Clinical Pharmacology and Therapeutics

338 MYCOBACTERIAL INFECTIONS
Mechanism of action
Like other aminoglycosides, it is actively transported across
the bacterial cell wall, and its antibacterial activity is due to
specific binding to the P12 protein on the 30S subunit of the
bacterial ribosome, inhibiting protein synthesis.
Adverse effects
These are the same as for other aminoglycosides (see Chapter 43).
The major side effects are eighth nerve toxicity (vestibulotoxicity
more than deafness), nephrotoxicity and, less commonly, allergic
reactions.
Contraindications
Streptomycin is contraindicated in patients with eighth nerve
dysfunction, in those who are pregnant and in those with myasthenia
gravis, as it has weak neuromuscular blocking activity.
Pharmacokinetics
Oral absorption is minimal and it is given intramuscularly.
Streptomycin is mainly excreted via the kidney and renal
impairment requires dose adjustment. The t 1/2 of streptomycin
is in the range of two to nine hours. It crosses the blood–brain
barrier when the meninges are inflamed.
PREPARATIONS CONTAINING COMBINED
ANTI-TUBERCULOUS DRUGS
Several combination preparations of the first-line drugs are
available. They are helpful when patients are established
on therapy, and the reduced number of tablets should aid compliance
and avoid monotherapy. Combined preparations available
include Mynah (ethambutol and INH, in varying
dosages), Rifinah and Rimactazid (containing rifampicin
and INH) and Rifater (containing INH, rifampicin and
pyrazinamide).
Table 44.1: Second-line antituberculous drugs, used mainly for multi-drugresistant
TB
Drug Route Major adverse effects
Ethionamide and Oral Hepatitis, gastro-intestinal and
prothionamide
CNS disturbances, insomnia
PAS Oral Gastro-intestinal, rash, hepatitis
Thiacetazone Oral Gastro-intestinal, rash, vertigo
and conjunctivitis
Capreomycin a i.m. Similar to streptomycin
Kanamycin a i.m. Similar to streptomycin
Cycloserine a Oral Depression, fits and psychosis
PAS, para-aminosalicylic acid.
a Adults only.
sensitivity defined. If the organisms are still sensitive to the
original drugs, then better supervised and prolonged therapy
with these drugs should be prescribed. Alternative drugs are
needed if bacterial resistance has arisen. Organisms that are
resistant to INH, rifampicin, pyrazinamide and ethambutol
are now emerging. Second-line antituberculous drugs are
listed in Table 44.1.
Key points
Mycobacterium tuberculosis infection
M. tuberculosis:
• is a slow-growing, obligate aerobe;
• pulmonary infections are the most common, in the
upper lobes;
• easily and rapidly develops resistance to antituberculous
drugs.
TUBERCULOSIS AND THE ACQUIRED
IMMUNE DEFICIENCY SYNDROME
It is difficult to eradicate the tubercle bacillus in patients with
HIV infection. The absence of a normal immune defence
necessitates prolonged courses of therapy. Treatment is continued
either for nine months or for six months after the time
of documented culture negativity, whichever is longer.
Quadruple drug therapy should be used initially, because of
increasing multi-drug resistance in this setting. Adverse drug
reactions and interactions are more common in HIV-positive
patients, who must be carefully monitored.
SECOND-LINE DRUGS AND TREATMENT
OF REFRACTORY TUBERCULOSIS
The commonest cause of M. tuberculosis treatment failure or
relapse is non-compliance with therapy. The previous drug
regimen used should be known and the current bacterial
Key points
Mycobacterium tuberculosis treatment
• Treatment is with drug combinations to minimize the
development of resistance.
• Triple (pyrazinamide plus rifampicin plus INH) or
quadruple (pyrazinamide plus rifampicin plus INH and
ethambutol or streptomycin) therapy is given for the
first two months.
• Two drugs (usually rifampicin and INH, depending on
sensitivity) are given for a further four months, or
longer if the patient is immunosuppressed.
• Formulations containing two (e.g. rifampicin/isoniazid)
or three (e.g. rifampicin/isoniazid/pyrazinamide) drugs
may improve compliance.
• Multi-drug-resistant M. tuberculosis requires four drugs
initially, while awaiting sensitivity results.
• Drug combinations using second-line agents (e.g.
ethionamide, cycloserine, capreomycin), based on
sensitivities, are required to treat multi-drug-resistant
M. tuberculosis. These drugs are toxic and should only
be used by a clinician experienced in their use.