Miroslav Votava AN OVERVIEW OF ANTIMICROBIAL AGENTS

1. Institute for Microbiology, Medical Faculty of Masaryk University and St. Anna Faculty Hospital in Brno Miroslav Votava AN OVERVIEW OF ANTIMICROBIAL AGENTS The 14th lecture for the 2nd-year students May 20th, 2013

2. Prevention, prophylaxis and therapy of infections I – revision Prevention of infection = avoiding an infection in the future Asthe specific prevention of infection serves the vaccination

3. Prevention, prophylaxis and therapy of infections II – revision Prophylaxisof infection = avoiding an imminentlythreatening 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)

4. 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

5. Immunization and its types – revision

6. Artificial passive immunization – revision = application of antibodiesin 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

7. 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 andcorticoids is essential)

8. Animal sera and globulins II – revision Examples: Antirabic serum(antigen used for its production=for the immunization of animals =inactivatedrabiesvirus) Globulin against botulismus(antigens used for its production =botulotoxins A, B, E) gas gangrene(antigens used for its production = α-toxins ofClostr. 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)

9. Human immunoglobulins – revision Two kinds of human (homologous) immunoglobulin: • Normalimmunoglobulin • Specificimmunoglobulins Use: • For the prophylaxis and therapy of some infections • As a substitution of antibodiesin some typesof immunodeficiencies

10. 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 incontacts with the ill • At the defects of antibody production • During therapy of serious infections(special intravenous preparations)

11. Specific immunoglobulins – revision Origin: from the plasma of actively immunized donors: • Human tetanic immunoglobulin for the prophylaxisof 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 ofchickenpox andzoster • Ig for the prophylaxis and therapy ofcytomegalovirus infections • Ig for the prophylaxisof tick-borne encefalitis • Ig for the prophylaxisof rabies • monoclonalAbagainst RSV (in premature newborns)

12. 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

13. ANTIMICROBIAL AGENTS = drugs used to treat infectious diseases antibiotics – naturally occuring microbial products chemotherapeutics – synthetic compounds Different types of agents: antibacterial antifungal antiviral antiparasitic

14. ANTIBACTERIAL AGENTS Inhibitors of 1) cell wall synthesis 2)protein synthesis 3)nucleic acid synthesis 4) miscelanous agents

15. 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

16. 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

17. 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

18. Penicillins resistant to staphylococcal penicillinase 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

19. Aminopenicillins Have a broader spectrum: most strainsof 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)

20. Ureidopenicillins 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

21. 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

22. 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 inflammedmeninges) Ertapenem (against ESBL-producing strains)

23. 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.

24. 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+)

25. Lincosamides Lincomycin Clindamycin Both for G+ (except enterococci), anaerobes, some protozoa Streptogramins quinupristin + dalfopristin (Synercid) (for G+)

26. Oxazolidinons linezolid (G+ incl. MRSA & anaerobes) Lipopeptides Daptomycin (kills MRSA) Glycylcyclins Tigecyclin (broad spectrum, ESBL producents)

27. 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)

28. 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)

29. ANTIFUNGAL AGENTS (ANTIMYCOTICS) Specific antimycotics • Imidazoles • Triazoles • Polyenic antimycotics • Other systemic antimycotics • Local antimycotics Nonspecific antimycotics (rather antiseptics then chemotherapeutics)

30. Imidazoles ketokonazole other imidazoles – for local use only e.g. clotrimazole, oxiconazole Triazoles flukonazole posaconazole vorikonazole

31. Polyenes amphothericine B Other systemic antimycotics flucytosin terbinaphine

32. Newer antimycotics Ecchinocandines: e.g. anidulafungin Pneumocandines: e.g. caspofungin Antipneumocystic agents co-trimoxazole pentamidine

33. Local antimycotics Imidazoles: e.g. clotrimazole, oxiconazole Polyenes: e.g. natamycin Broad-spectrum: amorolfine ciclopirox olamine nystatin Antimycotic antiseptics: undecylenic acid chlornitrophenol

34. ANTIVIRAL AGENTS Systemicaly used antivirotics • Antiherpetics • Anticytomegalovirotics • Antinfluenza agents • Antiretrovirotics • Interferons • Others systemic antivirotics Local antivirotics

35. Antiherpetics Systemic antiherpetics • aciclovir • valaciclovir • famciclovir • brivudin

36. Anticytomegalovirotics ganciclovir cidophovir foscarnet Antiinfluenza agents amantadin oseltamivir zanamivir

37. Antiretrovirotics – I Nucleoside inhibitors of reverse transcriptase • zidovudine • lamivudin • abacavir • adefovir dipivoxil • tenofovir Non-nucleoside inhibit. of reverse transcript. • nevirapin • efavirenz

38. Antiretrovirotics – II Inhibitors of viral protease • ritonavir • lopinavir Inhibitors of virion fusis with cell surface • enfuvirtid Inhibitors of viral entry into the cell • maraviroc

39. Interferons natural interferon α recombinant interferon α-2a recombinant interferon α-2b interferons β interferon γ pegylated interferons

40. Other systemic antivirotics ribavirin Local antivirotics idoxuridin trifluridin topically given aciclovir fluorouracil podophylotoxin

41. ANTIPARASITIC AGENTS Antiprotozoics Anthelminthics Antiectoparasitics

42. Antiprotozoics – I Vaginal trichomonosis: metronidazol ornidazol clotrimazol Giardiosis & amoebic dysentery: metronidazol ornidazol Naeglerial meningoencephalitis: amphothericin B Acantamoebic conjunctivitis: propamidin isethionate

43. Antiprotozoics – II Toxoplasmosis: pyrimethamine & sulphadiazine spiramycin Malaria: chloroquine, event. & proguanil mefloquine quinine primaquin derivatives of artemisin atovaquone

44. Antiprotozoics – III Leishmanioses: pentavalent antimony compounds new forms of amphotericin B Cryptosporidiosis: azithromycin Trypanosomiases: at first pentamidine later 3-valent arsenicals, e.g. tryparsamide

45. Anthelminthics Intestinal nematode infections: albendazole mebendazole Tissue nematodes: ivermectin albendazole Flukes: praziquantel Tapeworms: praziquantel

46. Antiectoparasitics Insecticids permethrin malathion carbaryl Repellents benzoic acid derivatives …

47. 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 Richard Gordon: Doctor in Love Please mail me other suggestions at: mvotava@med.muni.cz Thank you for your attention