OBJECTIVES: To compare the efficacy of ceftazidime/avibactam plus tedizolid-based combination regimens with the standard therapy of azithromycin, ethambutol and rifabutin for the treatment of pulmonary Mycobacterium avium complex (MAC) disease. METHODS: We mimicked the human pulmonary concentration-time profiles of ceftazidime/avibactam and tedizolid in combination, ceftazidime/avibactam, rifabutin, tedizolid and moxifloxacin (CARTM), and the standard regimen and examined microbial kill in triplicate hollow-fibre system model of intracellular pulmonary MAC (HFS-MAC) units. The tedizolid and moxifloxacin doses used were non-optimized; the tedizolid dose was that associated with bacteriostasis. Drugs were administered daily for 28 days. Each HFS-MAC was sampled in the central and peripheral compartment to ascertain that the intended drug exposures had been achieved. The peripheral compartments were sampled at regular intervals over the 28 days to quantify the burden of MAC. RESULTS: MAC-infected macrophages in the HFS-MAC achieved multi-fold higher intracellular versus extracellular concentrations of rifabutin, moxifloxacin, ceftazidime/avibactam. The non-optimized ceftazidime/avibactam plus tedizolid dual therapy held the bacterial burden at the same level as day 0 (stasis) throughout the 28 days. The standard therapy reduced the bacterial load 2 log10 cfu/mL below stasis on day 14 but started failing after that. The CARTM regimen achieved 3.2 log10 cfu/mL kill below stasis on day 21, but had started to fail by day 28. CONCLUSIONS: The CARTM regimen promises to have kill rates better than standard therapy. Experiments to identify exposures of each of the four drugs associated with optimal effect in the CARTM combination are needed in order to design a short-course chemotherapy regimen.
OBJECTIVES: To compare the efficacy of ceftazidime/avibactam plus tedizolid-based combination regimens with the standard therapy of azithromycin, ethambutol and rifabutin for the treatment of pulmonary Mycobacterium avium complex (MAC) disease. METHODS: We mimicked the human pulmonary concentration-time profiles of ceftazidime/avibactam and tedizolid in combination, ceftazidime/avibactam, rifabutin, tedizolid and moxifloxacin (CARTM), and the standard regimen and examined microbial kill in triplicate hollow-fibre system model of intracellular pulmonary MAC (HFS-MAC) units. The tedizolid and moxifloxacin doses used were non-optimized; the tedizolid dose was that associated with bacteriostasis. Drugs were administered daily for 28 days. Each HFS-MAC was sampled in the central and peripheral compartment to ascertain that the intended drug exposures had been achieved. The peripheral compartments were sampled at regular intervals over the 28 days to quantify the burden of MAC. RESULTS: MAC-infected macrophages in the HFS-MAC achieved multi-fold higher intracellular versus extracellular concentrations of rifabutin, moxifloxacin, ceftazidime/avibactam. The non-optimized ceftazidime/avibactam plus tedizolid dual therapy held the bacterial burden at the same level as day 0 (stasis) throughout the 28 days. The standard therapy reduced the bacterial load 2 log10 cfu/mL below stasis on day 14 but started failing after that. The CARTM regimen achieved 3.2 log10 cfu/mL kill below stasis on day 21, but had started to fail by day 28. CONCLUSIONS: The CARTM regimen promises to have kill rates better than standard therapy. Experiments to identify exposures of each of the four drugs associated with optimal effect in the CARTM combination are needed in order to design a short-course chemotherapy regimen.
Authors: Keertan Dheda; Laura Lenders; Gesham Magombedze; Shashikant Srivastava; Prithvi Raj; Erland Arning; Paula Ashcraft; Teodoro Bottiglieri; Helen Wainwright; Timothy Pennel; Anthony Linegar; Loven Moodley; Anil Pooran; Jotam G Pasipanodya; Frederick A Sirgel; Paul D van Helden; Edward Wakeland; Robin M Warren; Tawanda Gumbo Journal: Am J Respir Crit Care Med Date: 2018-11-01 Impact factor: 21.405
Authors: Dafna Yahav; Christian G Giske; Alise Grāmatniece; Henrietta Abodakpi; Vincent H Tam; Leonard Leibovici Journal: Clin Microbiol Rev Date: 2020-11-11 Impact factor: 26.132
Authors: Kelly M Pennington; Ann Vu; Douglas Challener; Christina G Rivera; F N U Shweta; John D Zeuli; Zelalem Temesgen Journal: J Clin Tuberc Other Mycobact Dis Date: 2021-05-08
Authors: Gunavanthi D Boorgula; Laxmi U M R Jakkula; Tawanda Gumbo; Bockgie Jung; Shashikant Srivastava Journal: Front Pharmacol Date: 2021-04-15 Impact factor: 5.810
Authors: Mike Marvin Ruth; Valerie A C M Koeken; Lian J Pennings; Elin M Svensson; Heiman F L Wertheim; Wouter Hoefsloot; Jakko van Ingen Journal: J Antimicrob Chemother Date: 2020-03-01 Impact factor: 5.790