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  Table of Contents  
INVITED COMMENTARY
Year : 2016  |  Volume : 34  |  Issue : 1  |  Page : 5-6
 

Macrolide resistance mechanisms in Streptococcus pneumoniae: Opening Pandora's box


Department of Microbiology, Pondicherry Institute of Medical Sciences, Kalapet, Puducherry, India

Date of Submission20-May-2015
Date of Acceptance12-Sep-2015
Date of Web Publication15-Jan-2016

Correspondence Address:
Reba Kanungo
Department of Microbiology, Pondicherry Institute of Medical Sciences, Kalapet, Puducherry
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0255-0857.174123

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How to cite this article:
Kanungo R. Macrolide resistance mechanisms in Streptococcus pneumoniae: Opening Pandora's box. Indian J Med Microbiol 2016;34:5-6

How to cite this URL:
Kanungo R. Macrolide resistance mechanisms in Streptococcus pneumoniae: Opening Pandora's box. Indian J Med Microbiol [serial online] 2016 [cited 2019 Feb 16];34:5-6. Available from: http://www.ijmm.org/text.asp?2016/34/1/5/174123


Dear Editor,

A study published in this issue of Indian Journal of Medical Microbiology entitled “Genotyping and serotyping of macrolide and multidrug resistant Streptococcus pneumoniae isolated from carrier children 5 years of age in Jordan,” looks at the presence of ermB and mefE genes in colonising S. pneumoniae. Macrolides azithromycin and clarithromycin have superseded the use of erythromycin in recent times due to the ease of administration and hence patient compliance. The study is relevant as S. pneumoniae remains persistent despite attempts at controlling the infections, through immunisation. Two major factors contributing to this, are its antigenic variation dependent on >90 capsular serotypes, and its ability to colonise healthy individuals.

The fallout of colonisation in the nasopharynx is its ability to acquire antibiotic resistance under the pressure of therapy for several unrelated infections. This has encouraged studies on detecting mechanisms of resistance to commonly used antibiotics in treating invasive pneumococcal infections. Resistance mechanisms to penicillin including other beta-lactams, fluroquinolones and macrolides have been prominent in the recent literature. Penicillin resistance is varied, depending on six penicillin binding proteins 1a, 1b, 2x, 2a, 2b and 3, often found as a mosaic.[1] Intricacies of the mosaic patterns, association with other antibiotics, namely cotrimoxazole resistance via alteration in the dihydrofolate reductase mechanism have been subjects of study.[2]

Macrolides have long been used to treat community-acquired pneumococcal pneumonia.

However, there have been recent reports of increasing resistance to these antibiotics.[3] Macrolide resistance has been associated with resistance to other first-line antibiotics. Macrolide resistance is conferred by several mechanisms.[4] Two major mechanisms are by ermB and mefE genes. The ermB gene regulates the production of a methylase thereby resulting in the macrolide, lincosamide and streptogramin resistance. On the other hand, the presence of several mef gene regulates the efflux pump mechanism. The mef genes were thought to be species specific, with mefA predominantly seen in Group A Streptococci and mefE in S. pneumoniae. Cocomitant expression of both the genes has been recorded in S. pneumoniae.[5] What is interesting in this paper is the presence of ermB gene, which indicated higher MIC requirements, whereas strains with combined presence of ermB and mefE had lower MIC of the macrolides. However, the presence of ermB and mefE genes and increased MIC to both the macrolides indicates the potential for the strains to increasingly become resistant. Surprisingly, strains with mefE genes showed much lower levels of MIC. These variable correlations with the genes requires further insight to understand the interplay of factors responsible for the expression of resistance and MIC levels in vitro which ultimately influence the drug dosage for treatment. The prevalence of strains with mefA and ermB genes is reported to be higher in Asia than Europe and the US.[6]

An important data missing from the study is the proportion of children who were vaccinated and the type of vaccine used to immunise these children. The author did not find any correlation with serotype prevalence and resistance pattern of the nasopharyngeal colonisers. However, the majority of serotype 19F which has been attributed to harbouring several resistance genes was found to be resistant to macrolides. Some strains did not possess either ermB or mefE genes but were resistant by the in vitro test, suggesting alternate mechanism, which the authors have hypothesised could be due to mutation at the 23S r RNA. This needs observation of the authors to be validated. Serotypes 19F, 6A/B, 11A and 19A, 14 and 15B/), 9V, 15A and 23F, 16F, 18, 22F and 33F reported in this study, are commonly encountered invasive strains, which were found colonising the nasopharynx of healthy children. The authors have not discussed the resistance pattern of these isolates, although 19F was shown to be the only serotype associated with resistance. Serotype distribution among the resistant isolates would have been an interesting observation, even though there was no statistically significant correlation between the two. Invasive isolates have not been studied, hence one cannot comment on the invasive disease serotypes. In the absence of data on invasive infection, several reports on colonising pneumococci have reflected on the serotype prevalence and resistance pattern in the children. Clonal diversity, persistence of clones over a period of time and resistant clones among nonvaccine types have all been the subjects of interest. In a classic study spanning over 24 years in Alaska, rising trend of resistance to macrolides (ermB and mef) in vaccine as well as nonvaccine serotypes have been demonstrated in invasive pneumococcal isolates.[7] Mechanism of maintenance of antibiotic resistance among circulating pneumococcal clones, during the period of pneumococcal conjugate vaccination of children in Portugal, has been reported by Simões et al.[3] Serotype diversity and dual macrolide resistance has also been reported from noninvasive isolates of S. pneumoniae[8] With the potential of colonisers becoming invasive, there is a need to understand the intricacies of macrolides resistance mechanisms and mechanisms of other commonly used antibiotics to monitor emerging resistant clones.

 
 ~ References Top

1.
Coffey TJ, Dowson CG, Daniels M, Spratt BG. Genetics and molecular biology of beta-lactam-resistant pneumococci. Microb Drug Resist 1995;1:29-34.  Back to cited text no. 1
    
2.
Gherardi G, Whitney CG, Facklam RR, Beall B. Major related sets of antibiotic-resistant Pneumococci in the United States as determined by pulsed-field gel electrophoresis and pbp1a-pbp2b-pbp2x-dhf restriction profiles. J Infect Dis 2000;181:216-29.  Back to cited text no. 2
    
3.
Simões AS, Pereira L, Nunes S, Brito-Avô A, de Lencastre H, Sá-Leão R. Clonal evolution leading to maintenance of antibiotic resistance rates among colonizing Pneumococci in the PCV7 era in Portugal. J Clin Microbiol 2011;49:2810-7.  Back to cited text no. 3
    
4.
Reinert RR. The antimicrobial resistance profile of Streptococcus pneumonia. Eur Soc Clin Microbiol Infect Dis ClinMicrobiol and Infect 2009;15 Suppl 3:7-11.  Back to cited text no. 4
    
5.
Del Grosso M, Iannelli F, Messina C, Santagati M, Petrosillo N, Stefani S, et al. Macrolide efflux genes mef(A) and mef(E) are carried by different genetic elements in Streptococcus pneumonia e. J Clin Microbiol 2002;40:774-8.  Back to cited text no. 5
    
6.
Farrell DJ, Jenkins SG, Brown SD, Patel M, Lavin BS, Klugman KP. Emergence and spread of Streptococcus pneumoniae with erm(B) and mef(A) resistance. Emerg Infect Dis 2005;11:851-8.  Back to cited text no. 6
    
7.
Rudolph K, Bulkow L, Bruce M, Zulz T, Reasonover A, Harker-Jones M, et al. Molecular resistance mechanisms of macrolide-resistant invasive Streptococcus pneumoniae isolates from Alaska, 1986 to 2010. Antimicrob Agents Chemother 2013;57:5415-22.  Back to cited text no. 7
    
8.
Mayanskiy N, Alyabieva N, Ponomarenko O, Lazareva A, Katosova L, Ivanenko A, et al. Serotypes and antibiotic resistance of non-invasive Streptococcus pneumoniae circulating in pediatric hospitals in Moscow, Russia. Int J Infect Dis 2014;20:58-62.  Back to cited text no. 8
    




 

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