Oxazolidinones can replace clarithromycin in combination with rifampin in a mouse model of Buruli ulcer

Deepak V. Almeida, Till F. Omansen, Si Yang Li, Jin Lee, Jacques H. Grosset, Paul J. Converse, Eric Nuermberger

Research output: Contribution to journalArticle

Abstract

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. RIFSZD was the most active test regimen, while RIFLZD was also no less active than RIFCLR. 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.

Original languageEnglish (US)
Article numbere02171-18
JournalAntimicrobial agents and chemotherapy
DOIs
StatePublished - Mar 1 2019

Fingerprint

Buruli Ulcer
Linezolid
Oxazolidinones
Clarithromycin
Rifampin
Rifamycins
Mycobacterium ulcerans
Streptomycin
Standard of Care
Drug Interactions
PNU-100480

Keywords

  • Buruli ulcer
  • Linezolid
  • Mycobacterium ulcerans
  • Oxazolidinones
  • Sutezolid
  • Tedizolid

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Oxazolidinones can replace clarithromycin in combination with rifampin in a mouse model of Buruli ulcer. / Almeida, Deepak V.; Omansen, Till F.; Li, Si Yang; Lee, Jin; Grosset, Jacques H.; Converse, Paul J.; Nuermberger, Eric.

In: Antimicrobial agents and chemotherapy, 01.03.2019.

Research output: Contribution to journalArticle

Almeida, Deepak V. ; Omansen, Till F. ; Li, Si Yang ; Lee, Jin ; Grosset, Jacques H. ; Converse, Paul J. ; Nuermberger, Eric. / Oxazolidinones can replace clarithromycin in combination with rifampin in a mouse model of Buruli ulcer. In: Antimicrobial agents and chemotherapy. 2019.
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abstract = "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. RIFSZD was the most active test regimen, while RIFLZD was also no less active than RIFCLR. 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.",
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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

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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. RIFSZD was the most active test regimen, while RIFLZD was also no less active than RIFCLR. 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.

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