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Safety of high-dose amikacin in the first week of all-oral rifampicin-resistant tuberculosis treatment for the prevention of acquired resistance

J Snobre(1,2) J Gasana(3) B K.M. Jacobs(1) I C Martin(1) F Hakizayezu(3) L Rigouts(1) N Herssens(1) J B Ntihumbya(4) A Van Deun(1) D Affolabi(5) C S Merle(6) A Kilibazayire(4) E de Viron(1) D Runyambo(3) C Ndayishimiye(4) C M Muvunyi(3) M G G Sturkenboom(7) P Migambi(3) T Decroo(1) Y Mucyo(3) J C S Ngabonziza(3) B de Jong(1)

1:Institute of Tropical Medicine Antwerpen; 2:Vrije Universiteit Brussel (VUB); 3:Rwanda Biomedical Centre, Kigali; 4:Kabutare District Hospital, Kabutare, Rwanda; 5:Centre National Hospitalier Universitaire de Pneumo-Phtisiologie de Cotonou, Cotonou, Benin; 6:The Special Programme for Research & Training in Tropical Diseases (TDR) World Health Organization, Geneva, Switzerland; 7:University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands

Effective strategies against rifampicin-resistant tuberculosis (RR-TB) should also prevent resistance. Resistance to bedaquiline (BDQ), a central drug for RR-TB treatment, is emerging, possibly due to the slow onset of BDQ's bactericidal action. We evaluated the safety of two injections of high-dose AMK co-administred with lidocaine to strengthen the first week of treatment.

For this purpose, in a single-arm phase-2 clinical trial, 20 RR-TB patients received two doses of 30mg/kg of intramuscular AMK on the first and fourth day of treatment. The primary endpoint is any grade 3-4 adverse event during the first 2 weeks of treatment related to the use of AMK. Secondary safety endpoints included assessments of ototoxicity and nephrotoxicity, other adverse events and post-injection pain using the Wong-Baker FACES Pain Rating Scale (0-10).

In our study, no grade 3-4 adverse events were observed (95% CI 0-0.139, p0.049). Ototoxicity and nephrotoxicity assessments did not reveal adverse effects. Pain assessment post-AMK injections with lidocaine revealed minimal discomfort, with immediate post-injection pain on day 1 showing a median score of 0 and an interquartile range (IQR) of 0.25 (range 0-5) while subsequent evaluations indicated negligible pain (median 0, IQR 0, range 0-2). As expected, AMK levels in serum were undetectable before the second dose.

In conclusion, the intervention involving two high doses of AMK in the first week of treatment was safe in our small cohort. Post-injection pain was minimal with lidocaine. These safety data will inform a multi-country study evaluating effectiveness to prevent acquired resistance.

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