Resistant Mycoplasma pneumoniae in children

Abstract

Question

A 5-year-old child was seen in our clinic with a clinical presentation consistent with community-acquired pneumonia. She was prescribed a course of amoxicillin and azithromycin, but remained febrile and returned to the clinic 3 days later. The family just returned from a trip to Japan. What is the current available evidence for treatment of macrolide-resistant Mycoplasma pneumoniae pneumonia?

Answer

Macrolide-resistant M pneumoniae (MRMP) rates are increasing worldwide, with especially high prevalence in China, Japan, and Taiwan. Most evidence in children supports the use of tetracyclines for MRMP with more limited evidence supporting fluoroquinolones for this indication. Children with M pneumoniae pneumonia and a history of recent travel to countries with high rates of resistance or who do not improve within 48 to 72 hours of macrolide treatment should be treated with 2 mg/kg of doxycycline orally twice daily (maximum 100 mg per dose).

Community-acquired pneumonia (CAP) is a lower respiratory tract infection caused by both viruses and bacteria and is commonly treated by community health care providers.¹ Clinical presentation in children primarily includes fever and cough, but may also include malaise, poor feeding, difficulty breathing, and chest pain.² Streptococcus pneumoniae remains the most common bacterial cause of CAP, with guidelines recommending amoxicillin as first-line therapy.^1,2 If a child does not improve clinically within 48 to 72 hours of first-line treatment, providers should consider alternative causes, including uncontrolled sources of infection and alternate pathogens, including Mycoplasma pneumoniae.¹

CAP caused by M pneumoniae is very common, mostly among children aged 5 to 15 years old, with cyclic epidemics occurring approximately every 3 to 6 years.³ Aside from pneumonia, M pneumoniae has also been implicated in extrapulmonary complications, including encephalitis, hemolytic anemia, and dermatologic manifestations.⁴ Beginning in the summer of 2024, there was a notable increase in the number of M pneumoniae infections compared with the previous year in several parts of Canada.^5,6

M pneumoniae is resistant to β-lactam antibiotics like amoxicillin. Instead, treatment of CAP due to M pneumoniae includes supportive care (hydration, symptom management) and macrolide antibiotics, with a 5-day course of azithromycin being the most common antibiotic treatment regimen.¹ The emergence of mutations over the past 2 decades conferring macrolide resistance has complicated treatment, necessitating alternative antibiotic treatments.⁷

Macrolide resistance

M pneumoniae resistance to macrolides was first reported in Japan in 2000 and is increasingly reported worldwide, with resistance rates as high as 79% in China.⁷ In areas of China where macrolide-resistant M pneumoniae (MRMP) has grown over decades, so too has the incidence of severe M pneumoniae pneumonia.⁸ While resistance rates in Canada are not well described, clinicians should suspect resistance in patients returning from countries such as China, Japan, and Taiwan, where resistance is prevalent or for whom fever persists beyond 48 to 72 hours of macrolide therapy.⁷ Common nonmacrolide treatment alternatives include tetracyclines and fluoroquinolones.

Tetracyclines

Providers should consider the tetracycline class, including doxycycline and minocycline, as an alternative in the treatment of MRMP. Tetracyclines inhibit bacterial protein synthesis and have demonstrated efficacy against MRMP.⁹ In a Japanese prospective multicentre study of 176 children with MRMP diagnosed based on symptoms, chest x-ray scans, and polymerase chain reaction test results, identification of macrolide resistance was made by culturing bacterial samples and identifying resistance genes. Defervescence within 24 hours was noted significantly more often when a tetracycline was used compared with macrolides or tosufloxacin (a fluoroquinolone available in Japan) (57.7% to 81.3% vs 30.8%; P=.03).¹⁰ A recent meta-analysis of 11 cohort studies and randomized controlled trials, including 1143 children in China, Japan, and Korea with MRMP treated with either macrolides or tetracyclines, found that treatment with macrolides was associated with significantly lower therapeutic efficacy (odds ratio=0.33, 95% CI 0.20 to 0.57),⁹ which was defined as the rate of achieving clinical recovery with fever, improvement or disappearance of cough, and improved (or normal) laboratory values.⁹ Macrolide treatment was also associated with a significantly longer fever duration (weighted mean difference=1.64 days) compared with tetracyclines. Treatment duration with tetracyclines varied widely among studies, from 2 to 10 days.^9,10

Fluoroquinolones

These are another class of antibiotics with action against MRMP. The literature supporting the use of fluoroquinolones for MRMP in children is less robust than the literature supporting the use of tetracyclines for MRMP in children, with most of these studies in adults. One case series of 6 children in China who were treated for MRMP for 10 days used 8 to 10 mg/kg of oral levofloxacin twice daily for children less than 5 years old and once daily for children 5 years old or older.¹¹ Time to defervescence was 1 to 2 days for patients treated with levofloxacin.

A network meta-analysis including 85 studies, 82 of which were conducted in China, compared different antibiotic treatments for M pneumoniae in both adults and children.¹² Fluoroquinolone and tetracycline use resulted in shortened time to defervescence compared with macrolides; however, there was no statistically significant benefit for either tetracyclines or fluoroquinolones when compared to one another.¹²

Safety in children

Both tetracyclines and fluoroquinolones are associated with safety concerns when used in children. While tetracycline is known to bind to calcium in developing teeth and bones and can cause permanent staining of the teeth, leading to concerns for children younger than 8 years, doxycycline’s lower affinity for calcium suggests a lower risk of this side effect. In a retrospective study of 58 children receiving doxycycline for Rocky Mountain spotted fever, no cases of doxycycline-induced teeth staining, or enamel hypoplasia, were reported.¹³ Other retrospective studies of doxycycline use in children found no association with teeth staining,^14,15 leading guidelines from the Canadian Pediatric Society and the American Academy of Pediatrics to support its use for courses less than 21 days in children younger than 8 years when indicated.^16,17

Fluoroquinolones are typically avoided in younger children due to concerns about antibiotic resistance in Gram-negative organisms and serious adverse effects, including cartilage toxicity. A 1-year surveillance trial among 2230 children reported an increased incidence of musculoskeletal adverse events, most commonly arthralgia, in children treated with fluoroquinolones early in treatment, but this effect was not present at the 1-year follow-up endpoint.¹⁸ A meta-analysis of 10 studies found no statistically significant difference in bone and muscle damage between children who received fluoroquinolones compared with those who did not (risk ratio=1.145; 95% CI 0.974 to 1.345).¹⁹ However, given other possible adverse effects and increased risk of antibiotic resistance, fluoroquinolones are reserved for cases where tetracyclines are not indicated.

Refractory M pneumoniae pneumonia

This type of pneumonia in children is defined as persistent fever and worsening symptoms despite appropriate antibiotic therapy for at least 7 days.²⁰ The current understanding of the mechanism of refractory M pneumoniae is an excessive host immune response rather than direct microbial damage, which may or may not be associated with resistant strains.²⁰ Treatment regimens vary but corticosteroids are often used in hospitalized patients to improve clinical outcomes, including faster fever resolution and shorter hospital stays.²⁰ Pediatric patients presenting with severe respiratory distress, extrapulmonary complications, or persistent symptoms despite appropriate therapy should be referred to a higher level of care.

Conclusion

The increasing prevalence of MRMP worldwide has complicated management and requires clinicians to consider alternate treatment strategies. Children with pneumonia who are managed as outpatients should continue to receive amoxicillin as first-line treatment, as most cases are caused by S pneumoniae. For patients in whom M pneumoniae is suspected, azithromycin remains first-line therapy; however, clinicians should consider doxycycline for patients who have recently travelled to areas with high resistance rates and in whom fever persists beyond 48 to 72 hours after initiation of a macrolide. Fluoroquinolones should be reserved for cases where tetracyclines are contraindicated given their risk of serious adverse effects and contribution to antimicrobial resistance. As M pneumoniae resistance patterns evolve, judicious use of antibiotics is essential to avoid development of further resistance.

Child Health Update is produced by the Pediatric Research in Emergency Therapeutics (PRETx) program (http://www.pretx.org) at the BC Children’s Hospital in Vancouver, BC. Dr Caeleigh Smith, Karin Ng, Dr Kendra Sih, Dr Alastair Mcalpine are members and Dr Ran D. Goldman is Director of the PRETx program. The mission of the PRETx program is to promote child health through evidence-based research in therapeutics in pediatric emergency medicine.