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ANTIMICROBIAL VIVASBeta-lactams and cell wall inhibitors2011-2, 2008-1, 2006-2, 2003-2What is the mechanism of action of penicillins?B-lactam antibioticBacteriocidalCovalently binds to the active site of Penicillin-binding protein (PBP)Inhibits bacterial cell wall synthesis by interfering with transpeptidation reaction of bacterial cell wall synthesis (the final step in cell wall synthesis)Structural analogue of D-Ala-D-Ala substrate present in cell wallAlso activates autolytic enzymes that cause lesions in the cell wallHigh intracellular osmotic pressure bursts weakened cell wallWhat are the important mechanisms of resistance to pencillins?Inactivation by B-lactamase (e.g. Staph) – overcome w/ b-lactamase inhibitor e.g. clavulanic acid, sulbactam or tazobactam (the plasmin-encoded, not the inducible chromosomal one formed by Enterobacter and Pseudomonas)Modification of target PBPs (e.g. MRSA, Pneumococci, Enterococci)Reduced penetration (Gram-ve organisms)Efflux pump (Gram-ve organisms)In general, what is the anti-microbial spectrum of penicillin G?Streptococci, meningococci, enterococci, some pneumococci, treponema pallidum, clostridia, non-betalactamase producing staphylococciDescribe the pharmacokinetics 2006-2Variable resistance to gastric acidPoorly absorbed with foodWidely distributed but only enter meninges when inflammedPolar so not much metabolism -> excreted unchanged by filtration 10% and secretion 90%Tubular secretion can be blocked (probenecid)Some excreted in bile (naficillin and ampicillin undergoes enterohepatic circulation)t? 30mins – 1 hour usuallyProcaine and benzathine forms given IM have long t? b/c slow release to blood stream2005-1What are the clinical manifestations of penicillin allergy?Hypersensitivity reactions (~5-6% and <1% of people who have been ok w/ previous)Anaphylaxis (rare, 0.05% of people)Fever Skin (Maculopapular rash, Urticarial skin rash , Exfoliative dermatitis)Serum sickness Stevens Johnson Syndrome (Erythema multiforme major)What other side effects of penicillin treatment do you know of?Renal failureSeizures at high dosesGI disturbanceCandidal infectionsHepatitis (fluclox/oxacillin)Pseudomembranous colitis2010-2What is the mechanism of action of cephalosporinsInhibit bacterial cell wall synthesis, cell division and growthSimilar to penicillins, contain b-lactam ringBactericidal Most effective in rapidly dividing cells.How does the spectrum of microbiological activity for the 4th generation cephalosporins compare to that of earlier generations?Gram-ve as for 3rd generation e.g. E. coli, H. influenza, KlebsiellaSome gram+ve (S. pneumonia) but less than 1st generationMore resistant to B-lactamases than earlier generationsWhat is the relationship between penicillin allergy and cephalosporin allergy.5-15% possibility of cross-reaction with penicillin allergy.2010-1, 2008-2, 2004-2How are cephalosporin’s classified – what are the differencesBased on their order of introduction into clinical practice, but vary in their antibacterial activity:1st gen: GPs (Strep and Staph) – e.g. cefazolin and cephalexin, cephalothin2nd gen: Slightly less GP, but >GN (Haemophilus & Kleb) – e.g. ceflaclor, cefuroxime, cefamandole, cefotetan, cefoxitin3rd gen: Even less GP but even more GN and can penetrate BBB – e.g. ceftriaxone, ceftazidime, cefoperazone, ceftizoxime, cefixime (All end in –one or –ime, exceptions: cefuroxime and cefepime)None of the above active against MRSA, Pseudomonas or Enterobacter4th gen: Good GP and GN (Pseudomonas), only one is cefepimeWhy are 3rd generation cephalosporin’s used in CNS infectionExpanded GN activityCross the BBBPenetrate body fluids wellGood toxicity profileAre there any bacteria responsible or CNS infection that cephalosporins don’t coverListeriaResistant pneumococci may need vancomycinResistant E ColiUse with aminoglycoside to cover PseudomonasWhat are the adverse effects of the Cephalosporins? 2008-2Hypersensitivity reactions (~2%) identical to penicillins: anaphylaxis, fever, skin rashes, nephritis, granulocytopenia, & hemolytic anemiaSome individuals with a history of penicillin allergy may tolerate cephalosporin’sFrequency of cross-allergenicity uncertain, probably around 5 - 10%Severe pain IMIThrombophlebitis IVIRenal toxicity: interstitial nephritis & ATNCephalosporins with a methylthiotetrazole group (eg, cefamandole, cefotetan) may cause: hypoprothrombinemia, bleeding (preventable with Vit K1 10 mg twice weekly) and severe disulfiram-like reactions with alcohol.2009-1What classes of antibiotic are used in staphylococcal infectionBeta-lactamase negative staph: Penicillin, 1st Generation CephalosporinsBeta-lactamase positive staph:Beta-lactamase resistant penicillins (Methicillin, Naficillin) or Isoxazolyl Penicillins (dicloxacillin, flucloxacillin) 1st Generation CephalosporinsBeta-lactamase inhibitor with penicillin combination – amoxicillin with clavulinic acid, sulbactam, tazobactamVancomycin (MRSA), Aminogycosides, MacrolidesWhat are the mechanisms of resistance in MRSABeta-lactam antibiotics normally bind to PBP's (Penicillin Binding Proteins) causing inhibition of transpeptidation, thus blocking cell wall synthesis and lead to cell wall deathMRSA produce PBP's that have a low affinity for binding beta-lactam antibiotics and hence render them ineffectiveMay be overcome if used in high enough concentrations, but not clinically achievableWhat are the adverse effects of vancomycinLocal phlebitisChills & fever Flushing due to histamine release (Red Man Syndrome)Ototoxicity / nephrotoxicity (esp if administered with aminoglycoside)Additional: Vancomycin PD: Bactericidal glycoprotein, binds D-Ala-D-Ala, inhibits cross linkingResistance by replacing terminal D-ala with D-lactateNarrow spectrum, used for MRSA, or w/ 3rd gen for penicillin resistant pneumococci, or as backup agent for C. difPK: No oral absorbtion (IV only), widely distributed, excreted unchanged, needs dose monitoringWhat circumstances encourage the development of bacterial resistance to antimicrobial agents? 2005-2Resistance is an example of natural selection, and arises through spontaneous mutations or DNA exchange between different species of bacteria (either directly by piasmids or via bacteriophages)Therefore resistance is promoted by:1. Dirty hospital environments with multiple species of bacteria co-existing and "exchanging" between environment, patients and staff2. A course of antibiotics that only partially treats a target population (inadequate potency, dose or duration)(Thus, paradoxically, both under-use and overuse of antibiotics plays a role in the development of resistance!)Overall, however, total consumption of antibiotics within a human population is the critical factor in development of resistant strainsInhibitors of microbial protein synthesis2007-1What are the adverse effects of chloramphenicolGIT: nausea, vomiting and diarrhoeaBone marrow suppression: reversible RBC suppression, idiosyncratic aplastic anaemia: 1/24000 – 1/40000 Newborn: gray baby syndrome Drug interaction: Phenytoin, chlorpropamide ,warfarin prolongs half life and raises concentrationWhich bacteria does it affect: What is mechanism of action?Aerobic and anaerobic Gram+ve and Gram-ve, also rickettsia but not ChlamydiaPotent inhibitor of microbial protein synthesis-binds to 50S subunit of bacterial ribosome by inhibiting peptidyl transferaseBacteriostatic2003-2, 2003-1(doxycycline)How do tetracyclines exert their antimicrobial activity?BacteriostaticEnter cells by diffusion and active transportBind irreversibly to 30S sub-unit of the ribosomeBlock binding of tRNA to mRNA – ribosome complexStop addition of amino-acids to peptide (and thus inhibitor of protein synthesis)PD: used for Mycoplasma, Chlamydia, Rickettsia and some protoza e.g. malaria Used for: Atypical pneumonia, STDs, H. pylori infections, Acne, Malaria prophylaxis Describe the pharmacokinetics of the tetracyclines.Variable oral absorption depending on which drugGenerally greater than 60% absorbedAbsorption occurs mainly in upper small intestine.Food, calcium, dairy products and alkaline pH impair absorption40-80% protein boundDistributed widely to tissues except CSF, and cross placentaChelate to Ca and are bound to growing teeth and bonesExcreted in bile and in urineConcentrated in bile (up to 10x serum conc.)Undergo enterohepatic circulationDoxycycline excreted mainly in bile/faeces, the others mostly in the urineAre their any group of patients where tetracyclines are contraindicated and why?Pregnancy, children < 8 yrs, breast feedingCause tooth enamel dysplasia and irregularities in bone growthHow does resistance to doxycycline develop? 2003-1Decreased intracellular accumulation: by impaired influx and increased efflux by active transport protein pump that is encoded on plasmid (commonly encodes resistance genes for other drugs: aminoglycosides, sulfonamides, CAM etc)Ribosome protection: proteins interfere with tetracycline binding to ribosomeEnzymatic inactivation of tetracyclines2011-2, 2010-2 (erythromycin), 2009-1, 2005-1(azithromycin)Give some examples of macrolide antibioticsErythromycin (prototype drug), roxithromycin, azithromycin, clarithromycinWhat is their mechanism of action?Inhibit protein synthesis by binding to 50S ribosomal RNA blocking transpeptidationErythromycin may be inhibitory or bacteriocidal at higher concentrationsWhat organisms are usually sensitive to macrolides 2009-1Gram+ve cocci: Pneumocci and StaphyloccciGram-ves: Chlamydia, Legionella, Neisseria, Bordatella pertussis, Campylobacter, Treponema pallidumMycoplasmaClarithromycin in triple therapy for H. pyloriWhat are the adverse effects of erythromycin?Gastrointestinal (anorexia, nausea, vomiting, diarrhoea)Liver toxicity (acute cholestatic hepatitis, particularly with estolate)Allergic reaction (fever, eosinophilia, rash)Drug interactions (inhibits cytochrome P450 – except azithromycin)QT prolongationWhat is the mechanism for the drug interactions associated with erythromycin & give some examples? 2010-2Inhibits hepatic CYP3A4 => inhibits metabolism of other drugs causing increased activityExamples: benzodiazepines, carbamazepine, cisapride (cardiotoxicity), digoxin, warfarin, theophylline, cyclosporin, tacrolimusHow does azithromycin differ from other antibiotics in its class? 2005-1Absorption affected by foodMuch longer t? - 2-4 daysLevels considereably higher in tissues and phagocytes c.f. plasmaDoesn't activate cytochrome P450Very active against ChlamydiaExcreted in urine unchangedAdditional: Pharmacokinetics Good oral bioavailabilityGood tissue distribution (esp azithromycin)Erythromycin: biliary excretion, t? 2hrClarithromycin: hepatic -> urinary t? 6hrAdditional: Clindamycin PharmacodynamicsA lincosamide w/ similar mechanism to macrolides via binding the 50s subunitStructurally dissimilarGram-ve aerobes resistant b/c poor penetration of outer membraneUsed for anaerobes, MRSA, penicillin allergy, Pneumocystis jiroveci???Toxicity: GI upset, skin rashes, neutropaenia, hepatic dysfunction, C. dif -> pseudomembranous colitisPharmacokineticsGood tissue penetration after oral administrationHepatic metabolism -> renal excretion of both changed and unchanged drugAminoglycosides2010-1, 2008-2, 2007-1, 2003-2Describe the mechanism of action of gentamicinBactericidal inhibitor of protein synthesisPassive diffusion via porin channels across outer membrane, then active transport into cytoplasm by an O2 dependant process (anaerobes protected)Inside the cell, binds 30S ribosome & inhibits protein synthesis by:Inducing misreading of mRNA thus producing toxic or nonfunctional proteinInterfere with initiation complex of peptide formationCause break up of polysomes into non-functional monosomesWhat are the benfits of once daily dosing of gentamicinConcentration-dependant killing - at increased concentration kill increased numbers of bacteria at a more rapid ratePostantiobiotic effect - activity lasts longer than detectable serum levelsReduced toxicity - toxicity is time and concentration dependant, so time above critical level will be longer with multi dose than single dose scheduleLess nursing time and OPD therapy possibleDrug level not required unless >3 day therapyDosage still needs to be adjusted according to renal functionHow do penicillins enhance the efficacy of gentamicinAntimicrobial synergismLow ECF pH and anaerobic conditions inhibits (O2 dependant) transportTransport enhanced by cell wall active drugs e.g. β-lactam, vancomycin What are the mechanisms of resistance 2007-1Group transferases that inactivates drug, carried by plasmids (esp in Gram-ve)Impaired cell entry (cell wall)Changes in the ribosomal binding siteRegarding gentamicin, outline its pharmacokinetic properties 2003-2Polar compounds w/ no oral absorptionWell absorbed IM and usually given IVHighly polar and thus does not enter cells wellWater solubleCSF: 20% plasma levels, Bile: 30% plasma level, Pleural/synovial: 50-90%Most tissues low except renal cortexNot metabolisedMay be inactivated by bacteriaCleared by the kidneyt? : 2-3 hours 40-60% removed by HD Dosage adjustment needed for renal impairmentAdditional: ToxicityOtoxoticity: risk proportional to plasma levels, e.g. is no dose adjustment for renal impairmentNephrotoxicity (ATN), esp if co-aministration of amphotericin B, cephalopsporins, vancomycinNeuromuscular blockade (rare w/ high doses => respiratory paralysis, reverse w/ Ca2+ and neostigmine)Skin reactions (contact dermatitis)Sulphonamides, trimethoprim and fluroquinolonesSample viva, 2006-2What is the mechanism of action of trimethoprim?Inhibit microbial enzymes involved in folic acid synthesis thus inhibiting growthDihydrofolic acid =(dihydrofolate reductase inhibited by trimethoprim)=> tetrahydrofolic acid => purines => DNADescribe the mechanism of antimicrobial activity of the sulphonamides. 2005-1Inhibit microbial enzymes involved in folic acid synthesis thus inhibiting growthStructurally similar to PABA and compete with itPABA =(dihydropteroate synthase)=> dihydrofolic acidWhy is trimethoprim commonly administered in combination with sulfamethoxazole?Antibacterial synergism via sequential blockade of steps in folic acid dependent purine synthesisUsually bacteriostatic but the combination is frequently bacteriocidalWhat are mechanisms of bacterial resistance to trimethoprim?Reduced cell permeabilityIncreased production of dihydrofolic reductaseAlteration in dihydrofolic acid reductase with reducing binding2008-1, 2004-2, 2003-1What is the mechanism of action of fluoroquinolones?DNA gyrase inhibitor/blocks DNA synthesisWhat are the mechanisms of resistance to fluoroquinolones?Decreased intracellular entry by change in the permeability of the organism or efflux pumpOne or more point mutations in the quinolone binding region of the target enzymeWhat are the clinical uses ciprofloxacin ?Broad spectrumUTIBacterial diarrhoea caused by Shigella, Salmonella, toxigenic E. coli, CampylobacterSoft tissue, bone, joint, intra-abdominal and respiratory tract infectionsTreatment against multidrug-resistant organisms (pseudomonas and enterobacter)Prophylaxis and treatment against anthraxGonococcal infectionChlamydial urethritis or cervicitis TB and atypical mycobacterial infections Eradication of meningococcal carrier state Prophylaxis in neutropenic patientsAdditional:1st gen = norfloxacin for UTI2nd gen = ciprofloxacin for Gram-ve and gonnococus3rd gen = moxifloxacin – less Gram-ve, but more Gram+ve and even anaerobes 2003-1, 2004-2 (in children)What are the adverse effects of ciprofloxacinWell toleratedNausea, vomiting, diarrhea > headache, dizzy, insomnia, rash, LFT abnormalities May damage growing cartilage, cause arthropathy not for use <18 yrs Tendinitis in adults – risk of tendon rupture Avoid during pregnancy and lactationMiscellaneous2011-1In treatment of a new case of Tuberculosis, what are the important principles of drug use?Multiple drugs used initially (usually 4) ensures efficacyProlonged course, usually 6 monthsClose supervision to ensure compliance and detect adverse effectsDescribe the pharmacology of RifampicinBactericidal vs TB – inhibits DNA dependant RNA polymeraseResistance emerges rapidly if used aloneWell absorbed orallyHighly lipid soluble - widely distributed in tissuesMetabolism in liver, excreted in faecesInduces P450 enzymes – many drug interactionsDiscolouration (orange) of body fluidsCan be used in prophylaxisAdditional: IsoniazidPD: Structural congener of pyridoxine => inhibition of mycobacteral cell wallsRapid resistance if used alone (although is for prophylaxis)PK:Well absorbed orally => penetrates cells to act intracellularlyActetylation in the liver (genetic control)t? in fast acetylators = 60-90, in slow = 3-4hrFast (higher proportion in Asians) require higher dosingTox:Neurotoxic: peripheral neuritis, reslestness, twitching - relieved by pyridoxineHepatotoxicInhibition of metabolism of carbamazepine, phenytoin, warfarin2011-1, 2009-1What are the indications for acyclovir in the ED?HSV – encephalitisVZVPatients with HIVTo which class of antiviral drugs does acyclovir belong?DNA polymerase inhibitorsGuanosine analogSpecificity for virus-infected cell (virus-specific thymidine synthase)Inhibition of viral DNA synthesis (irreversible binding to viral DNA polymerase)Describe the pharmacokinetics of acyclovir?Short half life 2.5 hrs (5 times daily dosing oral)Low oral bioavailabilityMostly excreted unchanged in urineCSF 50% of plasmaWide distribution2008-2Describe the pharmacokinetics of metronidazoleClass: Nitroimidazole antiprotozoal drugPD: imidazole derivative -> reductive bioactivation (in anaerobic parasites) -> cytotoxic products that interfer with nucleic acid synthesisWell absorbed orallyOral/IV/suppository (99% oral bio-availability)Metabolised in liver (can accumulate in hepatic insufficiency) and excreted in kidneyLow protein binding (10-20%)Dosage: 500mg tds or single dose of 2g for vaginitisHalf life 7.5 hoursWhat are the adverse effects of metronidazole?GI: Nausea, diarrhoea, dry mouth, hairy black tongueCNS: Headache, paraesthesia, dizziness, insomniaGU: Dysuria, dark urineDisulfiram-like effect, hence avoid alcoholInteractions: Potentiate the effect of coumarin anticoagulants, LithiumTeratogenic effect on mice, but not proven in human2007-1What is an antiseptic?A chemical disinfectant applied to living tissue (skin, mucous membranes and wounds) which decreases the number of organisms by killing, removing and diluting and has generally low toxicity to tissues.Describe the actions and uses of chlorhexidineContains chlorinated phenolsSlower than alcohols but has residual activityLow skin sensitising or irritating capacityLow oral toxicity (poorly absorbed from the alimentary tract)Active against many bacteria but most effective against Gram+ve cocci) and mycobacteriaModerate against fungi & viruses - not inhibited by blood or organic productsSpore germination is inhibitedWhen is chlorhexidine contraindicatedMiddle ear surgery (causes sensorineural deafness)Neurosurgery as neural toxicityAllergy ................
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