TREATMENT OF PANS/PANDAS WITH ANTIBIOTICS
Antibiotics can be used as a therapeutic tool to alleviate symptoms and/or as a prophylactic dose to prevent or reduce future flare-ups post immunotherapy.
Antimicrobial based treatment should be based on each child’s specific presentation. Clearly, children with symptoms of streptococcal infection should be tested and treated appropriately. Additionally, research has shown that current commercially available serology for Group A strep has an approximate 37% false negative rate (even when both ASO and anti-DNase B are done). Throat cultures may also miss 5% – 15% of GAS infections (more if the swab is inadequate to reach nasopharyngeal bacteria). Thus, therapeutic antibiotic therapy is recommended for all PANDAS/PANS patients who have history of GAS exposure (family member or close peer contacts).
So-called “beta-lactams” are the most effective antibiotics for GAS infections; these include penicillin, amoxicillin (including Augmentin) and cephalosporins. Erythromycin, azithromycin and clindamycin are also reported to be effective in the treatment of GAS infections; however, regional resistance has been reported. The response to antibiotics can occur quickly – full or partial remission of OCD, anxiety, and many of the comorbid symptoms of PANS and PANDAS within 24-48 hours. Typically, however, the response occurs after a week or two of therapy. If no improvement is seen after 10-14 days, a physician may consider an alternate class of antibiotic treatment. If the antibiotics produce significant symptomatic improvements, they might be continued at treatment-level doses for an additional 2 – 4 weeks. Following the initial treatment course, prophylactic antibiotics may be useful for PANDAS (but are less clearly indicated for PANS, since they are effective only in preventing GAS infections). If the decision is made to use prophylactic antibiotics, the dosage and choice of antibiotics can be guided by AHA recommendations for prophylaxis in acute rheumatic fever (see AAP Redbook). If the child’s symptoms return at a lower prophylactic dose, the dose may need to be adjusted.
If no improvement is seen by two weeks, an alternate class of antibiotics might be used for an additional 10-14 days. If a child has a poor response to both antibiotics, or continues to have frequent exacerbations, his family members should be examined for illness and tested for GAS. Recurrent exposure to GAS can trigger symptoms in PANDAS children, even if the patient does not develop a full-blown infection.
SUPPORT FOR ANTIBIOTICS IN PANDAS
Azithromycin and penicillin have been utilized in the treatment of PANDAS with observations of improvement in neuropsychiatric symptoms. In a study designed to decrease Group A strep (GAS) infections, researchers at NIMH conducted a twelve-month parallel design comparing prophylactic doses of penicillin and azithromycin. Eleven subjects were maintained on penicillin and 12 were maintained on azithromycin during the 12-month study. During the study year, the mean number of neuropsychiatric exacerbations was reduced as well as the mean number of streptococcal infections. No side effects or reports of any adverse effects from the medications were reported. The authors suggest that both antibiotics may be safe and effective in preventing Group A strep infections and in decreasing the number of neuropsychiatric exacerbations in these children without any significant differences between groups. In a small pilot study of cefdinir at treatment doses (14mg/kg), children with recent onset neuropsychiatric symptoms had improvements in OCD and tics, with the OCD improvement reaching clinical significance (TK Murphy 2015). In addition to these controlled trials, there is a large pool of anecdotal reports from practitioners and parents that antibiotics can significantly reduce the severity of symptoms.
While there have been short-term (1 year) studies that proved prophylaxis effective post IVIG and plasmapheresis, there have been no long-term studies. The PPN recommends a minimum of 2 years of prophylaxis post immunotherapy. However, physicians could consult the American Heart Association guidelines for prophylaxis for rheumatic fever.
Because an infection of strep or other pathogen can interrupt the healing process post immunotherapy, treatment is to be accompanied by prophylaxis antibiotic treatment. Typical antibiotics used for prophylaxis include Augmentin (approximately 400mg/day), azithromycin (approximately 250mg/day) or penicillin (250mg po bid). (Note that dosing depends on weight and patient tolerance.)
A brief summary of AHA guidelines for rheumatic fever:
- Greater of 5 years or until age 21 if the patient does not have carditis
- Greater of 10 years or age 21 if the patient has carditis but no residual heart diseas
- Greater of 10 years or age 40 if the patient has carditis and persistent heart disease (i.e, valve disease)
(Please consult the actual guidelines when determining the length of prophylactic therapy.)
It has been well established that during certain types of dental work, patients may be at increased risk of bacteremia during the dental work.¹ This is the rational for the American Heart Association’s 2007 endocarditis guidelines to recommend that patients who are high risk for endocarditis, receive antibiotic prophylaxis, during certain types of dental procedures.² For certain high risk patients, prophylaxis is reasonable for all dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa.
PPN’s expert committee members have experienced that PANS/PANDAS patients may have exacerbations of their symptoms after dental work, which involves manipulation of the gingival tissue, pericardial regions of the teeth or perforation of oral tissue as well (procedures such as extraction, cleaning, fillings, and oral surgery). Although the exact mechanisms are not known, this bacteremia may stimulate an immune response which is responsible for worsening clinical status.
Therefore, patients may benefit from antibiotic prophylaxis starting the day before, until 4-7 days after the procedure. The dosing to prevent PANS/PANDAS exacerbation is higher than that used for endocarditis prophylaxis for dental procedures and should be at least equivalent to the dosing for therapeutic strep pharyngitis.
¹CDC Guidelines for Infection Control in Dental Health-Care Settings — 2003 https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5217a1.htm
²(2007) Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 116:1736–1754 http://circ.ahajournals.org/content/116/15/1736?ijkey=4755ce08aa7a6ad25a88ddf7d52c34609fb4970e&keytype2=tf_ipsecsha
There are risks of long-term use of antibiotics, including the potential for allergic reactions (at any point during therapy) and development of antibiotic-resistant microbes. In the most serious cases, this could result in intestinal overgrowth with pathologic organisms, such as C. difficile, and serious gastrointestinal complications. Use of narrow-spectrum antibiotics (particularly penicillin) minimizes this risk. Some clinicians advocate use of probiotics, such as Culturelle (but not at the same time of the day; allow 2-3 hour window in between).
FURTHER ANTIBIOTICS RESEARCH
Antibiotics have been demonstrated to have benefits to the patient beyond the eradication of pathogens. Given the complex and enmeshed relationship between the brain and the immune system, it is not surprising that a number of classical psychotropic compounds have been found to have immunomodulatory properties and that antimicrobial agents display psychotropic effects. Research studies are being planned to explore direct effects of antibiotics on CNS function.
Current Antibiotic Trials
Current clinical trials underway to measure the effectiveness of antibiotics on PANDAS patients:
- Azithromycin Treatment for PANS, Tanya Murphy, University of South Florida
- SSRI plus Antibiotic Treatment vs SSRI Trial for PANDAS; StefanoPallanti, Florence Italy
- EMTICS:Efficacy of Amoxicilline/Clavulanic Acid in Patients Affected by Tic Disorder Colonized by Group AStreptococcus (AntibioTICS) Francesco Cardona, University of Roma
- Augmentin Treatment for PANS, Dan Geller, MGH
BETA-LACTAM ANTIBIOTICS (PENICILLINS & CEPHALOSPORINS)
Beta-lactam antibiotics (penicillins and cephalosporins) were found to promote the expression of glutamate transporter GLT1 and have a neuroprotective role in vivo and in vitro models. Given the potential role of glutamatergic therapies in OCD, beta-lactams could be expected to exhibit efficacy in these neuropsychiatric disorders, but further study is needed. In a recent study investigating the effects of cephalosporin in a mouse model of major depressive disorder (MDD), ceftriaxone, of the cephalosporin family, was shown to exhibit antidepressant properties increasing glutamate uptake, thought to be impaired in MDD2.
COMBINATION OF AMOXICILLIN AND CLAVULANATE (AUGMENTIN)
The combination of amoxicillin and clavulanate (Augmentin) is a particularly useful β-lactamase inhibitor, but it appears to have therapeutic effects that extend beyond its antimicrobial properties. These are thought to be related to the clavulanate (clavulinic acid), as it readily crosses the BBB and has demonstrated anxiolytic properties in rodents and non-human primates. It also displays significant potential as an antidepressant and anxiolytic agent, and Phase IIb clinical trials for major depressive disorder are pending. Additionally, an informal study by ENTs who looked at tonsillectomy patients post procedure with and without Augmentin, found that those on Augmentin had a materially lower level of complaints.
MACROLIDES (SUCH AS ERYTHROMYCIN & AZITHROMYCIN)
Macrolides (such as erythromycin and azithromycin) antibiotic effects are mediated by inhibition of bacterial protein synthesis. They are often used to treat upper respiratory tract infections (URIs), including GAS pharyngitis with adequate efficacy (>90%). Despite high intracellular penetration and extensive tissue distribution, CNS penetration of azithromycin is poor. The main drawback of AZM for GAS eradication has been reports of macrolide-resistant GAS as well as an increased risk of selection for resistant endemic pathogens over a longer course treatment. Effects on immunomodulation appear to extend beyond their antimicrobial actions as the macrolides have been shown to alter cytokines balance in animal studies and human trials. For example, after stimulation with a combination of lipopolysaccharide (LPS) and IFN, AZM has been shown to act primarily on the lymphokine CD4 T helper 1 cell line reducing the production of the pro-inflammatory cytokines IL-12 and IL-6, and increase the production of the anti-inflammatory cytokine IL-10 in macrophage cell lines. Azithromycin has also been reported to suppress iNOS mediated nitric oxide production and to decrease mRNA expression, thereby promoting apoptosis of inflammatory cells and a decrease in nuclear transcription factors. Consistent with this hypothesis, a few in vitro studies point to azithromycin’s actions to downregulate NF-kB signaling, costimulatory molecules and alter the function of antigen presenting cells. Innate immunity is thus impacted as well. TLR4 and IL-12 are reduced after azithromycin treatment; both of these signaling pathways are involved in inflammatory processes as well as in immune responses to streptococcal infections. A recent clinical study investigating the occurrence of polymorphisms in TLR4 and TLR2 susceptibility to GAS infections suggested mutations in TLR4 (D299G, T399I) were associated with vulnerability to recurrent GAS infection. Further, soluble immune activating factors such as IL-12, IL-6 and TNF-a released during GAS infection may contribute to autoantibody production.
Tetracyclines are not typically used for PANDAS (but shown here for illustrative purposes of non-microbial benefits). Tetracyclines are broad spectrum antibiotics which exert their antibiotic effects through inhibition of protein translation. They are not typically used to treat PANDAS, as they have limited effects on GAS and other upper respiratory pathogens. However, minocycline and doxycycline have been shown to exhibit immunomodulatory properties that may be useful in PANS/PANDAS, including inhibition of oxidative stress9. In Fragile X Syndrome (FXS), where matrix metalloproteinases (MMP) have been thought to play a major role in the pathological mechanism, minocycline has been shown to lower MMP9 levels which are high in FXS, and it also strengthens brain connections in the animal models of FXS9, 10. MMPs have been implicated in axonal guidance, synaptogenesis, neurotransmission, synaptic plasticity and behavioral learning11, 12 and highlight the need for more research in humans in order to guide clinical management.
The interplay between the immune system and the Central Nervous System (“CNS”) makes antimicrobial agents potential therapeutic alternatives for some neuropsychiatric disorders. The overlap between immune and CNS pathways and signaling molecules suggests that disruption of the immune system may have secondary effects that extend beyond its localized actions. With this knowledge, the potential exists to characterize the mechanism driving the clinical pathologies in disorders that seem to have a clear immunological component, as many neuropsychiatric disorders have now been observed to have. Similarly, in autoimmune disorders with observed psychiatric presentations, and neuropsychiatric symptoms following infection, this area may be an opportunity to both understand the pathological mechanism and develop more targeted therapeutic alternatives. Characteristic markers of immune activation including increased expression of pro-inflammatory cytokines have been observed in psychiatric disorders and have been implicated in their pathological mechanism. Although promising, it must be noted that, as with any therapeutic intervention, the application of antibiotics for these disorders may rest heavily on clinician judgment and medical history and future research. In disorders such as PANDAS where onset is usually sudden and a clear connection has been delineated, the choice may be clear.
1. Rothstein JD, Patel S, Regan MR, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. Jan 6 2005;433(7021):73-77.
2. Mineur YS, Picciotto MR, Sanacora G. Antidepressant-Like Effects of Ceftriaxone in Male C57BL/6J Mice. Biol Psychiatry. Jan 15 2007;61(2):250-252.
3. Pickles HG, Simmonds M. Antagonism by penicillin of Î³-aminobutyric acid depolarizations at presynaptic sites in rat olfactory cortex and cuneate nucleus in vitro. Neuropharmacology. 1980;19(1):35-38.
4. Kim DJ, King JA, Zuccarelli L, et al. Clavulanic acid: a competitive inhibitor of beta-lactamases with novel anxiolytic-like activity and minimal side effects. Pharmacol Biochem Behav. Aug 2009;93(2):112-120.
5. Kost GC, Selvaraj S, Lee YB, Kim DJ, Ahn CH, Singh BB. Clavulanic acid increases dopamine release in neuronal cells through a mechanism involving enhanced vesicle trafficking. Neurosci Lett. Oct 24 2011;504(2):170-175.
6. Palucha A, Tatarczynska E, Branski P, et al. Group III mGlu receptor agonists produce anxiolytic- and antidepressant-like effects after central administration in rats. Neuropharmacology. Feb 2004;46(2):151-159.
7. Zhou J, Neale JH, Pomper MG, Kozikowski AP. NAAG peptidase inhibitors and their potential for diagnosis and therapy. Nat Rev Drug Discov. Dec 2005;4(12):1015-1026.
8. Semenkov Yu P, Makarov EM, Makhno VI, Kirillov SV. Kinetic aspects of tetracycline action on the acceptor (A) site of Escherichia coli ribosomes. FEBS letters. Jul 19 1982;144(1):125-129.
9. Paribello C, Tao L, Folino A, et al. Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC neurology. 2010;10:91.
10. Siller SS, Broadie K. Neural circuit architecture defects in a Drosophila model of Fragile X syndrome are alleviated by minocycline treatment and genetic removal of matrix metalloproteinase. Disease models & mechanisms. Sep-Oct 2011;4(5):673-685.
11. Agrawal SM, Lau L, Yong VW. MMPs in the central nervous system: where the good guys go bad. Seminars in cell & developmental biology. Feb 2008;19(1):42-51.
12. Ethell IM, Ethell DW. Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. Journal of neuroscience research. Oct 2007;85(13):2813-2823.
13. Levkovitz Y, Mendlovich S, Riwkes S, et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. The Journal of clinical psychiatry. Feb 2010;71(2):138-149.
14. Yolken RH, Torrey EF. Viruses, schizophrenia, and bipolar disorder. Clinical microbiology reviews. 1995;8(1):131-145.
15. Tedla Y, Shibre T, Ali O, et al. Serum antibodies to Toxoplasma gondii and Herpesvidae family viruses in individuals with schizophrenia and bipolar disorder: a case-control study. Ethiopian medical journal. 2011;49(3):211.
16. Winter C, Reutiman TJ, Folsom TD, et al. Dopamine and serotonin levels following prenatal viral infection in mouseâ€”implications for psychiatric disorders such as schizophrenia and autism. European Neuropsychopharmacology. 2008;18(10):712-716.
17. Zink MC, Uhrlaub J, DeWitt J, et al. Neuroprotective and anti-human immunodeficiency virus activity of minocycline. JAMA : the journal of the American Medical Association. Apr 27 2005;293(16):2003-2011.
18. Dutta K, Basu A. Use of minocycline in viral infections. The Indian journal of medical research. May 2011;133(5):467-470.
19. Mazzei T, Mini E, Novelli A, Periti P. Chemistry and mode of action of macrolides. Journal of Antimicrobial Chemotherapy. 1993;31(suppl C):1-9.
20. Jacobs MR, Johnson CE. Macrolide resistance: an increasing concern for treatment failure in children. Pediatr Infect Dis J. Aug 2003;22(8 Suppl):S131-138.
21. Goodman LS, Brunton LL, Chabner B, Knollmann BC. Goodman & Gilman’s pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill; 2011.
22. Richter SS, Heilmann KP, Beekmann SE, et al. Macrolide-resistant Streptococcus pyogenes in the United States, 2002â€“2003. Clinical infectious diseases. 2005;41(5):599-608.
23. Guchev I, Klochkov O, Ivanitsa G, IuA P, Shturmina S, Rosman S. Efficacy and safety of azithromycin prophylaxis of respiratory tract infections in military community. Antibiotiki i khimioterapiia= Antibiotics and chemoterapy [sic]/Ministerstvo meditsinskoi i mikrobiologicheskoi promyshlennosti SSSR. 2003;49(8-9):34-35, 37-42.
24. Zarogoulidis P, Papanas N, Kioumis I, Chatzaki E, Maltezos E, Zarogoulidis K. Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases. Eur J Clin Pharmacol. Nov 22 2011.
25. Murphy BS, Sundareshan V, Cory TJ, Hayes D, Anstead MI, Feola DJ. Azithromycin alters macrophage phenotype. Journal of Antimicrobial Chemotherapy. 2008;61(3):554-560.
26. Morikawa K, Torii I, Morikawa S. Modulation of IgD and CD20 by ligation of CD5 on tonsillar B cells. Scandinavian journal of immunology. 2002;55(1):44-52.
27. Liadaki K, Petinaki E, Skoulakis C, et al. Toll-like receptor 4 gene (TLR4), but not TLR2, polymorphisms modify the risk of tonsillar disease due to Streptococcus pyogenes and Haemophilus influenzae. Clin Vaccine Immunol. Feb 2011;18(2):217-222.
28. Loof TG, Goldmann O, Medina E. Immune recognition of Streptococcus pyogenes by dendritic cells. Infection and immunity. Jun 2008;76(6):2785-2792.
29. Banks WA, Kastin AJ, Broadwell RD. Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation. Jul-Aug 1995;2(4):241-248.
30. Snider LA, Lougee L, Slattery M, Grant P, Swedo SE. Antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders. Biological psychiatry. 2005;57(7):788-792.
31. Toufexis MD, DeOleo C, Elia J, Murphy TK. A Link Between Perianal Strep and Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection (PANDAS). The Journal of Neuropsychiatry and Clinical Neurosciences. in press.
32. Ayoub EM, Wannamaker LW. Streptococcal antibody titers in Sydenham’s chorea. Pediatrics. 1966;38(6):946-956.
33. Murphy ML, Pichichero ME. Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS). Archives of pediatrics & adolescent medicine. 2002;156(4):356.
34. Storch EA, Murphy TK, Geffken GR, et al. Cognitive-behavioral therapy for PANDAS-related obsessive-compulsive disorder: findings from a preliminary waitlist controlled open trial. Journal of the American Academy of Child & Adolescent Psychiatry. 2006;45(10):1171-1178.
35. Murphy TK, Storch EA, Strawser MS. Selective Serotonin Reuptake Inhibitor Induced Behavioral Activation in the PANDAS Subtype. Primary psychiatry. 2006;13(8):87-89.