azithromycin, erm41, and mycobacterium abscessus

  • Mycobacterium abscessus is common infection in CF patients
  • check erm gene before treatment
  • if erm gene negative: use azithromycin, highly effective
  • if erm gene positive: only use azithromycin as immunomodulator and not as active treatment

Source

The most important of the resistance mechanisms determining the benefit of azithromycin relates to an inducible erm gene, which is present in some members of the Mycobacterium abscessus complex and confers macrolide resistance that is expressed on macrolide exposure (choice C is correct). This genetic marker of this resistance mechanism is notable both for the important role macrolides play in management of nontuberculous mycobacteria (NTM) infections and because of the difficulty in identifying its presence. M abscessus complex is the second most common NTM group causing human disease after Mycobacterium avium complex. In 2006, M abscessus was reclassified to represent a complex containing three subspecies: abscessus, massiliense, and bolletii. The spectrum of infection severity is heterogeneous, ranging from asymptomatic colonization to progressive and deadly disease.

Unfortunately, M abscessus complex is a highly drug-resistant microorganism, and few oral antibiotics show in vitro activity, making long-term treatment extremely complicated and challenging. This susceptibility to infection is particularly observed in patients with cystic fibrosis (CF). These patients have bronchiectasis and airway ciliary deficiencies creating a unique clinical phenotype with important challenges. A high proportion of individuals with CF have pulmonary colonization with NTM, ranging from 5% to 30%, with a rising incidence of M abscessus infections. Once M abscessus pulmonary disease develops, the same principles that relate to M abscessus treatment in the non-CF population should be applied. The NTM guidelines recommend that patients with M abscessus pulmonary disease caused by strains without inducible mutational resistance should receive a macrolide-containing multidrug treatment regimen. In contrast, patients infected by strains with inducible or mutational macrolide resistance may be treated with a macrolide-containing regimen, if the drug is being used for its immunomodulatory properties, and the macrolide should not be counted on as an active drug in the multidrug regimen. The guidelines also remark that M abscessus infections can be life-threatening, and the use of macrolides is potentially of great benefit. Macrolides are very active against M abscessus strains without a functional erm(41) gene, and evidence supports the use of macrolides in patients with disease caused by macrolide-susceptible M abscessus. It is important to perform in vitro macrolide susceptibility testing, including detection of a functional or nonfunctional erm(41) gene. Since it is an inducible enzyme, the mechanism will not be identified by means of in vitro antibiotic susceptibility testing unless this testing is done after incubating the organism in the presence of macrolides for 14 days. As a result, the Clinical and Laboratory Standards Institute recommends that macrolide testing for this complex include prolonged incubation testing for inducible macrolide resistance. Currently, advance macrolide and genetic testing is performed at specialized or referral centers. Additionally, the erm gene can be present and inactive, so molecular tests that only probe for the presence of the gene do not conclusively prove macrolide resistance. An active erm gene is present in most M abscessus subspecies abscessus isolates, in some subspecies bolletii, and in a small proportion of subspecies massiliense.   

M abscessus complex bacteria are closely related species that currently are identified by the sequencing of the _rpo_B gene. Mutations in the _rpo_B gene, encoding the β subunit of RNA polymerase, reportedly result in resistance to rifampin in several mycobacterial diseases but lack significance in the management of patients with M abscessus pulmonary disease (choice A is incorrect).

Aminoglycoside resistance with mutation in the ribosomal RNA (rRNA) or rrs gene are mostly isolated from patients with extensive exposure to amikacin and/or related aminoglycosides (choice B is incorrect).  Because of specific genetic polymorphisms within the M abscessus complex, these organisms are less susceptible to antibiotics than most other mycobacteria (they exhibit higher minimum inhibitory concentrations). Classic in this regard are two base-pair substitutions in the embB (ethambutol) gene resistance-determining region that confer high-level (minimum inhibitory concentrations >64 mg/L) ethambutol resistance to all members of the M abscessus complex (choice D is incorrect).1

Footnotes

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