Background The “fitness” of an infectious pathogen is defined as the ability of the pathogen to survive, reproduce, be transmitted, and cause disease. The fitness of multidrug-resistant tuberculosis (MDRTB) relative to drug-susceptible tuberculosis is cited as one of the most important determinants of MDRTB spread and epidemic size. To estimate the relative fitness of drug-resistant tuberculosis cases, we compared the incidence of tuberculosis disease among the household contacts of MDRTB index patients to that among the contacts of drug-susceptible index patients. Methods and Findings This 3-y (2010–2013) prospective cohort household follow-up study in South Lima and Callao, Peru, measured the incidence of tuberculosis disease among 1,055 household contacts of 213 MDRTB index cases and 2,362 household contacts of 487 drug-susceptible index cases. A total of 35/1,055 (3.3%) household contacts of 213 MDRTB index cases developed tuberculosis disease, while 114/2,362 (4.8%) household contacts of 487 drug-susceptible index patients developed tuberculosis disease. The total follow-up time for drug-susceptible tuberculosis contacts was 2,620 person-years, while the total follow-up time for MDRTB contacts was 1,425 person-years. Using multivariate Cox regression to adjust for confounding variables including contact HIV status, contact age, socio-economic status, and index case sputum smear grade, the hazard ratio for tuberculosis disease among MDRTB household contacts was found to be half that for drug-susceptible contacts (hazard ratio 0.56, 95% CI 0.34–0.90, p = 0.017). The inference of transmission in this study was limited by the lack of genotyping data for household contacts. Capturing incident disease only among household contacts may also limit the extrapolation of these findings to the community setting. Conclusions The low relative fitness of MDRTB estimated by this study improves the chances of controlling drug-resistant tuberculosis. However, fitter multidrug-resistant strains that emerge over time may make this increasingly difficult.
References
[1]
Cohen T, Sommers B, Murray M. The effect of drug resistance on the fitness of Mycobacterium tuberculosis. Lancet Infect Dis. 2003;3:13–21. pmid:12505028 doi: 10.1016/s1473-3099(03)00483-3
Cohen T, Murray M. Modeling epidemics of multidrug-resistant M. tuberculosis of heterogeneous fitness. Nat Med. 2004;10:1117–1121. pmid:15378056 doi: 10.1038/nm1110
[4]
Dye C, Espinal MA. Will tuberculosis become resistant to all antibiotics? Proc Biol Sci. 2001;268:45–52. pmid:12123297 doi: 10.1098/rspb.2000.1328
[5]
Dye C, Williams BG, Espinal MA, Raviglione MC. Erasing the world’s slow stain: strategies to beat multidrug-resistant tuberculosis. Science. 2002;295:2042–2046. pmid:11896268 doi: 10.1126/science.1063814
[6]
Mitchison DA. Tubercle bacilli resistant to isoniazid; virulence and response to treatment with isoniazid in guinea-pigs. BMJ. 1954;1:128–130. pmid:13106496 doi: 10.1136/bmj.1.4854.128
[7]
Middlebrook G, Cohn ML. Some observations on the pathogenicity of isoniazid-resistant variants of tubercle bacilli. Science. 1953;118:297–299. pmid:13089681 doi: 10.1126/science.118.3063.297
[8]
García-García ML, Ponce de León A, Jiménez-Corona ME, Jiménez-Corona A, Palacios-Martínez M, Balandrano-Campos S, et al. Clinical consequences and transmissibility of drug-resistant tuberculosis in southern Mexico. Arch Intern Med. 2000;160:630–636. pmid:10724048 doi: 10.1001/archinte.160.5.630
[9]
Van Soolingen D, Borgdorff MW, de Haas PE, Sebek MM, Veen J, Dessens M, et al. Molecular epidemiology of tuberculosis in the Netherlands: a nationwide study from 1993 through 1997. J Infect Dis. 1999;180:726–736. doi: 10.1086/314930. pmid:10438361
[10]
Burgos M, DeRiemer K, Small PM, Hopewell PC, Daley CL. Effect of drug resistance on the generation of secondary cases of tuberculosis. J Infect Dis. 2003;188:1878–1884. doi: 10.1086/379895. pmid:14673768
[11]
Gagneux S. Fitness cost of drug resistance in Mycobacterium tuberculosis. Clin Microbiol Infect. 2009;15 (Suppl 1):66–68. doi: 10.1111/j.1469-0691.2008.02685.x. pmid:19220360
[12]
Gagneux S, Long CD, Small PM, Van T, Schoolnik GK, Bohannan BJ. The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science. 2006;312:1944–1946. pmid:16809538 doi: 10.1126/science.1124410
[13]
Davies AP, Billington OJ, Bannister BA, Weir WR, McHugh TD, Gillespie SH. Comparison of fitness of two isolates of Mycobacterium tuberculosis, one of which had developed multi-drug resistance during the course of treatment. J Infect. 2000;41:184–187. doi: 10.1053/jinf.2000.0711. pmid:11023769
[14]
Teixeira L, Perkins MD, Johnson JL, Keller R, Palaci M, do Valle Dettoni V, et al. Infection and disease among household contacts of patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2001;5:321–328. pmid:11334250
[15]
Attamna A, Chemtob D, Attamna S, Fraser A, Rorman E, Paul M, et al. Risk of tuberculosis in close contacts of patients with multidrug resistant tuberculosis: a nationwide cohort. Thorax. 2009;64:271. doi: 10.1136/thx.2008.100974. pmid:19252032
[16]
Becerra MC, Appleton SC, Franke MF, Chalco K, Arteaga F, Bayona J, et al. Tuberculosis burden in households of patients with multidrug-resistant and extensively drug-resistant tuberculosis: a retrospective cohort study. Lancet. 2011;377:147–152. doi: 10.1016/S0140-6736(10)61972-1. pmid:21145581
[17]
Morrison J, Pai M, Hopewell PC. Tuberculosis and latent tuberculosis infection in close contacts of people with pulmonary tuberculosis in low-income and middle-income countries: a systematic review and meta-analysis. Lancet Infect Dis. 2008;8:359–368. doi: 10.1016/S1473-3099(08)70071-9. pmid:18450516
[18]
Grandjean L, Crossa A, Gilman RH, Herrera C, Bonilla C, Jave O, et al. Tuberculosis in household contacts of multidrug-resistant tuberculosis patients. Int J Tuberc Lung Dis. 2011;15:1164–1169, i. doi: 10.5588/ijtld.11.0030. pmid:21943839
[19]
Peruvian Ministry of Health. Norma tecnica de salud para el control de la tuberculosis. Lima: Peruvian Ministry of Health; 2006. NTS No. 039-MINSA/DGSP-V.0.1.
[20]
Caviedes L, Lee TS, Gilman RH, Sheen P, Spellman E, Lee EH, et al. Rapid, efficient detection and drug susceptibility testing of Mycobacterium tuberculosis in sputum by microscopic observation of broth cultures. The Tuberculosis Working Group in Peru. J Clin Microbiol. 2000;38:1203–1208. pmid:10699023
[21]
Moore DA, Mendoza D, Gilman RH, Evans CA, Hollm Delgado MG, Guerra J, et al. Microscopic observation drug susceptibility assay, a rapid, reliable diagnostic test for multidrug-resistant tuberculosis suitable for use in resource-poor settings. J Clin Microbiol. 2004;42:4432–4437. pmid:15472289 doi: 10.1128/jcm.42.10.4432-4437.2004
[22]
Kamerbeek J, Schouls L, Kolk A, van Agterveld M, van Soolingen D, Kuijper S, et al. Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. J Clin Microbiol. 1997;35:907–914. pmid:9157152
[23]
Grandjean L, Gilman RH, Martin L, Soto E, Castro B, Lopez S, et al. Transmission of multidrug-resistant and drug susceptible tuberculosis within households: a prospective cohort study. Dryad Digital Repository.
[24]
Rogers WH. Regression standard errors in clustered samples. Stata Tech Bull. 1993;13:19–23.
[25]
Ordway DJ, Sonnenberg MG, Donahue SA, Belisle JT, Orme IM. Drug-resistant strains of Mycobacterium tuberculosis exhibit a range of virulence for mice. Infect Immun. 1995;63:741–743. pmid:7822053
[26]
World Health Organization. Global tuberculosis report 2014. Geneva: World Health Organization; 2014.
[27]
Drobniewski F, Balabanova Y, Nikolayevsky V, Ruddy M, Kuznetzov S, Zakharova S, et al. Drug-resistant tuberculosis, clinical virulence, and the dominance of the Beijing strain family in Russia. JAMA. 2005;293:2726–2731. doi: 10.1001/jama.293.22.2726. pmid:15941801
[28]
Cohen T, Murray M, Abubakar I, Zhang Z, Sloutsky A, Arteaga F, et al. Multiple introductions of multidrug-resistant tuberculosis into households, Lima, Peru. Emerg Infect Dis. 2011;17:969–975. doi: 10.3201/eid/1706.101471. pmid:21749756
[29]
Lillebaek T, Dirksen A, Baess I, Strunge B, Thomsen V？, Andersen AB. Molecular evidence of endogenous reactivation of Mycobacterium tuberculosis after 33 years of latent infection. J Infect Dis. 2002;185:401–404. doi: 10.1086/338342. pmid:11807725
