ADVERTISEMENT
Levofloxacin-Induced Acute Psychosis in an Elderly Man
Patients with delirium have a higher risk of in-hospital mortality, prolonged hospital stay, worse functional outcomes, and higher rates of institutionalization than individuals without delirium.1-4 Yet despite such devastating risks and its frequent occurrence, delirium remains a poorly understood syndrome, and studies on mediating pathophysiology mechanisms in delirium are largely lacking.1 A possible cause for delirium, however, that should never be forgotten is the medical and iatrogenic adverse side effects of many pharmacotherapies, including antibiotics.5 One such antibiotic is levofloxacin, a third-generation fluoroquinolone.
We report the case of an 83-year-old man who presented to the emergency department with levofloxacin therapy–induced, acute-onset psychosis. We identified one other similar case in the medical literature.6
Case Report
An 83-year-old man was admitted to our institution for decompensated, New York Heart Association (NYHA) class IV heart failure, which was attributed to a suboptimal daily dose of diuretics. The patient’s medical history included atrial fibrillation, heart failure, essential hypertension, and controlled type 2 diabetes mellitus. His chronic medications included furosemide, metolazone, warfarin, candesartan, spironolactone, theophylline, pravastatin, sitagliptin, and glipizide. During his hospital stay, the patient was always alert and oriented, and there was no evidence of an acute coronary syndrome, infection, or uncontrolled hypertension. Before being discharged from the hospital, the patient was found to have urinary retention secondary to benign prostatic hypertrophy, and a urinary catheter was placed.
During an evaluation of the patient 2 weeks following his hospital discharge, he appeared to be feeling well, was oriented, and demonstrated normal speech, concentration, and recall. His heart failure was classified as NYHA class II. The urinary catheter was removed, but was reintroduced 12 hours later when evidence of urinary retention was found once again after an examination revealed a vesical globe. Levofloxacin 500 mg once daily was prescribed to treat his urinary tract infection, which was diagnosed by laboratory studies that revealed leukocyturia and hematuria.
Twenty-four hours after receiving his first dose of levofloxacin, the patient returned to our institution after he started to exhibit some bizarre behavior and incoherent speech. In the days that followed, he became aggressive, delirious, and did not sleep. On day 4 of levofloxacin therapy, mianserin 30 mg was administered to treat his insomnia, but he slept for only a few hours and his symptoms of delirium and agitation continued to worsen. The patient never developed a fever and his heart failure symptoms did not worsen. A review of his medical history demonstrated no head trauma, loss of consciousness, psychiatric illness, psychotropic drug use, or any signs of focal neurological deficit. There was also no recent history of alcohol consumption.
Levofloxacin was continued, but on day 7 of treatment, he was brought to the emergency department for persistent abnormal behavior. Upon hospital admission, he appeared alert, but was aggressive and exhibited persecutory delusions and unstable thoughts. The neurological examination did not reveal any motor or sensitive focal deficit or signs of meningeal irritation. His seated arterial blood pressure was 100/60 mm Hg, axillary temperature was 36ºC, and pulse oximetry revealed an oxygen saturation of 98% on room air. Lung auscultation demonstrated fine inspiratory crackles in the lung bases, and cardiac auscultation revealed an arrhythmic heart rate with a frequency of approximately 80 beats per minute. There was evidence of slight bilateral edema in the patient’s legs. A cranial computed tomography scan showed no acute hemorrhagic or ischemic lesions, other masses, or signs of elevated intracranial pressure. The electrocardiogram revealed atrial fibrillation with stable ventricular frequency and no signs of ischemia. The laboratory panel revealed a hemoglobin of 11.3 g/dL (normal, 14.0-17.5 g/dL); a total white blood cell count of 8600/µL (normal, 4500-11,000/µL); an international normalized ratio of 2.8; a C-reactive protein of 27.5 mg/L (normal, 0.08-2.1 mg/L); a random blood glucose of 83 mg/dL (normal, 70-110 mg/dL); a blood urea nitrogen of 59.5 mg/dL (normal, 4.7-23.4 mg/dL); a serum creatinine of 1.3 mg/dL (normal, 0.6-1.2 mg/dL), with a creatinine clearance of 48.7 mL/min/1.73m2 (normal, 75-125 mL/min/1.73m2); a theophylline level of 14 µg/mL (normal, 10-20 µg/mL); and serum electrolytes within normal limits. Arterial blood gas analysis on room air showed a partial pressure of oxygen of 88.2 mm Hg (normal, 80-100 mm Hg), a partial pressure of carbon dioxide of 28.6 mm Hg (35-45 mm Hg), a pH of 7.467 (normal, 7.35-7.45), a bicarbonate of 20.2 mEq/L (normal, 21-28 mEq/L), and a lactate of 1.61 mg/dL (normal, 5.0-15 mg/dL). The patient was admitted to the intensive care unit and levofloxacin was discontinued.
Forty-eight hours after stopping levofloxacin, the patient was oriented and no longer exhibited signs or symptoms of a psychiatric or neurologic illness and did not require any antipsychotic medication. The laboratory assessment was stable and the urine culture was negative for infection, so no other antibiotics were prescribed. Because the patient no longer demonstrated urinary retention or other genitourinary symptoms, evaluation of his benign prostatic hypertrophy was deferred to the outpatient setting.
Discussion
Levofloxacin is an optically active levo isomer (L-isomer) of the racemate ofloxacin. The L-isomer represents the active component of levofloxacin, with the D-isomer being inactive, making levofloxacin more potent in vitro against both gram-positive and gram-negative bacteria than ofloxacin. Levofloxacin works by inhibiting bacterial topoisomerase IV and DNA gyrase, preventing bacterial DNA replication, transcription, repair, and recombination.7 Levofloxacin is stereochemically stable (ie, its inactive D-isomer does not become active in the plasma or urine), conferring less toxicity. The mean apparent total body clearance and renal clearance range from approximately 144 to 226 mL/min and 96 to 142 mL/min, respectively, suggesting minimal extrarenal clearance.7 Compared with the structurally similar ofloxacin, levofloxacin appears to be associated with fewer central nervous system (CNS) disturbances. The reason for this is unclear, but may be associated with levofloxacin’s decreased affinity to bind to gamma-aminobutyric acid (GABA) receptors in the CNS.8,9 Levofloxacin’s excellent bioavailability, reduced neurotoxicity, widespread tissue penetration, oral or parenteral formulation, and once-daily dosing option (ofloxacin requires two daily doses), make it an appropriate therapeutic choice to treat many types of infections (Table).7,8,10
CNS side effects are known to occur with fluoroquinolones, but are fairly rare, with a reported incidence between 1% and 2%; however, this class of antibiotics is more likely to cause CNS side effects than other antibiotics.11 Some of the CNS side effects that have been reported include headache, dizziness, tremor, restlessness, convulsions, and psychoses, all of which may vary in intensity.6,12-14 Seizures and hallucinations have been reported less commonly, but have been noted to occur with greater frequency in individuals with conditions that predispose them to CNS disorders, or in those who receive both quinolones and theophylline or a nonsteroidal anti-inflammatory drug.5,15 A 2001 European study assessing the side effects of levofloxacin found psychosis to occur in only 1 out of every 6 million prescriptions.16 Risk factors for neurotoxicity include renal insufficiency and underlying CNS disease.13
In our patient’s case, levofloxacin was the most probable cause of his acute psychosis, as we did not find any other possible causes and there was a temporal relationship between the administration of the drug and the beginning of the clinical picture. In addition, his psychosis disappeared after the drug was discontinued, and he did not require administration of any antipsychotic medications. The Naranjo adverse drug reaction probability scale also indicated a probable link between the acute psychosis and levofloxacin therapy.17 Had our patient’s dose of levofloxacin been adjusted to his renal function before initiating therapy, this episode of delirium may have been prevented. Althought our patient was taking theophylline before starting levoloxacin, an assay of serum theophylline ruled out this medication as a concomitant neurotoxin. In reviewing the literature, we identified a case by Moorthy and colleagues that was similar to ours.6 Their patient also became psychotic, aggressive, and developed insomnia following levofloxacin therapy. Within 48 hours o discontinuing this treatment, a repeat psychiatric evaluation revealed the patient to be alert and oriented, and he experienced no further hallucinations, had normal speech, and his concentration and recall were intact. Like our patient, he did not require any antipsychotic medications to recover. Because clinicians may not always associate such findings with a pharmacotherapy, particulary an antibiotic, our case report and that of Moorthy and colleagues serve to highlight the importance of considering the potential effects of all pharmacotherapies when presented with such a clinical picture.
The mechanism underlying levofloxacin-induced delirium remains to be elucidated; however, some studies indicate that these effects may be related to the degree to which the fluoroquinolones bind to GABA receptors and their differing potential to act as GABA antagonists and bind to the N-methyl-D-aspartate receptor.6,13 Abnormal electroencephalograms have been reported in a few patients receiving levofloxacin therapy.7,18,19 We did not perform an electroencephalogram to exclude the existence of an association with nonconvulsive status epilepticus because our patient improved 48 hours after stopping levofloxacin. Our patient’s partial response to mianserin may indicate that serotonin receptor involvement contributed to his delirium.
Conclusion
Levofloxacin has a better pharmacokinetic profile than other fluoroquinolones, including ofloxacin, and allows for convenient once-daily dosing in either an oral or parenteral formulation, making it an attractive pharmacotherapy. While CNS side effects are rare with levofloxacin, they can occur. Elderly patients may be especially vulnerable because their renal functional reserve may be diminished; thus, renal function should be assessed in this population before administering levofloxacin, and dose adjustment may be necessary in the presence of a diminished renal functional reserve.
The authors report no relevant financial relationships.
Dr. Pires is internal medicine resident; Dr. Mariz is internal medicine specialist; Dr. Esperança is internal medicine specialist; and Dr. Rua is internal medicine specialist and chief head of department, Internal Medicine Department, São Marcos Hospital Braga, Braga, Portugal.
References
1. Santos F. Pathophysiological mechanisms of delirium. Rev Psiquiatr Clín. 2005;32(3):104-112.
2. Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderly. JAMA. 1990;263(8):1097-1101.
3. Thomas RI, Cameron DJ, Fahs MC. A prospective study of delirium and prolonged hospital stay. Exploratory study. Arch Gen Psychiatry. 1988;45(10):937-940.
4. van Hemert AM, van der Mast RC, Hengeveld MW, Vorstenbosch M. Excess mortality in general hospital patients with delirium: a 5-year follow-up of 519 patients seen in psychiatric consultation. J Psychosom Res. 1994;38(4):339-346.
5. Farrington J, Stoudemire A, Tierney J. The role of ciprofloxacin in a patient with delirium due to multiple etiologies. Gen Hosp Psychiatry. 1995;17(1):47-53.
6. Moorthy N, Raghavendra N, Venkatarathnamma P. Levofloxacin-induced acute psychosis. Indian J Psychiatry. 2008;50(1):57-58.
7. Levaquin (levofloxacin) [package insert]. Raritan, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc; 2009.
8. Davis R, Bryson HM. Levofloxacin. A review of its antibacterial activity, pharmacokinetics and therapeutic efficacy [published correction appears in Drugs. 1994;48(1):132]. Drugs. 1994;47(4):677-700.
9. Martin SJ, Meyer JM, Chuck SK, et al. Levofloxacin and sparfloxacin: new quinolone antibiotics. Ann Pharmacother. 1998;32(3):320-336.
10. Wimer SM, Schoonover L, Garrison MW. Levofloxacin: a therapeutic review. Clin Ther. 1998;20(6):1049-1070.
11. Owens RC, Ambrose PG. Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis. 2005;41(suppl 2):S144–S157.
12. Ball P, Mandell L, Niki Y, Tillotson G. Comparative tolerability of the newer fluoroquinolone antibacterials. Drug Saf. 1999;21(5):407-421.
13. Kiangkitiwan B, Doppalapudi A, Fonder M, et al. Levofloxacin-induced delirium with psychotic features. Gen Hosp Psychiatry. 2008;30(4):381-383.
14. Hakko E, Mete B, Ozaras R, et al. Levofloxacin-induced delirium. Clin Neurol Neurosurg. 2005;107(2):158-159.
15. Segev S, Rehavi M, Rubinstein E. Quinolones, theophylline, and diclofenac interactions with the gamma-aminobutyric acid receptor. Antimicrob Agents Chemother. 1988;32(11):1624-1626.
16. Carbon C. Comparison of side effects of levofloxacin versus other fluoroquinolones. Chemotherapy. 2001;47(suppl 3):9-14, 44-48.
17. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239-245.
18. Isaacson SH, Carr J, Rowan AJ. Ciprofloxacin-induced complex partial status epilepticus manifesting as an acute confusional state. Neurology. 1993;43(8):1619-1621.
19. Fernández-Torre JL. Levofloxacin-induced delirium: diagnostic considerations. Clin Neurol Neurosurg. 2006;108(6):614-618.
