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

Abstract

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.

MexXY efflux pump overexpression and aminoglycoside resistance in cystic fibrosis isolates of Pseudomonas aeruginosa from chronic infections

“…Even though the true minimum inhibitory concentrations for some of the antibiotics tested might be outside the concentrations range used in the Sensititre panel, the method effectively helped in determining the susceptibility of the isolates to respective antibiotics. Aminoglycoside resistance was prevalent in these isolates, which is not unexpected given that chronic P. aeruginosa infections in CF patients are routinely treated with long-term tobramycin inhalation therapy (Ratjen et al 2009;Young et al 2013). Colistin was the most effective antibiotic against these isolates, with all but 2 susceptible to the antibiotic, likely reflecting, at least partially, the fact it is less commonly used as therapy in CF patients in Canada.…”

Assessing Predictive Performance of Published Population Pharmacokinetic Models of Intravenous Tobramycin in Pediatric Patients

“…Treatment success and a decreased incidence of antibiotic resistance have been correlated with a ratio of the peak (maximum) tobramycin concentration (C max ) to the MIC of Ͼ7 to 10 (5, 6) and a ratio of the area under the concentration-time curve (AUC) to the MIC of Ͼ80 (7,8). A prolonged high level of exposure to tobramycin and, in particular, sustained, elevated trough (minimum) serum concentrations (C min ) have been associated with significant adverse effects (9, 10), such as nephrotoxicity, which is typically reversible, and ototoxicity, which can be permanent and result in hearing loss (4). Consequently, tobramycin dosing aims to achieve a sufficiently high C max and AUC for effective bactericidal activity while producing a sufficiently low C min to minimize the potential for toxicity (11) and the emergence of resistant microorganisms (12).…”

“…Tobramycin is particularly effective against Pseudomonas aeruginosa and is commonly used in patients with cystic fibrosis (2). Tobramycin exhibits concentration-dependent bactericidal action, whereby higher drug concentrations are correlated with a greater magnitude and a higher speed of bacterial eradication (3,4). Treatment success and a decreased incidence of antibiotic resistance have been correlated with a ratio of the peak (maximum) tobramycin concentration (C max ) to the MIC of Ͼ7 to 10 (5, 6) and a ratio of the area under the concentration-time curve (AUC) to the MIC of Ͼ80 (7,8).…”

Current Perspectives: Therapeutic Uses of Tobramycin

“…Studies have shown that CF patients tend to have a larger volume of distribution and greater renal and total clearance for aminoglycosides [9,16]. This translates to higher doses of tobramycin in the CF patients in order to achieve similar serum concentrations to those without CF.…”

“…The Cystic Fibrosis Pulmonary Guidelines recommend treating an APE with an aminoglycoside (IV) and an anti-pseudomonal agent for synergy and to reduce development of resistance [8]. Tobramycin is the most commonly utilized aminoglycoside among 98% of CFF-accredited care pediatric centers in the US; amikacin, second [9]. The routine use of gentamicin in the treatment of APE is not recommended due to a lack of studies showing efficacy and evidence indicating an increased risk of nephrotoxicity compared to tobramycin.…”