Jeffery T. Zobell

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.

A survey of the utilization of anti-pseudomonal beta-lactam therapy in cystic fibrosis patients.

The purpose of this study was to characterize the utilization of anti‐pseudomonal beta‐lactam antibiotics in the treatment of acute pulmonary exacerbations (APE) among Cystic Fibrosis Foundation (CFF)‐accredited care centers. An anonymous national cross‐sectional survey of CFF‐accredited care centers was performed using an electronic survey tool (SurveyMonkey.com®). One hundred and twenty‐one of 261 centers completed the survey (46%) representing 56% (14,856/26,740) of patients in the CFF Patient Registry. One hundred and nineteen of 121 (98%) respondents reported using beta‐lactams for the treatment of APE. Intermittent dosing regimens constituted 155/167 (93%) reported regimens, while extended infusions were 12/167 (7%). Ceftazidime was the most commonly utilized beta‐lactam comprising 74/167 (44%) of all infusions (intermittent and extended) of which 70/74 (95%) were intermittent infusions. The majority of intermittent ceftazidime regimens (56/70; 80%) were at doses lower than CFF and European guidelines recommended doses. In conclusion, a great majority of respondents use intermittent anti‐pseudomonal beta‐lactam antibiotics, with over half of respondents utilizing lower than guidelines recommended doses. While this is of concern, it is not known if optimization of dosing strategies according to guidelines recommendations will result in clinical benefit. Pediatr. Pulmonol. 2011; 46:987–990.

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.

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.

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.

Utilization of antibiotics for methicillin-resistant Staphylococcus aureus infection in cystic fibrosis.

The purpose of this study was to characterize the utilization of antibiotics for chronic methicillin‐resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis (CF) patients with acute pulmonary exacerbations (PEx).

Frequency and Severity of Parenteral Nutrition Medication Errors at a Large Children’s Hospital After Implementation of Electronic Ordering and Compounding

INTRODUCTION The Institute for Safe Medication Practices has stated that parenteral nutrition (PN) is considered a high-risk medication and has the potential of causing harm. Three organizations--American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), American Society of Health-System Pharmacists, and National Advisory Group--have published guidelines for ordering, transcribing, compounding and administering PN. These national organizations have published data on compliance to the guidelines and the risk of errors. The purpose of this article is to compare total compliance with ordering, transcription, compounding, administration, and error rate with a large pediatric institution. METHOD A computerized prescriber order entry (CPOE) program was developed that incorporates dosing with soft and hard stop recommendations and simultaneously eliminating the need for paper transcription. A CPOE team prioritized and identified issues, then developed solutions and integrated innovative CPOE and automated compounding device (ACD) technologies and practice changes to minimize opportunities for medication errors in PN prescription, transcription, preparation, and administration. Thirty developmental processes were identified and integrated in the CPOE program, resulting in practices that were compliant with A.S.P.E.N. safety consensus recommendations. Data from 7 years of development and implementation were analyzed and compared with published literature comparing error, harm rates, and cost reductions to determine if our process showed lower error rates compared with national outcomes. RESULTS The CPOE program developed was in total compliance with the A.S.P.E.N. guidelines for PN. The frequency of PN medication errors at our hospital over the 7 years was 230 errors/84,503 PN prescriptions, or 0.27% compared with national data that determined that 74 of 4730 (1.6%) of prescriptions over 1.5 years were associated with a medication error. Errors were categorized by steps in the PN process: prescribing, transcription, preparation, and administration. There were no transcription errors, and most (95%) errors occurred during administration. CONCLUSION We conclude that PN practices that conferred a meaningful cost reduction and a lower error rate (2.7/1000 PN) than reported in the literature (15.6/1000 PN) were ascribed to the development and implementation of practices that conform to national PN guidelines and recommendations. Electronic ordering and compounding programs eliminated all transcription and related opportunities for errors.

Optimization of anti‐pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: IV. colistimethate sodium

Patients with cystic fibrosis (CF) often experience acute pulmonary exacerbations (APE) and may be treated with a wide variety of intravenous antibiotics. The aim of this review is to provide an evidence‐based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing the intravenous (IV) polymixin antibiotic colistimethate sodium (CMS) in the treatment of APE and to identify areas where further study is warranted. Currently, there is not an international standard on the labeling of CMS products. As a result, this has lead to confusion in the interpretation of the literature with respect to efficacy, tolerance, and optimal dosing strategy. The dosing ranges of IV CMS from the literature are 5.3–12.9 mg/kg/day, maximum 480 mg per day for 60 kg patient (Colomycin® injection‐European product) and 8–21.3 mg/kg/day, maximum 800 mg per day for 60 kg patient (Coly‐Mycin M® parenteral‐US product).The literature supports a CMS dose of 8 mg/kg/day divided every 8 hr (maximum 480 mg/day) for the treatment of APE secondary to Pseudomonas aeruginosa. The maximum recommended CMS dose of 480 mg/day is less than is recommended by the FDA‐approved and CFF dosing guidelines but in agreement with UK CF Trust Antibiotic Working Group recommendations. There is debate over the frequency of CMS administration (once daily vs. thrice‐daily) and its impact on resistance and clinical efficacy. Further study is needed to determine the tolerability and efficacy of extended‐interval dosing of CMS in the treatment of APE. Pediatr Pulmonol. 2013; 48:1–7.