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Azithromycin-Induced Agitation and Choreoathetosis
Azithromycin-Induced Agitation and Choreoathetosis
ments of his upper extremities while receiving azithromycin therapy on 2 separate occasions. A search was performed on PubMed (1966 to August 2010), Bing and Google with terms including ‘‘azithromycin,’’ ‘‘Zithromax,’’ and ‘‘choreoathetosis.’’ We found no published descriptions of choreoathetoid movements induced by azithromycin.
Osman Farooq, MD*†¶#**, Zebunnissa Memon, MD*¶**, Sasko D. Stojanovski, PharmD §¶**, and Howard S. Faden, MD*‡¶**
Case Report
We report a child who developed agitation and choreoathetoid movements with azithromycin therapy on 2 separate occasions. In both instances, the symptoms resolved when the antibiotic was discontinued. By means of the Naranjo adverse drug reaction probability scale, we classified this event as a probable adverse drug reaction (score of 6 points). To our knowledge, this is the first published case of azithromycin-induced agitation with choreoathetosis. Because this is a widely used medication for many common infectious conditions, including otitis media and pneumonia, this potential serious adverse reaction should be considered. Ó 2011 Elsevier Inc. All rights reserved. Farooq O, Memon Z, Stojanovski SD, Faden HS. Azithromycin-induced agitation and choreoathetosis. Pediatr Neurol 2011;44:311-313.
An 11-year-old boy with a history of developmental delay was seen by his primary doctor for an upper respiratory infection and tested positive for influenza A. With no relief of his symptoms 3 days later, he was taken back to his doctor, and oral azithromycin therapy was initiated to treat suspected pneumonia. He became slightly agitated after the first dose of medication. By the third day of treatment, he had developed worsened agitation, insomnia, and choreoathetoid movements of his upper extremities. His symptoms continued despite withdrawal of the medication, and he was therefore referred to the Women and Children’s Hospital of Buffalo for further evaluation. At admission, he was briefly provided with clonazepam, which resulted in relief of his symptoms. Within 36 hours of hospitalization, his symptoms completely resolved. The patient had had a similar reaction to azithromycin 2 years before, when he was treated for pneumonia. At that time, he had initially manifested flulike symptoms and tested positive for influenza B. After 3 days of supportive care, his symptoms did not improve, and therapy was thus initiated with azithromycin to treat suspected pneumonia. Six days into his treatment, he developed agitation and backache, and he manifested choreoathetoid movements of his upper extremities. The medication was discontinued, and his symptoms improved with brief therapy with chlorpromazine and lorazepam. Within 48 hours of discontinuation of azithromycin, his symptoms had completely resolved. With the patient’s first episode of agitation and choreoathetoid movements, it was thought that perhaps this was a behavioral reaction to his influenza illness, given his pre-existing developmental delay. However, after the second episode, similarities between the 2 events seemed more than mere coincidence, with the common denominator being treatment with azithromycin. In both instances, his symptoms briefly continued after discontinuation of the azithromycin before completely resolving within 36 to 48 hours.
Introduction Discussion Azithromycin is an erythromycin derivative that belongs to a subgroup of macrolides known as azalides. It was first approved for use in the United States in 1991. It is noted for its activity against certain gram-negative organisms, including Haemophilus influenzae. Because of its ease of administration plus good gastrointestinal tolerability, azithromycin is widely used for uncomplicated otitis media, respiratory infections, and certain urinary tract infections and venereal diseases. We present the case of an 11-yearold boy who developed agitation and choreoathetoid move-
Macrolide antibiotics have been in use for approximately 50 years, and reports of major side effects have been rare. This family of antibiotics, particularly erythromycin and clarithromycin, are known to inhibit the hepatic cytochrome P450 (CYP) isoenzymes, subclass CYP3A4. Clarithromycin in particular has been reported to cause delusions, paranoia, and hallucinations when coadministered with amoxicillin [1]. The phenomenon has been labeled ‘‘Hoigne syndrome’’ or ‘‘antibiomania’’ [1,2]. Adverse
From the *Department of Pediatrics, †Division of Pediatric Neurology, ‡ Department of Pediatric Infectious Diseases, and §Department of Pharmacy, ¶Women and Children’s Hospital of Buffalo, Buffalo, New York; #Jacobs Neurological Institute, Buffalo, New York; and **State University of New York, University of Buffalo, Buffalo, New York.
Communication should be addressed to: Dr. Farooq; Women and Children’s Hospital of Buffalo; Division of Pediatric Neurology; 219 Bryant Street; Buffalo, NY 14222. E-mail: [email protected] Received September 21, 2010; accepted November 22, 2010.
Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2010.11.014 0887-8994/$ - see front matter
Farooq et al: Azithromycin-induced Agitation and Choreoathetosis
311
Table 1. Naranjo adverse drug reaction probability scale 1. Are there previous conclusive reports on this reaction? 2. Did the adverse event appear after the suspected drug was provided? 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was provided? 4. Did the adverse reaction appear when the drug was readministered? 5. Are there alternative causes that could have caused the reaction? 6. Did the reaction reappear when a placebo was provided? 7. Was the drug detected in any body fluid in toxic concentrations? 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence?
Yes (+1) Yes (+2)* Yes (+1)*
No (0)* No ( 1) No (0)
Do not know or not done (0) Do not know or not done (0) Do not know or not done (0)
Yes (+2) Yes ( 1) Yes ( 1) Yes (+1) Yes (+1)
No ( 2) No (+2)* No (+1) No (0) No (0)
Do not know or not done (0)* Do not know or not done (0) Do not know or not done (0)* Do not know or not done (0)* Do not know or not done (0)*
Yes (+1)*
No (0)
Do not know or not done (0)
Yes (+1)
No (0)
Do not know or not done (0)*
Adapted from the Naranjo adverse drug reaction probability scale [12]. Scoring: >9 = definite ADR, 5-8 = probable ADR, 1-4 = possible ADR, 0 = doubtful ADR. * Items which pertain to our patient, cumulating to a score of 6. Abbreviation: ADR = Adverse drug reaction
effects involving the central and peripheral nervous systems have been observed with use of macrolides (incidence of 0.2-1.3%), predominantly manifesting as headache, insomnia, and/or dizziness [3]. Azithromycin is one of the most commonly prescribed macrolides. Unlike the other members of the macrolide family, azithromycin has been demonstrated to have little interaction with the cytochrome P450 system. Therefore, many of the undesirable side effects and drug interactions are avoided. Some adverse effects that have been reported after use of azithromycin include hypersensitivity syndrome [4], agranulocytosis [5], and myocarditis [6]. Some neurologic complications that have been reported include hiccups [7], myasthenic crisis [8], hearing loss [9], and dysgeusia [10]. To our knowledge, neither agitation nor choreoathetosis has been reported in the literature in association with the use of azithromycin or other macrolides. Neurologic and psychiatric side effects to azithromycin have also been reported. Plana et al. [11] reported a patient who developed toxic catatonia as a result of azithromycin use. The authors demonstrated that although their patient had other health concerns and was receiving other medications, the close temporal relationship between treatment with azithromycin and the development of catatonic symptoms was clinically relevant. Furthermore, they described how their patient had no history of psychiatric disorder and then experienced rapid and complete remission once the azithromycin was discontinued. Our patient developed agitation and choreoathetoid movements of his upper extremities not just once, but after 2 separate instances of administration of azithromycin. The diagnosis of drug-induced agitation and choreoathetoid movements is difficult and is generally achieved only by
312 PEDIATRIC NEUROLOGY Vol. 44 No. 4
a process of elimination of other potential causes. In both instances, our patient developed this reaction within 3 to 6 days of medication administration. His symptoms briefly continued after cessation of medication; however, this can be attributed to the drug’s prolonged half-life of up to 72 hours. This behavior was completely new to this patient; he had not previously exhibited any such behavior, and he only had these problems in conjunction with azithromycin. Therefore, we think that this was in fact a true drug reaction. Causality was assessed by means of the Naranjo adverse drug reaction probability scale [12]. We classified the association as probable (score of 6 points) for the following reasons: close temporal relationship to azithromycin administration; adverse reaction improved when the drug was discontinued; absence of any alternative explanation for the symptoms; and similar reaction to the same drug noted in a previous exposure (Table 1). A rechallenge could not be justified on clinical grounds. It is difficult to know how this antibiotic can induce such symptoms, and thus an idiosyncratic reaction could be the explanation. As health care providers, we must be aware of this rare but worrisome complication of this commonly used antibiotic. The challenges that we may face with reactions such as this include patient safety, parental/ guardian concern and/or anxiety, treatment, and knowledge to avoid the offending agent in the future.
References [1] Przybylo HJ, Przybylo JH, Todd Davis A, Cote CJ. Acute psychosis after anesthesia: The case for antibiomania. Paediatr Anaesth 2005;15: 703-5. [2] Ahuja N. Azithromycin and catatonia symptoms. J Clin Psychiatry 2007;68:336-7.
[3] Principi N, Esposito S. Comparative tolerability if erythromycin and newer macrolide antibacterials in paediatric patients. Drug Saf 1999; 20:25-41. [4] Cascaval R, Lancaster DJ. Hypersensitivity syndrome associated with azithromycin. Am J Med 2001;110:330-1. [5] Kajiguchi T, Ohno T. Azithromycin-related agranulocytosis in an elderly man with acute otitis media. Intern Med 2009;48:1089-91. [6] Pursnani A, Yee H, Slater W, Sarswat N. Hypersensitivity myocarditis associated with azithromycin exposure. Ann Intern Med 2009;150:225-6. [7] Jover F, Cuadrado JM, Merino J. Possible azithromycinassociated hiccups. J Clin Pharm Ther 2005;30:413-6.
[8] Pradhan S, Pardasani V, Ramteke K. Azithromycin-induced maysthenic crisis: Reversibility with calcium gluconate. Neurol India 2009;57:352-3. [9] Lo SH, Kotabe S, Mitsunaga L. Azithromycin-induced hearing loss. Am J Health Syst Pharm 1999;56:380-3. [10] Drew H, Harasty L. Dysgeusia following a course of zithromax: A case report. J N J Dent Assoc 2007;78:24-7. [11] Plana MT, Blanch J, Romero S, Serra M, Gastro C. Toxic catatonia secondary to azithromycin. J Clin Psychiatry 2006;67:492-3. [12] Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30:239-45.
Farooq et al: Azithromycin-induced Agitation and Choreoathetosis
313
ments of his upper extremities while receiving azithromycin therapy on 2 separate occasions. A search was performed on PubMed (1966 to August 2010), Bing and Google with terms including ‘‘azithromycin,’’ ‘‘Zithromax,’’ and ‘‘choreoathetosis.’’ We found no published descriptions of choreoathetoid movements induced by azithromycin.
Osman Farooq, MD*†¶#**, Zebunnissa Memon, MD*¶**, Sasko D. Stojanovski, PharmD §¶**, and Howard S. Faden, MD*‡¶**
Case Report
We report a child who developed agitation and choreoathetoid movements with azithromycin therapy on 2 separate occasions. In both instances, the symptoms resolved when the antibiotic was discontinued. By means of the Naranjo adverse drug reaction probability scale, we classified this event as a probable adverse drug reaction (score of 6 points). To our knowledge, this is the first published case of azithromycin-induced agitation with choreoathetosis. Because this is a widely used medication for many common infectious conditions, including otitis media and pneumonia, this potential serious adverse reaction should be considered. Ó 2011 Elsevier Inc. All rights reserved. Farooq O, Memon Z, Stojanovski SD, Faden HS. Azithromycin-induced agitation and choreoathetosis. Pediatr Neurol 2011;44:311-313.
An 11-year-old boy with a history of developmental delay was seen by his primary doctor for an upper respiratory infection and tested positive for influenza A. With no relief of his symptoms 3 days later, he was taken back to his doctor, and oral azithromycin therapy was initiated to treat suspected pneumonia. He became slightly agitated after the first dose of medication. By the third day of treatment, he had developed worsened agitation, insomnia, and choreoathetoid movements of his upper extremities. His symptoms continued despite withdrawal of the medication, and he was therefore referred to the Women and Children’s Hospital of Buffalo for further evaluation. At admission, he was briefly provided with clonazepam, which resulted in relief of his symptoms. Within 36 hours of hospitalization, his symptoms completely resolved. The patient had had a similar reaction to azithromycin 2 years before, when he was treated for pneumonia. At that time, he had initially manifested flulike symptoms and tested positive for influenza B. After 3 days of supportive care, his symptoms did not improve, and therapy was thus initiated with azithromycin to treat suspected pneumonia. Six days into his treatment, he developed agitation and backache, and he manifested choreoathetoid movements of his upper extremities. The medication was discontinued, and his symptoms improved with brief therapy with chlorpromazine and lorazepam. Within 48 hours of discontinuation of azithromycin, his symptoms had completely resolved. With the patient’s first episode of agitation and choreoathetoid movements, it was thought that perhaps this was a behavioral reaction to his influenza illness, given his pre-existing developmental delay. However, after the second episode, similarities between the 2 events seemed more than mere coincidence, with the common denominator being treatment with azithromycin. In both instances, his symptoms briefly continued after discontinuation of the azithromycin before completely resolving within 36 to 48 hours.
Introduction Discussion Azithromycin is an erythromycin derivative that belongs to a subgroup of macrolides known as azalides. It was first approved for use in the United States in 1991. It is noted for its activity against certain gram-negative organisms, including Haemophilus influenzae. Because of its ease of administration plus good gastrointestinal tolerability, azithromycin is widely used for uncomplicated otitis media, respiratory infections, and certain urinary tract infections and venereal diseases. We present the case of an 11-yearold boy who developed agitation and choreoathetoid move-
Macrolide antibiotics have been in use for approximately 50 years, and reports of major side effects have been rare. This family of antibiotics, particularly erythromycin and clarithromycin, are known to inhibit the hepatic cytochrome P450 (CYP) isoenzymes, subclass CYP3A4. Clarithromycin in particular has been reported to cause delusions, paranoia, and hallucinations when coadministered with amoxicillin [1]. The phenomenon has been labeled ‘‘Hoigne syndrome’’ or ‘‘antibiomania’’ [1,2]. Adverse
From the *Department of Pediatrics, †Division of Pediatric Neurology, ‡ Department of Pediatric Infectious Diseases, and §Department of Pharmacy, ¶Women and Children’s Hospital of Buffalo, Buffalo, New York; #Jacobs Neurological Institute, Buffalo, New York; and **State University of New York, University of Buffalo, Buffalo, New York.
Communication should be addressed to: Dr. Farooq; Women and Children’s Hospital of Buffalo; Division of Pediatric Neurology; 219 Bryant Street; Buffalo, NY 14222. E-mail: [email protected] Received September 21, 2010; accepted November 22, 2010.
Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2010.11.014 0887-8994/$ - see front matter
Farooq et al: Azithromycin-induced Agitation and Choreoathetosis
311
Table 1. Naranjo adverse drug reaction probability scale 1. Are there previous conclusive reports on this reaction? 2. Did the adverse event appear after the suspected drug was provided? 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was provided? 4. Did the adverse reaction appear when the drug was readministered? 5. Are there alternative causes that could have caused the reaction? 6. Did the reaction reappear when a placebo was provided? 7. Was the drug detected in any body fluid in toxic concentrations? 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence?
Yes (+1) Yes (+2)* Yes (+1)*
No (0)* No ( 1) No (0)
Do not know or not done (0) Do not know or not done (0) Do not know or not done (0)
Yes (+2) Yes ( 1) Yes ( 1) Yes (+1) Yes (+1)
No ( 2) No (+2)* No (+1) No (0) No (0)
Do not know or not done (0)* Do not know or not done (0) Do not know or not done (0)* Do not know or not done (0)* Do not know or not done (0)*
Yes (+1)*
No (0)
Do not know or not done (0)
Yes (+1)
No (0)
Do not know or not done (0)*
Adapted from the Naranjo adverse drug reaction probability scale [12]. Scoring: >9 = definite ADR, 5-8 = probable ADR, 1-4 = possible ADR, 0 = doubtful ADR. * Items which pertain to our patient, cumulating to a score of 6. Abbreviation: ADR = Adverse drug reaction
effects involving the central and peripheral nervous systems have been observed with use of macrolides (incidence of 0.2-1.3%), predominantly manifesting as headache, insomnia, and/or dizziness [3]. Azithromycin is one of the most commonly prescribed macrolides. Unlike the other members of the macrolide family, azithromycin has been demonstrated to have little interaction with the cytochrome P450 system. Therefore, many of the undesirable side effects and drug interactions are avoided. Some adverse effects that have been reported after use of azithromycin include hypersensitivity syndrome [4], agranulocytosis [5], and myocarditis [6]. Some neurologic complications that have been reported include hiccups [7], myasthenic crisis [8], hearing loss [9], and dysgeusia [10]. To our knowledge, neither agitation nor choreoathetosis has been reported in the literature in association with the use of azithromycin or other macrolides. Neurologic and psychiatric side effects to azithromycin have also been reported. Plana et al. [11] reported a patient who developed toxic catatonia as a result of azithromycin use. The authors demonstrated that although their patient had other health concerns and was receiving other medications, the close temporal relationship between treatment with azithromycin and the development of catatonic symptoms was clinically relevant. Furthermore, they described how their patient had no history of psychiatric disorder and then experienced rapid and complete remission once the azithromycin was discontinued. Our patient developed agitation and choreoathetoid movements of his upper extremities not just once, but after 2 separate instances of administration of azithromycin. The diagnosis of drug-induced agitation and choreoathetoid movements is difficult and is generally achieved only by
312 PEDIATRIC NEUROLOGY Vol. 44 No. 4
a process of elimination of other potential causes. In both instances, our patient developed this reaction within 3 to 6 days of medication administration. His symptoms briefly continued after cessation of medication; however, this can be attributed to the drug’s prolonged half-life of up to 72 hours. This behavior was completely new to this patient; he had not previously exhibited any such behavior, and he only had these problems in conjunction with azithromycin. Therefore, we think that this was in fact a true drug reaction. Causality was assessed by means of the Naranjo adverse drug reaction probability scale [12]. We classified the association as probable (score of 6 points) for the following reasons: close temporal relationship to azithromycin administration; adverse reaction improved when the drug was discontinued; absence of any alternative explanation for the symptoms; and similar reaction to the same drug noted in a previous exposure (Table 1). A rechallenge could not be justified on clinical grounds. It is difficult to know how this antibiotic can induce such symptoms, and thus an idiosyncratic reaction could be the explanation. As health care providers, we must be aware of this rare but worrisome complication of this commonly used antibiotic. The challenges that we may face with reactions such as this include patient safety, parental/ guardian concern and/or anxiety, treatment, and knowledge to avoid the offending agent in the future.
References [1] Przybylo HJ, Przybylo JH, Todd Davis A, Cote CJ. Acute psychosis after anesthesia: The case for antibiomania. Paediatr Anaesth 2005;15: 703-5. [2] Ahuja N. Azithromycin and catatonia symptoms. J Clin Psychiatry 2007;68:336-7.
[3] Principi N, Esposito S. Comparative tolerability if erythromycin and newer macrolide antibacterials in paediatric patients. Drug Saf 1999; 20:25-41. [4] Cascaval R, Lancaster DJ. Hypersensitivity syndrome associated with azithromycin. Am J Med 2001;110:330-1. [5] Kajiguchi T, Ohno T. Azithromycin-related agranulocytosis in an elderly man with acute otitis media. Intern Med 2009;48:1089-91. [6] Pursnani A, Yee H, Slater W, Sarswat N. Hypersensitivity myocarditis associated with azithromycin exposure. Ann Intern Med 2009;150:225-6. [7] Jover F, Cuadrado JM, Merino J. Possible azithromycinassociated hiccups. J Clin Pharm Ther 2005;30:413-6.
[8] Pradhan S, Pardasani V, Ramteke K. Azithromycin-induced maysthenic crisis: Reversibility with calcium gluconate. Neurol India 2009;57:352-3. [9] Lo SH, Kotabe S, Mitsunaga L. Azithromycin-induced hearing loss. Am J Health Syst Pharm 1999;56:380-3. [10] Drew H, Harasty L. Dysgeusia following a course of zithromax: A case report. J N J Dent Assoc 2007;78:24-7. [11] Plana MT, Blanch J, Romero S, Serra M, Gastro C. Toxic catatonia secondary to azithromycin. J Clin Psychiatry 2006;67:492-3. [12] Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30:239-45.
Farooq et al: Azithromycin-induced Agitation and Choreoathetosis
313