M J: Assay of antimicrobiaI agents, in deLouvois J, editor: Selected topics in clinical bacteriology, London, 1976, Baili6re Tindall, pp 21-79. 8. Chamberlain J, Coombes JD, Dell D, Fromson JM, Ings R J, Macdonald CM, and McEwen J: Metabolism of cefotaxime in animals and man, J Antimicrob Chemother 6(Suppt):69, 1980. 9. Reeves DS, White, LO, Holt HA, Bahari D, Bywater M J, and Bax RP: Human metabolism of cefotaxime, J Antimicrob Chemother 6(Suppl):93, 1980. 10. Sedman A J, and Wagner JG: CSTRIP, a fortran IV computer program for obtaining initial polyexponential parameter estimates, J Pharm Sci 65:1006, 1976. 11. Metzler CM, Elfring GL, and McEwen A J: A package of computer programs for pharmacokinetic modeling, Biometrics 30:562, 1974 (abstr). 12. Boxenbaum HG, Riegelman S, and Elashoff RM: Statistical estimations in pharmacokinetics, J Pharmacokinet Biopharm 2:123, 1974. 13. Wagner JG: Linear pharmacokinetic equations allowing direct calculation of many needed pharmacokinetic parameters from the coefficients and exponents of polyexponential equation which have been fitted to the data, J Pharmacokinet Biopharm 4:443, 1976. 14. Fillastre JP, Leroy A, Humbert G, and Godin M: Pharmacokinetics of cefotaxime in subjects with normal and impaired renal function, J Antimicrob Chemother 6(Suppl):103, 1980. 15. Fu KP, Aswapokee P, Ho I, Matthijssen C, and Neu, HC: Pharmacokinetics of cefotaxime, Antimicrob Agents Chemother 16:592, 1979. t6. Luthy R, Munch R, Blaser J, Bhend H, and Siegenthaler W: Human pharmacology of cefotaxime (HR 756), a new cephalosporin, Antimicrob Agents Chemother 16:127, 1979.

Cloxacillin absorption and disposition in cystic fibrosis

Because of reports of lowered antibiotic serum concentrations in patients with cystic fibrosis (CF), a bioavailability and pharmacokinetic study of cloxacillin was conducted in 12 control and 16 patients with CF after intravenously and orally administered doses of cloxacillin 25 mg/kg. The patients had mild to moderate CF and were in stable condition. Significantly lower serum concentrations in CF were a result of a 78% increase in total body clearance (P less than 0.005) and a 38% increase in the apparent volume of distribution (P less than 0.025). The bioavailability in CF (0.50) was not significantly different than in controls (0.38), but more variability was seen in the group with CF. After the intravenously given dose the fraction of cloxacillin excreted in the urine unchanged was similar in controls (0.644) and patients with CF (0.547). Compared with that in the control subjects, the mean renal clearance in patients with CF was 30% greater (P less than 0.10) and the nonrenal clearance was 144% greater (P less than 0.07). Enhanced nonrenal clearance explains most of the demonstrated difference between serum concentrations in controls and patients with CF after identical weight-adjusted doses. The data suggest enhanced cloxacillin biotransformation in CF.

Assessment of glomerular filtration rate and effective renal plasma flow in cystic fibrosis.

A study was conducted to examine renal function in 10 healthy control subjects and eight patients with cystic fibrosis in stable condition. Sequential bolus injections of 99mTc-DTPA and 125I-OIH were administered to assess glomerular filtration rate and effective renal plasma flow, respectively. Blood was subsequently collected for 3 hours, and urine for 24 hours. Renal clearances of both radioisotope markers were virtually identical in patients and controls. Inasmuch as neither glomerular filtration rate nor effective renal plasma flow was enhanced in patients with cystic fibrosis, increased clearance of drugs in these patients is unlikely to be the result of enhanced glomerular filtration or tubular secretion.

Temporal variation in the disposition of theophylline and its metabolites

The temporal aspects of theophylline disposition are of interest, as there are predictable time‐dependent fluctuations in the pulmonary function of patients with asthma and theophylline serum concentrations may vary throughout a 24‐hour period. We studied the extent to which there are significant temporal changes in theophylline kinetics and the relative contribution of distribution, metabolism, and excretion to this phenomenon. Eight healthy men received an intravenous dose (6 mg/kg) of theophylline at 8 AM and 8 PM at 1‐week intervals. Serum and urine were analyzed for theophylline and its three major metabolites by HPLC. Distribution volumes and total body and nonrenal clearances showed no differences between morning and evening dosing. The elimination rate was 12% greater after morning dosing. Renal clearance was 24% greater after morning dosing and was accompanied by an increased excretion fraction of unchanged theophylline. Based on total urinary metabolite excretion and the metabolite serum AUCs, there was no evidence of time‐dependent variation in theophylline biotransformation. Although theophylline renal clearance is greater after morning dosing, it is only a small fraction of the overall drug elimination and does not change the total body clearance after morning or evening dosing.

Response: Asthma in childhood

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