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   Antibiotics Underrecognized Cause of Delirium    
   Nancy A. Melville    
   March 04, 2016    
        
   Antibiotic toxicity can represent an unrecognized cause of delirium in   
   hospital patients, with manifestations observed in three distinct phenotypes,   
   new research shows.    
      
   "While toxicity from antibiotics has certainly been reported in the past, this   
   is the largest analysis of the spectrum of toxicity from antibiotics," lead   
   author Shamik Bhattacharyya, MD, from Harvard Medical School and Brigham and   
   Women's Hospital in    
   Boston, Massachusetts, told Medscape Medical News.    
      
   "As far as we know, these three phenotypes have not been described   
   individually in such terms before."    
      
   Awareness of these three core clinical patterns "can lead to earlier   
   discontinuation of causative medications, reducing time spent in a delirious   
   state and thereby improving outcomes in patients with delirium," they add.    
      
   Their findings were published online February 17 in Neurology.    
      
   While reports of serious central nervous system adverse effects related to   
   antibiotic treatment are uncommon, and encephalopathy represents only a small   
   proportion of those effects, one recent study reported an encephalopathy rate   
   as high as 15% among    
   100 critically ill patients, with cases linked to the use of the   
   fourth-generation cephalosporin cefepime, the researchers say.    
      
   For the new review, Dr Bhattacharyya and colleagues conducted a literature   
   search, identifying 391 cases from 1946 through 2013 involving patients   
   experiencing delirium or alterations of cognition or consciousness after the   
   initiation of treatment with    
   antibiotics, with the effects diminishing upon treatment cessation.    
      
   Patients who experienced encephalopathy before initiation of the antibiotics   
   were not included.    
      
   The likelihood of the antibiotic as the cause of the effects was determined   
   with the Naranjo Adverse Drug Reaction Probability Scale. Among the patients,   
   54% were male and the median age was 54 years; the cases involved 54 different   
   antibiotics in 12    
   different drug classes.    
      
   In the assessment of a variety of clinical characteristics of cases, patterns   
   emerged suggestive of three distinct clinical syndromes of antib   
   otic-associated encephalopathy (AAE):    
      
   Type 1 AAE: Associated with penicillin and cephalosporins and characterized by   
   onset of symptoms within days of introduction, the authors reported.   
   Characteristics include myoclonus or seizures, abnormal electroencephalogram   
   (EEG), but normal MRI    
   findings, with symptoms typically resolving within days. Encephalopathy   
   associated with cephalosporin use was most commonly reported in the setting of   
   renal insufficiency. In terms of pathophysiology, type 1 is thought to involve   
   disruption of inhibitory    
   synaptic transmission, resulting in excitotoxicity.    
      
   Type 2 AAE: Associated with procaine penicillin, sulfonamides, f   
   uoroquinolones, and macrolides. Symptoms also appear within days of initiation   
   and include psychosis and the rare occurrence of seizures. Also characterized   
   by infrequently abnormal EEG,    
   normal MRI findings, and resolution within days. Type 2 has unique features   
   that "closely resemble drug-induced psychotic syndromes caused by   
   perturbations of the D2 dopamine and NMDA glutamate receptors (including   
   cocaine, amphetamines, and    
   phencyclidine)," the authors write.    
      
   Type 3 AAE: Associated only with metronidazole; onset more commonly occurs   
   weeks after initiation, instead of days. The syndrome frequently involves   
   cerebellar dysfunction and more rarely involves seizures or EEG abnormalities.   
   The metronidazole toxicity    
   results in "characteristic reversible MRI signal abnormalities in the   
   cerebellar dentate nuclei, dorsal brainstem, or splenium of the corpus   
   callosum," the authors said.    
      
   Falling outside of the three categories was isoniazid, which was associated   
   with symptom onset within weeks to months and commonly involving psychosis.   
   Seizures are rare, and the EEG is commonly abnormal. Cases involving isoniazid   
   intoxication due to    
   overdose were not included.    
      
   Although the prevalence of AAE is unclear, Dr Bhattacharyya noted that the   
   description of the subtypes should be a first step in improving understanding   
   of various aspects of the syndrome.    
      
   "The goal of our present study was to describe what antibiotic toxicity looks   
   like clinically," he said.    
      
   "We hope that if we know how to recognize antibiotic toxicity, we will have a   
   better chance of accomplishing the second step of estimating its prevalence."    
      
   In the meantime, clinicians should maintain awareness of the potential role of   
   antibiotics when patients experience delirium, Dr Bhattacharyya said.    
      
   "The primary message from this is that when patients become confused when   
   suffering from infections, antibiotics should be included in the list of many   
   potential causes," he said.    
      
   "There are instances when antibiotics are overlooked as a potential treatable   
   cause of delirium."    
      
   The review provides important insights in the understanding of AAE, commented   
   Alejandro A. Rabinstein, MD, from the Division of Critical Care Neurology at   
   the Mayo Clinic, Rochester, Minnesota.    
      
   "This review is an elegant summary of available evidence and introduces a   
   reasonable categorization of types of neurotoxicity by family of antibiotic,"   
   he told Medscape Medical News.    
      
   "In my practice, I have seen toxicity with β-lactams, especially cefepime,   
   and metronidazole. I have no personal experience with the delayed psychosis   
   reported with various very different antibiotics [such as] quinolones,   
   macrolides, procaine, and    
   penicillin, and I find that toxicity more questionable and difficult to   
   characterize."    
      
   Dr Rabinstein was a coauthor on the previous study reporting on cefepime   
   neurotoxicity. Those findings supported type 1 AAE, showing particular   
   susceptibility among critically ill patients with chronic kidney disease and   
   symptoms more likely when the    
   cefepime dose is not adjusted for renal function; however, the neurotoxicity   
   was still seen regardless of adjustment.    
      
   "Other β-lactams that do not require renal adjustment can also cause   
   neurotoxicity, albeit much less frequently in my experience," Dr Rabinstein   
   said.    
      
      
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