Tuberculosis cycloserine

Antituberculin Agents. Rifampin [13292-46-17, a semisynthetic derivative of rifamycin SV, is a most valuable dmg for treatment of tuberculosis, an infection caused by mycobacteria, leprosy, and an expanding range of other infections (23). Cycloserine [64-41-7] has been used to a limited extent for treatment of tuberculosis as a reserve dmg. Although cycloserine inhibits bacteria by interfering with their cell wall biosynthesis, it has toxic side effects in humans in the form of neurotoxicity. Capreomycin [11003-38-6] and to a much lesser extent viomycin [32988-50-4] both of which are peptides, have also been used for treatment of this disease. 

The first stage occurs in the cytoplasm, which results in the synthesis of precursor units—uridindiphospho-A -acetyhnuramyl pentapeptide. Such an antibiotic, for example, cycloserine, the drug most frequently used to treat tuberculosis, blocks synthesis of cell membranes at this stage by competitive inhibition of the stage of introducing alanine into a pentapeptide. 

D-alanine that is involved in bacterial cell wall synthesis. Cycloserine is inhibitory to M. tuberculosis and active against Escherichia coli, S. aureus, and Enterococcus, Nocardia, and Chlamydia spp. It is used in the treatment of MDR tuberculosis and is useful in renal tuberculosis, since most of the drug is excreted unchanged in the urine. 

C. Pyrazinamide is known to cause hyperuricemia and precipitate gouty arthritis. Pyrazinamide-induced gouty arthritis does not respond to uricosuric therapy with probenecid but may respond to acetylsalicylic acid. Cycloserine (A) can cause headaches, confusion, tremors, and seizures, possibly secondary to low levels of magnesium in the cerebrospinal fluid cycloserine should be avoided in patients with epilepsy and mental depression. It is not associated with hyperuricemia. Thiacetazone (B) is an antibiotic that is rarely used in tuberculosis. The most common adverse reactions are general rashes and GI intolerance. Its use is not associated with hy-... 

Cycloserine is an inhibitor of cell wall synthesis and is discussed in Chapter 43. Concentrations of 15-20 mcg/mL inhibit many strains of M tuberculosis. The dosage of cycloserine in tuberculosis is 0.5-1 g/d in two divided doses. Cycloserine is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min. 

Mycobacterium tuberculosis Isoniazid + rifampin + ethambutol + pyrazinamide Streptomycin, moxifloxacin, amikacin, ethionamide, cycloserine, PAS, linezolid... 

Not all mycobacterial infections are caused by M. tuberculosis or M. leprae. These atypical mycobacteria require treatment with secondary medications as well as other chemotherapeutic agents. For example, M. marinum causes skin granulomas, and effective drugs in the treatment of infection are rifampin or minocycline. Mycobacterium fortuitum causes skin ulcers and the medications recommended for treatment are ethambutol, cycloserine, and rifampin in combination with amikacin. 

A number of drugs—aminosalicylic acid [a mee noe sal i SIL ik], ethionamide [e thye on AM ide], cycloserine [sye kloe SER een]— are considered second-line drugs because they are no more effective than the first-line agents and their toxicities are often more serious. Streptomycin, the first antibiotic effective in the treatment of tuberculosis, has been discussed wth the aminoglycosides (see p. 314). Its action is directed against extracellular organisms. 

Mitchell RS, Lester W. Clinical experience with cycloserine in the treatment of tuberculosis. Scand J Respir Dis Suppl 1970 71 94-108. 

This can be achieved in a variety of ways. For instance, it is possible to inhibit an essential pathway in the pathogen that does not exist in the host. o-Cycloserine (1) (Fig. 17.1), for example, inhibits alanine race-mase, an enzyme involved in bacterial cell wall biosynthesis and not found in humans (8, 9). D-Cycloserine is active against a broad spectrum of both gram-positive and gramnegative bacteria (10), but plays its major role in the treatment of tuberculosis (11). Conversely, even if both host and pathogen contain the same enzymes, it may be possi-... 

Patients with CNS tuberculosis usually are treated for longer periods (9 to 12 months instead of 6 months) (Table 110-4). In general, isoniazid, pyrazinamide, ethionamide, and cycloserine penetrate the cerebrospinal fluid (CSF) readily, but rifampin, ethambutol, and streptomycin have variable CNS penetration." Of the quinolones, levofloxacin may be preferred based on current data. Extrapulmonary TB of the soft tissues can be treated with conventional regimens. 

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

M. tuberculosis Isoniazid -1- rifampin - -pyrazinamide -1- ethambutol or streptomycin Moxifloxacin or gatifloxacin cycloserine capreomycin kanamycin amikacin ethionamide clofazimine aminosalicylic acid... 

Cycloserine (seromycin) is a broad-spectrum antibiotic that is used with other drugs in the treatment of tuberculosis when primary agents have failed. Cycloserine is D-4-amino-3-isoxazolidone. 

Cycloserine inhibits M. tuberculosis in concentrations of 5-20 jlg/mL in vitro. There is no crossresistance between cycloserine and other tuberculostatic agents. 

The 4,5-dihydroisoxazole structure is found in some pharmacologically interesting natural products, e.g. in the antibiotic cycloserin 5, which is used in the treatment of tuberculosis. It is also found in the antibiotic acivicine 6, an a-amino acid with antitumour action. 

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