Biomedical subjects

H G Heijerman

Publications and source records attributed to H G Heijerman.

At least 19 recordsLinked to original sources

PubMed2004

[Expression of the cystic fibrosis gene in the lungs].

Cystic fibrosis (CF) is one of the most common hereditary diseases with a potentially lethal outcome. CF is caused by mutations in a gene on chromosome 7 that encodes for a polypeptide called 'cystic fibrosis transmembrane conductance regulator' (CFTR). Pulmonary complications in CF are a direct consequence of a fault in the production or function of CFTR. The consequences of these faults are a change in the viscosity and volume of the air-surface liquid in the airways and possible malfunctioning of the immunological defence system. The result is stasis of mucus and obstruction of the smaller airways. Secondary to this process, a (chronic) infection with an uncontrolled inflammatory response, leads to destruction of lung tissue and a reduction in lung function. Mutations in CFTR can be classified in five types, which reflect the level of production or the function of CFTR. This classification permits discrimination between mild and severe mutations. The clinical image and the course of CF are often related to the combination of mutations present. This may explain, in part, why some CF patients are diagnosed at a later age with a normal sweat test and a clinical image that is predominantly limited to respiratory symptoms.

Chromosomes, Human, Pair 7↗

PubMed2001

Effect of oral prednisolone on the bronchoprotective effect of formoterol in patients with persistent asthma.

Tolerance to the bronchoprotective effects by long-acting beta2-agonists (LAB) in patients with asthma is not prevented by inhaled corticosteroids (ICS). This study examined whether oral prednisolone can restore the bronchoprotective effects of formoterol in 24 patients with persistent asthma already treated with ICS (at least 800 microg budesonide x day(-1) or equivalent) and LAB, using a parallel-group design. During a 2-week run-in period and during the study, patients used formoterol 12 microg twice daily by Turbuhaler, instead of their own LAB. At baseline and at the end of 7-days treatment with oral placebo or prednisolone (30 mg x day(-1)), provocative concentration of histamine causing a 20% fall in forced expiratory volume in one second (PC20 histamine) was measured on two separate days after randomized single-dose inhalation of placebo (postP) or formoterol (postF). In addition, PC20postF was measured 24 h after starting oral treatment. The protective effect by formoterol at baseline and during treatment was calculated as the difference between the logs of PC20postP and PC20postF. The mean+/-SEM in doubling dose (DD) bronchoprotective effect at baseline was 0.8+/-0.4 DD in the placebo group and 1.0+/-0.4 DD in the prednisolone group. At the end of the treatment period, the protective effect changed to 1.0+/-0.5 DD and 0.8+/-0.6 DD in the placebo and prednisolone treated groups, respectively. This change was not different between the groups (p > 0.4). In conclusion, the bronchoprotective effect by formoterol is not influenced by 1 week prednisolone treatment in patients with asthma who are using regular inhaled corticosteroids and long-acting beta2-agonists. These findings indicate that tolerance to long-acting beta2-agonists cannot be restored by oral steroid therapy.

Administration, Oral↗

PubMed2000

A review of the technical aspects of drug nebulization.

Nebulizers are widely used for the inhalation of drug solutions in a variety of respiratory diseases. The efficacy of nebulizer therapy is influenced by a great number of factors, including the design of the device and the characteristics of the drug solution. Incorrect cleaning, maintenance and disinfection procedures may change the nebulizer performance in time, whereas patient factors can influence the lung deposition of the generated aerosol. In this review the technical aspects of nebulization of drug solutions will be discussed. Two main parameters are generally used to evaluate the performance of nebulizers: the droplet size distribution of the aerosol and the drug output rate. The droplet size distribution and the drug output rate are basically determined by the design and user conditions of the nebulizer. A higher gas flow of the compressor in a jet nebulizer or a higher vibration frequency of the piezo electric crystal in an ultrasonic nebulizer, decreases the droplet size. The choice of the type of nebulizer for nebulization of a certain drug solution may initially be based on laboratory evaluation. The major part of the mass or volume distribution should preferably correspond with aerodynamic particle diameters in the range of 1 to 5 micrometer. The intended drug output must be realized within a reasonable nebulization time (less than 30 min). From the drug output only a minor fraction will be deposited in the lung. The relation between in vitro and in vivo deposition is only partly understood and to date it has not been possible to predict drug delivery only from in vitro studies on nebulizers. Therefore, studies in patients should be performed before a drug solution for nebulization can be recommended for clinical practice. The mechanical properties of nebulizers are likely to change during use. An average utilization time of nebulizers is not available. Therefore, the performance of nebulizers should be checked periodically. Patient compliance in nebulizer therapy is relatively low. This is partly due to the fact that, at present, drug solutions for nebulizers cannot be administered efficiently within a short period of time. More efficient systems should be developed. If possible, nebulizers should be substituted to more efficient systems, e.g. dry powder inhalers or metered dose inhalers.

Administration, Inhalation↗

PubMed2000

Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus.

Cystic fibrosis (CF) is the most common lethal hereditary disorder with autosomal recessive heredity in caucasians. The majority of CF patients suffer from chronic respiratory infection with the opportunistic bacterial pathogen Pseudomonas aeruginosa. No consensus among clinicians has been reached so far concerning antibiotic treatment against P. aeruginosa in CF patients. Consensus answers to 24 important questions in this context, based on current evidence, are presented, given by a panel of 34 European experts. Questions addressed and answered are: The diagnosis of P. aeruginosa lung colonization in CF; The impact of P. aeruginosa on the clinical state of CF patients; The assessment of P. aeruginosa susceptibility against antibiotics and the importance of these results for the clinician; The use of monotherapy versus combination therapy; The development of microbial resistance; The achievement of optimal airway concentrations; The effects of subinhibitory concentrations of antibiotics on P. aeruginosa; Statements on the pharmacokinetics of antibiotics in CF patients; Recommendations for doses and dosing intervals and length of treatment regimens; and Toxic side effects due to repeated antibiotic therapy was addressed. The expert panel answered further questions on the use of fluoroquinolones in children with CF, on the administration of nebulized antibiotics and whether prevention of P. aeruginosa lung colonization is possible in CF using antibiotic therapy. Problems of antibiotic therapy at home and in the hospital were addressed, a consensus statement on regular maintenance treatment, or treatment on demand, was given and different routes of administration of antibiotics were recommended for different clinical situations. Finally, the factors which determine the choice of the antibiotic, the dosage, and the duration of the treatment in cystic fibrosis patients were addressed and the design of future antibiotic studies in the context of Pseudomonas aeruginosa lung infection in cystic fibrosis patients were recommended.

Anti-Bacterial Agents↗

PubMed1999

Inhalation of tobramycin in cystic fibrosis. Part 1: the choice of a nebulizer.

Forteen commercially available jet and ultrasonic nebulizers were investigated with the aim to select the most suitable type of apparatus for the inhalation of a 10% tobramycin solution. Two different techniques for measurement of particle size distribution were evaluated: laser diffraction and cascade impactor analysis. The final selection of the nebulizers is based on particle size distribution, output and stable performance during nebulization. All 14 nebulizers (eight jet and six ultrasonic) were filled with a solution of 10% m/v tobramycin (as sulphate) in water. The volume in the tested devices ranged from 4.5 to 10 ml (=450-1000 mg tobramycin) in accordance with the prescribed usage by the suppliers. The nebulizers were connected with a special designed adapter to a laser diffraction analyser in order to measure particle size distribution of the aerosol. Inhalation was simulated with a static flow of 40 l/min. The particle size distribution (expressed as X(10), X(50), and X(90)) was determined after 10 s, 1.5, 3, 4.5, 6, 9 and 12 min of nebulization. Furthermore, the tobramycin solutions were assayed for tobramycin content before and after nebulization. For all nebulizers, the mean particle size distribution, depicted as X(50), was within the range of 1-5 mm. There were no relevant differences between the nebulizers in concentration or particle size distribution during nebulization. The output of the nebulizers is a result of both nebulization and evaporation. The output, expressed as volume of tobramycin solution, ranged from 0.06 to 0.50 ml/min. The output of tobramycin ranged from 1.2 to 39.5 mg/min. For clinical practice 300-600 mg have to be nebulized within 20-30 min. It was concluded that only three jet nebulizers [Porta-Neb Sidestream (PNS), Porta-Neb Ventstream (PNV) and Pariboy Pari LC+ (PLC)] have a reasonable output and an acceptable particle size distribution for the administration of a 10% tobramycin solution in the therapeutic dosage range.

Administration, Inhalation↗

PubMed1999

Inhalation of tobramycin in cystic fibrosis. Part 2: optimization of the tobramycin solution for a jet and an ultrasonic nebulizer.

The inhalation of tobramycin is part of current cystic fibrosis (CF) therapy. Local therapy with inhaled antibiotics has demonstrated improvements in pulmonary function. Current inhalation therapy is limited by the available drug formulations in combination with the nebulization time. The aim of this study is to develop a highly concentrated tobramycin solution for inhalation. Several tobramycin solutions, ranging from 5 to 30% (m/v), were compared after aerosolation with a jet and with an ultrasonic nebulizer. Laser diffraction and cascade impactor analysis were used for characterization of the aerosolized solutions. The output rate was determined in volume and mass output per minute. From the output rate measurements, it was concluded that a 20% tobramycin solution is the optimal and maximal concentration to be aerosolized. The jet nebulizer was most suitable. Using the jet nebulizer and the 20% solution, it is possible to administer a dosage of 1000 mg tobramycin by inhalation within 30 min.

Administration, Inhalation↗

PubMed1999

Can tobramycin inhalation be improved with a jet nebulizer?

Data on the pharmacokinetics of antibiotics after inhalation are limited. The aim of this pilot study was to assess the pharmacokinetics of tobramycin under optimalized and standardized aerosol circumstances and, furthermore, to be able to consider possible treatment of exacerbations with inhalation therapy. Six patients were studied after inhalation of 600 mg tobramycin. A jet nebulizer loaded with a 10% solution of tobramycin in water was used. The percentage of the dose that was systemically absorbed ranged from 1.0% to 16.6%. The maximum serum levels of tobramycin ranged from 0.77 mg/L to 3.63 mg/L (mean 1.70 +/- 1.01). The pharmacokinetic data were best described by a two-compartment model. Compared to intravenous administration, the long terminal half-life (mean 9.47 h +/- 3.28 h) could be explained by the slow absorption of tobramycin from the site of administration (flip-flop model). Despite standardized aerosol conditions, considerable interpatient variability was observed. However, the relatively low serum levels allow a further increase of the dose.

Administration, Inhalation↗

PubMed1998

Multicenter, open-label study of recombinant human DNase in cystic fibrosis patients with moderate lung disease. DNase International Study Group.

Cystic fibrosis is characterized by the accumulation of thick viscous purulent secretions. Recombinant human deoxyribonuclease I (rhDNase) breaks down extracellular DNA, which contributes to the increased viscosity of sputum. A multinational, open-label study was conducted in 974 cystic fibrosis patients with moderate lung disease [forced vital capacity (FVC) 40-70% of predicted values] to examine the safety and efficacy of aerosolized rhDNase, 2.5 mg, once daily over a period of at least 12 weeks. Patients were assessed under conditions reflecting routine clinical practice. During rhDNase therapy, at least one respiratory tract infection (RTI) requiring intravenous antibiotics was experienced by 29.5% of patients. Forced expiratory volume in 1 second (FEV1) and FVC were significantly improved from baseline by a mean of 10.5% and 7.2%, respectively. Voice alteration and pharyngitis were the most frequent rhDNase-related adverse events, but only 2% of all patients discontinued treatment due to adverse events. The results obtained were similar to a subanalysis of data from the first 3 months of a placebo-controlled U.S. study. The patients in the present study had a similar frequency of RTIs and improvement in pulmonary function, and reported fewer rhDNase-related and cystic fibrosis-related adverse events than patients in the U.S. study. We conclude that administration of rhDNase is safe, well tolerated, and effective under conditions reflecting routine clinical practice in patients with cystic fibrosis and moderate lung disease.

Administration, Inhalation↗

PubMed1998

Can helical CT replace scintigraphy in the diagnostic process in suspected pulmonary embolism? A retrolective-prolective cohort study focusing on total diagnostic yield.

The aim of our study was to compare the diagnostic value of helical CT vs that of ventilation-perfusion (V/Q) scintigraphy as a first-line test in a diagnostic strategy in patients suspected of pulmonary embolism (PE). In a retrolective-prolective cohort study we tested the accuracy of helical CT vs V/Q scintigraphy in 123 patients suspected of PE. A diagnostic panel was asked to formulate the presumptive diagnosis on the presence or absence of PE, or of alternative disease by using two competing diagnostic strategies. These consisted of the patient history, laboratory tests and chest X-ray (together baseline tests) in combination with either helical CT or V/Q scintigraphy (CT strategy and V/Q strategy, respectively). The results were compared with the final diagnosis in each patient that was established from various reference tests (which included V/Q scintigraphy, pulmonary angiography and clinical follow-up). The CT and V/Q strategies were compared with regard to the accuracy for PE, for alternative diseases and with regard to the proportion of conclusive diagnoses that were made. The CT strategy was more accurate than the V/Q strategy for detecting or excluding PE. Sensitivity and specificity were 49 and 74 % for the V/Q strategy and 75 and 90 % for the CT strategy, respectively (P = 0.01). The CT strategy provided a conclusive diagnosis in a significantly larger proportion of patients than the V/Q strategy, 92 vs 72 % (P < 0.001). The CT strategy detected more alternative diagnosis than the V/Q strategy, 93 vs 51 %, respectively (P < 0.001). Helical CT seems more useful than V/Q scintigraphy as a first-line test in patients suspected of PE.

Adult↗

PubMed1997

[Cystic fibrosis: special value of treatment at a center].

A woman aged 30 and a man aged 40, both with a bad general condition due to cystic fibrosis, showed a clear clinical improvement after they were treated in a cystic fibrosis centre, while in a young adult male patient the diagnosis of cystic fibrosis could be rejected. In the Netherlands there are approximately 1000 patients with cystic fibrosis. As a consequence most doctors have hardly any experience of the treatment of such patients. To optimize the treatment of patients with cystic fibrosis, it would seem wise to concentrate experience and knowledge in several cystic fibrosis centres.

Adult↗

PubMed1997

Effect of omeprazole 40 mg once daily on intraduodenal and intragastric pH in H. pylori-negative healthy subjects.

There is a lack of information about the effect of omeprazole or other antisecretory drugs on intraduodenal pH. Aim of the study was to document the variation over time of intraduodenal pH during a 24-hr period and to simultaneously study the effect of omeprazole 40 mg once daily on intragastric and intraduodenal pH in healthy H. pylori-negative subjects. In a randomized, placebo-controlled study, eight subjects (five women, three men, mean age 22.7 years) received oral 40 mg omeprazole or placebo once daily for eight days. On day 7, intragastric and intraduodenal pH was measured continuously for 24 hr, using two miniature glass-membrane electrodes placed in the stomach (fundus) and in the distal third of the duodenum. The 24-hr median intraduodenal pH was 5.95 with placebo and 5.85 with omeprazole. Median intragastric pH was 1.68 without and 4.93 with omeprazole. During omeprazole therapy, intragastric pH fell below 4.0 in five of eight subjects. In the 2- and 3-hr postprandial periods, the percentage of time with pH < 5 was significantly reduced with omeprazole. In healthy subjects, 24-hr median and postprandial pH in the distal part of the duodenum was lower than previously thought. Omeprazole significantly reduced the percentage of time with pH < 5 postprandially. At night, intragastric pH fell below 4.0 with omeprazole 40 mg once daily. Omeprazole does not change 24-hr median intraduodenal pH significantly.

Adult↗

PubMed1997

Continuous infusion of ceftazidime in cystic fibrosis patients during home treatment: clinical outcome, microbiology and pharmacokinetics.

Acute exacerbations of Pseudomonas aeruginosa lung infections were treated with ceftazidime by continuous infusion in 17 adult patients with cystic fibrosis at home. Ceftazidime was delivered via an infusion pump and the effects of this 3 week home intravenous antibiotic treatment (HIVAT) were prospectively studied over a 2 year period. Patients with cystic fibrosis (eight male and nine female patients; mean age 26.9 +/- 7.6 years, range 15-52 years), received a total of 33 courses of continuous ceftazidime (100 mg/kg/24 h). Clinical data were collected at the start, the end and 4-6 weeks after the end of treatment in 12 patients. Ceftazidime pharmacokinetic data during continuous infusion were obtained from ten patients. The treatment was supervised by the clinician without home visits. All 25 clinically evaluable courses in 12 patients proved efficacious. The mean duration of the courses was 21 days. The entire antibiotic course was administered at home in 88% of the courses. The other 12% was started for 2-3 days as an inpatient. Objective clinical parameters significantly improved. Clinical improvement was noted in 91% of the patients, and lasted at least until 4-6 weeks after the end of the treatment in 70%. The number of cultures positive for P. aeruginosa decreased significantly during antibiotic treatment. Bacterial count returned to pretreatment values 4-6 weeks after treatment. Multiple courses of ceftazidime monotherapy did not result in a lasting increase of ceftazidime-resistant pseudomonas strains. Total body clearance was 9.1 +/- 1.3 L/h. The steady-state ceftazidime serum concentration during continuous infusion was 28.4 +/- 5.0 mg/L. Sputum concentrations were in the range of 0.5-13 mg/L (3.9 +/- 4.0 mg/L). In conclusion, HIVAT with ceftazidime administered by continuous infusion proved clinically effective and did not result in an increase in lasting resistance.

Adolescent↗

PubMed1997

Pharmacokinetics of aerosolized tobramycin in adult patients with cystic fibrosis.

This study was performed to determine the clinical pharmacokinetics of tobramycin in six patients with cystic fibrosis (CF) after inhalation of 600 mg. Tobramycin was administered with an ultrasonic nebulizer (WISTO SENIOR). Blood and urine were sampled until 24 h after inhalation. Maximum tobramycin levels in serum varied from 0.19 to 2.57 mg/liter (mean 1.27 mg/liter; standard deviation, 1.07 mg/liter). Systemic availability (calculated from urinary output) ranged from 6.0 to 27.4% (mean, 17.5%; standard deviation, 8.8%). The results illustrate that, provided that the systemic availability of tobramycin is a reflection of pulmonary deposition, inhalation studies with CF patients should have a concentration-controlled design. Furthermore, reliance on dose recommendations from the literature for a new patient starting on this treatment is not justified, but it is mandatory that deposition kinetics be studied for each patient and for each nebulizer. It may well be that, with higher levels of deposition, dosages lower than those recommended in the literature will suffice to obtain the desired clinical effect. In addition, the reverse may also be the case.

Administration, Inhalation↗

PubMed1997

Low-dose versus high-dose ursodeoxycholic acid in cystic fibrosis-related cholestatic liver disease. Results of a randomized study with 1-year follow-up.

BACKGROUND: Ursodeoxycholic acid (UDCA) is beneficial in cholestasis related to cystic fibrosis (CF). High-dose treatment has been recommended to compensate for bile salt malabsorption. We compared the results of low-dose (10 mg/kg/day) and high-dose (20 mg/kg/day) UDCA treatment on liver biochemistry after 3 and 12 months' treatment. METHODS: Thirty CF patients (age > 5 years) with biochemical cholestasis and compensated liver disease were randomized for low-dose (n = 17) or high-dose (n = 13) UDCA. Baseline clinical variables were comparable. RESULTS: After 1 year one patient had died of liver failure (low dose), and three had dropped out because of pruritus (one in each group) or personal choice (low dose). In the high-dose group improvement in gamma-glutamyl transferase values was more pronounced after 3 months and 1 year (P < 0.004), and improvement of alanine aminotransferase was better after 1 yer (P < 0.02). Improvement of alkaline phosphatase and aspartate aminotransferase was comparable. Complete normalization of liver enzymes and bilirubin occurred more often in the high-dose group. CONCLUSION: High-dose UDCA induces a better response of liver biochemistry values than low-dose UDCA in CF patients with cholestatic liver disease.

Adolescent↗

PubMed1996

Stability of aztreonam in a portable pump reservoir used for home intravenous antibiotic treatment (HIVAT).

The stability of the monocyclic beta-lactam antibiotic aztreonam in portable pump reservoirs was studied during storage at temperatures of -20 degrees C and +5 degrees C and during drug delivery at 37 degrees C. Three 100-ml drug reservoirs and three glass containers containing 60 mg/ml aztreonam were stored at -20 degrees C and 2-ml samples were analysed in the freshly prepared solution and after thawing at days 7, 21, 28, 70 and after 6 months of storage. A separate triplicate batch of 100-ml prefilled drug reservoirs and glass containers containing a similar aztreonam concentration (60 mg/ml) were refrigerated and tested immediately after preparation and daily for 8 days and after 70 days. Solutions of aztreonam in duplicate freshly prepared reservoirs were tested for stability when the solution was pumped at 37 degrees C over a 24-h period. All solutions were inspected for visual changes and tested for pH. Drug concentration was analysed by high-performance liquid chromatography. No colour changes or pH differences were observed in any of the solutions in the reservoirs of containers. No statistically significant decrease in aztreonam concentration could be detected after 6 months of storage at -20 degrees C. Aztreonam was stable at 5 degrees C for at least 8 days. A 24-h pumping period at 37 degrees C showed a 3.6% decrease in aztreonam concentration. Aztreonam at a concentration of 60 mg/ml in a pump reservoir is sufficiently stable to be used in home intravenous antibiotic treatment programmes.

Aztreonam↗

PubMed1996

In vitro dissolution profiles of enteric-coated microsphere/microtablet pancreatin preparations at different pH values.

OBJECTIVES: Enteric-coated microsphere/microtablet pancreatin should stay intact in the stomach and dissolve promptly on entering the duodenum. Postprandial intraluminal pH in the distal duodenum is 5.75 and is lower in exocrine pancreatic insufficiency. The aim of the study was to measure in vitro dissolution times in buffer solutions with pH 4.0-6.0 for five currently available enteric-coated microsphere/microtablet pancreatin preparations. METHODS: The following preparations were tested: Creon, Creon Forte, Pancrease, Pancrease HL and Panzytrat. Two capsules were placed in the buffer solution at 37 degrees C in a USP dissolution testing apparatus. Buffer solutions with pH between 4.0 and 6.0 were used. Solutions were stirred at 125 r.p.m. and the rate of dissolution was monitored by taking 2-mL samples at regular intervals and measuring extinction at 280 nm. Measurements were repeated six times. RESULTS: All preparations failed to dissolve at pH 4.0. At pH 5.0 Pancrease HL showed 43% dissolution within 30 min, all other preparations 15% or less. Panzytrat and Pancrease HL showed more than 50% dissolution within 30 min at pH 5.2. Panzytrat, Pancrease HL and Creon Forte had more than 90% dissolution within 30 min at pH 5.6, and all preparations more than 90% dissolution within 30 min at pH 5.8 and higher. CONCLUSIONS: For the treatment of exocrine pancreatic insufficiency conventional strength enteric-coated microsphere/microtablet pancreatin preparations do not have an optimal dissolution profile. The newer, high lipase preparations such as Pancrease HL perform better, although still not optimally, at pH 5.4 and lower.

Buffers↗

PubMed1996

Prospective evaluation of a dose prediction algorithm for intravenous tobramycin in adolescent and adult patients with cystic fibrosis.

The predictive performance of a new algorithm to calculate the initial daily dose of tobramycin in patients with cystic fibrosis (CF) was prospectively evaluated. Twenty-six patients with CF (15 men, 11 women, 18-45 years of age) with an acute exacerbation of their chronic pulmonary infection were treated with intravenous tobramycin. The initial dose was calculated with a previously presented algorithm. This algorithm was derived from correlation analysis performed on the adjusted daily dose guided by the determination of serum concentrations: dose (mg three times daily) = 90 + 2.13 x LBM (kg), where LBM (male) = (1.1 x body weight [BW]) - (128 x BW2/height2) and LBM (female) = (1.07 x BW) - (148 x BW2/height2). The predictive performance of this algorithm was evaluated comparing the calculated initial daily dose with the adjusted daily dose for peak and trough levels of 9-11 mg/L and 1.0 mg/L, respectively. Mean squared error and mean error were determined as reflections of precision and bias. The predictive performance of the algorithm was compared with historical data on the predictive performance of the standard equation to dose of 3.3 mg/kg body weight three times daily. The dose calculated with the algorithm proved to give peak serum concentrations in a narrower range and to have a greater precision, but bias was equal. Applying the algorithm, more patients had initial peak serum concentrations in the pre-determined range of 9-11 mg/L than when using the standard equation, so fewer dose adjustments had to be made.

Adolescent↗

PubMed1996

Creatinine clearance as predictor of tobramycin elimination in adult patients with cystic fibrosis.

Assessment of renal function and relating this parameter to amino-glycoside clearance is important for an appropriate individualization of dosage regimens in patients with impaired renal function. However, it has been suggested that in cystic fibrosis (CF), creatinine clearance (CrCl) is not a good predictor of tobramycin clearance because of a lack of correlation. The aim of this study was to investigate the correlation between the tobramycin clearance and the measured CrCl. In addition, because most pharmacokinetic computer models use an a priori relationship between CrCl and tobramycin elimination rate constant [k(el)], regression analysis of k(el) on CrCl was performed. Eighteen CF patients (12 men, 6 women, ages 21-55 years) were treated with intravenous tobramycin. Blood and urine samples were collected for tobramycin analysis and determination of the CrCl. For each patient, CrCl was also estimated using the formulas of Cockcroft and Gault (C/G), Jelliffe I (J I), and Jelliffe II (J II). Predictive performance of these formulas was evaluated using mean error and mean squared error as reflections of bias and precision. Tobramycin total body clearance as well as renal clearance correlated significantly with CrCl (r = 0.52; p = 0.02 and r = 0.78; p = 0.02, respectively). Regression of the tobramycin k(el) versus CrCl gave the following equation: k(el) = 0.135 + 0.00134*CrCl/1.73 m2 (r = 0.64; p = 0.004). The 95% confidence interval of intercept and slope of the regression line were 0.019-0.251 and 0.00049-0.00219, respectively. The formulas of C/G, J I, and J II all overpredicted CrCl. Bias was 19, 24, and 8 ml/min, and precision was 37, 42, and 33 ml/min, respectively, for the C/G, J I, and J II formulas. In our CF population the J II formula gave the best estimation of the CrCl but calculated estimates deviated -25(-)+62% from measured values.

Adult↗