Editorial Commentary: Infections Due to Macrolide-Resistant Mycoplasma pneumoniae: Now What?

(See the Major Article by Okada et al, on pages 1642–9.) In this issue of Clinical Infectious Diseases, Okada et al describe the first large outbreak of macrolide-resistant Mycoplasma pneumoniae infections in Japan [1]. Furthermore, they provide the first data describing the responses of a large number of these cases to treatment with several nonmacrolide antibiotics. The significance of macrolide resistance in M. pneumoniae has become much more apparent in the past decade; it has become widespread in Japan and China and is now spreading through Europe and North America. Reports of macrolide resistance during 2008–2010 include rates of >40% in Japan, 80%–90% in China, and 3%–10% in Europe and the United States [2]. Mycoplasma pneumoniae infections occur both endemically and epidemically worldwide, especially in children and young adults. A substantial increase in incidence was reported in 2010 and 2011 in several countries in Northern Europe [3, 4] and in Israel [5]. The outbreak reported in Israel was shown to be polyclonal by multilocus variable-number analysis (MLVA). A similar epidemic was described in Japan in 2011. The P1 adhesin-based genotyping method used in the study, which differentiated the strains into only 2 types, identified a type 1 M. pneumoniae surge [1]. However, that typing method was not discriminant enough to determine whether the epidemic was polyclonal. Interestingly, the epidemics of M. pneumoniae in 2010–2011 in Denmark, Sweden, and Norway were associated with the high consumption of macrolides and an increase in macrolide prescriptions [3]. However, to date, this does not seem to have affected levels of macrolide resistance in M. pneumoniae, which remain low in these countries [6]. In contrast, in Japan [1], the authors linked the increase in macrolide-resistant M. pneumoniae (up to 87% of the 202 isolates in the 2011 surge) to extensive macrolide use (30% of oral prescribed antibiotics) and observed a parallel rise in macrolide resistance in other respiratory pathogens, apparently as a result of antibiotic selective pressure in children. M. pneumoniae is susceptible to macrolides and related antibiotics, the tetracyclines and fluoroquinolones [2]. Macrolides have generally been the treatment of choice for pneumonia, especially in children, because they are the most potent treatments for this disease, and fluoroquinolones and tetracyclines are contraindicated in all children and in children <8 years of age, respectively. The presence of macrolide-resistant M. pneumoniae may lead to treatment failure, which translates into more febrile days and a longer duration of persistent cough than are observed in patients with macrolide-susceptible isolates. Furthermore, children with macrolide-resistant M. pneumoniae required therapeutic switching because of either persistent symptoms or unresolved or worsening chest radiographic abnormalities. Several sporadic cases of infections with macrolide-resistant M. pneumoniae requiring the change of macrolides to either tetracyclines (minocycline or doxycycline) or fluoroquinolones (levofloxacin or ciprofloxacin) have been described; some of these cases were associated with severe symptoms such as life-threatening pneumonia [7] or Stevens-Johnson syndrome [8]. The control of macrolide-resistant M. pneumoniae infections has become a major therapeutic challenge in Asia with resistance rates exceeding 80% in both Japan and China in 2011 [1, 9]. In contrast to Europe and the United States, minocycline and tosufloxacin, a fluoroquinolone agent, have been approved in Japan for pediatric use to treat macrolide-resistant M. pneumoniae infections and community-acquired pneumonia or acute otitis, respectively. Thus, of the 176 patients diagnosed with macrolide-resistant M. pneumoniae, 125 were treated with minocycline or doxycycline, and 15 were treated with tosufloxacin or levofloxacin [1]. Tetracyclines were significantly more effective than fluoroquinolones in achieving clinical improvement within 24 hours and in decreasing M. pneumoniae DNA copy number after 3 days of treatment. Although this was not a randomized trial to compare the efficacy of tetracyclines vs fluoroquinolones against macrolide-resistant strains, and although the tetracycline- and fluoroquinolone-treated patient groups treated are not comparable in size, this is the first description of a large number of children infected with macrolide-resistant M. pneumoniae and successfully treated with other antimicrobials. In the future, it should be interesting to evaluate the activity of streptogramin combinations, such as parenteral quinupristin-dalfopristin and especially oral pristinamycin, which are known to retain activity against 23S ribosomal RNA (rRNA) mutant M. pneumoniae [2]. Real-time polymerase chain reaction methods and pyrosequencing assays for the rapid detection of macrolide resistance-associated mutations in 23S rRNA isolated directly from respiratory specimens are now available and should allow treatment to be adjusted rapidly in the event that a resistant genotype is detected [2]. Further studies are also needed to clarify the impact of macrolide resistance on the outcomes of respiratory tract infections, and randomized therapeutic trials are necessary to establish clinical guidelines regarding the most appropriate antimicrobial agents (including molecule, dose, and duration) to use against these resistant strains. These guidelines are all the more necessary because no acquired resistance to tetracyclines or fluoroquinolones has been described clinically in patients to date; however, resistant strains have been selected in vitro for both classes of drugs, with target mutations identified in the mutants. Thus, the risk of the emergence of clinical resistance, especially for fluoroquinolones, is an important possibility if these antibiotics are used inappropriately. It should be noted that this resistance already exists in clinical isolates of urogenital mycoplasmas [2]. What measures might be taken to prevent an increase in the prevalence of resistance to macrolides in M. pneumoniae, especially in Europe and the United States, where this prevalence is still low? A vaccine against M. pneumoniae is not yet available, and the results from vaccine trials performed during the 1960s to the 1990s were not encouraging [10]. Linde et al [11] emphasized that macrolides should be used carefully and that many patients with mild symptoms during the Swedish 2011 outbreak were likely treated unnecessarily. Thus, the rapid detection of resistance-associated mutations is necessary in cases of persistent or recurrent M. pneumoniae infection and must be used widely to enable the prompt prescription of an alternative antimicrobial regimen. This could lead to the control and prevention of macrolide-resistant M. pneumoniae outbreaks by decreasing the numbers of pharyngeal M. pneumoniae and the dissemination of the infection. Acknowledgments. The author thanks Christiane Bébéar and Sabine Pereyre for helpful reading of the manuscript. Potential conflicts of interest. The author certifies no potential conflicts. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.