Shashikant Srivastava1, Moti Chapagain2, Johanna van Zyl3, Devyani Deshpande3, Tawanda Gumbo4. 1. Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX, USA; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA. 2. Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX, USA; Quantitative Preclinical and Clinical Sciences Department, Praedicare Inc., Dallas, TX, USA. 3. Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX, USA. 4. Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX, USA; Quantitative Preclinical and Clinical Sciences Department, Praedicare Inc., Dallas, TX, USA; Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa. Electronic address: rozvi1@praedicarelabs.com.
Abstract
OBJECTIVES: To determine whether an inhaled vancomycin formulation resulting in high intrapulmonary 24-h area under the concentration-time curve (AUC0-24) could be optimised for tuberculosis treatment. We also explored vancomycin synergy and antagonism with d-cycloserine and benzylpenicillin. METHODS: We determined MICs of two Mycobacterium tuberculosis (Mtb) laboratory strains (H37Ra and H37Rv) and two drug-susceptible and nine multidrug resistant clinical strains. Second, in the hollow fiber system model of TB [HFS-TB] using Mtb H37Ra strain, we recapitulated vancomycin intrapulmonary pharmacokinetics of eight doses administered twice daily over 28 days, mimicking a 6-h half-life. Using the HFS-TB, vancomycin was tested in combination with d-cycloserine and benzylpenicillin to determine synergy or antagonism between drugs targeting the same pathway. RESULTS: Vancomycin MICs were 12 and 48 mg/L in drug-susceptible clinical isolates but >96 mg/L in all MDR isolates.In the HFS-TB, vancomycin killed 3.9 ± 0.6 log10 CFU/mL Mtb. The EC50 was calculated as AUC0-24/MIC of 184.6 ± 106.5. Compared with day 0, 1.0 and 2.0 log10 CFU/mL kill was achieved by AUC0-24/MIC of 168 and 685, respectively. Acquired vancomycin resistance developed to all vancomycin doses tested in the HFS-TB. In the HFS-TB, vancomycin was antagonistic to benzylpenicillin, which works downstream to glycopeptides in peptidoglycan synthesis, but synergistic with d-cycloserine, which inhibits upstream d-Ala-d-Ala ligase and alanine racemase. CONCLUSION: Our proof-of-concept studies show that vancomycin optimal exposure target for Mtb kill could be achieved via inhalational drug delivery. Addition of drugs synergistic with vancomycin, e.g. d-cycloserine, may lower the vancomycin concentrations required to kill Mtb.
OBJECTIVES: To determine whether an inhaled vancomycin formulation resulting in high intrapulmonary 24-h area under the concentration-time curve (AUC0-24) could be optimised for tuberculosis treatment. We also explored vancomycin synergy and antagonism with d-cycloserine and benzylpenicillin. METHODS: We determined MICs of two Mycobacterium tuberculosis (Mtb) laboratory strains (H37Ra and H37Rv) and two drug-susceptible and nine multidrug resistant clinical strains. Second, in the hollow fiber system model of TB [HFS-TB] using MtbH37Ra strain, we recapitulated vancomycin intrapulmonary pharmacokinetics of eight doses administered twice daily over 28 days, mimicking a 6-h half-life. Using the HFS-TB, vancomycin was tested in combination with d-cycloserine and benzylpenicillin to determine synergy or antagonism between drugs targeting the same pathway. RESULTS:Vancomycin MICs were 12 and 48 mg/L in drug-susceptible clinical isolates but >96 mg/L in all MDR isolates.In the HFS-TB, vancomycin killed 3.9 ± 0.6 log10 CFU/mL Mtb. The EC50 was calculated as AUC0-24/MIC of 184.6 ± 106.5. Compared with day 0, 1.0 and 2.0 log10 CFU/mL kill was achieved by AUC0-24/MIC of 168 and 685, respectively. Acquired vancomycin resistance developed to all vancomycin doses tested in the HFS-TB. In the HFS-TB, vancomycin was antagonistic to benzylpenicillin, which works downstream to glycopeptides in peptidoglycan synthesis, but synergistic with d-cycloserine, which inhibits upstream d-Ala-d-Ala ligase and alanine racemase. CONCLUSION: Our proof-of-concept studies show that vancomycin optimal exposure target for Mtb kill could be achieved via inhalational drug delivery. Addition of drugs synergistic with vancomycin, e.g. d-cycloserine, may lower the vancomycin concentrations required to kill Mtb.
Authors: Saniya S Khan; Thanuja D Sudasinghe; Alexander D Landgraf; Donald R Ronning; Steven J Sucheck Journal: ACS Infect Dis Date: 2021-09-03 Impact factor: 5.578