Activity of colistin combined with doripenem at clinically relevant concentrations against multidrug-resistant Pseudomonas aeruginosa in an in vitro dynamic biofilm model.
OBJECTIVE
Colistin combination therapy may be required to treat biofilm-associated infections. We evaluated bacterial killing and emergence of colistin resistance with colistin and doripenem combinations against biofilm-embedded and planktonic multidrug-resistant (MDR) Pseudomonas aeruginosa.


METHODS
One colistin-susceptible reference strain (PAO1) and two colistin-susceptible MDR clinical isolates (HUB1 and HUB2; both carbapenem resistant) were investigated over 72 h in the CDC biofilm reactor, a dynamic biofilm model. Two colistin regimens (constant concentrations of 1.25 and 3.50 mg/L), one doripenem regimen (Cmax 25 mg/L 8 hourly) and their combination were employed. Microbiological response was examined as log changes and absolute bacterial counts.


RESULTS
For biofilm-embedded bacteria, bactericidal activity was only observed with monotherapy with colistin at 3.50 mg/L. The emergence of colistin resistance occurred with colistin monotherapy against two strains (PAO1 and HUB1), but only with the colistin 3.50 mg/L regimen. Colistin 3.50 mg/L plus doripenem resulted in ∼2-3 log10 cfu/cm(2) initial killing against both clinical isolates and remained synergistic at 72 h. The emergence of colistin resistance was not observed in biofilm-embedded bacteria with either combination. For planktonic bacteria, bactericidal activity was not observed with any monotherapy regimen, although enhanced bacterial killing was observed with doripenem plus colistin 3.50 mg/L against all isolates. Colistin resistance was observed with colistin monotherapy against two isolates, but did not emerge with combination regimens.


CONCLUSIONS
Doripenem enhanced killing by colistin of biofilm-embedded cells in both carbapenem-susceptible and -resistant strains, and the combination minimized the emergence of colistin resistance.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia Department of Infectious Diseases, Hospital Universitario de Bellvitge, Universidad de Barcelona, Barcelona, Spain.
Jaime
J
Lora-Tamayo
Department of Infectious Diseases, Hospital Universitario de Bellvitge, Universidad de Barcelona, Barcelona, Spain.
Oscar
O
Murillo
Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia.
Phillip J
PJ
Bergen
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
Roger L
RL
Nation
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
Anima
A
Poudyal
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
Xianling
X
Luo
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
Heidi Y
HY
Yu
Department of Infectious Diseases, Hospital Universitario de Bellvitge, Universidad de Barcelona, Barcelona, Spain.
Javier
J
Ariza
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia jian.li@monash.edu.
Jian
J
Li
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D015780:Carbapenems / Q000494:pharmacology*; D003091:Colistin / Q000494:pharmacology*; D015169:Colony Count, Microbial; D000077726:Doripenem; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D006801:Humans; D050296:Microbial Viability / Q000187:drug effects; D011552:Pseudomonas Infections / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology; D013997:Time Factors
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem; D003091:Colistin
CDC reactors; PK/PD; carbapenem resistant; foreign body; infections; polymyxins