Ciprofloxacin and Clozapine Interaction in a Patient Requiring Intensive Care

Clozapine is a potent second-generation antipsychotic that remains the treatment of choice for refractory schizophrenia. Despite its efficacy, clinicians may be hesitant to prescribe clozapine because of its side-effect profile, narrow therapeutic window, and the intensity of monitoring required. Common adverse effects include sedation, constipation, and sialorrhea. Serious side effects include neutropenia, seizures, myocarditis, ileus, and cardiomyopathy. Clozapine has been associated with significant autonomic side effects, such as orthostatic hypotension, paradoxical hypertension, tachycardia, and increased heart rate variability (1). Clozapine is metabolized through the cytochrome p450 enzyme system, with primary metabolism through CYP1A2. Although individual responses may vary, the current response threshold for clozapine is generally considered to be a serum concentration of at least 350 ng/mL (2).

Ciprofloxacin, a fluoroquinolone antibiotic, is a CYP1A2 inhibitor and has been demonstrated in case reports to increase serum clozapine concentrations (3–6). Previous case reports have documented side effects, such as asymptomatic tachycardia, rhabdomyolysis, and higher than expected serum levels of clozapine resulting from the coadministration of the two drugs (3). In this article, we report on a case of drug-drug interaction between ciprofloxacin and clozapine in a patient without toxic clozapine levels who required intensive care for hypotension and altered mental status.

Case

"Ms. C" is a 70-year-old female with a psychiatric history of schizophrenia, well controlled on a consistent daily dose of clozapine 500 mg daily for the last 10 years. She presented from her residence to the emergency department with bright red blood per rectum. CT abdomen indicated a small bowel ileus, thought to be caused by clozapine. Accordingly, clozapine was discontinued, and Ms. C was admitted to inpatient medicine for suspected intra-abdominal infection. She was prescribed metronidazole, vancomycin, and cefepime. Her ileus resolved without further episodes of hematochezia. Repeat X-ray did not show evidence of ileus or obstruction. Because the patient had not taken clozapine for 7 days, clozapine was initiated at a starting dose of 50 mg with a plan to titrate the dose in outpatient follow-up.

Four days after Ms. C. was discharged from the floor, she presented to the emergency department with disorganized thought processes, rambling speech, and evidence of internal preoccupations. Emergency department workup at the time included CT head, CT abdomen/pelvis, chest X-ray, complete blood count, and comprehensive metabolic panel—all of which were unremarkable. However, her urinalysis was positive for a urinary tract infection (UTI), and she was prescribed ciprofloxacin 500 mg twice a day. She was medically cleared for admission to inpatient psychiatry, and she was continued on her home dose of clozapine 50 mg daily. On the floor, her thought process was illogical and delusional. She was unable to meaningfully participate in conversation. However, her speech was fluent, she could ambulate without assistance, and she did not appear to have any focal neurological deficits. Her vitals were stable, with no clinical indications of infection. Her laboratory results, including a CBC, also did not indicate signs of infection. That evening after she received her first dose of clozapine, Ms. C. became hypotensive and unresponsive. The rapid response team was called, and she was transferred to the intensive care unit (ICU).

In the ICU, notable vital sign abnormalities included a blood pressure of 76/39 and a temperature of 97.1 F. EKG indicated normal sinus rhythm, and laboratory studies were unrevealing, including a venous blood gas that was within normal limits. On physical exam, she was obtunded and responded only to painful stimuli, although she could spontaneously move all extremities. She had brisk reflexes and fixed pinpoint pupils. Her cardiac and respiratory findings were normal. Intravenous fluids were started, and head CT without contrast was emergently done, which showed no acute intracranial abnormalities. Blood pressure improved with intravenous fluids to 90/44, but there was no notable improvement in mental status. She was also loaded with intravenous valproic acid and lorazepam for seizure prophylaxis. Intravenous fluids were continued with improvements in blood pressure. However, she remained difficult to arouse and was not oriented to person, place, or time.

Clozapine and ciprofloxacin were withheld throughout her 3-day ICU stay. Her laboratory work and imaging showed no metabolic or structural abnormalities to cause the acute obtundation. An electroencephalogram showed no epileptiform discharges. There were no clinical signs of infection, and she did not meet systemic inflammatory response syndrome criteria. The following day, a clozapine level was drawn, with serum level of 72 ng/mL, well below the threshold of toxicity. She ultimately regained alertness and orientation without further intervention. She was transferred back to the psychiatric unit, where her clozapine was restarted at 50 mg daily with incremental daily titration of 25 mg, followed by 50 mg, which she tolerated well. She was stabilized on a monotherapy of clozapine 400 mg daily and discharged home.

Discussion

Ms. C had been stabilized on clozapine for 10 years and had been medication adherent during this period. In this time, she was independent in her activities of daily living. When her clozapine was stopped during her hospital stay, Ms. C was agreeable to titration back to her original dosing. Because of her demonstrated tolerance of high doses of clozapine monotherapy and history of consistent adherence to clozapine 500 mg daily, she was initiated at a higher starting dose than current guidelines (50 mg versus 25 mg). Current guidelines of clozapine titration suggest a starting dose of 12.5 to 25 mg, which can be increased by 25 mg daily. She was also provided ciprofloxacin for empiric treatment of a UTI. Ms. C’s acute change in mental status, accompanied by significant hypotension and pinpoint pupils, was likely a result of autonomic dysregulation exacerbated by the pharmacokinetic interactions of clozapine and ciprofloxacin (1, 7). There were no findings to support infectious, cardiovascular, metabolic, or acute neurological causes of her presentation. Because the symptom onset coincided with the initiation of clozapine, differential diagnoses included catatonia, neuroleptic malignant syndrome, and seizures. However, her recovery was not correlated with administration of benzodiazepines, there was no elevated creatine phosphokinase, and her electroencephalogram was unrevealing for seizure activity. Her altered mental status and disorientation resolved without major intervention other than intravenous fluids. This, in conjunction with the temporal association of altered mental status with initiation of clozapine and ciprofloxacin, points to coadministration of the two medications as the likely cause of the increased autonomic instability.

This case suggests that the pharmacokinetic interactions of CYP1A2 inhibitors, such as ciprofloxacin, cimetidine, and fluvoxamine, with clozapine significantly affect patient outcomes at serum levels well below what is considered toxic. The coadministration of these medications potentiated an autonomic response similar to a rapid initiation of clozapine, enhancing the adverse profiles. The variety of autonomic side effects of clozapine are well documented, but the mechanisms remain poorly understood, because clozapine has one of the most diverse receptor-binding profiles of the second-generation antipsychotics. Clozapine has affinities for adrenergic receptors α1, α2, dopamine receptors D₁, D₂, D₄, serotonin receptors 5-HT₆, 5-HT₇, muscarinic receptors, and histaminergic receptors H₁ and H₃ (1, 8). It should be noted that Ms. C was at higher risk of autonomic dysregulation because of her elderly age and her recent medical comorbidities.

Clinicians prescribing clozapine should be mindful of the kinetic interactions with CYP1A2 inhibitors even at lower dosing. In patients with poor cognition at baseline, cardiovascular disease, or neurocognitive changes, this combination of medications should be avoided.

Key Points/Clinical Pearls