Emergence and Spread of Extensively and Totally Drug-Resistant Tuberculosis, South Africa

Marisa Klopper, Robin Mark Warren

, Cindy Hayes, Nicolaas Claudius Gey van Pittius, Elizabeth Maria Streicher, Borna Müller, Frederick Adriaan Sirgel, Mamisa Chabula-Nxiweni, Ebrahim Hoosain, Gerrit Coetzee, Paul David van Helden, Thomas Calldo Victor, and André Phillip Trollip

Author affiliations: Author affiliations: Stellenbosch University, Cape Town, South Africa (M. Klopper, R.M. Warren, N.C. Gey van Pittius, E.M. Streicher, B. Müller, F.A. Sirgel, P.D. van Helden, T.C. Victor, AP.. Trollip); National Health Laboratory Services, Port Elizabeth, South Africa (C. Hayes, G. Coetzee); Swiss Tropical and Public Health Institute, Basel, Switzerland (B. Müller); University of Basel, Basel (B. Müller); Nelson Mandela Metropolitan Municipality, Port Elizabeth (M. Chabula-Nxiweni); Human Sciences Research Council, Port Elizabeth (E. Hoosain)

Abstract

Factors driving the increase in drug-resistant tuberculosis (TB) in the Eastern Cape Province, South Africa, are not understood. A convenience sample of 309 drug-susceptible and 342 multidrug-resistant (MDR) TB isolates, collected July 2008–July 2009, were characterized by spoligotyping, DNA fingerprinting, insertion site mapping, and targeted DNA sequencing. Analysis of molecular-based data showed diverse genetic backgrounds among drug-sensitive and MDR TB sensu stricto isolates in contrast to restricted genetic backgrounds among pre–extensively drug-resistant (pre-XDR) TB and XDR TB isolates. Second-line drug resistance was significantly associated with the atypical Beijing genotype. DNA fingerprinting and sequencing demonstrated that the pre-XDR and XDR atypical Beijing isolates evolved from a common progenitor; 85% and 92%, respectively, were clustered, indicating transmission. Ninety-three percent of atypical XDR Beijing isolates had mutations that confer resistance to 10 anti-TB drugs, and some isolates also were resistant to para-aminosalicylic acid. These findings suggest the emergence of totally drug-resistant TB.

The emergence of drug-resistant tuberculosis (TB) is of major concern to TB control in South Africa. A countrywide survey in 2002 revealed that 1.8% of all new TB patients and 6.7% of TB patients who had undergone previous treatment had multidrug-resistant (MDR) TB (resistant to at least isoniazid and rifampin) (1). This finding translates to an estimated annual case load of 13,000 MDR TB cases, placing South Africa fourth among countries where MDR TB is highly prevalent (1). However, this number may be an underestimation; 2 recent studies (2,3) suggested that the proportion of MDR TB cases may be substantially higher than the World Health Organization (WHO) estimate (3). In addition, only 4,143 of the 9,070 patients (46%) who received a diagnosis of MDR TB in 2009 received treatment, possibly because of resource constraints, creating a situation in which control was bound to fail (4). This conclusion is supported by the diagnosis of 594 extensively drug- resistant (XDR) TB cases (MDR plus additional resistance to a fluoroquinolone and any second-line injectable drug) in that year (4). The cure rate of patients with drug-resistant TB is <50 a="" for="" href="http://wwwnc.cdc.gov/eid/article/19/3/12-0246_article.htm?s_cid=eid-gDev-email#r5" mdr="" tb="" those="" title="5" with="">5
), whereas culture conversion was observed in only 19% of XDR TB case-patients during the follow-up period, irrespective of HIV status (6). Most cases of MDR TB and XDR TB in South Africa have been detected in KwaZulu-Natal, Western Cape, and Eastern Cape Provinces (4). Statistics from the Eastern Cape showed the largest increase in the number of MDR TB cases, rising from 836 cases in 2006 to 1,858 cases in 2009 (2.2 fold increase) (4). The reason for this dramatic increase in MDR TB cases remains to be determined.
Molecular epidemiologic data from the neighboring Western Cape Province have demonstrated that MDR TB is spread by primary transmission (7–9), which accounts for nearly 80% of reported MDR TB cases (2). To date, only 1 molecular epidemiologic study has been reported for the Eastern Cape (10), and it showed that 50% of rifampin-resistant TB isolates (including MDR TB isolates) belonged to the Beijing genotype and that “atypical” Beijing strains were significantly overrepresented. These strains harbored rare mutations in the inhA gene promoter (G-17A) and rpoB gene (GAC→GTC nucleotide substitutions in codon 516), which have previously been associated with a high fitness cost (11). The authors demonstrated that the spread of these strains was facilitated by HIV co-infection, thereby raising concern for the spread of drug-resistant strains in vulnerable populations (10).
A recent epidemiologic study conducted in the Eastern Cape estimated that 75.6% of XDR TB cases with complete data were a result of ongoing transmission (12). Treatment outcomes were dismal; 58% of case-patients died within 1 year, and culture conversion was observed in only 8.4% of case-patients after 143 days of treatment (12), raising concern that these patients had an untreatable form of TB. This situation is similar to the Tugela Ferry outbreak in KwaZulu-Natal Province (13), which highlighted the need for improved basic control measures, including rapid diagnostics and infection control methods (14).
This study aimed to describe the Mycobacterium tuberculosis strain population structure among MDR TB and XDR TB case-patients in Eastern Cape Province, South Africa, in order to determine whether the epidemic was driven by acquisition or transmission of resistance and to describe the extent of resistance within these strains. These findings will inform TB control efforts to better implement measures to curb emergence or the spread of drug-resistance.