Macrolides and Lincosamide-Resistance In

Macrolides and lincosamide- resistance in Streptococcus sp

Waleria© by Hryniewicz author National Medicines Institute, Poland ESCMID Online Lecture Library Macrolides, lincosamides, and streptogramins (MLS) are classified in the same group of antibiotics although they are chemically distinct

• Inhibition of protein synthesis by binding to the 50S ribosomal subunit and blocking peptide bond formation and/or© by authortranslation

ESCMID Online Lecture Library Binding site of MLS antibiotics in ribosome (inhibitionof protein synthesis)

MACROLIDES

14 membered ring 16 membered ring

NATURAL ERYTHROMYCIN A derivatives SEMISYNTHETIC DERIVATIVES NATURAL SEMISYNTHETIC Erythromycin A (1952) DERIVATIVES Saccharopolyspora erythraea Spiramycin Miokamycin S. ambofaciens Substituent alterations Josamycin Sugar alterations S. narbonensis Midecamycin KETOLIDES S. mycarofaciens Roxitromycin © by author Clarithromycin Telithromycin Dirithromycin Aglycone A alterations ESCMID Online Lecture Library 15 MEMBERED RING AZALIDES

Azithromycin Spectrum of activity of macrolides in vitro Active against: Lack or limited activity against:

• Streptococcus group A, B, C, G • S. pneumoniae • Gram-negative rods of Enterobacteriaceae • Staphylococcus sp. (variable depending on species and drug) • C. diphtheriae (including toxinogenic strains) • Gram-negative non-fermenting (CF pts) • L. monocytogenes- bacteriostatic • B. anthracis-bacteriostatic • Atypical bacteria (M. pneumoniae, L. pneumophila, U. urealiticum, Chlamydia sp.) • H.influenzae • M. catarrhalis • Neisseria sp. • Campylobacter jejuni • H. pylori • Mycobacterium avium complex (azithromycin) • Toxoplasma gondii © by author • Gram (+) anaerobes, excluding C. difficile • Gram(-) anaerobes (excluding Bacteroides fragilis and Fusobacterium) ESCMID Online Lecture Library Macrolides – clinical indications Varied efficacy of different compounds

• Upper and Lower Respiratory Tract Infections caused by Streptococcus pneumoniae and Streptococcus β-haemolytic (gr A, C, G) as an alternative to penicillin/ β -lactams in allergic patients • Atypical pneumonia (M. pneumoniae, C. pneumoniae , L. pneumophila) • Exacerbations of COPD© by author • Skin and Soft Tissue Infections caused by S. pyogenes and S. aureus • ESCMIDSTD Online Lecture Library

Macrolides- clinical indications Varied efficacy of different compounds • Pertussis • Diphteria • Clostridium sp. infections except C. difficile • H. pylori eradication (combined therapy) • Conjunctivitis (Gram-positive cocci, C. trachomatis) • Entamoeba histolytica • Toxoplasmosis in ©pregnant by author (Spiramycyna) • Chemoprophylaxis ESCMID Online Lecture Library Ketolides

• They have a 3-keto groups instead of α-L-cladinose at position 3 of erythromycin A • High acid stability • Better drug absorption • Registration includes: mild to moderate community acquired pneumonia caused by S. pneumoniae (PRP), H. influenzae, M. catarrhalis, C. pneumoniae,© by author M. pneumoniae • For patients aged 18 or above • ESCMIDMay evoke severe Online adverse reaction Lecture and should Library be used when no other drugs with better safety profile can be administered Lincosamides

• Lincomycin - natural product of Streptomyces lincolnensis • Clindamycin - semisynthetic 7- chloro- 7-deoxy derivative© by , author clinically superior to clindamycin lincomycin, in many ESCMIDcountries completelyOnline Lecture Library replaced lincomycin Spectrum of clindamycin activity in vitro Active against: No activity against:

• Staphylococcus spp. (also against some • Aerobic Gram (-) species resistant to erythromycin) • Enterococcus sp. • S. pneumoniae • H. influenzae • Streptococcus beta-haemolytic • N. meningitidis • S. viridans group • N. gonorrhoeae • Gram(-) anaerobes, including B. fragilis, • L. monocytogenes Fusobacterium sp., Prevotella sp., • L. pneumophila Porphyromonas sp., G. vaginalis • M. pneumoniae • Gram (+) anaerobes, including C. tetani, C. perfringens,Veillonella sp, Gram(+) • U. urealyticum cocci , P. acnes © by author • Pneumocystis jirovecii • Topxoplasma gondii • Babesia ESCMID Online Lecture Library

Clindamycin – clinical indications, very often as combination therapy or to replace β-lactam when contraindicated

• Infections of lower respiratory tract : - aspiration pneumonia -lung abscess

• Recurrent bacterial tonsillitis • Skin and soft tissue infections, including infections caused by toxin – producing bacteria (S. pyogenes, S. aureus, C. perfringens) • Intraabdominal infections • Human and animal bites • Pelvic inflammatory disease© by author • Osteomyelitis and septic arthtitis( anaerobes) • Babesiosis • Pneumocystis jirovecii pneumonia • ESCMIDToxoplasma encephalitis Online Lecture Library

Streptogramines

• Natural mixtures of cyclic peptides produced by Streptomyces sp • Display synergistic inhibitory effect • Combination of dalfopristin (derivative of pristinamycin) and quinupristin (SYNERCID) • Mostly active against© by Gram author (+) but Enterococcus faecalis resistant ESCMID Online Lecture Library Dalfopristin/quinopristin indications:

• Vancomycin-resistant E. faecium • VC related staphylococcal infections • Skin and soft tissues infections (S. aureus) • Nosocomial pneumonia© by author (S. aureus)

ESCMID Online Lecture Library Resistance mechanisms in Streptococcus sp.(1)

• Target site methylation encoded by the erm gene (methylase) modyfying 23S rRNA (A2058) • Methylation alters the site of attachment such that the macrolide no longer recognizes and binds to the ribosome • Monomethylation confers a high level of resistance (>64mg/L) to lincosamides and streptogramins and a lower level of resistance to macrolides and susceptibility to ketolides © by author • Dimethylation confers high level of resistance to all three ESCMIDclasses of drugs, Online conferring Lecture the MLSB phenotype Library of cross - resistance 1. 1. Leclercq R.: Mechanisms of resistance to macrolides and lincosamides: nature of the resistance elements and their clinical implications, Clin Infect Dis 2002, 34, 482–92. Methylases encoded by: ermA (TR) gene mainly in staphylococci and S.pyogenes ermB (AM) gene in S. pneumoniae and other streptococci

Resistance could© be by inducible author (iMLS B ) or constitutive (cMLSB) ESCMID Online Lecture Library Resistance to all MLS antibiotics Erm genes

E Cli E Cli

cMLSB susceptible © by author MKLSB

ESCMID OnlineE LectureCli Library

iMLSB Resistance mechanisms in Streptococcus sp (2)

Drug efflux due to membrane pumps in streptococci

• Encoded by a mef gene (A or E) located on conjugative transposon • Confers resistance to 14-, 15-membered macrolides (M-©phenotype), by author usually of low level • Susceptibility to lincosamides ESCMID Online Lecture Library

E E Cli Cli © by author

ESCMIDsusceptible Online Lecture M-Library phenotype MIC ery 1-4 mg/l Resistance mechanisms (3)

• Mutations in the genes encoding 23S rRNA and L4 & L22 ribosomal proteins, resulting in a modification of the drug target and loss of drug binding (a rare mechanism, but may occur during therapy)

• Confers resistance to 14-15-16-membered macrolides and© lincosamides by author

ESCMID• Susceptibility Online to streptogramines Lecture and Library ketolides

1. 1. Leclercq R.: Mechanisms of resistance to macrolides and lincosamides: nature of the resistance elements and their clinical implications, Clin Infect Dis 2002, 34, 482–92. How does the resistance to macrolides spread in S. pneumoniae? (1) Pneumococci have a combination of acquired resistance genes, mutations, and mosaic genes, the latter of which carry parts of genes found in the related species.

• Clonal spread, associated with so-called international epidemic clones, often cross-resistant to penicillin and other© by antimicrobials author in S. pneumoniae (e.g. Poland23F-16, Poland6B-20) ESCMID Online Lecture Library

McGee L. et al. J Clin Microbiol, 2001;39:2565,;Hyde TB et al., 2001,JAMA;286:1857; Tait-Konradt A. et al. Antimicrob Ag Chemother,2000;44,2118 Clonal structure of erythromycin-resistant pneumococci in Poland: the importance of international clones

1995-2009 Sadowy E. et al. unpublished How does the resistance to macrolides spread in S. pneumoniae? (2)

• Sporadic resistance acquisition associated with the transfer of resistance genes erm and mef carried on mobile genetic elements

• Development of© resistance by author during therapy through mutation(s) (pneumonia, otitis ESCMIDmedia) Online Lecture Library

McGee L. et al. J Clin Microbiol, 2001;39:2565,;Hyde TB et al., 2001,JAMA;286:1857; Tait-Konradt A. et al. Antimicrob Ag Chemother,2000;44,2118 © by author ESCMID Online Lecture Library

EARSS Consumption of MLS antibiotics, ESAC 2003

dark green < 1.7 DDD Light green < 2.4 DDD yellow < 3.2 DDD czerwony ; >3.2 DDD Gray = no data; © by author biały = not in ESAC ESCMID Online Lecture Library Susceptibility to macrolides of S. pneumoniae isolated in Poland from RTI and IPD, 2010

90 81.3 RTI 80 76 IPD 72 70.8 70 67.8 63.5 58.9 60 60

50 40 © by author 30

20 % izolatów % izolatów wrazliwych ESCMID10 Online Lecture Library bd bd 0 2007 2008 2009 2010 2011 NRL © by author ESCMID Online Lecture Library GAS in Poland

• 1996 -2002 816 isolates– 12% eryR (increase from 1.8% to 25%)

• 5% mefA, 86% ermA (iMLSb i cMLSb), 9% ermB (cMLSb) • 2 major clones,© related by author to emm 44/61 i emm77 ESCMID Online Lecture Library Susceptibilty of S. pyogenes to macrolides, Poland 2009)

Ery-S Ery-I Ery-S Ery-R Ery-R 80% 88%

pharyngitis Invasive infections Data from NRL Distribution of macrolide resistance determinants among S. pyogenes strains in Poland

17 16 15 ermA 14 ermB 13 mefA 12 all 11 10 9 8 7 6

2006 2007 2008 2009 2010 2011

1996-2002 year I. Sitkiewicz et al. unpublished Distribution of emm types among macrolide resistant S. pyogenes strains isolated in Poland (2006-2011)

100%

90% M89;

80% 14,9%

70% M77; 59,5% 60% M28; 57,1% 50%

I. Sitkiewicz et al. unpublished Frequency* of macrolide resistant S. agalactiae among strains isolated in European countries

ESCMID OnlineSPAIN LectureITALY Library POLAND FRANCE NORWAY GERMANY ROMANIA

*Average values for each country from multiple reports 2000-2010 Susceptibility of GBS in Poland

• 114 isolates 1996-2005 • 21 (18%) resistant to erythromycin, mainly from serotype V • 14, 4 and 3 isolates represented fenotypy cMLSb, iMLSb and M phenotypes respectively and harboured © geny by ermB, author ermA and mefA genes ESCMID Online Lecture Library

Sadowy E., unpublished How does the resistance to macrolides spread in S. pyogenes and S. agalactiae ?

• Clonal spread, associated with so-called international epidemic clones (e.g. M/emm1, M/emm28)

• Sporadic resistance acquisition associated with the transfer of resistance© by genes author erm and mef carried on mobile genetic elements often associated with tetracycline resistance ESCMID Online Lecture Library

Lamagni TL et al., Jclin Microbiol,2008;46:2359; Sadowy E. et al.,J Antimicrob Chemother,2010;65:1907 Resistance mechanisms (4)

• In Group B streptococci and S. uberis : modification of the drug - lnu genes active on lincomycin (O-nucleotidyltransferasse) • Lnu genes confer resistance to lincomycin and decreased resistance to clindamycin © by author • Lnu (C) gene is carried by a transposon ESCMID Online Lecture Library

1. 2. Achard A.et al. New lnuC gene conferring resistance to lincomycin by nucleotidylation in Streptococcus agalactiae UCN36 Antimic Ag Chemother 2005;49:2716-19 Conclusions

• Most common mechanisms of resistant are: methylation and efflux • Both prevalence of resistance and its mechanisms differ significantly between countries • Rapidly increasing© by resistant author to ML(S) antibiotics limits therapeutic options ESCMID Online Lecture Library