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163 Use of PA-824 in mice suggested synergism with moxifloxacin and pyrazinamide and potential for shortening treatment.164,165 Likewise, use of OPC-67683 with rifampicin and pyrazinamide in mice demonstrated TB treatment-shortening potential and considerable intracellular post-antibiotic effects.162 A randomized trial that compared delamanid with placebo used alongside a background MDR-TB treatment regimen showed that delamanid significantly improved 2-month sputum culture conversion from 29.6% to 41.9%/45.4%,166 with a substantially increased risk of asymptomatic QT prolongation as a side-effect.166 Without specific evidence-based guidelines on treatment of difficult MDR-TB/XDR-TB, we may perhaps adapt the latest WHO guidelines on programmatic management of MDR-TB in designing treatment regimens for these formidable diseases. On [http://www.selleckchem.com/products/Vorinostat-saha.html SAHA HDAC research buy] the basis of low-quality clinical evidence for non-XDR-TB, WHO has recommended the following principles.121 First, the intensive-phase treatment should include pyrazinamide in addition to at least four second-line anti-TB drugs likely to be effective. Although pyrazinamide may improve fluoroquinolone-based treatment of MDR-TB,122 its role in the treatment of difficult MDR-TB/XDR-TB may be substantially reduced by the high prevalence of pyrazinamide resistance in fluoroquinolone-resistant MDR-TB167 and XDR-TB.168 To balance treatment efficacy and toxicity, it appears prudent to identify pyrazinamide susceptibility with molecular assays whenever possible.116 Second, the four second-line drugs should include a fluoroquinolone, a SLID, a thioamide and cycloserine, which may be replaced by para-aminosalicylic acid if necessary. A rule of thumb is to include [https://en.wikipedia.org/wiki/GSK3B GSK3B] two core drugs with potent bactericidal activity plus two accompanying drugs. Third, the number of second-line drugs may be further increased in case of uncertainty about effectiveness but not for extensive disease per se. Thus, for the reasons given earlier, linezolid and high-dose isoniazid may be included [http://www.selleckchem.com/products/tariquidar.html Selleck Tariquidar] after carefully weighing tolerability and safety. Daily rather than intermittent scheduling is generally recommended in MDR-TB treatment.101 For patients at risk of otovestibular or renal toxicity, especially those aged ��60 years or with mild renal insufficiency (creatinine clearance 30�C60?mL/min), dosing frequency of SLID may be reduced to five times per week, which is generally considered to be effective,101 in the initial 2�C3 months and then thrice weekly.101 When renal dysfunction is significant (creatinine clearance