Principles and Definitions• Antimicrobial drugs frequently play a role in the treatment of both purulent and mucosal infection in the head and neck region• Antimicrobial agents may also be used prophylactically for example in the prevention of infective endocarditis among susceptible patients receiving dental treatment. – The ideal antimicrobial agent3. Selective toxicity against microbial target4. Minimal toxicity to the host5. Cidal activity6. Long plasma half life7. Good tissue distribution8. Oral and parenteral preparation9. No adverse interactions with other drugs
Principles and Definitions• Antibiotic are natural product of bact. or fungi which kill or inhibit the growth of other micro-orginisms• Most of antimicrobial drugs in current use have been chemically modified. • classification Bactericidal; agents KILL bacteria. • Bacteriostatic; agents INHIBIT GROWTH of bacteria • Target site 6. Cell wall synthesis 3. nucleic acid synthesis 7. Protein synthesis 4. membrane function
Principles and Definitions• Combination therapy – Prevent emergence of resistant strains – Take advantage of antibiotic synergism • Penicillins and aminoglycosides inhibit cell wall synthesis and allow aminoglycosides to enter the bacterium and inhibit protein synthesis. • CAUTION: Antibiotic antagonism – Penicillins and bacteriostatic antibiotics. Cell wall synthesis is not occurring in cells that are not growing. – Susceptibility tests are a valuable aid to antibiotic management of infection. There are tow main types; diffusion tests and dilution tests.
Antibiotic that inhibit cell-wall synthesis• BETA-LACTAMSIncludes the penicillins and cephalosporinsStructurally these agents all contain the beta-lactam ring• Mode of action• They prevent cell wall synthesis by binding to the enzyme known as penicillin binding proteins which are responsible for the final stages of cross-linking of the cell wall during growth and division.• Many are active against G+ve bacteria.• New beta-lactum with activity against G-ve bacteria.• Some patients are allergic to beta-lactum antibiotic
Antibiotic that inhibit cell-wall synthesis• GLYCOPEPTIDS• Include vancomycin and teicoplaninMode of action• Interfere with cell wall synthesis by binding to terminal D- ala-D-ala residue at the end of pentapeptide chains.• This prevents the subsequent incorporation of new subunits into growing cell wall.• They are active against G+ve bacteria.
Review of Initiation of Protein Synthesis 1 3 30S 2 GTP 1 2 3 GTP Initiation Factors f-met-tRNA mRNA Spectinomycin 3 GDP + Pi 2 50S P A 1 1 2 GTP 70S Aminoglycosides 30SInitiation InitiationComplex Complex
Review of Elongation of Protein SynthesisP A Tetracycline P A Tu GTP Tu GDP + Pi GTP Ts Ts Tu Ts GDP Chloramphenicol GDP Fusidic Acid + GTP G G GDP + Pi G GTP P A P A Erythromycin
QuickTime™ and aTIFF (Uncompressed) decompressor are needed to see this picture. Inhibitor of protein synthesis Aminoglycosides (only bactericidal protein synthesis inhibitor) streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical) • Modes of action - – Irreversibly bind to the 30S initiation complex (30S-mRNA- tRNA) and prevents initiation of translation. – must be given I.V or I.M. – Their main indication is for treatment for serious G-ve infection. – They are potentially nephrotoxic & ototoxic. – They are not indicated for the treatment of oral and dental infection.
QuickTime™ and aTIFF (Uncompressed) decompressor Tetracyclines (bacteriostatic) are needed to see this picture. tetracycline, minocycline and doxycycline • Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome. • Spectrum of activity - Broad spectrum; Useful against intracellular bacteria (chlamydiae) • Resistance – Common • Tetracycline mouthwashes sometimes used for treatment of oral ulceration • Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections (Candida spp.); staining and impairment of the structure of bone and teeth. Not used in children.
QuickTime™ and aTIFF (Uncompressed) decompressor are needed to see this picture. Chloramphenicol, Lincomycin, Clindamycin (bacteriostatic) • Mode of action - These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase activity. No new peptide bonds formed. • Spectrum of activity - Chloramphenicol - Broad range; Lincomycin and clindamycin - Restricted range It used for the prophylaxis of infective endocarditic in patients who are allergic to penicillin. • Resistance - Common • Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but is used in life threatening situations such as the treatment of bacterial meningitis.
QuickTime™ and aTIFF (Uncompressed) decompressor are needed to see this picture. Macrolides (bacteriostatic) erythromycin, clarithromycin, azithromycin, spiramycin • Mode of action - The macrolides inhibit translocation of the ribosome. • Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella • Resistance - Common
QuickTime™ and aTIFF (Uncompressed) decompressor are needed to see this picture. Fusidic acid (bacteriostatic) • Mode of action - Fusidic acid binds to elongation factor G (EF-G) and inhibits release of EF-GDP from the EF-G/GDP complex. Can’t reload EF-G with GTP. • Spectrum of activity - Gram-positive cocci • Topical preparation including an ointment for treatment of angular cheilitis. • Main use is in the treatment of staphylococcal infection resistant to beta-lactum or in penicillin-allergic patients
QuickTime™ and aTIFF (Uncompressed) decompressor inhibitor of nucleic acid Rifampin, Rifamycin, are needed to see this picture. Rifampicin, Rifabutin (bactericidal) Mode of action - These antimicrobials bind to RNA polymerase and inhibit of mRNA synthesis. • Spectrum of activity - Broad spectrum but is used most commonly in the treatment of tuberculosis. • Resistance - Common. Develops rapidly (RNA polymerase mutations) • Combination therapy - Since resistance is common, rifampin is usually used in combination therapy to treat tuberculosis.
Quinolones (bactericidal) QuickTime™ and aTIFF (Uncompressed) decompressor nalidixic acid, ciprofloxacin, ofloxacin, are needed to see this picture. norfloxacin, levofloxacin, lomefloxacin, sparfloxacin • Mode of action - These antimicrobials inhibit an enzyme called DNA gyrase and prevent supercoiling of DNA, thereby inhibiting DNA synthesis. • Spectrum of activity - Gram-positive cocci and urinary tract infections • The commonest side-effects are gastrointestinal. • METRONIDAZOLE; the active intermediates of the drug interact with and break the bacterial DNA • It is active against anaerobic bacteria • It is widely used by dentists.
Inhibitors of Folic Acid Synthesis• Basis of Selectivity- p-aminobenzoic acid + Pteridine Bacteria synthesize Sulfonamides Pteridine folic acid, humans synthetase do not. We get it Dihydropteroic acid from our diet. Dihydrofolate• Review of Folic synthetase Acid Metabolism Dihydrofolic acid• Tetrahydrofolate Dihydrofolate required for the Trimethoprim reductase methyl group on methionine, and for Tetrahydrofolic acid thymidine and purine Thymidine Methionine synthesis. Purines
QuickTime™ and aTIFF (Uncompressed) decompressor are needed to see this picture. Sulfonamides, Sulfones (bacteriostatic) • Mode of action - These antimicrobials are analogues of para- aminobenzoic acid and competitively inhibit dihydropteroate synthetase, block the formation of tetrahydrofolic acid and inhibits synthesis of purines and pyrimidine • Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. • Resistance - Common • Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.
QuickTime™ and aTIFF (Uncompressed) decompressor are needed to see this picture. QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. Trimethoprim, Methotrexate, Pyrimethamine (bacteriostatic) • Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid. • Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. • Resistance - Common • Combination therapy - These antimicrobials are used in combination with the sulfonamides; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.
Antifungal agentsMost act on synthesis or function of the fungal cell membrane.• POLYENESIncludes nystatin & amphotericin BMode of action; bind to sterol in eukaryotic cell membranes resulting in impairment of barrier function.Spectrum of activity- amphotericin B;broad spectrum but is very toxic. Used in treatment of systemic mycosis.New formalation of amphotericin B (AmBisome) is better tolerated. Used for treatment of oral candidosisNystatin; prescribed for topical use.
Antifungal agents• AZOLESIncludes fluconazole, itraconazol and miconazole• Mode of action- bind to cytochrome P450 which lead to inhibition of lanosterol C14-demethylase resulting in inhibition of ergosterol synthesis• Spectrum activity- fluconazole ; oropharyngeal candidosis Resistance- common Itraconazole; broad spectrum
Antiviral agents• ACICLOVIR- is the only one likely to be prescribed by dental surgeons• Mode of action- inhibition of herpesvirus DNA polymerase, and lead to DNA chain terminationIt is an analogue of guanosine• Spectrum activity- herpes simplex virusIt is valuable in the mangement of orofacial herpes simplex infections (herpetic gingivostomatitis, herpes labialis)• INTERFERONS- are naturally produced protein with potent antiviral activity• Spectrum activity- hepatitis B & C virus• Adverse effect- flu-like symptom.
Important antiviral agentsInterfere with DNA/RNAAciclovir Herpes simplex virusGanciclovir CytomegalovirusZidovudine Human immunodeficiency v.Ribavirin Respiratory syncytial virusInterfere with virusuncoatingamentidine Influenza type a virusInterferon ά Hepatitis B and C virus
Antimicrobial Drug Resistance Principles and Definitions• Some species of bacteria are innately resist to certain antibiotic.• Some strains may develop or acquire resistance to particular antibiotics.• Acquired resistance may arise by a single, spontaneous chromosome mutation .• Bacteria can acquire resistance genes via plasmids• An individual plasmid may code for resistance to several types of antibiotics
Antimicrobial Drug Resistance Mechanisms• Altered target- target enzyme may change perhaps by mutation.( penicillin binding protein) – Alteration in access to the target site (altered uptake)- through change permeability or by actively pumping the drug out of the cell (tetracycline) – Drug inactivation- enzyme may produced that inactivate the antibacterial agent. beta lactamase)