Antimicrobial Agents

1. Antimicrobial Agents

2. History • Antimicrobial chemotherapy started • Clinical use of sulfonamide 1936 • Golden age – 1941 production of penicillin • 30% of hospitalized patients 1 or more ATB • Among most misused agents in practice • Wide spread use- emerging resistance

3. Antibiotics • Substances produced by various species of microorganisms: bacteria, fungi, actinomycetes- to supress the growth of other microorganisms and to destroy them. • Today the term ATB extends to include synthetic antibacterial agents: sulphonamides and quinolones.

4. Classification on chemical structure and mechanism of action • Inhibition of synthesis of bacterial cell wall • Acting directly on cell membrane, permeability, leakage • Inhibition of protein synthesis • Inhibition of DNA gyrase, RNA polymerase • Inhibiton of folic acid metabolism

6. Classification on mechanism of action • Inhibition of synthesis of bacterial cell wall (PEN, CEP, MONOBACT. VANCO, BACIT, imidazol antifungal agents:miconazol, ketokonazol, clotrimazol) • Directly on cell membrane, permeability, leakage (Polymixins, antifugals: nystatin, amfotericin B-binds to cell wall sterols)

7. Classification on mechanism of action (cont.) • Inhibition of protein synthesis • Affecting function of 30S and 50S ribosomal subunits-reversibal inhibition of protein synthesis . Bacteriostatic: (Chloramphenicol, TTC, ERY, Clindamycin) • Bind to 30S subunit, alter protein synthesis, cell death (Aminoglycoside)

8. Classification on mechanism of action (cont.) • Affecting Nucleic Acid metabolism: DNA-dependent RNA polymerase (rifamycins) DNA gyrase (quinolones) • Inhibitonof folic acid metabolism • Antimetabolites :(Trimethoprim, sulphonamides) • Nucleic acid analogues (zidovudin, ganciclovir, vidarabine, acyclovir)

10. Bacteriostatic Bactericidal Classification of Antibiotics

11. Susceptibility vs. Resistanceof microorganisms to Antimicrobial Agents • Success of therapeutic outcome depends on: • Achieving concentration of ATB at the site of infection that is sufficient to inhibit bacterial growth. • Host defenses maximally effective –MI effect is sufficient – bacteriostatic agents (slow protein synthesis, prevent bacterial division) • Host defenses impaired- bactericidal agents • Complete ATB-mediated killing is necessary

12. Susceptibility vs. Resistance(cont.) • Dose of drug has to be sufficient to produce effect inhibit or kill the microorganism: • However concentration of the drug must remain below those that are toxic to human cells – • If can be achieved – microorganism susceptible to the ATB • If effective concentration is higher than toxic- microorganism is resistant

13. Susceptibility vs. Resistance(cont.) • Limitation of in vitro tests • In vitro sensitivity tests are based on non-toxic plasma concentrations –cut off • Do not reflect concentration at the site of infection • E.g.: G- aer.bacilli like Ps.aeruginosa inhibited by 2 – 4 ug/ml of gentamycin or tobramycin. Susceptible !?

14. Susceptibility vs. Resistance(cont.) • Plasma concentration above 6-10 ug/ml may result in ototoxicity or nephrotoxicity • Ration of toxic to therapeutic concentration is very low –agents difficult to use. • Concentration in certain compartments – vitreous fluid or cerebrospinal fluid much lower than those in plasma.

15. Susceptibility vs. Resistance(cont.) • Therefore can be only marginally effective or ineffective even those in vitro test states „sensitive“. • Conversely – concentration of drug in urine may be much higher than in plasma , so „resistant“ agents can be effective in infection limited to urine tract

16. Resistance • To be effective ATB must reach the target and bind to it. • Resistance: • Failure to reach the target • The drug is inactivated • The target is altered

18. Resistance (cont.) • Bacteria produce enzymes at or within the cell surface –inactivate drug • Bacteria possess impermeable cell membrane prevent influx of drug. • Transport mechanism for certain drug is energy dependent- not effective in anaerobic environment. • ATB as organic acids penetration is pH –dependent.

19. Resistance (cont.) • Acquired by mutation and passed vertically by selection to daughter cells. • More commonly – horizontal transfer of resistance determinant from donor cell, often another bacterial species, by transformation, transduction, or conjugation. • Horizontal transfer can be rapidly disseminated • By clonal spread or resistant strain itself • Or genetic exchange between resistant and further susceptible strains.

20. Resistance (cont.) • Methicilin resistant strains of Staphylococcus aureus clonally derived from few ancestral strains with mecA gene • Encodes low-affinity penicillin-binding protein that confers methicillin resistance. • Staphylococcal beta-lactamase gene, which is plasmid encoded, presumambly transferred on numerous occasions. Because is widely distributed among unrelated strains, identified also in enterococci

21. Selection of the ATB • Requires clinical judgement, detailed knowledge of pharmacological and microbiological factors. • Empirical therapy – initial – infecting organism not identified – single broad spectrum agent • Definitive therapy- microorganism identified – a narrow –spectrum low toxicity regiment to complete the course of treatment

22. Empirical and Definite Therapy • Knowledge of the most likely infecting microorganism and its susceptibility • Gram stain • Pending isolation and identification of the pathogen • Specimen for culture from site of infection should be obtain before initiation of therapy • Definite therapy

23. Rational ATB therapy • Precise diagnosis (clinical./microbiology) • Regional sensitivity/resistance patterns • ATB centre / Narional reference lab • Clinical state (renal, liver functions) • PK / PD relations • To reach the effectice concentration in the infection site

24. Pk/PD of antibiotics conc. in the site of infection Antimicrobial effect Conc. in the blood dose other effects conc. in other tissues ADME PHARMACOKINETICS PHARMACODYNAMICS

25. PK/PD classif. of ATB • T>MIC (maximum exposure time) – TIME DEPENDENT • peniciliny, cefalosporiny, karbapenemy, eryth, clarith, clindamycin, linezolid • Cmax : MIC (maximum safe concentration; PAE) • = CONCENTRATION DEPENDENT • fluorochinolony, aminoglykosidy, metronidazol

26. aminoglycosides1x vs. 2-3x daily

27. PK / PD...-lactams

28. co-amoxicillin BID vs. TID

29. Penicillins • Penicillins contain a b-lactam ring which inhibits the formation of peptidoglycan crosslinks in bacterial cell walls (especially in Gram-positive organisms) • Penicillins are bactericidal but can act only on dividing cells • They are not toxic to animal cells which have no cell wall

31. Penicillins (cont.)Clinical Pharmacokinetics • Penicillins are poorly lipid soluble and do not cross the blood-brain barrier in appreciable concentrations unless it is inflammed (so they are effective in meningitis) • They are actively excreted unchanged by the kidney, so the dose should be reduced in severe renal failure • This tubular secretion can be blocked by probenecid to potentiate penicillins`s action

32. Penicillins (cont.)Resistance • This is the result of production of b-lactamase in the bacteria which destroys the b-lactam ring • It occurs in e.g. Staphylococcus aureus, Haemophilus influenzae and Neisseria gonorrhoea

33. Penicillins (cont.)Examples • There are now a wide variety of penicillins, which may be acid labile (i.e. broken down by the stomach acid and so inactive when given orally) or acid stable, or may be narrow or broad spectrum in action

35. Penicillins (cont.)Examples • Benzylpenicillin (Penicillin G) is acid labile and b-lactamase sensitive and is given only parenterally • It is the most potent penicillin but has a relatively narrow spectrum covering Strepptococcus pyogenes, S. pneumoniae, Neisseria meningitis or N. gonorrhoeae, treponemes, Listeria, Actinomycetes, Clostridia

36. Penicillins (cont.)Examples • Phenoxymethylpenicillin (Penicillin V) is acid stable and is given orally for minor infections • it is otherwise similar to benzylpenicillin

37. Penicillins (cont.)Examples • Ampicillin is less active than benzylpenicillin against Gram-possitive bacteria but has a wider spectrum including (in addition in those above) Strept. faecalis, Haemophilus influenza, and some E. coli, Klebsiella and Proteus strains • It is acid stable, is given orally or parenterally, but is b-laclamase sensitive

38. Penicillins (cont.)Examples • Amoxicillin is similar but better absorbed orally • It is sometimes combined with clavulanic acid, which is a b-lactam with little antibacterial effect but which binds strongly to b-lactamase and blocks the action of b-lactamase in this way • It extends the spectrum of amoxycillin

39. Penicillins (cont.)Examples • Antistaphyloccocal penicilins • Flucloxacillin is acid stable and is given orally or parenterally • It is b-lactamase resistant • It is used as a narrow spectrum drug for Staphylococcus aureus infections

40. Penicillins (cont.)Examples • Azlocillin is acid labile and is only used parenterally • Piperacillinthe most potent and popular • It is b-lactamase sensitive and has a broad spectrum, which includes Pseudomonas aeruginosa and Proteus species • It is used intravenously for life-threatening infections,i.e. in immunocompromised patients together with an aminoglycoside

41. Penicillins (cont.)Examples • Timentin is a combination of of ticarcillin and clavulanic acid ( a beta lactamase inhibitor) designed to overcome the problems of beta-lactamase formation by Pseudomonas • It is used intravenously for life-threatening infections, given i.v. every 4-6 hours , half-life 1 – 1.5 hours, renally excreted

42. Penicillins (cont.)Adverse effects • Allergy (in 0.7% to 1.0% patients). Patient should be always asked about a history of previous exposure and adverse effects • Superinfections(e.g.caused by Candida ) • Diarrhoea : especially with ampicillin, less common with amoxycillin • Rare: haemolysis, nephritis

43. Penicillins (cont.)Drug interactions • The use of ampicillin (or other broad-spectrum antibiotics) may decrease the effectiveness of oral conraceptives by diminishing enterohepatic circulation

44. Cephalosporins • They also owe their activity to b-lactam ring and are bactericidal. • They are broad-spectrum antibiotics. • They are relatively expensive but good alternatives to penicillins when a broad -spectrum drug is required, should not be used as first choice unless the organism is known to be sensitive

45. Cephalosporins • Some cephalosporins (e.g.cefotaxime) may be indicated for empirical use to treat life-threatening infections where the organism is probably sensitive

46. CephalosporinsExamples and pharmacokinetics • Cephradine and cephalexin are well absorbed orally • Cephradine can be also given parenterally. • They cover mostly Gram-positive organism, such as Streptococcus pyogenes, S. pneumoniae and Staphylococcus aureus, as well as some Gram-negative bacteria,

47. Cephalosporins (cont.)Examples and pharmacokinetics • alhough they are less effective in this than later cephalosporins. • They are excreted by the kidney (reduce dose in renal failure)

48. Cephalosporins (cont.)Examples and pharmacokinetics • Cefuroxime can be given parenterally or as an oral prodrug. • It has a broader spectrum, including many Gram-negative bacilli. • Cefotaxime is given parenterally. • It has an even broader spectrum, including many Enterobacter, E.coli, Proteus strains.

49. Cephalosporins (cont.)Adverse effects • Allergy (10-20% of patients wit penicillin allergy are also allergic to cephalosporins) • Nephritis and acute renal failure • Superinfections • Gastrointestinal upsets when given orally

50. Aminoglycosides • They cause misreading of mRNA by the ribosome, leading to abnormal protein production. • They are bactericidal. • To enter the bacterium, they need to be actively transported across the cell membrane. • Anaerobic organisms are resistant.