Antibiotic Toxicity Needs to be Recognized

A recent article endeavors to draw new—and perhaps increased—attention to the issue of neurologic side effects associated with antibiotic use in hospitalized patients.

The review article, printed in the February 17 issue of Neurology, notes that neurologic complications associated with antibiotic use are often under-reported and thus, under-diagnosed. Although research suggests that medication-associated delirium affects as many as half of all hospitalized patients—and 80% of those admitted to the intensive care unit (ICU)—the incidence of similar cognitive effects caused by antibiotic-associated encephalopathy (AAE) remains largely unknown.

Following on the heels of a 2013 study that identified a 15% rate of encephalopathy associated with the use of the fourth-generation cephalosporin cefepime among 100 critically ill patients, the authors of the Neurology review identified 292 articles describing 391 individual cases of AAE over a 60-plus year period. In all, 54% of the cases involved male patients, with the median age for all patients being 54 years; 25% of these cases involved patients with documented renal insufficiency.

Among the 391 cases, AAE manifested itself in different ways, with psychosis (defined as delusions or hallucinations) being the most common (47% of cases), particularly among patients treated with sulfonamides, quinolones, macrolides, and penicillin procaine. The authors found that seizures were present in 14% of the reviewed cases, and were most common among patients treated with penicillin and drugs in the cephalosporin class.

Overall, myoclonus was present in 15% of the reviewed cases (most common in patients treated with penicillin and cephalosporins), and cerebellar symptoms (ataxia or dysmetria) were present in 5% of the cases (usually metronidazole-associated). Median time to onset of all cases of AAE reviewed was five days from antibiotic initiation.

The authors also highlighted a potential reason for the under-diagnosis of AAE: among the 391 reviewed cases, the vast majority had normal MRI results. However, EEG results were abnormal in 70% of AAE cases. Based on their findings, the authors identified three phenotypes of AAE: Type 1, Type 2, and Type 3.

They defined Type 1 AAE as having symptoms appearing within days of antibiotic initiation. This phenotype is characterized by myoclonus, or seizures, which in turn yields abnormal EEG results, along with normal MRI results. Type 1 AAE is seen among those treated with penicillin and cephalosporins, and usually resolves within a few days.

Likewise, Type 2 AAE has symptoms appearing within days of antibiotic initiation; however, it is most commonly characterized by psychosis. Seizures are rare with this phenotype, therefore, patients have normal EEG results, as well as normal MRI results. The authors associate this phenotype with the use of procaine penicillin, sulfonamides, fluoroquinolones and macrolides.

Finally, the authors describe Type 3 AAE as the phenotype in which symptoms surface within weeks of antibiotic initiation. It is seen only with the use of metronidazole, and is characterized by frequent occurrence of cerebellar dysfunction, “nonspecific” EEG abnormalities and abnormal MRI results.

“Our study addresses the fact that even for individual patients, antibiotic usage carries risk in the form of cognitive side effects,” explains study co-author Shamik Bhattacharyya, MD, of Brigham and Women’s Hospital in Boston. “We would certainly not advocate avoiding antibiotics [when or if they are] necessary. However, we hope that when a patient suffering from an infection becomes confused, antibiotic toxicity is part of the list of [potential diagnoses]. Recognizing that this entity exists is a first step to timely diagnosis and treatment.”

Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.