Measurements of the in vitro anti-mycobacterial activity of ivermectin are method-dependent--authors' response

Sir, Discovering and developing new drugs for treating tuberculosis (TB) is a complex and challenging endeavour and very few drugs have been found that are clinically effective. To be effective, drugs must enter the plasma and move to disperse tissues in which mycobacterial cells reside, both intracellularly and extracellularly. Furthermore, mycobacterial cells residing in these environments are in different physiological states, and therefore likely to have associated differences in drug susceptibilities.1 It is clear that no single drug in our limited TB drug pool can effectively reach and kill all mycobacterial subpopulations. Discarding potential TB drugs based only on plasma indices or intracellular activity, as Muhammed Ameen and Drancourt2 propose, might be a relevant selection criterion if large numbers of clinically tested drugs with activity in vitro were available; however, this is currently not the case for TB drugs. Given this situation, we cannot afford to ignore active drug candidates that have been used clinically for other purposes. Ivermectin is approved for human use in many countries to treat onchocerciasis, lymphatic filariasis, strongyloidiasis and scabies. Muhammed Ameen and Drancourt2 emphasize that effective dosage levels for these conditions are unusually low and would not be effective for TB treatment. Ivermectin is typically administered once a month at a standard dose of 12 mg (maximal concentration in plasma of ∼50 ng/mL3). However, very little is known about the safety and tolerability of ivermectin at higher doses or after more frequent administration. A study in healthy volunteers showed that doses 10 times higher (120 mg) were safe and correlated with higher plasma concentrations (∼0.25 μg/mL).4 In fact, the more severe reactions observed in the treatment of onchocerciasis and lymphatic filariasis with ivermectin are most likely to be secondary immunological effects triggered by the death of the parasite. Thus, higher ivermectin dosages should be explored for TB treatment. Furthermore, we have recently demonstrated that synergistic drug combinations could allow the use of drugs that normally do not inhibit Mycobacterium tuberculosis at clinically relevant concentrations.5 Exploring the synergistic interactions of ivermectin with current anti-TB drugs could allow its use in combinatorial therapies for multidrug-resistant and extensively drug-resistant TB at dosages lower than the MICs of the individual drugs. In summary, our recent discovery showing direct in vitro anti-mycobacterial activity of the avermectins represents only a first step in the long, complex and challenging process of TB drug selection and development. Determining whether ivermectin, or other avermectins, could supplement the current TB armamentarium would require a highly interdisciplinary and comprehensive drug development approach. None to declare.

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