Medical oral microbiology I – lecture (ZLLM0421p)

1. Medical oral microbiology I – lecture (ZLLM0421p) Antibiotics I (introduction, survey, cell-wall acting antibiotics) Ondřej Zahradníček zahradnicek@fnusa.cz

2. How to fight with microbes • Imunisation – use of natural processes in the organism • Decontamination methods – crude physical and chemical influences, action outside the organism • Antimicrobial drugs – fine, targeted action inside the organism, the aim is maximal action against the microbe and minimal influence to the host organism

3. Types of antimicrobial drugs • Drugs for general treatment • Antiparasitarian drugs against parasites • Antimycoticsagainst mycotic organisms • Antiviroticsagainst viruses • Antituberculoticsagainst mycobacteria • Antibioticsagainst other bacteria, including former antibacterial chemoterapeutics (originally only natural origin drugs were counted into antibiotics) • Drugs for topic treatment: antiseptics (originally disinfectants that may be used inside the organism, or antibiotics, especially those too toxic to be used for general tratment)

4. Why are antibiotics the most important group • Fungal and parasital infections are important, nevertheless far from being as frequent as bacterial diseases • Viral diseases are very common, but usually self-limited  for majority of them symptomatic treatment is recommended (exceptions: herpesviral diseases, HIV, heavy influenza etc.) • Bacterial diseases are nearly always treaded with antibiotics (causal treatment) – so knowledge about them is important

5. Should we kill microorganisms? • At decontaminationwe always have to kill microbes (microbicidal effect) • At use of antimicrobial drugs it may be sufficient to inhibit bacterial growth; patient‘s immunity helps us • Nevertheless, this is not valid for acute situations and immunocompromised patients, when we always try to use microbicidal effect

6. Action of influences on microbes I At action of an influence like pH the axe has both upper and lower extremes lower survival limit (bactericidal) lower growth limit (inhibitory) upper growth limit (inhibitory) upper survival limit (bactericidal) upper growth limit (inhibitory) upper survival limit (bactericidal) • At action of antimicrobial agents (but also e. g. disinfectants)only right part of the axe has a logical sense

7. MIC, MBC, MBEC MIC – minimal inhibitory concentration means the limit concentration that is just sufficient to stop the growth of microbes MBC – minimal bactericidal concentration – survival limit for bacteria. (For viruses we use „minimal virucidal concentration“ etc.) MBEC–minimal biofilm erradication concentration: concentration destroying „forever“ microbioal biofilm

8. Primarily bactericidal and primarily bacteriostatic antibiotics Primarily bactericidal antibiotics = effect of drug is primarilly killing (e. g. action of cytoplasmic membrane – bacteria cannot survive it) Primarily bacteriostatic antibiotics usually stop bacterial growth (we get the MIC, but not MBC level). MBC is usually very high for them and cannot be used in practice (the antibiotic in such concentration would be toxic also for human cells)

9. Primarily bactericidal and primarily bacteriostatic atb Primarily bactericidal antibiotic THERAPEUTICAL CONCENTRATIONS atb concentration toxicity for the macroorganism Primarily bacteriostatic antibiotic

10. Mechanisms of antibiotic action To the cell wall (bactericidal) β-lactamic antibiotics Glycopeptidic antibiotics (partially) To cytoplasmic membrane – polypeptids (bactericidal) To nucleic acids – quinolones (bactericidal) To proteosynthesis:aminoglykosides (bactericidal); makrolids, tetracyclins, linkosamids, amphenicols (bacteriostatic) To metabolism – sulfonamids, bacteriostatic Primarily bacteriostatic antibiotics are not recommended for treatment in acute states and immunocompromised persons! BAKTERICIDAL BAKTERIO- STATIC

11. β-lactamic antibiotics • Their structure contains β-lactamic circle • They act on the cell wall • They are baktericidal, but they act well only on multiplying bacteria that build their cell wall • They are nearly non-toxic (human cells have no cell wall), but they have allergic side effect • This „super-group“ is subdivided into • Penicillins (derrivatives of penicilanic acid) • Cephalosporins (derrivatives of cephalosporanic acid) • Monobactams • Carbapenems

12. Various forms of „classic“ (Fleming‘s) penicillin • Parenteric (injection) forms (acidolabile) • Benzylpenicillin(G-penicilin), intavenous, drug of choice for many infections (see further) • Procaine-benzylpenicillin, intramuscullar. More difficult keeping the level in blood – even higher doses have no effect • Benzatin-benzylpenicillin, intramuscullar, for Streptococcus and Treponema only • Orally administered forms (acidostabile) • Fenoxymetylpenicilin (V-penicillin). Drug of choice for streptococcal tonsillitis, in sequention therapy after G-penicilln etc. • Penamecillin *Sequention therapy = we start with an injection antibiotic and we continue by an orally administered one

13. Oral penicillins: V-penicillin… … and penamecillin

14. G-penicillin as a drug of choice(just for illustration) • Meningitis and sepsis caused by meningococci, pneumococci and streptococci • Pneumococcal pneumonia. • Endokarditis caused by so called „alpha-streptococci“ • Heavy streptococcal and clostridial infections of soft tissues. • Anaerobic infections caused by spore-non-forming anaerobes (except Bacteroides fragilis), e. g. aspiration pneumonia and lung abscess • Actinomycosis. • Neuroborreliosis. • Anthrax, diphtheria, erysipelois • Neurosyphilis, congenital syphilis. Source: Consensus of use of antibiotics of Subcomission for antimicrobial use of J. E. Purkyně Czech Medical Society

15. Depot forms of penicillin(the level of antibiotic is maintanted in the body after administration) Depot forms of penicillin for long-term use

16. Antistaphylococcal penicillins Spectre is enlarged: it works against staphylococci, but not other bacteria • Methicillin – used in some countries, exists in abbreviation „MRSA“ (methicillin resistant S.aureus) • Oxacillin – used in some other countries (including Czechia). Only used for staphylococcal and mixed staphylococcal/streptococcal infections. On the other hand, it should not be replaced by other drugs except if there is a reason for it (allergy etc.) • Nafcillin is an alternative for both, used especially in the U. S.

18. Aminopenicillins: Ampicillin and amoxicillin • Effect is enlarged to some Gram-negative bacteria, but also Gram-positive enterococci and other bacteria • Ampicillinis useful mostly in injection form, oral use is not recommended (it should be replaced by amoxicillin) • Amoxicillin(Amoclen) is recommended e. g. for treatment of middle ear infection, sinusitis, even if we do not know the causative agent (common agents are susceptible)

20. Problem: β-lactamases • Many bacteria produce various types of β-lactamases, either primarily (always) or secondarily (just some strains). In that case, amoxicillin might have no effect • Possible solution: support the antibiotic by so called β-lactamase inhibitor, that enables effect of that aminopenicillin.

21. β-lactamase inhibitors – 1 Bacterium „BELA“ The Dog (a β-lactamase) • When we act by a single antibiotic, it is inactivated by a bacterial β-lactamase.

22. β-lactamase inhibitors – 2 • When a β-lactamase has a more attractive substrate to be chosen, it is used instead, and the antibiotic can act. ACID

23. Examples of antibiotics potentiated by β-lactamase inhibitors From FN USA intranet

24. β-lactamase inhibitors are not always sufficiently effective Unfortunately, β-lactamase inhibitors are effective only in some „not so strong“ types of β-lactamases There exist also extended specter β-lactamases (ESBL – see later), where inhibitors are not sufficient (the treatment is not effective although we use them) and we have just a few β-lactam antibiotics that have effect against them Nevertheless, some effect can be seen also in these β-lactamases. This is used in diagnostics, where we observe difference in effect of certain antibiotic with : without inhibitor

25. Co-ampicilin and co-amoxicilin • Co-ampicillin = ampicillin (antibiotic) + sulbactam (β-lactamase inhibitor), known for example as a drug Unasyn • Co-amoxicilin = amoxicillin (antibiotic) + clavullanic acid (Augmentin, Amoksiklav etc.) • These combinations should not be used in situation where amoxicillin alone is sufficient: they induce formation of β-lactamases. On the other hand, they are useful in resistant bacteria.

28. Carboxypenicillins: Carbenicillin and ticarcillinUreidopenicillins: Piperacillin • Unlike the previous, they have larger spectre against so called Gram-negative non-fermenters (e. g. genus Pseudomonas). • They cannot be used against enterobacteria producing β-lactamases; also here, there exist combinations with β-lactamase inhibitors • They are drug of choice in Pseudomonas infections and infections caused by other Gram-negative non-fermenters

29. Cephalosporins 1 • They arepartially related to penicillins • Cross allergies between penicillins and cephalosporinsare less frequent than between penicillins mutually. In urgent need it is possible to use cephalosporins when the patient is referred to be allergic to penicillins (the continual monitoring is needed) • Some resistences are common, some other are particular for penicillins only/cephalosporins only/only some preparations • In comparison with penicillins they are more frequently eliminated by urine, so they can be used for some UTI rather than penicillins

30. Cephalosporins 2 • Allenterococci andlisteriasare resistantto all cephalosporins – although some penicillins (not „Fleming‘s“ penicillin) are well effective • Sometimes a group of cephamycinsis concidered a specific group. This group containscefoxitin(Mefoxin), eventuallycefotetan. They have better effect against anaerobic bacteria. Other authors consider cephamycins to be just a special subgroup inside 2nd generation cephalosporins • Cephamycinsare also used in diagnostics, e. g. for checking, if the strain is MRSA or not they are better than direct use of methicillin/oxacillin

31. Cephalosporins 3 • I. generation:effect mostly against G+ bacteria, but also some enterobacteria. Examples: Cefalotin (Keflin), cefazolin (cephazolin; Ancef, Kefzol), cephalexin, cefadroxil (Duracef, Duricef, Cefadroxyl) • II. generation:better effect againstbacteria from Enterobacteriaceae family, nevertheless, some of them (Enterobacter sp., Serratia sp.,Proteus vulgarisetc.) are primarily resistant. Effect against G+ bacteria is slightly worse. Examples: Cefuroxime (Zefu, Zinnat, Zinacef, Ceftin, Biofuroksym, Xorimax), cefaclor (Ceclor , Distaclor, Keflor, Raniclor), cefprozil

32. Cephalosporins4 • III. generation:much better effect against enterobacteria (including those resistant to I. and II. generation), some also against G– non-fermenters including Pseudomonas. Not suitable (although may be effective) againts G+ bacteria. Disadvantage: they are selectors of so called extended spectre β-lactamases. Examples: • No anti-Pseudomonas effect:Ceftriaxone (Rocephin, good access to CSF  used for meningitis treatment), cefotaxime (Claforan), cefdinir (Sefdin, Zinir, Omnicef, Kefnir) • Can be used against Pseudomonas:cefoperazone (Cefobid), ceftazidime (Meezat, Fortum, Fortaz)

33. Cephalosporins5 • IV. generation: effective also against producers of so called ampC β-lactamases (but not ESBL β-lactamases). Examples: cefepime (Maxipime), cefpirome (Cefrom) • V. generation: the only β-lactam antibiotics effective against MRSA strains*. Example: ceftaroline (Zinforo) *MRSA are strains of Staphylococcus aureus with alteration of penicillin binding protein (PBP), restistant not only against methicillin/oxacillin, but also all other β-lactam antibiotic. More later.

34. Cephalosporinsof I. and II. generation

35. 3. generation

36. Monobactams • Monobactamsare β-lactam antibiotics related to penicillins and cephalospoins. Their β-lactam ring is alone and not fused to another ring (in contrast to most other β-lactams). They work only against aerobic Gram negative bacteria (e.g., Neisseria, Pseudomonas). • The only commercially available monobactam antibiotic is aztreonam (Azactam).

37. Carbapenems • Carbapenemsare β-lactam antibiotics used for the treatment of infections known or suspected to be caused by multidrug-resistant (MDR) bacteria. Their use is primarily in people who are hospitalized. • They are the only betalactams with effect against ESBL-producers. On the other hand, carbapenemase producers are resistant. • Examples: Imipenem (Tienam) and Meropenem (Meronem) for both Pseudomonas and ESBL caused infections; Ertapenem (Invanz) for ESBL, but not Pseudomonas caused infection

38. Glycopeptidic antibiotics • Also have effect tocell wall synthesis, but they are unrelated with β-lactams. They are only suitable for G+ bacteria. • Side-effects: red man syndrome, an idiosyncratic reaction to bolus caused by histamine release; nephrotoxicity including renal failure and interstitial nephritis;deafness, which is reversible once therapy has stopped. • They are used as reserve drugs, for example for MRSA strains • Examples: vancomycin (Edicin) and less toxic, but more expensiveteicoplanin (Targocid). New lipo-glycopeptide telavancin (Vibativ) is now also used, and also related lipopeptide daptomycin (Cubicin).

39. Good bye! http://medicineworld.org/news/news-archives/health-news/1243577370-Sep-28-2006.html