Oxazolidinones Can Replace Clarithromycin in Combination with Rifampin in a Mouse Model of Buruli Ulcer

TY - JOUR

T1 - Oxazolidinones Can Replace Clarithromycin in Combination with Rifampin in a Mouse Model of Buruli Ulcer

AU - Almeida, Deepak V

AU - Omansen, Till F

AU - Li, Si-Yang

AU - Lee, Jin

AU - Grosset, Jacques H

AU - Converse, Paul J

AU - Nuermberger, Eric L

N1 - Copyright © 2019 American Society for Microbiology.

PY - 2019/3

Y1 - 2019/3

N2 - Rifampin (RIF) plus clarithromycin (CLR) for 8 weeks is now the standard of care for Buruli ulcer (BU) treatment, but CLR may not be an ideal companion for rifamycins due to bidirectional drug-drug interactions. The oxazolidinone linezolid (LZD) was previously shown to be active against Mycobacterium ulcerans infection in mice but has dose- and duration-dependent toxicity in humans. Sutezolid (SZD) and tedizolid (TZD) may be safer than LZD. Here, we evaluated the efficacy of these oxazolidinones in combination with rifampin in a murine BU model. Mice with M. ulcerans-infected footpads received control regimens of RIF plus either streptomycin (STR) or CLR or test regimens of RIF plus either LZD (1 of 2 doses), SZD, or TZD for up to 8 weeks. All combination regimens reduced the swelling and bacterial burden in footpads after two weeks of treatment compared with RIF alone. RIF+SZD was the most active test regimen, while RIF+LZD was also no less active than RIF+CLR. After 4 and 6 weeks of treatment, neither CLR nor the oxazolidinones added significant bactericidal activity to RIF alone. By the end of 8 weeks of treatment, all regimens rendered footpads culture negative. We conclude that SZD and LZD warrant consideration as alternative companion agents to CLR in combination with RIF to treat BU, especially when CLR is contraindicated, intolerable, or unavailable. Further evaluation could prove SZD superior to CLR in this combination.

AB - Rifampin (RIF) plus clarithromycin (CLR) for 8 weeks is now the standard of care for Buruli ulcer (BU) treatment, but CLR may not be an ideal companion for rifamycins due to bidirectional drug-drug interactions. The oxazolidinone linezolid (LZD) was previously shown to be active against Mycobacterium ulcerans infection in mice but has dose- and duration-dependent toxicity in humans. Sutezolid (SZD) and tedizolid (TZD) may be safer than LZD. Here, we evaluated the efficacy of these oxazolidinones in combination with rifampin in a murine BU model. Mice with M. ulcerans-infected footpads received control regimens of RIF plus either streptomycin (STR) or CLR or test regimens of RIF plus either LZD (1 of 2 doses), SZD, or TZD for up to 8 weeks. All combination regimens reduced the swelling and bacterial burden in footpads after two weeks of treatment compared with RIF alone. RIF+SZD was the most active test regimen, while RIF+LZD was also no less active than RIF+CLR. After 4 and 6 weeks of treatment, neither CLR nor the oxazolidinones added significant bactericidal activity to RIF alone. By the end of 8 weeks of treatment, all regimens rendered footpads culture negative. We conclude that SZD and LZD warrant consideration as alternative companion agents to CLR in combination with RIF to treat BU, especially when CLR is contraindicated, intolerable, or unavailable. Further evaluation could prove SZD superior to CLR in this combination.

KW - Animals

KW - Anti-Bacterial Agents/therapeutic use

KW - Buruli Ulcer/drug therapy

KW - Clarithromycin/therapeutic use

KW - Disease Models, Animal

KW - Female

KW - Linezolid/adverse effects

KW - Mice

KW - Mice, Inbred BALB C

KW - Mycobacterium ulcerans/drug effects

KW - Oxazolidinones/adverse effects

KW - Rifampin/therapeutic use

KW - Tetrazoles/adverse effects

U2 - 10.1128/AAC.02171-18

DO - 10.1128/AAC.02171-18

M3 - SCORING: Journal article

C2 - 30559131

VL - 63

SP - e02171-18

JO - ANTIMICROB AGENTS CH

JF - ANTIMICROB AGENTS CH

SN - 0066-4804

IS - 3

ER -