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New developments in tuberculosis diagnosis and treatment

Cara M. Gill, Lorraine Dolan, Laura M. Piggott, Anne Marie McLaughlin
Breathe 2022 18: 210149; DOI: 10.1183/20734735.0149-2021
Cara M. Gill
Dept of Respiratory Medicine, Saint James's Hospital, Dublin, Ireland
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  • ORCID record for Cara M. Gill
  • For correspondence: cagill@tcd.ie
Lorraine Dolan
Dept of Respiratory Medicine, Saint James's Hospital, Dublin, Ireland
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Laura M. Piggott
Dept of Respiratory Medicine, Saint James's Hospital, Dublin, Ireland
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Anne Marie McLaughlin
Dept of Respiratory Medicine, Saint James's Hospital, Dublin, Ireland
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    FIGURE 1

    New anti-tuberculous drugs currently in development. Data from [104].

Tables

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  • TABLE 1

    Current medications in use for TB treatment and their notable side-effects

    DrugNotable side-effects
    Rifampicin (RIF)Hepatotoxicity, nausea, dyspepsia, abdominal pain, rash, CYP450 interactions
    Isoniazid (INH)Hepatotoxicity, peripheral neuropathy#, optic neuritis, CYP450 interactions
    Pyrazinamide (PZA)GI disturbance, hepatotoxicity, gout
    Ethambutol (EMB)Optic neuropathy
    Levofloxacin (LFX)/Moxifloxacin (MFX)QT prolongation, tendonitis, hypoglycaemia, psychiatric disturbance
    Bedaquiline (BDQ)QT prolongation, CYP450 interactions
    Linezolid (LZD)Myelosuppression, dysglycaemia, peripheral neuropathy#, optic neuropathy
    Clofazimine (CFZ)Hepatotoxicity, GI disturbance, neurological disturbance, QT prolongation, altered skin pigmentation
    Cycloserine (CYS)Psychiatric disturbance, peripheral neuropathy
    Delamanid (DLM)QT prolongation, CYP450 interactions
    Aminoglycosides (AMK,CAP, STR)Nephrotoxicity, ototoxicity
    Ethionamide (ETH)/Prothionamide (Pro)Psychiatric disturbance, peripheral neuropathy, hepatotoxicity, hypothyroidism, dysglycaemia
    p-Aminosalicylic acid (PAS)Hepatotoxicity, dysglycaemia, hypothyroidism
    Amoxicillin–Clavulanate¶ with Meropenem or Imipenem–CilastatinDiarrhoea, candidiasis

    #: given with pyridoxine prophylaxis to ameliorate risk; ¶: beta-lactams must be given with Clavulanate for success in TB treatment; however, the only available preparations include Amoxicillin. Information from [50].

    • TABLE 2

      Current ATS/CDC/ERS/IDSA consolidated guidelines on treating drug-resistant TB

      RR-TB
       As per MDR-TB
      INH-resistant TB
       RIF+PZA+ETM+FLQ for 6 months (can discontinue PZA after 2 months; FLQ only required in patients with extensive disease, i.e. cavitary or bilateral infiltrates)
      MDR-TB
       First lineLevofloxacin or Moxifloxacin with all 4 of: Bedaquiline + Linezolid + Clofazimine# + Cycloserine#
       Second lineConsider Delamanid¶2 or Pyrazinamide¶3 or Ethambutol¶1 or Amikacin or Streptomycin¶5
       Third lineConsider ETH¶6 or Prothionamide or Imipenem-Cilastatin/Clavulante or Meropenem/Clavulanate¶4 or p-Aminosalicylic Acid¶7 or High Dose Isoniazid

      ATS: American Thoracic Society; CDC: US Centers For Disease Control And Prevention; ERS: European Respiratory Society; IDSA: Infectious Diseases Society of America. #: in contrast, the WHO suggests only one of these drugs are required, comprising a 4-drug regimen (see text for full details); ¶: superscript numbers refer to the order in which the WHO suggests drugs be incorporated into regimes. Information from [50].

      • TABLE 3

        New drug regimens under evaluation

        TrialDrugsPurposeStatusTrial ID#
        ReDEFINeRIF (HD)Assess high-dose RIF on treatment outcomes and duration in TB meningitisPhase IINCT02169882
        TB-PRACTECALBDQ, Pa, LZD, MFX, CFZAssess 6 months of regimen for MDR-TBPhase III (data Analysis)NCT02589782
        Stream stage 2CFZ, ETM, MFX, PZA, INH, Kan, Pro, BDQ, LFXVarying combinations at differing durations for RR-TB and MDR-TBPhase IIINCT02409290
        SimpliciTBBDQ, Pa, MFX, PZA4 months for DS-TB
        6 months for MDR-TB
        Phase IIINCT03338621
        Truncate-TBBDQ, RFP, LZD, MFX2 months for DS TBPhase IIINCT03474198
        TBTC study 31RFP, INH, ETM, PZA, MFXEvaluate 4 months treatment for DS-TBPhase IIINCT02410772
        endTBBDQ, DLM, LZD, MFX, PZA, LFX, CFZ47 weeks treatment with combinations of 5 drugs for MDR-TBPhase IIINCT02754765
        RIFASHORTRIF (HD)Evaluate 4 months of RIF (HD)Phase IIINCT02581527
        NEXT trialLZD, BDQ, PZA, ETH or INH (HD)Evaluate efficacy of ETH or INH (HD) with 6–9 months treatment for MDR-TBPhase III (data Analysis)NCT02454205
        ZeNixPa, LZD, BDQ, PlEvaluate 26 weeks treatmentPhase IIINCT03086486
        DELIBERATEBDQ, DLMEvaluate safety in MDR-TBPhase IIINCT02583048
        BEAT TBBDQ, DLM, LZD, LFX, CFZEvaluate safety and efficacy of 6 months treatment for RR-TBPhase IIINCT04062201

        HD: high dose; RIF: rifampicin; INH: isoniazid; RFP: rifapentine; ETM: ethambutol; PZA: pyrazinamide; MFX: moxifloxacin; LFX: levofloxacin; LZD: linezolid; ETH: ethionamide; BDQ: bedaquiline; DLM: delamanid; Pa: pretomanid; CFZ: clofazamine; Kan: kanamycin; Pro: prothionamide; Pl: Placebo. #: ClinicalTrials.gov identifier. Information from [1, 104].

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        New developments in tuberculosis diagnosis and treatment
        Cara M. Gill, Lorraine Dolan, Laura M. Piggott, Anne Marie McLaughlin
        Breathe Mar 2022, 18 (1) 210149; DOI: 10.1183/20734735.0149-2021

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        New developments in tuberculosis diagnosis and treatment
        Cara M. Gill, Lorraine Dolan, Laura M. Piggott, Anne Marie McLaughlin
        Breathe Mar 2022, 18 (1) 210149; DOI: 10.1183/20734735.0149-2021
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