Mycoplasma pneumoniae: Current Knowledge on Macrolide Resistance and Treatment

Abstract

Mycoplasma pneumoniae causes community-acquired respiratory tract infections, particularly in school-aged children and young adults. These infections occur both endemically and epidemically worldwide. M. pneumoniae lacks cell wall and is subsequently resistant to beta-lactams and to all antimicrobials targeting the cell wall. This mycoplasma is intrinsically susceptible to macrolides and related antibiotics, to tetracyclines and to fluoroquinolones. Macrolides and related antibiotics are the first-line treatment of M. pneumoniae respiratory tract infections mainly because of their low MIC against the bacteria, their low toxicity and the absence of contraindication in young children. The newer macrolides are now the preferred agents with a 7-to-14 day course of oral clarithromycin or a 5-day course of oral azithromycin for treatment of community-acquired pneumonia due to M. pneumoniae, according to the different guidelines worldwide. However, macrolide resistance has been spreading for 15 years worldwide, with prevalence now ranging between 0 and 15% in Europe and the USA, approximately 30% in Israel and up to 90–100% in Asia. This resistance is associated with point mutations in the peptidyl-transferase loop of the 23S rRNA and leads to high-level resistance to macrolides. Macrolide resistance-associated mutations can be detected using several molecular methods applicable directly from respiratory specimens. Because this resistance has clinical outcomes such as longer duration of fever, cough and hospital stay, alternative antibiotic treatment can be required, including tetracyclines such as doxycycline and minocycline or fluoroquinolones, primarily levofloxacin, during 7–14 days, even though fluoroquinolones and tetracyclines are contraindicated in all children and in children < 8 year-old, respectively. Acquired resistance to tetracyclines and fluoroquinolones has never been reported in M. pneumoniae clinical isolates but reduced susceptibility was reported in in vitro selected mutants. This article focuses on M. pneumoniae antibiotic susceptibility and on the development and the evolution of acquired resistance. Molecular detection of resistant mutants and therapeutic options in case of macrolide resistance will also be assessed.

Cambiando los paradigmas de la infección por M. pneumoniae en pediatría

“…69 En adultos, los macrólidos, las fluoroquinolonas y las tetraciclinas son los tratamientos de elección y en pacientes pediátricos únicamente los macróli-dos. Aún es desconocido el valor terapéutico del uso de antibióticos en niños hospitalizados con neumonía por M. pneumoniae.…”

“…Antes del año 2000 las infecciones por M. pneumoniae eran tratadas esencialmente con macrólidos, ya que los aislamientos clínicos con resistencia a estos antimicrobianos era muy rara. 69 En el año 2001, se reportó en Japón la primera mutación en el gen 23S rRNA en M. pneumoniae, en un paciente pediátrico con neumonía; a partir de entonces, la resistencia se ha ido extendiendo a nivel mundial. Los índices de resistencia a macrólidos varían de acuerdo a la región del mundo.…”

“…39,40 Esto constituye un problema en el tratamiento de infecciones en pacientes pediátricos debido a que las alternativas terapéuticas como tetraciclinas, no son recomendadas para niños. 75 El mecanismo molecular de la resistencia se basa en mutaciones puntuales en el dominio V de la subunidad 23S del rRNA (posiciones 2058, 2059, 2062, 2611), lo que reduce la afinidad del antibiótico al ribosoma 69 y ocasionalmente también involucra mutaciones en las proteínas ribosomales L4 y L22. 69,76 Existe la evidencia de que las cepas de M. pneumoniae con resistencia a macrólidos pueden cursar con cuadros más graves y con mayor frecuencia manifestaciones extrapulmonares.…”

Clinical features and seasonal variations in the prevalence of macrolide‐resistant Mycoplasma pneumoniae

“…However, macrolide resistance of M. pneumoniae, which is acquired by mutations of the ribosomal target of macrolides,11 has been spreading rapidly and widely since 2000,12 resulting in enhanced disease severity with increased complications 13, 14…”

“…The prevalence of macrolide‐resistant M. pneumoniae is 23.3%‐100% in East Asian regions, 3.5%‐13.2% in North America, and below 10% in European countries, except Italy, which has a higher rate of 26% 11. Tanaka et al15 reported a year‐by‐year variation in the prevalence of macrolide‐resistant M. pneumoniae in Japan, demonstrating an increase from 55.6% to 81.6% between 2008 and 2012, with a gradual decrease thereafter, reaching 43.6% by 2015.…”