Antimicrobial agents PharmDr. Ondřej Zendulka, Ph.D.

Antimicrobial agents difference antibiotics-chemotherapeutics classification: chem. structure mechanism of action extent of effect antibacterial spectrum

Antimicrobial agents Mechanisms of action: selective toxicity interference with the cell wall block of bact. cell metabolism nucleic acid synthesis inhibition proteosynthesis inhibition

Bacterial cell wall Antimicrobial agents

Bacterial cell wall Antimicrobial agents

Bacterial cell wall Antimicrobial agents

selective toxicity antimicrobial spectrum MIC, MBC, MAC postantibiotic effect resistance Terminology

Mechanisms of resistance: decrease of ATB‘s intracelullar conc. inactivation of ATB modification of ATB‘s target site Antimicrobial agents Resistance = ability of microbial cells to withstand the effect of ATB

absolute relative coupled cross Antimicrobial agents primary secondary

Combinations of ATBs: spectrum widening resistance development restriction decrease in AE incidence increase in effectivity effects: synergistic, additive, indifferent, antagonistic Antimicrobial agents

Which ATB? empirical x bacterial sensitivity pharmacokinetics Antibiotic policy in CR prophylactic administration of ATBs Antimicrobial agents

Antibiotics β-lactams amphenicols tetracyclines macrolides azalides streptogramines ketolides oxazolidinones lincosamides aminoglycosides glycopeptides miscellaneous ATBs local ATBs sulphonamides quinolones imidazoles Antimicrobial agents

β-lactams penicillins cephalosporins cephamycins monobactams carbapenems + inhibitors of β-lactamases

Penicillins MofA: binding to PBP, inhibition of transpeptidases, autolysis => bactericidal

Penicillins produced by Penicillium mould resistance : β-lactamases modification of PBP cell wall penetration block low toxicity, AE hypersensitivity

Narrow spectrum penicillines Benzylpenicillin (Penicillin G) for parenteral use only destroyed by β-lactamases spectrum: Streptococc., Meningococc. and gonococc. crystalic, procain or benzathin salt

Fenoxymethylpenicillin (Penicillin V) for peroral administration Penamecillin ester of penicilline G for peroral use Narrow spectrum penicillines

Penicillines stable against lactamases efective only against Staphylococc. and Streptococc. oxacillin, cloxacillin, flucloxacillin, dicloxacillin 4-6h 0,5-1g p.o. or parent. Narrow spectrum penicillines

Wide spectrum penicillines Aminopenicillins wider spectrum - Haemophilus influenzae lower efficacy against β-hemolytic streptoc. combination with inhibitors of lactamases ampicillin (becampicillin, pivampicillin), amoxycillin

Carboxypenicillins effective against Pseudomonas aeruginosa nonstable in stomach combination with lactamases inhibitors ticarcillin, carbenicillin Wide spectrum penicillines

Ureidopenicillins widest spectrum, pseudomonades, klebsiellas not stable in acid environment combined with lactamases inhibitors piperacillin, azlocillin, mezlocillin Wide spectrum penicillines

Inhibitors of β-lactamases usually without own antimicrobial properties clavulanic acid, sulbactam, tazobactam coamoxicillin (clavulanic ac.) cotikarcillin (clavulanic ac.) coampicillin (sulbactam) sultamicillin (sulbactam) copiperacillin (tazobactam)

Cephalosporins MofA: the same as in penicillins produced by Cephalosporinum

Spectrum: differs between generations NOT EFFECTIVE: Campylobacter jejuni Legionella pneumophilla Clostridium difficile Enterococcus fecalis mycoplasmas, mycobacterias, chlamydias Cephalosporins

Cephalosporins I. generation high efficacy against G+ (streptoc., staphyloc.) from G- against E. coli, K. pneumoniae, H. influenza partially stable against lactamases crossed resistance with penicillines cefazolin, cefalotin, cefapirin – parenteral cefalexin, cefadroxil - peroral

high efficacy against G+ (streptoc., staphyloc.), enteroc. from G- like I. gen, Shigella, Enterobacter mainly against respeiratory infections cefuroxim, cefamandol – parenteral cefuroxim-axetil, cefaclor, cefprosil, cefpodoxim-proxetil - peroral Cephalosporins II. generation

high efficacy against G+ but lower on staphyloc. G- sensitive including Pseudomonas more resistant to lactamases than I. And II. gen. cefotaxim, ceftriaxon, cefmenoxim, ceftazidim, cefoperazon, cocefoperazon, cefsulodin – parenteral cefixim, ceftibuten, cefetamet-pivoxil - peroral Cephalosporins III. generation

wide spectrum, high efficacy serious infections cefpirom, cefepim Cephamycins good results against anaerobes cefoxitin Cephalosporins IV. generation

Monobactams bactericidal G- aerobes β-lactamases resistant aztreonam, carumonam wide spectrum imipenem, meropenem Carbapenems

Amphenicols Mof A.: proteosynthesis inhibition – 50S subunit Spectrum: majority of G + i G -, anaerobes, ricketsias, chlamydias, mycoplasmas per os or parenterally interferention with metabolism of other drugs reversible or irreversible myelosuppresion, contraindicated in newborns chloramphenicol, thiamphenicol

Tetracyclines M ofA : proteosynthesis inhibition- 30S subunit Spe c trum: most of G + i G -, chlamydi as, my c opla s ma s parenterally or per os crossed resistance deposition into bones and cartilages = discoloration, contraindicated in pregnant women and childrens (to 8 yrs) doxycy c lin e, minocy c lin e

Macrolides MofA: proteosynthesis inhibition, 50S subunit Spectrum: majority of G + i G -, chlamydias, mycoplasmas bacteriostatic eff. alternative for penicillines crossed resistance GIT intoleration, metabolism via CYP 450 3A erythromycin, spiramycin, josamycin, roxithromycin, clarithromycin, dirithromycin

Azalides MofA: like macrolides Spectrum: like erytromycin bacteriostatic eff. resistance crossed with erythromycin GIT intolerance, metabolization via CYP 450A3 azithromycin

ATBs related to macrolides Streptogramins quinupristin, dalfopristin parenterally, multiresistant G+ cocci Ketolides telithromycin does not inhibit CYP450 Oxazolidinones linezolid against resistant strains

Lincosamides MofA.: proteosynthesis inhibition – 50S subunit Spectrum: G+ cocc. and bacill., G- cocc. AE: GIT, pseudomembraneous colitis clindamycin, lincomycin

Aminoglycosides MofA: proteosynthesis inhibition, binding to different ribosomal sites Spectrum: G -, staphylococcus, brucellias slow developing resistance only parenterally postantibiotic effect nephro-, oto-, neurotoxicity streptomycin, sisomicin, tobramycin, netilmicin, amikacin, isepamicin

Glycopeptides Mof A: inhibition of cell wall synthesis Spectrum: only G + slow developing resistance not absorbed from GIT nephro-, ototoxicity, release of histamine vancomycin, teicoplanin

Miscellaneous ATBs Fusidic acid MofA: inhibition of cell waal proteins synthesis Spectrum: penicillin resistant staphyloc. fast resistance => combinations Rifampicin MofA.: inhibition of bacterial DNA-dependent RNA-polymerases Spectrum: Staphylococc., Haemophilus, neisserias, mycoplasmas colours urine and salivas, induces CYP450

Rifaximin rifampicin derivative Phosphomycin MofA.: inhibition of peptidoglycane synthesis Spectrum: Staphylococc. and Enterococc. synergistic with cephalosporines and aminoglycosides Miscellaneous ATBs

Polymyxin B, colistin (polymixin E) polypeptides high system toxicity => locally nephrotoxicity, neurotoxicity Spectinomycin MofA.: proteosynthesis inhibition Spectrum: Neiseria gonorrhoae therapy of gonorrhea Miscellaneous ATBs

ATBs for local use Neomycin aminoglycoside in combination with bacitracin (Framykoin) Bacitracin polypeptide low resistance and allergy Mupirocin inhibition of proteosynthesis skin infections therapy

Chemotherapeutics Sulphonamides Trimethoprim Quinolones Metronidazole Nitrofurantoin

Sulphonamides one of the oldest basic structure – sulfanilamide small therapeutic importance MofA: competitive inhibition of bacterial cell metabolism on the level of folic acid bacteriostatic effect spectrum: streptococcus, haemophillus, nocardia, actinomycets, chlamydia, Toxoplasma gondi, Neisseria meningitidis today – therapy of urinary tract infections and in the combination with trimethoprim

strong binding to plasmatic proteins = drug interactions AE: skin – phototoxicity, Stevens-John‘s syndrome; myelotoxicity; haemolytic anaemia; allergic reaction; crystalluria Sulphonamides

Sulfisoxazole short acting, fast absorption and elimination protein binding up to 92% urinary infections Sulfathiazole for topicall administration Sulfamethoxazole in combination with trimethoprim - cotrimoxazole protein binding 70% Sulfasalazine poor absorption from GIT = local effect in the intestine, ulcerative colitis Sulphonamides

Trimethoprim blocks dihydrofolate reductase (50 000x more selective to bacterial enzyme) synergistic effect with sulphonamides high levels in prostate and vaginal mucus (lower pH) CYP metabolism urine (low pH = faster elimination) combination: trimethoprim a sulfamethoxazole = co-trimoxazole 1:5: Triprim, Biseptol Kotrimoxazol, Sumetrolin I: respiratory infections, prevention and therapy of pneumonia, urinary infections

Quinolones MofA: inhibition of DNA gyrase - nucleic acid synthesis inhibition (topoisomerase II) bactericidal spectrum: older molecules mainly G-; modern drugs wide spectrum

high F after p.o. administration, good distribution except CNS, excreted into urine AE: 2-8% nemocných GIT problems, – cephalgia, sleeping disorders – skin symptoms – risk of tendons rupture I: urinary tract infections – prostatitits – bone and joint infections – skin infections – prophylaxis in neutropenic patients CI: children, breastfeeding, pregnancy Quinolones

Quinolones for the therapy of urinary infections poor tissue distribution, excreted unchanged oxoline and nalidixic acid norfloxacine – partial systemic effect, therapy of gonorrhea high rate of mild adverse effects (GIT) Quinolones

Quinolones for therapy of systemic infections- Fluoroquinolones ciprofloxacin, ofloxacin, lomefloxacin, pefloxacin…. good tissue distribution therapy of respiratory, skin, GIT and other severe infections sparfloxacin, trovafloxacin, rufloxacin, grepafloxacin bile elimination life-threatening infections caused by multiresistant strains AE: often, mild, GIT, artralgia, cartilage disruption Quinolones

Imidazoles MofA: inhibition of DNA replication spectrum: anaerobes and protozoa : Bacteroides, Clostrididum, Giardia Metronidazole metabolized in liver and excreted into urine AE: metallic taste – nausea, vommiting, diarrhoea – CNS (cephalgia, sleping disorders, depression) – disulfiram reaction Ornidazole Tinidazole – antiparasitic agent

Others Nitrofurantoin MofA: interferes with bacterial DNA spectrum: E.coli, Klebsiella, Enterobacter, enterococci, staphylococci administered orally effective levels in urine, alkaline pH decreases the efficacy AE: often – GIT irritation, polyneuropathy, myelotoxicity, chronic hepatitis, pulmonary disorders I: therapy and prophylaxy of urinary tract infections Furantoin, Nitrofurantoin