Antimicrobial Agents

jmburk07
Flashcards by jmburk07, updated more than 1 year ago
jmburk07
Created by jmburk07 almost 6 years ago
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Flash Cards created from Dr. Chand's lecture on 5/6/15

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Ludwig's Angina -Serious life-threatening cellulitis or connective tissue infection, of the floor of the mouth, usually ocuring in adults with concomitant dental infections -May obstruct the airway, necessitating tracheotomy
Anti-Infection Agents Substances that act against or destroy infections (Fungal/Viral/Bacterial)
Antibacterial Agent Substances that destroy or suppress the growth or multiplication of bacteria
Antibiotics Substances produced by bacteria that can destroy or suppress the growth or multiplication of bacteria or prevent the action of bacteria
Antimicrobials Natural or Synthetic substances used to suppress growth to kill bacteria/single cell organisms
Concept of Selective Toxicity -Goal of antimicrobial and anticancer Therapy -Inhibition of pathways/targets that are critical for pathogen / cancer cell survival -dose needed should be ideally affective host cells
Mechanisms of Selective Toxicity 1. Attacking a target unique to pathogen 2. Targets that are similar to host but not identical 3. targets shared by host and pathogen but are vital for pathogen/ cancer cell survival.
Unique Drug Targets -Metabolic pathways, enzymes and mutated genes lacking in the host -Bacterial peptidoglycan cell wall -Penicillins and other beta-lactam abx inhibits transpeptidases which catalyze cross linking of peptidoglycan strand formation -Weak cell wall and cell lysis -Fungi: Beta 1,3-D-Glycan in fungal cell wall as well as Ergosterol (Azole and Polyenes) -Amphotericin B: systemic antifungal may affect cholesterol metabolism in humans.
Selective Inhibition -Organisms have similar metabolic pathways -Evolutionary divergence distinct enzymes -Receptor isoforms may not be totally distinct -Dihydrofolate reductase (DHFR) is a crucial enzyme in synthesis of purines and pyrimidines -Trimethoprim and pyrimethamine have selectivity for organisms while methotrexate is non-selective -Bacterial protein synthesis involves binding of mRNA to ribosome, decoding, translocation of peptide chain (Macrolides and Aminoglycosides)
Common Targets -Tumor Cells arise from normal cells and share common pathways for growth/mutation -Recently: mutated and over expressed proteins in cancer cells help in targeting them. -Cancer cell growth behavior, apoptosis and senescence differ from normal cells -Rapidly proliferating cells targeting easily -5-FU (Flurouracil) inhibits thymidilate synthase which is essential for building pyrimide in DNA -This results in DNA damage and early apoptosis in Cancer cells as well as normal cells
Mechanisms of Antibacterial Action -Inhibition of Cell wall Synthesis -Alteration of cell membrane permeability -Inhibition of Ribosomal Protein Synthesis -Suppression of DNA synthesis -Inhibition of Folic Acid synthesis
Abx which affect Cell Wall Synthesis -Beta Lactams: Penicillins, Cephalosporins, Carbapenems, Monobactams -Vancomycin, Bacitracin -Cell Membrane: Polymyxins
Abx that act on Protein Synthesis -50S Subunit: Macrolides, Clindamycin, Linezolid, Chloramphenicol, Streptogramins -30S Subunit: Tetracyclines, Aminoglycosides
Abx that act on Nucleic Acid Synthesis -Folate synthesis: sulfonamides -DNA Gyrase: Quinolones -RNA Polymerase: Rifampin
Inhibition of Cell Wall Synthesis -Cell walls contain alternating Peptidoglycan units, cross linked with amide linkages -Bacterial enzymes termed Penicillin binding proteins (PBP) catalyze the formation of the wall by incorporating new peptidoglycan strands -Beta-Lactam abx competitively inhibit this final process, thus preventing a rigid cell wall from forming -Internal osmotic pressure causes lysis: Penicillins and Cephalosporins
Alterations in Cell Membrane -Bacterial cell membrane contain a lipopolysaccharide component -This maintains cell membrane integrity -Abx s/a Polymixin B displace Ca++ and Mg++ from the cell membrane and disrupt the membrane
Inhibition of Protein Synthesis -Bacterial Ribosomes have subunits s/a 30S and 50S where proteins are synthesized -Abx bind to the "P" site of these subunits and inhibit Peptidyl transferase -This inhibits binding of tRNA to mRNA -30S: tetracyclines, aminoglycosides -50S: Macrolides, Clindamycin
Inhibition of Nucleic Acid Synthesis -Supercoiling of DNA, DNA replicaiton, Recombination, and DNA repair occurs by DNA Gyrase and Topoismerase enzymes -Fluroquinolones and Metronidazole inhibits these enzymes -Results: Vacuoles, filamentation and cell lysis
Inhibition of Folic Acid Synthesis -Humans do not produce Folic Acid, it is available from dietary sources -Bacteria synthesise their own Folic Acid from PABA (Para amino benzoic acid) -PABA converts into dihydrofolic acid by enzyme Dihydrofolate reductase -Sulfonamides are structural analogues of PABA and block the conversion -Sulfamethaxazole and Trimethoprim
Microbial Resistance 1. Enzymatic Inactivation 2. Modification of target site 3. Altered cell membrane permeability 4. Active Drug Efflux 5. Failure to activate the abx 6. Insensitivity to apoptosis 7. Overproduction of target sites
Natural Resistance Bacterial has always been resistant d/t inherent properties of the bacteria
Acquired Resistane Resistance seen in bacteria which were previously sensitive to an antimicrobial agent. This develops over time with long term use.
Enzyme Inactivation -Beta-lactamase inhibit the Beta Lactam ring -Staphylococci and enterococci produce this enzyme -Cross transfer this gene for resistance -A single beta-lactamase enzyme can hydrolyze 100 penicillin molecules -Penicillins & Cephalosporins
Genetic Mechanisms -There are various genetic mechanism by which abx resistance to antimicrobials may develop -Chromosomal mutations may be transferred to the daughter cell (vertical transmission) or to other bacteria by sharing genetic material (horizontal) -Bacteriophages: bacterial viruses that may be shared -Integrons: genetic elements that capture and disseminate genes through a "Gene cassette" -Transposon: Mobile genetic element which may be transferred from one organism to another -Plasmid: DNA molecule that can survive independently and inject itself into a naive bacteria
Intensity to apoptosis -Drug resistance in CA cells occur through chromosomal mutations that are passed to daughter cells -Resistant tumor is created which is insensitive to apoptosis -Chemotherapeutic Agents cause molecular lesionswhich cause cell cycle arrest, inactivation of repair process and apoptosis. -Mutations in key proteins s/a p53 and Bcl-2 lead to failure of apoptosis -Pancreatic, lung and colon cancers have high incidence of such p53 mutations
Superinfections A new infection while pt is being tx for a primary infection. -More likely w/ broad spectrum abx -May also be opportunistic infections w/ fungi s/a Candida albicans and Histoplasmosis -May occur d/t inhibition of normal flora s/a Clostridium difficile and pseudomembranous colitis -Often difficult to treat -Drug resistant microbes usually involved -Genetic messages (Plasmids, Transposons) transferred to new bacteria
Antibiotic Therapy -Empiric: begin tx immediately in severe infection; consider taking sample for culture -Tx w/ combination drugs usually prevents resistance and superinfection development -Standard of care in HIV/TB
Chemoprophylaxis Before a potential exposure. Used in high risk patients. Used in surgery to prevent wound infections. Dental procedures to prevent endocarditis. Immunocompromised pts to prevent reactivation of latent infections.
Spectrum of Activity -Narrow spectrum: Agents that are active against a single species or a limited group of pathogens [Penicillin G; Cloxacillin, nafcillin, methicillin, penicillin V; ERythromycin; Clindamycin] -Extended: agents that activity greater than a limited group but narrower than broad spectrum [Amoxycillin, Ampicillin, Pipercillin, Ticarcillin] -Broad Spectrum: agents that are active against a wide range of pathogens [Tetracyclines; Chloramphenicol, sulfamethoxazole]
Antibiotic Failure -Blood concentration too low -Patient compliance -IMpaired host immune system -Inappropriate choice of drug -Limited vascularity or blood flow to tissue -Emergence of bacterial resistance -Delay in diagnosis -Incorrect diagnosis -Abx antagonism or interactions
Bactericidal Bacteriostatic Penicillin V; Amoxicillin; Cephalexin; Cefadroxil; Metronidazole; Cipro; Aminoglycoside; Erythromycin; Clarithromycin; Azithromycin; Clindamycin; Tetracycline; Doxycycline
Antibiotic Adverse Effects -Abx teratology: FDA class B or C -Long QT Syndrome: Genetic or acquired by drug use. Fluroquinolones, Macrolides may cause sudden syncope and cardiac arrest -Agranulocytosis: reduced netorphil counts w/ septicemia and shock. May be caused by sulfonamides and penicillins -Superinfection: Destruction of normal flora (diarrhea and pseudomembranous colitis) -Oral contraceptives: CYP 450 induction or decreased GIT absorption of OC [Loss of contraception] -Photosensitivity, Stevens Johnson, Allergy, and Toxicity
Penicillins Parenteral Penicillin G/ Oral Penicillin V Used for mixed aerobic-anaerobic infections of the head and neck and dental infections.
Penicillins Antistaphylococcal Penicillins Structurally resistant to beta lactamase. Skin and soft tissue infections Oxacillin, Cloxacillin, Methicillin, Nafcillin
Penicillins Aminopenicillins -Used for ear, nose, and throat and H. pylori Ampicillin, Amoxicillin, Clavulinic Acid
Penicillins Ureidopenicillins Used for Klebsiella and enterococci Pipericillin and Mezlocillin
Penicillins Mechanism of action Bind to penicillin binding proteins (PBP). -Inhibit Transpeptidase: inhibit the cross-linkages between the peptidoglycan polymer strands -Promote Autolycins: autolycins is an enzyme that breaks section of cell wall to permit bacteria cell growth and cell lysis. -Most effect against growing and dividing cells
Penicillin G (Benzylpenicillin) -Parenteral use only (IV) -Narrow spectrum (Gram + & some gram +) -Bactericidal -Susceptible to Beta Lactamase _Administration: IM or IV (BUT NOT oral) *not used routinely for outpt *Emergency Rx: IV for Ludwig Angina
Penicillins ADRx Incidence less frequent: allergy, candidiasis, exfoliatie dermatitis, GI reactions[loss of taste and appetite, mild diarrhea, N/V] Incidence Rare: clostridium difficile [pseudomembranous colitis], mental disturbances, leukopenia (fever), thrombocytopenia (unusual bleeding or bruising), seizures (very high dose & renal impairment)
Penicillin Allergy -All penicillins are cross-sensitizing and cross-reacting although mainly nontoxic -Antigens are degradation products - 1-8% of population are sensitive -400-800 deaths/years in US -Mild anaphylaxis: 1/200 courses -Severe anaphylaxis: ~1/2,000 courses -Fatality Rate: 1/60,000 - >95% of fatal reactions occur w/in 60 minutes
Penicillin Allergy -All penicillins are cross-sensitizing and cross-reacting although mainly non-toxic -Antigens are degradation products -1-8% of population are sensitive -400-800 deaths/year in US -Mild anaphylaxis: 1/200 courses -Severe anaphylaxis: 1/2,000 courses -Fatality rate: 1/60,000 >95% of fatal reactions occur w/in 60 min
Penicillin Anaphylaxis -Serum sickness type -Fever, urticaria, joint pain and swelling, pruritus, skin rash -Oral lesion, interstitial nephritis, eosinophilia, hemolytic anemia and vasculitis -Anaphylactic shock and death
Penicillins-Drug Interactions -Probenecid- decreased renal tubular secretion of penicillin, thus used therapeutically for increasing serum concentrations -Aminoglycosides (Gentamicin)-Inactivation -Oral Contraceptives: Hepatic enzyme induction CYP 450, thus failure of OC and resultant pregnancy -Combination use w/ other abx
Aminopenicillins [Ampicillin, Amoxicillin, Bacampicillin] -Effective against: Gram +ve cocci, gram -ve cocci s/a Neisseria g and m (?) and gram -ve rod such as Hemophilus and E. Coli -Not resistant to beta lactams -Extended Spectrum -Used for uncomplicated ENT infections and component of triple therapy for H. pylori -Amoxicillin: Better oral absorption; can be taken with food, less adverse effects than Ampicillin.
Betalactamases: Penicillinase An enzyme produced by some bacteria. -Penicillin V and Amoxicillin are ineffective against these bacteria. -The enzyme degrades or inactivates these abx -Two strategies to overcome these resistant bacteria: *Use Penicillins that are resistant t othe enzyme (Cloxacillin) * Use amoxicillin and clavulanic acid combination
Penicillin + Beta-lactamase Inhibitor Amoxicillin + Clavulanate (Augmentin) -Clavulanic acid (cluvalanate) inhibits B-lactamase -Molecular structure is similar to Beta lactam -Effective against S. aureus, H influenza, N gonorrhea, Salmonella, and E. coli -Used in immunocompromised pts w/ mixed infections
Cephalosporins -Similar structure to Penicillins except a 6 membered ring instead of 5 in penicillin -Stable against Beta Lactamases -Possesses 7-aminocephalosporanic acid ring instead of 6-aminopenicillanic acid -4 generations
Cephalosporins -1st generation: destroy by beta lactamases. *Cephalexin, Cefazolin: streptococci, pneumonococci, and Staph *Used for UTI and soft tissue abscess * Drug of choice for surgical prophylaxis -2nd Generation: more resistance to lactamase: cerfuroxime and Cefoxitin *Effective against all bacterial of first gen plust gram -ve (Klebsiella, H. influenza) *Cefuroxime: used to tx sinusitis, otitis, and lower respiratory infections
Third Generation Cephalosporins -Cefotaxime, Ceftriaxone -Expanded Gram (-) coverage w/ resistance to beta lactamases -Able to cross BBB -Used in meningitis caused by Pneumococci, Meningococci, and H influenza -Sepsis in immunocompromised patients
Fourth Generation Cephalosporins -Cefepime -Highly active against Neisseria, H. Influenza, P Aeruginosa -Not approved for tx of meningitis
Fifth Generation Cephalosporins -Ceftaroline is distinct in being active against MDR S Aureus, methicillin resistant (MRSA), Vancomycin resistant staph aureus -Approved by the FDA for community acquired skin infections and pneumonia
Cephalosporins Adverse Effects -Similar to penicillins -Allergic rxn: GI -Allergic rxn have penicillin cross-sensitivity -Toxicity: local irritation after IM injection and thrombophlebitis after IV injection. -Renal toxicity: Nephritis and tubular necrosis -Have been known to cause hypothrombinemia and bleeding disorders in some
Protein Synthesis Inhibitors -Erythromycin, Azithromycin, Clarithromycin, Clindamycin, Tetracycline, Chloramphenicol, Aminoglycosides -Referred to as "Broad spectrum abx" -Greater affinity for microbial ribosomal subunits 30S, 50S, and 70S -Protein synthesis occurs at a much faster rate in microbial cells and therefore abx activity is strong
Protein Synthesis Inhibitors -Bacteriostatic *Tetracyclines [tetracycline, doxycycline] *Macrolides [erythromycin, azithromycin, clarithromycin] *Clindamycin *Chloramphenicol *Streptomycin
Tetracycline *Broad spectrum, gram (+) and gram (-) *Also anerobes, Rickettsia, Chlamydia, and some Protazoans (Amoeba) *Tetracycline; Doxycycline; Minocycline *Block protein synthesis by penetrating through the bacterial cell wall by passive diffusion and binding to 30S subunit *Prevent binding to tRNA and mRNA-ribosome complex *Prevent addition of Amino Acids to chain
Macrolides: Erythromycin -Narrow spectrum (newer classified as broad spectrum) -Gram (+) (Pneumococci, strep, staph, chlamydia, legionella) -Gram (-) (Treponema pallidum and Campylobacter) -Alternative for patients allergic to Penicillins -Binds to 50S subunit of ribosomes: Blocks addition of new amino acids to the growing peptides (Blocks protein synthesis) -Bacteriostatic at normal or bactericidal at larger concentrations
Newer Macrolides Telithromycin -FDA approved 2004 semi-synthetic derivative -FKA Ketolide -High affinity for 50S ribosomal binding -Bind to an additional site on 23S ribosome -May be used where resistance to Macrolides has developed in bacterial strains -Large number of drug interactions -Rare cases of fulminant hepatic necrosis
Chloramhenicol -Bacteriostatic: Aerobic/anaerobic/Gram (+)/(-) -H. influenza, N meningitidis, Bacteroides -Salmonella: typhoid fever, bacterial meningitis -Rickettsia -Binds to 50S and 23S ribosomes -Resistance: Plasmid encoded acetyltransferases that inactivate the drug -Toxicity: inhibition of mitochondrial protein synthesis. Gray baby Syndrome -Lack of conjugation: vomiting, flaccidity, hypothermia, respiratory distress, gray color
Clindamycin (Cleocin) -Derivative of Lincomycin -Lincosamide -Binds to 50S subunit of bacteria ribosomes -Bacteriostatic for Strep, Staph, and Pneumo -Spectrum: anaerobic (gram + & -), Aerobes (gram +), used for skin and soft tissue infections, penetrating wound of abdomen, septic abortion, prophylaxis of infective endocarditis
Clindamycin ADRx Incidence More frequent: -GI disturbances: pseudomembranous colitis, abdominal pain and cramps, N/V/D -Fungal overgrowth Incidence less frequent: allergy, neutropenia, Thrombocytopenia
Pseudomembranous Colitis Risk factors: -Abx: clindamycin, cephalosporins, ampicillin, erythromycin -Elderly -Female w/ GU disease Clinical Features: cramp abd pain, lower quadran abdominal tenderness, watery diarrhea, fever, leukocytosis Tx: Stop all abx, hydration, vancomycin (oral; 500 mg QID for first 2 days or 125 mg QID 10-14 days) -Metronidazole (500 mg TID, 7-14 days)
Sulfonamides: Sulfamethoxazole -Bacteria manufacture their own folic acid -Sulfonamides inhibit folic acid synthesis -Sulfonamides resemble PABA as structural analogues -Resistance may occur: increase synthesis of PABA, Alter enzyme structure, Reduce sulfonamide uptake -Clinical Uses: Systemic urinary tract infection, Topical: conjunctivitis; corneal ulcer
Bacteriostatic Erythromycin; Clarithromycin; Azithromycin; Clindamycin; Tetracycline; Doxycycline
Sulfonamides-Adverse Effects Blood dyscrasias Steven-Johnson Syndrome Allergy-metabolite (PABA) Renal damage from crystalluria
Trimethoprim Bactrim, Septra, Cotrim, Co-trimoxazole -40,000 times greater affinity for bacterial DHFR -Minimal effects on mammalian cells -Trimethoprim and Sufamethoxazole (1:5 ratio) act in concert with each other -Resistance: increase synthesis of enzyme (DHFR), reduce permeability to trimethoprim
Nucleic Acid Synthesis Inhibitors -Fluoroquinolones (Quinolones): Ciprofloxacin (Cipro), Norfloxacin, Orfloxacin -Metronidazole (Flagyl) -Chemically reduced to a toxic metabolite; this rxn is unique to anaerobic bacteria -Toxic metabolite interacts w/ DNA -Results in loss of helical structure, strand breakage and resultant inhibition of nucleic acid synthesis and cell death -Bactericidal
Metronidazole Adverse Effects -CNS disturbances: dizziness, lightheadedness -GI disturbances: Abdominal pain & Cramps; N/V/D -Taste: changes in sensation; sharp metallic taste -Dry mouth, Dark urine -Seizures (high doses) -Disulfiram like reaction
Metronidazole Drug Interactions -Alcohol-Disulfiram-like reaction: nausea, giddiness, flushing, abdominal cramps; accumulation of acetaldehyde -The result due to the non-conversion of acetaldehyde -Disulfiram: confusion, psychotic rxn, convulsions; 2 week washout period recommended -Barbiturates: decreased metronidazole effect -Phenytoin-Phenytoin toxicity
Fluoroquinolones Ciprofloxacin, Norfoxacin, Levofloxacin -Mechanism of Action: Inhibits bacterial DNA gyrase (DNA gyrase converts closed circular DNA into supercoiled configuration); prevents supercoiling, stops DNA replication -Resistance: alteration of DNA gyrase, decrease permeability
Fluoroquinolones Ciprofloxacin -Broad spectrum: Most aerobic gram (-) and some gram (+)--bacterialcidal -Adverse effects, mild (relative) *GI upset: N/V/D * CNS: dizziness, HA, confusion *Children: cartilage damage *Not used in children under 18 y/o *Not used in elderly pts d/t tendonitis
What Abx would you use on a woman during her first trimester of pregnancy? Amoxicillin
Aminoglycosides -Streptomycin is protype drug -Gentamycin, Tobramycin, Amikacin -Bind to 30S subunit and inhibit protein synthesis -Binds to 30S subunit and inhibit protein synthesis -Virtually the same spectrum as Fluroquinolones plus Enterococci -Used for sepsis, penumonia -Given only IV, at lost cost ($3/day) -Drug monitoring required -Hardest drug to dose
Aminoglycosides Side Effects -Vestibular toxicity (irreversible) loss of balance, hearing and dizziness (ototoxic) -Renal toxicity (reversible) Monitor Cr (nephrotoxic) -Neuromuscular blockade can occur during surgery because Aminoglycosides can have an additive effect w/ paralyzing agents -Adding furosemide or other nephrotic drugs increased risk of renal damage -Can also happen if pt is given an overdose
MRSA Methicillin resistant Staph aureus -Isolate pt and wash hands!!! -Rx: vancomycin 1 g IV q12H -resistant to all penicillins and cephalosporins
VRE Vancomycin Resistant Enterococci -Infects immunocompromised patients -Routine identification procedures in critical care areas w/ isolation of colonized pts
VRSA Vancomycin Resistant S aureus -Appearance has been feared and predicted the last 20 years -Has the potential to set medicine back 100 yrs -1st reported case in Detroit MI 9/2002
STreptogramins -FDA 1999 -Mix of Dalfoprastin (GpA) and Quinupristin (GpB) -Used for Vancomycin resistant strep pyogenes -50S binding along with binding to tRNA
Oxazolidinones FDA 2000 Linezolid Gram + including MRSA/VRE 50 S binding along with binding to tRNA
Pleuromutilins FDA 2007: Retapamulin Topical Therapy for bacterial infections Bind to 50S
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