Introduction: Tuberculosis (TB), a common condition worldwide, is still among the main infectious diseases with high mortality rates, both in adults and infants. Drug-resistant tuberculosis (DR-TB) drugs, revised by the World Health Organization (WHO) in 2018, are a prolonged and complex therapy associated with many adverse drug effects (ADEs). Aim: To systematically review the ADEs of second-line anti-TB drugs reported in multicentric studies published after the latest WHO guidelines, compared with those from clinical trials published before 2018. Material and methods: A PubMed search, using keywords (TB OR DR-TB) AND (adverse effects) AND “second-line anti-TB drugs”, resulted in 56 studies. Only two studies, published after the last update of WHO guidelines in 2018, reported ADEs. Results: A total of 223 participants were included in the two selected studies. The use of multidrug regimens has been associated with an increased incidence of ADEs: 42 ADEs were recorded in 30 patients (26.3%) in the first study, while all patients had at least one ADE that occurred or worsened during treatment; and 19 (17%) had severe ADEs in the second study. However, both studies had a good favourable outcome rate (90% and 79.8%, respectively). Gastrointestinal disturbances, hepatotoxicity, headache and dizziness are the most common ADEs induced by a majority of second-line DR-TB treatments. A special attention should be given in the case of association of drugs determining QT interval (QT) prolongation on electrocardiogram, or psychiatric disorders. Conclusions: Proper strategies about ADE management have to be planned for timely detection of the possible ADEs that can be induced by second-line anti-TB therapy.

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