Author Affiliations: Dr. Sohn is Associate Director, Sepulveda VA Nursing Home Care Unit, VA Greater Los Angeles Health Care System, and Assistant Clinical Professor, UCLA School of Medicine/Geriatrics, CA.
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Ciprofloxacin is a broad-spectrum fluoroquinolone antibiotic. The newer drugs in this class differ from earlier agents with increased potency, broader spectrum of antibacterial activity, and pharmacokinetics that permit treatment of systemic bacterial infections. The fluoroquinolone antibiotics have a relatively benign side-effect profile, but there have been case reports of behavioral changes in patients after initiation of this class of antibiotics.

We present a case of mania after ciprofloxacin antibiotic use. Elderly patients are especially at risk for adverse effects of medications. Multiple medical comorbidities, polypharmacy, and the potential of drug-drug interactions all increase the risk. Changes in mood or behavior such as mania are a serious adverse effect that can occur. Adverse drug reactions after the addition of a new medication always need to be considered.

The Case

Mr. W is an 85-year-old Caucasian male who was admitted for long-term care (LTC) to the Nursing Home Care Unit (NHCU) in November 2000 due to an inability to care for himself. He is a World War II veteran. One morning several years after his admission he was noted to be talking incessantly with an elevated mood. He was alert and oriented on interview; however, it was difficult to engage him in a focused conversation. He insisted on telling stories from his past and was difficult to interrupt. He stated that he had not slept for the past 25 years and admitted to having racing thoughts and feeling “out of control.” Prior to this episode he was described as a calm, pleasant man of few words who enjoyed reading the newspaper.

Ciprofloxacin was started on February 26, 2007, for increased lethargy and poor oral intake. Preliminary lab tests were consistent with a UTI. On March 1, 2007, the patient was noted to be talking incessantly with an elevated mood. On exam, he was lying in bed comfortably, well groomed, speech was pressured, and mood was elevated. His affect was excited, and he was often laughing inappropriately. His thought process was tangential and appeared delusional. Ciprofloxacin was the only new medication that had been started. It was immediately discontinued. Mr. W returned to his baseline after stopping the ciprofloxacin.

Discussion

This elderly resident exhibited an acute change in his behavior after starting ciprofloxacin. As with many other older patients, he had multiple comorbidities and was taking multiple medications. Mental status evaluation clearly showed abnormalities in speech, mood, affect, thought process, and content consistent with mania. After stopping the ciprofloxacin, the patient’s episode of acute mania resolved. Currently, there are no diagnostic procedures or laboratory tests for mania. However, the onset and resolution of symptoms consistent with mania was related to initiation and discontinuation of the medication ciprofloxacin. Prior case reports of behavioral changes related to initiation of ciprofloxacin makes ciprofloxacin the most likely culprit. The case illustrates the importance of reviewing the patient’s medications when there are acute changes to a patient’s condition.

Significant adverse reactions related to ciprofloxacin (< 1%) listed as limited to important or life-threatening include mania reaction, agitation, and delirium in Lexi-comp, a medication reference resource. There have been other case reports of ciprofloxacin-induced mania.1,2 One case documented mania associated with the use of topical ciprofloxacin ophthalmic solution.3

The pharmacology of ciprofloxacin has been well studied.4,5 Ciprofloxacin is a broad-spectrum, commonly used fluoroquinolone antibiotic (Figure). The first clinical use in this class of antibiotics was with nalidixic acid in 1962 for UTIs.6 Ciprofloxacin has potent activity against Gram-negative organisms and has been in use since the 1980s. Ciprofloxacin is widely used in hospital, community, and LTC settings and is available in oral suspension, tablet, ophthalmic, and parenteral forms. Absorption of the oral form of the immediate-release tablet is rapid. Tissue concentrations often exceed serum concentrations, especially in kidneys, gallbladder, liver, lungs, gynecological tissue, and prostatic tissue. Cerebrospinal fluid concentrations are variable but may reach 10% of serum concentrations in noninflamed meninges and anywhere from 14% to 37% of serum concentrations in inflamed meninges. The drug can cross the placenta and may be present in breast milk. About 20-40% of the drug is protein-bound.

Ciprofloxacin is partially metabolized in the liver and degrades into four metabolites with limited activity. The half-life in children is about 2.5 hours and in adults with normal renal function about 3-5 hours. It is excreted in the urine (30-50%) and the remainder in feces. Immediate-release and extended-release tablet forms are available. The primary mechanism of action involves the inhibition of deoxyribonucleic acid (DNA)-gyrase in susceptible organisms. This results in the inhibition of the relaxation of supercoiled DNA and promotes breakage of double-stranded DNA.

Recently, inhibition of topoisomerase IV has also been discovered as a mechanism of activity of the fluoroquinolone class.4 Dosage adjustments are recommended in people with severe renal disease or a creatinine clearance less than 30 mL/min/1.73 m2.4

Pharmacokinetically, ciprofloxacin is a potent inhibitor of cytochrome (CYP) 1A2 and 3A4.7 The CYP450 enzymes are numerous important metabolic enzymes that play a central role in the metabolism of drugs and toxins. Some medications can either induce or inhibit CYP enzymes, which thereby can affect other medications by affecting their metabolism. Therefore, ciprofloxacin, being a powerful inhibitor of CYP1A2, can cause increased levels of other medications that would be metabolized at this cytochrome.

Mirtazapine, which the patient was taking, is a substrate for the CYP1A2 site. There have been case reports of mania associated with the use of mirtazapine.8,9 Therefore, it is conceivable that the patient may have become manic after initiation of ciprofloxacin, a CYP1A2 inhibitor resulting from elevated levels of mirtazapine.

This mechanism also accounts for the drug interactions involving the xanthine derivatives. Two well-documented drug interactions involve the xanthine derivatives and multivalent cation-derived drugs. Ciprofloxacin reduces xanthine metabolism, increasing serum concentrations of theophylline. Therefore, for patients taking theophylline, careful monitoring is necessary. Ciprofloxacin bioavailability is reduced with concurrent administration of multivalent cation-containing agents. Cations such as aluminum, calcium, iron, magnesium, and zinc bind to the fluoroquinolones in the gastrointestinal tract and inhibit absorption.

Mania is characterized by an abnormally elevated or irritable mood. It may be accompanied by one or more of the following: grandiosity, decreased need for sleep, increased talkativeness, flight of ideas, distractibility, increased goal-directed activity, psychomotor agitation, and excess involvement in potentially harmful activities.10 Mania is divided into primary and secondary mania. Secondary mania is often a consequence of drugs, toxic/metabolic effects, medical conditions such as infections, physical insults to the brain such as cerebrovascular accidents, traumatic brain injuries, and brain space–occupying lesions.11-14 Aside from antibiotics, medications such as antidepressants, antipsychotics, steroids, and others have been associated with secondary mania.15-23

The exact prevalence and incidence of primary and secondary mania is unknown. Secondary mania due to medications is a rare occurrence. When an older adult presents with new- or first-onset mania it is most commonly secondary to another condition or medication.2 Older adults are more at risk of adverse effects from medications due to medical comorbidities, in addition to physiological changes that occur with aging. Changes in the CYP450 system in older patients result in increased plasma concentrations of drugs. The alterations in the P450 system make older adults more susceptible to potential adverse effects.

Summary

There are several points to note from this case. When a patient has an acute change in condition in addition to infection/illness, the differential should also include drug-drug interactions between medications, additions, or changes of medication. Older adults have chronic medical problems and are often taking many medications. The side effects, interactions of medications, and even withdrawal of some medications can precipitate a change in mental status. Mania when occurring in older patients is often secondary mania.

The author reports no relevant financial relationships.