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Aminoglycosides) – Inhibition of Transpeptidation (Chloramphenicol) – Inhibition of Trna Translocation (Erythromycin) Resistance

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Aminoglycosides) – Inhibition of Transpeptidation (Chloramphenicol) – Inhibition of Trna Translocation (Erythromycin) Resistance Antibiotics Antibiotics – mode of action • Interference with of bacterial wall synthesis - (betalactams, glycopeptides) • Interference with DNA synthesis - (gyrase inhibitors) • Antimetabolites - (sulfonamides, trimethoprim) • Interference with proteosynthesis on various levels – prevention of tRNA link (tetracycline) – mRNA reading failure (aminoglycosides) – Inhibition of transpeptidation (chloramphenicol) – Inhibition of tRNA translocation (erythromycin) Resistance • Natural (target structure not present) • Acquired – Chromosomal - mutations - rare – Extra chromosomal - plasmids - frequent • plasmids – segments of DNA with ability of independent replication carrying gens coding resistence – Transfer – conjugation of bacteria - plasmids – Transduction by means of fags – Transposes - plasmid/plasmid, plasmid/chromosome and vice versa – Transformation - DNA Antibiotics - biochemical mechanisms of resistance • Production of inactivating enzymes – betalactamases - (penicillins, cefalosporins) – acetyltransferases - (chloramphenicol) – kinases - (aminoglycosides) – methylases - (tetracyclines) • Alteration of binding site - (betalactams, macrolides, aminoglycosides) • Reduction of antibiotic uptake - (tetracyclines) • Alteration of dihydrofolat reductase - (sulfonamides) • Efflux pumps - (more groups of antibiotics) • Change in bacterial wall permeability - (betalactams) Bacterial wall: G+ bacteria Bacterial wall: G- bacteria Penetration of IV. generation cephalosporins accross bacterial wall in G- bacteria Penetration of antibiotics across bacterial wall in G- bacteria Hypothetic structure of efflux pump Beta-lactams Od objevu penicilinu k širokospektrým b-laktamům 1944 první b-laktamázy 1941 začátek používání penicilinu 1929 objev penicilinu A. Fleming, W. Florey, E. B. Chain – 1945 Nobelova Cena za Fyziologii a medicínu Za objev penicilinu a jeho léčivého účinku na různé infekční choroby Od objevu penicilinu k širokospektrým b-laktamům methicilin 1960 ampicilin 1961 kloxacilin 1963 karbenicilin 1967 pivampicilin 1970 ... 1960 semisyntetické peniciliny 1957 6-APA 1948 penicilin V 1947 penicilin G Od objevu penicilinu k širokospektrým b-laktamům 1981 amoxicilinklavulanát 1977 kyselina klavulanová 1973 amoxicilin Pharmacokinetics of penicillins Penicillin Clearance t1/2 VD Protein binding (%) (l/h) (h) (l/kg) Benzathinpenicillin 30,0 0,5 0,5 80 Benzylpenicillin 30,0 1,0 0,3 65 Amoxycillin 25,0 1,2 0,4 18 Ampicillin 13,0 1,0 0,4 18 Oxacillin 27,0 0,6 0,4 94 Azlocillin 9,0 1,0 0,2 30 Piperacillin 10,0 1,0 0,2 50 Tikarcillin 9,0 1,2 0,2 60 Division of cephalosporins according to pharmacokinetic properties (examples) Antibacterial Standard pk Nonstandard PK Metabolic spectrum instability G+ Cefazolin Cefradin Cefalotin (p.o., i.v., i.m.) (deacetyl) G(+)/- Cefuroxim Ceftriaxon Cefotaxim (t0,5, bile) (deacetyl) G- Ceftazidim Cefoperazon / (bile) anaerobes cefoxitin Cefotetan / (t0,5) Absorption and bioavailability (F) of esterified cephalosporins Influence of food intake on absorption of esterified cephalosorins mg/l After food No food h Beta-lactam distribution and volume of distribution TBF 100% ICF ECF 80 % 20 % intravascular compartment extravascuar compartment interstitium connective tissue GIT Plasma, intersticium and muscle concentration of ceftazidim (25 mg/kg i.v.) mg/l * mg/kg min Drug concentration – fast transport between vascular and extra vascular space Drug concentration – slow transport between vascular and extra vascular space Penetration of cephalosorins across hematoencephalic barrier in meningitis (% of serum concentration) cephalosporin penetration into CSF ceftriaxon 5 - 15 cefotaxim 15 - 30 ceftazidim 20 - 40 cefuroxim 18 - 35 Penetration above 10% is clinically sufficient Drug concentration – transport accross blood-brain barrier Bile excretion of penicilins (without obstruction) Concentration ratio Penicilin bile / plasm penicilin-G 0,5 Ampicilin 1,0 - 2,0 Karbenicilin 0,5 - 0,8 Methicilin 0,2 - 0,5 Mezlocilin 10,0 Nafcilin 40,0 Oxacilin 0,2 - 0,4 Dikloxacilin 0,05 - 0,08 Piperacilin 10,0 -15,0 Penetration above 0,5 (50%) is clinically sufficient Bile excretion of cephalosporins (without obstruction) Concentration ratio bile: plasm Penetration above 0,5 (50%) is clinically sufficient Elimination half life (t0,5) and dosage interval in parenteral cephalosporins 1 x d 2 x d 3 x d hh Elimination half life (t0,5) and dosage interval in parenteral cephalosporins 2 x d 3 x d 4 x d h Elimination half life (t0,5) and dosage interval in oral cephalosporins 3 x d 2 x d 1 x d h Relationship between t0,5 and GFR in cephalosporins (example ceftazidim) t0,5b (h) GFR (ml/min) Macrolides RNA polymerase Rifampicin mRNA Subunit 30S Tetracyklins, glycylcyklins 30S iniciating complex Subunit 50S Aminoglycosides 70S iniciating complex Peptidyl transferase Chloramphenicol Creation of peptidic link Makrolides, clindamycin Peptide elongation Site of proteosyntetic inhibition on ribosome Pharmacokinetics of erythromyci and its esters after single p.o. dose (expressed as erythromycine basis) Erythromycin D (mg) Cmax Tmax (h) t0,5 (h) AUC (mg x h/l) (mg/l) Basis 500 2,00 3,7 2,0 7,7 Stearat 500 2,43 1,8 1,9 8,8 Ethylsukcinat 500 1,19 1,1 1,7 4,5 Acistrat 400 2,23 2,6 3,0 12,3 Plasma and tissue concentration of azithromycin risk of resistance Influence of renal and liver function and age on macrolide PK Serious renal Serious liver Age failure failure erythromycin ? 0 ? klarithromycin ++ 0 + roxithromycin ++ ++ ++ azithromycin 0 - 0 0 no clinical changes - data not available, probably no changes + data not available, probably elevated plasma levels ++ significantly elevated plasma levels, elavated Cmax, AUC and extended t05, ? not reliable results Interaction of macrolides according to clinical significance Teofylin Karbamazepin Ciklosporin Terfenadin Warfarin Ergotamin Methyl- prednisolon Erythromycin ++ ++ ++ ++ ++ ++ ++ Klarithromycin + + + ++ n ++ n Roxithromycin + 0 + n 0 n n Azithromycin 0 0 n 0 0 n 0 ++ clinically significant + influence on PK with potential clinical consequences 0 – interactions not observed n – data not available Macrolide (=drug A) interaction with other drugs metabolised by cytochrome P 450 drugB Resulting interaction (A+B) Teofylin Serum concentration increase (B) ciklosporin, takrolimus, sirolimus (Enzyme inhibition) Digoxin Astemizol, terfenadin, loratadin Námelové alkaloidy Kortikosteroidy Cisaprid Midazolam, triazolam Diltiazem, verapamil Ethynil estradiol, destoden Itrakonazol, mikonazol, ketokonazol, flukonazol Fluoxetin, paroxetin, sertalin Warfarin indinavir, ritonavir Serum concentration increase (both A and B) fenytoin, fenobarbital, karbamazepin Omeprazol rifabutin, rifampicin Zidovudin Serum concentration decrease (B) (Enzyme induction) Cytochrome P 450 and macrolides Enzym Inhibitor Induktor CYP1A2 macrolides – erythromycin, troleandomycin, Omeprazol klarithromycin, roxitromycin, diritromycin Antiepileptika – fenytoin, chinolones – but not all chinolones [Andriole] fenobarbital, karbamazepin estrogeny – ethynilestradiol ethanol CYP3A4 makrolides – erythromycin, troleandomycin, rifampicin klarithromycin, roxitromycin, diritromycin antiepileptika – fenytoin, chinolony – but not all chinolones [Andriole] fenobarbital, karbamazepin imidazoly – ketokonazol, itrakonazol, flukonazol, troglytazon antidepresiva – SSRI (fluoxetin, paroxetin, sertalin and others), grapefruit juice Seriousness of patients condition and clinical perception of resistance kritický Telithromycin • Macrolide of the ketolide group • Mode of action, AE profile and interactions (CYP 3A4 a CYP 2P6) – same as other macrolides Postantibiotic effect (PAE) in selected makrolides – Staphylococcus aureus Macrolid Concentration Testing dose PAE (h) (exposure 2 h) mg/l erythromycin 0,50 4 – 5 x MIC 3,1 klarithromycin 0,25 4 – 5 x MIC 2,9 azithromycin 0,50 4 – 5 x MIC 2,5 Mechanism of resistance S. pyogenes and S. pneumoniae to macrolides • erm gens (production of methylase rRNA, postranslation methylation 23S rRNA) • Constitutive resistance (erm gens - chromosomal) – MLSB resistance (macrolides, lincosamides, streptogramin B) • Inducibile resistance (erm gens - plazmids) – Resistance to macrolides - 14 and 15 membered lactone ring, low resistance to 16 membered lactone ring macrolides and lincosamides • mefA gen (eflux of antibiotic) • Resistance to 14 and 15-membered lactone ring macrolides - M fenotyp End of part 1 Tetracyclins RNA polymerase Rifampicin mRNA Subunit 30S Tetracyklins, glycylcyklins 30S iniciating complex Subunit 50S Aminoglycosides 70S iniciating complex Peptidyl transferase Chloramphenicol Creation of peptidic link Makrolides, clindamycin Peptide elongation Site of proteosyntetic inhibition on ribozome Tetracyclins - characteristics • Broad spectrum bakteriostatic antibiotics introduced in1949 oxyteracyclin (I. generation), doxycyclin since1967 (II. genaration) • Mode of action - proteosyntetic inhibitors in bacteial cell • Many bacteria straine resistent – result of frequent use Tetracyclins - mode of action • Tetracyclins inhibit tRNA-aminoacids complex link on 30s bacterial ribosome subunit • Tetracyclins prevent the link aminoacyl-tRNA on acceptor site of the mRNA complex with ribosome Tetracyclins - resistance • Plasmid resistance • Gen for tetracycline resistance is close to gen coding resistance to aminoglycosides, sulfonamides a chloramphenicol • Cross resistance with this ATBs frequent Tetracyclins - mechanism of resistance • Decrease of accumulation or decrease of influx resp. increase of efflux • Limited
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