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Antimicrob Agents Chemother. 2019 Aug 19. pii: AAC.01293-19. doi: 10.1128/AAC.01293-19. [Epub ahead of print]

Synergistic meropenem-tobramycin combination dosage regimens against clinical hypermutable Pseudomonas aeruginosa at simulated epithelial lining fluid concentrations in a dynamic biofilm model.

Author information

1
Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
2
Daegu Catholic University, College of Pharmacy, Gyeongbuk, Korea.
3
Sungkyunkwan University, School of Pharmacy, Seoul, Korea.
4
Department of Infectious Diseases, The Alfred Hospital and Central Clinical School, Monash University, Melbourne, Australia.
5
Hospital Universitario Son Espases, Palma de Mallorca, Spain.
6
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
7
Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia cornelia.landersdorfer@monash.edu.

Abstract

Exacerbations of chronic Pseudomonas aeruginosa infections are a major treatment challenge in cystic fibrosis due to biofilm formation and hypermutation. We aimed to evaluate different dosage regimens of meropenem and tobramycin in monotherapies and combination against hypermutable carbapenem-resistant P. aeruginosa A hypermutable P. aeruginosa isolate (MICmeropenem and MICtobramycin 8 mg/L) was investigated in the dynamic CDC biofilm reactor over 120 h. Regimens were meropenem as standard (2 g 8-hourly, 30% epithelial lining fluid (ELF) penetration) and continuous infusion (CI, 6 g/day, 30% and 60% ELF penetration), and tobramycin 10 mg/kg 24-hourly (50% ELF penetration). The time-courses of total and less-susceptible bacteria and MICs were determined and antibiotic concentrations quantified by LC-MS/MS. All monotherapies failed with substantial regrowth of planktonic (>6 log10 CFU/mL) and biofilm (≥6 log10 CFU/cm2) bacteria. Except for meropenem CI (60% ELF penetration) all monotherapies amplified less-susceptible planktonic and biofilm bacteria by 120 h. The meropenem standard regimen with tobramycin caused initial killing followed by considerable regrowth with resistance (MICmeropenem 64 mg/L, MICtobramycin 32 mg/L) for planktonic and biofilm bacteria. The combination containing the meropenem CI, at both levels of ELF penetration, synergistically suppressed regrowth of total planktonic bacteria and resistance of planktonic and biofilm bacteria. The combination with meropenem CI at 60% ELF penetration in addition synergistically suppressed regrowth of total biofilm bacteria. Standard regimens of meropenem and tobramycin were ineffective against planktonic and biofilm bacteria. The combination with meropenem CI exhibited enhanced bacterial killing and resistance suppression of carbapenem-resistant hypermutable P. aeruginosa.

PMID:
31427301
DOI:
10.1128/AAC.01293-19

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