Global surveillance has shown that drug resistant tuberculosis is widespread and is now a threat to tuberculosis control programs in many countries. Isoniazid resistant tb hrtb, refers to mycobacterium tuberculosis strains in which resistance to. Whole genome sequencing wgs is a current alternative to the whoapproved probebased methods for tb diagnosis and detection of drug resistance, genetic diversity and transmission dynamics of mycobacterium tuberculosis complex mtbc. The emergence of drug resistant mtb strains has exacerbated this already alarming epidemic. The effect of mutational events that lead to antibioticresistant phenotypes may or may not have a predictable effect on the. The amount of rifampin resistance tuberculosis rrtb was estimated to be 201. Tuberculosis tb patients would greatly benefit from shorter treatment options. Understanding molecular consequences of putative drug. Drug resistance in mycobacterium tuberculosis tai man chan scientific essay biology diseases, health, nutrition publish your bachelors or masters thesis, dissertation, term paper or essay. Its situation is worsened by the presence of multidrug resistant mdr strains of. However, in mycobacterium tuberculosis mtb, drug resistance is exclusively associated with point mutations and chromosomal rearrangements. Detection of drug resistance in mycobacterium tuberculosis. Oct 18, 2019 drug resistance of mycobacterium tuberculosis mtb, especially multidrug resistant tuberculosis mdrtb, defined as resistance to at least rifampin and isoniazid has contributed to a significant health and economic burden on a global scale 1,2,3.
Who consolidated guidelines on drugresistant tuberculosis. Tb experts should be consulted in the treatment of mdr tb. Some key antituberculosis antibiotics are prodrugs, for which resistance mechanisms are mainly driven by mutations in the bacterial enzymatic pathway required for their bioactivation. In mycobacterium tuberculosis, the emergence of multidrugresistant mdr and extensively drug resistant xdr strains is threatening to make one of the most important infectious diseases untreatable 2. Critical concentration the lowest concentration of an antituberculous agent in vitro that will inhibit the growth of 99% of phenotypically wild type strains of mycobacterium tuberculosis. Genotype mtbdrplus is a molecular assay for detection of mycobacterium tuberculosis and drug resistance. In cavitary lesions of the lung parenchyma where oxygen concentration is high, m. The alarming rise of antibiotic resistance in mycobacterium tuberculosis, the etiological agent of tb, has made it exceedingly difficult to control the disease with the existing portfolio of anti. Drug resistance in mycobacterium tuberculosis isolated from tb patients in kerala. Drug resistant tb develops when the antibiotics used to treat tb are misused or mismanaged, and it can spread. The objective of this study was to determine the accuracy of the mtbdrplus test for direct detection of m. In addition to the recent emergence of antimicrobial resistance, mycobacteria are unusually challenging to treat clinically due to ancestral intrinsic antibiotic resistance. Current knowledge on the mechanisms of mtb drug resistance is presented in the subsequent section palomino and martin 2014.
Primary drug resistance of mycobacterium tuberculosis in. Genotype mtbdrplus for direct detection of mycobacterium. The treatment of drug susceptible tb, a disease caused by the bacillus mycobacterium tuberculosis, is a lengthy and strenuous process. A survival guide for clinicians, third edition was created through a collaboration of the curry international tuberculosis center citc and the state of california department of public health, tuberculosis control branch cdph. The incidence of primary resistance was as follows. For 23 candidate genes identified from the drug resistance scientific literature, we algorithmically characterised genetic mutations as not conferring resistance benign, resistance determinants, or uncharacterised. The effect of drug resistance on the fitness of mycobacterium. Resistance to tuberculosis tb drugs is a formidable obstacle to effective tb care and prevention globally. The use of nextgeneration sequencing technologies for the detection of mutations associated with drug resistance in mycobacterium tuberculosis complex.
Next generation sequencing in clinical and public health microbiology. The emergence of mycobacterium tuberculosis strains that cause xdr tb has prompted the issuance of interim guidelines for clinical and research laboratories handling xdr tb specimens. We have identified a small molecule, c10, that potentiates the activity of the frontline antibiotic isoniazid inh. Between sept 1, 2010, and dec 1, 20, we sequenced a training set of 2099 mycobacterium tuberculosis genomes. Mobile genetic elements such as plasmids and transposons, which are known to mediate drug resistance in various bacterial spe cies, do not do so in m. Multidrugresistant tb mdr tb is caused by tb bacteria that is resistant to at least isoniazid and rifampin, the two most potent tb drugs.
The correlation of drug resistance and virulence in. Drug resistance of mycobacterium tuberculosis in malawi. Pdf mechanisms of drug resistance in mycobacterium. Pdf drug resistance mechanisms in mycobacterium tuberculosis. Tuberculosis tb remains to be a serious health problem worldwide. The development of drug resistanceespecially rifampicin resistance rr, multidrug resistance mdr and extensive drug resistance xdris particularly worrisome for tuberculosis tb. Drug resistance in mycobacterium tuberculosis publish. We have developed a pyrosequencing method for simultaneous detection of mutations associated with resistance to rifampin, isoniazid, ethambutol. Mycobacterium tuberculosis since the publication of the previous article in 2009. Drug resistance is a major impediment to tb treatment and poses a. Multidrug resistant strains of mycobacterium tuberculosis seriously threaten tuberculosis tb control and prevention efforts.
Tuberculosis airborne disease caused by the bacterium mycobacterium tuberculosis m. A better knowledge of the mechanisms of drug resistance of m. Multidrug resistant tb mdrtb is multifactorial and fuelled by improper treatment of patients, poor management of supply and quality of drugs, and airborne transmission of bacteria in public. Pdf drug resistance in mycobacterium tuberculosis researchgate. Genetic determinants of drug resistance in mycobacterium. These drugs are used to treat all persons with tb disease. Fitness cost of drug resistance in mycobacterium tuberculosis.
Mycobacterium tuberculosis mtb causes the disease tuberculosis tb, which kills more people than any other infection. Citc is a project of the university of california, san francisco, funded by the centers for. Each year, more than half a million people become sick with rifampicin resistant forms of tuberculosis, but in 2017, only 160 684 people were diagnosed or notified, and only 9 114 were started on treatment. Recent updates on drug resistance in mycobacterium tuberculosis. Drug resistance and persistence in mycobacterium tuberculosis. In addition, consistent monitoring of the drug susceptibility patterns will help in the development and evaluation of effective tuberculosis control programs, in particular to.
This work was partially supported by instituto mexicano del seguro social fisimssprotg151457. Mechanisms of drug resistance in mycobacterium tuberculosis y. Drug resistant tuberculosis tb is a global issue and an important public health concern. Acquired drug resistance in mycobacterium tuberculosis and. Antibiotic resistance is one of the biggest threats to human health globally.
Multidrug resistant mdr and extensively drug resistant xdr tuberculosis tb is an emerging threat to tb control in ukraine, a country with the third highest xdr tb burden globally. Antibioticresistant mycobacterium tuberculosis strains are threatening progress in containing the global tuberculosis. One clear exception is mycobacterium tuberculosis mtb. Antimicrobial resistance in mycobacterium tuberculosis. Consequently, control of this disease has become a significant challenge despite the availability of chemotherapy and bcg vaccine. In many bacteria, drugresistance determinants are carried on mobile genetic elements. Drug resistance and poor outcomes in mdr tb acquired resistance in mycobacterium tuberculosis was observed in 19 14%. While they destroy pathogenic mycobacterium tuberculosis they also select for drug resistant bacteria against which those drugs are then ineffective. Some forms of tb are also resistant to secondline medications, and are called extensively drug resistant tb. The complex evolution of antibiotic resistance in mycobacterium. Genomic studies of mycobacterium tuberculosis bacteria have revealed loci associated with resistance to anti tuberculosis drugs. Drug resistance mechanisms in mycobacterium tuberculosis.
The methods developed here can be used to identify novel advantageous mutations, including new resistance loci, in m. The low success rates in the treatment of multidrugresistant tuberculosis mdrtb and extensively drug resistant tb xdrtb, which account for 55% and 34% respectively, led the who to conclude that mdrxdrtb is a serious public health crisis. Detection of first and secondline drug resistance in. Whole genome sequencing of mycobacterium tuberculosis. Jul 02, 2014 tuberculosis tb is a serious public health problem worldwide. Wholegenome and targeted sequencing of drugresistant.
Drug resistance in mycobacterium tuberculosis intechopen. Poor or intermittent therapy has long been thought to be the major explanation for drug resistance, and it is believed that drug resistant strains develop through. Drug resistance for all firstline anti tuberculosis agents and some secondline agents has been observed. Multi drug resistant tuberculosis mdrtb is a form of tuberculosis tb infection caused by bacteria that are resistant to treatment with at least two of the most powerful firstline antitb medications drugs, isoniazid and rifampin. Wholegenome sequencing for prediction of mycobacterium. Keywords mycobacterium tuberculosis, antibiotic resistance, evolution, genomics, positive selection received18august2017 accepted8. Reversion of antibiotic resistance in mycobacterium. Molecular studies of the mechanism of action of antitubercular drugs have elucidated the genetic basis of drug resistance in m. Mar 17, 2017 antibiotic resistance is a rapidly growing health concern and is observed for many antibacterial agents, both in hospital and in community settings 1, 2.
In recent years, even more serious forms of drug resistance have been reported. Fitness cost of drug resistance in mycobacterium tuberculosis s. Since 2006, it has been recognized the presence of even more resistant strains of m. The emergence of drugresistant mtb strains has exacerbated this already alarming epidemic. The development of molecular diagnostics that detect both the presence of mycobacterium tuberculosis in clinical samples and drug resistance conferring mutations promises to revolutionize patient care and interrupt transmission by ensuring early diagnosis. Increasing drug resistance of mycobacterium tuberculosis. Drug resistance of mycobacterium tuberculosis complex in a. Tb is caused by mycobacterium tuberculosis, bacteria that usually attack the lungs. Multi drugresistant tuberculosis mdrtb is a form of tuberculosis tb infection caused by bacteria that are resistant to treatment with at least two of the most powerful firstline antitb medications drugs, isoniazid and rifampin. Efflux as a mechanism for drug resistance in mycobacterium. Enhanced respiration prevents drug tolerance and drug.
During this phase, an injectable agent amikacin, capreomycin, kanamycin or streptomycin is used. Chiang number 1 in the series a version in french of this article is available from the editorial offi ce in paris and from the union website. Evolution of drug resistance in mycobacterium tuberculosis. Mycobacterium tuberculosis remains a leading infectious cause of morbidity and mortality. We used wholegenome sequencing of a convenience sample to identify bacterial genetic and patientrelated factors associated with mdrxdr tb in this country. Assay performance as applied directly to consecutive unselected sputum samples has not been established. To investigate the drug resistance characteristics of mycobacterium tuberculosis mtb isolates from patients with tuberculosis to 12. Drug resistance mechanisms in mycobacterium tuberculosis mdpi. Broadrange pcr coupled with massspectrometry for the detection of mycobacterium tuberculosis drug resistance, germs 2016 describes the use of a commercial pcr assay coupled with electrospray ionization mass spectrometry pcresims to detect isoniazid inh and rifampin rif resistance in 63 m. There is an increased transmission of mycobacterium tuberculosis strains with drug resistance, hence complicating tb control. The odd one out vegard eldholm1, and francois balloux2, antimicrobial resistance amr threats are typically represented by bacteria capable of extensive horizontal gene transfer hgt. Drugresistant tuberculosis drtb, including multi and extensively drug resistant tb, is posing a significant challenge to effective treatment and tb control. Drug resistance characteristics of mycobacterium tuberculosis.
We show that in laboratoryderived mutants of mycobacterium tuberculosis, rifampin resistance is universally associated with a competitive fitness cost and that this cost is determined by the specific resistance mutation and strain genetic. Our study demonstrates that timely, complete, and accurate data on antituberculous drug resistance of m. Extensively drugresistant tuberculosis xdrtb is defined as tuberculosis tb caused by mycobacterium tuberculosis mtb strains that are multidrug resistant mdr and also. Mdrtb is caused by strains of mycobacterium tuberculosis that are resistant to at least rifampicin and isoniazid, two key drugs in the treatment of the disease. Aug 21, 2012 drug resistance and persistence in mycobacterium tuberculosis leave a comment as weve discussed before, mycobacterium tuberculosis is the major cause of tuberculosis, a disease that has plagued humans for millennia. Early detection of drug resistant tuberculosis tb is essential for prevention and control of tb transmission. However, these tools require the identification of genetic determinants of resistance to the full range of antituberculosis drugs.
Multidrugresistant strains of mycobacterium tuberculosis seriously threaten tuberculosis tb control and prevention efforts. Regimens without an injectable agent are considered not to have an intensive phase. As mycobacterium tuberculosis is an aerobic pathogen, its growth rate is highly affected by oxygen concentrations. The emergence, management of cases, and spread of drug resistant strains of mycobacterium tuberculosis is one of the biggest challenges faced by national. Because antibiotic treatment is one of the main tools for tuberculosis control, knowledge of mycobacterium tuberculosis drug resistance is an important component for the disease control.
It has existed in humans since ancient times and had high mortality rates without adequate treatment options before the invention of antibiotics, specifically streptomycin in 1943, that were potent enough to kill the bacteria. The global burden of tb remains alarmingly high, with. Tuberculosis is a worldwide health problem posing increasing threat with the spread of hiv infection and drug resistant mycobacterium tuberculosis strains. Tuberculosis tb, particularly multi and or extensive drug resistant tb, is still a global medical emergency. Other combinations of drug resistance were identified in 40 17. Multidrug resistant and extensively drug resistant tuberculosis tb represent a major threat to the control of the disease worldwide. Multidrug and extensively drugresistant mycobacterium. Over 95% of tuberculosis tb cases and deaths among adults occur in developing countries. Resistance to antitb drugs is an escalating global health crisis. The low success rates in the treatment of multidrug resistant tuberculosis mdrtb and extensively drug resistant tb xdrtb, which account for 55% and 34% respectively, led the who to conclude that mdrxdrtb is a serious public health crisis. Tuberculosis tb is a potentially deadly disease caused by pathogenic bacteria, usually mycobacterium tuberculosis.
Tuberculosis tb is a serious public health problem worldwide. We have identified a small molecule, c10, that potentiates the activity of the frontline antibiotic isoniazid inh and prevents the selection for inh resistant. Signatures of selection at drug resistance loci in. Basic concepts in the development of drug resistant tuberculosis there are two types of drug resistance inm. While antibiotic resistance is cited as a potential threat to efforts aimed at controlling the spread of this pathogen, it is not clear how drug resistance affects disease dynamics. This long therapy is because of the ability of a small population of cells to become drug tolerant. Recent updates on drug resistance in mycobacterium. To characterize the genetic basis of drug resistance in mycobacterium tuberculosis in latvia, mutations involved in rifampin rpob gene and isoniazid katg gene resistance in dna from 19 drug susceptible and 51 multidrug resistant m. Interim laboratory biosafety guidance for extensively drug resistant xdr mycobacterium tuberculosis strains. Oct 01, 2011 tuberculosis remains an important global public health problem, with an estimated prevalence of 14 million individuals with tuberculosis worldwide in 2007. Mutations in the rpob and katg genes leading to drug. Review on molecular mechanism of first line antibiotic resistance in.
Conventional phenotypic drug susceptibility testing dst methods for mycobacterium tuberculosis are laborious and very timeconsuming. Drug resistance has become a problem of global proportions, with major consequences for public health and the world economy 1. Molecular studies of the mechanism of action of antitubercular drugs have elucidated the genetic basis of drug resistance in. The road to drug resistance in mycobacterium tuberculosis. Pdf drug resistance in mycobacterium tuberculosis freddie. Alarmingly, multidrug resistant and extensively drug resistant mycobacterium tuberculosis have now spread worldwide. Mathematical models predict that the future of the multidrug resistant tuberculosis epidemic will depend on the fitness cost of drug resistance. Drug resistance in mycobacterium tuberculosis microbewiki. Multidrug resistant tb mdrtb, caused by a strain of mycobacterium tuberculosis resistant to at least rifampicin and isoniazid, and extensively drug resistant tb xdrtb, caused by strains of m.
We have identified a small molecule, c10, that potentiates the activity of the frontline antibiotic isoniazid inh and prevents the selection for inhresistant mutants. Genetic resistance to an antituberculosis drug is due to spontaneous chro mosomal mutations at a frequency of 10. Pdf mycobacterium tuberculosis drug resistance, ghana. Isoniazidresistant tb hrtb, refers to mycobacterium tuberculosis strains in which resistance to. Gagneux division of mycobacterial research, mrc national institute for medical research, mill hill, london, uk abstract multidrug resistant mdr and extensively drug resistant xdr forms of tuberculosis are. The mechanisms and pathways that result in the emergence and subsequent fixation of resistant strains of mycobacterium tuberculosis are not fully understood and recent studies suggest that they are much more complex than initially thought. Pdf tuberculosis tb is a serious public health problem worldwide. Drug resistance testing, or antimicrobial susceptibility testing ast, is mandatory for mycobacterium tuberculosis in cases of failure on standard therapy.
Chemical disarming of isoniazid resistance in mycobacterium. The most frequent rpob gene mutations found by the line probe assay were the s531l 14 of 34 isolates. The use of nextgeneration sequencing technologies for the. Multidrugresistant tb mdrtb is multifactorial and fuelled by improper treatment of patients, poor management of supply and quality of drugs, and airborne transmission of bacteria in public. Xdr tb occurs when a mycobacterium tuberculosis strain is resistant to isoniazid and rifampin, two of the most powerful firstline drugs, as well as key drugs of the second line regimenany fluoroquinolone and at least one of the three injectable drugs shown above. Molecular basis and mechanisms of drug resistance in. Drugresistant tuberculosis drtb, including multi and extensively drugresistant tb, is posing a significant challenge to effective treatment and tb control. Multidrugresistant mycobacterium tuberculosis cdc stacks. Mechanisms of drug resistance in mycobacterium tuberculosis.
This work was partially supported by instituto mexicano del seguro social fis imssprotg151457. Review article recent updates on drug resistance in mycobacterium tuberculosis r. In many settings, drug resistant tuberculosis is also a major threat to tuberculosis control efforts. Its situation is worsened by the presence of multidrug resistant mdr strains of mycobacterium tuberculosis, the causative agent of the disease. Extensively drugresistant tb xdr tb extensively drugresistant tb xdr tb is a rare type of mdr tb that is resistant to isoniazid and rifampin, plus any fluoroquinolone and at least one of three injectable secondline drugs i.
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