Antibacterial action of penicillin against Mycobacterium avium complex
INTRODUCTION: β-lactam antibiotics are promising treatments for Mycobacterium avium complex (MAC) lung disease. We hypothesized that benzylpenicillin has efficacy against MAC. METHODS: Benzylpenicillin lung concentration–time profiles of seven doses in three dosing schedules were administered for 28...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
International Union Against Tuberculosis and Lung Disease (The Union)
2024-08-01
|
| Series: | IJTLD Open |
| Subjects: | |
| Online Access: | https://www.ingentaconnect.com/contentone/iuatld/ijtldo/2024/00000001/00000008/art00006 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832591396927700992 |
|---|---|
| author | D. Deshpande G. Magombedze S. Srivastava T. Gumbo |
| author_facet | D. Deshpande G. Magombedze S. Srivastava T. Gumbo |
| author_sort | D. Deshpande |
| collection | DOAJ |
| description | INTRODUCTION: β-lactam antibiotics are promising treatments for Mycobacterium avium complex (MAC) lung disease. We hypothesized that benzylpenicillin has efficacy against MAC. METHODS: Benzylpenicillin lung concentration–time profiles of seven doses in three dosing schedules were administered for 28 days using the hollow fiber system model of intracellular MAC (HFS-MAC). Data were analyzed using the inhibitory sigmoid maximal effect (E max) model for each sampling day, while two ordinary differential equations (ODEs) were used for the wild-type and penicillin-resistant mutants. RESULTS: Benzylpenicillin killed >2.1 log 10 colony-forming unit (CFU)/mL below Day 0, better than azithromycin, ethambutol, and rifabutin. Efficacy was terminated by acquired resistance. Sigmoid E max parameter estimates significantly differed between sampling days and were a poor fit. However, ODE model parameter estimates vs. exposure were a better fit. The exposure mediating E max was 84.6% (95% CI 76.91–82.98) of time concentration exceeded the minimum inhibitory concentration (MIC). In Monte Carlo experiments, 24 million international units of benzylpenicillin continuous infusion achieved the target exposure in lungs of >90% of 10,000 subjects until an MIC of 64 mg/L, designated the susceptibility breakpoint. CONCLUSIONS: Benzylpenicillin demonstrated a better bactericidal effect against MAC than guideline-recommended drugs before the development of resistance. Its role in combination therapy with other drugs with better efficacy than guideline-recommended drugs should be explored. |
| format | Article |
| id | doaj-art-b51b4ec18c3d446394c496f05b104073 |
| institution | Kabale University |
| issn | 3005-7590 |
| language | English |
| publishDate | 2024-08-01 |
| publisher | International Union Against Tuberculosis and Lung Disease (The Union) |
| record_format | Article |
| series | IJTLD Open |
| spelling | doaj-art-b51b4ec18c3d446394c496f05b1040732025-01-22T12:14:14ZengInternational Union Against Tuberculosis and Lung Disease (The Union)IJTLD Open3005-75902024-08-011836236810.5588/ijtldopen.24.02386Antibacterial action of penicillin against Mycobacterium avium complexD. Deshpande0G. Magombedze1S. Srivastava2T. Gumbo3Baylor University Medical Center, Dallas, TX, USA;Mathematical Modeling and AI Department, Praedicare Inc, Dallas, TX, USA;Department of Medicine, School of Medicine, University of Texas at Tyler, Tyler, TX, USA;Mathematical Modeling and AI Department, Praedicare Inc, Dallas, TX, USA;INTRODUCTION: β-lactam antibiotics are promising treatments for Mycobacterium avium complex (MAC) lung disease. We hypothesized that benzylpenicillin has efficacy against MAC. METHODS: Benzylpenicillin lung concentration–time profiles of seven doses in three dosing schedules were administered for 28 days using the hollow fiber system model of intracellular MAC (HFS-MAC). Data were analyzed using the inhibitory sigmoid maximal effect (E max) model for each sampling day, while two ordinary differential equations (ODEs) were used for the wild-type and penicillin-resistant mutants. RESULTS: Benzylpenicillin killed >2.1 log 10 colony-forming unit (CFU)/mL below Day 0, better than azithromycin, ethambutol, and rifabutin. Efficacy was terminated by acquired resistance. Sigmoid E max parameter estimates significantly differed between sampling days and were a poor fit. However, ODE model parameter estimates vs. exposure were a better fit. The exposure mediating E max was 84.6% (95% CI 76.91–82.98) of time concentration exceeded the minimum inhibitory concentration (MIC). In Monte Carlo experiments, 24 million international units of benzylpenicillin continuous infusion achieved the target exposure in lungs of >90% of 10,000 subjects until an MIC of 64 mg/L, designated the susceptibility breakpoint. CONCLUSIONS: Benzylpenicillin demonstrated a better bactericidal effect against MAC than guideline-recommended drugs before the development of resistance. Its role in combination therapy with other drugs with better efficacy than guideline-recommended drugs should be explored.https://www.ingentaconnect.com/contentone/iuatld/ijtldo/2024/00000001/00000008/art00006ordinary differential equationsantimicrobial resistancesusceptibility breakpointcontinuous dosingntm lung disease |
| spellingShingle | D. Deshpande G. Magombedze S. Srivastava T. Gumbo Antibacterial action of penicillin against Mycobacterium avium complex IJTLD Open ordinary differential equations antimicrobial resistance susceptibility breakpoint continuous dosing ntm lung disease |
| title | Antibacterial action of penicillin against Mycobacterium avium complex |
| title_full | Antibacterial action of penicillin against Mycobacterium avium complex |
| title_fullStr | Antibacterial action of penicillin against Mycobacterium avium complex |
| title_full_unstemmed | Antibacterial action of penicillin against Mycobacterium avium complex |
| title_short | Antibacterial action of penicillin against Mycobacterium avium complex |
| title_sort | antibacterial action of penicillin against mycobacterium avium complex |
| topic | ordinary differential equations antimicrobial resistance susceptibility breakpoint continuous dosing ntm lung disease |
| url | https://www.ingentaconnect.com/contentone/iuatld/ijtldo/2024/00000001/00000008/art00006 |
| work_keys_str_mv | AT ddeshpande antibacterialactionofpenicillinagainstmycobacteriumaviumcomplex AT gmagombedze antibacterialactionofpenicillinagainstmycobacteriumaviumcomplex AT ssrivastava antibacterialactionofpenicillinagainstmycobacteriumaviumcomplex AT tgumbo antibacterialactionofpenicillinagainstmycobacteriumaviumcomplex |