Given the rapid spread of macrolide resistance, alternative therapies without cross-resistance are urgently needed, particularly in children for whom macrolide resistance is more common, and tetracyclines and fluoroquinolones cannot be prescribed. Although a recent Cochrane review concluded that there is insufficient evidence on the efficacy of antibiotics for treating MPP in children, and MPP shows a self-limited course even without antibiotics³³⁾, macrolides are still recommended as the first-line antibiotics for treating M. pneumoniae infection because of their low toxicity in children. However, the widespread use and misuse of macrolides may cause the rapid emergence of MRMP¹⁹⁾. The prevalence of MRMP is highest in Asia, where M. pneumoniae infections are highly prevalent overall, and MRMP may develop during macrolide treatment³⁴⁾. Because there are no appropriate treatment alternatives for children, reducing the indiscriminate abuse of macrolides will be the only key solution to prevent further pandemics of MRMP.

Determination of the MIC is important for establishing the inhibitory activity of an antimicrobial against DNA metabolism and protein synthesis. Macrolides, tetracyclines, and fluoroquinolones have the best MIC values against M. pneumoniae; however, the use of the latter 2 antibiotics is limited owing to concerns of several side effects³⁵⁾. Not all cases of MRMP infection require treatment with a second-line drug such as tetracyclines and fluoroquinolones; some patients could be treated with macrolides even in the presence of macrolide resistance^36,37). Fever, which is the clinical decision point to evaluate the suseptibility for the first-line antibiotic, usually subsides within 48–72 hours after treatment in an individual infected with a macrolide-sensitive strain. If the clinical symptoms do not improve within 48–72 hours with the first-line antibiotics, a change to the second-line antibiotics is recommended⁶⁾. The Pediatric Infectious Diseases Society and the Infectious Diseases Society of America recommend azithromycin as the first-line antibiotic, and clarithromycin, erythromycin (not available in Korea), doxycycline (for children aged ≥8 years), levofloxacin, or moxifloxacin (for adolescents) as the second-line antibiotics³⁸⁾. The Japanese Society of Pediatric Pulmonology, Japanese Society for Pediatric Infectious Disease, Japan Pediatric Society, and Japanese Society of Mycoplasmology recommend macrolides as the first-line drug, and tosufloxacin or tetracyclines as the second-line drugs⁶⁾.

In Korea, tetracycline is not approved for use in children under 12 years old and can be cautiously used in 8- to 11-year-old children only when there are no alternative antibiotics available.

Doxycycline, minocycline, oxytetracycline, tetracycline, and tigecycline are the currently available Korean Food and Drug Administration (FDA)-approved tetracyclines. However, none of these drugs has been approved by the Korean FDA for children under 12 years old. The biological action of tetracyclines resides in their inhibitory activity against protein synthesis. Tooth discoloration, gastrointestinal disturbances, photosensitivity, and hepatotoxicity are the most common adverse drug reactions of tetracyclines. The degree of tooth discoloration is known to be dependent on the dose per body weight, duration of use, and stage of tooth development³⁹⁾. Since the calcification of permanent teeth is completed before 7–8 years of age⁴⁰⁾, this is the main rationale for the prohibition of its use in children under 8 years of age.

Among tetracyclines, minocycline is associated with greater adverse reactions in the bone, central nervous system, and skin than the others⁴¹⁾. In particular, the generation of black bones in the oral cavity is one of the most remarkable side effects of minocycline³⁹⁾. Minocycline is not approved in the United States or in the European Union. However, it is the only approved tetracycline in Japan⁶⁾. To date, only 2 clinical trials have evaluated the efficacy of minocycline in children with MRMP. Although both were non-randomized trials and did not release a safety report, they reported the excellent efficacy of minocycline treatment^42,43). A retrospective study on the effectiveness of doxycycline showed that it was more effective than macrolide treatment. The records of a total of 48 children with MPP were reviewed in this study. Among them, 19 children (16 in the MRMP group and 3 in the MSMP group) who were treated with doxycycline showed a faster time to defervescence⁴⁴⁾. Even though doxycycline is known to cause tooth discoloration due to the low binding affinity to calcium⁴⁵⁾, one observational study reported an absence of tooth staining with a short course of doxycycline in children under 8 years of age⁴⁶⁾. Analysis of the pathogens responsible for the MRMP epidemics during 2000–2011 in Korea showed a significantly higher MIC for 50% of the strains and MIC₉₀ for macrolides. However, all of the strains were susceptible to the second-line drugs, including tetracycline, doxycycline, levofloxacin, ciprofloxacin, and moxifloxacin¹⁾. In Korea, the needs for second-line antibiotics are increasing. Fortunately, advances in dental care techniques can now allow for the use of tetracyclines in children with severe MRMP with reduced concern about tooth discoloration.

Ciprofloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, and tosufloxacin are the currently available Korean FDA-approved fluoroquinolones. None of these drugs has been approved by the Korean FDA for children under 18 years old. A recent systematic review on the safety of ciprofloxacin in children reported a frequency of 1.6% musculoskeletal adverse events⁴⁷⁾. Levofloxacin has been referred to as a respiratory fluoroquinolone owing to its excellent activity against many respiratory bacteria such as Streptococcus pneumoniae and Mycoplasma pneumoniae. However, the results of levofloxacin-related adverse risks are inconsistent^48,49), and there is a lack of information on its safety in children. On May 12, 2016, the U.S. FDA advised restricting fluoroquinolone antibiotic use for treating certain uncomplicated infections because of the occurrence of serious adverse reactions such as tendinitis, tendon rupture, worsening of myasthenia gravis, risk of peripheral neuropathy and central nervous system effects, and dermatologic, cardiac, and hypersensitivity reactions⁵⁰⁾. In addition, the black box warning (FDA's strongest warning) was updated on July 26, 2016 for all oral and injectable fluoroquinolone antibiotics given the disabling and potentially permanent side effects on the tendon, muscle, joints, nerves, and central nervous system⁵¹⁾. In particular, they emphasized that “the risk of these serious side effects (of fluoroquinolones) generally outweighs the benefits for patients with acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections, and should be reserved for those who do not have alternative treatment options.” However, they also announced that for some serious bacterial infections, the benefits of fluoroquinolones outweigh the risks and it is appropriate for them to remain available as a therapeutic option. Among the fluoroquinolones, levofloxacin and ofloxacin seem to be associated with a higher risk of causing tendon damage than the other fluoroquinolones, and the tendinitis risk seems to be dependent on the dose and duration of use⁵²⁾. Therefore, prescribing physicians should be aware of balancing the relative risks and benefits associated with fluoroquinolones, and their use in children should be limited to the treatment of life-threatening infections without alternative therapeutic options.

To date, no tetracycline and fluoroquinolone resistance has been reported in cases of MRMP. However, clinicians should be aware of the possibility of second-line drug resistance.

Approximately 0.5%–2% of MPP cases progress to the fulminant type of pneumonia, including fatal respiratory failure, which is most prevalent in adolescents. To date, there is no specific biomarker to predict the progression of fulminant MPP; thus, the treatment strategy largely depends on close observation and the clinician's experience. Although there is no clear guideline yet, systemic corticosteroid or IVIG is considered to be a reasonable treatment option⁵³⁾. Recent evidence shows that the severity of M. pneumoniae infections is largely dependent on the host immune response; thus, use of an immunomodulator such as corticosteroids and IVIG should be considered in the treatment of severe M. pneumoniae infections, regardless of macrolide resistance^11,54,55).

Although there are no guidelines put forward for corticosteroid treatment in severe MRMP to date, numerous studies have reported the efficacy of corticosteroids in the treatment of severe MRMP^{11,12,13,54,56)}. Unfortunately, the indication, time, dose, and duration of corticosteroids remain unclear. The dose varies from oral prednisolone at 1 mg/kg/day to intravenous methylprednisolone at 30 mg/kg/day for 3 days. Long-lasting fever and a serum lactate dehydrogenase level of ≥480 IU/L are known indications of effective corticosteroid therapy⁵⁷⁾. A recent randomized controlled study showed that methylprednisolone (2 mg/kg/day for 3 days) and IVIG (400 mg/kg/day for 3 days) therapy in children with refractory MPP who had a fever for at least 7 days or persistent consolidation of more than one lobe despite appropriate macrolides could significantly reduce the fever duration, resorption of atelectasis, and pleural effusion compared to treatment with azithromycin alone¹²⁾.

IVIG has been used as an immunomodulator in the treatment of immune-mediated diseases. Several studies reported the efficacy of IVIG for severe MPP in children^12,58,59). Besides fulminant MPP, there are numerous reports showing that IVIG therapy was effective in treating hemophagocytic syndrome, encephalitis, myocarditis complicated with complete heart block, cold agglutinin-related severe hemolytic anemia, mucositis, Stevens-Johnson syndrome, and acquired hemophilia^58,60,61,62).

To date, many studies have reported the efficacy of corticosteroid therapy in refractory MPP. A recent randomized controlled trial showed that early adjunct corticosteroid treatment shortened the time to clinical stability in CAP⁶³⁾. In addition, recent studies reported the efficacy and effectiveness of an early systemic immunomodulator (corticosteroids and/or IVIG) in the treatment of MRMP^12,14). The severity and chronicity of infection-associated respiratory disease largely depends on the interaction between the respiratory pathogen and host immune response; thus, early treatment of a systemic immunomodulator to reduce aberrant immune responses in the potential stage of acute respiratory distress syndrome was emphasized⁶⁴⁾. Nevertheless, there is still controversy related to the optimal timing of immunomodulatory therapy.