Clinical Pharmacology and Therapeutics

COMMONLY PRESCRIBED ANTIBACTERIAL DRUGS 329
Mechanism of action
Macrolides bind to bacterial 50S ribosomes and inhibit protein
synthesis.
Pharmacokinetics
Well absorbed orally and distributed adequately to most sites
except the brain, macrolides are inactivated by hepatic
N-demethylation, 15% being eliminated unchanged in the
urine. Food delays absorption but may reduce gastro-intestinal
side effects.
Adverse effects
Erythromycin is remarkably safe and may be used in pregnancy
and in children. Nausea, vomiting, diarrhoea and abdominal
cramps are the most common adverse effects reported, related to
direct pharmacological actions rather than allergy. Cholestatic
jaundice has been reported following prolonged use.
Intravenous administration frequently causes local pain and
phlebitis.
Drug interactions
Erythromycin inhibits cytochrome P450 and causes accumulation
of theophylline, warfarin and terfenadine. This can
result in clinically important adverse effects.
AZITHROMYCIN AND CLARITHROMYCIN
Each of these has greater activity than erythromycin against
H. influenzae. Azithromycin is less effective against Grampositive
bacteria than erythromycin, but has a wider spectrum
of activity against Gram-negative organisms. Clarithromycin
is an erythromycin derivative with slightly greater activity
than the parent compound; tissue concentrations are higher
than with erythromycin. It is given twice daily.
Azithromycin and clarithromycin are more expensive than
erythromycin, but cause fewer gastro-intestinal side effects.
TETRACYCLINES
Uses
Tetracyclines (e.g. tetracycline, oxytetracycline, doxycycline)
have a broad range of antibacterial activity covering both
Gram-positive and Gram-negative organisms and, in addition
organisms such as Rickettsia, Chlamydia and Mycoplasma. They
are used in atypical pneumonias and chlamydial and rickettsial
infections, and remain useful in treating exacerbations
of chronic bronchitis or community-acquired pneumonia.
They are not used routinely for staphylococcal or streptococcal
infections because of the development of resistance.
Tetracyclines are used in the long-term treatment of acne
(Chapter 51).
Mechanism of action
Tetracyclines bind to the 30S subunit of bacterial ribosomes
and prevent binding of the aminoacyl-tRNA to the ribosome
acceptor site, thereby inhibiting protein synthesis.
Adverse effects
These include:
1. nausea, vomiting and diarrhoea (pseudomembranous
colitis due to Clostridium difficile reported occasionally);
2. hypersensitivity reactions (including rash, exfoliative
dermatitis, Stevens–Johnson syndrome, urticaria,
angioedema, anaphylaxis, pericarditis);
3. worsening of renal failure;
4. hepatotoxicity (rare);
5. discoloration and damage of the teeth and bones of the
fetus if the mother takes tetracyclines after the fifth month
of pregnancy, and of children; they should therefore be
avoided in pregnancy and children under 12 years.
Pharmacokinetics
Tetracyclines are well absorbed orally when fasting, but their
absorption is reduced by food and antacids. They undergo
elimination by both the liver and the kidney. The half-life
varies between different members of the group, ranging from
six to 12 hours. The shorter-acting drugs are given four times
daily and the longer-acting ones once daily. Doxycycline is
given once daily, can be taken with food and is not contraindicated
in renal impairment.
Drug interactions
Tetracyclines chelate calcium and iron in the stomach, and
their absorption is reduced by the presence of antacids or
food.
SODIUM FUSIDATE
Uses
Fusidic acid is combined with other drugs to treat staphylococcal
infections, including penicillin-resistant strains. It penetrates
tissues (including bone) well. It is normally used in
conjunction with flucloxacillin for serious staphylococcal
infections. It is also available as eyedrops for the treatment of
bacterial conjunctivitis.
Mechanism of action
It inhibits bacterial protein synthesis.
Adverse effects
Adverse effects are rare, but include cholestatic jaundice.
Pharmacokinetics
When administered either orally or intravenously, its half-life
is four to six hours and it is excreted primarily via the liver.
VANCOMYCIN
Uses and antibacterial spectrum
Vancomycin is valuable in the treatment of resistant infections
due to Staphylococcus pyogenes. It is also rarely used to treat