ANTIBIOTICS I. This study material is recommended specifically for practical courses from Pharmacology II for students of general medicine and stomatology. These brief notes could be used to prepare for the lesson and as a base for own notes during courses. Addititonal explanations and information are given in single lessons.

Terminology ANTIBIOTICS vs CHEMOTHERAPEUTICS X ANTISEPTICS vs DESINFECTANTS

CLASSIFICATION With regard to:

Modes of action Sites of ATB action

Terminology of ATB therapy Selective toxicity ATB spectrum MIC, MBC Postantibiotic effect Resistence

Resistence -mechanisms

Rezistence - types 1. Primary 2. Secondary 3. Coupled 4. Crossed 5. Absolute 6. Relative

Kombinace ATB Výhody: Nevhodné kombinace a) b)

Výběr vhodného ATB ATB politika v ČR Profylaktické podávání ATB

ATB classification Antibiotics β-lactams amphenicols tetracyclines macrolides azalides streptogramines ketolides oxazolidinones lincosamides aminoglykosides glycopeptides other ATBs ATB for local use (chemotherapeutics) sulphonamides quinolones imidazoles others

β-lactams Penicillines Cefalosporines Cefamycines Newer Monobactams Carbapenems Combined with beta lactamase inhibitors

β-lactams MofA: interference wit cell wall, PBP, trabnspeptidases, autolysis bactericidal orally/parenterally administered AE:low toxicity well tolerated alergic reactions (penicillines)

Penicillins from Penicillium chrysogeum basic structure 6-aminopenicilic acid semisynthetic – substitutionin position R Classification: basic penicillinase resistant broad-spectrum

Penicillines Basic Benzylpenicillin (PEN G) - procainpenicilin Phenoxymethylpenicillin (PEN V) -respiratory tract and other infections induced by G+ i G- cocci: streptococci, pneumococci, gonococci, meningococci, aktinomycosis, anaerobic inf. (gas gangrene), lues, borreliosis, gonorrhoea…

Penicillins Beta lactamase resistant - infections with S. aureus Cloxacillin Oxacillin Others: meticillin, dicloxacillin, flucloxacillin

Penicillins Broad-spectrum - spectrum spread to G - microbes: enterobacteriaceae Aminopenicillins –ampicillin –amoxicillin Carboxypenicillins –ticarcillin Acylureidopenicillins –piperacillin -E.coli, Salmonela spp., Shigella spp., pseudomonades, Haemophilus spp., Enterococcus spp., Proteus

Combinations with beta lactamase inhibitors clavulanic acid + amoxicillin sulbactam tazobactam -protection of penicillines agains some beta lactamases -spectrum widening G- (sulbactam) -E. coli, Proteus, Salmonella, Haemophilus, M. catarrhalis, Klebsiella, Neisseria, Enterobacter, Bactoroides -drugs of choice in the treatment of otitis media and sinusitis Penicillins

Cefalosporins - derived from 7- aminocephalosporanic acid - higher resistance to beta lactamases - classification to 4 generations with regard to theiur spectrum: increasing against G-, decrease in G+ sensitivity AE: hypersensitivity, often crossed with penicillins (5-10%) GIT disturbances changes in blood picture

I. generation cefazolin cefalotin cefalexin cefadroxil G+ cocci (staphylococci, streptococci), E.coli, Proteus, Klebsiela, Neisserie G- usually resistant I: S. aureus infections, prophylaxis in surgery parent. p.o. Cefalosporins

II. generation cefuroxim – parent. cefuroxim-axetil – p.o. cefaclor – p.o. wider spectrum G+ i G- : H. influ, enterobakterie, Neisseria, Proteus, E. coli, Klebsiella, M. catarrhalis, anaeroby a B. fragilis. less effective against S. aureus in comparison to 1st generation Cefalosporins

III. a IV. generation III : ceftriaxon cefotaxim ceftazidim cefoperazon (+ sulbactam) enterobacterias, partially. pseudomonades higher stability and activity (best towards G-) some of them cross BBB!!!! IV : cefepim cefpirom widest spectrum G+ i G- bacterias (NOT for anaerobes) higher stability, longer biological halftime parent. cefixim cefpodoxim p.o. parent. Cefalosporins

MONOBACTAMS Aztreonam resistent agains beta lactamases alternative for patient sensitive to penicillines narrow spectrum aerobe G- bacilli I: sepsis, abdominal infections Imipenem + cilastatin Meropenem Ertapenem -reserve antibiotics for serious and life-threatening infections AE: hypersensitivity, GIT CARBAPENEMS

Amphenicols Chloramphenicol MofA: protein synthesis inhibition, binds to 50S ribosomal subunit, broad spectrum including anaerobes I: bacterial meningitis, typhoid and parathypoid fever, serious pneumonias (with absceses), anaerobic inf. and mixed inf., abdominal inf., serious invasive haemophyllus inf. AE: myelosupression a) reversible b) irreversible grey baby syndrom neurotoxicity

Tetracyclines MofA: protein synthesis inhibitions –reversible binding to 30S subunit I: respiratory and urinary infections, chlamydia and mycoplasma inf., borelióza, leptospirosis, acne (minocyclin), gonorrhea, syphilis AE:- defects of tooth enamel and bones– deposits in newly produced bone tissue with growth interference - photosensibilisation - dysmicrobias –GIT disturbances - hepatotoxicity - superinfections Doxycyclin Minocyclin

Macrolides : MofA: reversibly bind to 50S ribosomal subunit and block of translocation ) Spectrum: G+ G- bacterias ( mykoplasmata, chlamydia, spirochets (Borelia burgdorferi), neisseria, leptospires, campylobacters, legionels, Toxoplasma gondii, Helicobacter pylori (together with proton pump inhibitor) ) increase in bacterial resistence AE: GIT intolerance hypersensitivity erythromycin oleandomycin, spiramycin, josamycin, roxithromycin, clarithromycin, dirithromycin

ATB related to macrolides Azalides –azithromycin Streptogramines –quinupristin –dalfopristin Ketolides –telithromycin Oxazolidindiones –linezolid

Linkosamines MofA: reversible binding to 50S ribosomal subunit and inhibition of proteosynthesis I: alternative treatment for patients with penicilline hypersensitivity AE:- minimal toxicity - resistence often crossed with macrolides Clindamycin Lincomycin

Aminoglycosides MofA: proteosynthesis inhibition by irreversible binding to ribosomal 30S subunit (block of binding of aminoacyl- tRNA to complex mRNA+ ribosom) I: - septicemia - serious uroinfections (pyelonefritis) - low respiratory tract infections (in combinations) - orthopedic infections… AE: nephrotoxicity ototoxicity  doses neurotoxicity streptomycin, kanamycin, spektinomycin, neomycin gentamicin, tobramycin, amikacin, isepamicin, netilmicin

GLYCOPEPTIDES MofA: cell wall synthesis inhibition I: reserve ATB for the teratment of serious, multiresistant G+ infections, locally(p.o.) intestinal infections AE: flush(red man syndrom) ototoxicity nefrotoxicity Vancomycin Teicoplanin

Other ATB Rifampicin –broad spectrum ATB –bactericidal effect-bacterial nucleid acid synthesisi inhibitionK –antiTBC Fusidic acid –bacteriostatic –inhibition of cell wall proteins –against staphylococcus Polymyxin B, colistin (polymyxin E) –toxicic – local administration(ophthalmology, ORL, intestinal decontamination)