Institute for Microbiology, Medical Faculty of Masaryk University and St. Anna Faculty Hospital in Brno Miroslav Votava AN OVERVIEW OF ANTIMICROBIAL AGENTS – I The 14th lecture for the 2nd-year students May 18th, 2015 Prevention, prophylaxis and therapy of infections I – revision • • •Prevention of infection = avoiding an infection in the future •As the specific prevention of infection serves the vaccination Prevention, prophylaxis and therapy of infections II – revision • • •Prophylaxis of infection = avoiding an imminently threatening infection •For the prophylaxis, passive immunization is usually used •Only rarely for the prophylaxis the vaccination is used (e.g. rabies) or the re-vaccination (e.g. tetanus) Prevention, prophylaxis and therapy of infections III – revision • • •Therapy of infection • For the therapy the passive immunization is used (of course apart from antibiotics); very rarely active immunization by means of autovaccines Immunization and its types – revision Immunization natural artificial active after infection after vaccination passive by transfer of antibodies through placenta and during breast-feeding after injecting antiserum (immuno-globulin) Artificial passive immunization – revision •= application of antibodies in the form of antisera or globulins •Formerly: complete animal sera •Present-day preparations for passive immunization: •animal (heterogenous) sera and globulins (purified and enzymatically split) •human (homologous) immunoglobulins • – normal • – specific • Animal sera and globulins I – revision • •Disadvantages: •They are very antigenic • → body tries quickly to get rid of them • → therefore the protection lasts few weeks only • •Complications (even after the first application): •Serum disease •Anaphylactic shock (applying adrenalin and corticoids is essential) • Animal sera and globulins II – revision •Examples: •Antirabic serum (antigen used for its production = for the immunization of animals = inactivated rabies virus) •Globulin against • botulismus (antigens used for its production = botulotoxins A, B, E) • gas gangrene (antigens used for its production = α-toxins of Clostr. perfringens, Cl. novyi and Cl. septicum) • viper toxins (antigens used for its production = toxins of some European vipers, e.g. Vipera ammodytes or V. berus) • Human immunoglobulins – revision •Two kinds of human (homologous) immunoglobulin: •Normal immunoglobulin •Specific immunoglobulins •Use: •For the prophylaxis and therapy of some infections •As a substitution of antibodies in some types of immunodeficiencies Normal immunoglobulin – revision •Normal immunoglobulin (formerly called normal gammaglobulin) •Origin: from the mix of plasmas from at least 1000 healthy donors → hence it contains antibodies against all common infections •Examples of the use: •For the prophylaxis of hepatitis A in contacts with the ill •At the defects of antibody production •During therapy of serious infections (special intravenous preparations) Specific immunoglobulins – revision • •Origin: from the plasma of actively immunized donors: •Human tetanic immunoglobulin for the prophylaxis of tetanus •Immune antistaphylococcal plasma •Ig with high titre of antibody against HBsAg for the prophylaxis of viral hepatitis B •Ig for the prophylaxis and therapy of chickenpox and zoster •Ig for the prophylaxis and therapy of cytomegalovirus infections •Ig for the prophylaxis of tick-borne encefalitis •Ig for the prophylaxis of rabies •monoclonal Ab against RSV (in premature newborns) • • Nonspecific build-up of immunity – revision •Replacement of missing factors: normal Ig, fresh plasma, transfer-factor from lymphocytes •Immunomodulators: components of common urinary and respiratory bacterial pathogens – e.g. peroral autovaccines, stockvaccines and a vast number of commercial preparations •Probiotics: live non-pathogenic strains of microbes reportedly able to re-establish normal mucosal microflora – e.g. strains of E. coli, Lactobacillus acidophilus, Saccharomyces boulardii •Interferon: for the treatment of hepatitis B and C and some malignancies • ANTIMICROBIAL AGENTS •= drugs used to treat infectious diseases •antibiotics – naturally occuring microbial products •chemotherapeutics – synthetic compounds • •Different types of agents: • antibacterial • antifungal • antiviral • antiparasitic ANTIBACTERIAL AGENTS • •Inhibitors of 1) cell wall synthesis • 2) protein synthesis • 3) nucleic acid synthesis • 4) other 1. Inhibitors of bacterial cell wall synthesis •β-lactam agents • penicillins • cephalosporins • monobactams • carbapenems •Glycopeptides • vancomycin • teicoplanin •Other inhibitors of bacterial cell wall • e.g. bacitracin • cycloserin • isoniazid • Penicillins •Acidolabile: • benzylpenicillin (penicillin G) • procaine penicillin •Acidostable: • phenoxymethylpenicillin (penicillin V) •Resistant to penicillinase: • methicillin, oxacillin, flucloxacillin •Aminopenicillins: • ampicillin, amoxicillin, co-amp., co-amox. •Ureidopenicillins & carboxypenicillins: • co-piperacillin, co-ticarcillin Acidolabile penicillins •Classical benzylpenicillin (penicillin G): • crystallic penicillin G – i.v. • procaine penicillin G – i.m. • benzathin penicillin G – i.m. •Spectrum: G+ cocci & rods, G- cocci, • G- spirals • •Acidostable penicillins • •phenoxymethylpenicillin (penicillin V): • - peroral; the same spectrum • • •Used against infections caused by S. aureus • •Originally methicillin • staphylococci resistant to penicillinase = MRSA, methicillin-resistant S. aureus •Now in use oxacillin (but MRSA are also resistant to it) •Combination with ampicillin: cloxacillin • • Penicillins resistant to staphylococcal penicillinase •Have a broader spectrum: • most strains of Enterococcus faecalis • Listeria monocytogenes is more sensit. •Above all many Gram-negative rods: • E. coli, Proteus mirabilis, bordetellae, • salmonellae, shigellae, hemophilli & oth. •Amoxicillin (p.os) •Co-amoxicillin (+ clavulanic acid) •Ampicillin (inj. prep. only) •Co-ampicillin (+ sulbactam) • • Aminopenicillins •Broad spectrum: • effective also against Ps. aeruginosa •Co-piperacillin (+ tazobactam) • •Carboxypenicillins • •Spectrum similar to ureidopenicillins • effective against resistant hospital strains incl. Pseud. aeruginosa •Co-ticarcillin Ureidopenicillins Cephalosporins •1st generation (spectrum like ampicillin) • cefazolin • cefadroxil (p.o.) •2nd generation (more resist. to β-lactamases) • cefuroxime • cefuroxime axetil (p.o.) •3rd generation (very effective against G-) • cefotaxime, ceftriaxone • ceftazidime, cefoperazone (P. aerug.) •4th generation (also against G+) • e.g. cefepime • Monobactams •Aztreonam (against G- only) • •Carbapenems •Imipenem (+ cilastatin = Thienam) • for multiresistant strains incl. G+ cocci and Kl. pneumoniae producing ESBL, extended spectrum beta-lactamases) •Meropenem (dtto; diffuses through inflammed meninges) •Ertapenem (against ESBL-producing strains) • 2. Inhibitors of bacterial protein synthesis •Tetracyclines: doxycycline (very broad spectrum) •Chloramphenicol (very toxic) •Aminoglycosides: • streptomycin (now for tbc only) • gentamicin, amikacin (G- rods & staphs) • neomycin (toxic, for topical use only) •Macrolides, azalides, ketolides •Lincosamides •Newer antïbiotics: e.g. oxazolidinons, • streptogramins, glycylglycines etc. • • • Macrolides, azalides, ketolides •Macrolides: • Erythromycin (like PNC, + some G- rods) • Roxithromycin (for atypical pneumoniae) • Spiramycin (little toxic, toxoplasmosis) •Azalides: • Azithromycin (better for G- rods) • Clarithromycin (better for G+) •Ketolides: • Telithromycin (even better for G+) Lincosamides •Lincomycin •Clindamycin •Both for G+ (except enterococci), anaerobes, some protozoa • •Streptogramins •quinupristin + dalfopristin (Synercid) (for G+) • • Oxazolidinons •Linezolid (G+ incl. MRSA & anaerobes) • •Lipopeptides •Daptomycin (kills MRSA) • •Glycylcyclins •Tigecyclin (broad spectrum, ESBL producents) 3. Inhibitors of nucleic acid synthesis •Sulphonamides: sulfamethoxazol (only in comb.) •Pyrimidines: trimethoprim (bacteriostatic), plus • sulphamethoxazol = bactericidic co-trimoxazole • (most G+ cocci & G- rods, nocardiae, Toxopl. gondii, Pneumocystis jirovecii) •Quinolones: • nalidixic acid & norfloxacin (urine tract inf.) • ciprofloxacin, ofloxacin (multiresistant G- rods) •Nitroimidazoles: metronidazol, ornidazol (anaerobes & some parasites) •Nitrofurans: nitrofurantoin, nifuratel (urine tract inf.) •Ansamycins: rifampicin, rifabutin (mainly tbc) • rifamixin (travellers diarrhoea) 4. Miscelanous antibacterial agents •Polypeptids: colistin (some G- rods incl. P. aerugin.) polymyxin B (for local use inly) •Antimycobacterial agents (in combinations only) • streptomycin • rifampicin • isoniazid • ethambutol • pyrazinamide • cycloserine • PAS • dapsone (for lepra) • • Recommended reading material •Paul de Kruif: Microbe Hunters •Paul de Kruif: Men against Death •Axel Munthe: The Story of San Michele •Sinclair Lewis: Arrowsmith •André Maurois: La vie de Sir Alexander Fleming •Hans Zinsser: Rats, Lice, and History •Michael Crichton: Andromeda Strain •Albert Camus: Peste •Victor Heisser: An American Doctor Odyssey •Richard Preston: The Hot Zone •Mika Waltari: The Egyptian •Richard Gordon: Doctor in the House •Richard Gordon: Doctor at Large •Richard Gordon: Doctor at Sea • • •Please mail me other suggestions at: •mvotava@med.muni.cz •Thank you for your attention •