Antibiotic complications during the treatment of <i>Mycobacterium ulcerans</i> disease in Australian patients

O’Brien, D. P.; Friedman, N. Deborah; Hughes, Andrew; Walton, Aaron; Athan, Eugene

doi:10.1111/imj.13511

Cited by 23 publications

(16 citation statements)

References 34 publications

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“…However, based on our published experience of successful outcomes with the combination of surgery and shortened antibiotic treatment durations,[ 17 ] in this study we found that both of these above surgical options have the additional advantage of permitting significantly shorter antibiotic courses (an average reduction of half the duration) to be used without affecting treatment success rates, with the potential to reduce antibiotic related treatment toxicity. [ 18 ] Therefore this provides clinicians in settings with access to appropriate surgical services an additional treatment option to antibiotics alone for small lesions that may reduce healing times and antibiotic toxicity. Surgical debridement was not associated with reduced healing times, but any beneficial effect may have been confounded by the fact that the majority of cases where it was used (75%) also experienced paradoxical reactions which would have biased the sample towards prolonged healing.…”

Section: Discussionmentioning

confidence: 99%

Wound healing: Natural history and risk factors for delay in Australian patients treated with antibiotics for Mycobacterium ulcerans disease

et al. 2018

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BackgroundHealing times following treatment with antibiotics, and factors that influence healing, have not been reported in Australian patients with Mycobacterium ulcerans.Methodology/Principal findingsHealing times were determined for all M. ulcerans cases treated by a single physician with antibiotics at Barwon Health, Victoria, from 1/1/13-31/12/16. Lesions were categorised by induration size: category A ≤ 400mm2, Category B 401-1600mm2 and Category C ≥1601mm2. A logistic regression analysis was performed to determine risk factors for prolonged wound healing (>150 days from antibiotic commencement).163 patients were included; 92 (56.4%) were male and median age was 58 years (IQR 39–73 years). Baseline lesion size [available in 145 (89.0%) patients] was categorised as A in 46 (31.7%), B in 67 (46.2%) and C in 32 (22.1%) patients. Fifty (30.7%) patients had surgery. In those treated with antibiotics alone, 83.0% experienced a reduction in induration size after 2 weeks, then 70.9% experienced an increase in induration size from the lowest point, and 71.7% experienced an increase in ulceration size. A linear relationship existed between the time induration resolved and wound healing began.Median time to heal was 91 days (IQR 70–148 days) for category A lesions; significantly shorter than for category B lesions (128 days, IQR 91–181 days, p = 0.05) and category C lesions (169 days, IQR 159–214 days, p<0.001). Fifty-seven (35.0%) patients experienced a paradoxical reaction. Of those treated with antibiotics alone, lesions experiencing a paradoxical reaction had longer healing times [median time to heal 177 days (IQR 154–224 days) compared to 107 days (IQR 79–153 days), p<0.001]. On multivariable logistic regression, lesion size at baseline (p<0.001) and paradoxical reactions (p<0.001) were independently associated with prolonged healing times.For category A and B lesions, healing time was significantly shorter with antibiotics plus excision and direct closure compared with antibiotics alone [Category A lesions median 55 days (IQR 21–63 days) compared with 91 days (IQR 70–148 days), p<0.001; Category B lesions median 74 days (IQR 21–121 days) compared to 128 days (IQR 97–181 days), p<0.001].ConclusionsIn Australian patients treated with antibiotics M. ulcerans lesions usually initially improve, then clinically deteriorate with increased induration and ulceration, before healing after the inflammation associated with lesions resolves. The time to complete healing of lesions is generally long, and is further prolonged in those with larger initial lesion size or who develop paradoxical reactions. For small lesions (<4cm2), excisional surgery may reduce healing times.

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Section: Discussionmentioning

confidence: 99%

Wound healing: Natural history and risk factors for delay in Australian patients treated with antibiotics for Mycobacterium ulcerans disease

et al. 2018

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“…Although ototoxicity and other complications of STR treatment were not initially observed in West African patients based on self-report, more objective audiometric testing showed that hearing loss does indeed occur [ 4 ]. In Australia, which also has a large number of cases, all-oral antibiotic therapy combined with surgery has been in practice for many years [ 5 ]. In March of 2017, the BU Technical Advisory Group for the World Health Organization Global BU Initiative, due to difficulties in obtaining STR and preliminary findings of non-inferiority in a clinical trial (NCT01659437) in West Africa, recommended replacing STR with oral clarithromycin (CLR, 15–30 mg/kg) [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer

Converse¹,

Almeida²,

Tasneen³

et al. 2018

PLoS Negl Trop Dis

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Starting in 2004, the standard regimen for treatment of Buruli ulcer (BU) recommended by the World Health Organization has been daily treatment for eight weeks with rifampin (RIF) and streptomycin. Based on recent clinical trials, treatment with an all-oral regimen of RIF and clarithromycin (CLR) may be an effective alternative. With the achievement of an all-oral regimen, a new goal is to find a regimen that can shorten the duration of treatment without compromising efficacy. We recently observed that increasing the dose of RIF from the standard 10 mg/kg dose to 20 or 40 mg/kg, or replacing RIF with the more potent long-acting rifamycin, rifapentine (RPT) at 10 mg/kg or 20 mg/kg increased the bactericidal activity of the RIF+CLR regimen in a mouse model of BU. We also recently showed that replacing CLR with clofazimine(CFZ) at 25 mg/kg may have greater sterilizing activity than the RIF+CLR regimen. Here, we demonstrate that combining high-dose rifamycins with CFZ at a lower dose of 12.5 mg/kg results in similar reductions in swelling, bacterial burden and mycolactone concentrations in mouse footpads compared to the standard regimens and more rapid sterilization of footpads as determined by the proportions of footpads harboring viable bacteria three months after completion of treatment. The potential of these high-dose rifamycin and CFZ combinations to shorten BU treatment to four weeks warrants evaluation in a clinical trial.Trial registrationClinicalTrials.gov NCT03474198, NCT01659437

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“…The ATP synthase inhibitor bedaquiline (BDQ) has significant treatment-shortening effects in mouse TB models and is a core component of novel treatment-shortening regimens for both drug-susceptible and multidrug-resistant TB (10)(11)(12)(13)(14)(15)(16). The cytochrome bc 1 :aa 3 complex inhibitor Q203 has efficacy in mouse TB models and is poised to enter phase 2 trials in TB patients (17,18). Clofazimine is reduced by NDH-2 (type II dehydrogenase), which is the point of entry of electrons into the respiratory chain (9,19).…”

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confidence: 99%

Shortening Buruli Ulcer Treatment with Combination Therapy Targeting the Respiratory Chain and Exploiting Mycobacterium ulcerans Gene Decay

Converse

Almeida

Tyagi

et al. 2019

Antimicrob Agents Chemother

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Buruli ulcer is treatable with antibiotics. An 8-week course of rifampin (RIF) and either streptomycin (STR) or clarithromycin (CLR) cures over 90% of patients. However, STR requires injections and may be toxic, and CLR shares an adverse drug-drug interaction with RIF and may be poorly tolerated. Studies in a mouse footpad infection model showed that increasing the dose of RIF or using the long-acting rifamycin rifapentine (RPT), in combination with clofazimine (CFZ), a relatively well-tolerated antibiotic, can shorten treatment to 4 weeks. CFZ is reduced by a component of the electron transport chain (ETC) to produce reactive oxygen species toxic to bacteria. Synergistic activity of CFZ with other ETC-targeting drugs, the ATP synthase inhibitor bedaquiline (BDQ) and the bc 1 :aa 3 oxidase inhibitor Q203 (now named telacebec), was recently described against Mycobacterium tuberculosis. Recognizing that M. tuberculosis mutants lacking the alternative bd oxidase are hypersusceptible to Q203 and that Mycobacterium ulcerans is a natural bd oxidasedeficient mutant, we tested the in vitro susceptibility of M. ulcerans to Q203 and evaluated the treatment-shortening potential of novel 3-and 4-drug regimens combining RPT, CFZ, Q203, and/or BDQ in a mouse footpad model. The MIC of Q203 was extremely low (0.000075 to 0.00015 g/ml). Footpad swelling decreased more rapidly in mice treated with Q203-containing regimens than in mice treated with RIF and STR (RIFϩSTR) and RPT and CFZ (RPTϩCFZ). Nearly all footpads were culture negative after only 2 weeks of treatment with regimens containing RPT, CFZ, and Q203. No relapse was detected after only 2 weeks of treatment in mice treated with any of the Q203-containing regimens. In contrast, 15% of mice receiving RIFϩSTR for 4 weeks relapsed. We conclude that it may be possible to cure patients with Buruli ulcer in 14 days or less using Q203-containing regimens rather than currently recommended 56-day regimens.

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Antibiotic complications during the treatment of Mycobacterium ulcerans disease in Australian patients

Abstract: Severe antibiotic complications during M. ulcerans treatment are high with increased rates independently associated with reduced renal function and female gender.

Cited by 23 publications

References 34 publications

Wound healing: Natural history and risk factors for delay in Australian patients treated with antibiotics for Mycobacterium ulcerans disease

Wound healing: Natural history and risk factors for delay in Australian patients treated with antibiotics for Mycobacterium ulcerans disease

Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer

Shortening Buruli Ulcer Treatment with Combination Therapy Targeting the Respiratory Chain and Exploiting Mycobacterium ulcerans Gene Decay

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