We thank Klis et al.  for contributing to the debate around our proposal to study the safety and effectiveness of moxifloxacin (MXF)–rifampicin (RIF) antibiotic regimens for Buruli ulcer treatment in HIV-infected individuals [1,2]. To further the debate, we would like to respond to some of the arguments made against the proposed research presented in their letter.
Firstly, they state that ‘the highest Buruli ulcer case rates are observed in rural areas of West Africa where HIV prevalence is low’. However, the estimated HIV prevalence in all 11 countries currently reporting Buruli ulcer cases in West and Central Africa is between 1% and 5% of the general adult population, which places them in the category of having generalized HIV epidemics . Therefore, addressing HIV coinfection in African Buruli ulcer patients is important.
Secondly, quoting the study of Ji et al. , Klis et al.  concluded that ‘In the mouse model, there were clear indications that MXF was inferior to clarithromycin (CLA) either given alone or in combination with RIF’. However, the study by Ji et al.  reported that in terms of microbiological cure and relapse rates ‘the combination of RIF–MXF was as effective as that of RIF–streptomycin (STR) against Mycobacterium ulcerans in mice’ and that ‘the bactericidal activity of RIF–CLR is indistinguishable from that of RIF–STR or RIF–MXF’. On the basis of the effectiveness of RIF–MFX regimens in their mouse studies, Ji et al.  have concluded that ‘a pilot clinical trial is proposed to test the efficacy of RIF–MXF for the treatment of Buruli ulcer’, providing support to our proposal to study these treatment regimes in Buruli ulcer/HIV coinfected populations.
Thirdly, we welcome the author's reference to the ongoing trial of RIF–CLA evaluating once-daily 15 mg/kg dosing of CLA (http://www.clinicaltrials.gov/ct2/show/NCT01659437 NLM Identifier: NCT01659437). This will be important to clarify the effectiveness of the once-daily CLA regimen in HIV-negative patients, which, if effective, will provide an important once-daily oral regimen for Buruli ulcer treatment. However, this trial is not designed to look at the safety and effectiveness of efavirenz (EFV) combined with RIF–CLA regimens, for which, as Klis et al.  acknowledge, there are important concerns regarding the reduction in CLA levels induced by EFV  and also the potential for increased toxicity . Until this has been clarified, RIF–CLA combinations should be used with caution in patients receiving EFV-containing antiretroviral therapy regimens. Furthermore, there remains a need for an alternative oral regimen to RIF and CLA for cases of intolerance or contra-indication to CLA.
Fourthly, we would like to clarify our position regarding MFX and tuberculosis (TB). We have not suggested that MXF be advocated for the treatment of TB – either active disease or latent infection – and we agree that there are clear WHO protocols that should be followed. Rather, we are trying to counter the argument that MXF should not be used for Buruli ulcer treatment on the grounds that if there was coexistent undetected TB disease, this would have negative consequences for the patient compared to the use of CLA. We suggest that the opposite situation exists: if coexistent undetected TB is present in a patient being treated for Buruli ulcer, then the patient would benefit from being on MXF, which has excellent anti-TB activity, compared to CLA, which has a limited anti-TB activity. If drug-sensitive TB is present and undetected, then Buruli ulcer treatment regimens of CLA and RIF will very likely lead to RIF-resistant TB due to monotherapy with RIF. In contrast, if RIF and MXF are used, the likelihood of RIF resistance developing in drug-sensitive TB during the Buruli ulcer treatment regimen is minimized due to the anti-TB activity of MXF. Further, there is no added benefit in the treatment of latent TB when using CLA combined with RIF for Buruli ulcer treatment. In contrast, there is likely to be an additional benefit with MXF due to its anti-TB activity. As TB infection is highly endemic in Buruli ulcer-endemic areas in Africa, TB is a major cause of morbidity and mortality for HIV-infected patients , and rates of isoniazid TB chemoprophylaxis in HIV-infected patients are low; this may provide additional significant secondary benefits from Buruli ulcer treatment to HIV-infected patients.
Klis et al.  raise concern about the development of resistance against gram-negative bacteria using MFX-containing regimens. However, we would counter this risk by emphasizing the fact that the activity of MFX against gram-negative bacteria may also be one of its strengths when compared to CLA-containing regimens. Mortality appears significantly increased amongst HIV-infected compared to HIV-negative Buruli ulcer patients , with death from bacterial sepsis, including that due to gram-negative and other organisms susceptible to MFX but not to CLA, being one of the leading causes of death among immunosuppressed HIV patients . The broad spectrum of antibacterial activity of MFX may reduce mortality from bacterial sepsis in this vulnerable group, providing a potential further compelling reason to study RIF–MFX-containing regimens.
Finally, the argument used against MFX-containing regimen use on the grounds that it is not recommended in those under 18 years of age is less relevant in Buruli ulcer/HIV coinfected populations, where, by far, the majority of the patients are adults .
Moxifloxacin offers a treatment alternative for Buruli ulcer/HIV coinfected patients that, when combined with rifampicin, is a fully oral regimen, with the benefits of improved treatment access, delivery, and adherence and reduced toxicity , does not interact with antiretroviral drugs, can be given once daily, has high oral bioavailability and bone and tissue penetration, has potential secondary benefits in TB-coinfected patients and may reduce mortality in severely immunosuppressed HIV patients. We believe the debate generated around the use of MFX-containing regimens underlines the importance of including these regimens as a key research priority for improving the management of Buruli ulcer/HIV coinfected patients.
Conflicts of interest
There are no conflicts of interest.
1. Klis S, Van der Graaf WT, Phillips R, Sarfo FS, wansbrough-Jones M, Stienstra Y. Oral treatment for patients with Buruli ulcer co-infected with HIV: think twice
2. O’Brien DP, Comte E, Ford N, Christinet V, du Cros P. Moxifloxacin for Buruli ulcer/HIV coinfected patients: kill two birds with one stone?
4. Ji B, Chauffour A, Robert J, Lefrancois S, Jarlier V. Orally administered combined regimens for treatment of Mycobacterium ulcerans infection in mice
. Antimicrob Agents Chemother
5. Ji B, Lefrancois S, Robert J, Chauffour A, Truffot C, Jarlier V. In vitro and in vivo activities of rifampin, streptomycin, amikacin, moxifloxacin, R207910, linezolid, and PA-824 against Mycobacterium ulcerans
. Antimicrob Agents Chemother
6. Kuper JI, D’Aprile M. Drug-Drug interactions of clinical significance in the treatment of patients with Mycobacterium avium complex disease
. Clin Pharmacokinet
7. Bristol-Myers-Squibb. Sustiva product information. Princetown, NJ; 2010.
8. Moh R, Danel C, Messou E, Ouassa T, Gabillard D, Anzian A, et al. Incidence and determinants of mortality and morbidity following early antiretroviral therapy initiation in HIV-infected adults in West Africa
9. Christinet V, Rossel L, Serafini M, Delhumeau C, Odermatt P, Ciaffi L, et al. Impact of HIV on the severity of Buruli ulcer disease: results from a retrospective study in Cameroon
. Open Forum Infect Dis
10. Klis S, Stienstra Y, Phillips RO, Abass KM, Tuah W, van der Werf TS. Long term streptomycin toxicity in the treatment of Buruli ulcer: follow-up of participants in the BURULICO Drug Trial
. PLoS Negl Trop Dis