Evaluation of Tobramycin and Ciprofloxacin as a Synergistic Combination Against Hypermutable Pseudomonas Aeruginosa Strains via Mechanism-Based Modelling
Abstract
:1. Introduction
2. Materials and Methods
2.1. Bacterial Strains and Antibiotics Tested
2.2. Static Concentration Time-Kill Assays
2.3. Viable Counting of the Total and Resistant Populations
2.4. Mechanism-Based Modelling of Bacterial Killing and Resistance
2.4.1. The Life-Cycle Growth Model
2.4.2. Synergy Modelling
2.4.3. Less-Susceptible Bacterial Populations
2.4.4. Initial Conditions and Observation Model
3. Results and Discussion
3.1. Antibacterial Effect of Common Antipseudomonal Antibiotics in Monotherapy vs PAO1 and PAO∆mutS
3.1.1. Antibacterial Effect of Beta-Lactam Antibiotics in Monotherapy
3.1.2. Antibacterial Effect of Fast-Acting Antipseudomonal Antibiotics in Monotherapy
3.2. Antibacterial Effect of Two Fast-Acting Antipseudomonal Antibiotics in Combination
3.2.1. Antibacterial Effect of Tobramycin and Ciprofloxacin against the Three Hypermutator Strains
3.2.2. Mechanism-Based Mathematical Modelling of the Tobramycin and Ciprofloxacin Combination
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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PAO1/PAOΔmutS 1 | CW19 2 | CW44 2 | |
---|---|---|---|
aztreonam | 4 | - | - |
ceftazidime | 2 | - | - |
imipenem | 2 | - | - |
meropenem | 1 | - | - |
tobramycin | 0.5 | 1 | 1 |
ciprofloxacin | 0.125 | 0.5 | 0.19 |
Parameter | Symbol (unit) | Population Mean Value (SE[%]) | |||
---|---|---|---|---|---|
PAO1 | PAOΔmutS | CW19 | CW44 | ||
Bacterial growth and subpopulations | |||||
Initial inoculum | Log10 CFU0 | 7.09 (2.05%) | 7.62 (1.71%) | 7.87 (2.75%) | 7.26 (1.39%) |
Maximum population size | Log10 CFUmax | 9.33 (2.00%) | 9.01 (1.79%) | 9.00 (1.31%) | 8.94 (1.01%) |
Mean generation time (MGT) | |||||
TOBS/CIPS | 1/k12,SS (min) | 50.9 (4.55%) 1 | 55.9 (4.81%) 1 | 115 (6.26%) 1 | 124 (6.48%) 1 |
TOBR/CIPI | 1/k12,RI (min) | 340 (13.1%) | 254 (19.4%) | 327 (4.96%) | 141 (8.57%) |
TOBI/CIPR | 1/k12,IR (min) | 50.9 (4.55%) 1 | 55.9 (4.81%) 1 | 115 (6.26%) 1 | 124 (6.48%) 1 |
Log10 mutation frequencies | |||||
TOB | Log10 MFTOB | −3.68 (5.43%) | −3.93 (6.52%) | −3.3 (16.6%) | −4.81 (4.01%) |
CIP | Log10 MFCIP | −7.68 (4.04%) | −8.39 (4.60%) | −5.79 (12.7%) | −7.47 (5.12%) |
Killing by TOB | |||||
Maximum killing rate constant | |||||
TOBS/CIPS | Kmax,SS,TOB (h−1) | 12.2 (11.2%) | 10.8 (34.1%) | 5.18 (36.1%) | 3.26 (19.4%) |
TOBR/CIPI | Kmax,RI,TOB (h−1) | 0.251 (22.9%) | 0.305 (42.1%) | 0.354 (15.1%) | 0.60 (18.0%) |
TOBI/CIPR | Kmax,IR,TOB (h−1) | 1.17 (15.1%) | 0.367 (47.2%) | 0.690 (62.5%) | 5.02 (20.0%) |
TOB concentration causing 50% of Kmax,TOB | KC50,TOB (mg/L) | 3.68 (21.5%) | 2.11 (41.9%) 2 | 53.4 (10.1%) | 18.5 (7.14%) |
7.33 (17.2%) 3 | |||||
4.50 (14.9%) 4 | |||||
Hill coefficient for TOB | HILLTOB | 0.790 (17.9%) 5 | |||
Killing by CIP | |||||
Maximum killing rate constant | |||||
TOBS/CIPS | Kmax,SS,CIP (h−1) | 16.4 (9.95%) | 17.1 (14.2%) | 2.43 (11.7%) | 5.11 (13.5%) |
TOBR/CIPI | Kmax,RI,CIP (h−1) | 0.392 (20.5%) | 0.307 (33.1%) | 0.730 (17.5%) | 1.14 (18.6%) |
TOBI/CIPR | Kmax,IR,CIP (h−1) | 1.83 (13.6%) | 0.812 (9.26%) | 0.562 (13.4%) | 0.226 (21.4%) |
CIP concentration causing 50% of Kmax,CIP | KC50,CIP (mg/L) | 1.29 (24.3%) | 1.09 (29.6%) | 7.07 (41.3%) | 8.30 (11.6%) |
Mechanistic synergy | |||||
Maximum fractional decrease of KC50,CIP via mechanistic synergy6 | Imax,SYN | 1 (fixed) | 1 (fixed) | 1 (fixed) | 1 (fixed) |
TOB concentration causing 50% of Imax,SYN | IC50,SYN (mg/L) | 2.16 (11.0%) | 1.10 (33.9%) | 2.01 (10.9%) | 1.74 (20.0%) |
Residual variability | |||||
SD of residual error on log10 scale | |||||
Total population | SDCFU | 0.303 (10.2%) | 0.383 (12.1%) | 0.296 (16.5%) | 0.273 (10.1%) |
Population on TOB plates | SDCFU,TOB | 1.05 (24.1%) | 0.401 (22.0%) | 0.883 (14.1%) | 0.197 (18.9%) |
Population on CIP plates | SDCFU,CIP | 3.64 (26.4%) | 1.18 (14.4%) | 0.586 (37.1%) | 0.740 (31.1%) |
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Rees, V.E.; Bulitta, J.B.; Oliver, A.; Nation, R.L.; Landersdorfer, C.B. Evaluation of Tobramycin and Ciprofloxacin as a Synergistic Combination Against Hypermutable Pseudomonas Aeruginosa Strains via Mechanism-Based Modelling. Pharmaceutics 2019, 11, 470. https://doi.org/10.3390/pharmaceutics11090470
Rees VE, Bulitta JB, Oliver A, Nation RL, Landersdorfer CB. Evaluation of Tobramycin and Ciprofloxacin as a Synergistic Combination Against Hypermutable Pseudomonas Aeruginosa Strains via Mechanism-Based Modelling. Pharmaceutics. 2019; 11(9):470. https://doi.org/10.3390/pharmaceutics11090470
Chicago/Turabian StyleRees, Vanessa E., Jürgen B. Bulitta, Antonio Oliver, Roger L. Nation, and Cornelia B. Landersdorfer. 2019. "Evaluation of Tobramycin and Ciprofloxacin as a Synergistic Combination Against Hypermutable Pseudomonas Aeruginosa Strains via Mechanism-Based Modelling" Pharmaceutics 11, no. 9: 470. https://doi.org/10.3390/pharmaceutics11090470