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In the search for improved drug regimens in antituberculosis therapy two have been found to offer distinct advantages over the conventional combination of isoniazid (INH), streptomycin (STM) and para-aminosalicylic acid (PAS). The two new regimens are INH/cthambutaol (EMB) a nd INH/rifampicin.

Initial therapy The tubercular patient's best chance of cure lies in the initial course of therapy and for routine initial treatment of minimal and moderate pulmonary tuberculosis INH (300mg) combined with EMB (25mg/kg/90d, then I5mg/mg/d) in single daily doses is suitable in most cases. The treatment period is 24 months for both drugs. This regimen has the advantages of low toxicity, excellent cure rates, ease of administration and patient acceptance. Studies have shown this regimen to have a drug toxicity of 7.8% and sputum conversion of 94.6% after 4 months therapy compared with 33.7% and 82.3%, respectively, with INH/PAS (12g/d).

For patients with far advanced cavitary tuberculosis 25/15 EMB/INH (450mg/d) plus pyridoxine (50mg/d) in single daily doses is suitable in most cases. Studies have shown 95.9% sputum conversion after six months, with the more rapid onset of sputum conversion in the first month when STM (I g/d) was added to the regimen, thereafter little diff~renc_e. H~weve~, dro~u~ r~t~ due to drug toxicity was higher when STM was included.

INH ( 300mg/d) combined with rifampicin (600mg/d) in single daily doses has given sputum conversion rates approaching I 00% within 4- 6 months and this regimen can be used for initial therapy, but opinions differ as to whether it should be reserved for cases failing to respond to INH/EMB in order to guard against increasing resistance to rifampicin.

"We feel that the routine initial treatment of minimal and moderate pulmonary tuberculosis can be carried out with JNH/ EMB. However, in patients with far advanced cavitary disease, INN/rifampicin should be used. Other drug combinations do not offer any advantage over either of these regimens in initial therapy and their use is not recommended."

Short-term therapy Alt hough a combination of INH/rifampicin and STM gave almost 100% sputum conversion after 6 months daily treatment and less than 2% relapses within 18 months after therapy was discontinued in a study of patients with moderately to far advanced tuberculosis, a further study s howed ambiguous results when STM was omitted from the regimen. A relapse rate of 5% was found after 12 months follow-up, although only one patient failed to convert his sputum after 6 months treatment. This seems to indicate that while INA/rifampicin converts sputum to negative in 6 months the combination needs to be given for longer. An extremely low relapse rate has been achieved with the addition of EMB to INH/ rifampicin and 6-12 months therapy. Short-term therapy for pulmonary tubercu­losis seems feasible but presently suitable only to those situations in which 1 8- 24 month therapy cannot be carried out.

Intermittent therapy After an initial period of 2- 6 months daily therapy, intermittent therapy should be considered as a substitute for long term hospitaUsation. If patients cannot be relied on to take daily medication at home, they can be treated · twice a week as outpatients. INH (1 5mg/kg) with either STM (25-30mg/kg) or EMB (50mg/kg) plus pyridoxine (SOmg/d) in bi-weekly doses is a regimen which has produced acceptable cure rates in a 24 month treatment period. Unfortunately, rifampicin has shown an adverse reaction rate as high as 20% when given twice a week, usually after 6 months therapy. The most common reaction i s systemic - fever, joint pain, abdominal and muscle cramps or an ant ibody-induced thrombocvtooenia. On ce a week rifamoicin (30me/k1!) combined with EMB (iOOmg/kg) ., ' . ' - ..,,

INPHARMA 24th July, 1976 p16

or INH (1 Smg/kg) has given sputum conversion without severe side-effects. However, rifampicin is not yet recommended for intermittent therapy.

Drug toxicity Isoniazid (300mg/d) is likely to give a usually benign change in liver function in from 10-20% of patients. A type of progressive hepatocellular damage occurs rarely and is almost non-existent in patients under 20 years old; it thereafter ranges in frequency from 0.3% to 2.3% at age SO and above. INH has also been involved in occasional cases of massive liver atrophy with death, although other contributory factors have been present. Peripheral neuropathy is the most common side-effect of INH but this is infrequent at a dosage 300mg/d and routine use of pyridoxine is not recommended unless pre-existing neuropathy is present. Other side-effects and reactions include central nervous system stimulation or depression, lupus erythematosus or rheumatoid·like syndromes, haematological disturbances, and hypersensitivity.

Ethambutol's major serious side-effect, optic neuritis, is dose related and is not common at dosages of 1 S or 25mg/kg/d, but is primarly observed at doses of50mg/kg/d. However, patients should be monitored monthly for visual acuity and colour discrimination.

Rifampicin (600mg/d) has produced a reaction rate of about 1%. Occasional elevation of liver enzymes and bilirubin values have been noted, isolated occurrences of clinical hepatitis and rare cases of generalised hypersensitivity. Some studies have shown reaction rates of 3-S%, with up to 18% incidence of asymptomatic rises in transaminase levels. Rifampicin/INH seems slightly more likely to induce hepatocellular damage than rifampicin/EMB. Rifampicin has been shown to diminish the activity of o ral contraceptives.

Streptomycin affects the vestibular branch of the 8th cranial nerve and to a lesser extent the auditory branch, also renal insufficiency can be observed. Monthly audiograms and careful monitoring of renal function is advisable, and the total dose should be limited to lg/d for 90 days, and then lg three times a week for 60 days.

Corticosteroids They are not indicated in routine therapy but have limited application in severely toxic patients. The benefits of corticosteroids are limited to the first l-3 months when there may be more rapid loss of fever, increased weight gain and feeling of well being. Corticosteroids must not be used unless antitubercl)lous coverage is adequate and steroid-induced side-effects are evaluated. Rapid progression of tuberculous lesions during steroid therapy and clinical or radiographic worsening after steroid withdrawal have been reported. Currently recommended dose is the equivalent of 40mg/d prednisone for up to six weeks and tapered gradually.

Pi_nsker, K.L. and Koerner, S.K.: American Journal of Hospital Pharmacy 33: 275 - 283 (Mar 1976) (37 references]