Marisa Vescovo

Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and thioridazine

OBJECTIVESnCurrent drug choices to treat extensively drug-resistant (XDR) tuberculosis (TB) are scarce; therefore, information on the safety, tolerability and efficacy of alternative regimens is of utmost importance. The aim of this study was to describe the management, drug adverse effects and outcome of alternative combined treatment in a series of XDR-TB patients.nnnPATIENTS AND METHODSnA retrospective study was performed on 17 non-AIDS, pulmonary adult patients with XDR-TB admitted to a referral treatment centre for infectious diseases in Buenos Aires from 2002 through 2008. Drug susceptibility testing was performed under regular proficiency testing and confirmed at the national TB reference laboratory.nnnRESULTSnLinezolid was included in the drug regimens of all patients; moxifloxacin and/or thioridazine were included in the regimens of 14 patients. Clinically tractable drug adverse effects were observed in nine patients, the most frequent being haematological disorders and neurotoxicity. In two patients, thioridazine was discontinued. Negative culture conversion was achieved in 15 patients, 11 completed treatment meeting cure criteria, 4 are still on follow-up with good evolution, 1 defaulted treatment and 1 was lost to follow-up.nnnCONCLUSIONSnThe combination of linezolid, moxifloxacin and thioridazine is recommended for compassionate use in specialized centres with expertise in the management of XDR-TB.

Patients with Multidrug-Resistant Tuberculosis Display Impaired Th1 Responses and Enhanced Regulatory T-Cell Levels in Response to an Outbreak of Multidrug-Resistant Mycobacterium tuberculosis M and Ra Strains

ABSTRACT In Argentina, multidrug-resistant tuberculosis (MDR-TB) outbreaks emerged among hospitalized patients with AIDS in the early 1990s and thereafter disseminated to the immunocompetent community. Epidemiological, bacteriological, and genotyping data allowed the identification of certain MDR Mycobacterium tuberculosis outbreak strains, such as the so-called strain M of the Haarlem lineage and strain Ra of the Latin America and Mediterranean lineage. In the current study, we evaluated the immune responses induced by strains M and Ra in peripheral blood mononuclear cells from patients with active MDR-TB or fully drug-susceptible tuberculosis (S-TB) and in purified protein derivative-positive healthy controls (group N). Our results demonstrated that strain M was a weaker gamma interferon (IFN-γ) inducer than H37Rv for group N. Strain M induced the highest interleukin-4 expression in CD4+ and CD8+ T cells from MDR- and S-TB patients, along with the lowest cytotoxic T-lymphocyte (CTL) activity in patients and controls. Hence, impairment of CTL activity is a hallmark of strain M and could be an evasion mechanism employed by this strain to avoid the killing of macrophages by M-specific CTL effectors. In addition, MDR-TB patients had an increased proportion of circulating regulatory T cells (Treg cells), and these cells were further expanded upon in vitro M. tuberculosis stimulation. Experimental Treg cell depletion increased IFN-γ expression and CTL activity in TB patients, with M- and Ra-induced CTL responses remaining low in MDR-TB patients. Altogether, these results suggest that immunity to MDR strains might depend upon a balance between the individual host response and the ability of different M. tuberculosis genotypes to drive Th1 or Th2 profiles.

Primera serie de pacientes con TB-XDR y pre-XDR tratados con esquemas que incluyeron meropenem-clavulanato en Argentina

XDR (extensively drug-resistant) and pre-XDR tuberculosis (TB) seriously compromise prognosis and treatment possibilities, and inevitably require the use of group V drugs (World Health Organization). The progress of all patients with XDR and pre-XDR TB seen in a specialized unit during 2012 and 2013 and treated with regimens that included at least 6 months of meropenem-clavulanate (MPC), capreomycin, moxifloxacin, linezolid, clofazimine, high-dose isoniazid, PAS, and bedaquiline in 1 case, were retrospectively analysed. Ten patients were treated, 9 with an extensive pattern of resistance to at least 6 drugs, and 1 because of adverse reactions and drug interactions leading to a similar situation. Eight of the 10 patients treated achieved bacteriological sputum conversion (2 consecutive negative monthly cultures) over a period of 2-7 months, while 2 died. No adverse reactions attributable to prolonged administration of MPC were observed.

Mycobacterium tuberculosis multi‐drug‐resistant strain M induces IL‐17+IFNγ– CD4+ T cell expansion through an IL‐23 and TGF‐β‐dependent mechanism in patients with MDR‐TB tuberculosis

We have reported previously that T cells from patients with multi‐drug‐resistant tuberculosis (MDR‐TB) express high levels of interleukin (IL)‐17 in response to the MDR strain M (Haarlem family) of Mycobacterium tuberculosis (M. tuberculosis). Herein, we explore the pathways involved in the induction of Th17 cells in MDR‐TB patients and healthy tuberculin reactors [purified protein derivative healthy donors (PPD+ HD)] by the M strain and the laboratory strain H37Rv. Our results show that IL‐1β and IL‐6 are crucial for the H37Rv and M‐induced expansion of IL‐17+interferon (IFN)‐γ– and IL‐17+IFN‐γ+ in CD4+ T cells from MDR‐TB and PPD+ HD. IL‐23 plays an ambiguous role in T helper type 1 (Th1) and Th17 profiles: alone, IL‐23 is responsible for M. tuberculosis‐induced IL‐17 and IFN‐γ expression in CD4+ T cells from PPD+ HD whereas, together with transforming growth factor (TGF‐β), it promotes IL‐17+IFN‐γ– expansion in MDR‐TB. In fact, spontaneous and M. tuberculosis‐induced TGF‐β secretion is increased in cells from MDR‐TB, the M strain being the highest inducer. Interestingly, Toll‐like receptor (TLR)‐2 signalling mediates the expansion of IL‐17+IFN‐γ– cells and the enhancement of latency‐associated protein (LAP) expression in CD14+ and CD4+ T cells from MDR‐TB, which suggests that the M strain promotes IL‐17+IFN‐γ– T cells through a strong TLR‐2‐dependent TGF‐β production by antigen‐presenting cells and CD4+ T cells. Finally, CD4+ T cells from MDR‐TB patients infected with MDR Haarlem strains show higher IL‐17+IFN‐γ– and lower IL‐17+IFN‐γ+ levels than LAM‐infected patients. The present findings deepen our understanding of the role of IL‐17 in MDR‐TB and highlight the influence of the genetic background of the infecting M. tuberculosis strain on the ex‐vivo Th17 response.