GAS on a stewardship fire: Treatment alternatives for pediatric group A strep pharyngitis
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The establishment of the field of medical microbiology and its vital role in infectious diseases paved the way to better understand the wide varieties of pneumococcal disease.
As far back as the late 1800s, chain-forming organisms from St. Anthony’s fire — or erysipelas — in humans were being recovered. The classification of the numerous types of streptococcal species and infections is complex. Patterns of hemolysis of blood agar and serotyping of certain proteins have been described. For this article, we will review a beta-hemolytic, group A streptococcal organism, Streptococcus pyogenes.
Group A Streptococcus (GAS) can cause a wide spectrum of invasive and noninvasive disease. These include but are not limited to strep throat, otitis media, pneumonia, scarlet fever, cellulitis, impetigo, rheumatic fever, necrotizing soft tissue infections, post-streptococcal glomerulonephritis, streptococcal toxic shock syndrome and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.
Globally, there are estimated to be 600 million cases of strep throat annually, with the most common responsible pathogen being GAS. If GAS pharyngitis is suspected, first, a rapid antigen detection test is recommended in children aged older than 3 years, followed by throat culture in those who test negative. Children aged younger than 3 years are unlikely to manifest acute rheumatic fever, which is the driving purpose of treating GAS pharyngitis, making the testing and treatment of this age group less beneficial. If a child has symptoms of GAS pharyngitis or relative with the same clinical presentation and diagnosis, testing and treatment in this age group is recommended.
Although associated with numerous infection types and varying degrees of virulence, GAS has largely remained susceptible to very narrow spectrum beta-lactams, for which penicillin and amoxicillin still play a frontline role. However, resistance to non-beta-lactam antimicrobials is present and rising in many countries. Knowledge of local resistance rates is crucial when a beta-lactam allergy or intolerance prevents their use.
More recently, an increase in the use of alternative therapy for GAS infections has been described, not because of a pandemic of new beta-lactam allergies but because of a shortage of beta-lactam availability.
Shortages
During the 2022-2023 respiratory syncytial virus season, cases of RSV skyrocketed in October and peaked in November. This came as influenza and SARS-CoV-2 variants also were circulating, causing increased cases in children.
Although postviral bacterial pneumonia is a known complication observed in these three viruses, determining the rate of secondary bacterial infections remains challenging because not all patients with pneumonia receive microbiological workup. Among adults, bacterial pneumonia is estimated to be a complication of 0.5% to 6% of influenza infections, with higher rates among hospitalized patients in ICUs and fatal cases.
The concurrent surge of these three viruses led to reported medication shortages, especially in pediatric formulations of supportive care medications like acetaminophen and ibuprofen, and antibiotics like amoxicillin. Despite the CDC and American Academy of Pediatrics recommending RSV, influenza and COVID-19 not be treated with antibiotics, pharmacies quickly found themselves running out of all formulations of amoxicillin. The shortage prompted the FDA to issue guidance on compounding beta- lactam oral suspensions to alleviate the shortage. Although this widespread overuse of inappropriate antibiotics is an unrelenting antimicrobial stewardship challenge, this leaves children with GAS infections stuck with the alternatives. The need to treat all cases of GAS pharyngitis in high-resource settings with low incidence of rheumatic fever is controversial, but current AAP guidance is to treat all GAS pharyngitis. In response to the amoxicillin shortage, on Nov. 21, the AAP published in the Red Book alternative options to amoxicillin for common infectious conditions. What are these antimicrobials alternatives to amoxicillin in GAS? Let’s dive in class by class.
Alternatives
Penicillin
In a way, amoxicillin is the common substitute for oral penicillin VK, in that amoxicillin can be dosed once daily. Another formulation, penicillin G benzathine, is available in a single dose, intramuscular administration. When compared with penicillin, amoxicillin is associated with more diarrhea, and the risk for rash is higher should the patient have mononucleosis instead of GAS.
Penicillin VK requires frequent dosing because of its much shorter half-life compared with amoxicillin (0.5 hours vs. 1.3 hours). Oral penicillin dosing intervals for children require administration two to three times daily, and in adolescents, up to four times daily. Penicillin given as an oral tablet or intramuscular injection is listed as an alternative to amoxicillin by the AAP in response to the amoxicillin shortage.
From an antimicrobial stewardship perspective, penicillin is the narrowest option available. Although amoxicillin with clavulanic acid can be considered, it is associated with significant diarrhea and is the broadest of the oral penicillins available.
At the time of publication, no formulation of penicillin was reported on the American Society of Health System Pharmacists’ drug shortage list, whereas amoxicillin and amoxicillin with clavulanate remained listed.
Cephalosporins
Among patients with a penicillin allergy without a systemic anaphylactic reaction, first-generation cephalosporins have long served as the next option. In the AAP response, cephalexin is listed at the next alternative if there is a vetted, anaphylactic allergy. Although cephalexin is only dosed twice daily, its antimicrobial coverage is broader than penicillin, and it is associated with more frequent gastrointestinal symptoms than narrow-spectrum penicillins. Data show no difference in symptom resolution between cephalosporins and penicillin in GAS pharyngitis.
Anecdotally, the formulation of cephalexin is associated with a terribly unpleasant smell, making administration of the drug to young children challenging. Type the words “Why does cephalexin smell like” into a search engine and you will understand what we mean.
Additional alternatives
There is a great appeal to using macrolides, when possible. Azithromycin, the most commonly prescribed, is administered once daily. It may be used in patients with a penicillin allergy.
Concern for rising macrolide resistance in Streptococcus species due to overuse has largely caused these agents to fall out of favor. Children experience greater side effects with macrolides and clindamycin compared with other antimicrobials. In a review of GAS infections from 2006 to 2017, 14.5% were resistant to erythromycin and 22% were resistant to clindamycin. Both of these agents are associated with significantly more gastrointestinal side effects compared with beta-lactams. There is substantial, widespread resistance exhibited by Streptococcus species to tetracyclines, which has kept them far from GAS treatment regimens.
Little information is available for sulfonamides for treating GAS, largely due to a controversial idea that Streptococcus species are intrinsically resistant to trimethoprim/sulfamethoxazole. Until more data become available, trimethoprim/sulfamethoxazole will likely continue to not play a role in GAS infections.
Conclusion
Shortages of antimicrobials have and will continue to plague treatment plans for infectious diseases. Fortunately, other amoxicillin concentrations and formulations have remained available. When preferred options vanish with no return date, knowledge of alternative treatments is imperative.
The treatment of GAS pharyngitis underscores the importance of de-labeling an inaccurate beta-lactam allergy because beta-lactams are the backbone for most infectious diseases. An untrue, anaphylactic penicillin allergy leaves your patient with suboptimal treatment options due to adherence concerns, growing resistance and poor tolerability.
- References:
- AAP. American Academy of Pediatrics offers guidance on RSV prophylaxis, handling surge of pediatric patients with respiratory infections. https://www.aap.org/en/news-room/news-releases/aap/2022/american-academy-of-pediatrics-offers-guidance-on-rsv-prophylaxis-handling-surge-of-pediatric-patients-with-respiratory-infections. Published Nov. 18, 2022. Accessed Jan. 14, 2023.
- American Society of Health-System Pharmacists. Drug shortages list. https://www.ashp.org/drug-shortages/current-shortages/drug-shortages-list. Accessed Jan. 14, 2023.
- Bennett JE, Dolin R, Blaser MJ, Douglas RG, Mandell GL. Streptococcus pyogenes. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 9th ed. Philadelphia: Elsevier; 2020.
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- FDA. Compounding certain beta-lactam products in shortage under section 503A of the federal food drug and cosmetic act. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/compounding-certain-beta-lactam-products-shortage-under-section-503a-federal-food-drug-and-cosmetic. Published Nov. 18, 2022. Accessed Jan. 14, 2023.
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- Stahl S. Low supply of antibiotic amoxicillin as RSV, flu spike in kids. CBS News. https://www.cbsnews.com/philadelphia/news/low-supply-of-antibiotic-amoxicillin-as-rsv-flu-spike-in-kids/. Published Nov. 11, 2022. Accessed Jan. 14, 2023.
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- For more information:
- Hunter O. Rondeau, PharmD, is a PGY2 infectious diseases resident at the University of Minnesota Medical Center.
- Jennifer Ross, PharmD, BCIDP, is an infectious diseases clinical pharmacist at M Health Fairview – University of Minnesota Medical Center. Ross can be reached at jross13@fairview.org.
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