Mycoplasma pneumoniae: Susceptibility and Resistance to Antibiotics

Cécile Bébéar; Sabine Pereyre; Olivia Peuchant


Future Microbiol. 2011;6(4):423-431. 

In This Article

Acquired Resistance

Among the various mechanisms of acquired resistance, the only ones described in vivo for mycoplasmas are antimicrobial target modification or protection. An active efflux mechanism has also been demonstrated in vitro.[20] Concerning the acquisition of new resistance genes from other bacteria, no extrachromosomal element has been described in M. pneumoniae or in other human species. Resistance is mediated either by chromosomal mutations or acquisition of a transposon. In M. pneumoniae, only target alterations by acquired mutations have been associated with antibiotic resistance.[6]

Mycoplasmas are characterized by high mutation rates. Sequencing studies of several mycoplasma genomes, including that of M. pneumoniae, have revealed that only a small amount of genetic information is dedicated to DNA repair.[21] It has been shown in other bacteria that the lack of some DNA repair systems such as, the mut gene, is associated with a mutator phenotype. Thus, a link could be hypothesized between high mutation rates and antibiotic resistance in mycoplasmas, as has been found for Pseudomonas aeruginosa.[22] Resistance through mutation concerns all classes of antibiotics used to treat M. pneumoniae infections.[8]

Until recently, few studies on in vitro or in vivo resistance of mycoplasmas to antibiotics were available. Research has since intensified and is now focusing not only on M. hominis and Ureaplasma spp., two species long known to be tetracycline-resistant, but also on M. pneumoniae and M. genitalium, two species with high antibiotic susceptibility in which macrolide resistance is now becoming a problem.[6,8] However, as M. pneumoniae is very rarely isolated from specimens and in vitro susceptibility testing is even less used for patient management purposes, the number of clinical strains tested is limited and the occurrence of acquired resistance worldwide is almost unknown.

MLSK Group

Mechanisms Macrolide resistance in mycoplasmas, which have a small number of ribosomal operons, is conferred by mutations in the ribosomal target (23S rRNA and ribosomal proteins L4 and L22). It has been described mainly in M. pneumoniae but resistant strains of M. hominis, Ureaplasma spp.[8,9] and, more recently, M. genitalium,[23,24] have been reported.

Most resistant strains of M. pneumoniae harbor a A2058G mutation (E. coli numbering) in the peptidyltransferase loop of 23S rRNA (Figure 1).[6] The other mutations found in clinical strains at positions 2059 and 2611[25,26] have been identified as macrolide resistance hot spots in other bacteria. No mutations in domain II or in the ribosomal proteins L4 or L22 genes have been described in vivo. Resistant strains do not show cross-resistance to other classes of antibiotics.

Figure 1.

The peptidyltransferase loop of domain V of 23S rRNA of Mycoplasma pneumoniae (Escherichia coli numbering). Squared nucleotides indicate positions mutated in vitro. Antibiotics in parentheses indicate the selective agent. Circled nucleotides indicate positions mutated in vivo.
Adapted with permission from [6].
AZM: Azithromycin; ERY: Erythromycin; JOS: Josamycin; Q–D: Quinupristin–dalfopristin; TEL: Telithromycin.

Resistant mutants of M. pneumoniae have been obtained by selection in vitro on erythromycin.[26,27] Resistance is due to mutations at positions 2058 and 2059, which were previously described in vivo. An exhaustive in vitro study described the selection of mutants resistant to different macrolides, streptogramins and a ketolide, testing a total of eight antibiotics.[28] The selected mutations were in domain V of 23S rRNA at positions 2611 and 2062 and in the genes encoding ribosomal proteins L4 and L22; these were point mutations, insertions or deletions. No mutations were detected in domain II of 23S rRNA.

Phenotype & Prevalence The resistant M. pneumoniae clinical isolates were resistant to macrolides, lincosamides, streptogramin B (phenotype MLSB) and ketolides, with different increases in the MICs according to the mutation (Table 2).[6] For example, for 16-membered macrolides there was a larger increase in the MICs for the mutation at position 2059 than at position 2058, whereas the reverse was true for ketolides. The mutation at position 2611 was associated with the lowest levels of resistance while mutations 2058 and 2059 led to a high-level resistance to macrolides. Quinupristin–dalfopristin retained activity against the mutants (Table 2).

Prior to the year 2000, very few clinical isolates of M. pneumoniae were resistant to macrolides. Rare strains resistant to erythromycin were reported in the literature between 1968 and 1999.[29–32] No erythromycin resistance was detected among 150 strains isolated from France and Denmark between 1962 and 1996.[9,31] Two macrolide-resistant isolates have been detected in a collection of 41 M. pneumoniae strains from North America and Europe between 1995 and 1999.[29] By contrast, since 2000 several Japanese studies[25,33–36] have reported a significant increase in macrolide resistance rates in M. pneumoniae, affecting more than 40% of strains in 2007 according to Morozumi et al. (Table 3).[37] Some Chinese studies described a higher percentage of macrolide-resistant isolates of M. pneumoniae, ranging from 69 to 92%, obtained from both children and adults between 2003 and 2009.[38–41] In a recent M. pneumoniae epidemic in the USA,[42] three of eleven isolates were resistant to macrolides. In Germany, Dumke et al. described three out of 99 strains, isolated between 1991 and 2009, that were resistant to macrolides.[43] In France, only two macrolide-resistant clinical isolates were described within a series of 155 strains isolated between 1994 and 2006.[31] More recently, however, macrolide resistance in M. pneumoniae has been on the rise in France, with a 10% rate (5/51) of resistant genotypes reported between 2005 and 2007.[44]

This increase in resistance has paralleled a similar rise in macrolide resistance in other respiratory pathogens apparently as a result of antibiotic selective pressure in children during a period of extensive macrolide use in many parts of the world, especially in Asia.[37–39]

Molecular Detection & Molecular Typing of Macrolide Resistance Several real-time PCR methods[42–45] with melt-curve analysis and pyrosequencing assays[46] were recently developed to detect mutations in the 23S rRNA gene, which confer macrolide resistance in M. pneumoniae. The advantage of these methods is that they can be used directly on respiratory specimens, thus allowing rapid screening for resistance and avoiding the need for lengthy isolation of the fastidious M. pneumoniae by culture.

Several French,[47] German,[43] Japanese[25,36] and Chinese[38–40] isolates were molecularly typed either by PCR-restriction fragment length polymorphism of the adhesin P1 gene or by multilocus variable-number-tandem-repeat analysis (MLVA). No clear association was observed between the macrolide-resistant isolates and the P1 subtypes while the more discriminant MLVA analysis on French and Japanese isolates did not reveal any link between a particular MLVA type and macrolide resistance.[47] These data confirmed the absence of a particular emerging macrolide-resistant clone.

Clinical Implications of Macrolide-resistance in M. Pneumoniae The isolation of macrolide-resistant M. pneumoniae may lead to treatment failure which, for the patients concerned, translates into more febrile days and longer duration of persistent cough than patients with macrolide-susceptible isolates.[33,48] Furthermore, children with macrolide-resistant M. pneumoniae required therapeutic changes with substitution of minocycline or levofloxacin because of either persistent symptoms or unresolved or worsening chest radiographic abnormalities.[34] Finally, another study reported that the efficacy rate of macrolide therapy was 91.5 and 22.7% in macrolide-susceptible and macrolide-resistant M. pneumoniae infections, respectively.[33]

Thus far, most infections with macrolide-resistant M. pneumoniae described in the past 10 years have occurred in children, but for fewer adults have been evaluated.[37,44] To date, no difference have been found between macrolide-resistant strains isolated in children and adults.


Mutations in the target genes gyrA and gyrB of DNA gyrase and parC and parE of topoisomerase IV are the main mechanisms conferring fluoroquinolones resistance in mycoplasmas. Resistance in vivo has been described only in genital mycoplasmas.[8,9]

For M. pneumoniae, mutants have been selected in vitro with mutations clustering within a conserved region referred to as the quinolone resistance-determining region. Regardless of which drug was used for selection, fluoroquinolone resistance hot spots described in the quinolone resistance-determining regions of other bacteria were found to be mutated in the resistant strains. However, mutation rates were lower for the newer fluoroquinolones, levofloxacin and moxifloxacin, than for the older ones such as ofloxacin and ciprofloxacin.[49]


Acquired resistance to tetracyclines has been well documented for almost two decades in the mollicutes of the urogenital tract, Ureaplasma spp. and M. hominis, but not M. pneumoniae.

Mycoplasma pneumoniae strains with reduced tetracycline susceptibility (MIC ≤ 2 µg/ml) have been obtained in vitro in the presence of increasing concentrations of tetracyclines.[50] Reduced susceptibility to tetracyclines was related to mutations in the tetracycline-binding pocket of 16S rRNA.


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