Michael G. Spigarelli

Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: I. aztreonam and carbapenems†‡

Acute pulmonary exacerbations (APE) in cystic fibrosis (CF) are associated with loss of lung function that may require aggressive management with intravenous antibiotics. The aim of this review is to provide an evidence‐based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing aztreonam and anti‐pseudomonal carbapenems (i.e., doripenem, imipenem–cilastatin, and meropenem) in the treatment of an APE, and to identify areas where further study is warranted. The current dosing recommendations in the United States and Europe for aztreonam are lower than the literature supported dosing range of 200–300 mg/kg/day divided every 6 hr, maximum 8–12 g/day. In vitro, PK/PD, and tolerability studies show the potential of doripenem 90 mg/kg/day divided every 8 hr, infused over 4 hr, maximum 6 g/day in the treatment of APE. Imipenem‐cilastatin 100 mg/kg/day divided every 6 hr, maximum 4 g/day and meropenem 120 mg/kg/day divided every 8 hr, maximum 6 g/day have been shown to be tolerable and effective in the treatment of APE. With availability issues of new anti‐pseudomonal agents and a large percentage of CF patients will not regain their lung function following an APE, we suggest the need to determine optimization of aztreonam and meropenem dosing in CF, as well as to determine the clinical efficacy of doripenem in the treatment of APE. The usefulness of imipenem‐cilastatin may be limited due to the rapid development of resistance. Pediatr Pulmonol. 2012; 47:1147–1158.

Optimization of Anti-Pseudomonal Antibiotics for Cystic Fibrosis Pulmonary Exacerbations: V. Aminoglycosides

Intravenous (IV) anti‐pseudomonal aminoglycosides (i.e., amikacin and tobramycin) have been shown to be tolerable and effective in the treatment of acute pulmonary exacerbations (APEs) in both pediatric and adult patients with cystic fibrosis. The aim of this review is to provide an evidence‐based summary of pharmacokinetic/pharmacodynamic, tolerability, and efficacy studies utilizing IV amikacin, gentamicin, and tobramycin in the treatment of APE and to highlight areas where further investigation is needed. The Cystic Fibrosis Foundation Pulmonary Guidelines recommend that once‐daily administration of aminoglycosides is preferred over three times per day in the treatment of an APE. The literature supports dosing ranges for amikacin and tobramycin of 30–35 and 7–15 mg/kg/day, respectively, given once daily, with subsequent doses determined by therapeutic drug concentration monitoring. The literature does not support the routine use of gentamicin in the treatment of APE due to a lack of studies showing efficacy and evidence indicating an increased risk of nephrotoxicity. Further studies are needed to determine the optimal dosing strategy of amikacin in the treatment of an APE, and to further identify risk factors and determinants that influence the development of P. aeruginosa resistance with once‐daily administration of tobramycin. Pediatr Pulmonol. 2013; 48:1047–1061.

Fundamentals of Population Pharmacokinetic Modelling

Population pharmacokinetic modelling is widely used within the field of clinical pharmacology as it helps to define the sources and correlates of pharmacokinetic variability in target patient populations and their impact upon drug disposition; and population pharmacokinetic modelling provides an estimation of drug pharmacokinetic parameters. This method’s defined outcome aims to understand how participants in population pharmacokinetic studies are representative of the population as opposed to the healthy volunteers or highly selected patients in traditional pharmacokinetic studies. This review focuses on the fundamentals of population pharmacokinetic modelling and how the results are evaluated and validated.This review defines the common aspects of population pharmacokinetic modelling through a discussion of the literature describing the techniques and placing them in the appropriate context. The concept of validation, as applied to population pharmacokinetic models, is explored focusing on the lack of consensus regarding both terminology and the concept of validation itself.Population pharmacokinetic modelling is a powerful approach where pharmacokinetic variability can be identified in a target patient population receiving a pharmacological agent. Given the lack of consensus on the best approaches in model building and validation, sound fundamentals are required to ensure the selected methodology is suitable for the particular data type and/or patient population. There is a need to further standardize and establish the best approaches in modelling so that any model created can be systematically evaluated and the results relied upon.

Fundamentals of population pharmacokinetic modelling: modelling and software.

Population pharmacokinetic modelling is widely used within the field of clinical pharmacology as it helps to define the sources and correlates of pharmacokinetic variability in target patient populations and their impact upon drug disposition. This review focuses on the fundamentals of population pharmacokinetic modelling and provides an overview of the commonly available software programs that perform these functions. This review attempts to define the common, fundamental aspects of population pharmacokinetic modelling through a discussion of the literature describing the techniques and placing them in the appropriate context. An overview of the most commonly available software programs is also provided. Population pharmacokinetic modelling is a powerful approach where sources and correlates of pharmacokinetic variability can be identified in a target patient population receiving a pharmacological agent. There is a need to further standardize and establish the best approaches in modelling so that any model created can be systematically evaluated and the results relied upon. Various nonlinear mixed-effects modelling methods, packaged in a variety of software programs, are available today. When selecting population pharmacokinetic software programs, the consumer needs to consider several factors, including usability (e.g. user interface, native platform, price, input and output specificity, as well as intuitiveness), content (e.g. algorithms and data output) and support (e.g. technical and clinical).

Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. cephalosporins and penicillins.

Acute pulmonary exacerbations (APE) are well‐described complications of cystic fibrosis (CF) and are associated with progressive morbidity and mortality. Despite aggressive management with two or more intravenous anti‐pseudomonal agents, approximately 25% of exacerbations will result in a loss of lung function. The aim of this review is to provide an evidence‐based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing anti‐pseudomonal cephalosporins (i.e., ceftazidime and cefepime) and penicillins (i.e., piperacillin–tazobactam and ticarcillin–clavulanate) in the treatment of APE and to identify areas where further study is warranted. The ceftazidime and cefepime dosing ranges from the literature are 200–400 mg/kg/day divided every 6–8 hr, maximum 8–12 g/day, and 150–200 mg/kg/day divided every 6–8 hr, up to 6–8 g/day, respectively. The literature supported dosing ranges for piperacillin and ticarcillin are 350–600 mg/kg/day divided every 4 hr, maximum 18–24 g/day of piperacillin component, and 400–750 mg/kg/day divided every 6 hr, up to 24–30 g/day of ticarcillin component, respectively. As a large portion of CF patients will not regain their lung function following an APE, we suggest the need to optimize antibiotic dosing and dosing regimens used to treat an APE in efforts to improve outcomes for CF patients infected with Pseudomonas aeruginosa. Future studies are needed to determine the clinical efficacy of higher than FDA‐approved doses of ceftazidime, cefepime, and ticarcillin–clavulanate in APE. The usefulness of high dose piperacillin (>600 mg/kg/day) may be limited due to treatment‐related adverse effects. Further understanding of these adverse effects in CF patients is needed. Pediatr Pulmonol. 2013; 48:107–122.

Fundamentals of population pharmacokinetic modelling: validation methods.

Population pharmacokinetic modelling is widely used within the field of clinical pharmacology as it helps to define the sources and correlates of pharmacokinetic variability in target patient populations and their impact upon drug disposition; and population pharmacokinetic modelling provides an estimation of drug pharmacokinetic parameters. This methods defined outcome aims to understand how participants in population pharmacokinetic studies are representative of the population as opposed to the healthy volunteers or highly selected patients in traditional pharmacokinetic studies. This review focuses on the fundamentals of population pharmacokinetic modelling and how the results are evaluated and validated. This review defines the common aspects of population pharmacokinetic modelling through a discussion of the literature describing the techniques and placing them in the appropriate context. The concept of validation, as applied to population pharmacokinetic models, is explored focusing on the lack of consensus regarding both terminology and the concept of validation itself. Population pharmacokinetic modelling is a powerful approach where pharmacokinetic variability can be identified in a target patient population receiving a pharmacological agent. Given the lack of consensus on the best approaches in model building and validation, sound fundamentals are required to ensure the selected methodology is suitable for the particular data type and/or patient population. There is a need to further standardize and establish the best approaches in modelling so that any model created can be systematically evaluated and the results relied upon.

Optimization of Anti-Pseudomonal Antibiotics for Cystic Fibrosis Pulmonary Exacerbations: III. Fluoroquinolones

This review is the third installment in a comprehensive State of the Art series and aims to evaluate the use of fluoroquinolones in the management of P. aeruginosa infection in both children and adults with cystic fibrosis (CF). Oral and intravenous ciprofloxacin have been shown to be well‐tolerated in the treatment of acute pulmonary exacerbations (APE) secondary to P. aeruginosa. Older literature supports an oral dosing regimen of 40 mg/kg/day divided every 12 hr, up to 2 g/day, and intravenous (IV) ciprofloxacin 30 mg/kg/day divided every 8 hr, maximum 1.2 g/day in children, and 750 mg administered orally twice a day or 400 mg IV every 8 hr in adults. However, a recent pharmacodynamic (PD) modeling study shows that the literature, U.S. Food and Drug Administration (FDA)‐approved, and Cystic Fibrosis Foundation (CFF) guideline dosing regimens may be suboptimal for the treatment of P. aeruginosa in APE. Further study is warranted to determine if higher doses of ciprofloxacin are needed. Limited pharmacokinetic (PK), PK/PD, and efficacy studies involving levofloxacin exist in adult patients with CF. No pediatric data exists for levofloxacin in CF patients. Further study is needed to determine the tolerability and efficacy of levofloxacin in APE. At this time, the routine use of levofloxacin in the treatment of APE in pediatric and adult patients cannot be recommended. Pediatr Pulmonol. 2013; 48:211–220.

Population Pharmacokinetics of Intermittent Vancomycin in Children with Cystic Fibrosis

Vancomycin is the drug‐of‐choice for the treatment of methicillin‐resistant Staphylococcus aureus (MRSA) infections in children with cystic fibrosis. However, no studies have characterized the pharmacokinetic profile of vancomycin among pediatric cystic fibrosis patients.

Considerations in the Pharmacologic Treatment and Prevention of Neonatal Sepsis

The management of neonatal sepsis is challenging owing to complex developmental and environmental factors that contribute to inter-individual variability in the pharmacokinetics and pharmacodynamics of many antimicrobial agents. In this review, we describe (i) the changing epidemiology of early- and late-onset neonatal sepsis; (ii) the pharmacologic considerations that influence the safety and efficacy of antibacterials, antifungals, and immunomodulatory adjuvants; and (iii) the recommended dosing regimens for pharmacologic agents commonly used in the treatment and prevention of neonatal sepsis. Neonatal sepsis is marked by high morbidity and mortality, such that prompt initiation of antimicrobial therapy is essential following culture collection. Before culture results are available, combination therapy with ampicillin and an aminoglycoside is recommended. When meningitis is suspected, ampicillin and cefotaxime may be considered. Following identification of the causative organism and in vitro susceptibility testing, antimicrobial therapy may be narrowed to provide targeted coverage. Therapeutic drug monitoring should be considered for neonates receiving vancomycin or aminoglycoside therapies. For neonates with invasive fungal infections, the development of new antifungal agents has significantly improved therapeutic outcomes in recent years. Liposomal amphotericin B has been found to be safe and efficacious in patients with renal impairment or toxicity caused by conventional amphotericin B. Antifungal prophylaxis with fluconazole has also been reported to dramatically reduce rates of neonatal invasive fungal infections and to improve long-term neurodevelopmental outcomes among treated children. Additionally, several large multicenter studies are currently investigating the safety and efficacy of oral lactoferrin as an immunoprophylactic agent for the prevention of neonatal sepsis.

Optimization of Anti-pseudomonal Antibiotics for Cystic Fibrosis Pulmonary Exacerbations: VI. Executive Summary

Acute pulmonary exacerbations (APE) are well‐described complications of cystic fibrosis (CF) and are associated with progressive morbidity and mortality. Despite aggressive management with two or more intravenous anti‐pseudomonal agents, approximately 25% of exacerbations will result in a loss of lung function. The aim of this review is to provide an overview of the classes of intravenous anti‐pseudomonal antibiotics, the findings of anti‐pseudomonal antibiotic utilization surveys, the current antibiotic dosing recommendations from the U.S. and Europe, and the pharmacokinetic (PK) and pharmacodynamic (PD) differences between CF and non‐CF individuals. Anti‐pseudomonal antibiotic classes include beta‐lactams, aminoglycosides, fluoroquinolones, and colistimethate sodium. Recent surveys of antibiotic utilization in CF Foundation‐accredited care centers have shown that a large number of centers are not following recommended dosing strategies despite published recommendations in the U.S. and Europe. The recommended doses for anti‐pseudomonal antibiotics may be higher than FDA‐approved doses due to PK and PD differences. As a large portion of CF patients will not regain their lung function following an APE, it seems possible that currently available anti‐pseudomonal agents are being used sub‐optimally. As new anti‐pseudomonal agents are not currently available, we suggest the need to optimize antibiotic dosing and dosing regimens used to treat pulmonary exacerbations in an effort to improve outcomes for CF patients infected with Pseudomonas aeruginosa. Pediatr Pulmonol. 2013; 48:525–537.