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Wise use of Antibiotics

September, 2018

Use of Antibiotics for the Treatment of Pediatric Neuropsychiatric Disorders

Angela Myers, MD, MPH, FAAP, FPIDS |Interim Director, Division of Infectious Diseases | Associate Director, Pediatric Infectious Diseases Fellowship Program | Associate Professor of Pediatrics, UMKC School of Medicine

I recently watched an episode of 20/20 featuring children who developed OCD, outbursts and tantrums, seizures, catatonia, and paranoia following a diagnosis of streptococcal pharyngitis. Some of the children improved over time. While it is mentioned that no one knows what improved their symptoms, a host of therapies were utilized, including a combination of antibiotics, corticosteroids, plasmapheresis and behavioral therapies. Several children had reported relapses temporally related to other infections, including common cold viruses. This has been a controversial topic in pediatrics, with some physicians drawing conclusions regarding the development of Pediatric Acute-onset Neuropsychiatric Disorder Associated with Streptococcus (PANDAS)/Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) from auto-antibodies following streptococcal and other infections, and others questioning the validity of this based on limited evidence supporting causation. While there are well-known risks to corticosteroid use and plasmapheresis, I want to focus this discussion on the use of antibiotics in the setting of this diagnosis.
A recent paper published in the Journal of Child and Adolescent Psychopharmacology described a randomized controlled trial including 32 children (aged 4-14 years) to receive four weeks of azithromycin (n=18) to placebo (n=14) in children with a diagnosis of PANDAS/PANS and acute onset or acute relapse of neuropsychiatric symptoms. In their introduction, they cite three previous studies in which various antibiotics were compared to either placebo or each other to evaluate a reduction in neuropsychiatric symptoms with prolonged antibiotic exposure. Two of the three studies found no statistically significant difference, and the one study that did reveal a reduction in neuropsychiatric exacerbations was small (n=23 children) and the standard deviation around the mean was large.
The authors used 12 different scales to assess the study participants on obsessive-compulsive behaviors, psychopathology, response to treatment, tic severity, mood lability, inattention and hyperactivity, emotional disorders and global functioning. Biologic measures including anti-deoxyribonuclease B, anti-streptolysin O, Mpneumoniae immunoglobulin (IgG/IgM), antinuclear antibody, complements (C3d, C1q), quantitative immunoglobulins, comprehensive metabolic panel, complete blood count and urinalysis were also measured.
They authors report that the majority of patients had an acute episode triggered by infection (GAS =19 [61%], URI =13 [42%]). They further report that when including elevated ASO or anti-DNase B titers, the acute events attributed to GAS rose to 84% (n=26). However, the authors never mention the cutoff for what is considered elevated for either of these serologic tests. They also do not discuss repeat serology to assess whether it is increasing or decreasing to get a better sense of when the infection occurred. Remember that ASO and anti-DNase B are not markers of acute infection. They generally take four weeks to rise and stay elevated for several months following infection. Given that children between the ages of 4-14 generally have several URI and sore throat illnesses every year, no conclusions can be made regarding the contribution of a particular infectious etiology from this data.
No significant improvements were found between the azithromycin and placebo groups in any of the scales or laboratory values, with the exception of modest improvement in OCD severity in the intention to treat analysis of the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) at the four-week assessment. However, no improvement was noted at the two-week assessment, and there was no difference in the percent reduction of symptoms between groups. Additionally, no improvement was found within either treatment group throughout the study. The authors admit that they did not account for multiple statistical analyses on a very small (and partially previously published) study population, and that this does increase the type I error rate. Remember that a type I error is the probability of finding statistical significance where none exists. This is typically set at the level of 0.05, in order to have a less than 5% chance of making a type I error. However, when making multiple comparisons within a data set, correction should be made by setting the level of significance to a lower number by using a mathematical correction method (e.g., the Bonferroni method). This correction accounts for the increasing probability of making a type I error by conducting many tests.
Finally, a higher proportion of children who received azithromycin developed diarrhea than those who received placebo. This makes sense as we know that side effects, including vomiting, diarrhea and rash are common when children receive antibiotics.
What does all this mean? It means that there is increasing evidence that antibiotics are not the answer for children with acute onset OCD and other neuropsychiatric symptoms. Antibiotics should be saved for children diagnosed with a bacterial infection, and provided for the shortest time possible to adequately treat the infection in order to mitigate unwanted side effects and reduce the risk of colonization and potentially subsequent infection with resistant bacteria. 

A Double-Blind Randomized Placebo-Controlled Pilot Study of Azithromycin in Youth with Acute-Onset Obsessive-Compulsive Disorder. Murphy TK, et al. J Child Adolesc Psychopharmacol. 2017; 27:640-651. 
Antibiotic Prophylaxis with Azithromycin or Penicillin for Childhood-onset Neuropsychiatric Disorders. Snider LA, et al. Biol Psychiatry. 2005; 57:788-92. 
Characterization of the Pediatric Acute-onset Neuropsychiatric Syndrome Phenotype. Murphy TK, et al. J Child Adolesc Psychopharmacol. 2015; 25:14-25.