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SULPHONAMIDES

Sulohadimide and sulphadiazine are well absorbed following oral administration. They are
metabolized mainly by acctylabon the rate of which is bimodally distributed (i.e. there are
slow and fast acetylators-see hydralizine, Chapter 15, for another example). These drugs are
used for treating ‘simple’ urinary tract infections but many Escherichia coli strains are
resistant.

Adverse effects. The most common side effects are allergic reactions and include skin rashes
( morbiliform or urticarial), sometimes with a fever. Much less common are more serious
reaction, e.g. the Stevens- Johnson syndrome, which is a form of erythema multiforme with a
high mortality rate. Sulphonamides with a low solubility such as sulphadiazine may crystal
lize from the urine in the kidneys ( crystalluria), causing damage. This can be prevented by
making the urine alkaline with sodium bicarbonate and by maintaining high fluid intake. It is
not a problem with more soluble sulphonamides, such as sulphamethoxacole. Various blood
dyscrasias may occur, rarely, including agranulocytosis, aplastic anemia and haemolytic
anaemia (especially in patients with glucose phosphodehydrogenase deficiency).

Sulphonamides should not be given to neonates or women in late pregnancy because they
displace bilirubin from plasma proteins. The increase in unbound bilirubin may result in it
being deposited in the neonatal brain, where it may cause characteristic yellow staining and
widespread destructive changes known as kernicterus.

Trimethoprim is well absorbed orally and can be given by injection. It is sometimes used
sometimes used alone for respiratory tract infection, but it has relatively poor activity against
streptococcus pneumoniae and streptococcus pyogenes. Cotrimoxazole (trimethoprim
combined with sulphamethoxazole) is used in urinary tract infections (E.coli), respiratory
infections (Haemophillus influenzae and pneumococci) and in high doses, unusual infections
such as toxoplasmosis and pneumocystis. The side effects of cotrimoxacole are mainly those
of the sulphonamide.

QUINOLONES

Nalidixic acid was the first 4=quinolone found to have antibanterial activity, but it does not
achieve systemic antibacterial levels and has been used only for urinary tract infections .
Ciprofloxacin has a 6-fluoro substituent which confers greatly enhanced antibacterial potency
against both gram positive and especially gram negative organism, including E. Coli,
Pseudomonas aeruginosa, salmonella and campylobacter. Resistance, so far, is uncommon.
Ciprofloxacin is well absorbed orally and can be given intravenously. It is eliminated, largely
unchanged, mainly by the kidneys. Side effects are infrequint but include nausea, vomiting,
rashes, dizziness and headache. Convulsions may occur because the quinolones are GABA
antagonis.

36 Antimicrobial Drugs That Inhibit Cell Wall Synthesis: Penicilins, Cephalosporins and
Vancomycin

The structure of the penicilins (top left) and cephalosporins (top right) share the common
feature of a beta lactam ring (B) . the integrity of which is esestial for antimicrobial activity.
Modification of group R1 and R2 have resulted in many semisynthetic antibiotics. Some of
which are acid resistants (and orally active), have a wide spectrum of antimicrobial activity,
or are resistant to bacterial beta lactamases. The penicilins (left) are the most important
antibiotics , the cephalosporins (right) having few specific indications. The beta lactam
antibiotics are bactericidal. They produce their antimicrobial action by preventing the cross
linkage between the lincar peptidoglycan polymerchains that make up the cell wall, e.g. by a
pentaglycine bridge. This action is because a part of their structure resembles the D-alanyl-D-
alanine of the peptide chains of the bacterial cell wall.

Benzylpenicilin was the first of the penicilins and remains important, but it is largely
destroyed by gastruc acid and must be given by injection. Phenoxymetthylpenicilin has a
similar antimicrobial spectrum, but is active orally. Many bacteria (including most
staphylococci) are resistant to benzylpenicilin because they produce enzymes (beta
lactamases, penicillinase) which open the beta lactam ring. The genetic control of beta
lactamases often resides in transmissible plasmids (Chapter 35). Some penicilins e.g.
flucloxacilin are effective against beta lactamase producing staphylococci.