Lecture 8: Antimicrobials

Antimicrobials Lecture 8 Early Antimicrobial Substances · damaged the host more than the pathogen · examples of early syphilis treatment: a) Mercury - 15th century b) Arsenic - 1910 "magic bullet" c) Fever - 1917 (induced by malaria -neurosyphilis) d) Penicillin - 1929 (seen as the magic bullet with selective activity on prokaryotes) · The first synthetic antimicrobial substance to act selectively on bacteria was SULFA (1932-"Prontosil") Antibiotic era: PENICILLIN "wonder drug" · discovered by Alexander Fleming as a mistake ↳ was not able to purify the drug himself · Howard Florey and Ernst Chain were successful at purifying and isolating penicillin Antibiotics don't kill human cells because we can produce antibiotics that will have a selective effect on bacteria What can we use to fight infection? · Antiparasitic agents · Antifungal agents · Antiviral agents · Antibiotics · some immunoactive substances, eg. interferon (unwanted side effects tho) · maintenance of immune integrity, hygiene Antiparasitic Agents · Anti-protozoan and anti-helminthic drugs · Quinine and derivatives (fight malaria) ↳ increased resistance of malaria to the drugs Anti-fungal Agents · problems with toxicity: Fungi are eukaryotic organisms ↳ humans and fungi are both eukaryotes so aspects of the drugs can affect us too ↳ all drugs have some toxicity which affects our kidneys · the most successful agents affect the plasma membrane of fungi (which contains ergosterol instead of cholesterol) · Most common drug for systemic fungal illness: - amphotericin B (inhibits ergosterol synthesis in the cytoplasmic membrane of the fungal cell) Anti-Viral Agents (affects the different life stages of the virus) · DNA/RNA synthesis inhibitors · Entry inhibitors (blocks attachment of virus to host cell) · Uncoating inhibitor - M2 proton channel (virus cannot release its genome) · Nucleoside analogue · Protease inhibitors eg. Azidothymidine (AZT) or Zidovudine (treats HIV) ↳ inhibits the reverse transcriptase (Synthesis of DNA from RNA) vs. Bacteriostatic antibiotics Bactericidal antibiotics · stops the replication of bacteria · Kills the bacteria eg. erythromycin (macrolides) eg. penicillin (beta-lactam) · does NOT kill the bacteria already present · stops bacterial metabolism Why use bacteriostatic? ↳ the immune system can simply remove the useless bacteria since they cannot replicate anymore Antibiotics (Anti-bacterial) Major Classes of Antimicrobials (know these and common examples from the antibacterial picture) 1. Inhibition of cell wall synthesis 2. Inhibition of protein synthesis 3. Injury to the plasma membrane 4. Inhibit nucleic acid synthesis 5. Inhibit the synthesis of essential metabolites Erythromycin (Not being tested on 50S and 30S ) Cell wall synthesis, nucleic acids synthesis, cell membrane, protein synthesis, penicillins, cephalosporins, carbapenems, monobactams, folate synthesis, sulfonamides, trimethoprim, quinolones, cyprofloxacin, rifampin, rifampicin, polymyxins, tetracyclines, aminoglycosides, gentamicin, macrolides, clindamycin, linezolid, chloramphenicol Specific Antibiotics · only inhibits certain groups of bacteria · inhibits gram negative OR gram positive OR certain species Broad Spectrum antibiotics Penicillin = narrow spectrum Amoxicillin = broad spectrum · inhibit both gram negative AND gram positive bacteria (Use as narrow of a spectrum as possible) Who are most susceptible to bacterial infection? · Diabetics (hard to heal skin infections) · Children (developing immunity) · Elderly (immunosenescence) · Burn wound: skin and soft tissues ("sterile" tissues are exposed) · Immunocompromised (deficient immune system, neutropenia, chemotherapy) Antibiotics can be harmful Antimicrobial Side effects/Complications: · Pregnant women eg. tetracycline · Liver - fluoroquinolones · Allergies eg. penicillin · Children · People with liver or kidney damage ↳ liver: fluoroquinolones, macrolides ↳ Kidneys: aminoglycosides Too late for Antibiotics: · too many bacteria · too much tissue damage · kidney - aminoglycosides · Rash, allergy - penicillin · GI upsets - penicillin · Nerve damage - Fluoroquinolones · Ototoxicity - aminoglycosides · Teeth and bone formation in children - tetracyclines · Cartilage formation in children - fluoroquinolones Gentamycin can cause neurological damage and kidney damage · formation of walled-off abscesses that cant be penetrated by antibiotics · poor absorption of drug IV antibiotics: when to use them Polymicrobial Infections · GI problems · require broad spectrum drugs · Only drug possible (eg. Vancomycin) specific bacteria types because · serious infections: meningitis, septicaemia, endocarditis eg. enterobacter, staphylococcus, ↳ problems with absorbing (IV is also faster) · Rapid bioavailability (quick absorption) Pseudomonas aeruginosa because you do not know the there are so many streptococcus · gram negative, bacillus · "Opportunistic pathogens" ↳ normal inhabitants of soil and water, infect when they can · Very hardy, can even live in liquid soaps · needs very few nutrients · can infect many body sites · Common in burn victims, and cystic fibrosis · has endotoxin, also produces exotoxins Penicillin vs. Bacterial Mutation · penicillin was used for a while (very good for staph) until bacteria mutated · the mutation led to the enzyme beta-lactamase or "penicillinase" ↳ inactivation of penicillin by breaking the beta-lactam ring · to combat the mutation synthesis of semi-synthetic penicillins were made ↳ the active portion of the antibiotic was protected from the enzymes Pseudomonas How do Bacteria become resistant to antibiotics? 4 ways: · prevent penetration · destruction of drug · target site alteration · ejection of drug from bacterium (drug efflux) R-factors · r-factors are plasmids that carry genes with antimicrobial or antibiotic resistance · genes coded on small circular independently replicating pieces of DNA called plasmids, which are located in the cytoplasm of bacteria · genes can be transferred by conjugation (sex pilus) · R-factors can also be transferred between different bacterial species!!! What are Superbugs? ↳ bacteria that can't be controlled by antibiotics Superbug resistance · Overuse · inappropriate treatment · incomplete treatment regimens · all bugs don't need drugs! Different synthetic penicillins MRSA and VRSA · Staphylococci mutated again and are resistant to the semi-synthetic penicillin · MRSA: methicillin resistant S. aureus (Staph. With the mec gene) ↳ MSSA: methicillin susceptible S. aureus · changed the penicillin binding site on the bacterium to produce a variant resistant to the methicillin · penicillin binding protein 2 (PBP2) mutates to PBP2a (encoded by MeCA) = low affinity for binding penicillin · penicillin will not be effective for inhibiting the cross-linking of peptidoglycan ↳ only treatment left is vancomycin · VRSA: Vancomycin resistant S. aureus ↳ Will we have antibiotics in the future? VRE (vancomycin resistant enterococci) · genetic mutations - several in genes Van A, Van B, Van C · resistance developed after use of "avoparcin" (glycopeptide) in animal feed · avoparcin looked similar to vancomycin so it forced bacteria to resist ESBL (extended spectrum beta-lactamase) · essentially a supervillain form of beta lactamase that can inactivate the new really good beta-lactams like meropenem · enterobacteriaceae like E. coli: genetic mutations, many resistant genes · resistance to penicillins and cephalosporin · NDM-1 (new delhi metallobetalactamase ) XDR-TB · a strain of tuberculosis · resistant to both first and second line anti-TB drugs · new hope: pretomanid + Bedaquiline + Linezolid for 6 months (90-95% cure rate) MIC: minimum inhibitory concentration · minimum amount of antimicrobial that will inhibit (not kill) the microorganism · every important bacterial isolate must be tested · need to know for appropriate dosing levels and intervals "Drug of choice" · drug that is deemed to be the most effective with the least toxicity for a specific infection eg. penicillin is the "drug of choice" for streptococcal infections in the throat (pharyngitis) Kirby Bauer/disk diffusion test · tests for antimicrobial susceptibility · SIR: Each circle around the disks is the zone of inhibition ↳ sensitive/susceptible ↳ intermediate ↳ resistant · interpretation: measure the zones of inhibition and compare to standard charts to get SIR E-Test (Ellipse Test) · determines MIC · an easy way to determine MIC for a drug on a specific bacterial stain Monitoring of serum antimicrobial levels ① attain effective levels (over MIC) ② prevent toxic side effects · chloramphenicol: bone marrow · aminoglycosides: ototoxic and nephrotoxic. May cause permanent damage (deafness & kidney dysfunction) ③ ascertain dosing intervals (every 8/2/24 hours etc. ) Escherichia coil is gram negative bacillus