Pharmacokinetics of tobramycin in cystic fibrosis

Kelly, H. Bill; Pharm, D; Menendez, Rogelio; Fan, Leland L.; Murphy, Shirley

doi:10.1016/s0022-3476(82)80664-1

Cited by 73 publications

(32 citation statements)

References 9 publications

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“…Cystic fibrosis patients appear to display a larger apparent volume of distribution and an increased total body clearance. These data and others (8,9) support the increased antibiotic dosage requirements for treating acute pulmonary exacerbations in these patients.…”

Section: Resultssupporting

confidence: 62%

Single-dose pharmacokinetics of cefsulodin in patients with cystic fibrosis

Reed¹,

Stern²,

Yamashita³

et al. 1984

Antimicrob Agents Chemother

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The single-dose pharmacokinetics of cefsulodin were evaluated in 12 patients with cystic fibrosis. Each patient received 3 g of cefsulodin intravenously over 30 min. Multiple plasma and urine samples were obtained during the 6-h study period for the determination of cefsulodin. Pharmacokinetic parameters were determined by model-independent methods. Mean values for t1/2, Vs,, and CLp were 1.53 h, 0.242 liters/kg, and 117.3 ml/min per 1.73 m2, respectively. Six-hour urine recovery revealed 73.2% of the administered dose with a corresponding cefsulodin urinary clearance of 75.1 ml/min. These pharmacokinetic data in patients with cystic fibrosis appear consistent with data reported for unaffected individuals.Cefsulodin is a unique new 1-lactam antibiotic with activity virtually restricted to Pseudomonas aeruginosa (11, 13). Because of its narrow spectrum, this agent might be expected to be used in the management of acute pulmonary exacerbations in patients with cystic fibrosis.The pharmacokinetics of several ,-lactam antibiotics are altered in children with cystic fibrosis (J. S. Bertino, Jr., M. D. Reed, C. Myers, and J. L. Blumer, Abstr. Drug Intell. Clin. Pharm. 16:469, 1982) (7, 15). The single-dose pharmacokinetics of cefsulodin have been described in normal adults and in adult patients with various degrees of renal dysfunction (4, 6, 12). We report here the pharmacokinetics of cefsulodin in patients with cystic fibrosis. MATERIALS AND METHODSPatients .12 years of age with cystic fibrosis were eligible for enrollment in this study. The study protocol was approved by the Institutional Review Board for Human Subject Investigation of the University Hospitals of Cleveland. Written, informed consent was obtained from each patient or parent or both. Before drug administration, each patient underwent a complete physical examination and had a laboratory evaluation which included electrolyte analysis, tests of liver and renal function, urinalysis, complete blood count with differential, prothrombin and partial thromboplastin times, and Coomb's test.Each patient received a 3-g intravenous dose of sodium cefsulodin (Abbott Laboratories, North Chicago, Ill.; lot 37011AR) dissolved in 50 ml of 5% dextrose in water. This dose was chosen because it was the highest for which safety data were available at the time of the study. Blood samples (3 ml) were collected in heparinized tubes at 0, 0.5, 0.75, 1, 1.5, 2, 4, and 6 h after the initiation of a 30-min infusion. Blood samples were placed on ice immediately and centrifuged within 1 h of collection. An equal volume of 1 M potassium phosphate (pH 6.0) was added to each plasma sample to protect against hydrolysis (5).Patients were asked to void before drug administration, and all urine excreted during the 6-h study period was collected as 2-h aliquots in iced containers. Urine samples were measured, buffered, and immediately frozen. Plasma and urine samples were frozen at -70°C until analyzed. * Corresponding author.Under these conditions, plasma and urine cefsulodin standards w...

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Section: Resultssupporting

confidence: 62%

Single-dose pharmacokinetics of cefsulodin in patients with cystic fibrosis

Reed¹,

Stern²,

Yamashita³

et al. 1984

Antimicrob Agents Chemother

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“…Pharmacokinetic studies in CF show that the elimination half-life is y2 h [30]. Assuming first-order pharmacokinetics, tobramycin concentrations will fall below 1 mg?L -1 after six half-lives, leaving a period of y12 h when there are sub-inhibitory plasma concentrations.…”

Section: Resultsmentioning

confidence: 99%

Once-daily tobramycin in the treatment of adult patients with cystic fibrosis

Whitehead¹,

Conway²,

Etherington³

et al. 2002

Eur Respir J

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Once-daily tobramycin in the treatment of adult patients with cystic fibrosis. A. Whitehead, S.P. Conway, C. Etherington, N.A. Caldwell, N. Setchfield, S. Bogle. #ERS Journals Ltd 2002. ABSTRACT: The aim of this study was to test the equivalence of once-and thrice-daily dosing with tobramycin by comparing efficacy and safety in adult patients with cystic fibrosis.Sixty adult patients with an acute respiratory exacerbation were randomized to receive either 10 mg?kg -1 tobramycin once-daily or 3.3 mg?kg -1 tobramycin thricedaily. Primary efficacy and safety endpoints were defined as changes in respiratory function and changes in renal function and hearing.Both groups showed a significant increase in respiratory function without a clinically significant change in renal function. For changes in forced vital capacity % predicted and serum potassium and magnesium levels, equivalence was demonstrated. For the variables forced expiratory volume in one second and forced mid-expiratory flow % pred and serum creatinine levels, there was insufficient power to demonstrate equivalence. One patient in each group showed bilateral impairment in pure tone audiogram after treatment.This study demonstrated significant clinical improvement with both once-and thricedaily tobramycin dosing. Equivalence between the two regimens was shown for some, but not all primary endpoints. Once-daily dosing should be used with careful monitoring of safety and efficacy until large multicentre studies confirm these encouraging results.

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“…This drug association could not explain the variabilities of the pharmacokinetic parameters; indeed, in contrast to cefsulodin, another cephalosporin that is efficient against Pseudomonas strains, the concentration of ceftazidime in plasma is not influenced by the combined treatment with tobramycin (23). Kelly et al (16) suggested that these variations may be caused by the degree of right-sided heart failure present in the patient during the period of treatment. These variabilities could also be due to hemodynamic status and pathological conditions in hospitalized patients in ICUs and could explain the difference between CLR of ceftazidime and CLc in some patients.…”

Section: Resultsmentioning

confidence: 99%

“…Samples were collected from the arm contralateral to the arm used for drug administration (i.v. infusion) immediately before and at 10, 20, 30, 40, 50, 60, and 90 min and 2, 4,6,8,10,12,14,16,18,20,22, and 24 h after each administration. Plasma samples were obtained by centrifugation at 3,000 x g for 10 min.…”

Section: Methodsmentioning

confidence: 99%

Endotracheal and aerosol administrations of ceftazidime in patients with nosocomial pneumonia: pharmacokinetics and absolute bioavailability

Bressolle

Coussaye

Ayoub

et al. 1992

Antimicrob Agents Chemother

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Pharmacokinetic studies on ceftazidime, an aminothiazole cephalosporin with a wide spectrum of antibacterial activity, including activity against Pseudomonas aeruginosa, were performed in patients with nosocomial pneumonia. The concentration-time profiles of ceftazidime in plasma, urine, and bronchial secretions of 12 patients were investigated after intravenous (i.v.) (n = 12), endotracheal (n = 10), and aerosol (n = 5) administrations. In all cases a 1-g dose was administered. Concentrations of drug in all samples were assayed by high-performance liquid chromatography with UV detection. The elimination of the drug from the blood followed a biexponential (i.v. administration) or a monoexponential (endotracheal and aerosol administrations) decay, with an elimination half-life of 6 h and a total body clearance of 4.2 liters/h. The apparent volume of distribution was 0.36 liter/kg of body weight. Renal clearance of the drug accounted for 58% of the total clearance; 66% ± 17.7%, 33.5% ± 17.3%, and 6.59%o ± 3.45% of the administered dose were eliminated in urine as parent drug after i.v., endotracheal, and aerosol administrations, respectively. The absolute bioavailabilities were 0.47 and 0.08 for endotracheal and aerosol administrations, respectively. Very high concentrations were found in bronchial secretions after local administration. The MICs for 90%o of the most important pathogens responsible for nosocomial infections were exceeded by concentrations in bronchial secretion for up to 12 h after i.v. infusion and for up to 24 h after endotracheal and aerosol administrations.Nosocomial pneumonia is associated with high levels of mortality and is a well-recognized complication in hospitalized patients, particularly those cared for in intensive care units (ICUs) (13, 21). The problem is particularly severe in intubated patients receiving mechanical ventilation. Patients with tracheostomies, especially when they are unconscious and cannot collaborate in obtaining adequate bronchial drainage, have a high incidence of bronchopulmonary infections caused by Pseudomonas aeruginosa and other gramnegative enteric bacilli. These organisms are the most troublesome nosocomial infections in the ICU and are often resistant to many antibiotics (15). The concentrations of antibiotics in respiratory secretions following parenteral administration are sufficient to suppress the normal bacteria flora but cannot generally inhibit the growth of bacilli responsible for hospital-acquired infections (15). Topical administration of antimicrobial agents results in very high local concentrations. This approach has been studied extensively as prophylaxis against pneumonia in humans, with mixed results (10,12,18,19).Ceftazidime is a cephalosporin with exceptionally high activity against a wide spectrum of bacteria. It is highly stable against a wide range of 1-lactamases and is bactericidal. It may therefore offer a wider spectrum of activity and a low incidence of toxicity. Ceftazidime was found to be safe and effective in a variety of seriou...

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Pharmacokinetics of tobramycin in cystic fibrosis

Cited by 73 publications

References 9 publications

Single-dose pharmacokinetics of cefsulodin in patients with cystic fibrosis

Single-dose pharmacokinetics of cefsulodin in patients with cystic fibrosis

Once-daily tobramycin in the treatment of adult patients with cystic fibrosis

Endotracheal and aerosol administrations of ceftazidime in patients with nosocomial pneumonia: pharmacokinetics and absolute bioavailability

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