Mycobacterium tuberculosis isoniazid resistance

Isoniazid (INH) is still the most widely used drug in the treatment of tuberculosis (TB) and has high activity against Mycobacterium tuberculosis, although resistant strains have emerged. INH is used in combination with drugs such as rifampicin and pyrazinamide to reduce the chance of inducing resistant strains of the mycobacterium. 

Pharmacology Aminosalicylic acid is bacteriostatic against Mycobacterium tuberculosis. It inhibits the onset of bacterial resistance to streptomycin and isoniazid. The mechanism of action has been postulated to be inhibition of folic acid synthesis (but without potentiation with antifolic compounds) or inhibition of synthesis of the cell wall component, mycobactin, thus reducing iron uptake by M. tuberculosis. 

Mycobacterium tuberculosis Add streptomycin or ethambutol as a fourth drug in a regimen containing isoniazid (INH), rifampin, and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH or rifampin resistance is very low. Streptomycin also is indicated for therapy of tuberculosis when one or more of the above drugs is contraindicated because of toxicity or intolerance. 

Intended for use concomitantly with other antituberculosis agents in pulmonary infections caused by capreomycin-susceptible strains of Mycobacterium tuberculosis, when the primary agents (eg, isoniazid, rifampin) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli. Administration and Dosage... 

The most commonly used regimen for drug-susceptible tuberculosis consists of isoniazid, rifampin, and pyrazinamide daily for 2 months, followed by isoniazid and rifampin daily or two to three times a week for 4 months. If isoniazid resistance is suspected, ethambutol or streptomycin should be added to the regimen until the susceptibility of the mycobacterium is determined. This... 

Mycobacterium tuberculosis Tuberculosis Isoniazid plus pyridoxine rifampin (if isoniazid resistant)... 

Cooksey RC, Holloway BP, Oldenburg MC, Listenbee S, Miller CW. Evaluation of the invader assay, a linear signal amplification method, for identification of mutations associated with resistance to rifampin and isoniazid in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2000 44(5) 1296-1301. 

Ghiladi RA, Medzihradszky KF, Rusnak FM et al (2005) Correlation between isoniazid resistance and superoxide reactivity in Mycobacterium tuberculosis KatG. J Am Chem Soc 127 13428-13442... 

Musser JM, Kapur V, Wilhams DL, Kreiswirth BN, van Soolingen D, van Embden JD. Characterization of the catalase-peroxidase gene (katG) and inhA locus in isoniazid-resistant and -susceptible strains of Mycobacterium tuberculosis by automated DNA sequencing restricted array of mutatins associated with drag re- 45. sistance. J. Infect. Dis. 1996 173 196-202. 

Treatment problems that can arise are mainly of two types adverse reactions (collateral, toxic, or hypersusceptibility reactions), and initial or acquired resistance of Mycobacterium tuberculosis, Mycobacterium bovis, or non-tuberculous mycobacteria to one or more of the antituberculosis drugs. The latter probably only occurs when the patient has not taken the full combination or the full doses of the drugs all the time. Combination formulations are thus particularly useful. Multidrug-resistant tuberculosis, defined as resistance against at least isoniazid and rifampicin, is the most clinically relevant form of resistance to treatment worldwide. 

Ethambutol is tuberculostatic and acts against Mycobacterium tuberculosis and Mycobacterium kansasii as well as some strains of Mycobacterium avium complex. It has no effect on other bacteria. The sensitivities of non-tuberculous mycobacteria are variable. Ethambutol suppresses the growth of most isoniazid-resistant and streptomycin-resistant tubercle bacilli (1). 

Isoniazid + rifampin Prevents emergence of resistant strains Mycobacterium tuberculosis... 

Somoskovi A, Parsons EM, Salfinger M. The molecular basis of resistance to isoniazid, rifampin, and pyrazinamide in Mycobacterium tuberculosis. RespirRes 2001 2 164-168. 

Marin M, Garcia de Viedma D, Ruiz-Serrano MJ, Bouza E. Rapid direct detection of multiple rifampin and isoniazid resistance mutations in Mycobacterium tuberculosis in respiratory samples by real-time PCR. Antimicrob Agents Chemother 2004 48 4293M300. 

High-level resistance of Mycobacterium tuberculosis to isoniazid (INH) involves... 

Ethambutol inhibits synthesis of one or more metabolites, causing impairment of cell metabolism, arrest of multiplication, and cell death. It is indicated in the treatment of tuberculosis, in combination with other agents in patients with Mycobacterium tuberculosis resistant to isoniazid or rifampin, or when there is intolerance to other antituberculous agents. 

John S. Blanchard received his BS in chemistry from Lake Forest College and obtained his Ph.D. from the laboratory of W. W. Cleland at the University of Wisconsin. After a 3-year NIH-sponsored postdoctoral fellowship, he was appointed assistant professor of biochemistry at the Albert Einstein College of Medicine in New York City in 1983. In 1998, he became the Dan Danciger Professor of Biochemistry. His early research interests focused on the determination of kinetic isotope effects exhibited by flavin-containing enzymes. His collaborative studies on the mechanism of action, and resistance, to isoniazid in Mycobacterium tuberculosis led to his current interests in antibiotic resistance. His present interests include the structure and function of essential biosynthetic enzymes in M. tuberculosis, resistance to aminoglycosides and fluoroquinolones, and proteome-wide identification of acetylated proteins. He is the author of over 140 research papers and 20 reviews and has been awarded seven United States patents. His work has been generously supported by the United States National Institutes of Health for the last 24 years. 

Drug inactivation. Bacterial resistance to aminoglycosides and /3-lactam antibiotics usually results from production of enzymes that modify or destroy the antibiotic, respectively. A variation in this mechanism—the failure of bacteria to activate a prodrug—commonly underlies resistance of Mycobacterium tuberculosis to isoniazid. 

Infections caused by Mycobacterium tuberculosis are treated with combination therapy. The primary dmgs used are isoniazid, rifampin, ethambutol, and pyrazinamide. Highly resistant organisms may require the use of additional agents. Backup drugs include streptomycin, fluoroquinolones, capreomycin, and cycloserine. 

A useful distinction can be made between resistance acquired (a) in the patient and (b) apart from him. Thus, in patients undergoing treatment for tuberculosis with streptomycin, isoniazid, or / -aminosalicylic acid, the causative organism Mycobacterium tuberculosis) often becomes resistant to one or more of these drugs. This has been found to take place, stepwise, by a selection of resistant strains within the patient s body. Resistant staphylococci, on the other hand, are very often acquired from other infected people (Knox, 1962). 

Gopinathan KP, Saroja D (1973) Transduction of isoniazid susceptibility-resistance and streptomycin resistance in mycobacteria. Antimicrob Agents Chemother 4 643-645 Gopinathan KP (1973) Protein synthesis in mycobacterium tuberculosis H 37 Ru and the effect of streptomycin in streptomycin-susceptible and -resistant strains. Antimicrob Agents Chemother 4 205... 

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