In vitro susceptibility testing and totally drug-resistant tuberculosis.

We find the article by MIGLIORI et al. [1], on extensively drug-resistant tuberculosis (XDR-TB), very informative and would like to commend them for the excellent meta-analysis. Without any doubt, XDR-TB is an extensive global problem; the use of the lower susceptibility breaking points that we recently suggested [2] mean that the burden of XDR-TB could be even higher. Although there are recent reports of ‘‘totally drug-resistant (TDR)’’ TB, the World Health Organization does not recognise this term [3]. There is already a social stigma attached to having TB in many parts of the world and a label of TDR poses further challenges for patients. Antibiotic susceptibility testing is ideal for all patients, and is even more of a requirement when a patient is not responding to the anti-TB therapy. Lessons from other infectious diseases suggest that an even better approach would be to record actual minimum inhibitory concentrations (MICs), but clearly these are difficult to perform for TB in many laboratories and need further standardisation. Management of TB always involves a combination therapy, whereas drug sensitivity is measured for a single drug and not for the combination of drugs used for the treatment. Therefore, there is a possibility that even though the bacteria is resistant to the drug in vitro, combination therapy may still work, as evidenced by the results of the present report [1], and another article by UDWADIA and VENDOTI [4]. This is because there could be a number of other factors beyond ‘‘resistance’’ or MIC that lead to the unfavourable response to the treatment. These include, but are not limited to, the interindividual differences in pharmacokinetics as well as genetic makeup of an individual [5]. While there is no quick measure to prevent the emergence of resistance, knowledge acquired from scientific research should be translated to develop new tools to improve patient care. We suggest that patients with suspected or confirmed XDR-TB should be subjected to therapeutic drug monitoring (TDM) to make sure that the desired drug concentration is achieved with the administration of the prescribed drug doses. For those drugs with a good therapeutic window, and for drugs without concentration driven toxicity, higher doses can then be administered. Such doses can also be customised to achieve concentrations above those that define drug resistance or above the MIC, a solution already applied to other bacterial infections. We recognise that TDM for treatment of TB is in its infancy, and is potentially costly in resource limited settings. Nevertheless, it is a logical solution for these resistance patterns that are clearly associated with high mortality, as shown by the analysis of MIGLIORI et al. [1]. Although drug susceptibility testing provides valuable information on the resistance pattern and remains an important tool to design therapeutic regimens, we should not give up by labelling patients as having ‘‘totally’’ drug-resistant TB, but instead continue with the XDR-TB label.