A recently published report of tuberculosis strains resistant to all tested first- and second-line anti-TB drugs in Mumbai has garnered much attention in the media. What has actually been reported: Is this a new form of TB? What is the significance for global TB control?
The correspondence in Clinical Infectious Diseases describes four adults with M. tuberculosis isolates resistant to all tested first- and second-line drugs. All four patients had been previously treated with first-line drugs and for at least 12 months with one or more second-line agent. The timing of any specific diagnosis of MDR-TB or XDR-TB and the relation to the treatment provided in the four cases is not made clear. Drug susceptibility testing (DST) was performed for the following drugs: isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, amikacin, kanamycin, capreomycin, moxifloxacin, ofloxacin, para-aminosalicylate (PAS), and ethionamide. Genotypic analysis (with the Genotype MTBDRplus and MTBDRsl assays) gave supportive evidence of mutations conferring resistance to rifampicin (rpoB), isoniazid (katG/inhA), fluoroquinolones (gyrA), and injectables (rrs). Interestingly, there is no mention of embB mutations (which can be detected by the MTBDRsl assay) for any of the four patients, although the assay is known to be less reliable in detecting ethambutol resistance.
Is this a novel finding?
The simple answer is no. There have been previous reports of M. tuberculosis strains resistant to all tested first- and second-line drugs. Terms used previously include 'extremely drug-resistant TB (XXDR-TB)', 'super extensively drug-resistant TB', and the term used in this report, 'totally drug-resistant TB'. In 2007, Migliori et al. reported XDR-TB cases from Italy with additional phenotypic resistance to PAS and ethionamide, i.e. the same pattern as the isolates in the Mumbai report. In 2009 Velayati et al. reported 15 patients with phenotypic resistance to all the tested first- and second-line agents (this included DST for cycloserine which was not performed for the Mumbai cases). Since the publication of this Indian report many TB physicians have argued that similar cases have been seen in their practice, usually in XDR-TB patients who fail treatment. It should be noted that the term 'totally drug-resistant TB has not been recognised by the WHO for reasons outlined here.
So why so much attention?
The fact that this report originates from India is clearly important. India, with 1.5 million TB cases in 2009, accounts for about a quarter of all TB cases worldwide and is estimated to have a similar proportion of global MDR-TB cases. There is a huge gap between estimated MDR-TB cases and notified cases (only 2.3% of estimated cases were notified in 2009). There is a huge shortage in laboratory capacity for culture and drug resistance testing (one lab per 50 million population) so access to diagnosis and treatment of drug-resistant TB is extremely limited. Budgets for MDR-TB are inadequate and it is concerning to note that the Global Fund is the main source of funding for the MDR-TB budget. The latest WHO MDR/XDR-TB progress report highlights significant expansion of laboratory capacity for diagnosis of drug-resistant TB (see p13 of report) yet it is clear that huge challenges exist in India. Seen in this context, it is not surprising that this report has been used to stress the dangers of inadequate attention to drug-resistant TB.
Who is to blame for these drug-resistant cases?
The authors of the report point the finger of blame on private practitioners who provided treatment to the four cases. It would seem that private doctors are easy scapegoats but surely they are not the main source of the problem. The patients described in the report presumably sought care in the private sector because they had limited or no access to diagnosis or treatment in the public health system. There is a need for significant scale-up of diagnostic and treatment services for drug-resistant TB worldwide and simultaneous investment in research and development to generate better tools with which to manage the disease.
What is the relevance for global TB control?
TB is a global disease and drug resistant strains emerge in all settings. XDR-TB has been reported from 69 countries and so the potential exists for the emergence of cases similar to those reported from India. Drug-resistant TB also spreads internationally, as highlighted recently in a paper from our colleague Graham Cooke at Imperial College, London. In this report, MDR-TB was diagnosed in London in a South African immigrant and both the patient and the isolate could be linked to the outbreak of drug-resistant TB centred on Tugela Ferry in KwaZulu-Natal, South Africa. This emphasises that drug-resistant TB must not be seen as a problem constrained to certain countries, but rather as a broader challenge for global health.
References and links
Udwadia ZF et al. Totally drug-resistant tuberculosis in India. Clin Infect Dis 2011 Dec 21 [Epub ahead of print]
Genotypic analysis with the Genotype MTBDRplus and MTBDRsl assays.
Migliori et al. reported XDR-TB cases from Italy.
Velayati et al. reported XDR-TB cases from Iran .
The latest WHO MDR/XDR-TB progress report.
Cooke and colleagues. International Spread of MDR TB from Tugela Ferry, South Africa. EID, volume 17, number 11 (2011).