Q: What is an antibiotic? A: An antimicrobial agent derived at least in part from a natural biological product. Q: What are some of the attributes of an ideal microbial agent? A: * Ability to damage microorganism not host * Solubility in body fluids * Non allergenic * Stability * Resistance by microorganisms not easily acquired * Long shelf life * Reasonable cost Q: Who discovered penicillin? A: Alexander Fleming in 1928. Q: What does selective toxicity mean in the context of antibiotics? A: The ability of an agent to target the bacterium with minimal toxic effects in the host. Q: Why is it easier to achieve selective toxicity in prokaryotes than eukaryotes? A: Selective toxicity works by exploiting the differences in structure and metabolism of microorganisms and host cells. Prokaryotes are structurally more distinct from human cells than eukaryotes. Q: What is the minimal inhibitory concentration (MIC)? A: The lowest concentration of an antibiotic able to inhibit the growth of a microorganism. Q: What is the minimal bacteriocidal concentration (MBC)? A: The lowest concentration of an antibiotic able to kill a microorganism. Q: What does bacteriostatic mean? A: Reversibly inhibits growth. (If antibiotic removed, the organisms may recover and continue to grow.) Q: What does bacteriocidal mean? A: Kills the microorganism. Q: What are some of the factors influencing the selection of an antibiotic? A: * Clinical assessment (urgency and need for antibiotic) * Laboratory assessment (in vitro testing) * Dose * Duration of therapy Q: What are some of the factors influencing the clinical assessment of a patient with an infection? A: * Infectious aetiology * Site of infection * Most likely pathogen/s * Known antimicrobial sensitivity profiles * Need for empirical therapy * Age and gender of the patient Q: Why is the site of infection so important when considering the selection of an antibiotic? A: The drug must be able to reach the site of infection. (E.g. * Meninges - cross the blood-brain barrier * Urinary tract - secretion by the kidney * Osteomyelitis - poor blood supply, pus, poor diffusion of antibiotic to site of infection * Intracellular infection - cross cell membranes, concentrate in cell) Q: What is the post-antibiotic effect? A: The period of stasis or other biologically detectable effect following withdrawal of an antibiotic from the environment where viable microorganisms remain. Q: What is the therapeutic index? A: The ratio of the toxic concentration to the therapeutic concentration. Q: What are 3 main reasons why you might use combination therapy with antibiotics? A: * Empirical (Use combination to cover all likely pathogens) * Synergy (Use combination to increase ability to kill pathogens - e.g. infective endocarditis use penicillin and gentamicin) * Prevent emergence of drug resistance (e.g. tuberculosis treatment) Q: True or false? Most selective antibiotics interfere with the synthesis of the bacterial cell wall. A: True. E.g. penicillins, cephalosporins, vancomycin, bacitracin Q: What are the various mechanisms of action of antimicrobial agents? A: * Cell wall inhibitors * Cell membrane inhibitors * DNA function/synthesis inhibitors * Protein synthesis and assembly inhibitors * Metabolic analogues Q: True or false? Beta-Lactam antibiotics are Bacteriostatic and Concentration dependent. A: False. Beta-Lactam antibiotics are bacteriocidal and time-dependent killers. Q: True or false? Beta-Lactam antibiotics inhibit peptidoglycan crosslinking enzyme systems. A: True. Q: What is the name for the enzymes that bind to Beta-Lactam antibiotics? A: Penicillin Binding Proteins (PBP). Q: How do Beta-Lactam antibiotics kill? A: They stop the crosslinking of the cell wall and cells lyse. Q: What conditions are necessary for Beta-Lactam antibiotics to kill? A: The microorganisms must be actively dividing. (Growth.) Q: What are penicillin G and penicillin V effective against? A: * Gram positive bacteria * A limited number of gram negative species (e.g. Neisseria sp.) Q: What are ampicillin and amoxicillin effective against? A: * Gram negative bacteria * Gram positive bacteria Q: What is the major mechanism microbes have for resistance against penicillin? A: Beta-Lactamase, an enzyme which breaks the Beta-Lactam ring inactivating Beta-Lactam antibiotics such as penicillin. Q: What was the antibiotic developed to overcome Beta-Lactamase activity? A: Methicillin. A Beta-Lactamase resistant penicillin, active against a range of gram positive bacteria. Q: What are some methicillin-like antibiotics? A: * Cloxacillin (less reliably absorbed from the gut) * Flucloxacillin and Dicloxacillin (reliably absorbed from the gut, less GI upset, Dicloxacillin has less hepatic toxicity but may induce thrombophelebitis when given IV) Q: What does MRSA stand for? A: Methicillin Resistant Staphylococcus Aureus. Q: What is the major mechanism methicillin resistant staphylococcus aureus has for resistance against methicillin? A: * Methicillin resistant staphylococcus aureus has altered penicillin binding proteins which methicillin has a decreased binding affinity for. Note that this is the same mechanism which some Neisseria gonorrheae and Streptococcus pneumoniae can develop resistance to Penicillin G by. Q: What factors lead to the intrinsic resistance of pseudo sp. to penicillin? A: * Periplasmic Beta-Lactamase * Reduced outer membrane permeability * Altered affinity of PBP for Beta-Lactams Q: What are some Anti-Pseudo penicillins? A: * Ticarcillin * Piperacillin Q: What are the adverse effects of penicillin? A: * Hypersensitivity reaction - rash (frequent) * Interstitial nephritis (infrequent) * Anaphylaxis (infrequent) * Encephalopathy (infrequent) * Haematological toxicity (infrequent) Q: True or false? Cephalosporins are concentration dependent killers. A: False. Cephalosporins are time dependent killers. Q: What are the moderate spectrum cephalosporins, cephalothin, cephazolin and cephalexin, active against? A: * Streptococci * Staphylococci * Penicillinase (Beta-Lactamase) producing Staphylococci * Escherichia coli and Klebsiella spp. NOT active against: * Many gram negatives * Enterococcus faecalis * Bacteroides fragilis * Listeria monocytogenes Q: What are the cephalosporins with anti-Haemophilus activity? A: * Cephamandole * Cefaclor * Cefuroxime Q: What are the cephalosporins with anti-Anaerobic activity? A: * Cefoxitin * Cefotetan Note: 60-70% Bacteroides fragilis are susceptible. Less active than Cephamandole against aerobes. Cefotetan has the longer half life of the two. Q: What are the 2 major broad spectrum cephalosporins? A: * Cefotaxime * Ceftriaxone (Activity against majority of community acquired enteric gram negative rods) Q: What are the broad spectrum cephalosporins with anti-pseudomonal activity? A: * Ceftazidime * Cefepime * Cefpirome Q: Which of the following has the least activity against gram positive organisms? Ceftazidime, cefepime and cefpirome. A: Ceftazidime. Q: What are the adverse effects of cephalosporins? A: * Hypersensitivity rash (frequent) * Candida overgrowth (frequent) * Nephrotoxicity (infrequent) * Anaphylaxis (infrequent) * Haematological toxicity (infrequent) Q: What are the 2 major classes of Beta Lactam Antibiotics? A: * Penicillins * Cephalosporins Q: True or false? Neither Cefotaxime nor Ceftriaxone enter the CSF. A: False. Both Cefotaxime and Ceftriaxone enter the CSF. Q: What class of Beta Lactam Antibiotics is Aztreonam a member of? A: Monobactams. Q: What is Aztreonam active against? A: * Gram negative aerobic bacteria * Beta-Lactamase producing H. influenzae * Gram negative rods * Pseudomonas sp Note: INACTIVE against gram positives and anaerobes. Q: What class of Beta Lactam Antibiotics is Imipenem a member of? A: Carbapenems. Q: True or false? Clavulinic Acid and Sulbactam are competitive inhibitors of a select range of Beta-Lactamases encoded by plasmids in bacteria. A: False. Clavulinic Acid and Sulbactam are *suicide* inhibitors of a select range of Beta-Lactamases encoded by plasmids in bacteria. Note: These are combined with an active drug in therapy. Q: What is the usual clinical situation when Aztreonam is used? A: In patients with a severe hypersensitivity of penicillin and/or cephalosporin. There is little cross reactivity between the monobactams and the penicillins/cephalosporins. Q: What are 2 cell wall inhibitors which are not beta-lactamases, cephalosporins or vancomycin? A: * Cycloserine * Bacitracin (Also Isoniazid and Fosfomycin) Q: True or false? Cycloserine work by decarboxylating serine. A: False. Cycloserine works by inhibiting the incorporation of alanine into the cell wall. Q: How does bacitracin work? A: It prevents de-phosporylation of a phospoholipid carrier preventing regeneration of the carrier. Q: What are the 2 main glycopetide antibiotics? A: * Vancomycin * Teicoplanin Q: How does vancomycin work? A: It binds to the terminal D-ala-D-ala residues and prevents incorporation of the subunit into the growing peptidoglycan. Q: Why are glycopeptide antibiotics inactive against gram negative bacteria? A: They are very large molecules and are therefore unable to get into gram negative bacteria's cell walls. Q: What situations is vancomycin usually used in? A: * MRSA * Severe penicillin allergy Q: What methods of administration may be used for vancomycin? A: Vancomycin must be given parentally. It must NOT be given through the GIT. So you can give it intramuscularly, IV, subcutaneous, etc. Q: What additional factors does VRSA have compared to community acquired Staphylococcus aureus? A: * 3-5 times more PBP2 and PBP' * 3 times more peptidoglycan monomer * Cell wall twice as thick as 'normal' staphylococci Q: What are vancomycin's adverse effects? A: * 'Red Man' syndrome - too rapid IV infusion resulting in histamine release (frequent) * Nephrotoxicity Q: What kind of therapeutic range does vancomycin have? A: Very narrow. Need to monitor antibiotic levels in blood. Q: In reference to classes of antibiotics, what does the acronym MASK stand for? A: The inhibitors of protein synthesis: * Macrolides * Azalides * Streptogramins * Ketolides Q: What are some of the chemical/structural properties of macrolide antibiotics? A: * Macrocyclic antibiotics containing a lactone * Polyenes * Contain either 12, 14, 15 or 16 member ring. Q: True or false? Most macrolides contain a 12 member ring. A: False. Most macrolides contain a 14 member ring. Q: True or false? Erythromycin contains a 15 member ring. A: False. Erythromycin contains a 14 member ring. Q: True or false? Roxithromycin contains a 16 member ring. A: False. Roxithromycin contains a 14 member ring. Q: True or false? Clarithromycin contains a 13 member ring. A: False. Clarithromycin contains a 14 member ring. Q: True or false? Azithromycin contains a 15 member ring. A: True. Q: What is the mechanism of action of the macrolides? A: They interfere with the process of peptide elongation by binding with 23S rRNA. Q: What is the macrolides spectrum of activity? A: * Gram positive cocci * Haemophilus influenzae * Legionella * Bordetella * Cornebacteria * Gram negative cocci * Mycoplasma * Chlamydia * Gram negative anaerobes Q: True or false? Macrolide antibiotics cannot be given orally as they cause severe mucosal irritation in 45% of patients. A: False. Macrolide antibiotics are well tolerated orally. Q: True or false? The macrolide antibiotics have a spectrum of activity suitable for the treatment of respiratory infections, soft tissue disease and intracellular bacteria. A: True. Q: What was the earliest macrolide? A: Erythromycin. Q: What is erythromycin active against? A: * Sensitive Staphylococci * Sensitive Streptococci * Mycoplasma * Chlamydia * Anaerobes * Gram negative cocci Q: What is the drug of choice in the treatment of pneumonia due to Legionella spp.? A: Erythromycin. Q: True or false? Erythromycin is active against enteric Gram negative rods. A: False. Erythromycin is not active against enteric Gram negative rods. Q: What are the side effects of erythromycin? A: Gastrointestinal symptoms such as abdominal cramps and nausea. Note: If there is severe vomiting or diarrhoea the antibiotic may not be absorbed in the correct dosage. Q: Name 3 of the newer macrolide derivatives. A: * Azithromycin * Clarithromycin * Roxithromycin Q: What advantages do the newer macrolide derivatives have over erythromycin? A: * Improved pharmacological activity * Less gastrointestinal side effects * Acid lability modified * Enhanced tissue penetration * Increased plasma half life Q: What are some of the features of azithromycin? A: * Similar spectrum of activity to erythromycin * Good oral availability * More active against H. influenzae and Legionella spp. than erythromycin * Good as a 2nd line treatment for cerebral toxoplasmosis in AIDS patients * More expensive than erythromycin Q: What are some of the features of clarithromycin? A: * Similar spectrum of activity to erythromycin * Activity against Mycobacterium avium complex (MAC) * Treatment of Helicobacter pylori infection in combination with Amoxicillin and a proton pump inhibitor * Good tissue penetration * EXPENSIVE Q: What are some of the features of roxithromycin? A: * Similar spectrum of activity to erythromycin * Good oral availability * Less GI upset Q: How does resistance to the macrolide antibiotics occur? A: * Alteration in the 23S rRNA target. (Methylation of two adenine nucleotide.) * Methylase enzyme. (Plasmid mediated, inducible.) Q: What are the adverse effects of the macrolide antibiotics? A: * Nausea (frequent) * Upper GI discomfort (frequent) * Deafness (infrequent) * Cholestatic jaundice (infrequent) Q: True or false? Tetracyclines are concentration dependent killers. A: False. Tetracyclines are time dependent killers. Q: What organisms are tetracyclines active against? A: * Gram positive * Gram negative * Rickettsia and Chlamydia * Mycoplasma * Some spirochetes Q: True or false? Tetracyclines have activity against obligate intracellular pathogens. A: True. Tetracyclines have activity against obligate intracellular pathogens such as rickettsia and chlamydia. Q: True or false? Tetracyclines have activity against cell wall deficient bacteria. A: True. Tetracyclines have activity against cell wall deficient bacteria such as mycoplasma. Q: What are the 3 major tetracyclines? A: * Tetracycline * Doxycycline * Minocycline Q: True or false? Tetracycline, doxycycline and minocycline all have similar pharmacokinetics but vary in regard to their spectrum of activity. A: False. Tetracycline, doxycycline and minocycline all have similar spectrum of activity but vary in regard to their pharmacokinetics. Q: What are some of the features of tetracyclines? A: * Large molecules * Bacteriostatic agents * Uptake of tetracyclines involves an energy dependent 'suicidal' active transport into the cell * Tetracyclines, when taken up, accumulate inside the cell * Tetracyclines bind to the 30S ribosome subunit (preventing aminoacyl tRNA binding to the active site of the ribosome inhibiting protein synthesis) * Use is limited by resistance Q: What are the features of Doxycycline? A: * Long half life (therefore used in most situations requiring a tetracycline) * Lipophilic (absorption not affected by food) * Must be given with liquid to avoid oesophagitis * Used in malaria prophylaxis Q: What are the features of resistance to tetracyclines? A: * Plasmid mediated * Common in Gram negative and Gram positive * Associated with synthesis of an additional membrane protein which mediates a rapid efflux of tetracycline from resistant cell Q: What conditions do tetracyclines remain important in the treatment of? A: * Pelvic inflammatory disease * Acute bacterial sinusitis * Acne * Exacerbations of chronic obstructive airways disease * Cholera * Brucellosis * Lyme disease (spirochete) Q: What are the adverse effects of tetracyclines? A: * Gastrointestinal intolerance (frequent) * Candidiasis (frequent) * Dental staining and hypoplasia in children (frequent) * Nephrotoxicity (infrequent) * Photosensitivity (infrequent) * Staphylococcal enterocolitis (infrequent) Q: True or false? Aminoglycosides are concentration dependent killers. A: True. Q: What are the features of aminoglycosides? A: * Broad spectrum class of antibiotics * Must be given systemically * Penetrate tissue poorly * They have no useful activity against: - Anaerobes - Intracellular bacteria - Streptococci Q: What are the 3 major groups of aminoglycosides? A: * Streptomycin * Neomycin * Kanamycin group Q: What are the 4 major antibiotics in the kanamycin group? A: * Kanamycin * Gentamicin * Tobramycin * Amikacin Q: What is the mode of action of the aminoglycosides? A: * Enter cell by active transport * Inhibit protein synthesis by binding to 30S ribosome subunit and inhibiting initiation of peptide chain * Cause misreading of mRNA * Bacterial agents Q: Which antibiotic was the first aminoglycoside? A: Streptomycin. Q: True or false? Streptomycin is a component of antituberculosis therapies as recommended by the WHO. A: True. Q: What are the features of neomycin? A: * Toxic * Topical agent * Not absorbed if given orally * Has been used to 'sterilise' the gut prior to surgery * Does not kill anaerobes Q: What are the features of kanamycin? A: * Its spectrum of activity includes; Staphylococci, Enterobacteria and Mycobacterium tuberculosis * It is active against streptomycin resistant strains of bacteria Q: What are the features of gentamicin? A: * The most commonly used aminoglycoside * Its spectrum of activity includes; Staphylococci, Enterobacteria and Pseudomonas aeruginosa * Lacks activity against Streptococci * Activity against Streptococci improved by use of penicillin (important synergistic drug combination in bacterial endocarditis for both Streptococci and Staphylococci) Q: What are the features of Tobramycin? A: * Better activity against Pseudomonas aeruginosa than kanamycin * Less effective against enterobacteria than kanamycin * Has restricted usage * More expensive than gentamicin Q: Name 3 mechanisms in which bacteria become resistant to aminoglycosides. A: * Aminoglycoside-modifying enzymes (most important mechanism) * Alteration of target site (streptomycin) * Alteration of cell wall permeability (gram negative rods) Q: True or false? Genes for aminoglycoside-modifying enzymes are always plasmid encoded. A: False. Genes for aminoglycoside-modifying enzymes are *often* but not always plasmid encoded. Q: What are the features of Amikacin? A: * Semisynthetic derivative of kanamycin * Less active than gentamicin * Resistant to most aminoglycoside-modifying enzymes * Reserved usage Q: True or false? The aminoglycosides are used frequently in therapeutic medicine because of the high therapeutic index. A: False. The aminoglycosides have a very low (narrow) therapeutic index and patients receiving aminoglycosides need to have their blood levels monitored. Q: What are the side effects of aminoglycoside antibiotics? A: * Ototoxicity (frequent) * Nephrotoxicity (frequent) * Rash (infrequent) Q: What is the spectrum of activity for chloramphenicol? A: * Includes Gram positives and Gram negatives * Staphylococci * Streptococci * Neisseria spp. * Haemophilus influenzae * Rickettsia * Chlamydia * Anaerobes Q: What are the features of chloramphenicol? A: * Bacteriostatic *or* bacteriocidal agent * Inhibits protein synthesis by binding to the 50S ribosome sub-unit preventing peptide bond formation * Absorbed well * penetrates CSF * Toxicity limits use * Reserved agent Q: What are some of the serious infections Chloroamphenicol is used to treat? A: * Typhoid * Acute epiglottitis (Hib) * Meningitis * Q fever Q: What is the mechanism for resistance to chloramphenicol? A: An enzyme called chloramphenicol acetyl transferase acetylates chloramphenicol to inactivate it. Q: What are the adverse effects of chloramphenicol? A: * Dose-related potentially fatal bone marrow toxicity (frequent) * Aplastic anaemia (infrequent) * Optic neuritis (infrequent) * 'Grey baby' syndrome (infrequent)- In newborns many liver enzymes are not mature. Deficiency of glucoronyl transferase activity delays metabolism of the chloramphenicol. Elevated chloramphenicol may cause cardiovascular collapse and death. Careful monitoring is required. Q: What are the 2 major lincosamides? A: * Lincomycin * Clindamycin Q: What is the mechanism of action of the lincosamides? A: They bind to 50S ribosomal subunit interfering with the process of peptide elongation. The ribosome binding site is similar to that of the macrolide antibiotics. Note: Erythromycin resistance due to methylation of ribosome binding site affects clindamycin Q: What organisms are clindamycin and lincomycin active against? A: * Gram positive aerobes * Most anaerobes Q: What diseases are clindamycin and lincomycin used in the treatment of? A: * Gingivitis * Osteomyelitis * Septic arthritis * Mastitis (when penicillin allergy exists) * Bacterial vaginosis (clindamycin in cream form) * Propionibacterium acnes (clindamycin in lotion or gel form) Q: What are the adverse effects of the lincosamides? A: * Diarrhoea (frequent) * Rash (frequent) * Pseudomembranous colitis - overgrowth of Clostrium difficile (infrequent) * Hepatitis (infrequent) Q: True or false? Mupirocin in a DNA synthesis inhibitor? A: False. Mupirocin is an inhibitor of protein synthesis. Q: What are the features of mupirocin (pseudomonic acid A)? A: * Topical antibiotic * Toxic as a systemic agent * Active against Gram positive bacteria * Competitive inhibitor of isoleucyl-transfer RNA-synthetase * Blocks incorporation of isoleucine into polypeptides (inhibiting protein synthesis) * Can be used in the treatment of nasal carriage of MRSA * Has been used in treatment of impetigo (associated with Staph. aureus and Strep. pyogenes) Q: True or false? Fusidic acid is an inhibitor of protein synthesis. A: True. Q: What are the features of fusidic acid? A: * Steroid like structure * Penetrates well into tissue and bone * Very good activity against Staph. aureus * Inhibits protein synthesis Q: What is the mechanism of action for fusidic acid? A: It inhibits transloaction of the growing polypeptide chain by inhibiting 'elongation factor G' which is esssential for this reaction. (Inhibits protein sysnthesis.) Q: What organisms does fusidic acid have activity against? A: * Staphylococci * Streptococci * Neiserria spp. * Mycobacterium tuberculosis * Anaerobes Note: NOT active against most Gram negative bacteria. Q: What are the adverse effects of fusidic acid? A: * Gastrointestinal intolerance - oral (frequent) * Hepatotoxicity - IV (infrequent) Q: What are the 2 major classes of antibiotics that inhibit DNA replication? A: * Nitroimidazoles * Quinolones Q: Name the 2 major 5-nitroimidazoles. A: * Metronidazole * Tinidazole Q: True or false? 5-nitroimidazoles are concentration dependent killers? A: True. Q: What are the features of metronidazole? A: * Important agent in the treatment of infections due to; anaerobic bacteria, certain protozoans and H. pylori * Available as an IV preparation * Excellent absorption (oral preparations + suppositories) * Aka flagyl * Used to treat clostridium difficile in pseudomembranous collitis * NOT active against aerobic or facultative bacteria (even under anaerobic conditions) * Requires reduction of nitro group intracellularly at a highly reduced REDOX potential Q: What are the features of Tinidazole? A: * 5-nitroimidazole * Only available as an oral preparation * Longer half life than metronidazole Q: True or false? Below is the mechanism of action of metronidazole. Reduction of nitro group intracellularly at a highly reduced REDOX potential -> Production of shortlived toxic intermediaries and free radicals -> Damages DNA and inhibits replication A: True. Q: True or false? Metrinidazole does not penetrate cells well because equilibrium is quickly reached at subtherapeutic levels within the cell. A: False. Reduction of metronidazole within the cell generates a concentration gradient which facilitates the diffusion of more metronidazole into the cell. Q: What are the adverse effects of metronidazole? A: * Black hairy tongue (induces low compliance) * No alcohol (otherwise can cause paralysis, peripheral neuropathy, etc -> but not long lasting) Q: What is the parent compound of all the quinolones? A: Nalidixic acid. Q: Name the 3 major Fluorinated 4-Quinolones. A: * Norfloxacin * Ciprofloxacin * Ofloxacin Q: True or false? Quinolones are concentration dependent killers. A: True. Q: What is Norfloxacin's spectrum of activity? A: * Gram negatove bacteria * Enterococci * Staphylococci * Pseudomonas Used in UTI and GIT infections. Q: True or false? The quinolone parent compound Naladixic acid has no therapeutic use. A: False. Naladixic acid is occasionally used in the management of UTI (Gram negatives). Q: What is the spectrum of activity of Ciproflozacin, Enoxacin and Ofloxacin? A: * Gram negative rods * Gram negative cocci * P. aeruginosa * Gram positice cocci * Various species of Mycobacteria Q: True or false? The quinolones are always used in preference to metronidazole in the treatment of Gram negative bacteria. A: False. The quinolones are expensive and RESERVED for infection where cheaper agents have a resistance problem. Q: What is the mechanism of action of the quinolones? A: * Quinolones inhibit DNA gyrase (a bacterial enzyme not found in mammalian cells essential for bacterial DNA replication). * At high concentrations, its effect on RNA may result in bacteriostatic effects. See below: Dose Response Curve R | | | \Naladixic A. _ e | | `\ `\ ,/ l | \ \Norflox. `\_ | . | | \_ `'--,,__,/ | \ `\ __ S | | \ __,,--' u | \Ciprof. | __,,-' __,,--- r | | `\_ ,-'____,,--' v | \ \___,,/-'' . | '--,,,__,,--''|_,/ ---------------------------------------------- |0.01 |0.1 |1 |10 |100 4-Quinolone concentration (mg/L) Q: What mechanism do bacteria have for resistance to the quinolone antibiotics? A: * Changes in DNA gyrase subunit structure (lower affinity for drug) * Changes in cell wall permeability (decreased uptake of drug) Q: What are the adverse effects of the quinolones? A: * Nausea and upper GI discomfort (frequent) * Rashes (frequent) * Headache (infrequent) * Dizziness - self limited, rarely required discontinuation of therapy (infrequent) * Photosensitivity (infrequent) Q: True or false? The rifamycins are inhibitors of DNA transcription. A: True. Q: What are the 2 major rifamycins? A: * Rifampicin * Rifabutin Q: What is the spectrum of activity of the rifamycins? A: * Gram positive cocci (including Staphylococcus) * Mycobacterial sp. Q: True or false? There is rapid emergence of resistance to rifamycin antibiotics. A: True. Q: What is the mechanism for resistance to the rifamycin antibiotics? A: Rifamycins normally act by binding to the beta subunit of DNA dependent RNA polymerase and thereby interfering with mRNA formation. Resistant strains of bacteria have a structural alteration of the beta subunit of RNA polymerase. Q: What diseases is rifampicin used as a prophylaxis for? A: * Meningococcal disease * Haemophylus influenzae in children <4 years and adults in contact with patient with meningitis due to that organism Note: Hib vaccine Q: What other antibiotic is rifampicin used in combination with to treat MRSA following IV vancomycin? A: Fusidic acid. Q: What is Rifabutin used to treat? A: Mycobacterium avium complex (MAC) infection. Note: Rifabutin can be used prohylactically for MAC as well. Q: What are the adverse effects of rifampicin? A: * Hepatoxicity (frequent) * Liver enzyme induction - can interfere with drugs like warfarrin, oral contraceptives, etc. (frequent) * Hypersensitivity (infrequent) * 'Influenza syndrome' (infrequent) * Haematological toxicity (infrequent) Q: What is sulfonamide a metabolic analogue to? A: Para-aminobenzoic acid (PABA) Q: What is the mechanism of action for the sulphonamides? A: Bacterial growth is inhibited because the sulfonamide has affinity for pteridine synthetase and competes with PABA for binding of the dihydropteroate synthetase enzyme. Mammals obtain folic acid in their diet, but bacteria lack a transport system for folic acid and so make their folate from PABA. A few bacteria can utilise exogenous folate; they are resistant to sulfonamides. Q: Why are sulphonamides not often uses in infections with a lot of pus? A: Pus contains a lot of PABA and the sulphonamides are not able to effectively competitively inhibit folate synthesis. Q: What are the adverse effects of the sulphonamides? A: * Rashes (frequent) * Megaloblastic anaemia (infrequent) * Other serious and sometimes fatal side effects Note: Little use in general practice due to side effects. Q: Name some examples of sulphonamides. A: * Sulphonamide * Sulfamethoxazole * Sulfisoxazole * Sulfanilamide * Sulfadiazine Q: What is trimethoprim a metabolic analogue for? A: Dihydrofolate. Q: What are the features of trimethoprim? A: * Broad spectrum bacteriocidal agent * Inhibits dihydrofolate reductase * Inhibits folate synthesis in bacteria * Has a much lower (10^(-4) to 10^(-5) fold) affinity for the mammalian than for the bacterial enzyme. * Toxicity appears limited * Used in treatment (and prophylaxis) of UTI * Must not be given to pregnant women * Has synergistic action with sulphonamides Q: What is co-trimoxazole? A: Sulphonamide plus trimethoprim. (These two antibiotics are inhibitors are different points in the same pathway.) Q: What is co-trimoxazole used in treatment of? A: * Pneumocystis carinii in HIV/AIDS patients * Listeria monocytogenes * Nocardia infections Q: What are the features of dapsone? A: * Dapsone is a sulphone (related to the sulphonamides) * Inhibits dihydropteroate synthase * can be used in combination with trimethoprim to treat Pneumocystis carinii (alternative to co-trimoxazole) Q: What are the side effects of co-trimoxazole? A: * Hypersensitivity (frequent) * Megaloblastic anaemia (infrequent) * Other serious and sometimes fatal side effects Q: What are the features of Polymyxin B and E (colistin)? A: * Cell membrane inhibitors (renders cells leaky) * Acts like a cationic detergent on bacterial membrane * Simple polypeptides * Toxic and poorly diffusible * Topical treatment only * Active against Gram-negative bacteria Q: Polymyxin B may be used in the treatment of severe conjunctivitis in young children in combination with which 2 other antibiotics? A: * Neomycin (aminoglycoside) * Gramicidin (acts against Gram positive) Note: An alternative for the Polymixin B + Neomycin + Gramicidin treatment is Chloramphenicol. Q: True or false? Fungi are hard to target because they are neither prokayotic not eukaryotic. A: False. Fungi and eukaryotic. Q: True or false? There are many anti-fungal agents on the market but they are prohibitively expensive. A: False. There are very few antifungal agents on the market. Q: What are the polyene antifungal agents? A: * Amphotericin B * Nystatin Q: How do the polyene antifungal agents work? A: They interact with ergosterol in fungal membrane rendering it leaky and allowing K+ ions and small metabolites to escape. Ergosterol is similar to cholesterol found in mammalian cells. The polyenes have a preferential binding to ergosterol but binding to cholesterol can produce toxic effects. Liposome presentation reduces toxicity. Q: What are the features of amphotericin B? A: * Treatment of choice for majority of serious fungal infections * Poorly absorbed from the GIT (cannot be given orally) * For treatment of systemic infections it must be given IV * Toxic (to limit toxicity administer saline prior to amphotericin B) * Side effects - renal toxicity Q: What are the features of nystatin? A: * Poorly absorbed from the Gastrointestinal tract * Not absorbed through skin or mucous membranes when appled topically * Maily active against Candida albicans - commonly used in vaginal thrush and in babies for oral thrush. Q: What are some of the major imidazoles? A: * Ketoconazole * Clotrimazole * Econazole * Miconazole * Fluconazole Q: What is the mechanism by which azoles work? A: The azoles inhibit cytochrome-P450 activity. This decreases conversion of 14-alpha-methylsterols to ergosterol, an important membrane component in fungi. Failure of ergosterol synthesis causes altered membrane permeability leading to loss of ability to maintain a normal intracellular environment. Q: What are some of the conditions azole are used to treat? A: * Mucotaneous candidiasis * Dermatophytosis * Tinea versicolor * Chronic paronychia * seborrhoeic dermatitis Q: What are the features of Fluconazole? A: * Good tissue pentration * Enters CSF * IV administration (meningitis, septicemia) * Oral administration (well absorbed) * Used to treat Crytococcus neoformans in imunocompromised patients Q: What are the features of Itraconazole? A: * Acid dependent oral absorption (give with an acidic drink) * Similar activity to fluconazole but with increased activity against filamentous fungi. Q: What are the features of Ketoconazole? A: * Active against a variety of fungal infections (particularly yeasts) * Acid dependent oral absorption (give with an acidic drink) * Hepatotoxicity Q: What are 2 major inhibitors of fungal DNA? A: * Griseofulvin * 5-Fluorocytosine Q: What are the features of griseofulvin? A: * Interferes with the structure/function of fungal DNA * Toxic - fungal DNA is very similar to human DNA * Used in the treatment of dermatophyte infections which fail to respond to topical therapy * Given orally Q: What are the features of 5-fluorocytosine? A: * Converted to 5-fluorouracil (5-FU) which inhibits thymidylate synthetase (used in DNA synthesis). Vertebrate cells have little of the enzyme which converts fluorocytosine to 5-FU. * Toxic effects similar to 5-FU (causes bone marrow depression and gastrointestinal disturbances) * Used in treatment of systemic fungal infections * Can be used in combination with amphotericin B Q: What features distinguish mycobacteria from other bacteria? A: * Waxy cell wall - mycolic acids * Acid fast bacilli * Very slow growth (hence must treat over a long time -> compliance suffers) Q: Which antimycobacterials interfere with DNA gyrase? A: Quinolones. Q: Which antimycobacterials inhibit cell wall synthesis? A: * Isonazid * Ethambutol Q: Which antimycobacterials inhibit protein synthesis? A: Streptomycin. Q: Which antimycobacterials interfere with folate metabolism? A: * p-Aminosalicylic acid (PAS) * Dapsone Q: What is the recommended combination therapy for TB? A: * Rifampicin * Isoniazide * Pyrazinamide * Ethambutol Note: Giving multiple drugs together reduces the chance of resistance to any or all of the drugs being used developing. Q: What are the features of ethambutol? A: * Bacteriostatic agent on proliferating cells * Inhibition of incorporation of glucose into arabinogalactan and arabinomannan components of cell wall Q: What are the features of Isoniazid (INH)? A: * Active only against TB * Prodrug * Concentration dependent killing * Catalase activation * Targets mycolic acid synthesis Q: What are the features of Pyrazinamide? A: * Effective on *intracellular* Mycobacteria * Mechanism of action uncertain * Hepatotoxic