MMBIO 221: Chemotherapeutic Agents - Week 4
MMBIO 221: Chemotherapeutic Agents - Week 4 MMBIO221
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This 8 page Class Notes was uploaded by Kirsten Notetaker on Friday September 23, 2016. The Class Notes belongs to MMBIO221 at Brigham Young University taught by Donald Breakwell in Fall 2016. Since its upload, it has received 5 views. For similar materials see General Microbiology in Biology at Brigham Young University.
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Date Created: 09/23/16
Chemotherapeutic Agents – Fighting Microbes ***It is a NECESSITY to know the pink antibiotics cheat sheet very well!!*** Gram + vs gram - bacteria Gram +: thick, rigid plasma membrane with 90% peptidoglycan, multiple layers of protection Gram -: thin plasma membrane with 10% peptidoglycan, with an additional phospholipid outer membrane called lipopolysaccharide (LPS) or endotoxin (our bodies don’t like endotoxin- it sends us into shock) Periplasm = the space between plasma membrane & outer membrane Two fathers of antibiotic chemotherapy – Fleming and Waxman (refer to pink cheat sheet) Technically, any medicine is a chemotherapeutic agent – we will talk mostly about antibiotics Ideal qualities of antibiotics (abx) – these are rarely achieved Broad spectrum (can kill more than just one specific strain of microbes) Work so as to prevent evolution of antibiotic-resistant strains of pathogens Not realistic, but still ideal No undesirable side-effects Don’t destroy normal flora (normal microbes living in & on body) Not inactivated by body fluids Highly soluble in body Reach high enough concentration to work (with abx small quantities are usually enough) Minimum Inhibitory Concentration (MIC) = lowest concentration of an abx at which the growth of a strain of bacteria will be prevented Broth dilution method – testing various concentrations of abx using a broth solution in the lab Each successive tube has ½ the concentration of abx as the previous tube The tube with the lowest concentration of abx that still shows no growth of bacteria is the MIC Growth is evident by cloudiness or abnormal color in the broth It is recommended that serum (blood fluid) abx levels be maintained above the MIC for at least 50% of the time of treatment (much better if this 50% is a continuous block of time) Therefore, you would want to take a dose higher than the MIC to keep it above that level Strategies for abx therapy 1. Decide whether or not the patient actually has a bacterial infection 2. Make a reasonable statistical guess as to the possible pathogens 3. Be aware of susceptibility patterns in your area a. This info is provided by the health department 4. Take into account previous abx treatment & its effectiveness 5. Take into consideration important host factors a. Site of infection, peripheral white blood cell (wbc) count, age and underlying diseases, duration of hospitalization, severity of disease 6. Use the fewest drugs possible 7. If necessary, switch to narrower spectrum abx 8. When all things are equal, pick the least expensive abx Bactericidal vs Bacteriostatic Bactericidal = kill bacteria Bacteriostatic = stop or suspend further growth of bacteria Allows immune system to “catch up” to the bacteria Antibiotics Natural chemotherapeutic agents Typically produced by microorganisms, particularly actinomycetes & gram-positive bacteria Modes of action through which antibiotics work 1. Prevention of cell wall synthesis a. Ex: β-lactams 2. Inhibit function of ribosome (interferes with protein synthesis) 3. Interference with nucleic acid synthesis 4. Interference with metabolism See slides on Learning Suite for image showing various modes of action for selected abx Β-lactam antibiotics: bactericidal, inhibit cell wall synthesis, contains square structure in chemical representations (susceptible to β-lactamases which break this square) Penicillin G and V Original penicillin used medically, usually for gram positive bacteria Administered IM (intramuscular) or IV (intravenous), but can be oral Resistance is high Still used for Streptococcus pneumoniae Penicillin V is oral form (PO = by mouth), acid stable (can survive acidity of stomach) Used for streptococcal pharyngitis (group A strep) Aminopenicillins Ampicillin & amoxicillin Broader spectrum than Pen G Also affects gram negatives (penetrates bacterial outer membrane better) Oral, especially amoxicillin IV used with gentamicin Carboxypenicillins Carbenicillin & ticarcillin Gram negatives, including Pseudomonas aeruginosa, Bacteroides, and anaerobes Susceptible to penicillinases Penicillinase-resistant (β-lactamase resistant) penicillins Methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin Anagram: I MET a NAsty OX Staphylococcus aureus infections Usually IV Methicillin not really used in US Penems Imapenem (“I’m a pen”) and meropenem Broadest antibacterial activity of any antibiotic known Kill gram positives, anaerobes, Pseudomonas aeruginosa MRSA, some pseudomonads, mycoplasmas are resistant “plasma” in bacteria name means it doesn’t have a cell wall Often given with cilastin (which inhibits dihydropeptidase, found in kidneys) Monobactams Aztreonam (only a β-lactam ring with side groups) Gram negative aerobic bacteria Cephalosporins (know if these are gram positive or negative) First generation: “ph” Cephalothin, cephapirin, cephradine, cephalexin Good for gram positives (i.e. staph & strep) Second generation: “fam”, “fa”, “fur”, “fox”, “tea” Cefamandole, cefaclor, cefuroxime, cefoxitin, cefotetan Good for gram negatives Third generation: “t” Ceftriaxone, ceftazidime, cefotoaxime, ceftizominem, ceftibuten Good for gram negatives Fourth generation: fep, pir Cefepime Good for gram positives Vancomycin – this one doesn’t actually have the β-lactam square Covers all gram positive bacteria Synergistic with penicillins Inhibits 1 step earlier than penicillins Not absorbed orally, great for pseudomembranous colitis (i.e. c. dif) Inhibitors of ribosomal function (protein synthesis) Ribosomes have a large and a small subunit 5 classes of protein synthesis inhibitors TAG inhibit small subunits, LOAM inhibit large subunits T = tetracycline - 4 circles (or hexagons) in chemical shape Venereal diseases, walking pneumonia, animal and tick-borne diseases, 2+ 2+ Chelates with Ca , Mg , cations in milk (inactivates tetracyclines) Doxycycline chelates poorly, so is not as affected by this Can cause GI irritations, phototoxic dermatitis, renal and hepatic toxicity, discolored teeth and depressed bone growth AG = aminoglycosides Often used with penicillin because they diffuse across the cell wall Kill aerobic gram negative enterics th Side effects include 8 cranial nerve toxicity – vertigo, hearing loss, kidney damage, neuromuscular blockade L = lincosamides Clindamycin is a classic example Used against anaerobes Clin + aminoglycoside for penetrating wound infections of abdomen Aminoglycoside treats gram negative aerobes Infections of female genital tract Our normal flora in gut are anaerobes, so can negatively impact those Can cause pseudomembranous colitis O = oxazolidinones Ex: linezolid Inhibits gram positives VRE (vancomycin-resistant enterococcus) Side effects include headaches, GI upset (nausea, vomiting, diarrhea) A = chloramphenicol (bacteriostatic) Kills most clinically important bacteria Rare, but severe side effects Aplastic anemia Irreversible destruction of bone marrow Gray baby syndrome resulting from improper metabolism and excretion of the abx Used for bacterial meningitis when pt is allergic to penicillins Used for young children with Rocky Mountain Spotted Fever Really inexpensive – used extensively in developing countries M = macrolides Classic example is erythromycin Really only effective against gram positives Gram neg exceptions – mycoplasma, legionella, chlamydia Community-acquired pneumonia that do not require hospitalization One of the safest antibiotics Other macrolides include clarithromycin, azithromycin, roxithromycin Fluoroquinolones – bacterial DNA synthesis inhibitors, have “floxacin” in name Inhibits DNA gyrase, which unwinds DNA double helix Great advantages – safe, achieve high blood levels w/ oral absorption, penetrate well into tissues Few adverse effects – GI irritability, damage to cartilage, headache, insomnia Great against gram negatives, not anaerobes or gram positives (except Staph and B. anthracis) Nitroimidazoles Ex: metronidazole (Flagyl) NOT used to treat fungal infections, like other “-azoles” Reduced when it enters the cell and then damages the DNA by breaking the sugar-phosphate backbone and destabilizing the double helix Antimetabolites – “sulfa” drugs, have sulfur group in chemical structure Trimethoprim-sulfamethoxazole (TMP-SMX) Sulfa drugs are structural analogs of p-aminobenzoic acid (folic acid biosynthesis) TMP also affects the pathway, but different step Inhibit both gram positive and gram negative (not anaerobes) Used for TMP (Tree, Mouth, Pee) Respiratory tree – respiratory infections Mouth – oral infections Pee – urinary tract infections Antiviral agents Prevent the uncoating of virus when virus enters cell Interfere with the synthesis and translation of viral mRNA Interferon Inhibit viral RNA or DNA replication Nucleoside analogs Antifungal agents – interferes w/ cell membrane or cell wall Polyenes Interfere w/ membrane permeability Allylamines Prevents early steps in sterol biosynthesis Imidazoles and triazoles Inhibit a late step in the formation of ergosterol Echinocandins Inhibit formation of fungal cell wall Antiprotozoal agents – don’t need to know these Flagyl – giardia Atovaquone – pneumocystis pneumonia, malaria, babesia, toxoplasmosis Iodoquinol – amebiasis, balantidiasis Chloroquine – malaria Pentamidine – pneumocystis pneumonia Melarsoprol – trypanosomiasis Eflornithine – trypanosomiasis Paromomycin – amedbiasis, leishmaniasis, cryptosporidiosis
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