Macrolide resistance in pneumococci—is it relevant?

Pneumonia, Jul 2016

Macrolide antibiotics are widely used for a range of indications, including pneumonia. Both high-level and low-level resistance to macrolides is increasing in pneumococci globally. Macrolide resistance in pneumococci is of limited clinical relevance where ß-lactams remain the mainstay of treatment, such as for moderate/severe pneumonia; however, data suggest that macrolides may not be able to be relied on as monotherapy for serious pneumococcal infections.

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Macrolide resistance in pneumococci—is it relevant?

Cheng and Jenney Pneumonia Macrolide resistance in pneumococci-is it relevant? Allen C. Cheng 0 1 4 Adam W. J. Jenney 2 3 4 0 School of Public Health and Preventive Medicine , Melbourne , Australia 1 Infection Prevention and Healthcare Epidemiology Unit , Melbourne , Australia 2 Microbiology Unit, Alfred Health , Melbourne , Australia 3 College of Medicine, Nursing and Health Sciences Fiji National University , Suva , Fiji 4 Department of Infectious Diseases, Monash University , Melbourne , Australia Macrolide antibiotics are widely used for a range of indications, including pneumonia. Both high-level and low-level resistance to macrolides is increasing in pneumococci globally. Macrolide resistance in pneumococci is of limited clinical relevance where ß-lactams remain the mainstay of treatment, such as for moderate/severe pneumonia; however, data suggest that macrolides may not be able to be relied on as monotherapy for serious pneumococcal infections. Streptococcus pneumoniae; Antibiotic resistance; Macrolides; Community-acquired pneumonia - Macrolide antibiotics, including clarithromycin and azithromycin, remain an important class of antimicrobials for pneumococcal diseases. In Australia, azithromycin is recommended in combination with ceftriaxone as empiric therapy for severe pneumonia, and clarithromycin is a second line therapy for mild/moderate communityacquired pneumonia. United States (US) guidelines are currently being revised, but current recommendations list macrolides as monotherapy for outpatient pneumonia, and macrolides in combination with ß-lactams for more severe pneumonia [ 1 ]. Although antibiotics are not routinely recommended for otitis media, there is an exception for high-risk children with otitis media (with or without perforation), in which case azithromycin is listed as one of several therapeutic options [ 2 ]. However, the main selection pressure for resistant pneumococci may come from its use in other indications such as for non-pneumococcal respiratory tract infection [ 3 ], bronchiectasis and chronic obstructive pulmonary disease (COPD) [ 4 ], sexually transmitted diseases and trachoma [ 5 ] (in different settings). The increasing prevalence of macrolide-resistant pneumococci has raised concerns about its place in therapy. There are two major mechanisms mediating resistance to macrolides. The ermB gene encodes a methyltransferase that causes ribosomal methylation, resulting in the macrolide-lincosamide-streptogramin B (MLSB) phenotype that reduces susceptibility to macrolides, lincosamide, and streptogramin B. This may be expressed in a constitutive or inducible fashion [ 6 ]. mefA codes for an antibiotic efflux pump removing the drug from the target site. ermB tends to confer high level resistance to macrolides with MICs >64 mg/l, whereas the efflux mechanism results in lower MICs for erythromycin (typically in the 1–16 mg/l range), compared to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint for erythromycin (and clarithromycin and azithromycin) of 0.25 mg/l. Other resistance mechanisms also exist, including the mefE variant efflux pump carried on the macrolide efflux genetic assembly (mega), mutations in 23S rRNA and also in the L4 and L22 proteins, and the rare ermA methyltransferase [ 7 ]. There are significant global differences in susceptibility and the mechanisms of resistance. The highest rates of resistance have been reported in East Asia (particularly China, Japan, and South Korea) [ 8–10 ] and rapid increases in resistance are occurring in Malaysia [ 11 ]. Globally, ermB methyltransferase is more common, but the proportion of isolates carrying this gene was higher in several European countries, and less common in North America [ 12 ]. Co-existence of both ermB and mefA is relatively common in some settings. It has been reported at 15 % in South Africa [ 13 ], but as high as 38 % in Russia and nearly 50 % in Vietnam [ 9 ]. Because of the association between resistance and pneumococcal serotypes, conjugate pneumococcal vaccination has impacted on the epidemiology of resistance. In some places the 7-valent vaccine has been shown to cause a significant and lasting decline in macrolide resistance through reduction in carriage and disease due to serotypes 6B, 9 V, 19 F and 23 F that can carry the erm or mef genes [ 14, 15 ]. While the concerns about replacement with drug-resistant non-vaccine serotypes such as 19A have mostly been addressed by the 13-valent vaccine, replacement with other non-vaccine serotypes and capsular transformation remains a concern [ 16–19 ]. Newer macrolides are concentrated intracellularly, and this is thought to result in increased drug delivery to the site of infection, and exposure to high concentrations of drug following phagocytosis, which may overcome low level resistance [ 20 ]. However, it has been suggested that high-level resistance may be clinically relevant [ 2 (...truncated)


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Allen C. Cheng, Adam W. J. Jenney. Macrolide resistance in pneumococci—is it relevant?, Pneumonia, 2016, pp. 10, Volume 8, Issue 1, DOI: 10.1186/s41479-016-0010-1