Paradoxical reactions in Buruli ulcer after initiation of antibiotic therapy: Relationship to bacterial load

Frimpong, Michael; Agbavor, Bernadette; Duah, Mabel Sarpong; Loglo, Aloysius; Sarpong, Francisca Naana; Boakye-Appiah, Justice K.; Abass, Kabiru Mohammed; Dongyele, Mathias; Amofa, George; Wilson, Tracey E.; Frempong, Margaret; Amoako, Yaw Ampem; Wansbrough‐Jones, Mark; Phillips, Richard Odame

doi:10.1371/journal.pntd.0007689

Cited by 50 publications

(39 citation statements)

References 14 publications

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“…This regimen offers advantages over the previously recommended RIFϩSTR combination (2). However, it remains problematic because treatment duration inversely correlates with adherence, and patients are often hospitalized until there is clear-cut evidence of treatment response, including resolution of any paradoxical reaction (19), resulting in missed school or work activities. As an extremely potent inhibitor of M. ulcerans respiration, Q203 is an exceptional candidate for treatment-shortening regimens.…”

Section: Discussionmentioning

confidence: 99%

Telacebec for Ultrashort Treatment of Buruli Ulcer in a Mouse Model

Almeida

Converse

Omansen

et al. 2020

Antimicrob Agents Chemother

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Telacebec (Q203) is a new antitubercular drug with extremely potent activity against Mycobacterium ulcerans. Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most mouse footpads culture negative in 2 weeks. Combining Q203 with rifampin resulted in a relapse-free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in mice receiving RIF with clarithromycin, the current standard of care, for 4 weeks. The second study explored the dose-ranging activity of Q203 alone and with RIF, including the extended activity of Q203 after treatment discontinuation. The bactericidal activity of Q203 persisted for ≥ 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 2 to 10 mg/kg were culture negative 4 weeks after stopping treatment. Mice receiving 2 weeks of Q203 at 0.5, 2, and 10 mg/kg were culture negative 4 weeks after treatment. RIF did not increase the efficacy of Q203. A pharmacokinetics substudy revealed that Q203 doses of 2 to 10 mg/kg in mice produce plasma concentrations similar to those produced by 100 to 300 mg doses in humans, with no adverse effect of RIF on Q203 concentrations. These results indicate the extraordinary potential of Q203 to reduce the duration of treatment necessary for a cure to ≤ 1 week (or 5 doses of 2 to 10 mg/kg) in our mouse footpad infection model and warrant further evaluation of Q203 in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Telacebec for Ultrashort Treatment of Buruli Ulcer in a Mouse Model

Almeida

Converse

Omansen

et al. 2020

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…This regimen offers advantages over the previously recommended RIF+STR combination (2). However, it remains problematic because treatment duration inversely correlates with adherence and patients are often hospitalized until there is clear-cut evidence of efficacy treatment response, including resolution of any paradoxical reaction (20), resulting in missed school or work activities. As an extremely potent inhibitor of M. ulcerans respiration, Q203 is an exceptional candidate for treatment-shortening regimens.…”

Section: Discussionmentioning

confidence: 99%

Telacebec for ultra-short treatment of Buruli ulcer in a mouse model

Almeida

Converse

Omansen

et al. 2020

Preprint

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24Telacebec (Q203) is a new anti-tubercular drug with extremely potent activity against 25 Mycobacterium ulcerans. Here, we explored the treatment-shortening potential of Q203 alone or 26 in combination with rifampin (RIF) in a mouse footpad infection model. The first study 27 compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most 28 mouse footpads culture-negative in 2 weeks. Combining Q203 with rifampin resulted in relapse-29 free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in 30 mice receiving RIF+clarithromycin, the current standard of care, for 4 weeks. 31The second study explored the dose-ranging activity of Q203 alone and with RIF, 32including the extended activity of Q203 after treatment discontinuation. The bactericidal activity 33 of Q203 persisted for ≥ 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 34 2-10 mg/kg were culture-negative 4 weeks after stopping treatment. Mice receiving 2 weeks of 35 Q203 at 0.5, 2 and 10 mg/kg were culture-negative 4 weeks after treatment. RIF did not increase 36 the efficacy of Q203. A pharmacokinetics sub-study revealed that Q203 doses of 2-10 mg/kg in 37 mice produce plasma concentrations similar to those produced by 100-300 mg doses in humans, 38 with no adverse effect of RIF on Q203 concentrations. 39These results indicate the extraordinary potential of Q203 to reduce the duration of 40 treatment necessary for cure to ≤ 1 week (or 5 doses of 2-10 mg/kg) in our mouse footpad 41 infection model and warrant further evaluation of Q203 in clinical trials. 42 43 44 45 46 Introduction 47The World Health Organization's recommended treatment for Buruli ulcer (BU), also 48 known as Mycobacterium ulcerans disease, recently evolved from an 8-week regimen of 49 rifampin (RIF, R) at 10 mg/kg of body weight plus streptomycin (STR) to an 8-week regimen of 50 RIF plus clarithromycin (CLR, C) to eliminate the need for the injectable agent STR and to avoid 51 its related ototoxicity (1, 2). However, CLR has more limited activity than STR against M. 52 ulcerans in mouse models of the disease and RIF induces the metabolism of CLR, which likely 53 limits the contribution of CLR to the regimen (3-5). Nonetheless, clinical studies have shown 54 good efficacy of the RIF+CLR regimen (6). 55Despite the success of the RIF+CLR regimen, shortening the duration of BU treatment 56 remains an important research objective. We previously investigated replacement of STR and/or 57 CLR with other drugs such as clofazimine and oxazolidinones in our mouse footpad infection 58 model, as well as the impact of increasing rifamycin exposures using high-dose RIF or 59 rifapentine (RPT), with the aim of reducing the treatment duration necessary for cure (7)(8)(9)(10)(11)(12). 60Although we identified novel combinations with efficacy superior to RIF+STR and/or 61 RIF+CLR, none of these 2-drug combinations showed a potential to reduce the duration of 62 treatment to less than 4 weeks in mice. 63Telacebec (Q203, Q) is ...

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“…Moreover, paradoxical worsening of the lesions, with enlargement of the treated ulcer and sometimes development of secondary lesions, are often observed after the start of anti-microbial treatment. [17][18][19][20][21][22] Such reactions may be interpreted as a treatment failure. However, histopathological and clinical examination of involved tissues argues that on the contrary, they result from immune-mediated reactions to effective, microbiologically sterilizing treatments (see Section 3).…”

Section: Treatmentmentioning

confidence: 99%