VIEWS & REVIEWS Antibiotic-associated encephalopathy Shamik Bhattacharyya, ABSTRACT * MD Delirium is a common and costly complication of hospitalization. Although medications are a * R. Ryan Darby, MD known cause of delirium, antibiotics are an underrecognized class of medications associated with Pooja Raibagkar, MD delirium. In this article, we comprehensively review the clinical, radiologic, and electrophysiologic L. Nicolas Gonzalez features of antibiotic-associated encephalopathy (AAE). AAE can be divided into 3 unique clinical Castro, MD, PhD phenotypes: encephalopathy commonly accompanied by seizures or myoclonus arising within Aaron L. Berkowitz, MD, days after antibiotic administration (caused by cephalosporins and penicillin); encephalopathy PhD characterized by psychosis arising within days of antibiotic administration (caused by quinolones, macrolides, and procaine penicillin); and encephalopathy accompanied by cerebellar signs and MRI abnormalities emerging weeks after initiation of antibiotics (caused by metronidazole). We Correspondence to Dr. Bhattacharyya: correlate these 3 clinical phenotypes with underlying pathophysiologic mechanisms of antibiotic [email protected] neurotoxicity. Familiarity with these types of antibiotic toxicity can improve timely diagnosis of AAE and prompt antibiotic discontinuation, reducing the time patients spend in the delirious state. Neurology® 2016;86:963–971 GLOSSARY AAE 5 antibiotic-associated encephalopathy; GABAAR 5 g-aminobutyric acid class A receptor; IPSP 5 inhibitory postsyn- aptic potential. Delirium occurs in up to half of hospitalized patients and up to 80% of patients in intensive care units.1 Delirium is associated with increased length of hospital stay,2–4 in-hospital complications,5 discharge to long-term care facilities,6 rehospitalization from long-term care facilities,7 subsequent cognitive impairment,4 subsequent dependence,8 and risk of in-hospital2,9 and 1-year mortality.10 This has led to ongoing efforts to recognize, prevent, and treat delirium to improve patient outcomes and reduce health care costs.11 Although medications are a commonly considered reversible cause of encephalopathy, antibiotics are an underrecognized etiology.12 Serious CNS adverse effects of antibiotics are generally reported with a frequency of less than 1%, with enceph- alopathy representing a small proportion of those adverse effects.13,14 However, a recent retro- spective study of 100 critically ill patients reported a 15% rate of encephalopathy associated with use of the fourth-generation cephalosporin cefepime, suggesting that antibiotic-associated enceph- alopathy (AAE) may be underdiagnosed.12 Identification of AAE as a cause of delirium is challenging since patients receiving antibiotics often have multiple potential causes of altered cognition, and data describing the clinical features of and risk factors for AAE are limited to case reports and small series.14,15 Here we present the results of a comprehensive review of reported cases of AAE to define the specific clinical features, EEG changes, and neuroimaging findings associated with encephalopathy from particular anti- biotic classes and individual antibiotics. Our synthesis of this data reveals 3 distinct clinical subtypes of AAE, each with unique pathophysiologic mechanisms. SEARCH METHODS AND CRITERIA We comprehensively searched PubMed using terms for antibiotics Supplemental data (antibiotic or “anti-bacterial agents” [MeSH] or “anti-bacterial agents” [pharmacologic action] or at Neurology.org *These authors contributed equally to this work. From the Department of Neurology (S.B., R.R.D., P.R., L.N.G.C., A.L.B.), Brigham and Women’s Hospital; Department of Neurology (R.R.D., P.R., L.N.G.C.), Massachusetts General Hospital; and Harvard Medical School (S.B., R.R.D., P.R., L.N.G.C., A.L.B.), Boston, MA. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2016 American Academy of Neurology 963 ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 2,4-diacetylphloroglucinol or 2-deoxystreptamine or which altered cognition/consciousness was due to a acedapsone or actinonin or actinorhodin . or postictal state after a clinically apparent seizure were tinidazole) (see supplemental data on the Neurology® excluded, but cases in which patients presented with Web site at Neurology.org for all antibiotic terms) encephalopathy accompanied by seizures or in whom and the search terms encephalopathy, confusion, nonconvulsive seizures were determined to be the cause delirium, seizure, neuropathy, neurotoxicity, mania, of encephalopathy were included. hallucination, or psychosis. The term neuropathy was For each described case, we extracted data on included to increase sensitivity since some antibiotics demographics (age, sex), antibiotic used, comorbid- such as metronidazole cause concurrent neuropathy ities (renal dysfunction, hepatic dysfunction, history and encephalopathy. We searched from the beginning of psychiatric disease), clinical symptoms accompany- of indexing to October 16, 2013, in English, French, ing encephalopathy (seizures, myoclonus, focal neuro- and Spanish. Results were screened by the authors to logic deficits), temporal evolution of onset and meet the following inclusion criteria: (1) The article improvement of toxicity, and laboratory investigations must present a case report or case series describing (EEG, MRI, serum or CSF drug levels). We calcu- individual patients experiencing alteration of cognition/ lated a Naranjo score for each case described (see sup- consciousness after administration of antibiotics and plemental data for Naranjo score table) assessing the improvement after cessation. We therefore excluded likelihood of causality of the association described.16 series not describing individual patient data, but reference lists from such articles were screened for CLINICAL CHARACTERISTICS OF AAE Our search additional case reports and series. (2) Case reports in yielded 292 articles describing 391 individual cases Table 1 Baseline characteristics and risk factors in patients with antibiotic-associated encephalopathy Median (range) Renal insufficiency, Hepatic dysfunction, Psychiatric history, No. of reports age, y Men, n (%) n(%) n(%) n(%) Penicillins 72 41 (4–87) 40 (56) 12 (17) 0 (0) 2 (3) Penicillin G procaine 34 28 (11–75) 20 (59) 0 (0) 0 (0) 0 (0) Penicillin 24 53 (10–84) 15 (63) 7 (29) 0 (0) 0 (0) Other 14 52 (4–87) 5 (36) 5 (36) 0 (0) 2 (14) Cephalosporins 69 65 (8–88) 35 (54) 50 (72) 2 (3) 2 (3) Cefepime 33 70 (14–86) 16 (55) 23 (70) 2 (6) 1 (3) Ceftazidime 12 71 (34–80) 7 (58) 11 (92) 0 (0) 0 (0) Other 24 61 (8–88) 12 (50) 16 (67) 0 (0) 1 (4) Antimycobacterials 65 40 (14–80) 40 (62) 8 (12) 1 (2) 4 (6) Isoniazid 49 43 (14–80) 30 (61) 8 (16) 1 (2) 4 (8) Other 16 32 (15–60) 10 (63) 0 (0) 0 (0) 0 (0) Quinolones 63 57 (,1–89) 27 (43) 14 (22) 0 (0) 9 (14) Ciprofloxacin 26 55 (,1–88) 13 (50) 8 (31) 0 (0) 2 (8) Ofloxacin 11 50 (5–75) 2 (18) 0 (0) 0 (0) 5 (45) Other 26 61 (17–89) 12 (46) 6 (23) 0 (0) 2 (8) Macrolides 54 51 (3–94) 32 (59) 4 (7) 2 (4) 11 (20) Clarithromycin 44 51 (3–94) 23 (52) 2 (5) 0 (0) 10 (23) Other 10 53 (4–81) 9 (90) 2 (20) 2 (20) 1 (10) Metronidazole 29 48 (19–75) 19 (66) 1 (3) 4 (14) 0 (0) Sulfonamides 19 54 (19–88) 11 (58) 4 (21) 0 (0) 3 (16) Trimethoprim-sulfamethoxazole 15 55 (19–88) 8 (53) 4 (27) 0 (0) 3 (20) Other 436(23–55) 3 (75) 0 (0) 0 (0) 0 (0) The table shows antibiotic classes and antibiotics (listed under each class) for which 10 or more clinical reports were available. Other antibiotics are aggregated under the subtitle “other.” The “other” category includes the following antibiotics: penicillins: amoxicillin (5 cases), piperacillin (4), ampicillin (1), cloxacillin (1), oxacillin (1), mix of procaine penicillin and benzathine penicillin (1), ticarcillin (1); cephalosporins: cefuroxime (5), ceftriaxone (4), cefazolin (3), cephalexin (3), cefixime (2), cefotaxime (2), cefditoren pivoxil (1), cefoperazone (1), cefoxitin (1), cephaloridine (1), cephalothin (1); antimycobacterials: dapsone (5), streptomycin (3), cycloserine (2), ethambutol (2), ethionamide (2), rifampin (2); quinolones: levofloxacin (9), gatifloxacin (7), norfloxacin (3), naldixic acid (2), pefloxacin (2), gemifloxacin (1), moxifloxacin (1), trovafloxacin (1); macrolides: azithromycin (5), erythromycin (5); sulfonamides: sulfadiazine (3), sulfanilamide (1). 964 Neurology 86 March 8, 2016 ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. from 1946 through 2013 inclusive.e1–e292 Toxicity was encephalopathy or exacerbation of psychiatric illness reported with 54 different antibiotics from 12 different in the setting of medical illness. classes of antibiotics. Of the 391 cases, 54% were male, Clinical features associated with AAE. Table 2 shows the and the median age was 54 years (range ,1–94 years). clinical characteristics of AAE. Psychosis (defined as Tables 1–3 show results by antibiotic class and indi- presence of delusions or hallucinations) was present in vidual antibiotics for which 10 or more cases of AAE 47% of cases overall and was most common among were reported. Antibiotics with fewer than 10 reported cases of encephalopathy associated with sulfonamides cases of AAE were compiled under the heading “other” (68%), quinolones (67%), macrolides (63%), and for each antibiotic class. penicillin procaine