Methenamine is used internally as a urinary antiseptic for the treatment of chronic urinary tract infections. The free base has practically no bacteriostatic power; formaldehyde release at the lower pH of the kidney is required. To optimize the antibacterial effect, an acidifying agent such as sodium biphosphate or ammonium chloride generally accompanies the administration of methenamine.
Certain bacterial strains are resistant to the action of methenamine because they elaborate urease, an enzyme that hydrolyzes urea to form ammonia. The resultant high urinary pH prevents the activation of methenamine, rendering it ineffective. This problem can be overcome by the coadministration of the urease inhibitor acetohydroxamic acid (Lithostat).
Hexamethylenetetramine mandelate (Mandelamine) is a white crystalline powder with a sour taste and practically no odor. It is very soluble in water and has the advantage of providing its own acidity, although in its use, the custom is to carry out a preliminary acidification of the urine for 24 to 36 hours before administration.
Methenamine hippurate (Hiprex) is the hippuric acid salt of methenamine. It is readily absorbed after oral administration and is concentrated in the urinary bladder, where it exerts its antibacterial activity. Its activity is increased in acid urine.
Pain and discomfort frequently accompany bacterial infections of the urinary tract. For this reason, certain analgesic agents, such as the salicylates or phenazopyridine, which concentrate in the urine because of their solubility properties, are combined with a urinary anti-infective agent.
Phenazopyridine hydrochloride, 2,6-diamino-3-(phenyla-zopyridine hydrochloride (Pyridium), is a brick-red, fine crystalline powder. It is slightly soluble in alcohol, in chloroform, and in water.
Phenazopyridine hydrochloride was formerly used as a urinary antiseptic. Although it is active in vitro against staphylococci, streptococci, gonococci, and E. coli, it has no useful antibacterial activity in the urine. Thus, its present utility lies in its local analgesic effect on the mucosa of the urinary tract.
Usually, phenazopyridine is given in combination with urinary antiseptics. For example, it is available as Azo-Gantrisin, a fixed-dose combination with the sulfonamide antibacterial sulfisoxazole, and as Urobiotic, a combination with the antibiotic oxytetracycline and the sulfonamide sulfamethi-zole (Chapter 8). The drug is rapidly excreted in the urine, to which it gives an orange-red color. Stains in fabrics may be removed by soaking in a 0.25% solution of sodium dithionite.
Ever since Koch identified the tubercle bacillus, Mycobacterium tuberculosis, there has been keen interest in the development of antitubercular drugs. The first breakthrough in antitubercular chemotherapy occurred in 1938 with the observation that sulfanilamide had weak bacteriostatic properties. Later, the sulfone derivative dapsone (4,4'-diamin-odiphenylsulfone) was investigated clinically. Unfortunately, this drug, which is still considered one of the most effective drugs for the treatment of leprosy and also has useful anti-malarial properties, was considered too toxic because of the high dosages used. The discovery of the antitubercular activity of the aminoglycoside antibiotic streptomycin by Waksman et al. in 1944 ushered in the modern era of tuberculosis treatment. This development was quickly followed by discoveries of the antitubercular properties of p-aminosali-cylic acid (PAS) first and then, in 1952, of isoniazid. Later, the usefulness of the synthetic drug ethambutol and, eventually, of the semisynthetic antibiotic rifampin was discovered.
Combination therapy, with the use of two or more antitubercular drugs, has been well documented to reduce the emergence of strains of M. tuberculosis resistant to individual agents and has become standard medical practice. The choice of antitubercular combination depends on various factors, including the location of the disease (pulmonary, urogenital, gastrointestinal, or neural), the results of susceptibility tests and the pattern of resistance in the locality, the physical condition and age of the patient, and the toxicities of the individual agents. For some time, a combination of isoniazid and ethambutol, with or without streptomycin, was the preferred choice of treatment among clinicians in this country. However, the discovery of the tuberculocidal properties of ri-fampin resulted in its replacement of the more toxic antibiotic streptomycin in most regimens. The synthetic drug pyrazi-namide, because of its sterilizing ability, is also considered a first-line agent and is frequently used in place of ethambutol in combination therapy. Second-line agents for tuberculosis include the antibiotics cycloserine, kanamycin, and capre-omycin and the synthetic compounds ethionamide and PAS.
A major advance in the treatment of tuberculosis was signaled by the introduction of the antibiotic rifampin into therapy. Clinical studies indicated that when rifampin is included in the regimen, particularly in combination with iso-niazid and ethambutol (or pyrazinamide), the period required for successful therapy is shortened significantly. Previous treatment schedules without rifampin required maintenance therapy for at least 2 years, whereas those based on the isoni-azid-rifampin combination achieved equal or better results in 6 to 9 months.
Once considered to be on the verge of worldwide eradication, as a result of aggressive public health measures and effective chemotherapy, tuberculosis has made a comeback of alarming proportions in recent years.65 A combination of factors has contributed to the observed increase in tuberculosis cases, including the worldwide AIDS epidemic, the general relaxation of public health policies in many countries, the increased overcrowding and homelessness in major cities, and the increased emergence of multidrug-resistant strains of M. tuberculosis.
The development of drugs useful for the treatment of leprosy has long been hampered, in part, by the failure of the causative organism, Mycobacterium leprae, to grow in cell culture. However, the recent availability of animal models, such as the infected mouse footpad, now permits in vivo drug evaluations. The increasing emergence of strains of M. leprae resistant to dapsone, long considered the mainstay for leprosy treatment, has caused public health officials to advocate combination therapy.
Mycobacteria other than M. tuberculosis and M. leprae, commonly known as "atypical" mycobacteria, were first established as etiological agents of diseases in the 1950s. Atypical mycobacteria are primarily saprophytic species that are widely distributed in soil and water. Such organisms are not normally considered particularly virulent or infectious. Diseases attributed to atypical mycobacteria are on the increase, however, in large part because of the increased numbers of immunocompromised individuals in the population resulting from the AIDS epidemic and the widespread use of immunosuppressive agents with organ transplantation.
The most common disease-causing species are Mycobac-terium avium and Mycobacterium intracellulare, which have similar geographical distributions, are difficult to distinguish microbiologically and diagnostically, and are thus considered a single complex (MAC). The initial disease attributed to MAC resembles tuberculosis, but skin and musculoskeletal tissues may also become involved. The association of MAC and HIV infection is dramatic. An overwhelming disseminated form of the disease occurs in severely immunocom-promised patients, leading to high morbidity and mortality. Another relatively common atypical mycobacterium, Myco-bacterium kansasii, also causes pulmonary disease and can become disseminated in immunocompromised patients. Patients infected with M. kansasii can usually be treated effectively with combinations of antitubercular drugs. MAC infections, in contrast, are resistant to currently available chemotherapeutic agents.
Isonicotinic acid hydrazide, isonicotinyl hydrazide, or INH (Nydrazid) occurs as a nearly colorless crystalline solid that is very soluble in water. It is prepared by reacting the methyl ester of isonicotinic acid with hydrazine.
Isoniazid is a remarkably effective agent and continues to be one of the primary drugs (along with rifampin, pyra-zinamide, and ethambutol) for the treatment of tuberculosis. It is not, however, uniformly effective against all forms of the disease. The frequent emergence of strains of the tubercle bacillus resistant to isoniazid during therapy was seen as the major shortcoming of the drug. This problem has been largely, but not entirely, overcome with the use of combinations.
The activity of isoniazid is manifested on the growing tubercle bacilli and not on resting forms. Its action, which is considered bactericidal, is to cause the bacilli to lose lipid content by a mechanism that has not been fully elucidated. The most generally accepted theory suggests that the principal effect of isoniazid is to inhibit the synthesis of mycolic acids,66,67 high-molecular-weight, branched ^-hydroxy fatty acids that constitute important components of the cell walls of mycobacteria.
A mycobacterial catalase-peroxidase enzyme complex is required for the bioactivation of isoniazid.68 A reactive species, generated through the action of these enzymes on the drug, is believed to attack a critical enzyme required for mycolic acid synthesis in mycobacteria.69 Resistance to INH, estimated to range from 25% to 50% of clinical isolates of INH-resistant strains, is associated with loss of cata-lase and peroxidase activities, both of which are encoded by a single gene, katG.10 The target for the action of INH has recently been identified as an enzyme that catalyzes the NADH-specific reduction of 2-trans-enoylacyl carrier protein, an essential step in fatty acid elongation.11 This enzyme is encoded by a specific gene, inhA, in M. tuberculosis.72 Approximately 20% to 25% of INH-resistant clinical isolates display mutations in the inhA gene, leading to altered proteins with apparently reduced affinity for the active form of the drug. Interestingly, such INH-resistant strains also display resistance to ethionamide, a structurally similar antitubercular drug.72 On the other hand, mycobacterial strains deficient in catalase-peroxidase activity are frequently susceptible to ethionamide.
Although treatment regimens generally require long-term administration of isoniazid, the incidence of toxic effects is remarkably low. The principal toxic reactions are peripheral neuritis, gastrointestinal disturbances (e.g., constipation, loss of appetite), and hepatotoxicity. Coadministration of pyridoxine is reported to prevent the symptoms of peripheral neuritis, suggesting that this adverse effect may result from antagonism of a coenzyme action of pyridoxal phosphate. Pyridoxine does not appear to interfere with the antitubercular effect of isoniazid. Severe hepatotoxicity rarely occurs with isoniazid alone; the incidence is much higher, however, when it is used in combination with rifampin.
Isoniazid is rapidly and almost completely absorbed following oral administration. It is widely distributed to all tissues and fluids within the body, including the CSF. Approximately 60% of an oral dose is excreted in the urine within 24 hours in the form of numerous metabolites as well as the unchanged drug. Although the metabolism of iso-niazid is very complex, the principal path of inactivation involves acetylation of the primary hydrazine nitrogen. In addition to acetylisoniazid, the isonicotinyl hydrazones of pyruvic and a-ketoglutaric acids, isonicotinic acid, and isonicotinuric acid have been isolated as metabolites in hu-mans.73 The capacity to inactivate isoniazid by acetylation is an inherited characteristic in humans. Approximately half of persons in the population are fast acetylators (plasma half-life, 45-80 minutes), and the remainder slow acetyla-tors (plasma half-life, 140-200 minutes).
2-Ethylthioisonicotinamide (Trecator SC) occurs as a yellow crystalline material that is sparingly soluble in water. This nicotinamide has weak bacteriostatic activity in vitro but, because of its lipid solubility, is effective in vivo. In contrast to the isoniazid series, 2-substitution enhances activity in the thioisonicotinamide series.
Ethionamide is rapidly and completely absorbed following oral administration. It is widely distributed throughout the body and extensively metabolized to predominantly inactive forms that are excreted in the urine. Less than 1% of the parent drug appears in the urine.
Ethionamide is considered a secondary drug for the treatment of tuberculosis. It is used in the treatment of isoniazid-resistant tuberculosis or when the patient is intolerant to isoniazid and other drugs. Because of its low potency, the highest tolerated dose of ethionamide is usually recommended. Gastrointestinal intolerance is the most common side effect associated with its use. Visual disturbances and hepatotoxicity have also been reported.
Pyrazinecarboxamide (PZA) occurs as a white crystalline powder that is sparingly soluble in water and slightly soluble in polar organic solvents. Its antitubercular properties were discovered as a result of an investigation of hetero-cyclic analogs of nicotinic acid, with which it is isosteric. Pyrazinamide has recently been elevated to first-line status in short-term tuberculosis treatment regimens because of its tuberculocidal activity and comparatively low short-term toxicity. Since pyrazinamide is not active against metabol-ically inactive tubercle bacilli, it is not considered suitable for long-term therapy. Potential hepatotoxicity also obviates long-term use of the drug. Pyrazinamide is maximally effective in the low pH environment that exists in macrophages (monocytes). Evidence suggests bioactivation of pyrazinamide to pyrazinoic acid by an amidase present in mycobacteria.74
Because bacterial resistance to pyrazinamide develops rapidly, it should always be used in combination with other drugs. Cross-resistance between pyrazinamide and either isoniazid or ethionamide is relatively rare. The mechanism of action of pyrazinamide is not known. Despite its structural similarities to isoniazid and ethionamide, pyrazinamide apparently does not inhibit mycolic acid biosynthesis in mycobacteria.
Pyrazinamide is well absorbed orally and widely distributed throughout the body. The drug penetrates inflamed meninges and, therefore, is recommended for the treatment of tuberculous meningitis. Unchanged pyrazinamide, the corresponding carboxylic acid (pyrazinoic acid), and the 5-hydroxy metabolite are excreted in the urine. The elimination half-life ranges from 12 to 24 hours, which allows the drug to be administered on either once-daily or even twice-weekly dosing schedules. Pyrazinamide and its metabolites are reported to interfere with uric acid excretion. Therefore, the drug should be used with great caution in patients with hyperuricemia or gout.
Ethambutol, (+)-2,2'-(ethylenediimino)-di-1-butanol dihy-drochloride, or EMB (Myambutol), is a white crystalline powder freely soluble in water and slightly soluble in alcohol.
Ethambutol is active only against dividing mycobacteria. It has no effect on encapsulated or other nonproliferating forms. The in vitro effect may be bacteriostatic or bactericidal, depending on the conditions. Its selective toxicity toward mycobacteria appears to be related to the inhibition of the incorporation of mycolic acids into the cell walls of these organisms.
This compound is remarkably stereospecific. Tests have shown that, although the toxicities of the dextro, levo, and meso isomers are about equal, their activities vary considerably. The dextro isomer is 16 times as active as the meso isomer. In addition, the length of the alkylene chain, the nature of the branching of the alkyl substituents on the nitrogens, and the extent of N-alkylation all have a pronounced effect on the activity.
Ethambutol is rapidly absorbed after oral administration, and peak serum levels occur in about 2 hours. It is rapidly excreted, mainly in the urine. Up to 80% is excreted unchanged, with the balance being metabolized and excreted as 2,2'-(ethylenediimino)dibutyric acid and the corresponding dialdehyde.
Ethambutol is not recommended for use alone, but in combinations with other antitubercular drugs in the chemotherapy of pulmonary tuberculosis.
4-Aminosalicylic acid occurs as a white to yellowish white crystalline solid that darkens on exposure to light or air. It is slightly soluble in water but more soluble in alcohol. Alkali metal salts and the nitric acid salt are soluble in water, but the salts of hydrochloric acid and sulfuric acid are not. The acid undergoes decarboxylation when heated. An aqueous solution has a pH of approximately 3.2.
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