Clinical Pharmacology and Therapeutics

MYCOBACTERIUM LEPRAE INFECTION 339
MYCOBACTERIUM LEPRAE INFECTION
Leprosy manifests in two forms, lepromatoid (the organism
being localized to skin or nerve) or lepromatous (a generalized
bacteraemic disease that effects many organs, analogous
to miliary tuberculosis). The main drugs used to treat leprosy
are dapsone, rifampicin and clofazimine. The current World
Health Organization (WHO) regimen for multibacillary
leprosy is:
1. rifampicin, once a month;
2. dapsone, daily unsupervised given for 24 months;
3. clofazimine, daily unsupervised, plus a larger dose under
supervision every four weeks.
Other anti-lepromatous drugs include ofloxacin, minocycline,
clarithromycin (see Chapter 43) and thalidomide.
DAPSONE
Uses
Dapsone (4,4-diaminodiphenyl sulphone) is a bacteriostatic
sulphone. It has been the standard drug for treating all forms
of leprosy, but irregular and inadequate duration of treatment
as a single agent has produced resistance. Dapsone is used to
treat dermatitis herpetiformis, as well as leprosy, pneumocystis
and, combined with pyrimethamine, for malaria prophylaxis.
Mechanism of action
Dapsone is a competitive inhibitor of dihydropteroate (folate)
synthase, thereby impairing production of dihydrofolic acid.
Adverse effects
These include:
• anaemia and agranulocytosis;
• gastro-intestinal disturbances and (rarely) hepatitis;
• allergy and rashes, including Stevens–Johnson
syndrome;
• peripheral neuropathy;
• methaemoglobinaemia;
• haemolytic anaemia, especially in glucose-6-phosphate
dehydrogenase (G6PDH)-deficient patients.
Pharmacokinetics
Dapsone is well absorbed (90%) from the gastro-intestinal
tract. The t 1/2 is on average 27 hours. It is extensively metabolized
in the liver, partly by N-acetylation, with only 10–20% of
the parent drug being excreted in the urine. There is some
enterohepatic circulation.
Drug interactions
The metabolism of dapsone is increased by hepatic enzyme
inducers (e.g. rifampicin) such that its t 1/2 is reduced to 12–15
hours.
Case history
A 27-year old Asian woman presents to her physician with a
history of streaky haemoptysis and weight loss for the past
two months. Clinical examination is reported as normal. Her
chest x-ray shows patchy right upper lobe consolidation and
her sputum is positive for acid-fast bacilli. After having
obtained three sputum samples, she is started, while in hospital,
on a four-drug regimen, pyrazinamide (800 mg/day),
ethambutol (600 mg/day), isoniazid (300 mg/day) and
rifampicin (450 mg/day). She is also prescribed pyridoxine
10 mg daily (to reduce the likelihood of developing peripheral
neuropathy secondary to INH). She tolerates the therapy
well, without evidence of hepatic dysfunction, and her
systemic symptoms improve. Three months later, when
reviewed in the outpatient clinic, she has been off pyrazinamide
and ethambutol for just over one month, and she
complains of daily nausea and vomiting, and is found to be
eight weeks pregnant. She is taking the low-dose oestrogen
contraceptive pill and is adamant that she has been meticulously
compliant with all of her anti-TB medications and the
contraceptive pill.
Question
What therapeutic problem has occurred here and how can
you explain the clinical situation?
How could this outcome have been avoided?
Answer
Ethambutol, isoniazid, rifampicin and pyrazinamide are all
inducers of hepatic CYP450 enzymes. Rifampicin is most
potent. and affects many CYPs. Over a period of several
weeks her drug therapy induced several CYP450 isoenzymes,
especially CYP3A4, so that hepatic metabolism of oestrogen
and progesterone was markedly enhanced, reducing their
systemic concentrations and efficacy as contraceptives.
Therefore, drug-induced hepatic CYP450 enzyme induction
caused a failure of contraceptive efficacy and so the patient
was ‘unprotected’ and became pregnant. The patient should
continue on her anti-TB drug regimen, as there is no evidence
that these agents are harmful to the developing fetus,
except for streptomycin, which should never be given in
pregnancy.
This outcome could have been prevented by advising the
patient to double her usual dose of her oral contraceptives
while taking anti-TB therapy, and to take additional contraceptive
precautions (e.g. barrier methods), or to abandon
the pill altogether and use alternative effective contraceptive
measures (e.g. an intrauterine contraceptive device)
during her anti-TB drug treatment.
FURTHER READING
Joint Tuberculosis Committee of the British Thoracic Society. Control
and prevention of tuberculosis in the United Kingdom: code of
practice 2000. Thorax 2000; 55: 887–901.
Joint Tuberculosis Committee Guidelines 1999. Management of
opportunist mycobacterial infections: Subcommittee of the Joint
Tuberculosis Committee of the British Thoracic Society. Thorax
2000; 55: 210–8.
Joint Tuberculosis Committee of the British Thoracic Society.
Chemotherapy and management of tuberculosis in the United
Kingdom: recommendations 1998. Thorax 1998; 53: 536–48.