Case Report

Levofloxacin-induced acute anxiety and insomnia Arun Kandasamy, D Srinath1 Departments of Psychiatry, and 1Pulmonology, SRM Medical College Hospital and Research Center, Kattankulathur, Kanchipuram, Tamil Nadu, India

ABSTRACT Fluoroquinolones can cause adverse neuropsychiatric side effects, which are more common in older age. We present three cases of levofloxacin-induced acute anxiety and insomnia in young adults. In all the cases, discontinuation of levofloxacin immediately lead to remission. Key words: Anxiety, γ-amino butyric acid, insomnia, levofloxacin, quinolones

Introduction sense the qualitative difference in the level of comfort in carrying out his daily routine. He also had severe Fluoro-quinolones are one of the most common anxiety and irritable mood the whole day. Again the used by clinicians all over the world. They sleep was disturbed in the night. Next day morning after are generally well tolerated.[1] The most common adverse consultation with his physician, he was prescribed a reactions of fluoro-quinolones involve the GI tract, with different class of . The same day night his sleep 3% to 17% of patients reporting mild , vomiting, was adequate and satisfactory. His anxiety was less on and/or abdominal discomfort. Neuropsychiatric adverse the next day and then it remitted. effects are not uncommon. Among them, mild headache and dizziness are the common adverse effects. Rarely Case 2 hallucinations and have been reported.[1] Mrs. S, a 30-year-old woman, developed lower We report three cases with interesting and clinically respiratory tract illness. She took levofloxacin 500 mg per significant presentation of acute anxiety and insomnia day as per her physician’s advice. She was not able to while treated with levofloxacin. sleep throughout the night. She was also feeling anxious without any clear reasons. She contacted her physician the next day. He stopped levofloxacin, after which her Case Reports neuropsychiatric symptoms remitted completely on the next day. Case 1 Mr. A, a 30-year-old male developed lower respiratory Case 3 tract illness. He was prescribed levofloxacin 500 mg for Mr. S, a 32-year-old doctor, medicated himself with 5 days, once daily in night. The first day he could not levofloxacin 750 mg for his acute lower respiratory tract sleep throughout the night. He started getting worries infection. He had taken complete courses of levofloxacin throughout the night about the next day routine. 500 mg for the same complaints in the past. This time This continued onto the next day also. He was able to he had samples of 750 mg tablets only and so he took it. Within 4 to 6 h, he started feeling restless and had Access this article online insomnia throughout the night. He was worrying about Quick Response Code: various day to day things in the night. He was irritable Website: towards his child and wife. The next day he consulted www.ruralneuropractice.com at psychiatry OPD and was diagnosed to have acute nonspecific anxiety. The same day levofloxacin was

DOI: stopped and his sleep and anxiety symptoms normalized 10.4103/0976-3147.98256 from the next day. There was no relapse of anxiety symptoms in the next 6 months of follow up.

Address for correspondence: Dr. Arun Kandasamy, Department of Psychiatry, SRM Medical College Hospital and Research Center, Kattankulathur, Kanchipuram - 603 203, Tamil Nadu, India. E-mail: [email protected]

212 Journal of Neurosciences in Rural Practice | May - August 2012 | Vol 3 | Issue 2 Kandasamy and Srinath: Levofloxacin induced acute anxiety and insomnia

All the three patients didn’t take any other medications neuropsychiatric adverse effects are frequently noted along with levofloxacin. They were evaluated by in elderly and people with CNS lesions.[7,9,10] psychiatrist to rule out any primary psychiatric disorder. But no significant psychiatric illness was found in the past and family history. All were followed up for a Conclusion minimum period of 6 months without any relapse. None Levofloxacin is prone to cause neuropsychiatric side of them were willing to restart levofloxacin at any point effects. Some of the side effects like insomnia and anxiety of time due to their past dreadful experiences. go unnoticed many a times. So by presenting the above three cases, we like to emphasize on the following points. Discussion 1. Physicians and psychiatrists should be aware of neuropsychiatric side effects of levofloxacin. Effects within the central nervous system (CNS) Although neuropsychiatric side effects of are generally some of the more frequent adverse fluoroquinolones are more common in the elderly, consequences of quinolones therapy.[2] One of the they can also affect younger patients. recent review on this subject had reported that mania, 2. Stopping the drug in time may prevent the insomnia, acute and delirium were the most progress of nonspecific anxiety and insomnia to frequently reported psychiatric adverse events; grand major psychiatric disorders like psychosis. mal convulsion, confusional state and myoclonus were 3. Although there are neuropsychiatric side effects the most frequently reported neurological adverse mentioned as rare in the drug leaflet provided events. , , and were by the pharmaceutical companies, this case series the quinolones with more neurological and psychiatric and other reports from the literature indicate adverse drug reactions reported in the literature.[3] that neuropsychiatric side effects are relevant CNS effects of quinolones correlate with its binding to and require more systematic research on their the receptors for γ-amino butyric acid (GABA) in the prevalence. brain. GABA is an inhibitory neurotransmitter of brain. 4. The research should also look whether there is a Quinolones prevent normal binding of GABA with their dose relation between levofloxacin and side-effects. receptors. So it increases CNS stimulation.[4] There are This is specifically important in MDRTB where reports on quinolones directly activating N-methyl- higher doses of levofloxacin are prescribed. d-aspartate (NMDA) and adenosine receptors. Thus, 5. There should also be a surveillance of the effect under specific conditions of sufficient CNS penetration, of combined prescriptions like NSAIDs, anti- associated with antagonism of inhibitory pathways histaminics, anti-tubercular drugs, etc with (GABA) and stimulation of excitatory pathways levofloxacin. (NMDA, adenosine), observable CNS symptoms are 6. Cooperation of psychiatrists, pulmonologists, manifested. This mechanism explains the pathogenesis and general practitioners is required in further of the acute anxiety and insomnia in the above cases interdisciplinary research on neuropsychiatric side with levofloxacin therapy.[5,6] These mechanisms are effects of levofloxacin and other fluoroquinolones. even correlating with non-dopaminergic pathways of psychosis. It is even possible that the above-said References cases might have progressed on to psychosis, if the full course of levofloxacin therapy was completed.[7] 1. Petri WA. Sulfonamides, -, Quinolones, In multi-drug-resistant (MDRTB), higher and agents for urinary tract infections. In: Brunton LL, Lazo J, Parker K, editors. Goodman and Gilman’s the pharmacological basis of doses of levofloxacin are prescribed. In this scenario, therapeutics. 11th ed. New York: McGraw-Hill; 2006. p. 718-29. the third case indicates a strong need for surveillance 2. Ball AP, Tillotson GS. Tolerability of fluoroquinolones antibiotics: Past, of neuropsychiatric symptoms in these patients. In the present and future. Drug Saf 1995;13:343-58. treatment of MDR-TB patients, the other agents like 3. Tomé AM, Filipe A. Quinolones: Review of psychiatric and neurological adverse reactions. Drug Saf 2011;34:465-88. cycloserine are already an established risk factor for 4. Tillotson GS. Quinolones: Structure-activity relationships and future neuropsychiatric side effects.[8] When levofloxacin is predictions. J Med Microbiol 1996;44:320-4. combined with them, it might have an additive effect on 5. Dang A, Kamat R, Padmanabh RV. Ciprofloxacin induced nightmares in an adult patient. Indian J Psychiatry 2008;50:305-6. the above unpleasant symptoms. The other interesting 6. Mandell L, Tillotson G. Safety of fluoroquinolones: An update. Can J thing to be noted from above 3 cases is that, they all were Infect Dis 2002;13:54-61. young adults and none of them had any CNS-related 7. Moorthy N, Raghavendra N, Venkatarathnamma PN. Levofloxacin- induced acute psychosis. Indian J Psychiatry 2008;50:57-8. disorders. This is important because the previous 8. Bankier RG. Psychosis associated with cycloserine. Can Med Assoc J literature available on fluoroquinolones suggest that 1965;93:35-7.

Journal of Neurosciences in Rural Practice | May - August 2012 | Vol 3 | Issue 2 213 Kandasamy and Srinath: Levofloxacin induced acute anxiety and insomnia

9. Available from: http://www.mhra.gov.uk/home/groups/par/documents/ websiteresources/con076101.pdf [Last accessed on 2011 Sep 12]. How to cite this article: Kandasamy A, Srinath D. Levofloxacin-induced acute anxiety and insomnia. J Neurosci Rural Pract 2012;3:212-4. 10. Slobodin G, Elias N, Zaygraikin N, Sheikh-Ahmad M, Sabetay S, WellerB, Source of Support: Nil. Conflict of Interest: None declared. et al. Neurol Sci 2009;30:59-61.

Commentary

In the paper “Levofloxacin induced acute anxiety fluoroquinolones is required to provide sufficient data and insomnia - a case series” published in the current for different age groups. Fluoroquinolones should be issue of the Journal of Neurosciences in Rural Practice, administered with cautions in patients with psychiatric authors report three cases of neuropsychiatric side disorders, until more precise data from studies are effects of levofloxacin.[1] Neuropsychiatric effects of available. fluoroquinolones are common in the elderly. In older age, fluoroquinolones can cause confusions, agitation, and In addition, there is another adverse effect of psychosis. In this case series, anxiety and insomnia were fluoroquinolones, which is important in patients reported to be neuropsychiatric side effects in young undergoing neurosurgical interventions or in patients with adults (30-32 years) taking levofloxacin. In the literature, traumatic lesions affecting tendons or ligaments. Tendinitis reports of psychiatric side effects of fluoroquinolones in and tendon ruptures can be induced by fluoroquinolones young adults are rare. Fluoroquinolones with the most during the drug treatment or as late as a couple of months reports on neuropsychiatric side effects are ciprofloxacin after treatment.[6] In vitro, fluoroquinolones decrease and ofloxacin.[2] Neuropsychiatric side effects of collagen and proteoglycan synthesis in fibroblast cultures levofloxacin are less studied. and increase matrix-degrading proteolytic activity.[7] Therefore, fluoroquinolones can prolongate or disturb In the recent review by Tome et al., who analyzed the recovery of surgical patients who have affection of 145 cases of neuropsychiatric side effects of tendons or ligaments. fluoroquinolones extracted from 83 publications, 46.9% of patients developed psychiatric disorders only and To conclude, fluoroquinolones, which are a wide- 40.7% of patients developed neurological disorders spread class of antibiotics, have potential severe only.[2] In addition to psychosis, delirium, agitation, neuropsychiatric side effects and impair regeneration anxiety, insomnia, and depression, it has been reported of ligaments and tendous structures. These side effects that fluoroquinolones can induce suicidal ideations. [3] can occur in younger and older patients and should be The epileptic seizures, myoclonus, and confusional considered in the treatment of neurological, psychiatric, state were the most frequently reported neurological and neurosurgical patients. side effects of fluoroquinolones. Less than 10% of patients had both psychiatric and neurological side Yaroslav Winter, Natalia Epifanova-Bertschi1, effects. Alexei Korchounov2 Departments of Neurology, Philipps-University, Marburg, 2Clinic of The gerontopsychiatrists and neurogeriatrists are aware Neurology, Marienhospital Kevelaer, Germany, 1Psychiatric Hospital of neuropsychiatric side effects of fluoroquinolones and Sanatorium Kilchberg, Kilchberg, Switzerland usually try to avoid administration of fluoroquinolones Address for correspondence: in older patients. In addition, there is growing evidence Dr. Yaroslav Winter, that neuropsychiatric adverse effects of this class of Department of Neurology, Philipps-University Marburg, drugs are also relevant in young adults. The current Baldingerstrasse, 35043 Marburg, Germany. E-mail: [email protected] paper reported on these side effects in young adults taking levofloxacin. In contrast to older patients, which References usually develop agitation, psychosis, or delirium,[4,5] younger patients in this series claimed to have anxiety 1. Kandasamy A, Srinath D. Levofloxacin-induced acute anxiety and and insomnia under levofloxacin. It is unclear, if these insomnia. J Neurosci Rural Pract 2012;3:212-4. 2. Tome AM, Filipe A. Quinolones: Review of psychiatric and neurological neuropsychiatric adverse effects are more typical for adverse reactions. Drug Saf 2011;34:465-88. younger age. More systematic research with different 3. LaSalvia EA, Domek GJ, Gitlin DF. Fluoroquinolone-induced suicidal

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