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Chemotherapy of bacterial infections. Part II. Antibiotics – after-effects: the increrase of drug resistance changeability of etiological agents the 40-ties Streptococcus pyogenes the 70-ties isoxasolyl penicillins the 80-ties III gen. cefalosp. )rods. Staphylococcus aureus Staphylococcus aureus Gram(-) rods resistant Gram (MRSA, MRCNS PRSP Enterococcus Candida Origin of drug resistance: intrinsic - inherent, natural acquired • nongenetic - lack of active replication - loss of the specific target structure (L-forms) - infection ocurring at sites where antimicrobials are excluded or not active • genetic - chromosomal resistance: mutation resistant mutants selection o stable o allow vertical transmission of resistance only (descending) o allow no horizontal transmission: not transferable from one bacterium to another o these genes cause intrinsic resistance - extrachromosomal resistance plasmids: o unstable in absence of antibiotic o transferable between bacteria of different species o these genes often cause acquired resistance transposons: genes capable of "jumping" from a chromosome to a plasmid found on either chromosomes or plasmids extrachromosomal resistance - transduction (phages) - transformation (naked DNA) - conjugation (sex pili) Phenotypic expression of resistance: - enzymatic inactivation of antimicrobial agent - target site modification - decreased membrane permeability - alternative metabolic pathway - active efflux (pumping out) 1. Modification of target of activity o PBPs for beta-lactams (MRSA, PRSP) o ribosomes for macrolides o girase for quinolones 2. Efflux phenomenon: bacteria pumps out the antibiotic; Enterobacteriaceae resistance to tetracycline 3. Enzymatic destruction of the antibiotic for beta-lactamases such as ESBL, cephalosporinases, penicillinase 4. No penetration of the antibiotic into the bacteria: impermeability E. faecium - penicillin 5. The cell membrane contains porin proteins which selectively allow molecules to enter the cell; Enterobacteriaceae resistance to macrolides 6. Changed methabolic pathway - sulphonamides constitutive resistance – independent on the presence of antibiotic inducible resistance β-lactamase - mediated resistance penicillinase S. aureus, N. gonorrhoeae o penicillins low-level cephalosporinase act against o penicillins o 1st generation cephalosporins beta-lactam/inhibitor combinations (cephalosporinase is not inhibited by beta-lactam inhibitors such as clavulanic acid, sulbactam, etc) high-level cephalosporinase act against o penicillins o all generation of cephalosporins o beta-lactam/inhibitor combinations (cephalosporinase is not inhibited by beta-lactam inhibitors such as clavulanic acid, sulbactam, etc) ESBL (extended spectrum beta-lactamase) – K. pneumoniae o o o act against all beta-lactams except: carbapenems (eg. imipenem) and cephamycins are not inactivated by ESBL susceptible to β-lactamase inhibitors AmpC beta-lactamases If the organism is sensitive to cefoxitin and is inhibited by beta-lactam inhibitors (clavulin, sulbactam), it has an ESBL. If the organism is resistant to cefoxitin and is not inhibited by beta-lactam inhibitors, it has an ampC gene PBP modification: S. pneumoniae; mosaic pbp genes (different level of β-lactams susceptibility); new, low-affinity PBP: S. aureus (resistant to all β-lactams) Macrolide-LincosamideStreptogramin Resistance • The MLS group: macrolides, lincosamides and streptogramins (A and B); resistance - due to efflux, target modification, drug enzymatic modification. • In staphs, erythromycin resistance is caused by the erm gene coding an enzyme which modifies the ribosome NONE of these antibiotics may bind to the ribosome. If the erm gene product is constitutively produced, testing will find the staph resistant to all of the MLS antibiotics. If the erm gene product is inducibly produced, it will only be expressed when the organism is exposed to a macrolide C14 and C15, but not C16 and ketolides. Acquired Resistance to Aminoglycosides • mainly enzymatic drug modification • KanHC GenHC - HLAR E. faecalis • Intermediate Intermediate Synergy with B-lactam and Kan or Gen • Resistant Resistant No synergy with Blactam and Kan or Gen • Resistant Intermediate No synergy with Blactam and Kan Glycopeptide resistance • GISA, VISA glycopeptide, vancomycin intermediate susceptible Staphylococcus aureus • Enterococci have natural susceptibility to vancomycin, except E. casseliflavus and E. galinarum (natural resistance to vancomycin). vanA vanB vanC vanA confers high level resistance to vancomycin vanB confers moderate level resistance to vancomycin vanC causes intrinsic vancomycin resistance in E. gallinarum and E. casseliflavus • VRE (Vancomycin Resistant Enterococci) refers to E.fecalis or E.faecium, which are normally sensitive to vancomycin. Vancomycin resistance in these organisms is due to the acquisition of vanA or vanB.