A Textbook of Clinical Pharmacology and Therapeutics

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

Streptomycinis contraindicated in patients with eighth nerve
dysfunction, in those who are pregnant and in those with myas-
thenia gravis, as it has weak neuromuscular blocking activity.

Pharmacokinetics

Oral absorption is minimal and it is given intramuscularly.
Streptomycinis mainly excreted via the kidney and renal
impairment requires dose adjustment. The t1/2of 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 com-
pliance and avoid monotherapy. Combined preparations avail-
able include Mynah (ethambutol and INH, in varying
dosages), Rifinahand Rimactazid (containingrifampicin
and INH) and Rifater (containing INH, rifampicin and
pyrazinamide).

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 con-
tinued 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. tuberculosistreatment failure or
relapse is non-compliance with therapy. The previous drug
regimen used should be known and the current bacterial

338 MYCOBACTERIAL INFECTIONS

Key points

Mycobacterium tuberculosisinfection

M. tuberculosis:

• is a slow-growing, obligate aerobe;


• pulmonary infections are the most common, in the
  upper lobes;


• easily and rapidly develops resistance to anti-
  tuberculous drugs.

Key points

Mycobacterium tuberculosistreatment

• 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-resistantM. tuberculosisrequires 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.

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,pyrazinamideandethambutol

are now emerging. Second-line antituberculous drugs are

listed in Table 44.1.

Table 44.1:Second-line antituberculous drugs, used mainly for multi-drug-

resistant 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

Capreomycina i.m. Similar to streptomycin

Kanamycina i.m. Similar to streptomycin

Cycloserinea Oral Depression, fits and psychosis

PAS, para-aminosalicylic acid.

aAdults only.