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

Abstract

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.

Clinical Pharmacokinetics of Inhaled Antimicrobials

“…Aminoglycosides, including tobramycin, display concentration-dependent bactericidal activity [17]. Aminoglycosides also feature low protein binding and high water solubility, which impede their ability to cross cellular membranes and limit their effectiveness in treating pulmonary infections when they are administered intravenously or orally [18][19][20].…”

Consenso español para la prevención y el tratamiento de la infección bronquial por Pseudomonas aeruginosa en el paciente con fibrosis quística

“…Por otra parte, la farmacocinética en sangre de los antimicrobianos en FQ difiere de la de los individuos sin esta enfermedad 17,61-63 ; por ello las dosis utilizadas en caso de emplear la vía sistémica (por ejemplo, en las exacerbaciones) son distintas de las empleadas en los pacientes sin FQ (tabla 4) y repercuten en los valores de los índices PK/PD de los antimicrobianos [58][59][60][64][65][66][67][68][69][70][71][72] .…”

“…En las exacerbaciones graves, o cuando el tratamiento oral no haya sido eficaz, suele recomendarse una combinación de un ␤-lactámico antipseudomónico (piperacilina/tazobactam, ceftazidima, cefepima, aztreonam, imipenem, meropenem o doripenem) con un aminoglucósido (habitualmente tobramicina) o una fluoroquinolona (II-B) 105,106 . Deben emplearse dosis altas por la dificultad que tienen para penetrar en las secreciones respiratorias y porque algunos antimicrobianos, especialmente los aminoglucósidos, tienen un aclaramiento renal más rápido en estos pacientes 60,64,107 .…”

Development of levofloxacin inhalation solution to treat Pseudomonas aeruginosa in patients with cystic fibrosis

“…Cystic fibrosis (CF) is an inherited disease that affects multiple organ systems [Ramsey, 1996; Zobell et al . 2012].…”