E-DRUG: Anti-TB programme induced resistance in South Africa?
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[A very important discussion on TB drug resistance! Crossposted partially from DRUGINFO and other sources. The comments are by Andy Gray. WB]
The recent paper in CID by Pillay and Sturm has really set the cat among the pigeons - is it possible that following WHO guidelines on standard TB regimens, without instituting a deliberate surveillance system for resistance to those standard drugs, helped drive development of MDR and eventually XDR strains in KZN, and perhaps the whole of SA? The full paper is available free at http://www.journals.uchicago.edu/CID/journal/issues/v45n11/51016/51016.html
(or in PDF at http://www.journals.uchicago.edu/CID/journal/issues/v45n11/51016/51016.web.pdf).
The full text is difficult to convey due to the large numbers of figures and tables. The commentary in the same issue is below.
Here's the gist of the argument from the original paper:
"A general observation in antibacterial therapy is that treatment with fixed combinations of drugs will lead to infections with organisms that are resistant to that combination. This was thought not to be applicable to M. tuberculosis for 2 reasons: (1) combination therapy would prevent in vivo survival of mutants that are resistant to one drug, and the chance of mutations leading to resistance to 2 drugs in the same cell is extremely small; and (2) the loss of fitness of drug-resistant strains limits their transmission [14, 15]. From this it follows that focussing on optimization of the TB-control programs for drug-susceptible TB will prevent resistance to spread. If the vast majority of patients fully adhere to their treatment regimens, no resistance will develop, and drug-resistant strains that develop in the small minority of persons who are not compliant will not spread.
However, this policy ignores the observations of spreading MDR strains such as the F15/LAM4/KZN strain (table 1). This means that, in the absence of susceptibility testing, a growing proportion of patients started receiving a regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol while infected with an MDR strain. MDR isolates of the F15/LAM4/KZN strain that are resistant to ethambutol were found already in 1995 (figure 1). Pyrazinamide susceptibility has not been tested regularly. However, resistance in a small percentage of isolates was found in a pilot study performed in our laboratory in 1994. Therefore, in the absence of susceptibility test results at the commencement of treatment, patients have been treated unintentionally with 1 or 2 active drugs only. This not only resulted in treatment failures, but also in further selection of drug-resistant strains. Failures are usually only recognized at 3 months of treatment. The process of culture and susceptibility testing that follows takes another 2 months, during which patients usually continue to receive the standard regimen.
South Africa adopted the directly observed therapy-plus strategy for identified MDR cases in 2001. This strategy did not include drug susceptibility testing for the second-line drugs. Depending on the susceptibility to ethambutol, patients commenced blinded treatment with either ethambutol or cycloserine, in combination with pyrazinamide, ethionamide, kanamycin, and ciprofloxacin or ofloxacin (depending on availability). Figure 1 shows that ethionamide resistance was already present in the MDR F15/LAM4/KZN strain in 1997, always in combination with ethambutol resistance. Kanamycin resistance was found in 1999, and fluoroquinolone resistance was found 1 year later. Cycloserine resistance is not reported, because the test for such resistance, like the test for pyrazinamide resistance, is associated with technical difficulties.
The first XDR F15/LAM4/KZN isolate was identified in 2001. This could have resulted in clonal spread of this particular isolate. However, it is obvious that, when the directly observed therapy-plus strategy was implemented in 2001, a proportion of patients again started receiving regimens that contained too few effective drugs. This has likely contributed to the development of XDR TB in different parts of the province, as indicated by its development into a family of strains (figure 2) and the difference in susceptibility between the 2001 XDR isolate and the isolates from Tugela Ferry (figure 1).
Another important observation regards to streptomycin resistance. The South African TB-control program uses streptomycin as a fifth drug in its re-treatment regimen. This is applied in cases in which patients interrupt their treatment. Figure 1 shows that one of the MDR variants of the F15/LAM4/KZN strain was already resistant to streptomycin in 1994. It is that arm out of which the XDR strain developed. It is tempting to postulate that the addition of streptomycin to the standard 4-drug regimen for patients who required re-treatment has assisted in the selection and spread of organisms from the isoniazid-rifamycin-streptomycin-resistant variant.
Although capreomycin had never been used in South Africa, resistance had been found in the F15/LAM4/KZN strain. This might have resulted from the use of aminoglycosides with which capreomycin shows some cross-resistance. Because capreomycin susceptibility testing is not routinely performed, it is presently unknown whether there are F15/LAM4/KZN variant strains that are resistant to that drug in any combination. This is now under investigation.
Although blinded, standardized treatment allowed for selection of increasingly resistant organisms, this happened in the background of an expanding epidemic of HIV infection. As a result, the number of immunocompromised individuals-and, with that, the number of those with increased susceptibility to M. tuberculosis-increased. As a result, the pool of patients in whom the F15/LAM4/KZN strain could spread increased as well.
The prominent presence of the F15/LAM4/KZN strain in patients with MDR-TB from 1994 onwards indicates that this strain is one of those that are more effectively transmitted than are other strains. However, another factor that undoubtedly has contributed to this effective transmission is the selective pressure associated with standardized treatment.
In conclusion, as with other bacteria, development of resistance in M. tuberculosis results from selection of resistant variants during treatment of patients. The increased pool of patients with HIV-associated immunocompromise in the population aided in this development. Empirical treatment, as applied in TB-control programs, needs to be supported by drug-resistance surveillance programs."
The real question now is how to respond - Iseman points out that, in many settings, "actual oversight of treatment has been rare" - is that true of SA? Certainly, claimed expansion of DOTS coverage over the past few years has not been associated with any improvement in cure rates. If routine susceptibility testing in every patient is impractical, what would the minimum level of targeted surveillance be, in order to inform rational selection? Lastly, what are the implications for other infectious diseases now managed with standard treatment guidelines?
regards
Andy