Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

METRONIDAZOLE
mended dose and occur within 1–2 days of beginning
administration. It is recommended that fluoroquinolones
be avoided in large breed dogs up to 18 months
of age (12 months for medium breeds, 9 months for
small breeds). If a fluoroquinolone must be used
because there is no suitable alternative, strict exercise
restriction (especially for large breed dogs) and use
of chondroprotectives (see Chapter 13) are advised.
METRONIDAZOLE
Mechanism of action and resistance
Metronidazole is bactericidal to anaerobic bacteria,
probably in a concentration-dependent manner. After
entry into the cell it undergoes reduction to produce
unstable intermediates, some of which have antibacterial
activity. These cause extensive breakage of DNA
strands and inhibit the DNA repair enzyme, DNAase-1.
This reduction reaction occurs under anaerobic conditions
and is insufficient to produce active metabolites in
aerobic bacteria. Hence metronidazole is only active
against those bacteria that are anaerobic. It is also active
against many protozoa but the mechanisms involved are
incompletely understood. Resistance is rare among susceptible
bacteria and involves reduced intracellular drug
activation.
Antibacterial spectrum (Fig. 8.23)
Metronidazole is bactericidal for many Gram-positive
and most Gram-negative obligate anaerobes; its activity
is equal to that of benzylpenicillin and of clindamycin.
It has no effect on aerobic bacteria. It is active against
Balantidium coli, Entamoeba histolytica, Giardia and
Trichomonas. Campylobacter are moderately susceptible.
Helicobacter pylori are commonly susceptible but
the susceptibility of animal-derived Helicobacter spp
has not been established. Resistance is rare amongst
susceptible species.
Gram positive
aerobes
Obligate
anaerobes
Gram negative
aerobes
Penicillinaseproducing
Staphylococcus
+ Giardia, Entomoeba histolytica, Trichomonas and
Balantidium coli.
Fig. 8.23 Antibacterial spectrum for metronidazole.
Clinical applications
● Gastrointestinal infections with Balantidium coli,
Entamoeba histolytica, Giardia, Trichomonas or
anaerobic bacteria.
● Mouth infections, periodontal disease, ulcerative
gingivitis – sometimes used in combination with
spiramycin for these.
● Bacterial overgrowth of the small intestine and
antibiotic-responsive diarrhea (other common drug
choices are tylosin and tetracyclines; choice appears
to reflect the clinician’s preference rather than
empirical data).
● Anaerobic soft tissue infections, especially where
good tissue penetration is important.
● In combination with a fluoroquinolone for serious
sepsis of unknown etiology or spillage of intestinal
contents.
● Metronidazole has some inhibitory action on cellmediated
immunity which may partly account for
its beneficial effects in some cases of diarrhea.
Pharmacokinetics
Metronidazole is relatively well absorbed after oral
administration PO and absorption is enhanced in dogs
by administration with food (in contrast to humans, in
whom absorption is delayed). Bioavailability is high but
varies individually from 50% to 100%. Metronidazole
HCl powder is available for injection IV.
Metronidazole is highly lipophilic and achieves excellent
penetration of tissues, including bone, CNS and
abscesses. It is extensively oxidized and conjugated in
the liver to less active metabolites but about two-thirds
of the dose is excreted in the urine, mostly in an active
form. Elimination half-life is reported to be 4–5 h in
dogs compared with 6–8 h in humans.
Adverse effects
● Adverse effects are uncommon but vomiting, nausea
or inappetence may occur.
● Dose-related neurotoxicity has been reported in
dogs given 67–129 mg/kg/day for 6–12 days. Signs
included severe ataxia, positional nystagmus, seizures
and head tilt.
● Cats often salivate profusely after administration of
metronidazole.
● Inappetence has been noted in horses.
● A marginal and contentious carcinogenic effect has
been observed in some laboratory studies. As a result
metronidazole and other nitroimidazoles are no
longer used in food-producing animals in some
countries.
● Metronidazole may be teratogenic and therefore
should not be used during pregnancy, especially in
the first 3 weeks, unless the benefits to the mother
outweigh potential risks to the fetus.
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