MUNI MED Antibacterial drugs Department of Pharmacology, 2020 Notes for Pharmacology II practicals This study material is exclusively for students of general medicine and stomatology in Pharmacology II course. It contains only basic notes of discussed topics, which should be completed with more details and actual information during practical courses to make a complete material for test or exam studies. Which means that without your own notes from the lesson this presentation IS NOT SUFFICIENT for proper preparation for neither tests in practicals nor the final exam. Terminology Selective toxicity Antiseptics vs disinfectants Antimicrobial spectrum Post-antibiotic effect MUNI ED Terminology MIC (minimum inhibitory concentration) - the minimum concentration of antibiotic to inhibit the growth of an organism MAC MPC - mutant prevention concentration (e.g. quinolones) MSW - mutant selection window Wild-type population B Time (h) ^Susceptible bacteria I Resistant mutant Emergence and spread of antibiotic resistance following exposure to antibiotics Rafael Canton , Maria-Isabel Morosini FEMS Microbiology Reviews Sep 2011, 35 (5) 977-991; DOI: 10.1111574-6976.2011.00295.x Terminology Resistance to antibiotics • chromosomal determinants • extrachromosomal determinants: genes for resistance to antibiotics („r genes") - R plasmids Drug resistance can be spread: • from person to person by bacteria • from bacterium to bacterium by plasmids • from plasmid to plasmid (or chromosomes) by transposons MUNI MED Mechanisms of resistance to antibiotics Inactivation INACTIVATION * (BY ENZYMES) (p-lactamases, acetylation, adenylation, phosphorylation etc.) DECREASED PERMEABILITY (AMG, peptides, chloramphenicol) Jmpermeability !■ ' E«t- INCREASED EFFLUX (TTC, macrolides) TARGET SITE (trimetoprim) Altered .arget ALTERATION OF TARGET SITE (AMG, erythromycine) Possible combination of mechanisms! MUNI ED Resistance - types 1. Primary (innate) 2. Secondary (acquired) 3. Coupled 4. Crossed MUNI MED Resistance to 3rd. gen of. cephalosporines III. in Klebsiella pneumoniae 2005 2015 European Centre for Disease Prevention and Control, EARS-Net https://ecdc.europa.eu/en/antimicrobial-resistance/surveillance-and-disease-data/data-ecdc MUNI ED Terminology Pharmacodynamic index Definition Effect Examples T>MIC Once the concentration of an antibiotic is above the MIC (typically 3-5 times greater than the MIC), there is not an increased rate of killing with increasing concentrations of antibiotic Time dependent beta-lactams Cmax/MIC As the concentration of an antibiotic increases, its rate of killing increases Concentration dependent aminoglycosides AUC 0-24/MIC The rate of bacterial killing is both related to the amount of time above the MIC and the total exposure of antibiotic to the organism AUC dependent glycopeptides Time-dependent bactericidal effect Leipzig 2009 Concentration dependent effect Cmax/ MIC AUC dependent killing AUC/MIC Time MIC AUC Dose 1 Clearance MIC MIC90 PD 11 CLASSIFICATION 1. Chemical structure betalactams, glycopeptides, macrolides, amphenicols etc. 2. Microbial spectrum wide spectrum narrow spectrum 3. Extent of the effect bacteriostatic Bactericidal 4. Mode of the action interfering with: cell wall plasma membrane inhibiting: proteosynthesis synthesis and metabolism of nucleic acids MUNI ED Peptldoglycan cell wall ^ Plasma — membrane iill 1 iitiii AAA |A| 1 SI II i 1 ifi !!! IS 11 Ill 1 III Outer membrane Inner membrane Cytoplasm Gram-positive bacteria Membrane Phospholipid protein Gram-negative bacteria MUNI MED http://simbac.qatech.edu/wordpress/wp-content/uploads/2013/04/cellwall- Modes of the action 1. Inhibition of cell wall synthesis: penicillins, cephalosporins, bacitracin, vancomycin 2. Inhibition of protein synthesis: chloramphenicol, erythromycin, tetracyclines, streptomycin arget sites Cell wall -G+ -G- Plasma membrane 4. Injury to plasma membrane: polymyxin B 5. Inhibition of synthesis of essential metabolites: sulfanilamide, trimethoprim Ribosomes Nucleic acids Ca^rigrteUIOtorHnEducation, i™ a) bacterial topoisomerase inhibition b) nucleotide synthesis inhibition - folic acid Key Concept Antimicrobial drugs function in one of the following five ways: inhibiting cell wall synthesis, inhibiting protein synthesis, inhibiting nucleic acid synthesis, injuring the plasma membrane, or inhibiting synthesis of essential metabolites. https://classconnection.s3.amazonaws.com/902/flashcards/2365902/pna/modes1355087607726.png MUNI ED Classification of antibacterial drugs Antibiotics I ß-lactams glycopeptides polypeptides amphenicols • tetracyclines • macrolides • ATB related macrolides lincosamides aminoglycosides other ATBs Antibiotics II (chemotherapeutics) • sulphonamides • quinolones • pyrimidines • nitroimidazoles nitrofurans ATBs damaging the cell wall or membrane ß-LACTAMS • penicillins • cephalosporins • monobactams • carbapenems - combination with beta lactamase inhibitors J ,lrN-1-CC AanMwa J CH3 COOH ^-Lactamase Penicillin nucleus N H R,-C— ,CH3 O xS03H Monobactam nucleus (^-lactamase resistant) O II H ß-Lactamase COOH CH, Cephalosporin nucleus H3C/W15Q^S-R* COOH Carfaapenem nucleus (high resistance to (^-lactamases) CH—CH,OH I COOH Clavulanic acid (inhibits many (J-lactamases) Rang and Dale; 2012 MUNI ED - g - m - g — CW cross linking Vanco blocks i L-Ala I D-Glu I DAP I D-Ala - I D-A!a D-Ala I DAP I D-Glu I L-Ala I - G - M — G — p-lactams (penicillin, etc.) i L-Ala I D-Glu I DAP-I D-Ala D-Ala I DAP I D-Glu I L-Ala I - M — G ß-lactams MofA: destruction of cell wall, PBP, transpeptidases, autolysis bactericidal effect oral and parenteral administration AE: low toxicity well tolerated allergic reactions p-Lactams prevent the cross-linking peptides from binding to the tetrapeplide side-chains i Fig. 49.2 Schematic diagram of a single layer of peptidoglycan from a bacterial cell (e.g. Staphylococcus aureus), showing the site of action of the ^-lactam antibiotics. In S. aureus, the peptide crossfnks consist of five glycine residues Gram-positive bacteria have several layers of peptidoglycan. (NAG. W-acetytglucosamine; NAMA, W-acstytmurarrnc add; more dotal in Fig. 49.3.) Rang and Dale; 2012 rUDP ^-^/*- (3^"Ccycloser'ne) f IV Glycine (gly) residues Amino acids of the peptide side-chain on muramic acid -UDP UMP G UDP UDP ®-C55 lipid ♦ [mJ-CEK^ lipid (Gfy)5 H-ImHpkp)- C55 lipid lipid CELL MEMBRANE (P>MIC main pharmacodynamic driver of effectiveness -dosing every 6-8h, SR drug forms MUNI MED Time-dependent bactericidal effect Leipzig 2009 Penicillins Narrow spectrum (basic) penicillins: benzylpenicillin (PEN G) • i.v. or i.m. (K+ salt) • procainpenicillin (depot form) Phenoxymethylpenicillin (PEN V) • for oral use (or benzathine-phenoxymethylpenicilin) • respiratory tract infections, skin infections, meningitis (high doses), endocarditis and others evoked by G+ and G- cocci, streptococci, pneumococci,gonococci, meningococci, actinomycosis, anaerobic infections (gas gangrene), syphilis, borreliosis M U l\l I MED Penicillins Anti-staphylococcus penicillins • stable against (3-lactamases • S. aureus and streptococcal infections methicillin oxacillin cloxacillin dicloxacillin flucloxacillin MUNI MED Penicillins Wide spectrum penicillins wider spectrum againts G-: enterobacterias (E.coli, Salmonela spp., Shigella spp., Proteus), Haemophilus spp., Enterococcus spp. Aminopenicillins ampicillin amoxicillin /s. respiratory infections, UTI, otitis media, E.coli, Salmonella spp., Shigella spp., Pseudomonas, Haemophilus spp., Enterococcus spp., Proteus, H. pylori (amoxicilin) With antipseudomonal activity Acylureidopenicillins • piperacillin/tazobactam (i.V.) Carboxypenicillins - tikarcillin - temocillin MUNI ED Potentiated penicillins Combination with ß-lactamase inhibitors clavulanic acid—► co-amoxicillin sulbactam —► i.e. sultamicillin (ampicillin + sulbactam) tazobactam —► i.e. co-piperacillin avibactam (+ ceftazidim) -protection against some types of ß lactamases -wider spectrum against G- (sulbactam) -E. coli, Proteus, Salmonella, Haemophilus, M. catarrhalis, Klebsiella, Neisseria, Enterobacter, Bacteroides -co-amoxicillin - drug of choice in otitis media and sinusitis -ESBL production -) the need of new ß-lactamase inhibitors CEPHALOSPORINS - more stable against (3-lactamases - classified into 5 generations with regard to their spectrum: increasing G-, decreasing G+ sensitivity PK: i.v., i.m., p.o. widely distributed, some cross BBB (cefuroxime, cefotaxime, ceftriaxone) renal excretion (ceftriaxone 40% biliary excretion) AE: allergy often crossed with penicillins (up to 10%) GIT dysmicrobia, changes in the blood counts disulphiram reaction MUNI MED Cephalosporins Ist generation cefazolin Cefadroxil (p.o.) G+ cocci (staphylococci, streptococci) , E. coli, Proteus, Klebsiella, Neisserie other G- are usually resistant (e.g. haemophilus) I: S. aureus infections, prophylaxis in surgery, tonsil pharyngitis, bronchitis, sinusitis, urinary infections IInd generation cefuroxime (cefuroxime axetil p.o.) cefprozil wider spectrum against G+ / G-: H. influ., enterobacterias, Neisseria, Proteus, E. coli, Klebsiella, Moraxella catarrhalis, anaerobes and B. fragilis. I: tonsil pharyngitis, bronchitis, sinusitis, urinary infections, borreliosis ^ " N I Cephalosporins i.v.: ceftriaxon Cefixim cefotaxim ceftazidim cefoperazon (+ sulbaktam) • enterobacterias, partially pseudomonades • more stable against ß-lactamases, higher efficacy (the best for G-) • all i.v. agents cross BBBÜÜ I: meningitis, UTI, respiratory infections, infections of skin, bones, joints; septicemia MUNI MED Cephalosporins IVth: cefepime, i.v. • the widest spectrum • G+ and G- bacterias (no anaerobes) • high stability against (3-lactamases, longer half life I: pneumonia, septicemia, meningitis, intraabdominal infections, febrile neutropenia Vth: ceftolozane, i.v. - MRSA ceftaroline, i.v. - UTI, intaabdominal infections MONOBACTAMS aztreonam (inn., inj.) resistant against ß-lactamases narrow spectrum aerobe G- bacilli (Pseudomonas, Neisseria, Haemophilus) I: Pseudomonas infections in patients with cystic fibrosis CARBAPENEMS meropenem, i.v. imipenem (+ cilastatin), i.v. ertapenem , doripenem, i.v. -reserved for the therapy of life-threatening infections caused by mixed or multiresistant flora AE: allergy, Gl intolerance, convulsions, headache I: pneumonia, UTI, intraabdominal inf., skin and soft tissue inf., meningitis, febrile neutropenia GLYCOPEPTIDES vancomycin, i.v. teicoplanin, i.v. MofA: cell wall synthesis inhibition - binding to pentapeptide precursor; bactericidal resistance, VRE; synergic effect with aminoglycosides TDM - vancomycin PK: i.v. infusion, min. mtb., renal excretion I: reserve ATB for the serious, resistant G+ infections (MRSA) - endocarditis, osteomyelitis, pneumonia; local (p.o.) intestinal infections (not absorbed from gut) AE: rashes (red man syndrome), ototoxicity, nephrotoxicity LIPOPEPTIDES daptomycin - only G+ (MRSA - skin, endocarditis); in combination therapy in G+- MUN1 MED AUC dependent killing AUC/MIC 4- PD WIPHP2009 34 LIPOGLYCOPEPTIDES dalbavancin telavancin oritavancin • similar antimicrobial spectrum with vancomycine, higher activity against G+ • dalbavancin - extremely long plasma half-life (14 days) • perspective therapy (skin infections, OPAT regimen - Outpatient Parenteral Antimicrobial Therapy) MUNI MED POLYPEPTIDES Colistin (colistimethate; polymyxin E), i.V., inh. polymyxin B MofA: disrupts the plasma membrane by its detergent activity I: aerobic, multiresistant G- (Ps. aeruginosa, Haemophilus, Klebsiella) local application (oph., ORL, GYN, gut decontamination, cystic fibrosis) or infusion/injection AE: nephrotoxicity, ototoxicity, neurotoxicity! return to use of Colistin in nosocomial infections ATBs damaging proteosynthesis TETRACYCLINES YyWy OH doxycykline, p.o. tigecycline (glycylcyclin), i.v. - Clostridium difficile therapy! minocycline, tetracycline MofA: proteosynthesis inhibition - reversible binding to 30S ribosomal subunit; bacteriostatic primary resistant staph., strept. + pneumococci! PK: doxycycline absorption p.o., (non-absorbable complexes with cations in GIT), lipophilic, widely distributed, high cone, in bile, enterohepatic recirculation AE: disrupts tooth enamel and bone matrix - interfere with growth —> CI in children and in pregnancy, lactation, phototoxicity, dysmicrobia - GIT disturbances, vaginal dysmicrobia, suprainfection, hepatotoxicity I: respiratory and urinary tract infections, ORL, therapy of biliary tract inf., borreliosis, syphilis, gonorrhea, ureaplasma, leptospirosis, chlamydiosis, mycoplasmosis, acne (minocycline) MUNI MED AMINOGLYCOSIDES ~P< gentamicin, amikacin (i.v.) isepamicin, netilmicin, tobramycin (inh.) kanamycin (oph.), neomycin (oph., drm., vag.) MofA: proteosynthesis inhibition, irreversible binding to 30S ribosomal subunit (bactericidal effect), not in anaerobic bact. post antibiotic effect and concentration-dependent effect PK: parent, (highly polar molecules), not cross BBB, T1/2 2-3hod, renal excretion (>50% unchanged) AE: nephrotoxicity, ototoxicity, tt doses - neurotoxicity I: sepsis, serious uroinfections (pyelonephritis), lower respiratory infections (in combination), orthopedic and surgical infections (postoperative) syst. toxicity (TDM!) - not drugs of choice, comb, therapy ((3-lactams) Concentration dependent effect Cmax/ MIC Administration of aminoglycosides • in combination therapy • in one daily dose • concentration dependent effect+ post antibiotic effect • more daily doses • synergic effect in comb, with ß-lactams (exceptionally glycopeptides) • in bacterial endocarditis caused G+ cocci (enterococci, staphylococci) MUNI MED AMPHENICOLS chloramphenicol, i.v., oph., drm. MofA: protein synthesis inhibition, binds to 50S ribosomal subunit, bacteriostatic, wide spectrum (incl. anaerobic bact.) PK: lipophilic, well absorbed from GIT, widely distributed to tissues and brain, glucuronated in liver, excreted into urine AE: myelosuppression: reversible vs. irreversible (aplastic anemia), grey baby syndrome, neurotoxicity, GIT intolerance, suprainfection I: bacterial meningitis, typhus and paratyphus, serious pneumonia (abscessing forms), anaerobic and mixed flora infections, abdominal and serious invasive haemophilus infections, loc. conjunctivitis MUNI MED Macrolides H3C •clarithromycin, azithromycin •roxithromycin, spiramycin •erythromycin (drm.) MofA: reversible binding to 50S ribosomal subunit, translocation block PK: p.o. admin., CYP3A4 inhibitors (strongest erythromycin, clarithromycin), P-gp inhibitors, Spectrum: G+ G- microbes (mycoplasmas, chlamydia, Campylobacters, Neisseria, Legionellla sp., Toxoplasma gondii, H. pylori) • increase in resistance in streptococci in the last years • crossed resistance - MLSB (macrolide-lincosamide-streptogramin B) phenotype Macrolides • AE: • GIT intolerance - diarrhea, anorexia, nausea, vomiting, cholestatic jaundice • allergies • suprainfections • prolong. QT int. • drug interactions • CYP inhibitors • increase in blood levels of statins, antiepileptic drugs, BZD, antidepressants, monoclonal antibodies, , immunosuppressant drugs (cyclosporine, tacrolimus), warfarin • decrease in effects of Clopidogrel, betalactams, lincosamides U\iU MED Macrolides clarithromycin, i.V., p.o. • both upper and lower respiratory infections, Mycobacterium leprae, otitis media, skin and soft tissues • in combination therapy Helicobacter pylori • not in pregnant women (interference with angiogenesis) • prolongs QT interval • high risk of drug interactions MUNI MED Macrolides azithromycin, p.o. best penetration to most tissues less drug interactions long T1/2 post-antibiotic effect DO NOT use in common infections, tonsillitis etc.. roxithromycin, p.o. safe in pregnant women (with allergy to betalactams) spiramycine, p.o. drug of choice in congenital toxoplasmosis safe in patients treated with theophylline ATB related to macrolides Oxazolidinones linezolid i.v, p.o. • novel MofA (inhibition of proteosynthesis - blocks formation of 70S ribosome) • G+ (MRSA, VRE, nosocomial/community pneumonia, CI. difficile) • non-selective MAO inhibitor - interactions • serotonin syndrome ATB related to macrolides Streptogramins quinupristin dalfopristin G+ (MRSA, VRE) Ketolides telithromycin pneumonia, bronchitis, sinusitis, tonsillitis/pharyngitis in infections resistant to beta lactam and macrolide therapy solithromycin - MRSA, gonococci MUNI ED LINCOSAMIDES clindamycin, p.o., i.v., i.m., loc. MofA: proteosynthesis inhibition - reversible binding to 50S ribosomal subunit PK: p.o. and parent., well penetrates to teeth and bones, placenta, milk, not cross BBB AE: allergy, pseudomembranous colitis -crossed-resistance with macrolide I: respiratory infections, skin and soft tissues infections, osteomyelitis, dental, intraabdominal, gyn., pneumonia, malaria, endocarditis prophylactic use, gynecologic infections (loc), alternative treatment of beta lactams hypersensitivity ^ y ^ MED Antibacterial drugs Antibiotics -1 (3-lactams glycopeptides polypeptides amphenicols tetracyclines • lincosamided makrolides • aminoglycosides makrolides related • ATBs for local ATBs treatment Antibiotics - II (previously called chemotherapy) sulphonamides pyrimidines quinolones nitroimidazoles • nitrofurans • ansamycins MUNI ED Drugs damaging synthesis of NA Sulphonamides Wide-spectrum: G+ and G- bacteria, streptococci, hemophilia, actinomycetes, nocardiosis, Pneumocystis jiroveci, chlamydia, Toxoplasma gondii, Neisseria meningitides ineffective in Pseudomonas, Proteus - resistance !!! Bacteriostatic, in combination - bactericidal MUNI MED Sulphonamides - Mechanism of Action SA PABA structural analogue of PABA competitive inhibitor of the enzyme necessary for folic acid synthesis NH, COOH PABA (metabolit) S02NH2 Sulfonamid (anti metabolit) dihydropteorate synthetase Dihydrofolicacid dihydrofolate reductase Tetrahydrofolic acid (FH4) Purines DNA Sulphonamides Long acting effect (8-10 hours) sulphamethoxazole in combination with trimethoprim (cotrimoxazol, SMZ-TMP) Local use: sulphasalazine microflora metabolizes it to sulphapyridine (SA) and 5-aminosalicylic acid (anti-inflammatory) - inflammatory bowel disease silver salt of sulfadiazine (local skin treatment) sulphacetamide (oph.) MUNI MED Sulphonamides - Pharmacokinetics • parenteral and p.o. administration, local use • good absorption >70% • great penetration into tissues and cells • hepatic metabolism via acetylation and glucuronidation • high binding to plasma proteins - displacement of other drugs and increase of their free fraction • Drug interactions!!! • p.o. anticoagulants, methotrexate, sulphonylureas • penetrate to the placenta and partly HEB • renal excretion MUNI MED Sulphonamides - Adverse Effects GIT disorders Allergic skin reactions - rash (Stevens-Johnson's and Lyell's syndrome), photosensitivity, drug fever (5-10 days after initiation of treatment) even with topical application Hematotoxicity - hematopoietic disorders, bone marrow suppression, anemia, leucopenia, thrombocytopenia Deficiency of folate - megaloblastic anemia Interstitial nephritis - risk of precipitation in the urinary tract - acid pH of the urine (avoid of acidic foods, vitamin C, acetylsalicylic acid ...) ■ ■ gravidity and breastfeeding newborns (until 2 months) with immature enzymatic system (hyperbilirubinemia) jjjjj Jj Sulphamethoxazole with trimethoprim • fixed combination of sulphamethoxazole with trimethoprim (5:1) = cotrimoxazol (p.o., i.v.) • synergistic effect of both substances in the inhibition of folic acid synthesis, reducing the risk of developing resistance, wide antimicrobial spectrum o2s—nh Indications: Treatment of urinary tract infection Treatment of pneumonia caused by Pneumocystis jiroveci (prophylaxis + treatment) H3^ Treatment of exacerbation of chronic bronchitis Treatment of otitis media acuta Treatment of nocardiosis, toxoplasmosis MUNI ED Sulphasalazine anti-inflammatory drug with an immunosuppressive effect derivate of aminosalicylic acid Indication: Treatment of ulcerative colitis, Crohn's disease, rheumatoid arthritis (DMARDs) after p.o. administration 30% of dose is absorbed 70% is degraded by intestinal bacteria in the colon: sulphapyridine inhibits the action of NK cells and transforms lymphocytes AE - nausea, vomiting, abdominal pain, drowsiness, anuria, crystalluria and / or hematuria, convulsions mesalasine (5-aminosalicylic salt) inhibits cyclooxygenase and lipoxygenase in the intestinal wall, thereby preventing the formation of prostaglandins, leukotrienes and other inflammatory mediators MUNI MED Silver salt of sulphadiazine Local use - cream, impregnated bandage Indications: • prophylaxis and treatment of infected skin lesions, wounds, abrasions and burns, leg ulcers and bed sores CI: • preterm infants and infants up to one month of age • pregnant and nursing women Sulphacetamide Local use - eye drops Indications: • Treatment of eye infection and inflammation • Prophylactically after injuries and burns of eye MUNI MED Sulphonamides - Indications • UTI (SMZ-TMP) • respiratory infection (Pneumocystis pneumonia) (SMZ-TMP) • otitis media acuta (SMZ-TMP) • malaria, nocardiosis (sulphadoxine) • Local treatment of eye infection (sulphacetamide) • Local treatment of skin - burns, dekubitus (silver salt of sulphadiazine) • ulcerative colitis, Crohn's disease (sulphasalazine s 5-aminosalicylic acid ) MUNI MED Trimethoprim • bacteriostatic effect, spectrum similar to SA • MA: inhibition of dihydrofolate reductase • AE: nausea, vomiting, rash, megaloblastic anemia, leukopenia, thrombocytopenia - • Leukemia deficiency in predisposed patients (alcoholics) • Significant - combined treatment with SA • Cotrimoxazole - sulphamethoxazole + trimethoprim (5: 1) • synergistic effect, bactericidal, decreased resistance PABA dihydropteoratesyntetase I Dihydrofolic acid 1 dihydrofolatereductase 1 Tetrahydrofolic acid 1 Purine basis i DNA MUNI MED Pyrimethamine Indication treatment and prophylaxis of protozoal infections - toxoplasmosis, malaria, nocardiosis only p.o. Adverse effects GIT disorders - nausea, vomiting hematopoietic disorders exacerbation of the deficiency of folic acid in the body (in alcoholics) convulsions renal toxicity - crystalluria, hepatotoxicity MUNI MED Quinolones • bactericidal drugs • divided into 4 generations according to their pharmacological characteristics and spectrum • quinolons (not fluorinated) and fluoroquinolons (fluorinated derivates) • newer generations - broader spectrum, better distribution in body • parenteral and p.o. administration MUNI MED Quinolones - Pharmacokinetics administration p.o., i.v., oph. after p.o. administration - well absorbed decreased p.o. absorption after co-administration of antacids, Mg2+, Al3+, Fe3+, Zn2+, Ca2+ good penetration into tissues fluoroquinolones are excreted renal way the dosage should be adjusted in renal failure Quinolones - Mechanism of action • selectively inhibit the synthesis of DNA, e.g. enzymatic activity of bacterial DNA gyrase: topoisomerase II (for most G-bacteria) topoisomerase IV (for most G+bacteria) • inhibit DNA transcription that are required for replication, transcription, repair and recombination of bacterial DNA • modern fluoroquinolones have a balanced activity on both enzymes - a broad-spectrum effect • AUC dependent killing • postantibiotic effect • the risk of developing and increasing resistance during treatment MUNI MED AUC dependent killing AUC/MIC Time MIC AUC Dose 1 Clearance MIC MIC90 PD 66 Escherichia coli and Fluoroquinolones 2001 8,1%, 2007 25,4% (EARSS) Orfrfvr RwsqLndon» w»l E coil K±st« in po^K^stna wct« n MUNI MED Quinolones - Indications in general Treatment of infections urogenital system (UTI) Treatment of respiratory infections Treatment of infections skin, bones, joints, soft tissues, gonorrhoea Fluoroquinolones are back-up drugs, indicated only in situations where other antibiotics are inactive in vitro or inappropriate for treatment because of toxicity or side effects. Usually administered in combination with other ATBs MUNI MED Quinolones - Adverse Effects • often, but mild (nausea, vomiting, neurotoxicity, cramps, vertigo, headache) • GIT disorders (5 %) - nausea, vomiting • CNS toxicity (1-4%) - headache, vertigo, spasm, convulsion, depression (elderly patients) • Prolongation of QT interval, malignant arrhythmia • allergy (1-2%), photo toxicity • hepatotoxicity IT - antacids, theophylline, caffeine, warfarin, cyclosporine tendinitis/tendinopathy, rupture of Achilles tendon arthropathy in animal models (in children with cartilage damage not shown except for arthralgia (1.3%) in patients with CF) Kl: newborns and children (inhibition of bone cartilage growth), 1. trimester of pregnancy, breastfeeding epilepsy MUNI MED Quinolones - generations Generation Drug Indication i. nalidixic acid, oxolinic acid Drugs with limited effect on G- (urinary ATBs) II. norfloxacine ofloxacine Treatment of UTI Ciprofloxacine Treatment of respiratory, UTI, GIT infections, bones, joints, soft tissue, skin infections enterobacteria, P. aeruginosa, neisseria, haemophilus, legionella, Neisseria meningitidis, Anthrax levofloxacine Drugs with higher activity on G + (pneumococcus), respiratory ATB in. sparfloxacine, gatifloxacine, tosufloxacine, pazufloxacine Drugs more effective against G+ (pneumococcus), respiratory ATBs IV. trovafloxacine, gemifloxacine, sitafioxacine, moxifloxacine Drugs more effective against anaerobes, same spectrum as III. generation of cephalosporines MUNI MED Nitroimidazoles primarily bactericidal effects on anaerobes and protozoa Mechanism of action: inhibition of DNA replication Indications: • treatment of peptic ulcers - Helicobacter pylori eradication • in combination with other antibiotics - peritonitis • amoebic dysentery - intestinal disease • trichomoniasis - caused by Trichomonas vaginalis - in women it is manifested by vaginal discharge, men show inflammation of the urethra, both partners should be treated simultaneously MUNI MED Nitroimidazoles Pharmacokinetics: • 80% absorption after p.o. administration • good penetration into tissues and cerebrospinal fluid, through the placenta into breast milk (Kl) • renal excretion AE: • GIT disorders - nausea, vomiting, diarrhea • CNS disorders (dizziness, insomnia, depression) • dark colored urine • long-term administration - neutropenia, leukopenia (blood count) metronidazole (disulfiram effect) • ornidazole • tinidazole MUNI MED Ansamycines • inhibit bacterial RNA polymerase, bactericidal effect Indications: Treatment of pulmonary tuberculosis, G +, G-bacteria Mycobacterium sp. easy resistance - always in combination! drug interactions: inductors of CYP 450 AE: GIT disorders (nausea, vomiting, increase in liver enzymes, jaundice) Hematopoietic disorders (leukopenia, thrombocytopenia, anemia) arthralgia, myalgia rifampicin rifabutin (i.v., p.o., local use) rifamixine (non-absorbable form) - p.o., local use ^ " " v MED Other MoA Nitrofurans bacteriostatic, at higher concentrations bactericidal ATBs G + and G-bacteria, protozoa Mechanism of action: • non-specific inhibition of bacterial enzymes • release of superoxides and other oxygen compound Indications: prophylaxis and treatment UTI (nitrofurantoin, p.o.) gynecological infections, including trichomoniasis (nifuratel, p.o., topical treatment) intestinal infection (nifuroxazid, p.o.) MUNI MED Nitrofurans AE: • allergy • GIT disorders • hepatotoxicity • hematopoietic disorders - megaloblastic and haemolytic anemia • neurotoxicity • pneumonia Kl: • pregnant, breastfeeding • children MUNI MED Topical antibiotics mupirocin MofA: proteosynthesis inhibition I: impetigo, folliculitis, furunculosis bacitracin + neomycin oph, drm., nas. fusidic acid inhibits synthesis of proteins in cell wall against G+ - staphylococci I: impetigo, superficial folliculitis, skin wounds with infection; with betamethasone atopic dermatitis and contact dermatitis retapamulin (fusafungin) MUNI MED ATB combinations Advantages: 1. Spectrum widening 2. Decrease of resistance development risk 3. Decrease of adverse reaction probability 4. Increase in ATB efficacy Unsuitable combinations drugs with similar AE (nephrotoxicity, hepatotoxicity, ...) MUNI MED Selection of antibacterial drugs Depends on: Patient Weight/Age Allergy Renal/hepatic functions Comorbidities Ambulant/in-patients care (ICU) Disease Antimicrobial drug Type/sensitivity of bacteria Localization of infection Disease severity PK/PD properties AE Drug interactions Administration MUNI MED Selection of antibacterial drugs ATB policy in Czechia Antibiotic centers, free and bound ATB National reference centre for healthcare associated infections (NRC-HAI) EARS-NET Antibiotic prophylaxis single dose in perioperative period during immunosuppression MUNI MED ATBs in dentistry Use • prevention - for risk patients (due to ADA) • artificial heart valves • a history of ineffective endocarditis • a cardiac transplant with developed valve problem • some of congenital heart conditions in some types of stomatosurgeries • for all dental procedures that involve manipulation of gingival tissue or the periapical region of the teeth, or perforation of the oral mucosa M U l\l I ED ATBs in dentistry Drugs - penicillin 1,5-3 mil. IU - amoxicillin/clavulanic acid 1,2 g i.v. /1g p. o. - ampicillin/sulbactam 2 g i.v./ 750 mg p.o. - beta lactams allergic patients - clindamycin 600 mg p.o./i.m./i.v. - vancomycin 500 mg/i.v. oral administration is recommended at least 1 hr before procedure and parenteral administration 15-30 mins before. In long lasting interventions can ATB be administered repeatedly after 4-6 hrs MUNI MED Local therapy in oropharyngeal cavity Hexetidine (Stopangin) • bacteriostatic, fungistatic effect Chlorhexidine digluconate (Corsodyl) • against G+,G-, Candida, viruses Other antiseptics Benzydamin hydrochloric! - Tantum Verde Oktenidin dihydrochlorid - PHYTENEO Neocide gel Benzalkonium chlorid - Septolette Benzoxonium chlorid - Orofar Cetylpyridinium chlorid - Neo Septolette, Calgel (+lidokain) Dichlorobenzenmethanol - Neoangin, Strepsils (2-slož.) Tridekanamin - Septisan Jj ^ ^ Antivirotics MofA: • block of viral penetration/uncoating • inhibition of virus specific proteins/enzymes - reverse transcriptase inhibition - DNA polymerase inhibition • inhibition of viral mRNA translation • inhibition of neuraminidases MUNI MED Viral replication adsorption penetration -^^^►uncoating — eiB5p®§ regulatory proteins structural proteins o viral NA V-v-' inons ^^^fc ^^^fc MUNI ED Antivirotics anti-herpetics flu medicines antiretroviral drugs drugs of viral hepatitis and other antiviral drugs Therapy of herpetic infections Aciclovir MofA: DNA synthesis inhibition - DNA competitive polymerase inhibition Efficacy: herpes labialis, herpes genitalis, varicella-zoster, less against cytomegalovirus and Epstein-Baar v AE: thromboflebitis after i.vinjections, neurologic symptoms (fuzziness, hallucination, depersonalisation) -more pronounced in renal failure Local antiviral drugs aciclovir Herpesin®, Zovirax® penciclovir Vectavir® docosanol Erazaban tromantadin Viru-Merz N I D MYCOSES • tincidence: immunodeficiency, DM, radiotherapy, chemotherapy, HIV Classification: • pathogen: candodisis, aspergillosis, cryptococcos zygomycosis • localization: systemic, organ, mucosal, skin UNI ED ANTIMYCOTICS Specific • selective toxicity for mycotic cell • targeted against mycotic cell specific structures Nonspecific toxic for all organisms MofA- protein denaturation, cell membrane disruption etc. antiseptic and disinfectant agents MUNI MED ANTIMYCOTICS squalene ALLYLAMINES squalenepoxidase oxidosqualene /->AZ0LES lanosterol 1 lanosterol-14a -demethylase ergosterol POLYENES UNI AZOLES ED MofA: inhibition of C-14-a-demethylase (CYP450) Classification: local x systemic imidazoles x triazoles MUNI ED Antifungals in dentistry Indications • oral fungal infections due to »immunosuppression »inadequate oral hygiene »wide spectrum antibiotics, glucocorticoids, chemotherapy • most often candidosis Antifungals in dentistry Drugs - topically: nystatin, natamycine, clotrimazole, miconazole - systemically: fluconazole, itraconazole, posaconazole MUNI MED