Tobramycin-Linked Efflux Pump Inhibitor Conjugates Synergize Fluoroquinolones, Rifampicin and Fosfomycin against Multidrug-Resistant Pseudomonas aeruginosa
Abstract
:1. Introduction
2. Materials and Methods
2.1. Bacterial Strains
2.2. Antimicrobial Agents
2.3. Antimicrobial Susceptibility Testing
2.4. Antimicrobial Combination Screening
3. Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Antibiotic | MICantibiotic alone (mg/L) | Adjuvant (ADJ) | MICADJ alone (mg/L) | FICI | Absolute MIC a (mg/L) | Potentiation (fold) b |
---|---|---|---|---|---|---|
MOX | 1 | 1 | 128 | 0.16 | 0.125 | 8 |
MOX | 1 | NMP | 512 | 2.00 | 1 | 1 |
MOX | 2 | 2 | 32 | 0.19 | 0.063 | 32 |
MOX | 1 | PAR | 256 | 2.00 | 1 | 1 |
MOX | 1 | 3 | 32 | 0.31 | 0.063 | 32 |
MOX | 1 | DBP | 128 | 0.19 | 0.25 | 4 |
RIF | 32 | 1 | 128 | 0.04 | ≤0.25 | ≥128 |
RIF | 32 | NMP | 512 | 1.02 | 32 | 1 |
RIF | 32 | 2 | 64 | 0.03 | ≤0.25 | ≥128 |
RIF | 32 | PAR | 512 | 0.63 | 32 | 1 |
RIF | 32 | 3 | 16 | 0.08 | ≤0.25 | ≥128 |
RIF | 32 | DBP | 256 | 0.09 | 4 | 8 |
FOF | 32 | 1 | 64 | 0.09 | 1 | 32 |
FOF | 16 | NMP | 512 | 1.00 | 16 | 1 |
FOF | 16 | 2 | 32 | 0.25 | 2 | 8 |
FOF | 16 | PAR | 256 | 0.75 | 16 | 1 |
FOF | 32 | 3 | 32 | 0.13 | 1 | 32 |
FOF | 16 | DBP | 128 | 0.16 | 1 | 16 |
P. aeruginosa | Antibiotic | MICantibiotic alone (mg/L) | Adjuvant (ADJ) | MICADJ alone (mg/L) | FICI | Absolute MIC (mg/L) |
---|---|---|---|---|---|---|
PA262-101856 | MOX | 64 | 1 | 64 | 0.188 | 8 a |
PA262-101856 | MOX | 128 | 2 | 32 | 0.125 | 2 a |
PA262-101856 | MOX | 128 | 3 | 32 | 0.188 | 4 a |
PA262-101856 | CIP | 32 | 1 | 64 | 0.188 | 4 a |
PA262-101856 | CIP | 32 | 2 | 32 | 0.250 | 4 a |
PA262-101856 | CIP | 32 | 3 | 64 | 0.250 | 4 a |
PA262-101856 | RIF | 1024 | 1 | 128 | 0.047 | 4 a |
PA262-101856 | RIF | 1024 | 2 | 32 | 0.070 | ≤2 a |
PA262-101856 | RIF | 1024 | 3 | 64 | 0.078 | ≤2 a |
PA262-101856 | FOF | 8 | 1 | 128 | 0.141 | 1 a |
PA262-101856 | FOF | 8 | 2 | 32 | 0.375 | 2 a |
PA262-101856 | FOF | 8 | 3 | 64 | 0.750 | 8 a |
PA260-97103 | MOX | 64 | 1 | 2 | 0.250 | 2 b |
PA260-97103 | MOX | 128 | 2 | 8 | 0.188 | 2 b |
PA260-97103 | MOX | 64 | 3 | 4 | 0.500 | 16 b |
PA260-97103 | CIP | 32 | 1 | 2 | 0.500 | 8 b |
PA260-97103 | CIP | 16 | 2 | 16 | 0.250 | ≤0.125 a |
PA260-97103 | CIP | 32 | 3 | 4 | 0.750 | 16 b |
PA260-97103 | RIF | 16 | 1 | 2 | 0.375 | 0.5 a |
PA260-97103 | RIF | 16 | 2 | 16 | 0.070 | ≤0.125 a |
PA260-97103 | RIF | 16 | 3 | 4 | 0.516 | 16 b |
PA260-97103 | FOF | 8 | 1 | 4 | 0.188 | ≤0.031 b |
PA260-97103 | FOF | 8 | 2 | 16 | 0.125 | ≤0.031 a |
PA260-97103 | FOF | 4 | 3 | 4 | 0.375 | 0.5 b |
100036 | MOX | 128 | 1 | 256 | 0.078 | 8 a |
100036 | MOX | 128 | 2 | 64 | 0.094 | 4 a |
100036 | MOX | 128 | 3 | 32 | 0.188 | 2 a |
100036 | CIP | 64 | 1 | 256 | 0.156 | 8 a |
100036 | CIP | 64 | 2 | 64 | 0.250 | 8 a |
100036 | CIP | 64 | 3 | 32 | 0.313 | 8 a |
100036 | RIF | 16 | 1 | 256 | 0.023 | ≤0.125 a |
100036 | RIF | 16 | 2 | 128 | 0.047 | ≤0.125 a |
100036 | RIF | 16 | 3 | 32 | 0.070 | ≤0.125 a |
100036 | FOF | 1024 | 1 | 256 | 0.063 x 0.313 | 512 a |
100036 | FOF | 1024 | 2 | 128 | 0.125 x 0.625 | 512 a |
100036 | FOF | 1024 | 3 | 32 | 0.250 x 0.375 | 128 a |
101885 | MOX | 64 | 1 | 256 | 0.141 | 8 a |
101885 | MOX | 64 | 2 | 64 | 0.188 | 4 a |
101885 | MOX | 64 | 3 | 8 | 0.375 | 8 b |
101885 | CIP | 32 | 1 | 256 | 0.258 | 8 a |
101885 | CIP | 32 | 2 | 32 | 0.375 | 4 a |
101885 | CIP | 32 | 3 | 8 | 0.500 | 8 b |
101885 | RIF | 16 | 1 | 256 | 0.031 | ≤0.125 a |
101885 | RIF | 16 | 2 | 32 | 0.125 | ≤0.125 a |
101885 | RIF | 16 | 3 | 16 | 0.094 | ≤0.125 a |
101885 | FOF | 32 | 1 | 256 | 0.125 | 4 a |
101885 | FOF | 32 | 2 | 32 | 0.188 | 4 a |
101885 | FOF | 32 | 3 | 32 | 0.125 | 2 a |
PA259-96918 | MOX | 512 | 1 | 1024 | 0.031 x 0.033 | 16 a |
PA259-96918 | MOX | 1024 | 2 | 512 | 0.008 x 0.031 | 16 a |
PA259-96918 | MOX | 512 | 3 | 64 | 0.047 | 4 a |
PA259-96918 | CIP | 256 | 1 | 1024 | 0.063 x 0.066 | 16 a |
PA259-96918 | CIP | 512 | 2 | 512 | 0.063 x 0.039 | 32 a |
PA259-96918 | CIP | 256 | 3 | 64 | 0.125 | 16 a |
PA259-96918 | RIF | 16 | 1 | 1024 | 0.008 x 0.009 | ≤0.125 a |
PA259-96918 | RIF | 16 | 2 | 512 | 0.008 x 0.012 | ≤0.125 a |
PA259-96918 | RIF | 16 | 3 | 32 | 0.039 | ≤0.125 a |
PA259-96918 | FOF | 8 | 1 | 1024 | 0.063 | 0.5 a |
PA259-96918 | FOF | 8 | 2 | 512 | 0.063 x 0.094 | 1 a |
PA259-96918 | FOF | 16 | 3 | 64 | 0.094 | 0.5 a |
PA264-104354 | MOX | 128 | 1 | 128 | 0.078 | 8 a |
PA264-104354 | MOX | 128 | 2 | 64 | 0.156 | 2 a |
PA264-104354 | MOX | 128 | 3 | 16 | 0.125 | 1 a |
PA264-104354 | CIP | 32 | 1 | 128 | 0.250 | 8 a |
PA264-104354 | CIP | 32 | 2 | 64 | 0.313 | 8 a |
PA264-104354 | CIP | 32 | 3 | 16 | 0.250 | 2 a |
PA264-104354 | RIF | 32 | 1 | 128 | 0.020 | ≤0.125 a |
PA264-104354 | RIF | 32 | 2 | 64 | 0.063 | ≤0.125 a |
PA264-104354 | RIF | 32 | 3 | 8 | 0.129 | ≤0.125 a |
PA264-104354 | FOF | 8 | 1 | 128 | 0.125 | 0.5 a |
PA264-104354 | FOF | 16 | 2 | 64 | 0.125 | 0.5 a |
PA264-104354 | FOF | 16 | 3 | 32 | 0.094 | 0.5 a |
91433 | MOX | 8 | 1 | 32 | 0.156 | 0.25 a |
91433 | MOX | 8 | 2 | 16 | 0.500 | 0.5 a |
91433 | MOX | 8 | 3 | 8 | 0.281 | 0.25 b |
91433 | CIP | 2 | 1 | 32 | 0.250 | 0.125 a |
91433 | CIP | 2 | 2 | 16 | 0.500 | 0.125 a |
91433 | CIP | 2 | 3 | 8 | 0.266 | 0.031 b |
91433 | RIF | 16 | 1 | 16 | 0.375 | 0.25 a |
91433 | RIF | 16 | 2 | 32 | 0.188 | 0.25 a |
91433 | RIF | 16 | 3 | 8 | 0.250 | ≤0.125 b |
91433 | FOF | 4 | 1 | 16 | 0.188 | 0.25 a |
91433 | FOF | 2 | 2 | 32 | 0.375 | ≤0.25 a |
91433 | FOF | 2 | 3 | 8 | 0.375 | 0.25 b |
101243 | MOX | 4 | 1 | 64 | 0.125 | 0.25 a |
101243 | MOX | 4 | 2 | 32 | 0.250 | 0.125 a |
101243 | MOX | 4 | 3 | 16 | 0.156 | ≤0.0625 a |
101243 | CIP | 2 | 1 | 64 | 0.281 | 0.5 a |
101243 | CIP | 2 | 2 | 32 | 0.375 | 0.5 a |
101243 | CIP | 2 | 3 | 16 | 0.188 | 0.125 a |
101243 | RIF | 8 | 1 | 64 | 0.063 | ≤0.0625 a |
101243 | RIF | 8 | 2 | 32 | 0.125 | ≤0.0625 a |
101243 | RIF | 16 | 3 | 16 | 0.094 | ≤0.031 a |
101243 | FOF | 256 | 1 | 64 | 0.125 | 8 a |
101243 | FOF | 256 | 2 | 32 | 0.188 | 16 a |
101243 | FOF | 256 | 3 | 32 | 0.047 | 4 a |
Antimicrobial | MIC50 (mg/L) | MIC80 (mg/L) | Range (mg/L) |
---|---|---|---|
MOX | 64 | 128 | 4–512 |
CIP | 32 | 64 | 2–512 |
RIF | 16 | 32 | 8–1024 |
FOF | 16 | 256 | 2–256 |
1 | 64 | 256 | 2–1024 |
2 | 32 | 128 | 8–512 |
3 | 16 | 32 | 4–64 |
MOX + 1 | 8 | 8 | 0.25–16 |
MOX + 2 | 2 | 4 | 0.125–16 |
MOX + 3 | 2 | 8 | 0.06–16 |
CIP + 1 | 8 | 8 | 0.125–8 |
CIP + 2 | 4 | 8 | 0.125–32 |
CIP + 3 | 4 | 16 | 0.03–16 |
RIF + 1 | 0.125 | 0.5 | 0.06–4 |
RIF + 2 | 0.125 | 0.25 | 0.06–2 |
RIF + 3 | 0.125 | 0.25 | 0.03–2 |
FOF + 1 | 0.5 | 8 | 0.03–512 |
FOF + 2 | 1 | 16 | 0.03–512 |
FOF + 3 | 0.5 | 8 | 0.25–128 |
Strain | MIC (mg/L) | FICI | |||||
---|---|---|---|---|---|---|---|
MOX | 1 | 2 | 3 | MOX + 1 | MOX + 2 | MOX + 3 | |
PAO1 | 1 | 128 | 32 | 32 | 0.16 | 0.19 | 0.31 |
PAO200 | 0.125 | 128 | 32 | 16 | 0.08 | 0.19 | 0.25 |
PAO750 | 0.008 | 8 | 8 | 8 | 0.31 | 0.63 | 0.63 |
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Yang, X.; Domalaon, R.; Lyu, Y.; Zhanel, G.G.; Schweizer, F. Tobramycin-Linked Efflux Pump Inhibitor Conjugates Synergize Fluoroquinolones, Rifampicin and Fosfomycin against Multidrug-Resistant Pseudomonas aeruginosa. J. Clin. Med. 2018, 7, 158. https://doi.org/10.3390/jcm7070158
Yang X, Domalaon R, Lyu Y, Zhanel GG, Schweizer F. Tobramycin-Linked Efflux Pump Inhibitor Conjugates Synergize Fluoroquinolones, Rifampicin and Fosfomycin against Multidrug-Resistant Pseudomonas aeruginosa. Journal of Clinical Medicine. 2018; 7(7):158. https://doi.org/10.3390/jcm7070158
Chicago/Turabian StyleYang, Xuan, Ronald Domalaon, Yinfeng Lyu, George G. Zhanel, and Frank Schweizer. 2018. "Tobramycin-Linked Efflux Pump Inhibitor Conjugates Synergize Fluoroquinolones, Rifampicin and Fosfomycin against Multidrug-Resistant Pseudomonas aeruginosa" Journal of Clinical Medicine 7, no. 7: 158. https://doi.org/10.3390/jcm7070158