Wise Use of Antibiotics

Management of Community-Acquired Pneumonia in the Era of COVID-19

Column Editor: Rana El Feghaly, MD, MSCI | Director, Clinical Services | Director, Outpatient Antibiotic Stewardship Program | Associate Professor of Pediatrics, UMKC School of Medicine

Community-acquired pneumonia (CAP) is one of the most common serious infections in childhood and accounts for over 900,000 deaths among children <5 years of age each year worldwide. While we continue to battle the COVID-19 pandemic along with this influenza season, questions regarding bacterial superinfection continue to be raised when a child presents with fever and respiratory symptoms.

How common is bacterial superinfection with COVID-19?

Bacterial co-infections are commonly identified with influenza, with rates reported as high as 20%-30% in severe cases. Data on COVID-19 co-infection (viral and bacterial) are still limited in children. Most studies have focused on adult patients admitted to the hospital or to the intensive care unit (ICU).

A metanalysis evaluating 30 studies including 3,834 adults found that only 7% of hospitalized COVID-19 patients had a bacterial co-infection (4% on wards vs. 14% in ICU), yet over 90% received empiric antibiotic therapy.¹ Youngs et al. evaluated adults with severe COVID-19 requiring mechanical ventilation and compared them to those with severe influenza. They found that the rate of early (<48 hour) bacterial superinfection was only 8% in COVID-19 compared to 58% with influenza.² Many additional adult studies have come to the same conclusion: primary bacterial co-infections with COVID-19 infections are rare (1%-5%). Most superinfections occur after 48 hours of hospitalization.^3-5

Very few studies describing co-infections in children with COVID-19 infection have been undertaken; however, viral co-infections may be more common than in adults. Bacterial co-infections, particularly in children not requiring ICU admissions, are quite rare.

What are the most common etiologic agents of CAP in children?

Viruses (RSV, influenza, parainfluenza, human metapneumovirus, adenovirus, coronavirus, bocavirus, rhinovirus, and of course COVID-19) continue to be the most common etiological agents identified in patients with CAP, particularly in children <2 years old.^6,7 For bacterial CAP, Streptococcus pneumoniae is the most common cause, followed by Haemophilus influenzae and Branhamella catarrhalis. Streptococcus pyogenes and Staphylococcus aureus may cause more severe disease that requires hospitalization and ICU admission. Atypical bacteria such as Mycoplasma pneumoniae are more commonly seen in older children and adolescents, who typically present with a more insidious onset and lower grade fevers.^6,7

What is the best management plan for a child with CAP?

Supportive measures are all that is necessary for patients with viral pneumonia. Fully immunized patients with uncomplicated bacterial CAP can be treated with high-dose amoxicillin (80-100 mg/kg/day divided in twice a day dosing).⁶ When S. aureus infection is suspected (e.g., complicated CAP, empyema), anti-staphylococcal coverage such as amoxicillin-clavulanate, clindamycin or vancomycin may be warranted, depending on methicillin-resistant S. aureus prevalence in the community and individual risk factors. Azithromycin is recommended only for atypical pneumonia.

What is the deal with azithromycin?

A study by Fleming-Dutra and colleagues evaluating antibiotic use in children 18 years and younger reported 12.2 million prescriptions for azithromycin in 2013, the second most common antibiotic after amoxicillin.⁸ It is important to remember that macrolides are rarely a first-line antibiotic option for common respiratory infections. Macrolide resistance is high among S. pneumoniae (up to 30%), H. influenzae (20%-40% depending on studies) and B. catarrhalis (up to 45%), making it a suboptimal option for most respiratory infections except for atypical pneumonia and pertussis.^9,10 The rationale for this high resistance is that due to their prolonged half-life, subinhibitory nasopharyngeal concentrations may persist, causing an increase in resistance rates. In addition, azithromycin is being used for many non-infectious indications due to its anti-inflammatory and immunomodulatory effects. Unfortunately, resistance among M. pneumoniae, where macrolides are considered first line, is becoming more prevalent as well.¹¹ Preserving macrolides for when they are clearly indicated is essential in our fight against antibiotic resistance.

How long should the antibiotic course be for a child with suspected bacterial CAP?

Although the 2011 national guidelines recommend seven to 10 days of antibiotics for CAP,⁶ new studies support a shorter course of antibiotic. Pernica et al. conducted a two-center, parallel-group, noninferiority randomized controlled trial, where children 6 months to 19 years of age with respiratory symptoms and chest radiology consistent with pneumonia were enrolled. They compared five days of amoxicillin followed by five days of placebo to 10 days of amoxicillin. Of the 281 children enrolled, clinical cure was achieved in 88.6% in the intervention group and 90.8% in the control group. Clinical cure at 14-21 days was achieved in 85.7% in the intervention group and 84.1% in the control group.¹² Williams et al. recently published a randomized double-blind, placebo-controlled clinical trial in outpatient settings completed in eight U.S. cities. This study again compared five days of antibiotics followed by five days of placebo to 10 days of antibiotics. Less than 10% of the 380 children enrolled had an inadequate clinical response, with no difference between the two groups. This study evaluated an end-of-treatment response adjusted for duration of antibiotic risk (RADAR), a composite end point that ranks each child’s clinical response, resolution of symptoms, and antibiotic-associated adverse effects. Interestingly, the short-course strategy had a 69% (95% CI, 63-75) probability of a more desirable RADAR outcome compared with the standard-course strategy. In addition, colonization with resistant bacteria was significantly lower in the short-course group.¹³ The new recommendation from the Committee on Infectious Diseases Red Book 2021 supports a five-day course for CAP.

In conclusion, bacterial superinfection appears to be less common in children with COVID-19 compared with influenza. Most cases of CAP are viral and do not require antibiotics. Bacterial CAP could be treated with a short five-day course of high-dose amoxicillin as long as the patient is responding well.

References:

1. Lansbury L, Lim B, Baskaran V, Lim WS. Co-infections in people with COVID-19: a systematic review and meta-analysis. J Infect. 2020;81(2):266-275.
2. Youngs J, Wyncoll D, Hopkins P, Arnold A, Ball J, Bicanic T. Improving antibiotic stewardship in COVID-19: bacterial co-infection is less common than with influenza. J Infect. 2020;81(3):e55-e57.
3. Russell CD, Fairfield CJ, Drake TM, et al. Co-infections, secondary infections, and antimicrobial use in patients hospitalised with COVID-19 during the first pandemic wave from the ISARIC WHO CCP-UK study: a multicentre, prospective cohort study. Lancet Microbe. 2021;2(8):e354-e365.
4. Vaughn VM, Gandhi TN, Petty LA, et al. Empiric antibacterial therapy and community-onset bacterial coinfection in patients hospitalized with coronavirus disease 2019 (COVID-19): a multi-hospital cohort study. Clin Infect Dis. 2021;72(10):e533-e541.
5. Wang L, Amin AK, Khanna P, et al. An observational cohort study of bacterial co-infection and implications for empirical antibiotic therapy in patients presenting with COVID-19 to hospitals in North West London. J Antimicrob Chemother. 2021;76(3):796-803.
6. Bradley JS, Byington CL, Shah SS, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011;53(7):e25-76.
7. Harris M, Clark J, Coote N, et al. British Thoracic Society guidelines for the management of community acquired pneumonia in children: update 2011. Thorax. 2011;66 Suppl 2:ii1-ii23.
8. Fleming-Dutra KE, Demirjian A, Bartoces M, Roberts RM, Taylor TH Jr, Hicks LA. Variations in antibiotic and azithromycin prescribing for children by geography and specialty-United States, 2013. Pediatr Infect Dis J. 2018;37(1):52-58.
9. Kim L, McGee L, Tomczyk S, Beall B. Biological and epidemiological features of antibiotic-resistant Streptococcus pneumoniae in pre- and post-conjugate vaccine eras: a United States perspective. Clin Microbiol Rev. 2016;29(3):525-552.
10. Maddi S, Kolsum U, Jackson S, et al. Ampicillin resistance in Haemophilus influenzae from COPD patients in the UK. Int J Chron Obstruct Pulmon Dis. 2017;12:1507-1518.
11. Xiao L, Ratliff AE, Crabb DM, et al. Molecular characterization of Mycoplasma pneumoniae isolates in the United States from 2012 to 2018. J Clin Microbiol. 2020;58(10).
12. Pernica JM, Harman S, Kam AJ, et al. Short-course antimicrobial therapy for pediatric community-acquired pneumonia: the SAFER randomized clinical trial. JAMA Pediatr. 2021;175(5):475-482.
13. Williams DJ, Creech CB, Walter EB, et al. Short- vs standard-course outpatient antibiotic therapy for community-acquired pneumonia in children: the SCOUT-CAP randomized clinical trial. JAMA Pediatr. 2022.