Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-Producing Klebsiella pneumoniae and the Inoculum Effect
Abstract
:1. Introduction
2. Results
2.1. MICs of Doripenem Alone and in the Presence of Relebactam
2.2. Doripenem and Doripenem/Relebactam Combination Pharmacokinetics
2.3. Doripenem and Doripenem/Relebactam Combination Pharmacodynamics with K. pneumoniae Total and Resistant Subpopulations
2.4. Doripenem and Doripenem/Relebactam Combination IE at Therapeutic Regimens
2.5. Predictive Potential of DOSE/MIC with MICs Estimated by Method 1 and Method 2 in Terms of Emergence of Resistance
3. Discussion
4. Materials and Methods
4.1. Antimicrobial Agents and Bacterial Strains
4.2. Susceptibility Testing
4.3. Antibiotic Dosing Regimens and Simulated Pharmacokinetic Profiles
4.4. In Vitro Dynamic Model
4.5. Quantitation of the Antimicrobial Effect and the Emergence of Resistance
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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K. pneumoniae Isolate | Doripenem | Doripenem+ Fixed Relebactam Concentration | Doripenem+ Relebactam Fixed PK-Based Concentration Ratio 1.5/1 | Doripenem+ Relebactam Fixed PK-Based Concentration Ratio 6/1 | Doripenem+ Relebactam Fixed PK-Based Concentration Ratio 1/3 | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
SI | HI | Fold MIC Increase | SI | HI | Fold MIC Increase | SI | HI | Fold MIC Increase | SI | HI | Fold MIC Increase | SI | HI | Fold MIC Increase | |
28 | 16 | 256 | 16 * | 0.25 | 16 | 64 * | 2 | 8 | 4 | 8 | 16 | 2 | 0.5 | 4 | 8 * |
19 | 4 | 128 | 32 * | 0.125 | 8 | 64 * | 0.5 | 4 | 8 * | 1 | 16 | 16 * | 0.25 | 4 | 16 * |
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Strukova, E.N.; Golikova, M.V.; Dovzhenko, S.A.; Kobrin, M.B.; Zinner, S.H. Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-Producing Klebsiella pneumoniae and the Inoculum Effect. Antibiotics 2023, 12, 1705. https://doi.org/10.3390/antibiotics12121705
Strukova EN, Golikova MV, Dovzhenko SA, Kobrin MB, Zinner SH. Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-Producing Klebsiella pneumoniae and the Inoculum Effect. Antibiotics. 2023; 12(12):1705. https://doi.org/10.3390/antibiotics12121705
Chicago/Turabian StyleStrukova, Elena N., Maria V. Golikova, Svetlana A. Dovzhenko, Mikhail B. Kobrin, and Stephen H. Zinner. 2023. "Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-Producing Klebsiella pneumoniae and the Inoculum Effect" Antibiotics 12, no. 12: 1705. https://doi.org/10.3390/antibiotics12121705