Defining Exposure Predictors of Meropenem That Are Associated with Improved Survival for Severe Bacterial Infection: A Preclinical PK/PD Study in Sepsis Rat Model
Abstract
:1. Introduction
2. Results
2.1. In Vitro Susceptibility Testing
2.2. Development of Sepsis Rat Model
2.3. Pharmacokinetic Parameters of Meropenem and Dosing Regimen Determination
2.4. PK/PD Outcomes of Meropenem in Sepsis Rat Model
3. Discussion
4. Materials and Methods
4.1. Drug, Organisms, and Media
4.2. Antimicrobial Susceptibility Test
4.3. Development of Sepsis Rat Model
4.4. Pharmacokinetics Study and Calculation of Free Drug Concentration
4.5. Pharmacokinetic Modeling and Dosing Regimen Simulation
4.6. Microbiological and Survival Outcomes of Meropenem in Sepsis Rat Model
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Singer, M.; Deutschman, C.S.; Seymour, C.W.; Shankar-Hari, M.; Annane, D.; Bauer, M.; Bellomo, R.; Bernard, G.R.; Chiche, J.-D.; Coopersmith, C.M.; et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016, 315, 801–810. [Google Scholar] [CrossRef]
- Kadri, S.S.; Rhee, C.; Strich, J.R.; Morales, M.; Hohmann, S.; Menchaca, J.; Suffredini, A.F.; Danner, R.L.; Klompas, M. Estimating Ten-Year Trends in Septic Shock Incidence and Mortality in United States Academic Medical Centers Using Clinical Data. Chest 2017, 151, 278–285. [Google Scholar] [CrossRef] [Green Version]
- Rudd, K.E.; Johnson, S.C.; Agesa, K.M.; Shackelford, K.A.; Tsoi, D.; Kievlan, D.R. Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the Global Burden of Disease Study. Lancet 2020, 395, 200–211. [Google Scholar] [CrossRef] [Green Version]
- Berg, M.V.D.; van Beuningen, F.; ter Maaten, J.; Bouma, H. Hospital-related costs of sepsis around the world: A systematic review exploring the economic burden of sepsis. J. Crit. Care 2022, 71, 154096. [Google Scholar] [CrossRef] [PubMed]
- Pant, A.; Mackraj, I.; Govender, T. Advances in sepsis diagnosis and management: A paradigm shift towards nanotech-nology. J. Biomed. Sci. 2021, 28, 6. [Google Scholar] [CrossRef] [PubMed]
- Zhang, H.; Zhang, Y.; Wu, J.; Li, Y.; Zhou, X.; Li, X.; Chen, H.; Guo, M.; Chen, S.; Sun, F.; et al. Risks and features of secondary infections in severe and critical ill COVID-19 patients. Emerg. Microb. Infect. 2020, 9, 1–45. [Google Scholar] [CrossRef]
- Evans, L.; Rhodes, A.; Alhazzani, W.; Antonelli, M.; Coopersmith, C.M.; French, C.; Machado, F.R.; Mcintyre, L.; Ostermann, M.; Prescott, H.C.; et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Intensiv. Care Med. 2021, 47, 1181–1247. [Google Scholar] [CrossRef]
- Ferrer, R.; Artigas, A.; Suarez, D.; Palencia, E.; Levy, M.M.; Arenzana, A.; Pérez, X.L.; Sirvent, J.M. Effectiveness of treatments for severe sepsis: A prospective, multicenter, observational study. Am. J. Respir Crit. Care Med. 2009, 180, 861–866. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kumar, A.; Roberts, D.; Wood, K.E.; Light, B.; Parrillo, J.E.; Sharma, S.; Suppes, R.; Feinstein, D.; Zanotti, S.; Taiberg, L.; et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock*. Crit. Care Med. 2006, 34, 1589–1596. [Google Scholar] [CrossRef] [PubMed]
- Liu, V.X.; Fielding-Singh, V.; Greene, J.D.; Baker, J.M.; Iwashyna, T.J.; Bhattacharya, J.; Escobar, G.J. The Timing of Early Antibiotics and Hospital Mortality in Sepsis. Am. J. Respir. Crit. Care Med. 2017, 196, 856–863. [Google Scholar] [CrossRef]
- Nielsen, E.I.; Friberg, L.E. Pharmacokinetic-Pharmacodynamic Modeling of Antibacterial Drugs. Pharmacol. Rev. 2013, 65, 1053–1090. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Drusano, G.L. Prevention of Resistance: A Goal for Dose Selection for Antimicrobial Agents. Clin. Infect. Dis. 2003, 36, S42–S50. [Google Scholar] [CrossRef] [PubMed]
- Hawkey, P.M.; Livermore, D.M. Carbapenem antibiotics for serious infections. BMJ 2012, 344, e3236. [Google Scholar] [CrossRef] [PubMed]
- Craig, W.A. Pharmacokinetic/pharmacodynamic parameters: Rationale for antibacterial dosing of mice and men. Clin. Infect. Dis. 1998, 26, 1–10. [Google Scholar] [CrossRef]
- Nightingale, C.H.; Ambrose, P.G.; Drusano, G.L.; Murakawa, T. Antimicrobial Pharmacodynamics in Theory and Clinical Practice; CRC Press: Boca Raton, FL, USA, 2007. [Google Scholar]
- Li, C.; Du, X.; Kuti, J.L.; Nicolau, D.P. Clinical Pharmacodynamics of Meropenem in Patients with Lower Respiratory Tract Infections. Antimicrob. Agents Chemother. 2007, 51, 1725–1730. [Google Scholar] [CrossRef] [Green Version]
- McKinnon, P.S.; Paladino, J.A.; Schentag, J.J. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int. J. Antimicrob. Agents 2008, 31, 345–351. [Google Scholar] [CrossRef]
- Mouton, J.W.; Hollander, J.G.D. Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model. Antimicrob. Agent. Chemother. 1994, 38, 931–936. [Google Scholar] [CrossRef] [Green Version]
- Mouton, J.W.; Vinks, A.A. Is continuous infusion of beta-lactam antibiotics worthwhile?—Efficacy and pharmacokinetic considerations. J. Antimicrob. Chemother. 1996, 38, 5–15. [Google Scholar] [CrossRef] [Green Version]
- Velkov, T.; Bergen, P.J.; Lora-Tamayo, J.; Landersdorfer, C.B.; Li, J. PK/PD models in antibacterial development. Curr. Opin. Microbiol. 2013, 16, 573–579. [Google Scholar] [CrossRef] [Green Version]
- Hecker, A.; Reichert, M.; Reuß, C.J.; Schmoch, T.; Riedel, J.G.; Schneck, E.; Padberg, W.; Weigand, M.A.; Hecker, M. Intra-abdominal sepsis: New definitions and current clinical standards. Langenbeck’s Arch. Surg. 2019, 404, 257–271. [Google Scholar] [CrossRef]
- Doi, K.; Leelahavanichkul, A.; Yuen, P.; Star, R.A. Animal models of sepsis and sepsis-induced kidney injury. J. Clin. Investig. 2009, 119, 2868–2878. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Diekema, D.J.; Hsueh, P.-R.; Mendes, R.E.; Pfaller, M.A.; Rolston, K.V.; Sader, H.; Jones, R.N. The Microbiology of Bloodstream Infection: 20-Year Trends from the SENTRY Antimicrobial Surveillance Program. Antimicrob. Agent. Chemother. 2019, 63, e00355-19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tam, V.H.; Schilling, A.N.; Neshat, S.; Poole, K.; Melnick, D.A.; Coyle, E.A. Optimization of meropenem minimum concen-tration/mic ratio to suppress in vitro resistance of pseudomonas aeruginosa. Antimicrob. Agent. Chemother. 2005, 49, 4920–4927. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Delattre, I.K.; Hites, M.; Laterre, P.-F.; Dugernier, T.; Spapen, H.; Wallemacq, P.E.; Jacobs, F.; Taccone, F.S. What is the optimal loading dose of broad-spectrum β-lactam antibiotics in septic patients? Results from pharmacokinetic simulation modelling. Int. J. Antimicrob. Agents 2020, 56, 106113. [Google Scholar] [CrossRef]
- Beumier, M.; Casu, G.S.; Hites, M.; Wolff, F.; Cotton, F.; Vincent, J.L.; Jacobs, F.; Taccone, F.S. Elevated β-lactam concentrations associated with neurological deterioration in icu septic patients. Minerva Anestesiol. 2015, 81, 497–506. [Google Scholar]
- Scott, R.E.; Robson, H.G. Synergistic Activity of Carbenicillin and Gentamicin in Experimental Pseudomonas Bacteremia in Neutropenic Rats. Antimicrob. Agents Chemother. 1976, 10, 646–651. [Google Scholar] [CrossRef] [Green Version]
- Tsuji, M.; Matsuda, H.; Miwa, H.; Miyazaki, S. Antimicrobial-induced release of endotoxin from Pseudomonas aeruginosa: Comparison of in vitro and animal models. J. Antimicrob. Chemother. 2003, 51, 353–359. [Google Scholar] [CrossRef] [Green Version]
- Sadouki, Z.; McHugh, T.D.; Aarnoutse, R.; Canseco, J.O.; Darlow, C.; Hope, W.; van Ingen, J.; Longshaw, C.; Manissero, D.; Mead, A.; et al. Application of the hollow fibre infection model (HFIM) in antimicrobial development: A systematic review and recommendations of reporting. J. Antimicrob. Chemother. 2021, 76, 2252–2259. [Google Scholar] [CrossRef]
- Clinical and Laboratory Standards Institute Antimicrobial Susceptibility, M100—Performance Standards for Antimicrobial Susceptibility Testing, 32nd ed. 2022. Available online: https://www.clsi.org/standards/products/microbiology/documents/m100/ (accessed on 10 September 2022).
- Johnson, D.E.; Calia, F.M.; Snyder, M.J.; Warren, J.W.; Schimpff, S.C. Imipenem therapy of pseudomonas aeruginosa bac-teraemia in neutropenic rats. J. Antimicrob. Chemother. 1983, 12, 89–96. [Google Scholar] [CrossRef]
- Mayr, F.B.; Yende, S.; Angus, D.C. Epidemiology of severe sepsis. Virulence 2013, 5, 4–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xie, F.; Liu, L.; Wang, Y.; Peng, Y.; Li, S. An UPLC-PDA assay for simultaneous determination of seven antibiotics in human plasma. J. Pharm. Biomed. Anal. 2022, 210, 114558. [Google Scholar] [CrossRef] [PubMed]
- Sparreboom, A.; Van Zuylen, L.; Brouwer, E.; Loos, W.J.; De Bruijn, P.; Gelderblom, H.; Pillay, M.; Nooter, K.; Stoter, G.; Verweij, J. Cremophor EL-mediated alteration of paclitaxel distribution in human blood: Clinical pharmacokinetic implications. Cancer Res. 1999, 59, 1454–1457. [Google Scholar] [PubMed]
Subject | 40%fT > MIC (75 mg/kg/q6h) | 100%fT > MIC (75 mg/kg/q2.4h) | 100%fT > MIC (50 mg/kg/q2.4h) | 100%fT > 4 × MIC (75 mg/kg/q2h) |
---|---|---|---|---|
1 | 41.0% | 100% | 100% | 100% |
2 | 78.1% | 100% | 100% | 100% |
3 | 60.7% | 100% | 80.6% | 100% |
4 | 49.7% | 100% | 86.8% | 94.4% |
5 | 46.9% | 100% | 87.1% | 100% |
6 | 45.8% | 100% | 100% | 100% |
7 | 56.1% | 92.9% | 100% | 100% |
8 | 58.1% | 100% | 100% | 100% |
9 | 42.3% | 100% | 100% | 100% |
10 | 39.1% | 95.5% | 100% | 93.7% |
11 | 43.8% | 100% | 98.6% | 100% |
12 | 64.8% | 100% | 100% | 89.6% |
Control | 40%fT > MIC (75 mg/kg/q6h) | 100%fT > MIC (75 mg/kg/q2.4h) | 100%fT > MIC (50 mg/kg/q2.4h) | 100%fT > 4 × MIC (75 mg/kg/q2h) | |
---|---|---|---|---|---|
Log-rank test (p value) | 0.0187 | 0.0004 | 0.0051 | 0.0008 | |
Median survival time (h) | 76.5 | 138 | Undefined | 167 | Undefined |
Hazard ratio (95% CI) | 0.3306 (0.1240, 0.8814) | 0.1709 (0.0578, 0.5059) | 0.2779 (0.1017, 0.7594) | 0.2096 (0.0730, 0.6017) |
B/A | C/A | D/A | B/C | B/D | D/C | |
---|---|---|---|---|---|---|
Log-rank test (p value) | 0.2831 | 0.8144 | 0.4819 | 0.4234 | 0.7042 | 0.6704 |
Hazard ratio (95% CI) | 0.5132 (0.1470, 1.7920) | 0.8742 (0.2812, 2.7180) | 0.6587 (0.2004, 2.1650) | 0.6016 (0.1739, 2.0820) | 0.7768 (0.2103, 2.8700) | 0.7744 (0.2373, 2.5270) |
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Wang, Y.; Liu, L.; Wu, Q.; Yin, Q.; Xie, F. Defining Exposure Predictors of Meropenem That Are Associated with Improved Survival for Severe Bacterial Infection: A Preclinical PK/PD Study in Sepsis Rat Model. Antibiotics 2022, 11, 1660. https://doi.org/10.3390/antibiotics11111660
Wang Y, Liu L, Wu Q, Yin Q, Xie F. Defining Exposure Predictors of Meropenem That Are Associated with Improved Survival for Severe Bacterial Infection: A Preclinical PK/PD Study in Sepsis Rat Model. Antibiotics. 2022; 11(11):1660. https://doi.org/10.3390/antibiotics11111660
Chicago/Turabian StyleWang, Yan, Lanyu Liu, Qiping Wu, Qiufen Yin, and Feifan Xie. 2022. "Defining Exposure Predictors of Meropenem That Are Associated with Improved Survival for Severe Bacterial Infection: A Preclinical PK/PD Study in Sepsis Rat Model" Antibiotics 11, no. 11: 1660. https://doi.org/10.3390/antibiotics11111660
APA StyleWang, Y., Liu, L., Wu, Q., Yin, Q., & Xie, F. (2022). Defining Exposure Predictors of Meropenem That Are Associated with Improved Survival for Severe Bacterial Infection: A Preclinical PK/PD Study in Sepsis Rat Model. Antibiotics, 11(11), 1660. https://doi.org/10.3390/antibiotics11111660