8131MED - Antibacterials.pdf

Antibacterials A/Prof Gary Grant Background information Chemotherapy is defined as the use of drugs to eradicate pathogenic organisms or neoplastic cells in the treatment of diseases or cancer Chemotherapy is based on the principle of selective toxicity Background information Antim...

Antibacterials A/Prof Gary Grant Background information Chemotherapy is defined as the use of drugs to eradicate pathogenic organisms or neoplastic cells in the treatment of diseases or cancer Chemotherapy is based on the principle of selective toxicity Background information Antimicrobial activity characterisation Bacteriostatic Inhibits the growth of bacterial but doesn’t kill them Bactericidal Kills sensitive organisms so that the number of viable organisms falls rapidly after exposure to the drug Immunological mechanisms are required to eliminate the organism give opportunity Examples Bactericidal Bacteriostatic Cell wall inhibitors Sulfonamides sulfamethaxozole inhibit folic acid synthesis (penicillins, cephalosporins, Tetracyclines (reversibly carbapenems, not allow crosslinking, cannot withhold pressure inhibits bacterial protein bind to 30s monobactams, synthesis) not cause misreading glycopeptides) Macrolides bind to 50S Aminoglycosides misread - different effect Lincosamides (irreversibly inhibits bacterial protein synthesis) Quinolones Inhibition of topoisomerase and gyrase Cidal effect target 30S ribosome - cause misreading and lead to false protein Background information Antibiotic combinations Antagonistic effects loss of activity remove activity of another Less than the effect of either agent alone avoid mixing antibiotics Additive effects Combined effect is equal to the sum of the independent effects Synergistic effects Penicillin + gentomycin Combined effect is greater than the sum of independent effects far larger think of setting dose to maintain synergistic effect Indifferent effects Combined effect is similar to the greatest effects produced by either drug alone Examples Gram negative have cell membrane and outer wall Transport with rate-limiting step Drug transported in Synergistic combinations Antagonistic combinations Beta-lactam antibiotic brek beta lactam ring Beta-lactam antibiotic slow down effect of most effective influence transpeptidase PLUS aminoglycoside in beta lactam ring PLUS tetracycline penicillins, cephalosporins, carbenems, monobactams - cell wall damage Glycopeptide PLUS Beta-lactam antibiotic punch a hold, but much slower aminoglycoside vancomycin and gentomycin PLUS chloramphenicol side by side - synergistic Sulfamethoxazole PLUS Penicillins PLUS protein synthesis inhibition but only bacteriostatic trimethoprim disruption and synergistic macrolides Amphotericin B PLUS Aminoglycoside PLUS flucytosine anti-fungal chloramphenicol Background information Australian Medicines Handbook Classifies, report the range of effect of drugs Spectrum of activity Primary determinant of its clinical use Broad resistance w/ broad spectrum antibiotics Narrow spectrum drugs narrow as possible if you know what agent is - not disrupt other bacteria in gut Active against a single or limited group of pathogens Often preferred because they target specific pathogens without disturbing normal flora of the gut and respiratory tract Extended spectrum drugs Intermediate range of activity Broad spectrum drugs Active against a wide range of organisms cover more suspected organisms Sometimes preferred for initial treatment when causative pathogen is not yet identified Examples MIC - minimum inhibitory concentration for drug to have anti-microbial effect continuous infusion to stay above MIC Time-dependent Concentration-dependent How long it stays above MIC effective concentration kill better w/ better peak Penicillins cell wall inhibition act on peptidoglycan - transpeptidase Aminoglycosides How big dose inhibition to stop cell wall growth Nephrotoxic Cephalosporins Fluoroquinolones auc/mic = time dependent Glycopeptides Macrolides Lincosamides Tetracyclines mRNA - read 30s + 50s = 70s ribosome - reads code bring in amino acid with tRNA Antibacterial - selective mechanism Difference in topoisomerase Block topoisomerase and DNA gyrase - not able to read codons of DNA DNA gyrase DNA-RNA polymerase targeted Background information Minimum inhibitory concentration (MIC) Lowest concentration of drug that inhibits bacterial growth Bacteria can then be classified as susceptible or resistant Concentration-dependent killing rate (CDKR) Aminoglycosides and fluoroquinolones gentomycin ciprofloxacin Post-antibiotic effect (PAE) concentration-dependent effect 4-5mg/kg daily - large peak, post-antibiotic effect if 1mg/kg every 8 hours - accumulates over time Cmax has to be much bigger than MIC and no post-antibiotic effect Still see loss of bacteria after concentration falls below MIC reduce risk of toxicity Background information Microbial sensitivity Broth dilution Disk diffusion method (Kirby-Bauer test) E-test method PK/PD AUC - total drug exposure Area under the curve Critical for bioavailability Time-dependent antibiotic AUC/MIC effects Concentration-dependent Cmax/MIC antibiotic effects Cmax relationship  Gram +ve - thick peptidoglycan Penicillins Have beta lactamases - cleave drug and destroy Simple/Standard Penicillins Benzylpenicillin Benzylpenicillin Very potent Staph and strep infections Pen G Beta lactam Narrow spectrum Staph produces beta lactamase 50% chance of not working Cleave ring - to zero activity acid labile Parenteral only Phenoxymethylpenicillin Pen V acid stable Can take orally Narrow spectrum, can lose some of activity less active than benzylpenicillin Less potent Reserved for situations were high tissue concentrations are not required (e.g., sore throat) Food has little effect on absorption Penicillins above MIC as long as possible Repository forms of standard/simple penicillins Modified benzylpenicillin different Benzathine penicillin, Procaine penicillin IM administration of Benzathine penicillin/procaine penicillin NOT IV Dosage form is a suspension NOT solution IV administration can cause death Penicillins Antistaphylococcus Penicillins F Cl susceptible to cleave Dicloxacillin, Flucloxacillin, Methicillin, Oxacillin methyl groups for steric hindrance Halogens Flucloxacillin and dicloxacillin have similar steric hindrance anti-staph Things cannot pharmacokinetics, antibacterial activity and get into the drug indications 2x Cl Methicillin-Resistant Staphylococcus aureus drug works on transpeptidase - for crosslinking of cell wall (MRSA) beta lactam stops this MRSA - produces new version of transpeptidase PDP different Penicillin cannot bind properly anymore blocks other transpeptidases, but PBP 2a - not able then crosslinking can occur and enough to function  New tool - ceftaroline Penicillins extended spectrum Aminopenicillins with clavulanic acid then becomes much broader in spectrum Amoxycillin, Ampicillin Beta lactam IV amoxycillin is an alternative to IV ampicillin extends the spectrum beyond to cover gram neg. Antipseudomonal penicillins Gram -ve Piperacillin, Ticarcillin Piperacillin (with/without tazobactam) also anti-pseudomonal very well genetically endowed for resistance clavulanic acid Ticarcillin with clavulanic acid Beta lactam is a decoy Drug can then escape beta lactam beta lactam β Lactamase inhibitors Clavulanate/clavulanic acid inhibits class-A β-lactamase enzymes, protecting the penicillin from destruction Tazobactam and sulbactam are other examples of a β-lactamase inhibitors cephalosporinases no beta-lactase inhibitor as drug very bulky kills penicillin carbanemases Beta-lactamase reducing organism ESBL - extended spectrum beta lactamase production big concern no activity  Type 1 allergy - B cells - IgE cause anaphylaxis - degradation of mast cells, histamine release - vasodilation leakiness, bronchoconstriction CV collapse Hypersensitivity Penicillin ADRs Type II - B-cells and IgG - cytotoxic death reaction Lost neutrophils and granulocytes (lupus) Type III - B-cell IgG and is flu like with serum sickness Type IV = T-cell - urticaria, hives and dermatitis Delayed GI upset Common: diarrhoea, nausea, rash, urticaria, pain and inflammation at injection site (less common with benzylpenicillin), superinfection (including candidiasis) especially during prolonged treatment with broad spectrum penicillins, allergy disrupt normal flora - other bacteria flourish Candidiasis, increased pH Cephalosporin - 5-10% of reaction Infrequent: fever, vomiting, erythema, exfoliative dermatitis, angioedmea, Clostridium difficile-associated disease (Superinfection) antibiotic associated pseudomembranous colitis Rare: Anaphylactic shock, bronchospasm, interstitial nephritis, serum sickness syndrome, haemolytic anaemia, electrolyte disturbances (due to their sodium or potassium content), neurotoxicity, bleeding, blood dyscrasias (e.g., neutropenia related to dose and duration of treatment), nephropathy (with parenteral use), Stevens-Johnson syndrome, toxic epidermal necrolysis kidney function key to clear Dicloxacillin/flucloxacillin ADRs class-dependent allergies Common: transient increases in liver enzymes and bilirubin Rare: Cholestatic hepatitis bilirubin... Flucloxacillin may have higher incidence of severe hepatic adverse effects than dicloxacillin, but a lower incidence of renal adverse effects treat for long period i.e. bone infection Monitor hepatic function for longer courses of treatment Consider risk factors Aminopenicillin ADRs Vomiting and diarrhoea are more common with ampicillin than with amoxycillin topoisomerase and DNA yse open DNA DNA-RNA polymerase to create mRNA Pseudoallergy (rash) strand conenct to 30S and affect this read codon to have tRNA bring in an amino acid for code develop allergy even though no immune markers Much higher risk of purple rash ' kissing disease' mononuclear cytosis Rashes appear with amoxycillin Virus creates the allergy Antipseudomonal ADRs Rare: transient increases in liver enzymes and bilirubin unique antiplatelet effect Bleeding abnormalities (prolonged bleeding times and altered platelet aggregation) with high doses Monitor serum potassium in those likely to develop hypokalaemia during treatment Vitamin K - for clotting factor in liver 2, 10, 9, 7 - critical in clotting cascade  lecture #2 started with recap of prev. antibiotics acid and base react = salt -penicillins -aminoglycosides -sulfonamides -tetracyclines side effects of drugs - allergy often Penicillin Precautions delayed hypersensitivity move to another beta lactam antibiotic understand allergy toxicity low 5-10% of rash Allergy to carbapenems Sodium restriction, or cephalosporins heart failure Cross-reactivity Parenteral dosage between penicillins, forms have high cephalosporins and sodium content carbapenems may issue of electrolytes broader consequences occur (in possibly 5- 10% of people) Benzylpenicillin sodium - salt form of drug lipid soluble to distribute reacts with NaOH - salt salt to become water soluble IgG - drives cytotoxic reactions B-cell mediated response - serum sickness Severe skin rashes complement involved severe aldo cytotoxic  Penicillin Precautions proximal fluclox PenG Pregnancy push substances into renal tubule that 20% are water soluble All penicillins are considered safe pumps allow pumping into tubule. Active transport Breastfeeding probenecid and beta lactam longer effect larger area under curve more time to eliminate All penicillins considered safe more drug for longer if flatten Renal impairment penicillins - can be nephrotoxic area under curve bigger water soluble - rely on kidney to clear longer therapeutic effect Dose should be reduced in severe impairment aminopenicillins, flucloxacillin - risk of hepatic toxicity Interactions PenG Na - mix with NaOH - create salt Gentamycin sulfate - from sulfuric acid Becomes weak base against strong acid Probenecid inhibits renal tubular secretion and increases serum levels influence how much uric acid into kidney IV penicillins are physically incompatible with many substances (including aminoglycosides) and should be given separately (applies to all penicillins) understand compatibility Check IV compatibility resources risks attached Cephalosporins ESBL - extended spectrum beta lactamase organisms Moderate spectrum original cephalosporins very concerning 1st Generation weighted to gram +ve on activity, but moderatively spectrumed target penicillin not touch cephalosporin - too large Cephazolin, cephalexin, cefalotin beta lactamase 2nd Generation carbapemase penicillinase cephalosprorinase Cefaclor, cefoxitin, cefuroxime respiratory coverage, some more gram negative Cephalosporins Broad spectrum what kind of allergy 3rd Generation Cefotaxime, ceftriaxone, ceftazidime Extremely good penetration of the BBB (DOC for treating meningitis caused by susceptible organisms) not penetrate as well anymore diffrence from peripheral - not good 4th Generation Cefepime Cephalosporin ADRs cannot forget allergies and risk Common Diarrhoea, nausea, rash, electrolyte disturbances, pain and inflammation at injection site Vomiting, headache, dizziness, oral and vaginal Infrequent candidiasis, Clostridium difficile-associated disease, superinfection, eosinophilia, drug fever Anaphylactic shock, bronchial obstruction, urticaria, haemolytic anaemia, angioedema, Rare Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, arthritis, serum sickness-like syndrome, neurotoxicity (incl. seizures), blood dyscrasias Cephalosporin Precautions Allergy to cephalosporins topoisomerase and DNA gyrase open DNA DNA-RNA polymerase to create mRNA strand conenct to 30S and affect this Severe of immediate allergic reaction (including urticaria, anaphylaxis or read codon to have tRNA bring in an amino acid for code intestinal nephritis) to peniciilin Allergy to penicillins or cabapenems Cross sensitivity of approx. 5-10% Impaired vitamin K synthesis, low vitamin K stores (chronic disease/malnutrition) Increased risk of bleeding with all cephalosporins (esp. cephazolin) Monitor INR carefully Consider the use of vitamin K for prophylaxis/treatment Carbapenems very broad spectrum - more than any other drug not ot use orally - resistance issue Ertapenem, imipenem, meropenem doripenem new - reduced CNS risk first one reduced risk of seizue induction failed in vivo Imipenem is given every 6 hours broad spectrum, less toxicity only carbapenem to be inactivated by renal dehydopeptidase I and is given metabolised and destroyed - no therapeutic dose with cilastin to prevent this Highest risk of seizure induction lowers threshold Ertapenem is given once daily block renal dehydropeptidase Meropenem is given every 8 hours to enable effect Spectrum of activity Carbapenems have the broadest spectrum of all the antibacterial classes (IV only) Carbapenem ADRs Neurotoxicity Imipenem is associated with neurotoxicity (myoclonic activity, confusion, and seizures) Especially when excessive doses are used in people with CNS disorders (e.g., history of seizures) or renal impairment Meropenem is less neurotoxic Ertapenem is also associated with seizures especially in those with CNS disorders or renal impairment Monobactams Aztreonam Parenteral dosage form only Less toxic than aminoglycosides Aztreonam is more stable than cephalosporins to inducible Amp C beta-lactamases produced by some enteric Gram-negative organism (ESCAPPM) Like, cephalosporins, aztreonam is susceptible to extended spectrum beta-lactamases (ESBLs) produced by some strains of Klebsiella, E. coli and Enterobacter spp. Mechanism of methicillin resistance (MRSA) changes in permeability Four native peptidoglycan synthetases (PBP 1,2,3 and 4) still bound and inactivated produce degrading enzymes Acquired penicillin binding protein (PBP2a) penicillin binding protein blocked by penicillin slight variant on 2 transpeptidase continues to crosslink, drug stops working Peptidoglycan transpeptidase need to switch class cephtaroline blocks PSP 2a mecA gene Harboured on staphylococcal chromosomal casette mec (SCCmec; types I, II, III, IV and V) Low affinity for β-lactams Effect cell-wall synthesis Boyle-Vavra and Daum, 2007. Laboratory Investigation. 87, 3-9 Glycopeptides amide bnds Vancomycin, teicoplanin clear via the kidney - water solubility reduced distribution due to water solubility Absorption - no absorption orally if water soluble near 0 - orally lots of oxygen weight to water solubility  MSA - produce beta lactamase Glycopeptide ADRs carries vestibular risk - risk Reversible ototoxicity: vestibular and cochlear of ear damage with aminoglycoside gentamycin (30Sr inhibitor, toxic, misread codon) + vancomycin (cell wall) synergism accumulate in ears Rarely nephrotoxicity get erythmatous rash - red man syndrome pseudoallergy rate infusion dependent comes off, strand weak Important points how much put in ala - beta lactam acts change ala to gly/ser - cannot bind VRSA - Vancomycin resistance different binding site? Excessive rate of infusion can cause erythematous rash on the face and upper body (red neck or red man syndrome) 0% oral absorption (May be used for GIT sterilization) Administered IV (not absorbed after PO administration) Macrolide Antibiotics Erythromycin, clarithromycin, roxithromycin, telithromycin, azithromycin inhibit = toxic cidal being anti-inflamamtory and antibiotic polymycin - affects cell wall topoisomerase and DNA glyrase open DNA DNA-RNA polymerase to create mRNA strand conenct to 30S and affect this read codon to have tRNA bring in an amino acid for code quinolone/fluoroquinolone halogen Br, F - Very lipid soluble anti-inflammatory cidal for COPD, ciprofloxacin norofloxacin lincomycin - lincosamides highest risk of antibiotic-associated pseudomembranous colitis C. difficile infection Rifampecin = block RNA polymerase older people, can blow colon - dangerous inhibitory, cidal effect orange drug select in high risk tears, urine and sweat orange very diffusible very costly to treat colitis for MRSA - orthopaedic related risk of freaking out make more enzyme that metabolises drugs faster gentomycin - very water soluble increase clearance of other drugs and reduce their erythromycin - increases gut motility effect pro-kinetic activiates motilin High risk of drug interaction 50S usually blocked by macrolides, lincosamides and chloramphenicol cytP450 - erythromycin, clarithromycin static effects reduce clearance and elimination anti-anaerobic - metronidozole hold onto longer, increased toxicity cP450 chlorithromycin Macrolide ADRs Nausea, vomiting, diarrhoea, abdominal Common pain, cramps, headache, dyspnoea, cough, candidal infections Infrequent Rash, fixed drug reactions Anaphylaxis, acute respiratory distress, Stevens-Johnsons syndrome, psychiatric Rare disturbances, hearing loss, seizures, Clostridium difficile-associated disease, cholestatic hepatitis, pancreatitis Macrolide Interactions Erythromycin inhibits cytochrome P450 enzymes and increases serum levels of many drugs, including theophylline, carbamazepine, cyclosporine, diazepam, felodipine, warfarin, lovastatin and other statins Azithromycin does not inhibit cytochrome P450 enzymes significantly Lincosamides Clindamycin, Lincomycin Adverse Drug Reactions (not limited to) Antibiotic associated pseudomembranous colitis very costly to treat colitis Tetracyclines Doxycycline Well absorbed orally, systemic adverse effects and GI upset common Best taken with food or milk Better tolerated than minocycline Minocycline acne Well absorbed orally, systemic adverse effects and GI upset common, best taken with food or milk High incidence of vestibular and CNS adverse effects (e.g., benign intracranial hypertension, lupus-like syndrome, serum sickness-like disease and hepatitis have occurred Less likely than doxycycline to cause photosensitivity moe likely to burn in sun risk of hepatic damage Tetracycline ADRs Nausea, vomiting, diarrhoea, epigastric Common burning, tooth discolouration, enamel dysplasia, reduced bone growth (in children < 8 years), photosensitivity Infrequent Rash, stomatitis, bone deformity, fungal overgrowth Photo-onycholysis and nail discolouration, oesophageal ulcers (due to partly swallowed tablets or capsules), Clostridium difficile- associated disease, hepatitis, fatty liver Rare degeneration, benign intracranial hypertension, allergic reactions including anaphylaxis, toxic epidermal necrolysis, worsening of systemic lupus erythematosus, serum sickness-like reactions. Tetracycline Precautions Systemic lupus erythematosus Treatment with oral retinoids (e.g., May increase risk of benign intracranial isotretinoin, acitretin) hypertension Careful with co-treatment with hepatotoxic drugs Doxycycline and minocycline can be used with Renal impairment dose adjustment doxycycline, minocycine Hepatic impairment Hepatotoxicity more likely Tetracycline Precautions Children In children 7-10 days, usually presents as gradually worsening non-oliguric renal failure, but may present as acute tubular necrosis; usually reversible gentamicin, tobramicin Ototoxicity Vestibular ototoxicity (nausea, vomiting, vertigo, nystagmus, difficulties with gait) and cochlea toxicity (noticeable hearing loss, tinnitus, feeling of fullness in the ear) occur in 2-4% of treated patients Aminoglycoside Precautions Serious allergic reactions to an aminoglycoside History of treatment with ototoxic or nephrotoxic drugs Tinnitus, vertigo, hearing impairment, abnormal audiogram Neuromuscular disease (e.g., myasthenia gravis) Hypocalcaemia, hypermagnesaemia, general anaesthesia, large transfusions of citrated blood Aminoglycoside Precautions Dehydration Increased risk of toxicity Renal impairment therefore need monitoring Increased risk of nephrotoxicity and ototoxicity Surgery Large doses during surgery have caused transient myasthenic syndrome with normal neuromuscular function Elderly Children Decrease dose in neonate due to prolonged half-life Quinolones Ciprofloxacin, norfloxacin, ofloxacin, gatifloxacin, moxifloxacin Norfloxacin has poor systemic bioavailability and is reserved for UTIs Quinolone ADRs Common Rash, itch, nausea, vomiting, diarrhoea, abdominal pain, dyspepsia Headache, dizziness, insomnia, depression, restlessness, tremors, arthralgia, arthritis, myalgia, tendonitis, crystalluria, interstitial nephritis, raised Infrequent liver enzymes Ensure adequate fluid intake and urine output; avoid excessively alkaline urine due to risk of crystalluria Hypoglycaemia, hyperglycaemia, blood dyscrasias, seizures, psychotic reactions, Rare angioedema, anaphylaxis, pseudomembranous colitis, tendon rupture, Stevens-Johnson syndrome, hepatitis, peripheral neuropathy Quinolone Precautions Serious allergic reaction to quinolones, Epilepsy, history of CNS disorders including nalidixic acid (Negram®, a May induce seizures topoisomerase and DNA e discontinued quinolone) open DNA DNA-RNA polymerase to create mRNA strand conenct to 30S and affect this read codon to have tRNA bring in an amino acid for code May increase risk of seizures Treatment with bupropion Combination should be avoided May exacerbate symptoms Myasthenia gravis Increased risk of haemolytic anaemia G6PD deficiency Increased risk of tendon damage Prior or concomitant use of corticosteroids Quinolone Precautions Elderly Increased risk of tendon damage Children Use is controversial Quinolones induce arthropathy in immature animals Only recommended for use in children and adolescents only in severe infections where benefit outweighs the risk of arthropathy (e.g., febrile neutropenia, P. aeruginosa infections in cystic fibrosis) Quinolone Drug Interactions Dairy products, antacids, iron, zinc, or calcium supplements may interfere with the absorption of quinolones (should not be taken within 2 hrs of quinolone dose) May increase the effects of caffeine (caffeine intake may need to be reduced) Ciprofloxacin inhibitor of CYP3A4 Gatifloxacin and moxifloxacin do not appear to interact with hepatically metabolised drugs (e.g., theophylline, caffeine, warfarin) Folate Inhibitors Trimethoprim Sulfamethoxazole Used in combination for synergistic effect Folate Inhibitor ADRs Fever, nausea, vomiting, diarrhoea, anorexia, Common rash, itch, sore mouth, hyperkalaemia, thrombocytopenia Infrequent Headache, drowsiness, photosensitivity, blood dyscrasias, e.g., neutropenia Megaloblastic anaemia, methaemoglobinaemia, erythema, hypoglycaemia (may affect consciousness and cause seizures), hepatitis, crystalluria, Rare urinary obstruction with anuria/oliguria, lowered mental acuity, depression, tremor, ataxia (after IV use in HIV patients), Clostridium difficile-associated disease, aseptic meningitis Sulfonamide Allergy ‘Sulfur Allergy’ = Arylamine – Sulfonamide functional groups May present with fever, dyspnoea, cough, rash, eosinophilia Most serious effects include anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, serum sickness-like syndrome, lupus-like syndrome, pneumonitis, hepatitis, interstitial nephritis, systemic vasculitis and pancytopenia Sulfonamide allergy Cross-sensitivity between sulfonamides and related drugs (e.g., sulfonylureas, thiazides diuretics, frusemide, celecoxib) Folate Inhibitor Precautions G6PD deficiency topoisomerase and DNA ye Increased risk of haemolysis with sulfonamides open DNA DNA-RNA polymerase to create mRNA strand conenct to 30S and affect this read codon to have tRNA bring in an amino acid for code Slow acetylator phenotype Greater risk of adverse effects with sulfonamides Folate Inhibitor Precautions Low urine pH Increased risk of crystalluria, sulfamethoxazole is poorly soluble at low pH Drugs which cause potassium retention (e.g., ACE inhibitors) TMP may contribute to hyperkalaemia Renal impairment Increased risk of hyperkalaemia or hypoglycaemia; reduce dose of sulfamethoxazole Folate Inhibitor Precautions C/I in preterm infants and neonates