Resistance to isoniazid

The drug can likely be used safely in older children but should be used with caution in children less than 5 years of age, in whom visual acuity cannot be monitored. In younger children, ethambutol at the dose of 15 mg/kg per day can be used if there is suspected or proven resistance to isoniazid or rifampin. 

W. B. Davis, D. M. Phillips, Differentiation of Catalases in Mycobacterium phlei on the Basis of Susceptibility to Isoniazid Association with Peroxidase and Acquired Resistance to Isoniazid , Antimicrob. Agents Chemother. 1977, 12, 529-533. 

Isoniazid (INH), rifampin, pyrazinamide, ethambutol, and streptomycin are the five first-line agents for treatment of tuberculosis (Table 47-1). Isoniazid and rifampin are the two most active drugs. An isoniazid-rifampin combination administered for 9 months will cure 95-98% of cases of tuberculosis caused by susceptible strains. The addition of pyrazinamide to an isoniazid-rifampin combination for the first 2 months allows the total duration of therapy to be reduced to 6 months without loss of efficacy (Table 47-2). In practice, therapy is initiated with a four-drug regimen of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin until susceptibility of the clinical isolate has been determined. Neither ethambutol nor streptomycin adds substantially to the overall activity of the regimen (ie, the duration of treatment cannot be further reduced if either drug is used), but they do provide additional coverage should the isolate prove to be resistant to isoniazid, rifampin, or both. Unfortunately, such resistance occurs in up to 10% of cases in the United States. Most patients with tuberculosis can be treated entirely as outpatients, with... 

As a rule, a regimen of two, three, or four of the five first-line antituberculosis drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin) is used in tuberculosis (1). The 6-month short-course regimen consists of isoniazid, rifampicin, and pyrazinamide for 2 months, followed by isoniazid and rifampicin for 4 months (1). It may be advisable to include ethambutol in the initial phase when isoniazid resistance is suspected or if the prevalence of primary resistance to isoniazid is over 4% in new cases. A 9-month regimen consisting of isoniazid and rifampicin is also highly successful (1). Treatment should always include at least two drugs to which the mycobacteria are susceptible. 

Isoniazid. Isoniazid is one of the two most important TB drugs. It is highly specific for mycobacteria, with an MIC againstM tuberculosis of 0.01 to 0.25 mcg/mL. Most NTM such as M. avium are resistant to isoniazid, although M. kansasii and M. xenopi are susceptible. The... 

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

Goble M, Iseman MD, Madsen LA, et al. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993 328 527-532. 

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. 

Isoniazid monotherapy leads to resistance. This resistance typically develops after a few weeks of therapy but can vary. Approximately 1 in 1(P tubercle bacilli will be genetically resistant to isoniazid since tuberculous cavities may contain as many as ICP microorganisms, it is not surprising that isoniazid selects for resistant bacteria. The incidence of primary resistance to isoniazid in the... 

Mutations in the kcUG gene result in the underproduction of mycobacterial catalase, an enzyme that bioactivates INH. facilitating its interaction with its target, keto-acyl carrier protein synthetase. The result is high-level resistance to isoniazid but without cross-resistance to pyrazinamide. Mutations in the inhA gene result in low-level resistance, with cross-resistance to pyrazinamide. The answer is (B). 

For known resistance to isoniazid (or if the patient cannot tolerate the drug), the currently recommended regimen involves directly observed therapy (EXDT) with rifampin plus ethambutol plus pyrazinamide for 18 months (< 12 months after a negative sputum culture is reported). 

Figure 17.2 shows spectra of M. tuberculosis BCG, sensitive and resistant to isoniazid, as well as spectra of BCG cells sensitive and resistant to the antitubercular diphenylthiourea derivative, namely Su 1906. The shoulder at 1735 cm" and the bands at 1409 and 893 cm" became exaggerated with the development of resistance. 

Multidrug-resistant tuberculosis (MDR-TB) no longer can be cured by the leading TB antibiotics isoniazid (2) and rifampicin (3). Extensively drug-resistant TB (XDR-TB) is a form of TB caused by organisms that are resistant to isoniazid (2) and rifampicin (3), as well as fluoroquinolones such as ciprofloxacin (7), and ofloxacin (8) and any of the second-line anti-TB injectable drugs such as amikacin, kanamycin, or capreomycin. 

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