Pharmacodynamics of once- versus twice-daily dosing of nebulized amikacin in an in vitro Hollow-Fiber Infection Model against 3 clinical isolates of Pseudomonas aeruginosa.

This study aims to compare the bacterial killing of once- versus twice-daily nebulized amikacin against Pseudomonas aeruginosa and to determine the optimal duration of therapy. Three clinical P. aeruginosa isolates (amikacin MICs 2, 8, and 64 mg/L) were exposed to simulated epithelial lining fluid exposures of nebulized amikacin with dosing regimens of 400 mg and 800 mg once- or twice-daily up to 7-days using the in vitro hollow-fiber infection model. Quantitative cultures were performed. Simulated amikacin dosing regimens of 400 mg twice-daily and 800 mg once-daily achieved ≥2-log reduction in the bacterial burden within the first 24-hours of therapy for all isolates tested. No dosing regimen suppressed the emergence of amikacin resistance. No difference in bacterial killing or regrowth was observed between 3- and 7-days of amikacin. Amikacin doses of 800 mg once-daily for up to 3-days may be considered for future clinical trials.

ß-lactam antibiotic versus combined ß-lactam antibiotics and single daily dosing regimens of aminoglycosides for treating serious infections: A meta-analysis.

BACKGROUND: Combining aminoglycosides with ß-lactam antibiotics for treating serious infections has not been associated with reduced mortality in previous meta-analyses. However, the multiple daily aminoglycoside dosing regimen principally used in most of the included studies is inconsistent with current practice. OBJECTIVE: To determine if a combination of an aminoglycoside administered as a single daily dose and a ß-lactam antibiotic reduces all-cause mortality in patients compared with ß-lactam antibiotic monotherapy. METHODS: A systematic review and meta-analysis of clinical studies was performed (Prospero registration number #68506). Studies were included if they compared ß-lactam antibiotic monotherapy with combined ß-lactam and single daily dose aminoglycoside therapy for treating serious infections. Studies investigating multiple daily dosing aminoglycoside regimens, infective endocarditis and febrile neutropaenia were excluded. Study quality was assessed using the PEDro and Newcastle-Ottawa scoring systems. The end points for outcome analyses were 30-day all-cause mortality, clinical cure and nephrotoxicity. RESULTS: Four randomised controlled trials and five retrospective cohort studies were analysed. Compared with ß-lactam antibiotic monotherapy, single daily aminoglycoside dosing in combination with ß-lactam antibiotics was not associated with reduced mortality compared with ß-lactam antibiotic monotherapy (n = 3686, OR 0.82, 95% CI 0.63-1.08, P = 0.10, I2 42%). A subgroup analysis of cohort studies suggested reduced mortality with combination therapy (n = 3563, OR 0.79, 95% CI 0.64-0.99, P = 0.04, I2 32%). No increased risk of nephrotoxicity was identified (n = 1110, OR 1.31, 95% CI 0.83-2.09, P = 0.40, I2 0%). CONCLUSIONS: The existing evidence suggests no added survival benefit from a single daily dosing regimen of an aminoglycoside when combined with ß-lactam antibiotics.