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Sungkyunkwan University School of Medicine
Macrolides, Clindamycin & KetolidesMacrolides, Clindamycin & KetolidesPolymyxinsPolymyxins
Kwan Soo Ko
Sungkyunkwan University School of Medicine
Macrolides- Erythromycin- Azithromycin- Clarithromycin
Unrelated chemicallyBut, many similar biological properties
Lincosamides- Lincomycin - Clindamycin
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Macrolides
14-membered 15-membered
Erythromycin Clarithromycin Azithromycin
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Erythromycin- in 1952- from a strain of Saccharopolyspora erythra
(Streptomyces erythreus) (soil from the Philippines)
- Active component, erythromycin A
14-member macrocyclic lactone ring,attached to two sugar moieties
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Erythromycin
Inhibits RNA-dependent protein synthesis at the step of chain elongation
Several functional groups binds to sequenceson domain V of 23S rRNA
(a component of 50S subunit of ribosome)
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Binding site near peptidyltrasnferase center
Prevention of peptide chain elongation by blocking of polypeptide exit tunnel
Dissociation of peptidyl-tRNA from ribosome
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Studies of E. coli and S. aureus
Erythromycin also inhibits formation of 50S ribosomal subunit
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Erythromycin resistance
Decreased microbial entry or increased export of drug
Target site alterations
Drug inactivation
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Cytoplasm
Ribosomes5030
5030
5030
Target site alterationby erm
Macrolide
Efflux by mef
Weisblum B. In: Gram-Positive Pathogens. 2000:694-710.Hyde TB et al. JAMA. 2001;286:1857-1862.
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Intrinsic decreased permeabilityof outer membrane to macrolides
- Enterobacteriaceae- Pseudomonas spp.- Acinetobacter spp.
- Cell-free systems and protoplasts of organisms are susceptible to macrolides
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Chromosomally encoded efflux pumps
- By proton active force or by hydrolysis of ATP- in S. epidermidis and S. aureus,
plasmid-mediated erythromycin resistance (MLSBphenotype) by active efflux encoded by msrA gene
- in S. pyogenes, S. pneumoniae & enterococci,M phenotype (14- and 15-member macrolides, but not 16-member macrolides, lincosamides, and streptogramin B): encoded by mefA gene
- Low-level resistance
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Target site alterations
- Mutations in genes for 50S ribosomal proteins or bases or critical domains of the 23S rRNA receptor site
- Be associated with a decreased binding affinity - High-level resistance- In some strains of S. pneumoniae, H. pylori, M. avium,
B. subtilis, S. pyogenes, Campylobacter spp., M. pneumoniae, E. coli & S. aureus
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Alterations in the 23S rRNA of the 50S ribosomal subunitby dimethylation of adenine at a defined position(A2058 residue of domain V)
- be associated with resistance to erythromycin and most other macrolides (M), and sometimes to the lincosamides (lincomycin & clindamycin)(L), and streptogramin B (SB)→ MLSB phenotype
- be mediated by the erm(erythromycin ribosome methylation)
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Drug inactivation
- By phosphotransferasesIn strains of S. aureus, E. coli & Nocardia spp.mphA, mphB & mphC
- By esterase genes (ereA & ereB) on plasmidsHydrolysis of macrocyclic lactone of erythromycinIn strains of E. coli, Klebsiella spp., Citrobacter spp., Proteus spp. & Enterobacter spp.
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Azithromycin & Clarithromycin
To improve the qualities of erythromycin- better oral absorption, a longer half-life, fewer
gastrointestinal side effect & a greater antimicrobial spectrum of activity
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Erythromycin
Azithromycin
methyl-substituted nitrogen
Clarithromycin
methoxy group
→ increase of stability in gastric acid, improving absorption by oral route
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Azithromycin, clarithromycin & erythromycin- bind to the same receptor on 50S ribosomal subunit
& inhibit RNA-dependent protein synthesis by the same mechanism
Azithromycin (15-member macrolides)- greater activity than the 14-member macrolides
against gram-negative bacteria (especially for M. catarrhalis and H. influenzae)due to better penetration the outer envelope
Resistance mechanisms to azithromycin & clarithromycin
- the same as or similar to those for erythromycin
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Ketolides
New class of semisynthetic agents derived from erythromycin
Increased acid stabilityIncreased antibacterial potency against many bacteria
resistant to macrolidesUnability to induce the MLSB phenotype
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Telithromycin
Be approved for clinical usein the US in April 2004in Europe in 2001
Serious and fatal hepatotoxicity in 2006
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Action mechanism essentially similar to that of erythromycin
By interacting closely to peptidyl transferase site of 50S ribosomal subunit
& by interfering with the formation of 50S ribosomal subunit
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Different nature of their interaction with the ribosome between telithromycin and erythromycin
Higher binding affinity of telithromycindue to the dual interaction with domains V and II of 23S rRNA
Direct interference with elongation polypeptide chain+
Inhibition of formation of the 50S ribosomal subunitInhibition of the 30S ribosomal subunit (at higher conc.)
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Uncommon resistance to telithromycin
- Poor inducer or poor substrate for bacterial strains expressing efflux mechanisms of resistance
- Poor inducer of the MLSB methylase genes; potent against S. pneumoniae isoaltes with the consitutive erm gene
Rare bacterial strains with increased MICs to telithromycin- by mutations in the bases of 23S rRNA of the 50S
ribosomal subunit or in ribosomal proteins- most, laboratory isolates
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Lincomycin
In 1962, From Streptomyces lincolnensis(soil near Lincoln, Nebraska)
Biological properties similar to those of erythromycin, but chemically unrelated(an amino acid linked to an amino sugar)
Chemical modification
Clindamycin
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Clindamycin
Increased antibacterial potency & absorption after oral administration
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The same or overlapping 50S ribosomal binding sites - as those for macrolides and chloramphenicol
Inhibition of protein synthesis in early chain elongationby interference with the transpeptidation reaction, possibly through blockade of the P site
Also stimulate the dissocation of peptidyl-tRNA from ribosomes (like macrolides)
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Resistance mechanisms
Alteration in the 23S rRNA of 50S ribosomal subunitby methylation of adenine (as in macrolides)
- usually plasmid-mediated - MLSB type of resistance
- In S. aureus, macrolide-inducible varietyby positive erythromycin-clindamycin “D-test”
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Exposure to clindamycin in vitro or in vivo may result in clindamycin resistance due to selection of preexisting constitutive erm mutants, especially if the organism is at high innoculum
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Resistance mechanisms
Mutations in the bacterial rRNA - in some strains of Mycobacterium smegmatis
Alteration in particular 50S ribosomal proteins of the receptor site (as in macrolides)
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Resistance mechanisms
Inactivation of lincomycin and clindamycin- by a few isolates staphylococci and Bacteroides spp.- plasmid-mediated 3-lincomycin 4-clindamycin 0-
nucleotidyltransferase- catalyze the nucleotidylation of the hydroxyl group in
position 4 of clindamycin
Enterobacteriaceae, Pseudomonas & Acinetobacter- intrisically resistance to clindamycin- due to poor permeability of the cellular outer envelop
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Polymyxins
Polymyxin B & polymyxin E (colistin)
Old drug, discovered in 1947 (Bacillus polymyxa)Colistin became available for clinical use in the 1960s
but has been abandoned sine 1970s because of neurotoxicity and nephrotoxicity
Re-introduction because of remarkable increase in resistance to antimicrobial agents currently available
- Polymyxins are sometimes the only available active antibiotics
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Action mechanism of colistin
Polycationic and with both hydrophilic and lipophilic moieties
- bactericidal drug binding to LPS and phospholipids in the outer cell membrane of gram-negative bacteria
- competitively displaces divalent cations from the phosphate groups of membrane lipids, leading to disruption of the outer cell membrane, leakage of intracellular contents, and bacterial death
Colistin can bind and neutralize LPS and prevent the pathophysiologic effects of endotoxin
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Colistin Resistance
AntibioticsMIC (mg/L)
% S / R50% 90% Range
Polymyxin B ≤1 2 ≤1 - >8 97.9 / 2.1
Ceftazidime 16 >16 ≤1 - >16 44.6 / 48.3
Cefepime 16 >16 ≤0.12 - >16 47.7 / 37.3
Ampicillin/sulbactam 8 >32 ≤0.25 - >32 56.2 / 31.6
Imipenem 0.5 >8 ≤0.06 - >8 81.1 / 15.8
Meropenem 1 >8 0.016 - >8 77.7 / 17.0
Ciprofloxacin >2 >2 ≤0.016 - >2 44.3 / 55.0
Amikacin 4 >32 ≤0.25 - >32 60.2 / 35.8
SENTRY Data 2001-2004 (Gales et al., 2006)
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Li et al. AAC 50:2946 (2006)Tan et al. AAC 51:3413 (2007)
Extensive emergence of colistin-resistant A. baumannii subpopulations provoked by exposure to colistin
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Colistin resistance
Specific modification of the lipid A component of the outer membrane lipopolysaccharide, resulting in a reduction of the net negative charge of the outer membrane
Proteolytic cleavage of the drug
Activation of a broad-spectrum efflux pump
Two-component signaling systems PmrAB and PhoPQ- be involved in sensing environmental pH, Fe3+, and Mg2+
levels, leading to altered expression of a set of genes involved in lipid A modification