Mycoplasma pneumoniae is one of the most common pathogens causing community-acquired pneumonia (CAP) in children and adolescents, accounting for 10%–40% of all cases of CAP, and is substantially more common in children or adolescents than in adults. The recent epidemics in Korea occurred in 2006–2007, 2011, and 2015–2016, and the rate of macrolide-resistant Mycoplasma pneumoniae (MRMP) has been on the rise, with a rate of 14.7% in 2006, 51.6% in 2011, and reaching up to 84.6% in 20151234). The rates of MRMP in Japan and China are similar to those in Korea567), whereas countries in North America and Europe reported an MRMP rate of only approximately 10%8). The high rates of MRMP may be associated with the excessive use of macrolides in Asian countries. Macrolide resistance is associated with point mutations in domain V of 23S rRNA5). The most common mutation is the A2063G transition, followed by the A2064G transition.

Macrolides have been traditionally used as first-line antibiotics in children with M. pneumoniae pneumonia (MPP) because of their low toxicity, low minimum inhibitory concentration (MIC), and no contraindications in children. The usual duration of treatment is recommended at 7–14 days with clarithromycin and 5 days with azithromycin8). Since MRMP pneumonia has more severe clinical outcomes such as a longer duration of fever, cough, and hospital days in addition to radiologic progression, second-line antibiotics or adjunctive immunomodulators are required. Tetracyclines such as doxycycline and minocycline or fluoroquinolones, primarily levofloxacin, can be used as alternative antibiotics in such cases6). However, tetracyclines and levofloxacin are not approved for use in children under 12 years old and under 18 years old, respectively, in Korea. Acquired resistance to tetracyclines and levofloxacin has not yet been reported1), although levofloxacin-resistant S. pneumoniae was isolated9).

The immunopathogenesis of the lung injury caused by MRMP is assumed to be related to an amplified host immune response such as cytokine overproduction and T-cell activation10). Accordingly, the use of immunomodulators such as corticosteroids or intravenous immunoglobulin (IVIG) can reduce the excessive host immune reaction and improve clinical outcomes11121314). However, the exact time point for the start, duration, or dose of immunomodulators has not been confirmed. This review focuses on the known mechanisms of resistance acquisition and treatment options of MRMP pneumonia.

M. pneumoniae is intrinsically resistant to beta-lactams and other antibiotics targeting the bacterial cell wall due to the lack of a cell wall. Therefore, antibiotics that interfere with protein or DNA synthesis, such as macrolides, lincosamides, streptogramin combinations, and ketolides (MLSK), tetracyclines, and quinolones, have been used in clinical practice to treat M. pneumoniae infections. Among these antibiotics, macrolides act on the 50S ribosomal subunit of the bacterial ribosome to inhibit protein synthesis15). The site of peptide bond formation on the large 50S ribosomal subunit forms the central peptidyltransferase loop in domain V of 23S rRNA (Fig. 1)16). Nucleotides on the central loop are necessary for macrolides binding.

The most common mechanisms of macrolide resistance are efflux of the antibiotics (extrusion of the drug from the cell) and target site modification by a post-transcriptional modification of 23S rRNA or mutations in 23S rRNA or ribosomal proteins17). However, only target site modifications through mutations have been associated with macrolide resistance in M. pneumoniae to date18). Although resistance acquired through a target site mutation was detected for all three classes of antibiotics commonly used against M. pneumoniae in mutants selected in vitro, this mechanism of resistance has only been reported in clinical isolates for the MLSK antibiotics8).

Macrolide resistance has been associated with mutations at the sites 2063, 2064, 2067, and 2617 in domain V of the 23S rRNA sequence51920). The A2063G transition is the most common mutation, followed by the A2064G transition5). Although mutations at positions A2067 and C2617 have also been linked to macrolide resistance, they are relatively rare. The resistance level to macrolides varies depending on the position at which the mutation occurs. Comparison of sequencing results with antimicrobial susceptibility testing confirmed that the A2063G and A2064G mutations conferred a high level of resistance to 14- and 15-membered macrolides. Although the A2063G mutation was related to an intermediate level of resistance to 16-membered macrolides, the A2067G transition conferred a high level of resistance to these antibiotics in a mutant selected in vitro (Fig. 1)212223).

Mutations of genes encoding ribosomal proteins L4 and L22 have also been associated with low-level macrolide resistance in a mutant selected in vitro24). However, mutations in ribosomal proteins L4 and L22 have rarely been reported in clinical isolates.

To date, no cross-resistance has been observed between MLSK and other antibiotic classes used to treat M. pneumoniae. In addition, all clinical isolates with macrolide resistance were found to be susceptible to tetracyclines and fluoroquinolones.

To make better clinical decisions in the treatment of MPP, early detection of MRMP is necessary. However, antimicrobial susceptibility testing for M. pneumoniae requires a long period of time because M. pneumoniae is fastidious and slow growing. Therefore, various molecular methods for the rapid detection of MRMP from respiratory samples have been developed. In addition to conventional polymerase chain reaction (PCR) and sequencing of the 23S rRNA gene, PCR-restriction fragment length polymorphism, real-time PCR and high-resolution melt analysis, Cycleave PCR, and a single nucleotide polymorphism-PCR have been introduced to detect macrolide resistance25262728). Although there are no commercially available sensitive kits to detect MRMP, such kits are expected to become available soon and will be useful for the appropriate management of patients with MPP.

To date, data collected from patients with MRMP pneumonia suggest that the infection does not increase the severity of disease or the risk of complications in children372930). That is, the clinical symptoms, laboratory and radiographic findings, and overall severity of pneumonia are generally similar between MRMP and macrolide-susceptible M. pneumoniae (MSMP) pneumonia.

However, the clinical efficacy of macrolide treatment tends to be lower in patients with MRMP pneumonia than in patients with MSMP pneumonia. Most patients with MRMP pneumonia show persistent signs and symptoms, with a prolonged duration of hospital stay and antibiotic administration compared with patients with MSMP pneumonia. In addition, recent reports demonstrated increased disease progression during therapy and complications in patients with MRMP pneumonia3132). Surveillance data from Japan also showed that the number of patients requiring hospitalization has gradually increased along with the increase in the prevalence of MRMP pneumonia in children30). Overall, these studies raise the possibility that MRMP infection could increase the severity of pneumonia.

One reason for the inconsistency among previous studies regarding the impact of MRMP on clinical outcomes may be that patients with MRMP pneumonia had more persistent signs and symptoms, which led physicians to add an adjunctive treatment such as corticosteroids or to replace antibiotics to achieve more rapid clinical improvement. Another reason may be related to differences among the populations reported. Most previous studies included patients with moderate to severe disease who required hospitalization, which might lead to an overestimation of the general severity of MSMP pneumonia, assuming that the majority of patients with MSMP pneumonia would have been treated in an outpatient clinic rather than in hospital. Therefore, at this point, the clinical relevance of the increased prevalence of MRMP cannot be definitively established. Continuous surveillance of the influence of MRMP on disease outcome is necessary to better define its clinical relevance and to develop appropriate treatment strategies.

Progression and severe complications are hypothesized to result from delayed diagnosis and treatment, macrolide resistance, coinfections with other microorganisms, or host hyper-immune responses53). Initial signs and symptoms cannot generally distinguish MRMP from MSMP. Cases of MRMP tend to show more persistent symptoms, including long-lasting fever, coughing, subsequent longer hospitalization, and the longer use of antibiotics or change to the second-line antibiotics. However, MRMP was not related to more rapid progression or severe complications than MSMP8). By contrast, recent studies reported that MRMP showed more rapid progression31) and a higher incidence of extrapulmonary complications than MSMP32).

MRMP can be associated with serious intra- or extrapulmonary complications, including pleural effusion, bronchiolitis obliterans, atelectasis, or acute respiratory distress syndrome as the intrapulmonary complications5365). Extrapulmonary complications vary from mild cases such as elevated levels of liver and pancreatic enzymes, rash, proteinuria, arthritis, and vestibular neuritis to more severe complications such as myocarditis, Stevens-Johnson syndrome, erythema multiforme, hemolytic anemia, hemophagocytic syndrome, encephalitis, transverse myelitis, Guillain-Barré syndrome, or cerebellitis55).

There are currently 3 therapeutic options for treating MRMP pneumonia. If patients have only persistent fever and coughing without respiratory difficulties or complications, only maintenance on first-line antibiotics and supportive care are required. If patients have respiratory difficulties, progressive consolidation, or complications, a change to second-line antibiotics and/or the addition of immunomodulators are recommended.

Since 2000, the rates of MRMP pneumonia have rapidly increased, especially in Asian countries where M. pneumoniae infections are highly prevalent. The excessive use of macrolides may contribute to the higher prevalence of MRMP in Asian countries. MRMP can develop during the course of macrolide treatment within an individual patient. Point mutations of 23S rRNA in the region of sites 2063 and 2064 are the most common mechanisms of MRMP. Tetracycline and levofloxacin can be alternative antibiotics for treating MRMP pneumonia, and no resistant strains have been reported to date. However, tetracyclines are not approved for children under 12 years old, and levofloxacin is not approved for children under 18 years of age in Korea. In addition, only a single rRNA of M. pneumonia can increase the possibility of mutation to alternative antibiotics. Excessive host immunity can contribute to refractory MPP; in such cases, immunomodulators such as corticosteroids or IVIG can be added to reduce the immune reaction in refractory MPP. Corticosteroids can attenuate inflammatory reaction associated with MRMP pneumonia. However, determination of the exact timing, duration, and dose of immunomodulators needs further study. Overuse or misuse of antibiotics should be restricted to reduce further acquisition of resistance in MPP.