Antimycobacterial Drugs-Henry F.Chambers,MD INTRODUCTION Mycobacteria are intrinsically resistant to most antibiotics.Because they grow slowly compared with other bacteria,antibiotics that are most active against growing cells are relatively ineffective. Mycobacterial cells can also be dormant and thus completely resistant to many drugs or killed only very slowly.The lipid-rich mycobacterial cell wall is impermeable to many agents. Mycobacterial species are intracellular pathogens,and organisms residing within macrophages are inaccessible to drugs that penetrate these cells poorly.Finally,mycobacteria are notorious for their ability to develop resistance.Combinations of two or more drugs are required to overcome these obstacles and to prevent emergence of resistance during the course of therapy.The response of mycobacterial infections to chemotherapy is slow,and treatment must be administered for months to years,depending on which drugs are used.The drugs used to treat tuberculosis,atypical mycobacterial infections,and leprosy are described in this chapter. DRUGS USED IN TUBERCULOSIS INTRODUCTION Isoniazid (INH),rifampin (or other rifamycin),pyrazinamide,ethambutol,and streptomycin are the five first-line agents for treatment of tuberculosis.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.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 provide additional coverage if the isolate proves to be resistant to isoniazid,rifampin,or both.The prevalence of isoniazid resistance among US clinical isolates is approximately 10%.Prevalence of resistance to both isoniazid and rifampin(ie, multiple drug resistance)is about 3%. ISONIAZID (INH) Introduction Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains.It is small(MW 137)and freely soluble in water.The structural similarity to pyridoxine is shown below.Antimycobacterial Drugs  Henry F. Chambers, MD INTRODUCTION Mycobacteria are intrinsically resistant to most antibiotics. Because they grow slowly compared with other bacteria, antibiotics that are most active against growing cells are relatively ineffective. Mycobacterial cells can also be dormant and thus completely resistant to many drugs or killed only very slowly. The lipid-rich mycobacterial cell wall is impermeable to many agents. Mycobacterial species are intracellular pathogens, and organisms residing within macrophages are inaccessible to drugs that penetrate these cells poorly. Finally, mycobacteria are notorious for their ability to develop resistance. Combinations of two or more drugs are required to overcome these obstacles and to prevent emergence of resistance during the course of therapy. The response of mycobacterial infections to chemotherapy is slow, and treatment must be administered for months to years, depending on which drugs are used. The drugs used to treat tuberculosis, atypical mycobacterial infections, and leprosy are described in this chapter. DRUGS USED IN TUBERCULOSIS INTRODUCTION Isoniazid (INH), rifampin (or other rifamycin), pyrazinamide, ethambutol, and streptomycin are the five first-line agents for treatment of tuberculosis. 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. 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 provide additional coverage if the isolate proves to be resistant to isoniazid, rifampin, or both. The prevalence of isoniazid resistance among US clinical isolates is approximately 10%. Prevalence of resistance to both isoniazid and rifampin (ie, multiple drug resistance) is about 3%. ISONIAZID (INH) Introduction Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains. It is small (MW 137) and freely soluble in water. The structural similarity to pyridoxine is shown below