Research Article: Putting in harm to cure: Drug related adverse events do not affect outcome of patients receiving treatment for multidrug-resistant Tuberculosis. Experience from a tertiary hospital in Italy

Date Published: February 28, 2019

Publisher: Public Library of Science

Author(s): Gina Gualano, Paola Mencarini, Maria Musso, Silvia Mosti, Laura Santangelo, Silvia Murachelli, Angela Cannas, Antonino Di Caro, Assunta Navarra, Delia Goletti, Enrico Girardi, Fabrizio Palmieri, Giuseppe Vittorio De Socio.


Treatment of multi-drug resistant Tuberculosis (MDR-TB) is challenging because it mostly relies on drugs with lower efficacy and greater toxicity than those used for drug-susceptible TB.

Aim of the study was to describe the frequency and type of adverse drug reactions in a cohort of MDR-TB patients and their potential impact on treatment outcome.

We conducted a retrospective study in a cohort of MDR-TB patients enrolled at a tertiary referral hospital in Italy from January 2008 to December 2016. The records of patients were reviewed for epidemiological, clinical, microbiological and adverse drug reactions data.

Seventy-four MDR-TB patients (mean age 32 years, 58.1% males, 2 XDR, 12 pre-XDR TB) were extracted from the Institute data base and included in the retrospective study cohort in the evaluation period (January 2008—December 2016). Median length of treatment duration was 20 months (IQR 14–24). Treatment outcome was successful in 57 patients (77%; 51 cured, 6 treatment completed); one patient died and one failed (2.7% overall); 15 patients were lost to follow-up (20.3%). Sixty-six (89.2%) presented adverse drug reactions during the whole treatment period. Total number of adverse drug reactions registered was 409. Three hundred forty-six (84.6%) were classified as adverse events (AEs) and 63 (15.4%) were serious AEs (SAEs). One third of the total adverse drug reactions (134/409; 32.8%) was of gastrointestinal origin, followed by 47/409 (11.5%) ototoxic drug reactions, thirty-five (8.6%) regarded central nervous system and 33 (8.1%) affected the liver. All 63 SAEs required treatment suspension with 61 SAEs out of 63 (96.8%) occurring during the first six months of treatment. Factors associated with unsuccessful treatment outcome were smoking (p = 0.039), alcohol abuse (p = 0.005) and homeless condition (p = 0.044). Neither the number of antitubercular drugs used in different combinations nor the number of AEs showed significant impact on outcome. Patients who completed the treatment experienced a greater number of AEs and SAEs (p < 0.001) if compared to lost to follow-up patients. Our data demonstrate that, despite the high frequency of adverse drug reactions and long term therapy, the clinical management of MDR-TB patients in a referral center could reach successful treatment according to WHO target, by implementing active and systematic clinical and laboratory assessment to detect, report and manage suspected and confirmed adverse drug reactions.

Partial Text

Multidrug-Resistant Tuberculosis (MDR-TB), caused by M. tuberculosis strain resistant to both major drugs, isoniazid and rifampicin, remains a public health crisis and a health security threat [1]. Treatment of MDR-TB and extensively drug-resistant TB (XDR TB; MDR-TB with additional resistance to any fluoroquinolone, and to at least one of the three injectable second-line drugs amikacin, capreomycin or kanamycin) is challenging because it relies on drugs with lower efficacy and greater toxicity than those used for drug-susceptible TB (DS-TB) [2]. Treatment outcomes for MDR-TB and XDR TB are generally poor if compared to DS-TB [3]. In a systematic review conducted on 74 studies with 17,494 participants the proportion of treatment success in patients with MDR TB was 60% and only 26% in XDR-TB, with 17% of patients lost to follow-up globally [4]. Loss to follow-up is one of the main factors affecting unsuccessful outcome in MDR- and XDR-TB. Drug toxicity, long duration of treatment, and other social determinants have been associated with loss to follow-up [5]. Adverse drug reactions represent a potential obstacle to treatment completion and could negatively affect outcome [6]. Documenting, assessing and managing adverse drug events is important to achieve better patient compliance and improve treatment outcomes. Aim of the study was to describe frequency and type of adverse drug reactions in a cohort of MDR-TB patients and their potential impact on treatment outcome, especially lost to follow-up.

Data on 74 MDR-TB patients hospitalized and followed at OPD from January 2008 to December 2016 at “L. Spallanzani” Hospital for Infectious Diseases in Rome have been extracted from the local database of TB patients and anonymized. WHO definition was adopted to define patient characteristics at diagnosis [7]. Respiratory samples collected from these patients underwent species identification and evaluation of resistance to rifampicin and isoniazid using the molecular assay GenoType MTBDRplus (Hain Lifescience, Germany), that are applied when there is a risk of MDR-TB. Furthermore, cultures isolated from these samples were subjected to susceptibility testing to first and second-line anti-tuberculous drugs. Drug-susceptibility testing procedures included testing on solid media (proportion method in Lowenstein-Jensen medium) and liquid media (MGIT 960 systems; Becton Dickinson, Sparks, MD, USA).

A total of 74 MDR-TB patients were extracted from database and included in the retrospective study cohort in the period from January 2008 till December 2016.

We found that adverse drug reactions during MDR-TB treatment were common and they did not significantly affect outcome.




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