Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-Producing <i>Klebsiella pneumoniae</i> and the Inoculum Effect
The emergence of bacteria resistant to beta-lactam/beta-lactamase inhibitor combinations is insufficiently studied, wherein the role of the inoculum effect (IE) in decreased efficacy is unclear. To address these issues, 5-day treatments with doripenem and doripenem/relebactam combination at differen...
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| Format: | Article |
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MDPI AG
2023-12-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/12/12/1705 |
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| author | Elena N. Strukova Maria V. Golikova Svetlana A. Dovzhenko Mikhail B. Kobrin Stephen H. Zinner |
| author_facet | Elena N. Strukova Maria V. Golikova Svetlana A. Dovzhenko Mikhail B. Kobrin Stephen H. Zinner |
| author_sort | Elena N. Strukova |
| collection | DOAJ |
| description | The emergence of bacteria resistant to beta-lactam/beta-lactamase inhibitor combinations is insufficiently studied, wherein the role of the inoculum effect (IE) in decreased efficacy is unclear. To address these issues, 5-day treatments with doripenem and doripenem/relebactam combination at different ratios of the agents were simulated in a hollow-fiber dynamic model against carbapenemase-producing <i>K. pneumoniae</i> at standard and high inocula. Minimal inhibitory concentrations (MICs) of doripenem alone and in the presence of relebactam at two inocula were determined. Combination MICs were tested using traditional (fixed relebactam concentration) and pharmacokinetic-based approach (fixed doripenem-to-relebactam concentration ratio equal to the therapeutic 24-h area under the concentration-time curve (AUC) ratio). In all experiments, resistant subpopulations were noted, but combined simulations reduced their numbers. With doripenem, the IE was apparent for both <i>K. pneumoniae</i> isolates in combined treatments for one strain. The pharmacokinetic-based approach to combination MIC estimation compared to traditional showed stronger correlation between DOSE/MIC and emergence of resistance. These results support (1) the constraint of relebactam combined with doripenem against the emergence of resistance and IE; (2) the applicability of a pharmacokinetic-based approach to estimate carbapenem MICs in the presence of an inhibitor to predict the IE and to describe the patterns of resistance occurrence. |
| first_indexed | 2024-03-08T21:03:12Z |
| format | Article |
| id | doaj.art-0eb162d7b0624be4a67414649c819b3a |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-08T21:03:12Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-0eb162d7b0624be4a67414649c819b3a2023-12-22T13:47:57ZengMDPI AGAntibiotics2079-63822023-12-011212170510.3390/antibiotics12121705Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-Producing <i>Klebsiella pneumoniae</i> and the Inoculum EffectElena N. Strukova0Maria V. Golikova1Svetlana A. Dovzhenko2Mikhail B. Kobrin3Stephen H. Zinner4Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, 11 Bolshaya Pirogovskaya Street, 119021 Moscow, RussiaDepartment of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, 11 Bolshaya Pirogovskaya Street, 119021 Moscow, RussiaDepartment of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, 11 Bolshaya Pirogovskaya Street, 119021 Moscow, RussiaDepartment of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, 11 Bolshaya Pirogovskaya Street, 119021 Moscow, RussiaHarvard Medical School, Department of Medicine, Mount Auburn Hospital, 330 Mount Auburn St., Cambridge, MA 02138, USAThe emergence of bacteria resistant to beta-lactam/beta-lactamase inhibitor combinations is insufficiently studied, wherein the role of the inoculum effect (IE) in decreased efficacy is unclear. To address these issues, 5-day treatments with doripenem and doripenem/relebactam combination at different ratios of the agents were simulated in a hollow-fiber dynamic model against carbapenemase-producing <i>K. pneumoniae</i> at standard and high inocula. Minimal inhibitory concentrations (MICs) of doripenem alone and in the presence of relebactam at two inocula were determined. Combination MICs were tested using traditional (fixed relebactam concentration) and pharmacokinetic-based approach (fixed doripenem-to-relebactam concentration ratio equal to the therapeutic 24-h area under the concentration-time curve (AUC) ratio). In all experiments, resistant subpopulations were noted, but combined simulations reduced their numbers. With doripenem, the IE was apparent for both <i>K. pneumoniae</i> isolates in combined treatments for one strain. The pharmacokinetic-based approach to combination MIC estimation compared to traditional showed stronger correlation between DOSE/MIC and emergence of resistance. These results support (1) the constraint of relebactam combined with doripenem against the emergence of resistance and IE; (2) the applicability of a pharmacokinetic-based approach to estimate carbapenem MICs in the presence of an inhibitor to predict the IE and to describe the patterns of resistance occurrence.https://www.mdpi.com/2079-6382/12/12/1705antibiotic resistanceinoculum effectin vitro hollow-fiber dynamic modelbeta-lactamsbeta-lactamase inhibitorsdoripenem |
| spellingShingle | Elena N. Strukova Maria V. Golikova Svetlana A. Dovzhenko Mikhail B. Kobrin Stephen H. Zinner Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-Producing <i>Klebsiella pneumoniae</i> and the Inoculum Effect Antibiotics antibiotic resistance inoculum effect in vitro hollow-fiber dynamic model beta-lactams beta-lactamase inhibitors doripenem |
| title | Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-Producing <i>Klebsiella pneumoniae</i> and the Inoculum Effect |
| title_full | Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-Producing <i>Klebsiella pneumoniae</i> and the Inoculum Effect |
| title_fullStr | Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-Producing <i>Klebsiella pneumoniae</i> and the Inoculum Effect |
| title_full_unstemmed | Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-Producing <i>Klebsiella pneumoniae</i> and the Inoculum Effect |
| title_short | Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-Producing <i>Klebsiella pneumoniae</i> and the Inoculum Effect |
| title_sort | pharmacodynamics of doripenem alone and in combination with relebactam in an in vitro hollow fiber dynamic model emergence of resistance of carbapenemase producing i klebsiella pneumoniae i and the inoculum effect |
| topic | antibiotic resistance inoculum effect in vitro hollow-fiber dynamic model beta-lactams beta-lactamase inhibitors doripenem |
| url | https://www.mdpi.com/2079-6382/12/12/1705 |
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