Towards Improved Management of Tuberculous Bloodstream Infections: Pharmacokinetic Considerations with Suggestions for Better Treatment Outcomes
<i>Mycobacterium tuberculosis</i> is the leading cause of sepsis among HIV-infected adults, yet effective treatment remains a challenge. Efficacy of antituberculous drugs is optimized by high Area Under Curve to Minimum Inhibitory Concentration (AUC/MIC) ratios, suggesting that both the...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-07-01
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| Series: | Antibiotics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-6382/11/7/895 |
| _version_ | 1797441250398306304 |
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| author | Charles Okot Odongo Lydia Nakiyingi Clovis Gatete Nkeramihigo Daniel Seifu Kuteesa Ronald Bisaso |
| author_facet | Charles Okot Odongo Lydia Nakiyingi Clovis Gatete Nkeramihigo Daniel Seifu Kuteesa Ronald Bisaso |
| author_sort | Charles Okot Odongo |
| collection | DOAJ |
| description | <i>Mycobacterium tuberculosis</i> is the leading cause of sepsis among HIV-infected adults, yet effective treatment remains a challenge. Efficacy of antituberculous drugs is optimized by high Area Under Curve to Minimum Inhibitory Concentration (AUC/MIC) ratios, suggesting that both the drug concentration at the disease site and time above MIC are critical to treatment outcomes. We elaborate on sepsis pathophysiology and show how it adversely affects antituberculous drug kinetics. Expanding distribution volumes secondary to an increased vascular permeability prevents the attainment of target C<sub>max</sub> concentrations for nearly all drugs. Furthermore, sepsis-induced metabolic acidosis promotes protonation, which increases renal clearance of basic drugs such as isoniazid and ethambutol, and hence AUCs are substantially reduced. Compared with the treatment of non-sepsis TB disease, these distorted kinetics underlie the poor treatment outcomes observed with bloodstream infections. In addition to aggressive hemodynamic management, an increase in both the dose and frequency of drug administration are warranted, at least in the early phase of treatment. |
| first_indexed | 2024-03-09T12:21:19Z |
| format | Article |
| id | doaj.art-e946eec15f994e3092c66356219eb8b7 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-09T12:21:19Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-e946eec15f994e3092c66356219eb8b72023-11-30T22:41:05ZengMDPI AGAntibiotics2079-63822022-07-0111789510.3390/antibiotics11070895Towards Improved Management of Tuberculous Bloodstream Infections: Pharmacokinetic Considerations with Suggestions for Better Treatment OutcomesCharles Okot Odongo0Lydia Nakiyingi1Clovis Gatete Nkeramihigo2Daniel Seifu3Kuteesa Ronald Bisaso4Division of Basic Medical Sciences, School of Medicine, University of Global Health Equity, Kigali P.O. Box 6955, RwandaDepartment of Internal Medicine, School of Medicine, College of Health Sciences, Makerere University, Kampala P.O. Box 7072, UgandaDivision of Basic Medical Sciences, School of Medicine, University of Global Health Equity, Kigali P.O. Box 6955, RwandaDivision of Basic Medical Sciences, School of Medicine, University of Global Health Equity, Kigali P.O. Box 6955, RwandaBreakthrough Analytics Ltd., Plot 17B Gasper Oda Close, Naguru, Kampala, Uganda<i>Mycobacterium tuberculosis</i> is the leading cause of sepsis among HIV-infected adults, yet effective treatment remains a challenge. Efficacy of antituberculous drugs is optimized by high Area Under Curve to Minimum Inhibitory Concentration (AUC/MIC) ratios, suggesting that both the drug concentration at the disease site and time above MIC are critical to treatment outcomes. We elaborate on sepsis pathophysiology and show how it adversely affects antituberculous drug kinetics. Expanding distribution volumes secondary to an increased vascular permeability prevents the attainment of target C<sub>max</sub> concentrations for nearly all drugs. Furthermore, sepsis-induced metabolic acidosis promotes protonation, which increases renal clearance of basic drugs such as isoniazid and ethambutol, and hence AUCs are substantially reduced. Compared with the treatment of non-sepsis TB disease, these distorted kinetics underlie the poor treatment outcomes observed with bloodstream infections. In addition to aggressive hemodynamic management, an increase in both the dose and frequency of drug administration are warranted, at least in the early phase of treatment.https://www.mdpi.com/2079-6382/11/7/895tuberculosissepsistreatmentpharmacokineticsC<sub>max</sub>AUC |
| spellingShingle | Charles Okot Odongo Lydia Nakiyingi Clovis Gatete Nkeramihigo Daniel Seifu Kuteesa Ronald Bisaso Towards Improved Management of Tuberculous Bloodstream Infections: Pharmacokinetic Considerations with Suggestions for Better Treatment Outcomes Antibiotics tuberculosis sepsis treatment pharmacokinetics C<sub>max</sub> AUC |
| title | Towards Improved Management of Tuberculous Bloodstream Infections: Pharmacokinetic Considerations with Suggestions for Better Treatment Outcomes |
| title_full | Towards Improved Management of Tuberculous Bloodstream Infections: Pharmacokinetic Considerations with Suggestions for Better Treatment Outcomes |
| title_fullStr | Towards Improved Management of Tuberculous Bloodstream Infections: Pharmacokinetic Considerations with Suggestions for Better Treatment Outcomes |
| title_full_unstemmed | Towards Improved Management of Tuberculous Bloodstream Infections: Pharmacokinetic Considerations with Suggestions for Better Treatment Outcomes |
| title_short | Towards Improved Management of Tuberculous Bloodstream Infections: Pharmacokinetic Considerations with Suggestions for Better Treatment Outcomes |
| title_sort | towards improved management of tuberculous bloodstream infections pharmacokinetic considerations with suggestions for better treatment outcomes |
| topic | tuberculosis sepsis treatment pharmacokinetics C<sub>max</sub> AUC |
| url | https://www.mdpi.com/2079-6382/11/7/895 |
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