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Overview
If bacteria make it past our immune system and start reproducing inside our bodies, they cause disease. Certain bacteria produce chemicals that damage or disable parts of our bodies. Antibiotics work to kill bacteria.Antibiotics are specific to certain bacteria and disrupt their function.
What is an antibiotic?
Literal definition: Against (anti-) life (biotic) The more correct term is antimicrobial agent
What is an Antibiotic?
An antibiotic is a selective poison. It has been chosen so that it will kill the desired bacteria, but not the cells in your body. Each different type of antibiotic affects different bacteria in different ways. For example, an antibiotic might inhibit a bacteria's ability to turn glucose into energy, or the bacteria's ability to construct its cell wall. Therefore the bacteria dies instead of reproducing.
Penicillin
Antibiotics Sources
1952 Makrolide
1950 Aminoglykoside 1949 Chloramphenicol 1949 Tetracycline 1940 Penicillin (Entdeckung 1928) 1936 Sulfonamide
Antimicrobial Therapy
Criteria that determine the effectiveness of antimicrobial agents selective destruction of the microorganism no or rare side effects on the host antimicrobial substances should have a specific action against molecules or enzymes or metabolism of the microorganism only
4. Development of resistant strains (producing enzymes that can destroy antibiotics; resistance genes e.g. in plasmids, transferred from to one bacterial cell to the other, mutation of the
target)
Antimicrobial Therapy
Natural antibiotic agents:
Metabolic products produced by microorganisms: Penicillium notatum penicillin Streptomyces spp. streptomycin
Classification of Antibiotics
Chemical Structure Spectrum of Activity Mechanism of Action
ANTIBIOTICS CLASSIFICATION
Very diverse class of compounds Generally grouped according chemical structures
Aminoglysides Cephalosporins and related beta lactams Glycopeptides Macrolides Penicillins Quinolones Sulphonamides and diaminopyrimidines Tetracyclines
bacteriostatic
bacteriocidal
bacteriostatic
bactericidal
cell-wall
protein-synthesis
protein-synthesis
cell-membrane
bacterial cell
Drug Vancomycin
Mode of Action Binds to D-Ala-D-Ala terminus; inhibits transpeptidation enzymes of cell wall
from: http://project.bio.iastate.edu/Courses/MIPM302/302new/9_1chemother.html
Beta-Lactam Antibiotics
Types of -Lactam Antibiotics Penicillins Examples Penicillin Amoxicillin Dicloxacillin Cephalexin, cefazolin (1st generation) Cefuroxime (2nd generation) Ceftriaxone, ceftazidime (3rd generation) Cefepime (4th generation) Ertapenem Imipenem Meropenem Aztreonam Amoxicillin-clavulinate Ampicillin-sulbactam Piperacillin-tazobactam
Cephalosporins
Carbapenems
Penicllins
Derived from the fungus Penicillium Therapeutic concentration in most tissues Poor CSF penetration Renal excretion Side effects: hypersensitivity, nephritis, neruotoxicity, platelet dysfunction
Cephalosporins
Structurally similar to penicillins Therapeutic concentration in many tissues, 3rd and 4th generation into CSF Renal Excretion Side Effects
allergy disulfiram-like effect anti-Vitamin K
Generations of Cephalosporins
Monobactams
Aztreonam
single beta lactam ring narrow spectrum: gramnegative aerobes
Enterobacteriacea Pseudomonas
given IV/IM renal excretion little cross-reactivity with other beta lactams side effects: phlebitis, rash, elevated LFTs
Carbapenems
Meropenem/Imipenem
broad spectrum active against MRSA given IV penetrates CSF renal metabolism and excretion addition of cilastin side effects: GI upset, eosinophilia, neutropenia, lowering of seizure threshold
Vancomycin
Tricyclic glycopeptide Inhibits synthesis of phospholipids and cross-linking of peptidoglycans Activity against gram-positive organisms Useful for beta lactam resistant infections Widely distributed, penetrates CSF Renal elimination, follows creatinine cl. Side effects: phlebitis, red man syndrome, ototoxicity, nephrotoxicity
Bacterial Ribosome
70S
30S 50S
Tetracyclines
Isolated from Streptomyces aureofaciens Reversibly bind 30S ribosomal subunit Penetrate sinus mucosa, saliva and tears Metabolized in liver-->excreted in bile--> reabsorbed-->eliminated in urine Side effects: GI upset, hepatotoxicity, photosensitivity, bony deposition Contraindicated in pregnant or breast feeding women, children under 8 y/o
Aminoglycosides
Derived from Streptomyces and Micormonospora Irreversible binding to 30S subunit Actively transported into bacterial cells Variable tissue penetration, unreliable CSF levels Concentrate within perilymph Renal elimination Nephrotoxicity, ototoxicity, neurotoxicity
Aminoglycosides
Macrolides
Macrocyclic lactone structure Irreversible binding to 50S subunit Therapeutic concentrations in oropharyngeal and respiratory secretions No CSF penetration Metabolized in liver, excreted in feces and urine Side effects: GI upset, ototoxicity, hepatotoxicity
Erythromycin
Alternate Macrolides
Clarithromycin Azithromycin
Chloramphenicol
Isolated from Streptomyces Reversible binding to 50S subunit Broad spectrum of activity Indicated for severe anaerobic infections or unresponsive life-threatening infections Widely distributed, enters CSF Metabolized in liver (inhibits P-450), eliminated in urine Toxicities: reversible anemia, hemolytic anemia, aplastic anemia, gray baby syndrome
Clindamycin
Semisynthetic derivative of Lincomycin Irreversible binding to 50S subunit Covers anaerobes and gram + aerobes Widely useful for head and neck infections Penetrates saliva, sputum, pleural fluid, and bone, but not CSF Metabolized in liver-->reabsorbed-->eliminated in urine Side effects: rash, neutropenia/thrombocytopenia, pseudomembranous colitis
Inhibitors of Metabolism
Sulfonamides Trimethoprim Interfere with the production of folic acid coenzymes that are required for purine and pyrimidine synthesis
Sulfonamides
Derived from prontosil Competitve antagonist of PABA Wide distribution, penetrate CSF, cross placenta Metabolized in liver, eliminated in urine Side effects: rash, angioedema, StevensJohnson syndrome, kernicterus Avoid in pregnancy and infants
Trimethoprim
Inhibits dihydrofolate reductase 1000x higher affinity for bacterial enzyme than human enzyme Similar spectrum and pharmacokinetic profile as sulfas Side effects: folate deficiency anemia, leukopenia, granulocytopenia
Co-Trimoxazole (TMP/SMX)
Combination gives synergistic antibacterial action
Fluoroquinolone Antibiotics
Fluoroquinolone Antibiotic Ciprofloxacin Spectrum of Activity Many Gram negative bacteria Some Pseudomonas Atypicals (Legionella, Mycoplasma) Mycobacteria Many Gram negative bacteria Some Pseudomonas Many Gram positives, including Strep Atypicals (Legionella, Mycoplasma) Mycobacteria Many Gram negative bacteria Many Gram positives, including Strep Anaerobes Atypicals (Legionella, Mycoplasma) Mycobacteria
Levofloxacin
Moxifloxacin
Fluoroquinolones
Antibiotic Resistance
innate (natural) resistance primary resistance, is based on a genetically caused insensitivity of a type of bacteria to a certain antibiotic e.g. inefficacy of penicillin to Ps. aeruginosa acquired resistance
Mechanisms of Resistance
1) Accumulation barriers to an antimicrobic due to impermeability or active efflux 2) Alterations of an antimicrobic target which render it insusceptible 3) Inactivation of an antimicrobic by an enzyme produced by the microorganism
-lactams, Erythromycin
Aminoglycosides, Chloramphenicol, Fosfomycin, Lincomycin -lactams, Fusidic Acid Sulfonamides, Trimethoprim Sulfonamides, Trimethoprim
hydrolysis
inactivation of antibiotic by enzymatic modification sequestering of the antibiotic by protein binding metabolic bypass of inhibited reaction overproduction of antibiotic target (titration)
Bleomycin
Influx/Efflux
Bacteria such as streptococci, enterococci, and anaerobes lack the necessary oxidative pathways for transport of aminoglycosides. Some bacteria have energy-dependent efflux mechanisms that pump either tetracyclines or fluoroquinolones from the cell
Altered Target
Antimicrobics act by binding and inactivating their target, which is typically a crucial enzyme or ribosomal site. Substitutions of one amino acid in a protein can alter its binding.
First generation aminoglycosides and quinolones only bind one site. Newer agents bind at multiple sites on their target making resistance improbable.
An important example : -lactam family In widely divergent gram-pos and gramneg species changes in one or more of peptidoglycan transpeptidase penicillinbinding proteins (PBP) have been correlated with decreased susceptibility to multiple -lactams Causes: point mutations, substitutions of amino acid sequence, and synthesis of a new enzyme.
Enzymatic Inactivation Most powerful and robust of resistance mechanisms -Lactamases - 100s of enzymes with variable activity against - lactam substrates Typically demonstrate high-level resistance with MICs above therapeutic range
The MIC is the lowest concentration that prevents ___________ MIC>1.6 mg/L This value is compared with the ___________ for that antibiotic The test organism is then classified as susceptible, intermediate or resistant
E-Test strips
E-Tests are 5 x 0.5 cm plastic strips
On the bottom is a gradient of stabilized antibiotic On the top is an exponential MIC reading scale (mg/L)
An agar plate is inoculated with a standard amount of test organism and the strip placed on top After incubation, the 'MIC' is read where the zone of inhibition intercepts the strip The advantage of this method is speed and different growth media can be used, allowing for the growth of fastidious bacteria
ANTITUBERCULOSIS CLASSIFICATION
Miscellaneous group of antibacterials Include
Antifungal Agents
Azoles Fluconazole Ketoconazole Itraconazole Posaconazole Voriconazole
Echinocandins Anidulafungin Caspofungin Micafungin Polyenes Amphotericin B Lipid formulations of Amphotericin B
Antiviral Agents
Virus Herpes simplex virus Antiviral Agents Acyclovir Famciclovir Valacyclovir
Varicella-Zoster virus
Cytomegalovirus
Influenza virus
Fixed Dose Combos ZDV/3TC ZDV/3TC/ABC ABC/3TC TDF/FTC TDF/FTC/EFV Entry Inhibitors enfuvirtide, T-20 maraviroc, MVC Integrase Inhibitors raltegravir, RAL
Protease Inhibitors saquinavir, SQV ritonavir, RTV indinavir, IDV nelfinavir, NFV amprenavir, APV lopinavir/r, LPV/r atazanavir, ATV fosamprenavir, FPV tipranavir, TPV darunavir, DRV