Metronidazole- and levofloxacin-induced psychotic disorders in chronic kidney patient

Abstract

We present a case which reports the occurrence of psychotic disorders after metronidazole and levofloxacin therapy in a chronic kidney patient while being treated for enterocolitis and urinary infection. A 48-year-old female was admitted to a hospital for the placement of a peritoneal dialysis catheter due to indicated peritoneal dialysis. During admission, symptoms of enterocolitis and urinary infection had occurred, so metronidazole and levofloxacin were introduced into therapy, respectively. After 4 days of metronidazole and 3 days of levofloxacin therapy, the patient became confused, disoriented, with signs of delirium. Since the diagnosis of psychoorganic disorder was made, the therapy with lorazepam and haloperidol was initiated, while metronidazole and levofloxacin were discontinued. Complete recovery 4 days after discontinuation indicates that the patient has experienced antibiotics-induced neurotoxicity. This is the first report of expressed neurotoxicity after the combination of metronidazole and levofloxacin in chronic kidney patients.

Background

This is the first report of expressed neurotoxicity after the combination of metronidazole and levofloxacin in dialysis patients.

Case presentation

A 48-year-old female was admitted to a hospital for the placement of a peritoneal dialysis catheter due to indicated peritoneal dialysis. Namely, she was being treated in Clinic of Nephrology as a chronic kidney patient and 2 days prior to admission, during a regular scheduled check-up her laboratory analyses showed a very high level of serum creatinine (sCr), the value of which was 532 µmol/L, without uremic symtoms. Using Cockcroft-Gault equation, it was found that creatinine clearance (CCr) was 15 mL/min, so, according to recommendations peritoneal dialysis was indicated. Before peritoneal catheter placement, the patient was on a dietary regime that was supposed to be continued afterwards. A day after the peritoneal catheter placement, she took a meal on her own, and soon after started to show symptoms of enterocolitis. She was subfebrile, exhausted, and had a persistent diarrhoea (up to 10 stools per day). The next day, a diagnosis of enterocolitis was established, so metronidazole (400 mg three times daily) and probiotic yeast culture Saccharomyces boulardii were prescribed due to a suspected Clostridium difficile infection, which was corroborated by laboratory analyses (white blood cell count was 16.1×10⁹ /L, C-reactive protein was 141.2 mg/L). On the fourth day of admission dysuria symptoms occurred with leukocyturia, bacteriuria while urine contained a trace amount of nitrites. Afterwards the assessment by a physician, levofloxacin (500 mg intravenous, first day) was chosen for the treatment of a urinary infection. After 4 days of metronidazole and 3 days of levofloxacin therapy, the patient became confused, disoriented, with signs of delirium. She was referred to a psychiatrist, and a diagnosis of psychoorganic disorder was made, even though her personal and family history had no evidence of psychiatric and mental illness. For this reason, we hypothesized the drug-induced neurotoxicity. After detailed examination, the psychiatrist prescribed lorazepam (1 mg twice daily) for the next 5 days. The antipsychotic drug haloperidol (2 mg daily) was also introduced into therapy the following day because of the development of delirium. The next day, both metronidazole and levofloxacin were discontinued. The patient recovered completely from the psychotic symptoms 4 days after discontinuation of metronidazole and levofloxacin. Rapid and complete recovery and a further follow-up of the patient did not indicate the need for additional diagnostics (MRI, EEG).

Investigations

We have used the Naranjo probability scale, which can indicate a probable adverse drug reaction.¹ The score was 7, which is indicative of interaction between metronidazole and levofloxacin. During the treatment, the patient was subjected to relevant laboratory tests and neurological examinations.

Treatment

Because of diagnosis of enterocolitis was established, metronidazole (400 mg three times daily) and probiotic yeast culture Saccharomyces boulardii were prescribed due to a suspected Clostridium difficile infection. Metronidazole is an antibacterial agent that is highly effective against gram-negative anaerobic bacteria (Bacteroides fragilis) and gram-positive anaerobic bacteria (Clostridium sp.). Nowadays, it is widely used for the treatment of anaerobic and protozoal infections. The pharmacokinetic profile of metronidazole is characterized by high bioavailability, low protein binding (<20%), high concentrations in most tissues (60–100% of plasma concentrations), extensive metabolism in the liver and the majority of excretion via urine and faeces. It successfully penetrates into the cerebrospinal fluid and central nervous system which may contribute to exhibition of neurological and psychiatric adverse effects.^{2 3} During the hospitalisation, due to symptoms of urinary infection, levofloxacin (500 mg intravenous) was introduced into existing therapy on the fourth day. Levofloxacin is the third generation of fluoroquinolone which exhibits high activity against gram-negative bacteria and atypical pathogens, and improved activity against gram-positive bacteria in comparison to the second generation.⁴ The main fields where levofloxacin represents the first line therapy are urinary and respiratory tract infections.⁵ Levofloxacin has high bioavailability (>95%) with very similar plasma concentrations after oral and intravenous administration. It penetrates into the central nervous system in the lowest degree in comparison with other fluoroquinolones. Both glomerular filtration and tubular secretion are the predominant mechanisms of levofloxacin excretion, so kidney disease may lead to a decrease in clearance and potential adverse effects.⁶ On the fifth day, routine laboratory examinations showed that the therapy gave positive results (white blood cell count was 7.6 ×10⁹ /L), but the level of C-reactive protein still remained high (101.3 mg/L), therefore therapy with both antibiotics continued. After 4 days of metronidazole and 3 days of levofloxacin therapy, the patient became confused, disoriented, with signs of delirium. After the assessment by a psychiatrist, the therapy with lorazepam (1 mg twice daily) and haloperidol (2 mg daily) was initiated. Because of the reasonable suspicion of drug-induced neurotoxicity both metronidazole and levofloxacin were discontinued. Other drugs the patient was receiving were carvedilol 12.5 mg per day, ranitidine 100 mg once a day, and calcium carbonate 2 g per day and B-complex vitamins, which are not known to cause such side-effects.

Discussion

A recommended dose of metronidazole is 500 mg three times daily, and given that our patient was taking 400 mg every 8 hours, we concluded that dosage regimen was quite appropriate.^{7 8} On the other hand, levofloxacin is primarily excreted by the kidney, so it is necessary to significantly adjust the dosage regimen for patients with kidney disease. Doses of 250 mg as daily dose or 500 mg every 48h are appropriate for patients on dialysis.^{6 7 9} Kocyigit at al. reported a case of delirium associated with levofloxacin in a 55-year-old male patient with acute renal failure, which proved that uremic toxins, half-life, and plasma concentration of fluoroquinolones are increased in patients with renal failure.¹⁰ Metronidazole and levofloxacin, although rarely, are mentioned in several published case reports as antibiotics that cause central nervous system toxicity. Metronidazole-induced neurotoxicity is manifested as cerebellar dysfunction, altered mental status, or seizures.¹¹ The mechanism of metronidazole-induced neurotoxicity is uncertain, but there are some proposed hypothesis. Befani et al suggested that metronidazole in vitro inhibits monoamino oxidase (MAO) by a noncompetitive and reversible mechanism, probably by interacting with imidazoline binding sites (I₂ BS). Taking into account that symptoms are withdrawn rapidly after the drug cessation due to proposed reversible inhibition, and the fact that other MAO inhibitors cause some similar neurological adverse effects as metronidazole, this hypothesis seems to be possible.¹² Other proposed mechanisms are binding of metronidazole to neural RNA to inhibit protein synthesis, reversible mitochondrial dysfunction, vasogenic and cytotoxic oedema, and modulation of γ-aminobutyric acid (GABA) receptor within the cerebellar and vestibular systems.^{11 13} As for neuropsychiatric side effects, psychoses were mainly reported, either in monotherapy or in combination with other drugs, including antibiotics.^{14 15} Most reported cases of central nervous system (CNS) toxicity are attributed to ciprofloxacin, ofloxacin and perfloxacin. Levofloxacin is the left optical isomer of ofloxacin, but it has a significantly better toxicity profile, which leads to the conclusion that the R(+) isomer of ofloxacin contributes to the adverse effects. Overall incidence of CNS adverse effects is only 0.2–1.1%, which is in accordance with the lowest penetration of levofloxacin into CNS. However, the data are conflicting whether CNS penetration is in direct correlation with neurological adverse effects of fluoroquinolones. Most common neuropsychiatric side effects of levofloxacin are headache, dizziness, tremors, insomnia, hallucinations, convulsions and anxiety.^{5 13} There are several reported cases of levofloxacin-induced neurological manifestations.^{10 16–18} There are no reported cases about delirium induced by metronidazole and levofloxacin in chronic kidney patients. A similar case of organic psychosis induced by ofloxacin and metronidazole in an 18-year-old female was reported by Koul et al The patient had no previous psychiatric history or any precipitating stresses. Since the onset of symptoms began soon after initiation of antibiotics, and a complete, stable and rapid recovery after their cessation, the authors suggested that psychosis was induced by an idiosyncratic reaction to a combination of ofloxacin and metronidazole.¹⁴ Based on the aforementioned data, we suggest that our patient experienced neurotoxicity due to a combination of antibiotics which potentiated the neurotoxic effects of each other. Chronic kidney disease, the patient being female and the overdose of levofloxacin may have contributed to neurotoxicity, given that the patient had no other predisposing factors (elderly age, diabetes mellitus, hypoxemia, neurological illnesses, severe atherosclerosis, acidosis, hyponatremia).

Learning points.

• Our patient experienced neurotoxicity due to a combination of antibiotics which potentiated the neurotoxic effects of each other.

• Chronic kidney disease, the patient being female and the overdose of levofloxacin may have contributed to neurotoxicity, given that the patient had no other predisposing factors (elderly age, diabetes mellitus, hypoxemia, neurological illnesses, severe atherosclerosis, acidosis, hyponatremia).