Antimicrobial Chemotherapy

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Antimicrobial Chemotherapy Antimicrobial chemotherapy Prof. Beata M. Sobieszczańska Department of Microbiology University of Medicine Antimicrobials • Antibiotic is a low molecular substance produced by microorganisms (molds, bacteria) that at a low concentration inhibits or kills other microorganisms • Antimicrobial is any substance of natural, semisynthetic or synthetic origin that kills or inhibits the growth of microorganisms but causes little or no damage to the host All antibiotics are antimicrobials but not all antimicrobials are antibiotics Antimicrobials • Bacteriostatic = they inhibit bacterial growth but generally do not kill the bacteria e.g. protein synthesis inhibitors (macrolides, tetracyclines, aminoglycosides, streptogramins, lincosamides, oxazolidinones, chloramfenicol) • Bactericidal = agent that kills the target bacteria (β- lactams, glycopeptides, bacitracin, polymyxin, fluoroquinolones, metronidazole, rifampin) Drug’s spectrum of activity Depending on the range of bacterial species susceptible to antimicrobials – they are classified as: narrow spectrum - have limited activity to some bacteria e.g. GP or GN (e.g. penicillin, glycopeptides) broad spectrum – are active against both GP and GN (e.g. amoxycillin, carbapenems, fluoroquinolones) Sites of action of different antimicrobial agents Bactericidal - without cell wall, osmotic pressure causes bacteria to burst Examples • β-lactams • Glycopeptides • Bacitracin PBP=penicillin binding proteins (enzymes e.g. transpeptydases) : Penicillins in blocking transpeptidase enzymes from assembling the peptide cross-links in peptidoglycan Cephalosporins First generation: GP, little activity against GN cephalothin, cephalexin Second generation: GN, less GP cefamandole, cefaclor, cefazolin, cefuroxime cefoxitin & cefotetan (cephamycins) – anaerobes Third generation: GN, GP variable, resistant to β-lactamases cefotaxime, ceftriaxone, cefoperazone, ceftazidine Fourth generation: GP & GN, enhanced stability against β- lactamases; cefepime & cefpirome Fifth generation: GP, GN & MRSA; ceftaproline Monobactams (Aztreonam) Aerobic GN bacteria + Pseudomonas and other nonfermentative rods except Stenotrophomonas maltophilia Carbapenems Imipenem, meropenem, ertapenem, doripenem Active against GP, GN aerobic and anaerobic Reserved for severe, life-threatening infections caused by resistant bacteria Bacitracin Polypeptide antibiotic • Inhibits cell wall synthesis of GP bacteria – mostly Staphylococci and Streptococcus pyogenes (narrow spectrum) • Used as a topical preparations (toxic – causes kidney damage) Glycopeptides Vancomycin & teicoplanin are glycopeptides that are effective against GP bacteria Antimicrobial agents that alter/disrupt the cytoplasmic membrane these antimicrobials are cidal Polymyxin B, polymyxin E (colistin) are used in severe infections caused by GN rods (also MDR) Several GN pathogens (Proteus, Burkholderia, Neisseria, Brucella) exhibit intrinsic resistance Daptomycin (lipopeptide antibiotic) – disrupts membrane potential (depolarization) Spectrum: GP pathogens (VRE, MRSA etc.) Used to treat complicated skin and soft tissue infections Antimicrobial agents that inhibit protein synthesis These agents prevent bacteria from synthesizing structural proteins and enzymes Alter bacterial ribosome, block translation & cause faulty protein synthesis These antibiotics are bacteriostatic or bactericidal depending on concentration Antimicrobial agents that inhibit protein synthesis Macrolides Glycylcyclines Tetracyclines Ketolides Aminoglycosides Fusidic acid Spectinomycin Mupirocin Streptogramins Oxazolidynones Lincozamides Chloramphenicol Tetracyclines • Broad-spectrum: GP & GN bacteria, Rickettsia, Chlamydia, Mycoplasma, spirochetes, some protozoa (malaria) tetracycline, oxytetracycline, doxycycline, minocycline • Resistance common • Used to treat: atypical pneumonia, syphilis, brucellosis, Lyme disease, acne, plague, leptospirosis, anthrax, cholera Glycylcyclines Tigecycline – derived from minocycline Broad-spectrum: GP+GN bacteria GP cocci: staphylococci, enterococci, streptococci - including resistant strains GN intestinal rods – except Proteus GN nonfermentative rods e.g. Acinetobacter spp. except Pseudomonas Obligatory anaerobic – Bacteroides fragilis Advantage over tetracyclines: active against bacteria resistant to tetracyclines, higher binding affinity, broader spectrum Aminoglycosides Bactericidal – except for staphylococci Active against most GN aerobic bacilli but lack activity against anaerobic & most GP bacteria, except for staphylococci streptomycin, kanamycin, tobramycin, amikacin, gentamycin Spectinomycin • Bacteriostatic antibiotic chemically related to aminoglycosides • Its activity is restricted to gonococci • Spectinomycin is given for gonococcal urethritis, cervicitis, proctitis Macrolides (erythromycin, roxithromycin, clarithromycin, azithromycin) – mainly affects GP cocci (streptococci, staphylococci, but NOT enterococci) and intracellular pathogens (Mycoplasma, Chlamydia, Legionella); other: Campylobacter, Helicobacter, Borrelia, Treponema, Corynebacterium sp. and some anaerobes (Propionibacterium) Ketolides (derived from erythromycin) – Telithromycin Active against bacterial strains resistant to macrolides Lincosamides (lincomycin, clindamycin) active against GP bacteria (but NOT GN), most anaerobes Principal therapeutic indications are staphylococcal infections of bones and joints, and anaerobic infections They all static or cidal depending on concentration, bacterial inoculum and species Streptogramins A combination of quinupristin & dalfopristin (Synercid) – exhibit dose-dependent cidal activity work synergistically to inhibit protein synthesis Active against: GP cocci (also multi-resistant), modest activity: common respiratory pathogens (Moraxella, Str.pneumoniae, Mycoplasma, Legionella, Chlamydophila) & anaerobes Oxazolidynones Linezolid - narrow spectrum of activity: GP bacteria (staphylococci, streptococci, enterococci, pneumococci – resistant strains, Listeria, corynebacteria), and GN bacteria: Moraxella, Pasteurella, Bacteroides but other GN are resistant Fusidic acid Fusidic acid Narrow spectrum of activity: staphylococci resistant strains in combination with other antibiotics (bone and joints infections) Activity against other GP cocci is poor Other: anaerobes (Bacteroides fragilis, Clostridium spp.) Moderate activity against mycobacteria: M. tuberculosis, bovis, leprae and certain protozoa (Giardia lamblia, Plasmodium falciparum) Mupirocin Mupirocin - cidal or static activity depends on concentration Narrow spectrum of activity: staphylococci + resistant strains Used for topical treatment of superficial skin infections e.g. furuncles, impetigo and decolonization of MRSA (intranasaly) Chloramphenicol Spectrum of activity: GP bacteria: streptococci, staphylococci, enterococci, B. anthracis, Listeria GN bacteria: H. influenzae, Moraxella, Neisseria, E. coli, Proteus mirabilis, Salmonella, Shigella, Stenotrophomonas matlophilia Many anaerobic bacteria Penetrates to CSF – meningitis treatment Side effects: fatal aplastic anemia, dose-dependent leucopenia, bone marrow suppression etc. – limit its use Antimicrobial that interfere with DNA synthesis bactericidal Rifampins Fluoroquinolones Metronidazole Fidaxomycin Rifampin (Rifampicin) Prevent the synthesis of mRNA by inhibiting the enzyme RNA polymerase Effective against some GP & GN bacteria Mycobacterium tuberculosis, M. leprae, Legionella pneumophila Used primarily to treat tuberculosis Prophylaxis in meningococcal meningitis Fluoroquinolones Synthetic chemicals Inhibit topoisomerases (DNA gyrases) involved in bacterial nucleic acid synthesis Generations: I – nalidixic acid (GN bacteria) – UTI II – ciprofloxacin, norfloxacin, ofloxacin (GN+ P. aeruginosa, S. aureus, some atypical) – UTI, STD, skin, soft tissue infections, GITI III – levofloxacin, gatifloxacin, moxifloxacin (GP, GN, atypical) – RTI, GITI IV – trovafloxacin (GP, GN, atypical, anaerobes) Nitroimidazoles: Metronidazole An antibiotic active against anaerobic bacteria & certain parasites (Entamoeba histolytica, Trichomonas, Giardia) Metronidazole puts nicks in the microbial DNA strands Macrocyclic antibiotics Fidaxomycin - binds to bacterial RNA polymerase active against GP bacteria, especially C. difficile (treatment of CDAD=Clostridium difficile associated diarrhea) Minimally absorbed into the bloodstream Competitive antagonistic antibiotics Inhibitors of metabolic pathways via competitive antagonism include: • Sulphonamides • Trimethoprim • Isoniazid These all inhibit folic acid biosynthesis Competitive antagonism Competitive antagonism - a drug chemically resembles a substrate in a metabolic pathway Because of their similarity, either the drug or the substrate can bind to the enzyme While the enzyme is bound to the drug, it is unable to bind to its natural substrate and blocks that step in the metabolic pathway Competitive antagonism Sulfonamides & trimethoprim Synthetic chemicals Co-trimoxazole is a combination of trimethoprim + sulfamethoxazole (TMP-SMX) Both of these drugs block enzymes in the bacterial pathway required for the synthesis of tetrahydrofolic acid - a cofactor needed for bacteria to produce nucleic acids Antimicrobial agents active against anaerobes β–lactams (penicillins; 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