Volume 96, Issue 5
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



In Saudi Arabia, there were no nationwide screening studies conducted so far to determine the aminoglycoside and fluoroquinolone resistance among multidrug-resistant tuberculosis (MDR-TB) isolates. Therefore, as the first attempt in the country, a retrospective analysis has been conducted on a nationwide collection of 2,956 clinical isolates screened with phenotypic drug susceptibility testing to define MDR-TB. Enrolled MDR-TB isolates were subjected to second-line drug susceptibility testing, detection of mutations conferring resistance to aminoglycosides and fluoroquinolone, followed by 24-loci mycobacterial interspersed repetitive unit–variable number of tandem repeat typing and spoligotyping. Overall, 83 isolates were identified as MDR-TB, and 13 (15.7%) isolates showed resistance to second-line drugs. Moxifloxacin (low level) showed higher resistant rates (10.8%) followed by ofloxacin (7.2%), capreomycin (3.6%), kanamycin (3.6%), and amikacin (2.4%). Overall fluoroquinolone resistance was 12%, whereas aminoglycoside resistance was 7.2%. Predominant mutations conferring resistance to fluoroquinolone were found in A90V and D94G, whereas aminoglycoside resistance was observed only with gene A1401G mutation. The corresponding strain lineages predominated with Indo-Oceanic and East-African Indian origin. Interestingly, none of the isolates with second-line drug resistance was defined as extensively drug-resistant TB (XDR-TB). Surprisingly, many isolates (50.6%) were panresistant to first-line drugs. Saudi Arabia faces considerable burden of fluoroquinolone- and aminoglycoside-resistant MDR-TB. Higher incidence of panresistant MDR-TB reveals a threat for the emergence of XDR-TB strains in the near future.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. Wright A, Zignol M, Van Deun A, Falzon D, Gerdes SR, Feldman K, Hoffner S, Drobniewski F, Barrera L, van Soolingen D, Boulabhal F, Paramasivan CN, Kam KM, Mitarai S, Nunn P, Raviglione M, , 2009. Epidemiology of antituberculosis drug resistance 2002–07: an updated analysis of the Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Lancet 373: 18611873.[Crossref] [Google Scholar]
  2. World Health Organization (WHO), 2012. Global Tuberculosis Control: 2012. Geneva, Switzerland: WHO. [Google Scholar]
  3. Muller B, Borrell S, Rose G, Gagneux S, , 2013. The heterogeneous evolution of multidrug-resistant Mycobacterium tuberculosis . Trends Genet 29: 160169.[Crossref] [Google Scholar]
  4. Gandhi NR, Nunn P, Dheda K, Schaaf HS, Zignol M, van Soolingen D, Jensen P, Bayona J, , 2010. Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis. Lancet 375: 18301843.[Crossref] [Google Scholar]
  5. Dukes Hamilton C, Sterling TR, Blumberg HM, Leonard M, McAuley J, Schlossberg D, Stout J, Huitt G, , 2007. Extensively drug-resistant tuberculosis: are we learning from history or repeating it? Clin Infect Dis 45: 338342.[Crossref] [Google Scholar]
  6. World Health Organization (WHO), 2010. Multi Drug and Extensively Drug Resistant TB (M/XDR-TB). 2010 Global Report on Surveillance and Response. Geneva, Switzerland: WHO. [Google Scholar]
  7. Cohen J, , 2006. Infectious disease. Extensively drug-resistant TB gets foothold in South Africa. Science 313: 1554.[Crossref] [Google Scholar]
  8. Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T, Lalloo U, Zeller K, Andrews J, Friedland G, , 2006. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 368: 15751580.[Crossref] [Google Scholar]
  9. Kwon YS, Kim YH, Suh GY, Chung MP, Kim H, Kwon OJ, Choi YS, Kim K, Kim J, Shim YM, Koh WJ, , 2008. Treatment outcomes for HIV-uninfected patients with multidrug-resistant and extensively drug-resistant tuberculosis. Clin Infect Dis 47: 496502.[Crossref] [Google Scholar]
  10. Kochi A, Vareldzis B, Styblo K, , 1993. Multidrug-resistant tuberculosis and its control. Res Microbiol 144: 104110.[Crossref] [Google Scholar]
  11. Telenti A, Imboden P, Marchesi F, Lowrie D, Cole S, Colston MJ, Matter L, Schopfer K, Bodmer T, , 1993. Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis . Lancet 341: 647650.[Crossref] [Google Scholar]
  12. Ramaswamy S, Musser JM, , 1998. Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis 79: 329.[Crossref] [Google Scholar]
  13. Ramaswamy SV, Reich R, Dou SJ, Jasperse L, Pan X, Wanger A, Quitugua T, Graviss EA, , 2003. Single nucleotide polymorphisms in genes associated with isoniazid resistance in Mycobacterium tuberculosis . Antimicrob Agents Chemother 47: 12411250.[Crossref] [Google Scholar]
  14. Zhang Y, Yew WW, , 2015. Mechanisms of drug resistance in Mycobacterium tuberculosis: update 2015. Int J Tuberc Lung Dis 19: 12761289.[Crossref] [Google Scholar]
  15. Takiff HE, Salazar L, Guerrero C, Philipp W, Huang WM, Kreiswirth B, Cole ST, Jacobs WR, Jr Telenti A, , 1994. Cloning and nucleotide sequence of Mycobacterium tuberculosis gyrA and gyrB genes and detection of quinolone resistance mutations. Antimicrob Agents Chemother 38: 773780.[Crossref] [Google Scholar]
  16. Jugheli L, Bzekalava N, de Rijk P, Fissette K, Portaels F, Rigouts L, , 2009. High level of cross-resistance between kanamycin, amikacin, and capreomycin among Mycobacterium tuberculosis isolates from Georgia and a close relation with mutations in the rrs gene. Antimicrob Agents Chemother 53: 50645068.[Crossref] [Google Scholar]
  17. Maus CE, Plikaytis BB, Shinnick TM, , 2005. Molecular analysis of cross-resistance to capreomycin, kanamycin, amikacin, and viomycin in Mycobacterium tuberculosis . Antimicrob Agents Chemother 49: 31923197.[Crossref] [Google Scholar]
  18. Chen W, Biswas T, Porter VR, Tsodikov OV, Garneau-Tsodikova S, , 2011. Unusual regioversatility of acetyltransferase Eis, a cause of drug resistance in XDR-TB. Proc Natl Acad Sci USA 108: 98049808.[Crossref] [Google Scholar]
  19. Maus CE, Plikaytis BB, Shinnick TM, , 2005. Mutation of tlyA confers capreomycin resistance in Mycobacterium tuberculosis . Antimicrob Agents Chemother 49: 571577.[Crossref] [Google Scholar]
  20. Al-Hajoj S, Varghese B, Shoukri MM, Al-Omari R, Al-Herbwai M, Alrabiah F, Alrajhi AA, Abuljadayel N, Al-Thawadi S, Zumla A, Zignol M, Raviglione MC, Memish Z, , 2013. Epidemiology of antituberculosis drug resistance in Saudi Arabia: findings of the first national survey. Antimicrob Agents Chemother 57: 21612166.[Crossref] [Google Scholar]
  21. Kamerbeek J, Schouls L, Kolk A, van Agterveld M, van Soolingen D, Kuijper S, Bunschoten A, Molhuizen H, Shaw R, Goyal M, van Embden J, , 1994. Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. J Clin Microbiol 35: 907914. [Google Scholar]
  22. Supply P, Allix C, Lesjean S, Cardoso-Oelemann M, Rusch-Gerdes S, Willery E, Savine E, de Haas P, van Deutekom H, Roring S, Bifani P, Kurepina N, Kreiswirth B, Sola C, Rastogi N, Vatin V, Gutierrez MC, Fauville M, Niemann S, Skuce R, Kremer K, Locht C, van Soolingen D, , 2006. Proposal for standardization of optimized mycobacterial interspersed repetitive unit-variable-number tandem repeat typing of Mycobacterium tuberculosis . J Clin Microbiol 44: 44984510.[Crossref] [Google Scholar]
  23. World Health Organization (WHO), 2009. Guidelines for Surveillance of Drug Resistance in Tuberculosis. Geneva, Switzerland: WHO. [Google Scholar]
  24. Varghese B, Hillemann A, Wijayanti DR, Shoukri M, Al-Rabiah F, Al-Omari R, Al-Hajoj S, , 2013. New insight into the molecular characterization of isoniazid and rifampicin resistant Mycobacterium tuberculosis strains from Saudi Arabia. Infect Genet Evol 12: 549556.[Crossref] [Google Scholar]
  25. Varghese B, Shoukri M, Memish Z, Abuljadayel N, Alhakeem R, Al-Rabiah F, Al-Hajoj S, , 2014. Occurrence of diverse mutations in isoniazid- and rifampicin-resistant Mycobacterium tuberculosis isolates from autochthonous and immigrant populations of Saudi Arabia. Microb Drug Resist 20: 623631.[Crossref] [Google Scholar]
  26. Varghese B, Supply P, Allix-Beguec C, Shoukri M, Al-Omari R, Herbawi M, Al-Hajoj S, , 2013. Admixed phylogenetic distribution of drug resistant Mycobacterium tuberculosis in Saudi Arabia. PLoS One 8: e55598.[Crossref] [Google Scholar]
  27. Varghese B, al-Omari R, Grimshaw C, Al-Hajoj S, , 2013. Endogenous reactivation followed by exogenous re-infection with drug resistant strains, a new challenge for tuberculosis control in Saudi Arabia. Tuberculosis (Edinb) 93: 246249.[Crossref] [Google Scholar]
  28. Shah NS, Wright A, Bai GH, Barrera L, Boulahbal F, Martin-Casabona N, Drobniewski F, Gilpin C, Havelkova M, Lepe R, Lumb R, Metchock B, Portaels F, Rodrigues MF, Rusch-Gerdes S, Van Deun A, Vincent V, Laserson K, Wells C, Cegielski JP, , 2007. Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis 13: 380387.[Crossref] [Google Scholar]
  29. Li X, Wang H, Jing H, Wang Y, Yu C, Wang J, Liu Z, Graviss EA, Ma X, , 2012. Population-based surveillance of extensively drug-resistant tuberculosis in Shandong Province, China. Int J Tuberc Lung Dis 16: 612614. [Google Scholar]
  30. Menon S, Dharmshale S, Chande C, Gohil A, Lilani S, Mohammad S, Joshi A, Chowdhary A, Bharadwaj R, , 2012. Drug resistance profiles of Mycobacterium tuberculosis isolates to first line anti-tuberculous drugs: a five years study. Lung India 29: 227231.[Crossref] [Google Scholar]
  31. Lee AS, Lim IH, Tang LL, Wong SY, , 2005. High frequency of mutations in the rpoB gene in rifampin-resistant clinical isolates of Mycobacterium tuberculosis from Singapore. J Clin Microbiol 43: 20262027.[Crossref] [Google Scholar]
  32. Madania A, Habous M, Zarzour H, Ghoury I, Hebbo B, , 2012. Characterization of mutations causing rifampicin and isoniazid resistance of Mycobacterium tuberculosis in Syria. Pol J Microbiol 61: 2332.[Crossref] [Google Scholar]
  33. Poudel A, Nakajima C, Fukushima Y, Suzuki H, Pandey BD, Maharjan B, Suzuki Y, , 2012. Molecular characterization of multidrug-resistant Mycobacterium tuberculosis isolated in Nepal. Antimicrob Agents Chemother 56: 28312836.[Crossref] [Google Scholar]
  34. Hu Y, Hoffner S, Wu L, Zhao Q, Jiang W, Xu B, , 2013. Prevalence and the genetic characterization of second-line and extensively drug resistant Mycobacterium tuberculosis in rural China. Antimicrob Agents Chemother 57: 38573863.[Crossref] [Google Scholar]
  35. Jnawali HN, Hwang SC, Park YK, Kim H, Lee YS, Chung GT, Choe KH, Ryoo S, , 2013. Characterization of mutations in multi- and extensive drug resistance among strains of Mycobacterium tuberculosis clinical isolates in Republic of Korea. Diagn Microbiol Infect Dis 76: 187196.[Crossref] [Google Scholar]
  36. Ali A, Hasan R, Jabeen K, Jabeen N, Qadeer E, Hasan Z, , 2011. Characterization of mutations conferring extensive drug resistance to Mycobacterium tuberculosis isolates in Pakistan. Antimicrob Agents Chemother 55: 56545659.[Crossref] [Google Scholar]
  37. Al-Mutairi NM, Ahmad S, Mokaddas E, , 2011. First report of molecular detection of fluoroquinolone resistance-associated gyrA mutations in multidrug-resistant clinical Mycobacterium tuberculosis isolates in Kuwait. BMC Res Notes 4: 123.[Crossref] [Google Scholar]
  38. General Authority for Statistics, Kingdom of Saudi Arabia, 2013. Statistical Year Book-1434. Riyadh, Kingdom of Saudi Arabia: CDSI. [Google Scholar]
  39. Abouzeid MS, Zumla AI, Felemban S, Alotaibi B, O'Grady J, Memish ZA, , 2012. Tuberculosis trends in Saudis and non-Saudis in the Kingdom of Saudi Arabia: a 10 year retrospective study (2000–2009). PLoS One 7: e39478.[Crossref] [Google Scholar]
  40. Said HM, Kock MM, Ismail NA, Mphahlele M, Baba K, Omar SV, Osman AG, Hoosen AA, Ehlers MM, , 2012. Molecular characterization and second-line antituberculosis drug resistance patterns of multidrug-resistant Mycobacterium tuberculosis isolates from the northern region of South Africa. J Clin Microbiol 50: 28572862.[Crossref] [Google Scholar]

Data & Media loading...

  • Received : 17 Jul 2016
  • Accepted : 12 Dec 2016
  • Published online : 27 Feb 2017

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error