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

Abstract

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.

Follow-up survey of the utilization of anti-pseudomonal beta-lactam antibiotics at U.S. cystic fibrosis centers

“…The intermittent and extended‐infusion dosing regimens utilized for each antibiotic were collected (Table ). Some of the reported dosing regimens were consistent with the evidence‐based dosing released in 2012–2013 …”

“…We are writing this letter regarding a follow‐up survey to one referred in the article “A Survey of the Utilization of Anti‐Pseudomonal Beta‐Lactam Therapy in Cystic Fibrosis Patients” by Zobell et al The purpose 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 after the release of evidence–based dosing for anti‐pseudomonal beta‐lactam antibiotics in 2012–2013 . This follow‐up study was an anonymous national cross‐sectional survey sent to all 282 CFF‐accredited care centers in the U.S. (122 pediatric centers, 107 adult centers, and 53 combined pediatric and adult centers).…”

How To Minimize Toxic Exposure to Pyridine during Continuous Infusion of Ceftazidime in Patients with Cystic Fibrosis?

“…To achieve maximal microbiological efficacy, the residual blood concentration has to be three to four times the MIC of the pathogen and to remain above the MIC for Ն20% to 70% of the dosing interval (19). Increasing the concentration above this multiple does not improve the killing effect of the drug against the targeted pathogens (18,20).…”

Optimization of anti‐pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: V. Aminoglycosides

“…Consensus regarding optimization of dosing and dosing intervals of anti‐pseudomonal antibiotics does not exist when comparing CFF, European Consensus Conference, United Kingdom (UK) CF Trust Working Group, and Food and Drug Administration (FDA) dosing recommendations (Table ) . Prior publications in this State‐of‐the‐Art series have examined the optimization of beta‐lactams (aztreonam, carbapenems, penicillins, and cephalosporins), fluoroquinolones, and colistimethate sodium for the treatment of an APE in CF patients . The optimal aminoglycoside dose, dosing interval, and pharmacokinetic/pharmacodynamic (PK/PD) targets for the treatment of an APE remain uncertain.…”