High rate of drug resistance among tuberculous meningitis cases in Shaanxi province, China

Abstract

The clinical and mycobacterial features of tuberculous meningitis (TBM) cases in China are not well described; especially in western provinces with poor tuberculosis control. We prospectively enrolled patients in whom TBM was considered in Shaanxi Province, northwestern China, over a 2-year period (September 2010 to December 2012). Cerebrospinal fluid specimens were cultured for Mycobacterium tuberculosis; with phenotypic and genotypic drug susceptibility testing (DST), as well as genotyping of all positive cultures. Among 350 patients included in the study, 27 (7.7%) had culture-confirmed TBM; 84 (24.0%) had probable and 239 (68.3%) had possible TBM. DST was performed on 25/27 (92.3%) culture positive specimens; 12/25 (48.0%) had "any resistance" detected and 3 (12.0%) were multi-drug resistant (MDR). Demographic and clinical features of drug resistant and drug susceptible TBM cases were similar. Beijing was the most common genotype (20/25; 80.0%) with 9/20 (45%) of the Beijing strains exhibiting drug resistance; including all 3 MDR strains. All (4/4) isoniazid resistant strains had mutations in the katG gene; 75% (3/4) of strains with phenotypic rifampicin resistance had mutations in the rpoB gene detected by Xpert MTB/RIF®. High rates of drug resistance were found among culture-confirmed TBM cases; most were Beijing strains.

Figure 1. Flow diagram of patients in whom tuberculous meningitis was considered and special investigations done.

TBM-tuberculous meningitis; M. tuberculosis-Mycobacterium tuberculosis; ZN-Ziehl-Neelsen; CSF-Cerebral Spinal Fluid; DST-Drug Susceptibility Testing; MIC-Minimal Inhibitory Concentration; Spoligo- spacer oligonucleotide; MIRU-25-25 locus Multiple Interspersed Repetitive Unit; *Classification according to consensus uniform research case definition criteria.

Figure 2. MIRU-25 phylogenetic relationship of M. tuberculosis genotypes identified in TBM patients; with associated spoligotype.

MIRU-25–25 locus Multiple Interspersed Repetitive Unit typing as defined in Methods; Strain No.- Liquid MGIT960 culture positive TBM isolates were assigned numbers 1–27 (2 isolates were not recovered successfully on Lowenstein-Jensen solid medium); SIT - Spoligo International Type; SpoIDB4.0-Fourth International Spoligotyping Database; SpolDB4 ID - Identification from the SpoIDB4.0 database; NA-Unclassified in SpoIDB4.0 database, we defined it as an atypical Beijing strain; *Reference strain.