Antibacterial Chemotherapy 2024 PDF

Antibacterial chemotherapy By: Dr. Shadi Zakai (PhD) Assistant Professor and Molecular Microbiology Scientist Department of Medical Microbiology Faculty of Medicine King Abdulaziz University Points to be covered: • Introduction to antibacterial agents. • Mechanism of action. • Bacterial resistanc...

Antibacterial chemotherapy By: Dr. Shadi Zakai (PhD) Assistant Professor and Molecular Microbiology Scientist Department of Medical Microbiology Faculty of Medicine King Abdulaziz University Points to be covered: • Introduction to antibacterial agents. • Mechanism of action. • Bacterial resistance to antimicrobial agents. • Combination therapy. • Complication of antimicrobial agents. • Chemoprophylaxis. Points to be covered: • Introduction to antibacterial agents. • Mechanism of action. • Bacterial resistance to antimicrobial agents. • Combination therapy. • Complication of antimicrobial agents. • Chemoprophylaxis. Definitions Item Definition Chemotherapy is the drug treatment for the diseases caused by bacteria and the other pathologic microorganisms, parasites, and tumor cells. Antibiotics are antimicrobial drugs produced by living “biotic” microorganisms. Synthetic drugs Antimicrobial drugs synthesized in the lab. Selective toxicity kills harmful microbes without damaging the host cells. Definitions Item Definition Antimicrobial spectrum of activity the target that the drug can kill or suppress the growth of microorganism. Broadspectrum effective against “wide range” of species (e.g. chloramphenicol, tetracyclin). Narrowspectrum specific for certain species (e.g. vancomycin, isoniazid). SO, What is an Antibiotic? Antibiotic = against life. Substances produced by organisms to kill or suppress the growth of other organisms. The ideal antimicrobial drug should: Have highly selective toxicity to the pathogen. Have no or Have low less toxicity tendency to to the host. develop resistance. Not induce Have no hyperinteractions sensitivities with other in the host. drugs. Be relatively in-expensive. Bactericidal Vs. bacteiostatic Bactericidal Baceriostatic Have a rapid lethal action (kill bacteria). Capable to inhibit the growth or reproduction of bacteria, no killing. Examples: penicillin, cephalosporins and aminoglycosides. Examples: sulphonamides, tetracycline and chloramphenicol. Points to be covered: • Introduction to antibacterial agents. • Mechanism of action. • Bacterial resistance to antimicrobial agents. • Combination therapy. • Complication of antimicrobial agents. • Chemoprophylaxis. How do antibacterial agents work? 1- Inhibition of cell wall synthesis • • • Agents that act on cell wall prevent the crosslinking of the peptidoglycan units. Thus, interfere with the cell wall synthesis, and lead to lose of integrity and therefore, cell lysis. The cell wall is an ideal point of attack by selective toxic agents. Examples: – β-lactams, vancomycin, and bacitracin. β-lactam antibiotics: • Binds to Penicillin-Binding Proteins (PBPs) in the cell wall. • Inhibits the final step in the peptidoglycan synthesis (transpeptidation) leading to cell lysis. Vancomycin: • Binds to the pentapeptides of the peptidoglycan monomers. • Prevents the transglycosylation step in peptidoglycan polymerization. 2- Inhibition of cytoplasmic membrane synthesis • Main compositions of membrane: • proteins and lipids • Selectively combine with phosphatide in the cell membrane • increase permeability → water, ions and nutrients outflow from the cells → cell dies. • Example: Polymyxins. • Polymyxins are not used as systemic (toxic for the kidneys and nervous system). 3- Inhibition of nucleic acid synthesis • A. Inhibition of DNA replication: • Quinolones such as nalidixic acid and novobiocin, bind to DNA gyrase. • inhibition of DNA replication • death of the bacterial cell. • Fluoroquinolones such as ciprofloxacin, norfloxacin, and ofloxacin also interact with DNA gyrase and possess a broad spectrum of antimicrobial activity. 3- Inhibition of nucleic acid synthesis • B. Inhibition of RNA synthesis (transcription). • Rifamycins are a class of antibiotics that inhibit RNA synthesis. Rifampicin binds to RNA polymerase and interferes with the initiation process. 4. Inhibition of protein synthesis Remember: • Bacterial ribosome → 70S (50S and 30S) • Human ribosome → 80S (60S and 40S) Examples of antimicrobials bind to 50S Examples of antimicrobials bind to 30S •Chloramphenicol •Clindamycin •Macrolides •Tetracycline •Aminoglycosides (azithromycin, erythromycin) (streptomycin, gentamycin, tobramycin, and amikacin) 4. Inhibition of protein synthesis 5. Inhibition of folic acid synthesis • The drug “mimics” the normal metabolite and act as a “competitive inhibitor”. • Enzyme of cell recognizes the drug instead of the normal metabolite ➔ Pathway stops. • Example: • Sulfonamides: Competitively block the conversion of p-aminobenzoic acid (PABA) to dihydrofolic acid by the enzyme synthetase. • Trimethoprim: Has an affinity for bacterial dihydrofolate reductase Mode of action of some antimicrobial drugs Target site Drug Comment Cell wall Vancomycin Bacitracin β-lactams (e.g. penicillin, cloxacillin, and cephalosporins) Monobactams (e.g. aztreonam) Inhibit peptidoglycan formation Interfere with crosslinkages of peptidoglycan molecules- in low concentrations septum formation is inhibited Cytoplasmic Membrane Polymyxins Affinity for membrane in Gramnegative bacilli Amphotericin B Affinity for ‘sterol’ in fungal membranes Nystatin Cidal/static Cidal (osmotic lysis of bacteria with defective cell walls when high concentration of drug present) Cidal Static Mode of action of some antimicrobial drugs Target site Drug Comment Cidal/static Ribosomes Tetracyclines Interfere with transfer RNA-amino acid attachment – inhibits protein synthesis Static Chloramphenicol Interfere with translocation Static Erythromycin Lincomycin Fusidic acid Interfere with translocation protein synthesis inhibited Static with low oncentrations, cidal with high concentrations Aminoglycosides Interfere with mRNA attachment to ribosome Cidal Mode of action of some antimicrobial drugs Target site Nucleic Acid Replication Drug Comment Cidal/static Rifampicin Nalidixic acid Ciprofloxacin Interfere with RNA replication Interfere with DNA replication Static Static with low concentrations Metronidazole Interfere with DNA replication Cidal with high concentrations 5-fluorocytosine Grisefulvin Nucleic acid synthesis inhibition of some fungi Cidal Idoxuridine Aciclovir DNA synthesis in DNA viruses interfere with Cidal Zidovudine (AZT) Nucleic acid synthesis inhibited by interfering with reverse transcriptase of HIV Cidal Points to be covered: • Introduction to antibacterial agents. • Mechanism of action. • Bacterial resistance to antimicrobial agents. • Combination therapy. • Complication of antimicrobial agents. • Chemoprophylaxis. Mechanism of bacterial resistance Susceptibility to drugs becomes lower or even loses after contact with drugs many times. Non-genetic drug resistance: • Metabolically dormant state. • Lose of target structure (protoplast and L-form). • Intrinsic resistance. Mechanism of bacterial resistance Genetic drug resistance: • Plasmid-mediated resistance (e.g. βlactamase). • Transposon-mediated resistance (carries drug-resistance genes). • Chromosomal-mediated resistance. Mechanism of bacterial resistance 1. Destroying the drug by production of enzymes 2. Alteration of the target site of the drug 3. Decreased Access to Target Site: (Decreased uptake or increased efflux) 4. Developing an altered metabolic pathway that bypasses the reaction inhibited by the drugs (1) Destroying the drug by production of enzymes: • ß-lactamases (as penicillinases or cephalosporinases). • Chloramphenicol acetyltransferase destroys chloramphenicol structure. • Aminoglycoside-modifying enzymes (common in Gram +ve and -ve. (2) Alteration of the target site of the drug – Example: Resistance to aminoglycosides is by alteration of the binding site on 30S ribosome. – In MRSA: PBP → PBP2a or PBP2’ (3) Decreased Access to Target Site: (Decreased uptake or increased efflux) • Example: Resistance to polymyxins – The organism changes its permeability to the drug by modification of protein in the cytoplasmic membrane – Thus impairing its active transport into the cell. (4) Developing an altered metabolic pathway that bypasses the reaction inhibited by the drugs: • Example: Sulphonamideresistant bacteria acquire the ability to use preformed folic acid with no need for extracellular PABA. How to avoid bacterial resistance? Points to be covered: • Introduction to antibacterial agents. • Mechanism of action. • Bacterial resistance to antimicrobial agents. • Combination therapy. • Complication of antimicrobial agents. • Chemoprophylaxis. Combination therapy Why combination therapy is EFFECTIVE in special situations? ✓ To treat life-threatening infections. ✓ To treat mixed infections of unknown sources. ✓ To prevent the emergence of resistant organisms (e.g. M. tuberculosis). ✓ For synergistic killing (e.g,β-lactam plus aminoglycoside for endocarditis). Combination therapy Why combination therapy is NOT USEFUL ALL THE TIME? ❖ ❖ ❖ ❖ Antagonism Cost Increased risk of side effects May actually enhance development of resistance ❖ Interactions between drugs of different classes ❖ Often unnecessary for maximal efficacy Combination therapy Examples of effective synergy of antimicrobial combination therapy: • Penicillin and aminoglycosides to treat Enterococcus faecalis . • Carbenicillin and gentamicin to treat P. aeruginosa • Clavulanic acid (β-lactamase inhibitor) and penicillins to inhibit S. aureus, Klebsiella, and H. Influenza (Augmentin). • Sulfamethoxazole and trimethoprim targets two steps of the folic acid cycle and synergistically to treat a wide variety of bacterial infections. Combination therapy However, not all combination therapy are usually effective.!!! Antagonism Can occur when a bacteriostatic agent is combined with a bactericidal agent. – Example: Tetracycline and Penicillin – Tetracycline inhibits the growth of the organism, thereby preventing the bactericidal effect of penicillin, which kills multiplying organisms only. Points to be covered: • Introduction to antibacterial agents. • Mechanism of action. • Bacterial resistance to antimicrobial agents. • Combination therapy. • Complication of antimicrobial agents. • Chemoprophylaxis. Complications of antimicrobial agents Drug toxicity: – Overdose – Prolonged use – Narrow margin of selective toxicity • Streptomycin affects the 8th cranial nerve leading to deafness. • Aminoglycosides are nephrotoxic. • Tetracyclines inhibit growth and development of bones and teeth in the developing foetus and infants. Complications of antimicrobial agents Development of drug resistance: – inadequate dosage – prolonged treatment – abuse of antibiotics without in vitro susceptibility testing • Example: More than 90% S. aureus becomes methicillinresistant (MRSA) in hospitals. Complications of antimicrobial agents Hypersenstivity: • Allergic reactions – penicillins → IgE-mediated, or delayed hypersensitivity reactions. (most serious: anaphylactic shock). • Milder manifestations – Urticaria – purpural eruption – skin rash – diarrhea, vomiting and jaundice. Complications of antimicrobial agents Superinfections: • By altering the gastrointestinal flora, almost all antibiotics can cause overgrowth of Clostridium difficile → produces a toxin → diarrhea and pseudomembranous colitis. • Alteration of intestinal flora by antibiotics → Candida in the mouth, vagina, or gastrointestinal tract. Complications of antimicrobial agents Others: • Hematologic reactions. • Depression of blood platelet activity. • Isoniazid metabolized in liver → liver damage. • Damage to the kidneys can follow the use of aminoglycosides. Points to be covered: • • • • • • Introduction to antibacterial agents. Mechanism of action. Bacterial resistance to antimicrobial agents. Combination therapy. Complication of antimicrobial agents. Chemoprophylaxis. Chemoprophylaxis A conservatory use of antibiotics to prevent further infections. ✓ Prior to surgery. ✓ In immunecompromised patients. ✓ In people with normal immunity who have been exposed to specific pathogens. Chemoprophylaxis Examples: • Penicillin G to prevent reinfection with S. pyogenes. • Oral administration of tetracycline to prevent cholera. • Oral administration of rifampicin during epidemics of meningococcal meningitis. • The use of ceftriaxone to prevent gonorrhea. FINALLY…..! • Antibiotic for FLU?