A Textbook of Clinical Pharmacology and Therapeutics

and considered non-infectious when they have been treated for
at least 14 days and three sputum examinations are negative
during a 14-day period. In cases where compliance with a daily
regimen is a problem, the initial two months of triple or quadru-
ple chemotherapy can be given on an intermittent supervised
basis two or three times a week. At the end of the two-month
period, the precise identification and sensitivities of the organ-
ism will be available. If they are fully sensitive, treatment will
continue with daily rifampicinplusisoniazidfor a further four
months. After six months, treatment can usually be discontin-
ued unless the sputum remains positive or the patient is
immunocompromised or poorly compliant. If the initial drug
sensitivities reveal isoniazid resistance, treatment with ethamb-
utolplusrifampicinmust be continued for a total of 12 months.
The duration of chemotherapy will also need to be extended if
eitherisoniazid,rifampicinorpyrazinamidehas to be discon-
tinued because of side effects.
The treatment of tuberculosis which is resistant to multiple
drugs is more difficult, and regimens have to be individual-
ized according to drug sensitivity.

FIRST-LINE DRUGS IN TUBERCULOSIS

THERAPY

ISONIAZID (ISONICOTINIC ACID HYDRAZIDE, INH)

Uses

Isoniazidis bactericidal only to Mycobacterium tuberculosis. It is
used as a single agent for chemoprophylaxis (a strategy used in
some countries, including the USA, that do not use bacillus
Calmette–Guérin (BCG)) as a preventive measure – where other-
wise healthy people who are Mantoux test positive are assumed
to be infected with very small numbers of organisms and are
treated for one year with isoniazidas a single agent. In countries
such as the UK, isoniazidis used only in combination with other
drugs, usually rifampicinpluspyrazinamideand/orethambu-
tol. When using high-dose isoniazid(e.g. treating tuberculous
meningitis) or in patients with special risk factors (e.g. diabetes,
alcoholism),pyridoxineis given to prevent peripheral neuro-
pathy (see Chapter 35).

Mechanism of action

Isoniazidis a competitive inhibitor of bacterial fatty acid syn-
thase II, an enzyme involved in the synthesis of mycolic acid,
a constituent of the M. tuberculosiscell wall. Isoniazidonly
acts on growing bacteria.

Adverse effects

Adverse effects include

• restlessness, insomnia and muscle twitching;


• sensory peripheral neuropathy, observed more commonly
  in slow acetylators, and prevented by supplemental
  pyridoxine;


• biochemical hepatitis, which is clinically significant in 1%
  of patients, and rarely progresses to hepatic necrosis.

Acetylisoniazid may be responsible for this effect, since

enzyme inducers, such as rifampicin, result in higher

production of this metabolite in the liver and are

associated with increased toxicity;

• bone marrow suppression, anaemia and agranulocytosis;


• drug-induced systemic lupus erythematosus.

Pharmacokinetics

Isoniazidis readily absorbed from the gut and is widely dis-

tributed to tissues, including the cerebrospinal fluid (CSF), and

into macrophages where it kills intracellular tubercle bacilli. It

undergoes acetylation in the liver. Between 40 and 45% of peo-

ple in European populations are rapid acetylators (Chapter 14).

Thet1/2ofisoniazidis less than 80 minutes in fast acetylators

and more than 140 minutes in slow acetylators. Approximately

50–70% of a dose is excreted in the urine within 24 hours as a

metabolite or free drug. Abnormally high and potentially toxic

concentrations of isoniazidmay occur in patients who are both

slow acetylators and have renal impairment.

Drug interactions

Isoniazid undergoes hepatic metabolism by CYP450s. It

inhibits the metabolism of several anticonvulsants, including

phenytoinandcarbamazepine, causing toxic concentrations

of these drugs in some patients.

RIFAMPICIN

Uses

Rifampicinis a derivative of rifamycin, which is produced by

Amycolatopsis mediterranei (known as Streptomyces mediter-

ranei). Because of its high lipophilicity, it diffuses easily

through cell membranes to kill intracellular organisms, such as

Mycobacterium tuberculosis. It is also used to treat nasopharyn-

geal meningococcal carriers (it enters well into saliva, tears and

nasal secretions), Legionnaires’ disease and refractory deep-

sited staphylococcal infections (e.g. osteomyelitis).

Mechanism of action

Rifampicinacts by binding to the β-subunit of the DNA-

directed bacterial RNA polymerase, forming a stable drug–

enzyme complex and suppressing initiation of chain formation

in RNA synthesis.

Adverse effects

Large doses of rifampicinproduce toxic effects in about one-

third of patients:

• after a few hours influenza-like symptoms, flushing and
  rashes;


• abdominal pain;


• hepatotoxicity – hepatitis and cholestatic jaundice. It is
  important to monitor hepatic transaminases, particularly
  in patients at high risk of liver dysfunction (e.g.
  alcoholics). Serious liver damage is uncommon.


• thrombocytopenia (rare);


• urine and tears become orangey-pink.

336 MYCOBACTERIAL INFECTIONS