Robert J. Kuhn

Cystic Fibrosis Pulmonary Guidelines: Treatment of Pulmonary Exacerbations

The natural history of cystic fibrosis lung disease is one of chronic progression with intermittent episodes of acute worsening of symptoms frequently called acute pulmonary exacerbations These exacerbations typically warrant medical intervention. It is important that appropriate therapies are recommended on the basis of available evidence of efficacy and safety. The Cystic Fibrosis Foundation therefore established a committee to define the key questions related to pulmonary exacerbations, review the clinical evidence using an evidence-based methodology, and provide recommendations to clinicians. It is hoped that these guidelines will be helpful to clinicians in the treatment of individuals with cystic fibrosis.

Active transport of cimetidine into human milk

Most xenobiotics are transferred from blood into breast milk by passive diffusion. However, an active transport mechanism has been speculated for cimetidine, and the purpose of this study was to characterize cimetidine transfer into human milk. Twelve healthy lactating volunteers received single oral doses of 100, 600, and 1200 mg cimetidine in a randomized, crossover design on 3 different days. Blood and milk specimens were collected and assayed for cimetidine. In vitro measurements, including skim to whole milk concentration ratio, milk pH, and free fractions in serum and milk were used for a diffusion model prediction of milk to serum concentration ratio of cimetidine; the mean milk/serum ratio (±SD) was 1.05 ± 0.18. The observed milk/serum ratio (5.77 ± 1.24) was 5.5 times higher than the milk/serum ratio predicted by diffusion. The observed milk/serum ratio for the three dosing regimens were not significantly different from one another. Time of peak concentration (tmax) in milk (3.3 ± 0.7 hours) displayed a delay compared with serum tmax (1.7 ± 0.6 hours). Oral clearance for 1200 mg cimetidine dose (0.47 ± 0.11 L/hr/kg) was significantly lower compared with oral clearance values for 100 and 600 mg cimetidine doses (0.59 ± 0.11 and 0.57 ± 0.13 L/hr/kg, respectively). The maternal dose of cimetidine ingested by a suckling infant based on body weight was estimated to be 6.7%, which appears to be safe under normal conditions. This study provides the first definitive evidence of an active transport system for drug transfer into human milk, which may have broader consequences for the suckling infant.

Sequential ciprofloxacin therapy in pediatric cystic fibrosis : comparative study vs. ceftazidime/tobramycin in the treatment of acute pulmonary exacerbations

BACKGROUND Cystic fibrosis patients have chronic bacterial infections of the respiratory tract, most commonly Pseudomonas aeruginosa. Although controversial, administration of antibiotic therapy during acute pulmonary exacerbations is standard practice. Fluoroquinolones are currently not indicated for use in young children because of the observation of arthropathy and damage to growing cartilage in beagle puppies. Because of its activity against P. aeruginosa and excellent oral bioavailability, ciprofloxacin offers a unique therapeutic alternative for this patient population. OBJECTIVE This prospective, randomized, double blind study compared the efficacy and safety of sequential intravenous/oral ciprofloxacin vs. ceftazidime/tobramycin in hospitalized pediatric cystic fibrosis patients with an acute pulmonary exacerbation associated with P. aeruginosa infection. METHODS One hundred thirty patients (ages 5 to 17 years) were randomized to receive either i.v. ciprofloxacin 10 mg/kg every 8 h for 7 days followed by oral ciprofloxacin 20 mg/kg every 12 h for a minimum of 3 days or i.v. ceftazidime 50 mg/kg every 8 h plus i.v. tobramycin 3 mg/kg every 8 h for a minimum of 10 days. Clinical, bacteriologic and safety responses were assessed throughout the study. RESULTS All 84 patients (median age, 11 years; range, 5 to 17 years) valid for efficacy in both treatment groups demonstrated clinical improvement. Five patients experienced clinical relapses (3 ciprofloxacin, 2 ceftazidime/tobramycin) by the 2- to 4-week follow-up. Intent-to-treat analysis demonstrated similar clinical findings between the two treatment groups at both the end of therapy and follow-up. Clinical improvement correlated with improvement in pulmonary function studies and the acute clinical scoring system but not with bacteriologic eradication of Pseudomonas. DNA profiles demonstrated that irrespective of colony morphology, usually one clonal strain was associated with each patients pulmonary exacerbation. Treatment-associated musculoskeletal events occurred with equal frequency (22% vs. 21%) in both study drug groups (n = 129), and arthralgias were within the range of rates for cystic fibrosis arthropathy. None of these events required study drug discontinuation. CONCLUSION Sequential i.v./oral ciprofloxacin monotherapy offers a safe and efficacious alternative to standard parenteral therapy for acute pulmonary exacerbations in pediatric cystic fibrosis patients.

Pharmacologic Management of Supraventricular Tachycardias in Children Part 1: Wolff-Parkinson-White and Atrioventricular Nodal Reentry

OBJECTIVE: To review the literature regarding the use of antiarrhythmic agents in the management of Wolff-Parkinson-White (WPW) syndrome and atrioventricular nodal reentry tachycardia (AVNRT) in infants and children, and to discuss the advantages and disadvantages of specific agents in each arrhythmia in an effort to develop treatment guidelines. DATA SOURCES: A MEDLINE search encompassing the years 1966–1996 was used to identify pertinent literature for discussion. Additional references were found in the articles that were retrieved via MEDLINE. STUDY SELECTION: Clinical trials that address the use of antiarrhythmic agents for the treatment of the supraventricular tachycardias WPW and AVNRT in children were selected. Literature pertaining to dosage, pharmacokinetics, efficacy, and toxicity of antiarrhythmic agents in children were considered for possible inclusion in the review, and information judged to be pertinent by the authors was included in the discussion. DATA EXTRACTION: Although there are numerous reports of antiarrhythmic use in children, very few large studies are designed to evaluate an individual antiarrhythmic agent for a specific arrhythmia. Controlled, comparison trials of antiarrhythmic agents in children are virtually nonexistent. Ideally, controlled clinical trials are used to develop clinical guidelines; however, in this situation, most data and information must be obtained from case series of children treated. Although the results from these type of studies may be useful in developing guidelines for the optimal use of these agents, controlled trials are required for establishing standard treatment guidelines for all patients. DATA SYNTHESIS: Despite limited scientific evaluation of conventional agents in the treatment of WPW and AVNRT in children, they continue to be used as standard of care. Most information regarding the use of conventional agents in children has been extrapolated from the adult literature. Little justification for the use of the agents or dosing in children is available. Controlled trials regarding the use of new antiarrhythmic agents (propafenone, amiodarone, flecainide) are available; however, the variance in dosing schemes, presence of structural heart disease, and patient age make the development of recommendations difficult. CONCLUSIONS: Because of greater clinical experience with these conventional antiarrhythmic agents, they continue to be first-line therapy in the management of most supraventricular tachycardia (SVT) in children. The management of SVT in children with WPW syndrome should begin with the use of a β-blocker with the addition of digoxin or procainamide for treatment failures. The use of digoxin monotherapy, although frequently used by many practitioners in infants and children with WPW, cannot be recommended. For failures to conventional agents, flecainide is the preferred agent, while therapy with propafenone, amiodarone, and sotalol remains to be elucidated. The management of AVRNT is similar to that of WPW; however, digoxin is the agent of first choice. Trials of β-blockers and procainamide should follow for treatment failures with flecainide again being the preferred “newer” antiarrhythmic for use in resistant cases. Additional well-designed, controlled trials are needed to further evaluate the comparative efficacy of antiarrhythmics in the management of WPW and AVNRT in children, as well as to evaluate dosing and toxicity in various age groups.

Pharmacologic Management of Supraventricular Tachycardias in Children. Part 2: Atrial Flutter, Atrial Fibrillation, and Junctional and Atrial Ectopic Tachycardia

OBJECTIVE: To review the literature regarding the use of antiarrhythmic agents in the management of atrial flutter (AF), atrial fibrillation (Afib), junctional ectopic tachycardia (JET), and atrial ectopic tachycardia (AET) in infants and children. To discuss the advantages and disadvantages of specific agents in each type of arrhythmia in an effort to develop treatment guidelines. DATA SOURCES: A MEDLINE search encompassing the years 1966-1996 was used to identify pertinent literature for discussion. Additional references were found in the articles, which were retrieved via MEDLINE. STUDY SELECTION: Clinical trials that address the use of antiarrhythmic agents for the treatment of supraventricular tachycardia, AF, Afib, JET, and AET in children were selected. Literature pertaining to dosage, pharmacokinetics, efficacy, and toxicity of antiarrhythmic agents in children were considered for possible inclusion in the review; information judged to be pertinent by the authors was included in the discussion. DATA EXTRACTION: Although there are numerous reports of antiarrhythmic use in children, there are very few large studies designed that evaluate the use of specific antiarrhythmic agents in the treatment of AF, Afib, JET, or AET. Ideally, controlled clinical trials are used to develop clinical guidelines; however, in this situation, most data and information must be obtained from case series of children treated. Although the results from these types of studies may be useful in developing guidelines for the optimal use of these agents for the treatment of AF, Afib, JET, and AET, controlled trials are required for establishing standard treatment guidelines for all patients. DATA SYNTHESIS: Despite limited scientific evaluation of conventional agents in the treatment of AF, Afib, JET, or AET in children, they continue to be the standards of care. Most information regarding the use of conventional agents in children has been extrapolated from the adult literature. Little justification for the use of the agents or dosing in children is available. Controlled trials regarding the use of newer antiarrhythmic agents (propafenone, amiodarone, flecainide) are available; however, the variance in dosing schemes, presence of structural heart disease, and patient age may confound the results. CONCLUSIONS: Because of greater clinical experience, conventional antiarrhythmic agents generally remain as first-line therapy in the management of most supraventricular tachycardias in children. Atrial pacing or cardioversion to reestablish sinus rhythm is indicated for initial episodes of AF in infants, followed by chronic prophylactic therapy in those with significant structural heart disease or in infants in whom AF recurs. Attempts to eliminate AF in children outside the neonatal or infancy period should begin with trials of traditional agents such as digoxin or procainamide, and if unsuccessful, subsequent trials of amiodarone. Digoxin and β-blockers remain the mainstay of therapy for children with Afib, followed by procainamide for treatment failures. Intravenous amiodarone, the newest addition to our antiarrhythmic armamentarium, is the most promising agent in the treatment of postoperative JET. This arrhythmia has been traditionally managed with corporal cooling and/or digoxin therapy; however, intravenous amiodarone may now be a valuable option. Although relatively unsuccessful in the management of congenital JET and AET, conventional agents are typically used prior to the initiation of long-term therapy with potentially more toxic agents such as amiodarone or propafenone. Additional well-designed, controlled trials are needed to further evaluate the comparative efficacy of agents such as flecainide, sotalol, moricizine, propafenone, and amiodarone in the management of AF, Afib, JET, and AET in children, as well as to evaluate the dosing and toxicity in various age groups.

Use of azithromycin for the prevention of bronchopulmonary dysplasia in preterm infants: a randomized, double‐blind, placebo controlled trial

Since preventive therapies for bronchopulmonary dysplasia (BPD) are limited we treated preterm infants with azithromycin to decrease the incidence of BPD.

Cystic fibrosis clinical score: A new scoring system to evaluate acute pulmonary exacerbation

Although pulmonary function tests are used to evaluate acute changes in obstructive airway disease in patients with cystic fibrosis (CF), these tests are relatively difficult to perform in young children or severely ill patients and may be costly. Other standard tests (eg, the Shwachman-Kulczycki and National Institutes of Health [NIH] scoring systems) evaluate disease severity and predict prognosis but do not measure day-to-day changes in clinical status. They thus provide little information for assessing the start of acute pulmonary exacerbation. Alternative scoring systems are needed to better identify the start of pulmonary exacerbation, to predict worsening or improvement of respiratory function after intervention, and to distinguish the scores from illness severity scores. This study was undertaken to compare a new 10-component, 50-point-maximum, acute clinical scoring system with forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) variables in children with CF who were experiencing an acute pulmonary exacerbation before antimicrobial therapy was initiated and until the end of therapy. One hundred thirty children aged 5 to 17 years (median age, 11 years) had a median NIH score of approximately 64 (range, 39 to 85) at admission. The cystic fibrosis clinical score (CFCS) at admission was found to correlate highly with the modified NIH score at study entry (r = -.68, P = 0.0001 ). The total CFCS at entry was correlated inversely with both FEV1 (r = -.57, P = 0.0001) and FVC (r = -.55, P = 0.0001) measurements; crackles, dyspnea, sputum production, and respiratory rate were the 4 components most highly associated with either pulmonary function variable. The change in total CFCS from start to end of antimicrobial therapy also correlated with changes in FEV1 (r = -.31, P = 0.0016) and change in FVC (r = -.47, P = 0.0001). Clinical improvement was observed in all patients at the end of therapy, and only 1 patient had an increase in total CFCS. Patients who experienced clinical relapse had a mean increase of 8.5 points in the CFCS from end of therapy to 2- to 4-week follow-up, indicating worsening signs and symptoms of acute exacerbation. These data suggest that the CFCS is a predictive and optional surrogate of pulmonary function in assessing the health of patients with CF. Following further validation, this scoring system could be used to evaluate health status in the outpatient setting, the need for hospitalization, and subsequent improvement during an acute pulmonary exacerbation, as well as to compare the efficacy of therapeutic regimens.

Pharmacokinetic disposition of sequential intravenous/oral ciprofloxacin in pediatric cystic fibrosis patients with acute pulmonary exacerbation.

OBJECTIVE Information about the pharmacokinetics of fluoroquinolone antibiotics in high risk children is scant. This study examined the disposition of sequentially administered intravenous and oral ciprofloxacin, as well as provided dosing recommendations, for the treatment of acute pulmonary exacerbations in pediatric cystic fibrosis patients. METHODS After enrollment in a Food and Drug Administration approved protocol, the pharmacokinetic profiles of ciprofloxacin (CIP) administered to 18 children with cystic fibrosis (ages 5 to 17 years) were studied at steady state after sequentially administered intravenous (10 mg/kg every 8 h) and oral (20 mg/kg every 12 h) doses. All children enrolled met published criteria for exacerbation of Pseudomonas aeruginosa lung infection and received CIP intravenously (given as a 1-h infusion) followed by oral administration, each for a minimum of 3 days. All patients were at a mild to moderate stage in their disease with National Institutes of Health scores between 37 and 83. Blood samples were drawn at 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0 (after both i.v. and oral dosing) and 12 h (oral only) after CIP administration. CIP serum concentrations were determined by high performance liquid chromatography. RESULTS After oral CIP mean +/- SD peak serum concentrations and peak times were 3.7 +/- 1.4 mg/l and 2.5 +/- 1.8 h, respectively, compared with 5.0 +/- 1.5 mg/l and 1.0 +/- 0.3 h after completion of the i.v. infusion. Maximum concentrations, when normalized for dose, were 0.52 +/- 0.12 and 0.19 +/- 0.07 mg/l/kg after i.v. and oral dosing, respectively. The mean bioavailability of oral CIP for all patients was 76%; younger patients appeared to absorb oral CIP less than older subjects, 68% vs. 95%, respectively. For all patients elimination half-lives were 2.6 +/- 0.6 and 3.4 +/- 0.7 h after i.v. and oral administration, respectively, and did not differ by age. Total clearance after i.v. administration was 19.5 +/- 10.9 liters/h. No significant CIP-related adverse effects were noted. CONCLUSIONS CIP doses of 30 mg/kg/day i.v. and 40 mg/kg/day orally must be administered to children with cystic fibrosis to achieve optimal therapeutic concentrations.

Pharmacokinetics of Anti-Infective Agents in Paediatric Patients

SummaryVarious differences in drug disposition exist between children and adults. For example, the volume of distribution (Vd) for many drugs is larger in children than in adults. Other parameters, including excretion and elimination may be altered in children compared with adults.The penicillins and cephalosporins are used commonly for the treatment of infection in paediatric patients. The increased Vd in children contributes to the increased elimination half-life of these agents. Clearance of the acylureido-penicillins is increased in children with cystic fibrosis, a disease that decreases the elimination half-life for these drugs. Aminoglycosides distribute into extracellular fluid and their pharmacokinetic profile is affected by changes in Vd. The Vd for aminoglycosides is slightly higher in children than in adults. Children with cystic fibrosis, bums, or cancer have higher clearance rates and larger Vd values for aminoglycosides.Few data in the literature address the pharmacokinetics of other anti-infective agents, including vancomycin, teicoplanin, erythromycin, metronidazole, chloramphenicol, and cotrimoxazole (trimethoprim-sulfamethoxazole), in children. Similarly, there is little information regarding the pharmacokinetic profile of antivirals and antifungals in children.Dosage guidelines are available to enable the clinician to initiate anti-infective therapy in children. Subsequent dosage requirements may change based on the patient’s current clinical condition.Although several studies have investigated the pharmacokinetics of anti-infectives in neonates and adults, data for children are limited. Therefore, further studies are required so that the ever growing arsenal of anti-infectives can be administered appropriately to children.

Design and physicochemical characterization of advanced spray-dried tacrolimus multifunctional particles for inhalation

The aim of this study was to design, develop, and optimize respirable tacrolimus microparticles and nanoparticles and multifunctional tacrolimus lung surfactant mimic particles for targeted dry powder inhalation delivery as a pulmonary nanomedicine. Particles were rationally designed and produced at different pump rates by advanced spray-drying particle engineering design from organic solution in closed mode. In addition, multifunctional tacrolimus lung surfactant mimic dry powder particles were prepared by co-dissolving tacrolimus and lung surfactant mimic phospholipids in methanol, followed by advanced co-spray-drying particle engineering design technology in closed mode. The lung surfactant mimic phospholipids were 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-1-glycerol]. Laser diffraction particle sizing indicated that the particle size distributions were suitable for pulmonary delivery, whereas scanning electron microscopy imaging indicated that these particles had both optimal particle morphology and surface morphology. Increasing the pump rate percent of tacrolimus solution resulted in a larger particle size. X-ray powder diffraction patterns and differential scanning calorimetry thermograms indicated that spray drying produced particles with higher amounts of amorphous phase. X-ray powder diffraction and differential scanning calorimetry also confirmed the preservation of the phospholipid bilayer structure in the solid state for all engineered respirable particles. Furthermore, it was observed in hot-stage micrographs that raw tacrolimus displayed a liquid crystal transition following the main phase transition, which is consistent with its interfacial properties. Water vapor uptake and lyotropic phase transitions in the solid state at varying levels of relative humidity were determined by gravimetric vapor sorption technique. Water content in the various powders was very low and well within the levels necessary for dry powder inhalation, as quantified by Karl Fisher coulometric titration. Conclusively, advanced spray-drying particle engineering design from organic solution in closed mode was successfully used to design and optimize solid-state particles in the respirable size range necessary for targeted pulmonary delivery, particularly for the deep lung. These particles were dry, stable, and had optimal properties for dry powder inhalation as a novel pulmonary nanomedicine.