[e-drug] Anti-TB programme induced resistance in South Africa?

["Leela McCullough" <leela@healthnet.org>]

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
~~~

http://www.businessday.co.za/articles/national.aspx?ID=BD4A597348
Failure to test helps spread of deadly TB   
Tamar Kahn
 
CAPE TOWN ? Health authorities? failure to test tuberculosis (TB) patients for drug susceptibility appears to have inadvertently fuelled the spread of deadly drug-resistant strains of the disease in KwaZulu- Natal, scientists report in the Clinical Infectious Diseases journal. 

Their research puts pressure on the health department to improve its monitoring of TB drug resistance and consider testing more patients before treating them. 

Health authorities test only a handful of patients for drug resistance as testing is expensive and not widely available; guidelines say the tests should be administered only to patients who fail to respond to standard (first-line) treatment, or have been exposed to people infected with drug-resistant strains.

KwaZulu-Natal shot into the headlines last year when scientists announced that 53 patients in Tugela Ferry had succumbed to extremely drug resistant (XDR) TB, all but one of whom died. XDR-TB is resistant to almost all known drugs, and growing numbers of cases have since been detected in all nine provinces.

In KwaZulu-Natal for instance, 135 new cases of XDR-TB were identified last year, and another 105 cases in the six months to June.

Scientists have now tracked the evolution of drug resistance in the province between 1994 and 2002 by analysing samples of a highly transmissible strain called F15/LAM4/KZN circulating in the region.

They found that some patients were already resistant to treatment in 1995 when the World Health Organisation advised SA to implement a four-drug combination for treating first-time TB patients ? isoniazid, rifampicin, pyrazinamide and ethambutol. 

This meant that some patients were inadvertently getting a drug cocktail with only one or two effective ingredients, and so they rapidly developed resistance to these drugs too.

?I said to the health department then that it was a recipe for disaster,? said study co-author Willem Sturm, of the University of KwaZulu Natal?s Nelson Mandela School of Medicine.

?No one listened, and multi-drug resistance (MDR) strains spread.? He said that drug resistant strains were more easily spread between people than scientists initially thought. 

Six years later, the same mistake was made when SA introduced World Health Organisation-approved guidelines stipulating which medicines to use for treating MDR-TB, and the absence of routine susceptibility testing for second-line drugs this time led to the emergence of XDR-TB.

Patients got either ethambutol or cycloserine, in combination with pyrazinamide, ethionamide, kanamycin, and ciprofloxacin or ofloxacin. Unknown to health authorities, there was already resistance to both ethionamide and ethambutol, dating back in fact to 1997. The scientists traced kanamycin resistance back to 1999, and fluroquinolone resistance back to 2000.

The researchers also found resistance to streptomycin as far back as 1994. The drug is added to the standard four in first line treatment for patients who have interrupted and then recommenced treatment.

The health department?s TB head, Dr Lindiwe Mvusi, said routine susceptibility testing would be impractical. ?It?s just not going to be possible to test everyone,? she said.

Mvusi said the health department?s most recent drug resistance survey was conducted in 2001. A new study was to commence at the end of this year. 

~~~ http://www.journals.uchicago.edu/CID/journal/issues/v45n11/51016/brief/51016.abstract.html

Evolution of the Extensively Drug-Resistant F15/LAM4/KZN Strain of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa 

Manormoney Pillay and A. Willem Sturm 

Department of Medical Microbiology, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, South Africa 

Background.     Although several hot spots of multidrug-resistant
tuberculosis have been identified on the African continent, extensive drug resistance (XDR) has not been reported until recently, when a large number of XDR cases were identified in KwaZulu-Natal. The majority of the patients involved were infected with the same strain of Mycobacterium tuberculosis (F15/LAM4/KZN). We report this strain's development from multidrug resistance to XDR.

Methods.     We searched databases for studies performed during the
period 1994?2005 that involved the resistance patterns of isolates of M. tuberculosis with the F15/LAM4/KZN strain fingerprint. 

Results.     As early as 1994, the F15/LAM4/KZN strain was responsible
for a number of cases of multidrug-resistant tuberculosis, indicating the ability of the strain to cause cases of primary resistant tuberculosis. Some of the isolates were also resistant to streptomycin. From 1994 onwards, multidrug-resistant isolates with resistance to additional drugs were found, and the first XDR isolate was discovered in 2001. 

Conclusions.     Drug resistance to as many as 7 drugs developed in a
local strain of M. tuberculosis in slightly more than a decade. This coincided with the introduction of the directly observed therapy?based and directly observed therapy?plus?based tuberculosis-control programs. It is postulated that the introduction of these programs in the absence of susceptibility testing or drug resistance surveillance has been instrumental in the development of XDR in this highly transmissible F15/LAM4/KZN strain. The expanding pool of human immunodeficiency virus?infected, tuberculosis-susceptible individuals has likely contributed to this development. 
 
~~~ http://www.journals.uchicago.edu/CID/journal/issues/v45n11/52172/52172.html

Extensively Drug-Resistant Mycobacterium tuberculosis: Charles Darwin Would Understand 

Michael D. Iseman 

University of Colorado School of Medicine, Denver 
Received 10 August 2007; accepted 13 August 2007; electronically published 22 October 2007. 

Reprints or correspondence: Dr. Michael D. Iseman, University of Colorado School of Medicine, National Jewish Medical and Research Center, Denver, CO 80206 (isemanm@njc.org).

     In this issue of Clinical Infectious Diseases, Pillay and Sturm [1] document the evolution over a decade of an extensively drug-resistant strain of Mycobacterium tuberculosis (XDR-TB) in the KwaZulu-Natal region of South Africa. This is the latest iteration in the on-going struggle between the tubercle bacillus and Homo sapiens. 

     In the most profound single insight in the history of biology, Darwin's The Origin of Species laid out the simple tenets of evolution: diversity among progeny and factors in the environment that favored the survival and replication of certain of those progeny. This is the modern story of tuberculosis (TB). 

     Consumption was rampant in Europe and North America in the past 400 years, estimated to take the life of 1 in 5 adults in Europe at the turn of the 19th century. However, with the discovery of para-aminosalicylic acid (PAS; in 1944), streptomycin (in 1944), and isoniazid (in 1951), the long-sought cure seemed at hand. An early study by the British Medical Research Council found that the combination treatment with PAS and streptomycin was more effective than treatment with either agent alone. By use of the novel technology of in vitro drug susceptibility testing, it was observed that 2-drug therapy delayed or inhibited the appearance of drug-resistant strains of M. tuberculosis. 

     Extraordinary researchers, such as Canetti, Grosset, and Mitchison, demonstrated that resistance occurred in response to spontaneous but rare chromosomal mutations. The mutations were seen in the range of 1 mutation per 100,000-10,000,000 replications, depending on the drug or class, and the mutations were not linked (i.e., each mutation conferred resistance to a single drug or class). Such mutants did not become the dominant strain unless selected by exposure to antimicrobials. 

     These observations were consonant with the developing practice of 3-drug therapy with isoniazid, PAS, and streptomycin: mutants resistant to one of the drugs would be killed by the other agents. The imperative for multidrug therapy was greatest early in the course of therapy, especially in the context of cavitary disease, wherein the population of rapidly multiplying bacilli (and the likelihood of drug-resistance
mutations) was greatest. 

     As a result of the administration of inadequate regimens and/or patient nonadherence to therapy, treatment failures were seen early in the TB chemotherapy era. Resistance to the most important agent, isoniazid, was associated with high rates of treatment failure, chronic illness, and death. However, Middlebrook, among others, noted that the strains with high-level isoniazid resistance had lost catalase activity, grew slowly in vitro, and were far less virulent in the guinea pig model. Clinical observations and the epidemiology of drug-resistant diseases in the United States then indicated that there was very limited spread of these highly isoniazid-resistant strains of M. tuberculosis, suggesting reduced transmissibility and/or impaired virulence. 

     By stark contrast, epidemics of TB due to bacilli that were resistant to isoniazid and rifampin (i.e., multidrug-resistant TB
[MDR-TB]) appeared in the early 1990s in New York City, New York; Miami, Florida; Buenos Aires, Argentina; and elsewhere. These outbreaks clearly involved high transmissibility and virulence. In multiple sites, the primary MDR-TB strain was the Beijing strain, with "strain W" being dominant in New York City. For unclear reasons, these organisms bore the cost of acquired drug resistance with little or no loss of pathogenicity. 

     AIDS abetted these epidemics by providing large populations of persons who were exquisitely vulnerable to TB. Also, the practice of cohorting patients who were hospitalized frequently in this era (for opportunistic infections or other complications of HIV infection) fostered the wholesale transmission of MDR-TB. 

     The World Health Organization has worked arduously to expand and improve services for treatment of routine TB cases, implementing their Directly Observed Therapy, Short-Course (DOTS), program widely over the past decade. DOTS programs made therapy available to many additional patients during this period and have doubtlessly had a substantial, positive impact. It should be noted, however, that the "directly observed therapy" element of this model did not have the same implications elsewhere that it has had in the United States. DOTS programs in the United States emphasize supervised administration of all or the great majority of doses of anti-TB medications during the 6-month standard regimen. Owing to inadequate resources and/or skepticism about the need for use of such a model, actual oversight of treatment has been rare elsewhere. Furthermore, given the universal propensity of a certain portion of patients to not take their medications consistently, we may be sure that an unwanted by-product of the expanded treatment program was the generation of new cases of drug-resistant TB. That is not to be second-guess DOTS; if we never had treated TB, there would be no drug resistance. 

     In response to the increasing prevalence of MDR-TB throughout the globe, the World Health Organization, national public health programs, and nongovernmental organizations joined forces to make second-line medications, including the fluoroquinolones, more available and affordable. The World Health Organization Green Light Committee made a functional DOTS program a prerequisite for access to the discounted second-line drugs. 

     Given the widened use of the fluoroquinolones and other second-line medications, including the injectable agents, the appearance of XDR-TB was inevitable. Clinicians who treated patients with presumed MDR-TB did not have access to in vitro susceptibility test data to guide their regimen selections, and despite the admonition that such cases be given highest priority for DOTS, true supervision was understandably rare. 

     With XDR-TB, we are seeing the appearance of cases of TB that are essentially incurable. In a study of 205 patients treated for MDR-TB between during the period 1983-1998 at the National Jewish Medical and Research Center (Denver), the most important variables associated with favorable outcome were fluoroquinolone use and resectional surgery. In settings where comprehensive mycobacterial laboratory services, full access to all anti-TB drugs, pharmacokinetic monitoring, and sophisticated surgical support are not available-and where many patients have AIDS-we may anticipate dismal cure rates. 

     In roughly 55 years, we have squandered our precchemotherapy for these XDR-TB cases. Darwin, though, would understand. 

Suggested Reading List 

Canetti G. The J. Burns Amberson lecture: present aspects of bacterial resistance in tuberculosis. Am Rev Respir Dis 1965; 92:687-703. 

Chan ED, Laurel V, Strand MJ, et al. Treatment and outcome analysis of 205 patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2004; 169:1103-9. 

Han LL, Sloutsky A, Canales R, et al. Acquisition of drug resistance in multidrug-resistant Mycobacterium tuberculosis during directly observed empiric retreatment with standardized regimens. Int J Tuberc Lung Dis 2005; 9:818-21. 

Raviglione MC, Smith IM. XDR tuberculosis-implications for global public health. N Engl J Med 2007; 356:656-9. 

Samper S, Martin C. Spread of extensively drug-resistant tuberculosis. Emerg Infect Dis 2007; 13:647. 

Wines M. Virulent TB in South Africa may imperil millions without quick action, experts warn. The New York Times 28 January 2007:A9. 

Acknowledgments 

Potential conflicts of interest.     M.D.I.: no conflicts. 

Reference 
 1.  Pillay M, Sturm AW. Evolution of the extensively drug-resistant F15/LAM4/KXZN strain of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa. Clin Infect Dis 2007; 47:XXX-XXX (in this issue) 

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Sharon Davis
23 October 2007
Source: SciDev.Net 
http://www.scidev.net/News/index.cfm?fuseaction=readNews&itemid=4001&language=1

A study has found that the WHO's tuberculosis (TB) programme in South Africa inadvertently helped a strain of TB-causing bacteria develop additional drug resistance.

The study will be published in the December issue of Clinical Infectious Diseases.

Researchers from the University of KwaZulu-Natal's Nelson Mandela School of Medicine tracked the development of drug resistance in a strain of Mycobacterium tuberculosis over a 12-year period.

They found that by the time the WHO introduced their programme in South Africa in 2001 ­ using a second-line medication to combat multidrug-resistant strains of TB ­ at least one strain had already developed resistance to one or more of the second-line drugs.

But because the programme didn't conduct drug susceptibility tests, the new second-line medication was not only useless to TB patients infected with the resistant strain, but also led to the strain developing additional drug resistance. 

This is because when an M. tuberculosis strain is resistant to a drug, it survives and can subsequently evolve resistance to additional drugs. 

The strain eventually became extensively drug-resistant (XDR-TB), resistant to seven anti-TB drugs in total, including first-line and several second-line drugs. 

"The spread of a highly transmissible strain of drug-resistant TB has been facilitated by applying standard treatment regimes for susceptible and multidrug-resistant TB in the absence of drug resistance surveillance," said Willem Strum, one of the authors and dean of the University's Nelson Mandela School of Medicine, in a press release.

XDR-TB poses a grave public health threat, especially to populations with high rates of HIV where TB/HIV co-infection is common as a result of lowered immunity. The greatest concern is that XDR-TB leaves some patients virtually untreatable with currently available drugs. 

The same strain caused a 2006 outbreak of XDR-TB in South Africa amongst an HIV-positive population in the rural town of Tugela Ferry in KwaZulu-Natal. Fifty-two of 53 XDR-TB patients died within an average of 25 days. 

The study authors call for the increased use of drug resistance surveillance programmes to help prevent the development of drug-resistant TB. 

"Public health programmes for the treatment and control of infectious diseases need to be supported by drug resistance surveillance programmes," said Strum.

<http://www.journals.uchicago.edu/CID/journal/issues/v45n11/51016/51016.html>Link to full paper in Clinical Infectious Diseases

Reference: Clinical Infectious Diseases doi 10.1086/522987 (2007)
 
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