MICROBIOLOGY & PUBLIC HEALTH Module 6 PDF

Diagnosis o Mantoux test (told) – tuberculin o Purified protein derivative (new) Treatment: o TB Directly Observed Treatment, Shortcourse (TB-DOTS) Mycobacterium leprae Causes Hansen’s disease aka Leprosy Found in scrapings from skin or mucous membrane in lepromatous leprosy Attacks colder tissues o...

Diagnosis o Mantoux test (told) – tuberculin o Purified protein derivative (new) Treatment: o TB Directly Observed Treatment, Shortcourse (TB-DOTS) Mycobacterium leprae Causes Hansen’s disease aka Leprosy Found in scrapings from skin or mucous membrane in lepromatous leprosy Attacks colder tissues of the body (ears, nose, cheeks, scrotum) Two types of Leprae o A. Tuberculoid (TL) ▪ Benign type ▪ CM: blotchy, flat lesions ▪ (+) in lepromin skin test o B. Lepromatous (LL) ▪ CM: disfiguring appearance (leonine/lion like), thickening of eyebrows, lips, cheeks ▪ Disintegration of boy parts, malignant type ▪ (-) in lepromin skin test Rx: Dapsone (DOC) o SE: erythema nodosum leprosum Narrow Spectrum Antibiotics – antagonize only a particular organism or group of microorganisms (e.g. Penicillins) Mechanisms of Action of Antibiotics Site of Action Antibiotic Bacitracin Cephalosporin Cell Wall Cycloserine Penicillins Vancomycin Amphotericin B Cell Membrane Nystatin Polymyxins Chloramphenic ol Erythromycin Mycoplasma pneumoniae Plastic, pleomorphic shape Lacks peptidoglycan cell wall Enclosed by lipid bilayer membrane Can’t synthesize sterol Smallest known free-living self-replicating prokaryotic cell Produces “walking pneumonia” Resistant to Penicillin, Cephalosporin, Vancomycin Ribosomes Lincomycins Aminoglycosid es Tetracyclines Actinomycin Nucleic Acids Griseofulvin ANTI-INFECTIVES Natural Sources: Microorganisms A. Bacillus – bacitracin, polymyxin B. Streptomyces - streptomycin, tetracyclines C. Micromonospora – gentamicin D. Penicillium, Acremonium (Aspergillaceae) – griseofulvin, penicillins and cephalosporins E. Pseudomonas & Gluconobacter monobactams Spectrum of Activity Broad Spectrum – ability of some antibiotics, to antagonize the growth of numerous pathogens (e.g. Tetracycline) 9 | Prepared by: Santi Raphael B. Lledo, RPh DNA and/or RNA Mitomycin C Rifampicin Process Interrupted Mucopepti de synthesis Cell wall cross-linking Synthesis of cell wall peptides Cell wall cross-linking Mucopepti de synthesis Membrane function Membrane function Membrane integrity Protein synthesis Protein synthesis Protein synthesis Protein synthesis and fidelity Protein synthesis DNA and mRNA synthesis Cell division, microtubule assemble DNA synthesis mRNA synthesis cidal -static ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ CHEMICAL CLASSIFICATIONS OF ANTIBIOTICS Beta lactam Antibiotics (PCN, Ceph) Macrolides Tetracyclines Aminoglycosides Polypeptides (Bacitracin and Polymyxin) Antifungal Antibiotics (Amphotericin and Nystatin) PENICILLINS Contains Beta Lactam Thiazolidine ring Naturally occuring Semisynthetic MOA OF PCNs Inhibition of the synthesis of peptidoglycan Penicillin G ANTISTAPHYLOCOCCAL PENICILLINS Strains of Staphylococcus became resistant and started producing an enzyme, Beta lactamase (penicillinase) which may inactivate PCNs by opening the B-lactam ring Bacterial Resistance to Penicillins Beta lactamase enzyme that catalyzes opening of the beta lactam ring to produce penicilloic acid Several strains are resistance due to altered penicillin binding proteins Some strains are resistant decreased entry or active efflux of antibiotic BETA LACTAMASE INHIBITORS Clavulanate potassium, USP isolated from Streptomyces clavuligerus irreversibly bindsw to beta lactamase in both Gram (+) and Gram (-) bacteria o Amoxicillin + Clavulanic acid ▪ Aka Co-amoxiclav (Augmentin ®) o Ticarcillin + Clavulanic acid (Timentin®) Sulbactam beta lactamse inhibitor that achieves synergistic effects with Ampicillin and Carbenicillin Ampicillin + Sulbactam o aka Sultamicillin (Unasyn ®) Tazobactam more potent than sulbactam and slightly broader activity than clavulanic acid o Piperacillin + Tazobactam (Zosyn ®) 10 | Prepared by: Santi Raphael B. Lledo, RPh CEPHALOSPORINS CEPHALOSPORINS: Structure consist of a six-membered dihydrothiazine ring fused to a beta lactam ring Broad spectrum and more resistant to beta lactamase inactivation that penicillins Very prone to hydrolytic degradation Classified by generations, each having their own spectrum of activity: CEPHALOSPORINS: 1st Gen excellent gram-positive and modest gram-negative activity alternatives for skin and soft-tissue infections, as well as for streptococcal pharyngitis. Cefadroxil, Cephalexin, Cephaloridine, Cephalothin, Cephapirin, Cefazolin, Cephradine CEPHALOSPORINS: 2nd Gen have somewhat better activity against gram-negative organisms with some gram positive action include some agents with antianaerobe activity treating URTI, LRTI, sinusitis and otitis media. active against E. coli, Klebsiella and Proteus Cefaclor, Cefoxitin, Cefprozil, Cefuroxime CEPHALOSPORINS: 3rd Gen activity against gram-positive organisms and much more activity against the Enterobacteriaceae, with a subset active against P. aeruginosa Broad-spectrum antibiotics Cefdinir, Cefixime, Cefpodoxime, Ceftibuten,Ceftriaxone, Cefotaxime CEPHALOSPORINS: 4thGen encompass the antimicrobial spectrum of all the third-generation agents and have increased stability to hydrolysis by inducible chromosomal -lactamases Cefepime, Cefluprenam, Cefozopran, Cefpirome, Cefquinome ADRs and DIs Hypoprothrombinemia deficiency of the clotting factor prothrombin in the blood, which results to an increased tendency to bleed Due to inhibition of Vitamin K by CPNs DI : anticoagulants and warfarin Cefamandole, Cefotetan, Cefmetazole, Moxalactam, Cefoperazone MONOBACTAMS AZTREONAM Binds with PBP3 in gram negative bacteria only coli, Klebsiella, Proteus, Serratia, Citrobacter and Pseudomonas Treats: o UTI o LRTI o Intra-abdominal infection o Gynecological infection o Septicemia TIGEMONAM PO Resistant to beta lactamases General Characteristics Used to treat systemic infections Basic compounds with good solubility CARBAPENEMS Olivanic acids, Thienamycin, Imipenem, Meropenem, Ertapenem Comprise a family of fused beta lactam rings Has broadest antimicrobial spectrum of any antibiotic Analogues of penicillins or clavams , the sulfur or oxygen being replaced with carbon OLIVANIC ACIDS Broad – spectrum antibiotics Potent inhibitors of beta-lactamases Naturally – occuring beta lactam antibiotics Isolated from culture fluids of Streptomyces olivaceus THIENAMYCINS Broad spectrum with high beta lactamase resistance Chemically unstable IMIPENEM N – formimidoyl derivative of thienamycin that is very resistant to beta lactamases From Streptomyces cattleya Readily hydrolysed by renal dehydropeptidase 11 | Prepared by: Santi Raphael B. Lledo, RPh Imipenem + Cilastatin (Primaxin ®) MEROPENEM Dimethylcarbamoyl pyrolidinyl derivative of thienamycin More stable against dehydropeptidase enzyme Meropenem (Merrem IV®) ERTAPENEM Similar properties with meropenem but administered less frequently Effective against Gram-positive bacteria and Enteribacteriaceae Ertapenem (Invanz®) AMINOGLYCOSIDES History and Source Aminoglycosides are natural products or semi-synthetic derivatives of compounds produced by a variety of soil actinomycetes Mechanism of Action Binds to 30s ribosomal subunit and interferes with initiation of protein synthesis resulting to: o Blocking of initiation of protein synthesis o Premature termination of translation o Incorporation of incorrect amino acid Streptomycin Administered deep IM or IV Poorly absorbed orally Uses: o Bacterial endocarditis o Tularemia o Plague o Tuberculosis Tobramycin Most active among Nebramycins Neomycin Tx of GI infections, skin infections and peritonitis Decreased absorption, no systemic effect Available topical and oral Nephrotoxic Spectinomycin Bactereostatic Most inferior aminoglycoside Use: uncomplicated gonorrhoea Netilmicin Latest aminoglycoside to be marketed Resistant to aminoglycoside modifying enzymes Kanamycin Obsolete Kantrex Amikacin Derivative of Kanamycin produced in Japan with broadest spectrum of activity Amikin Other Uses Pneumonia Meningitis UTI Peritoneal Dialysis associated Peritonitis Bacterial endocarditis Sepsis of polycyclic Mechanism of Action Inhibit bacterial protein synthesis by binding to the 30s subunit and blocking tRNA binding to the A site Bacterial Resistance Decreased antibiotic influx or acquisition of an energy-dependent efflux pathway Production of a ribosomal protection protein that displaces tetracycline from its target Enzymatic inactivation of tetracyclines Untoward Effects GI irritation Photosensitivity Hepatic and Renal toxicity Macrolides Erythromycin – discovered by McGuire and co-workers in the metabolic products of a strain Streptomyces erythraeus Chemistry Contain a many-membered lactone ring 14-membered ring: Erythromycin and Clarithromycin 15-membered ring: Azithromycin Basic in nature due to the presence of a glycosidically linked amino sugar Spectrum of Activity Resembles that of Penicillin Used as an alternative to PCN 12 | Prepared by: Santi Raphael B. Lledo, RPh G(+), Neisseria and Mechanism of Action Inhibits protein synthesis by binding reversibly to 50s ribosomal subunits of sensitive microorganisms Bacterial Resistance Reduced permeability of the cell membrane or active efflux Production of esterases that hydrolize macrolides Modification of the ribosomal binding site Tetracyclines Broad-spectrum, bacteriostatic agents Has activity against G(+) and G(-) Contains four fused rings with a system if conjugated double bonds Forms stable complexes with trivalent and divalent cations Chemistry Close congeners naphthacenecarboxamide Generally active against Treponema Low activity against G(-) Erythromycin From: Streptomyces erythraeus Free base is bitter and has irregular oral absorption Spectrum of Activity Alternative to PCN Prophylaxis for Bacterial Endocarditis Chlamydia Eaton agent pneumonia Bacterial enteritis Adverse Effects GIT distress Hepatotoxicity Acute cholestatic hepatitis Fever Eosinophilia Rashes CYP450 enzyme inhibitor Clarithromycin 6-methyl ether of erythromycin Increased stability and oral bioavailability than Erythromycin Reduced GI distress and less frequent dosing Spectrum of Activity Effective against Borrelia burgdorferi More active than Erythromycin against Strep. Pneumonia Presence of food does not significantly affect absorption AE: CYP3A4 inhibitor Azithromycin Does not inactivate CYP450 enzymes Not to be administered with food Ketolides Telithromycin (Ketek) Effective against macrolide-resistant G(+) Disadv: Reversible inhibitor of CYP3A4 enzyme CHLORAMPHENICOL History and Source Produced from Streptomyces venezuelae May cause blood dyscrasias Chemistry Contains a nitrobenzene moiety and is a derivative of dichloroacetic acid Clindamycin A congener of Lincomycin 7-chloro-7-deoxy Lincomycin Improved absorption and distribution than Lincomycin Most potent agent against anaerobes For Staph infections, cellulitis and osteomyelitis Cannot penetrate CSF Binds exclusively to the 50S subunit of bacterial cell Clindamycin, Erythromycin, Chloramphenicol o Binding by one of these antibiotics to the ribosome may inhibit the interaction of the others Spectrum of Activity Bacteriostatic o S. epidermidis o S. aureus o M. pneumonia o L. monocytogenes o C. diphtheria o L. multocida o Salmonella sp. o Shigella sp. o E. coli o Rickettsia o Anaerobes Bactericidal o H. influenzae o N. meningitides o B. fragilis Ineffective for chlamydial infections Mechanism of Action Inhibits protein synthesis in bacteria and to a lesser extent in humans Chloramphenicol binds to the 50S ribosomal subunit at the peptidyltransferase site and inhibits the transpeptidation reaction Chloramphenicol also can inhibit mitochondrial protein synthesis in mammalian cells Adverse Effects Hypersensitivity Reactions Hematological Disorders Nausea and Vomiting Unpleasant Taste Gray Baby Syndrome Blurring of Vision Digital Paresthesia Drug Interactions CYP450 inhibitor LINCOMYCINS Sulfur containing antibiotics isolated from Streptomyces lincolnensis Resemble macrolides in spectrum of activity Bactericidal activity is dependent on concentration 13 | Prepared by: Santi Raphael B. Lledo, RPh Used in osteomyelitis and infections of the peritoneal and pleural cavities Useful against G(+) and infections caused by nonspore forming anaerobes Adverse Effects: Diarrhea, nausea Rashes Impaired Liver Function Neutropenia Antibiotic associated colitis QUINOLONES Introduction of chlorinated 4-quinolones became one of the major advancements Mechanism of Action Acts through inhibition of Topoisomerase IV and DNA gyrase enzymes necessary for DNA replication DNA Gyrase Responsible for continuous introduction of negative supercoils in the DNA strand Topoisomerase IV Separates interlinked (catenated) daughter DNA molecules that are the product of DNA replication Spectrum of Activity Specific agents with activity against Streptococci Active against Chlamydia, Mycoplasma, Legionella, Brucella, and Mycobacterium Specific Agents Levofloxacin (Levaquin) Gatifloxacin (Tequin) Moxifloxacin (Avelox) Ofloxacin (Floxin) Ciprofloxacin (Ciprobay) Therapeutic Uses UTI Prostatitis STDs GI and Abdominal Infections RTI Bone, Joint, and Soft Tissue Infections Adverse Effects GI disturbances Inhibits enzymes for Theophylline (Ciprofloxacin and Pefloxacin) Rashes Photosensitivity (Cinafloxacin) Tendon Rupture Renal Disease Hepatotoxicity (Trovafloxacin) Cardiotoxicty (Grepafloxacin) MISCELLANEOUS ANTIBIOTICS Polypeptides Most powerful antibiotics Very Nephrotoxic Lack systemic activity following oral administration Source: Bacillus and Streptomyces spp. Mechanism of Action Interferes with bacterial cell wall synthesis and most are only effective against G(+) bacteria Vancomycin Streptomyces orientalis (Amycolopsis orientalis) Always administered via slow IV injection or infusion ADRs: Red Man or Red Neck Syndrome Decreased auditory acuity Renal Damage Phlebitis and rashes Vancocin® Teicoplanin Actinoplanes teichomyetius Used in the tx of Osteomyelitis and Endocarditis ADRs: Rash Hypersensitivity reactions Neutropenia Available for ophthalmic, otic and topical use in combination with a variety of other compounds. Colistin Bacillus colistinus Colistin sulphate – oral use Colistimethate sodium – parenteral Polymyxin B and Colistin MOA Surface-active agents Interact strongly with phospholipids and disrupt the structure of cell membranes, resulting to a change in permeability of cell membranes Polymyxin B and Colistin SoA Use are restricted to G(-) bacteria Enterobacter, E. coli, Klebsiella, Salmonella, Pasteurella, Bordetella, and Shigella. Also Pseudomonas Proteus spp. are intrinsically resistant Mupirocin Pseudomonas fluorescens For topical use only Available as 2% cream or ointment Mupirocin MOA Inhibits bacterial protein synthesis by reversible binding and inhibition of isoleucyl transfer-RNA synthetase Bactroban® Mupirocin SoA For treatment of infections caused by S. aureus or S. pyogenes SULFONAMIDES Chemistry Sulfonamide is a generic name of derivatives paraaminobenzenesulfonamide Mechanism of Action Competitive antagonists of PABA Prevent normal bacterial utilization of PABA for the synthesis of pteroglutamic acid Bacitracin Bacillus subtilis From debrided wound of 7-year old Margaret Tracy Very active against G(+) bacteria Orally, topically and parenterally Mechanisms of Resistance Low affinity to sulphonamides Efflux of the drug An alternative metabolic pathway for synthesis of an essential metabolite An increased production of an essential metabolite or drug antagonist Polymyxin B Bacillus polymyxa and Bacillus aeroporous Useful against G(-) bacteria Therapeutic Uses UTI Nocardiosis 14 | Prepared by: Santi Raphael B. Lledo, RPh