toxicity of azoles

1. Metronidazole
Toxicity
Duaa sadiq

2. Metronidazole is a bactericidal
antibiotic, antiprotozoal, and
amebicide commonly used in both
human and veterinary medicine to
treat anaerobic infections, giardiasis,
and protozoal organisms. It also has
effects on cell-mediated immunity and
is used in the treatment of
inflammatory bowel disease

4. Metronidazole is a very safe
medication with few side effects, but
toxicity is well-recognized in human
medicine and companion animals.
Acute signs of toxicosis occur most
often at doses greater than 60
mg/kg/day, but toxicity has been
reported with chronic administration
as low as 33 mg/kg/day.

5. With extended use, metronidazole can lead to
neurotoxicity. There have been few reports in the
literature demonstrating the classical MRI findings
associated with metronidazole-induced cerebellar
toxicity and the reversal of both clinical symptoms
and imaging findings with cessation of the
medication.

6. Magnetic resonance imaging (MRI)
abnormalities have been described with
metronidazole overdosage; however, it is
not clear why only few patients develop
these abnormalities and also with serum
levels in the therapeutic range.[2] MRI brain
lesions are hyperintense on T2-weighted
and FLAIR sequences with no mass effect.
The lesions may show restricted diffusion
and are non-enhancing on contrast
administration.

8. Characteristically, these lesions are mostly symmetric
and bilateral involving cerebellar dentate nuclei,
midbrain, dorsal pons (the vestibular nucleus,
abducens nucleus, and superior olivary nucleus),
splenium of the corpus callosum, and the dorsal
medulla. Unusual sites are the inferior olivary nucleus
and cerebellar white matter.[3-6] MR spectroscopy
abnormalities have been postulated to a reversible
mitochondrial dysfunction in susceptible
patients.Reversal of clinical as well as MRI
abnormalities after cessation of drug intake is
characteristic feature of metronidazole intoxication

9. Mechanism of toxicity
The mechanism of toxicity is uncertain. It
has been hypothesized that metronidazole
binds to benzodiazepine receptor sites on
GABA channels of cerebellar and central
vestibular inhibitory interneurons. Reduced
inhibition from these interneurons leads to
hyperexcitability of the cerebellum and
central vestibular nuclei and, thus

10. clinical signs of cerebellar or central
vestibular dysfunction. This theory is
supported by the recent finding that
administration of a benzodiazepine
(diazepam) shortens the duration of
clinical signs related to metronidazole
toxicity

11. Signalment
Metronidazole toxicosis
occurs in all ages and
breeds of dogs and cats

12. The onset of clinical signs appears to be
dose-dependent. Acute onset of signs
after starting metronidazole is more
common with higher doses ( >
60mg/kg/day), while delayed onset
occurs at lower doses ( > 30 mg/kg/day
Neurologic exam

13. Metronidazole intoxication in dogs most
commonly causes vomiting, vestibular
ataxia, and vertical nystagmus
suggestive of central vestibular
dysfunction. Clinical signs are usually
symmetrical so head tilt is uncommon.
Cats with metronidazole toxicity are
more likely to develop forebrain signs of
seizures, altered mental status,
behavior change, and visual deficits.

14. Diagnosis
A presumptive diagnosis of metronidazole
toxicity can be made with compatible
clinical signs in a patient receiving a dose
higher than 30 mg/kg/day. Serum
metronidazole level can be determined
but is usually unnecessary.

15. Treatment
Simply stopping the metronidazole
eventually leads to resolution of clinical
signs, but it might take 1-2 weeks for the
signs to resolve. Treatment with diazepam
has been shown to greatly reduce the
duration of clinical signs from an average
of 14 days

16. with discontinuation of metronidazole
alone to three days with administration
of diazepam. The recommended dose
is diazepam 0.5mg/kg IV once
followed by 0.5 mg/kg PO q8hr until
resolution of clinical signs.

17. Metronidazole dosing recommendation
Many veterinary formularies still list metronidazole
doses up to 90 mg/kg/day. Since intoxication has
been reported as low as 33 mg/kg/day, the dose of
metronidazole should be kept below 30mg/kg/day
unless necessary. Most conditions for which
metronidazole is used do not require a dose higher
than this.

18. Our first case is a young 22-year-old male with chronic
sinus inflammatory disease who presented with seizures at
an outside hospital. He underwent workup with an MRI
scan, which showed a small peripherally enhancing lesion
in the right frontal lobe with central contents showing
restricted diffusion suggestive of brain abscess. He was
evaluated by neurosurgery and no surgical intervention
was recommended based on its small size and lack of
surrounding edema. Ear, nose, and throat specialist was
consulted and ethmoidectomy performed due to concern
for contiguous spread from a sinus infection. Cultures from
his sinuses were reportedly positive for grampositive cocci
in clusters. Patient was started on antibiotics including
intravenous (IV) ceftriaxone (2 gm, q12h) and IV
metronidazole (500 mg q8h) as well as prophylactic anti-
epileptic with levetiracetam (500 mg oral tablet)
case

19. He was discharged on these medications after one week. Patient was on
these medications for around four months when he started developing
lethargy, weakness, gait abnormality and pain in lower extremities. His
symptoms had progressively worsening over the past two weeks. Patient
was admitted to our University hospital. Coordination tests including finger-
to-nose exam revealed mild dysmetria in both arms and the patient was
falling in all directions during gait assessment. Patient was diagnosed with
drug-induced neuropathy. Repeat MRI of the brain was performed which
showed near-complete resolution of the right frontal brain abscess. The
scan also revealed symmetric areas of increased FLAIR signal with
restricted diffusion involving the dentate, the facial nerve and the red nuclei,
bilaterally .Given the clinical symptoms, medication history and unique
imaging findings, the patient was diagnosed with metronidazole-induced
cerebellar toxicity. Patient was discharged after two days with
discontinuation of ceftriaxone and metronidazole. Patient was however
advised to continue intake of levetiracetam. Patient had significant
improvement in his symptoms over the next few weeks. Complete
resolution of signal changes was noted on the follow-up MRI of the brain
done after 5 weeks.