Antimicrobial Drugs

1. Antimicrobial Drugs

2. Antimicrobial Drugs • Chemicals used to treat microbial infections • Before antimicrobials, large number of people died from common illnesses • Now many illnesses easily treated with antimicrobials • However, many antimicrobial drugs are becoming less useful

3. Antimicrobial Drugs • Chemotherapeutic agent= • Antimicrobial drug= • Different types of antimicrobial drugs: • Antibacterial drugs • Antifungal drugs • Antiprotozoan drugs • Antihelminthic drugs

5. Features of Antimicrobial Drugs • Most modern antibiotics come from species of microorganisms that live in the soil • To commercially produce antibiotic: • Select strain and grow in broth • When maximum antibiotic concentration reached, extract from medium • Purify • Chemical alter to make it more stable

6. Features of Antimicrobial Drugs:Selective Toxicity • Cause greater harm to microorganisms than to host • Chemotherapeutic index: lowest dose toxic to patient divided by dose typically used for therapy

7. Features of Antimicrobial Drugs: Antimicrobial Action • Bacteriostatic: inhibit growth of microorganisms • Bactericidal: Kill microorganisms

8. Features of Antimicrobial Drugs:Spectrum of Activity • Antimicrobial medications vary with respect to the range of microorganisms they kill or inhibit • Some kill only limited range : Narrow-spectrum antimicrobial • While others kill wide range of microorganisms: Broad-spectrum antimicrobial

10. Features of Antimicrobial Drugs:Effects of Combining Drugs • Combinations are sometimes used to fight infections • Synergistic: action of one drug enhances the activity of another or vice versa. • Antagonistic: activity of one drug interferes with the action of another.

11. Features of Antimicrobial Drugs:Adverse Effects • Allergic Reactions: some people develop hypersensitivities to antimicrobials • Toxic Effects: some antimicrobials toxic at high concentrations or cause adverse effects • Suppression of normal flora: when normal flora killed, other pathogens may be able to grow to high numbers

12. Features of Antimicrobial Drugs:Resistance to Antimicrobials • Some microorganisms inherently resistant to effects of a particular drug • Other previously sensitive microorganisms can develop resistance through spontaneous mutations or acquisition of new genes (more later).

13. So, The Criteria of the Ideal Antibiotic: • Selectively toxic to microbe but nontoxic to host. • Soluble in body- tissue distribution – BBB. • Remains in body long enough to be effective - resists excretion and breakdown. • Shelf life. • Does not lead to resistance. • Cost not excessive. • Hypoallergenic. • Microbiocidal rather than microbiostatic. • Concerns suppression of normal flora - antibiotic associated colitis with Clostridium difficule and it’s toxins or Candida albicans.

14. Mechanisms of action of Antibacterial Drugs • Inhibit cell wall synthesis • Inhibit protein synthesis • Inhibit nucleic acid synthesis • Injury to plasma membrane • Inhibit synthesis of essential metabolites

15. Figure 20.2

16. Inhibition of Cell Wall Synthesis:b-Lactam Drugs • Irreversibly inhibit enzymes involved in the final steps of cell wall synthesis • These enzymes mediate formation of peptide bridges between adjacent stands of peptidoglycan • b-lactam ring similar in structure to normal substrate of enzyme • Drug binds to enzyme, competitively inhibit enzymatic activity

17. b-Lactam Drugs • Some bacteria produce b-lactamase- enzyme that breaks the critical b-lactam ring • b-lactam drugs include: penicillins and cephalosporins

19. Penicillins (Benzylpenicillin) • Acid-labile. • Gram+ bacteria. • So, take phenoxymethylpenicillin. • Large Vd, but penetration into brain: poor, except when the meninges are inflammed. • Broad spectrum penicillins: amoxicillin and ampicillin are more hydrophillic and therefore, are active against gram- bacteria.

20. Penicillins (Benzylpenicillin) Penicillinase-resistant penicillins – Flucloxacillin Indicated in infections caused by penicillinase-producing pen-resistant staphlococci. Has an isoxazolyl group at R1  sterically hinders access of the enzyme to the β-lactam ring. Less effective than benzylpen. So, should be used only for pen-resistant infections. Well-absorbed orally, but in severe infections, should be i.v. and not alone. Staphlococci aureas-resistant strains to flucloxicillin and MRSA (methicillin-resistant Staph aureas) – increasing problem.

21. Broad-Spectrum Penicillins • Ampicillin and amoxicillin – very active against non-β-lactamase-producing gram+ bacteria. • Because they diffuse readily into Gram- bacteria, also very active against many strains of E. coli, H. influenzae, and Salmonella typhimurium. • Orally, amoxicillin is better because absorption is better. • Ineffective against penicillinase-producing bacteria (e.g., S. aureus, 50% of E. coli strains, and up to 15 % of H. influenzae strains. • Many baterial β-lactamases are inhibited by clavulaic acid ± amoxicillin (co-amoxiclav)  antibiotic is effective against penicillinase-producing organisms. • Co-amoxiclav indicated in resp and UT infections, which are confirmed to be resistant to amoxicillin.

22. Cephalosporins • Used for treatment of meningitis, pneumonia, and septicemia. • Same mech and p’col as that of pens. • May  allergic rxn and cross-reactivity to pen. • Similar to pens in broad-spectrum antibacterial activity. Cedadroxil (for UTI) in case of antibact resist. Cefuroxime (prophylactic in surgery) – Resistant to inactivation by β-lactamases and used in severe infections (others ineffective). Ceftazidine – wide range of activity against gram- including Pseudomonas aeruginosa), but is less active than cefurozime against gram+ bact (S aureus). Used in meningitis (CNS-accessible) caused by gram- bacteria.

23. Vancomycin • Not well absorbed orally. • Inhibits peptidoglycan formation. • Active against most gram+ organisms. • I.v. treatment for septicemia or endocarditis caused by MRSA. • Used for pseudomembranous colitis (superinfection of the bowel by Clostridium difficile – produces a toxin that damages the colon mucosa)

24. Antibacterial Drugs that Inhibit Cell Wall Synthesis

25. Antibacterial Medications that Inhibit Protein Synthesis • Target ribosomes of bacteria • Aminoglycosides: bind to 30S subunit causing it to distort and malfunction; blocks initiation of translation • Tetracyclines: bind to 30S subunit blocking attachment of tRNA. • Macrolides: bind 50S subunit and prevents protein synthesis from continuing.

26. Aminoglycosides • Against many gram- and some gram+. • Narrow TI – very potentially toxic. • Most important adverse side-effect: VIIIth cranial n. (ototoxicity) and kidney damage. • Resistance – several mechs: inactivation of the drug by acetylation, phos, or adenylation, Δ envellope to prevent drug access, and Δ the binding site of the 30S subunit (streptomycin only).

27. Aminoglycosides • Gentamicin – used for acute, life-thretening gram- infections. Has synergism with pen and van and combo. • Amikacin – used for bact that are gent-resistant. • Netilmicin – less toxic than gentamicin. • Neomycin – too toxic for parenteral use. Used for topically for skin infections and orally for sterilizing bowel before surgery. • Streptomycin – active against Mycobacterium tuberculosis. But bec of its ototoxicity, rifampicin replaces. • Rifampicin – resistance develops quickly alone; so, with TB, combine with isoniazid, ethambutol, and pyrazinamide for the 1st 2 mos of treatment, followed by another 4 mos with rifampicin and isoniazid.

28. Macrolides • Very safe drugs. • Ususally given orally. • Erythromycin and clarithomycin • Effective against gram- bact and can be used as an alt to pen-sensitive patients, esp in infections caused by streptococci, staphylococci, pneumococci, and clostridia. • Don’t cross the BBB – ineffective against meningitis. • Resistance- occurs bec of plasmid-controlled Δ of their receptor on the 50S subunit. • Erythromycin – in high doses, may cause nausea and vomiting (less so with clarithromycin and azithromycin). • Azithromycin – very long t1/2 (~40-60 hr) and a single dose is as effective in treating chlamydial non-specific urethritis as tretracycline admin over 7 days,

29. Tetracyclines • Broad-spectrum. • Penetrate microorganisms well. • Sensitive organisms accumulate it through partly passive diffusion and partly through active transport. • Resistant organisms develop an efflux pump and do not accumulate the drug. • Genes for tet-resistance transmitted by plasmids. • Closely assoc with those for other drugs to which the organisms will also be resistant (e.g., sulphonamides, aminoglycosides, chloramphenicol). • Tets bind to Ca in growing bones and teeth  can discolor teeth. So, should be avoided in children < 8 yrs old.

30. Chloramphenicol • Broad-spectrum. • Serious side-effects: bone marrow aplasia, suppression of RBCs, WBCs, encephalopathy, optic neuritis. • So, periodic blood counts required, esp in high doses. • Large Vd, including CNS. • Inhibits the actions of other drugs and may incr the actions of phenytoin, sulphonlureas, and warfarin. • Neonates cannot met the drug rapidly  accum  ‘grey baby’ syndrome (pallor, abdominal distension, vomiting, and collapse).

32. Antibacterial Drugs that Inhibit Protein Synthesis

33. Antibacterial Medications that Inhibit Nucleic Acid Synthesis • Target enzymes required for nucleic acid synthesis • Fluoroquinolones: inhibit enzymes that maintain the supercoiling of closed circular DNA • Rifamycins: block prokaryotic DNA-dependent RNA polymerase from initiating transcription

34. Sulphonamides • Sulfadiazine well-absorbed orally. Used to treat UTIs. • But many strains of E. coli are resistant. • So, use less toxic drugs instead. • Adverse effects: allergic rxns, skin rashes, fever. • Trimethoprin – used for UTIs and Resp TIs • Co-trimoxazole (trimethoprin + sulfamethoxazole) – used mostly for pneumonia, neocarditis, and toxoplasmosis.

35. Sulfonamides (Sulfa drugs) Inhibit folic acid synthesis Broad spectrum Antibacterials – Competitive Inhibitors Figure 5.7

36. Figure 20.13

37. Quinolones (GABA antagonists) • Inhibit DNA gyrase. • Nalidixic acid – used only for UTIs. • Ciprofloxin (6-fluoro substituent) that greatly enhances its effectiveness against both gram- and gram+ bacteria. Well-absorbed both orally and i.v. Eliminated largely unchanged by the kidneys. Side-effects (headache, vomiting, nausea) are rare; but convulsions may occur.

38. 5-Nitroimidazoles • Wide-spectrum • Metronidazole – against anaerobic bacteria and protozoan infections. • Tinidazole – longer duration of action. • Diffuses into the organism where the nitro group is reduced  chemically reactive intermediates are formed that inhibit DNA synthesis and/or damage DNA.

39. Antibacterial Drugs that Inhibit Nucleic Acids

40. Antibacterial medications that Injure Plasma Membrane • Polymyxin B: binds to membrane of G- bacteria and alters permeability • This leads to leakage of cellular contents and cell death • These drugs also bind to eukaryotic cells to some extent, which limits their use to topical applications

41. Antibacterial Drugs that Inhibit Synthesis of Essential Metabolites • Competitive inhibition by substance that resembles normal substrate of enzyme • Sulfa drugs

42. Antiviral Drugs • Very few antiviral drugs approved for use in US • Effective against a very limited group of diseases • Targets for antiviral drugs are various points of viral reproduction

43. Drugs that Prevent the Virus from Entering or Leaving the Host Cells • Amantadine – interferes with replication of influenza A by inhibiting the transmembrane M2 protein that is essential for uncoating the virus. - Has a narrow spectrum; so, flu vaccine is usually preferable. • Zanamivir – inhibits both influenza A and B neuraminadase. Decr duration of symptoms if given within 48 hr of the onset of symptoms. Prophylactic in healthy adults. • Immunoglobulins – Human Ig contains specific Abs against superficial Ags of viruses  can interfere with their entry into host cells. Protection against hepA, measles, and rubellla (German measles).

44. Drugs that Inhibit Nucleic Acid SynthesisNucleoside and Nucleotide Analogs • Acyclovir- used to treat genital herpes • Cidofovir- used for treatment of cytomegaloviral infections of the eye • Lamivudine- used to treat Hepatitis B

45. Acyclovir • HSV and VZV contain a thymidine kinase (TK) that  acyclovir to a monophosphate phosphorylated by host cell enzymes to acycloguanosine triphosphate, which inhibits viral DNA pol and viral DNA synthesis. • Selectively toxic (TK of uninfected host cells activates only a little of the drug). • Viral enzymes have a much higher affinity than the host enzymes for the drug. • Effective against HSV, but does not eradicate them. • Need high doses to treat shingles.

48. Ganciclovir • Quite toxic (neutropenia) –so, given only for severe CMV infections in immunosuppressed patients. • CMV is resistant to acyclovir because it does not code for TK.

49. Antiretrovirals • Currently implies a drug used to treat HIV • Tenofovir- nucleotide reverse transcriptase inhibitor • Zidovudine- nucleoside analog – inhibits RT of HIV and is only used orally for AIDS. - Activated by triple phosphorylation and then binds RT (with100X affinity than for cellular DNA pols). - Incorporated into the DNA chain, but lacks a 3’OH; so another nucleoside cannot form a 3’-5’-phosphodiester bond  DNA chain elongation is terminated. -Severe adverse effects: anemia, neutropenia, myalgia, nausea, and headaches. • Stavudine, didanosine, zalcitabine – among other NRTIs. • Nevirapine, efavirenz – Non nucleoside RTIs - denature RT.

50. Life Cycle of HIV