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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2018  |  Volume : 29  |  Issue : 6  |  Page : 1511-1514
Short-course metronidazole-induced reversible acute neurotoxicity in a renal transplant recipient


Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India

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Date of Submission16-Dec-2017
Date of Decision18-Jan-2018
Date of Acceptance24-Jan-2018
Date of Web Publication27-Dec-2018
 

   Abstract 

Neurotoxic manifestations due to chronic metronidazole intake are well known, but neurotoxicity due to short-term use of metronidazole is very rare. We present a case of acute neurotoxicity due to short course of injectable metronidazole given in usual doses to a renal allograft recipient for persistent diarrhea. It responded to withdrawal of the offending drug. Tacrolimus trough concentration did not increase during neurotoxicity, thereby ruling out any metronidazole-tacrolimus interaction. Magnetic resonance imaging of the brain showed widespread osmotic demyelination and its recovery after drug withdrawal. This is the first reported case of a renal transplant recipient developing acute neurotoxicity due to short-term use of metronidazole, without any increase in tacrolimus trough concentrations.

How to cite this article:
Dogra PM, Bhatt AK, Agarwal SK, Bhowmik D. Short-course metronidazole-induced reversible acute neurotoxicity in a renal transplant recipient. Saudi J Kidney Dis Transpl 2018;29:1511-4

How to cite this URL:
Dogra PM, Bhatt AK, Agarwal SK, Bhowmik D. Short-course metronidazole-induced reversible acute neurotoxicity in a renal transplant recipient. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2019 Jan 23];29:1511-4. Available from: http://www.sjkdt.org/text.asp?2018/29/6/1511/248315

   Introduction Top


Metronidazole is an antibacterial and anti-protonzoal agent with predominant hepatic metabolism. It is a prodrug; unionized metro-nidazole is selective for anaerobic bacteria due to their ability to intracellularly reduce metro-nidazole to its active form. In reduced form, it covalently binds to DNA, disrupting its helical structure, inhibiting bacterial nucleic acid synthesis, and resulting in bacterial cell death. Its half-life is 6–8 h and <20% is protein bound. The major side effects are gastrointestinal and dermatological; however, neurotoxi-city is at higher cumulative doses.[1]

The use of antibiotics in renal allograft recipients may be challenging as it entails dose modification according to the creatinine clearance and risk of drug interaction with immu-nosuppressants, in addition to idiosyncratic reactions. Metronidazole-related neurotoxicity has been reported in the past with prolonged use (high cumulative dose).[2],[3],[4],[5] We report a case of renal allograft recipient who developed acute neurotoxicity following a short course of metronidazole, which resolved after drug discontinuation.


   Case Report Top


A 32-year-old male, with three-month-old renal allograft, was admitted for the evaluation of persistent diarrhea (6–8 episodes of loose stools per day for four weeks, without mucus or blood or fever) and weight loss of 6 kg. He was on regular follow-up at a transplant clinic and was on the following immunosuppres-sants: tacrolimus (2.5 mg/day), mycophenolate mofetil (MMF, 1500 mg/day), and predniso-lone (10 mg/day). His baseline creatinine was 1.3 mg/dL and tacrolimus trough concentration was adequate (8.0 ng/mL). His diarrhea did not respond to change of MMF to myco-phenolate sodium. He was hemodynamically stable and was not dehydrated. Systemic examination was normal. His laboratory parameters at admission were as follows: hemoglobin 12.6 g/dL, total leukocyte count 10,100/ mm3, polymorphs 68%, blood urea 46 mg/dL, serum creatinine 1.2 mg/dL, alanine amino-transferase 22 U/L, aspartate aminotransferase 26 U/L, and tacrolimus trough concentration 7.2 ng/mL. Stool examination did not reveal any pus cells or red blood cells or ova/cyst. Upper gastrointestinal endoscopy and contrast-enhanced computed tomography (CT) of the abdomen were normal. Cytomegalovirus DNA was not detectable in blood.

Injectable ceftriaxone [2 g intravenous (IV) q 12 h]) and metronidazole (500 mg IV q 8 h) were empirically started pending stool culture. Other medications included immunosuppres-sants as mentioned above. On day 3 of antibiotics, he developed slurring of speech and clumsy movements. There were no seizures or headache. Neurological examination revealed bilateral corticospinal tract signs [stiffness of all the four limbs with reduced power in all muscle groups (Grade 4+/5), exaggerated deep tendon jerks of all limbs, and positive Babinski’s sign] and left cerebellar signs (staccato speech, dysdiadochokinesia, finger–nose ataxia, gait ataxia, and gaze-evoked nystagmus). Higher mental function, cranial nerves, and sensory system examination were essentially normal. Neurological symptoms intensified over the next 24 h. Cerebrospinal fluid (CSF) evaluation ruled out the infection. Noncontrast CT of the brain was normal. T2 weighted (T2W) and fluid-attenuated inversion recovery (FLAIR) image sequences on magnetic resonance imaging (MRI) of the brain revealed symmetric hyperintensities with restricted diffusion in the central pons, bilateral basal ganglia, thalami, and periventricular white matter on suggesting osmotic demyelination [Figure 1]a and [Figure 1]b. The treating team noticed a peculiar phenomenon – intensification of cere-bellar signs on completion of ibid dose of metronidazole, followed by mild reduction in intensity prior to the next dose. This feature pinned metronidazole as the probable culprit and its withdrawal on the 6th day. He improved clinically in the next five days with only minimal cerebellar signs remaining, followed by complete disappearance of corticospinal signs at four weeks. Tacrolimus trough concentration during neurological dysfunction phase was 7.4 ng/mL.
Figure 1: (a and b) Multiple axial magnetic resonance images (fluid-attenuated inversion recovery) showing osmotic demyelination of bilateral basal ganglia, thalami, and periventricular white matter during acute metronidazole toxicity (red arrows).

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His diarrhea improved on conversion of mycophenolate sodium to azathioprine and was advised against the use of metronidazole and other nitroimidazoles in the future. A repeat MRI of the brain at four months showed resolution of hyperintensities in the bilateral basal ganglia, thalami, and corona radiata with some persisting altered signal intensities in the posterior limb of the internal capsule bilaterally [Figure 2]a and [Figure 2]b.
Figure 2: (a and b) Multiple axial magnetic resonance images (fluid-attenuated inversion recovery, 4 months later) showing resolution of hyperintensities in the bilateral ganglia, thalami, and corona radiata (red arrows), with persisting altered signal intensities in the posterior limb of the internal capsule (black arrow).

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   Discussion Top


Metronidazole-induced encephalopathy is a dose-related rare toxic encephalopathy. Metronidazole when given in high doses (>2 g/day) and for a prolonged period (>8 weeks, high cumulative dose) can lead to cerebellar dysfunction which reverses on stopping of drug.[2],[3],[4],[5] Central nervous system (CNS) penetration of drug is good, and its accumulation in the cerebellum and hippo-campus for longer period explains its neurotoxic effect.[1],[6] In addition, the suggested neuropathology is toxic osmotic demyelination (vasogenic and cytotoxic edema) of brain caused by drug accumulation.[7] In view of its hepatic metabolism, dose reduction is required in patients with severe hepatic disease, with concomitant administration of drugs inhibiting hepatic microsomal metabolism,[1] though some studies have depicted poor correlation between the serum levels of metronidazole, hepatic or renal function tests, and neurotoxicity.[8]

Neurological symptoms in renal transplant patients can be due to infections, drugs, stroke, cerebral venous sinus thrombosis, intracranial space-occupying lesions (ICSOL), etc. In our patient, CNS infection was ruled out by normal CSF analysis, vascular causes and ICSOL by neuroimaging, and tacrolimus toxicity by normal tacrolimus trough concentration. MRI of the brain aided the clinical suspicion in our patient. Characteristic MRI findings are symmetric T2W and FLAIR hyperintensities within the dentate nuclei of the cerebellum as well as other areas of the brain such as basal ganglia, thalami, internal capsule, midbrain, pons, medulla, and corpus callosum.[7]

Drug-induced neurotoxicity is a vast subset. In a renal transplant patient, tacrolimus can cause dose-related reversible neurotoxicity due to osmotic demyelination, but this effect correlates with high tacrolimus trough concentrations.[9],[10] Drug interaction between metronidazole and tacrolimus has been reported. Metronidazole causes a substantial increase in tacrolimus trough concentrations in vivo by weak inhibition of CYP3A4 and P-glycoprotein, thereby causing neurotoxicity.[11],[12] Compared to previous reports, the neurotoxicity profile in our patient was unique in the following ways: seen within 72 h of drug initiation, at a very low cumulative dose of metronidazole (4 g), and no increase in tacrolimus trough concentration. Metronidazole was shortlisted as the offending drug, the vigilant treating team noticed subtle waxing and waning cerebellar symptoms with each dose of metronidazole. In addition, there was clinical recovery of neurological manifestations on withdrawal of metronidazole, qualifying it as the offending drug. Sequential MRIs showed features of osmotic demyelination (drug induced) and its recovery after drug withdrawal. This evidence points to the direct causal effect of metronidazole to neurotoxicity and rules out the drug interaction between metronidazole and tacrolimus.

This patient generates the debate of the use of commonly used antimicrobials empirically in a clinical situation. It may still be possible that metronidazole-induced osmotic demyelination at a low cumulative dose is precipitated due to the additive presence of tacrolimus (despite normal tacrolimus trough concentrations), to cause additive neurotoxicity, though no direct evidence to this exists. We propose cautious monitoring while using these drugs together.

Conflict of interest: None declared.

 
   References Top

1.
Phillips MC, Stanley SL Jr. Chemotherapy of protozoal infections. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill; 2006. p. 1057-60.  Back to cited text no. 1
    
2.
Frytak S, Moertel CH, Childs DS. Neurologic toxicity associated with high-dose metronida-zole therapy. Ann Intern Med 1978;88:361-2.  Back to cited text no. 2
    
3.
Snavely SR, Hodges GR. The neurotoxicity of antibacterial agents. Ann Intern Med 1984; 101:92-104.  Back to cited text no. 3
    
4.
Agarwal A, Kanekar S, Sabat S, Thamburaj K. Metronidazole-induced cerebellar toxicity. Neurol Int 2016;8:6365.  Back to cited text no. 4
    
5.
Gupta AK, Agarwal MP, Avasthi R, Bhadoria DP, Rohatgi N. Metronidazole-induced neuro-toxicity. J Assoc Physicians India 2003;51: 617-8.  Back to cited text no. 5
    
6.
Placidi GF, Masuoka D, Alcaraz A, Taylor JA, Earle R. Distribution and metabolism of 14C-metronidazole in mice. Arch Int Pharmacodyn Ther 1970;188:168-79.  Back to cited text no. 6
    
7.
Kim E, Na DG, Kim EY, et al. MR imaging of metronidazole-induced encephalopathy: Lesion distribution and diffusion-weighted imaging findings. AJNR Am J Neuroradiol 2007;28: 1652-8.  Back to cited text no. 7
    
8.
Midha KK, McGilveray IJ, Cooper JK. Determination of therapeutic levels of metronidazole in plasma by gas-liquid chromatography. J Chromatogr 1973;87:491-7.  Back to cited text no. 8
    
9.
Eidelman BH, Abu-Elmagd K, Wilson J, et al. Neurologic complications of FK 506. Transplant Proc 1991;23:3175-8.  Back to cited text no. 9
    
10.
Fukazawa K, Nishida S, Aguina L, Pretto E Jr. Central pontine myelinolysis (CPM) associated with tacrolimus (FK506) after liver transplantation. Ann Transplant 2011;16:139-42.  Back to cited text no. 10
    
11.
Page RL 2nd, Klem PM, Rogers C. Potential elevation of tacrolimus trough concentrations with concomitant metronidazole therapy. Ann Pharmacother 2005;39:1109-13.  Back to cited text no. 11
    
12.
Early CR, Park JM, Dorsch MP, Pogue KT, Hanigan SM. Effect of metronidazole use on tacrolimus concentrations in transplant patients treated for clostridium difficile. Transpl Infect Dis 2016;18:714-20.  Back to cited text no. 12
    

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Correspondence Address:
Dr. Pavitra Manu Dogra
Department of Nephrology, All India Institute of Medical Sciences, New Delhi
India
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DOI: 10.4103/1319-2442.248315

PMID: 30588989

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