Antibiotics
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สำหรับเพื่อนแพทย์

สำหรับเพื่อนแพทย์

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Antibiotics Presentation Transcript

  • 1. Antibiotics
  • 2. Approach to ID Host setting + Clinical syndromeDisease ?  Possible pathogensBug ? Proper lab & investigations  Empyrical Rx Drug? F/U clinical parameters SPECIFIC treatment
  • 3. Gram-Positive Gram-Negative COCCI COCCIclusters- Moraxella catarrhalis Staphylococci Neisseria gonorrhoeae Neisseria meningitidispairs and chains - Sreptococci - Enterococcus sp. COCCOBACILLI BACILLI H. influenzae, AcinetobacterBacillus sp. BACILLICorynebacterium sp. Enterobacteriaceae (E. coli,Listeria Enterobacter sp. Citrobacter, monocytogenes Klebsiella sp.Proteus sp., Serratia Salmonella, Shigella)Nocardia sp. Pseudomonas aeruginosa Burkholderia pseudomallei Non fermentative GNB
  • 4. Anaerobes Higher bacteria Above Diaphragm Mycobacterium spp. Peptococcus sp. TB, NTM Peptostreptococcus sp. Prevotella Nocardia Veillonella Other Pathogen Actinomyces  Spirochete:  Leptospirosis Below Diaphragm Clostridium perfringens, tetani,  Syphilis and difficile  Ricketsia: Bacteroides fragilis, disastonis,  Scrub typhus ovatus, thetaiotamicron  Murine typhus Fusobacterium  Legionella  Mycoplasma  Chlamydia
  • 5. Bacteria by Site of InfectionMeningitis Skin/Soft Tissue EndocarditisS. pneumoniae S. aureus Viridian strepN. meningitidis S. pyogenes S.bovisH. influenza S. epidermidis EnterococcusStreptococci Exposed organismE. coli, listeriaAbdomen Urinary Tract Bone and JointE. coli, Proteus E. coli, Proteus S. aureusKlebsiella Klebsiella S. epidermidisEnterococcus Enterococcus StreptococciBacteroides sp. Staph saprophyticus Nram-negative rodsUpper Respiratory LRI Community LRI HospitalS. pneumoniae S. pneumoniae A. baumanniiH. influenzae H. influenzae P. aeruginosaM. catarrhalis K. pneumoniae K. pneumoniaeS. pyogenes Legionella,Mycoplasma, Enterobacter sp. Chlamydia, Ricketsia¤, S. aureus
  • 6. Antibiotic Mechanism of action Spectrum Resistance mechanism PK/PD:  Bioavailability  Absorption  Distribution: Intracellular, Extracellular, Tissue penetration  Elimination : Renal, Hepatic, HD, PD  Killing effect ( cidal / static)  Parameter correlated with efficacy ADR Drug interaction
  • 7. ATBs: Mechanism ofV. FOLIC ACID METABOLISMI. action CELL WALL SYNTHESIS • TMP/Sulfonamides • Vancomycin, Fosfomycin, bacitrac • Beta-lactams II. DNA Synthesis • Quinolones •Metronidazole THFA DNA mRNA III. DNA-DEPENDENT DHFA RNA POLYMERASE • Rifampicin ribosomes 30 IV. PROTEIN 50 SYNTHESIS - 30S INHIBITORS • Tetracycline • PABA VI. CELL MEMBRANE Aminoglycoside• • Polymyxin B - 50S INHIBITORS • Colistin • Macrolide
  • 8. Terminology of PK/PD ofATB
  • 9. T>MIC-dependent bactericidal activity Minimal or moderate Prolonged PAE PAEAntimicrobials Penicillins Azithromycin Clindamycin Cephalosporins Cotrimoxazole Carbapenems Tetracycline Vancomycin Goal of Optimize duration of Optimize amount of dosing exposure drug regimenParameters of Time above MIC>40-50 24-Hr AUC/MIC efficacy Cmax/MIC>4 Vancomycin (Cmax/MIC>10-20)
  • 10. Post-antibiotic effect (PAE) Antibiotics Gram Gram Pseudomonas Positive Negative aeruginosa bacteria bacteriaPenicillins 1-2 0 0Cephalosporins 1-2 0 0Carbapenems 1-2 (1) 1-2Quinolones 1-3 1-3 1-2Protein synthesis 3-5 3-8inhibitorsAminoglycosides 2-4 2-3
  • 11. Concentration-dependent bactericidal activity with prolonged PAE Goal of dosing regimen :Aminoglycosides Maximize concentrationsFluoroquinolones Parameters of efficacy Metronidazole 4. AUC/MIC > 125(-) 30(+) 5. Cmax/MIC> 8-10 6. In Vivo; T>MIC
  • 12. Concentration-vs-time profile of once-dailyand conventional regimens (normal CCr)
  • 13. Intracellular PharmacokineticsBetalactam ≤ 1XAminoglycosides < 1-2 XTetracyclines 2-4 XFluoroquinolones 10-20 XMacrolides 4 - >100 X
  • 14. β-Lactam Mechanism of action  Inhibit cell wall synthesis by binding to penicillin-binding proteins (PBPs)  Bactericidal (except against Enterococci) PK/PD  Time-dependent killers  Time above MIC correlates with efficacy Cross-allergenicity : except aztreonam
  • 15. β-lactams• Mechanisms of Resistance  production of beta-lactamase enzymes  most important and most common  hydrolyzes beta-lactam ring causing inactivation  Alteration in PBPs  binding affinity  Alteration of outer membrane  penetration
  • 16. Penicillinase-ResistantNatural Penicillins Penicillins (nafcillin, oxacillin, methicillin) Gram-positive  Streptococci  Gram-positive  DSSP  MSSA Gram-negative  Streptococci  Neisseria sp. Anaerobes  Above the diaphragm Other  syphilis
  • 17. Aminopenicillins Antipseudomonal(ampicillin, amoxicillin) penicillins (piperacillin)↑activity against gram- negative aerobes  ↑ activity against resistant gram-negative aerobes Gram-positive  Gram-positive  streptococci  Streptococci  some Enterococcus  Susc.Enterococcus  Gram-negative  Proteus mirabilis, Salmonella, Shigella Gram-negative  E. coli, βL- H. influenzae  Enterobacter sp.  Proteus mirabilis  Pseudomonas aeruginosa  Salmonella, Shigella  Serratia marcescens  some E. coli  some Klebsiella sp.  βL- H. influenzae  Anaerobes Fairly good activity  L. monocytogenes 
  • 18. BL/BI(β-lactams+ β-lactamase inhibitor)(Unasyn, Augmentin, Tazocin, Sulperazon) Developed to gain or enhance activity against β-lactamase producing organisms Gram-positive  MSSA Gram-negative  H. influenzae, E. coli, Proteus spp. Klebsiella spp., Moraxella catarrhalis Anaerobes  Bacteroides sp.
  • 19. Generation G+ G- Anaerobe MSSA E. coli no 1 st K. pneumoniae DSSPBest G + Streptococci P. mirabilisLess G - less H.Influenza Only 2 nd M.catarrhalisLess G + CefoxitinMore G - Neisseria 3 rd +DRSP no Citrobacter sp.,More G - (CTR/ CTX) Enterobacter sp., Acinetobacter sp. Pseudomonas less (CTZ) (CTZ/CPS) 4th no1st + 3rd
  • 20. 4 gen. Cephalosporinsth Extended spectrum of activity  gram-positives  gram-negatives  Pseudomonas aeruginosa  β-lactamase producing Enterobacter sp. against β-lactamases Stability poor inducer of ESBLs.
  • 21. Carbapenems• Most broad spectrum• Against G+/G-, aerobes/anaerobes• Bacteria not covered by carbapenems • MRSA, MRSE, • Enterococci HLAR, VRE • C. difficile • S. maltophilia
  • 22. β-Lactams: Adverse Effects• Hypersensitivity – 3 to 10 %  Cross-reactivity exists among all penicillins and other β-lactams  Desensitization is possible• Hematologic  Leukopenia, neutropenia, thrombocytopenia – prolonged therapy (> 2 weeks)• Neurologic – esp. penicillins, carbapenems, Cefipime, Especially in patients receiving high doses in the presence of renal insufficiency  Irritability, jerking, confusion, seizures
  • 23. β-Lactams:Adverse Effects• Gastrointestinal  Increased LFTs, n/v, diarrhea, AAC Interstitial Nephritis  Cellular infiltration in renal tubules  Especially with methicillin or nafcillin• Cephalosporin with MTT side chain (cefamandole, cefoperazone) • Hypoprothrombinemia due to reduction in vitamin K- producing bacteria in GI tract • Ethanol intolerance
  • 24. Fluoroquinolones Mechanism of action: inhibit DNA synthesis (enz. DNA gyrase, topoisomerase IV) Concentration dependent AUC/MIC correlate with efficacy Bactericidal
  • 25. FQs: Spectrum Gram-Negative Gram-positive levo,gati,moxi (cipro=levo>gati>moxi) MSSA PRSP• Enterobacteriaceae Enterococcus sp. – limited• (E. coli, Klebsiella sp, Enterobacter sp, Proteus Atypical Bacteria levo,gati,moxi sp, Salmonella, Shigella, Serratia marcescens, etc.) Legionella pneumophila• H. influenzae, M. Chlamydia sp. catarrhalis, Mycoplasma sp.• Neisseria sp. (GC ดือ ้ 60%) Others Mycobacterium• Pseudomonas aeruginosa Bacillus anthracis cipro, levo
  • 26. Fluoroquinolones: Pharmacology Absorption  Most FQs have good bioavailability Distribution  Extensive tissue distribution – prostate, liver, lung, S/ST and bone; urinary tract  Minimal CSF penetration Dose  Ciproflox 400 mg I.V. q 8 h  Levoflox 750 mg IV OD
  • 27. Fluoroquinolones:Adverse Effects• Gastrointestinal – 5 %  Nausea, vomiting, diarrhea, dyspepsia• Central Nervous System  Headache, agitation, insomnia, dizziness, rarely, hallucinations and seizures (elderly)• Hepatotoxicity  LFT elevation (led to withdrawal of trovafloxacin)• Cardiac  Variable prolongation in QTc interval  Led to withdrawal of grepafloxacin, sparfloxacin
  • 28. Fluoroquinolones Adverse Effects • Articular Damage  Arthopathy including articular cartilage damage, arthralgias, and joint swelling  Led to contraindication in pediatric patients and pregnant or breastfeeding women  Risk versus benefit • Other adverse reactions: tendon rupture, dysglycemias, hypersensitivity
  • 29. FluoroquinolonesDrug Interactions• Divalent and trivalent cations – ALL FQs  Zinc, Iron, Calcium, Aluminum, Magnesium  Antacids, Sucralfate, ddI, enteral feedings  Impair oral absorption of orally-administered FQs – may lead to CLINICAL FAILURE  Administer doses 2 to 4 hours apart; FQ first• Theophylline and Cyclosporine - ciproflox  inhibition of metabolism, ↑ levels, ↑ toxicity• Warfarin – idiosyncratic, all FQs
  • 30. Macrolides• Erythromycin is a naturally-occurring macrolide• Structural derivatives: clarithromycin and azithromycin:  Broader spectrum of activity  Improved PK properties – better bioavailability, better tissue penetration, prolonged half-lives  Improved tolerability
  • 31. Macrolides• Mechanism of Action  Inhibits protein synthesis by reversibly binding to the 50S ribosomal subunit  Suppression of RNA-dependent protein synthesis  Macrolides typically display bacteriostatic activity, but may be bactericidal when present at high concentrations against very susceptible organisms  Time-dependent activity  Prolonged PAE
  • 32. Macrolide: Spectrum Gram-Positive Aerobes (C>E>A)  MSSA  Streptococcus pneumoniae (only PSSP)  streptococci  Bacillus sp., Corynebacterium sp. Gram-Negative Aerobes – newer macrolides (A>C>E)  H. influenzae, M. catarrhalis, Neisseria sp. • Do NOT have activity against any Enterobacteriaceae• Atypical Bacteria• Legionella, Chlamydia, Mycoplasma• Ricketsia- Azithromycin• Anaerobes – activity against upper airway anaerobes• Other Bacteria – Mycobacterium avium complex (MAC – only A and C), Treponema pallidum, Campylobacter, Borrelia, Bordetella, Brucella. Pasteurella
  • 33. Macrolides:Adverse Effects• Gastrointestinal – up to 33 %  Nausea, vomiting, diarrhea, dyspepsia  Most common with erythro; less with new agents• Cholestatic hepatitis - rare  > 1 to 2 weeks of erythromycin estolate• Thrombophlebitis – IV Erythro and Azithro  Dilution of dose; slow administration• Other: ototoxicity (high dose erythro in patients with RI); QTc prolongation; allergy
  • 34. Aminoglycosides• Irreversibly bind to 30S ribosomes• Bactericidal• Distribution  primarily in extracellular fluid volume; are widely distributed into body fluids but NOT the CSF• Elimination  eliminated unchanged by the kidney via glomerular filtration; 85-95% of dose  elimination half-life dependent on renal function  normal renal function - 2.5 to 4 hours  impaired renal function - prolonged
  • 35. Aminoglycosides: Spectrum Gram-Positive Aerobes  Synergistic for Enterococcus sp. Gram-Negative Aerobes  E. coli, K. pneumoniae, Proteus sp.  Acinetobacter, Citrobacter, Enterobacter sp.  Morganella, Providencia, Serratia, Salmonella, Shigella  Pseudomonas aeruginosa Mycobacteria  tuberculosis  NTM
  • 36. Aminoglycosides Adverse Effects• Nephrotoxicity  Non-oliguric azotemia due to proximal tubule damage;  risk factors: prolonged high troughs, long duration of therapy (> 2 weeks), underlying renal dysfunction, elderly, other nephrotoxins• Ototoxicity  vestibular and auditory toxicity  irreversible  risk factors: same as for nephrotoxicity
  • 37. Vancomycin• Inhibits bacterial cell wall synthesis (at a site different than beta-lactams)• Bactericidal (except for Enterococcus)• Distribution  widely distributed into body tissues and fluids  inconsistent penetration into CSF, even with inflamed meninges• Elimination  primarily eliminated unchanged by the kidney via glomerular filtration  elimination half-life depends on renal function
  • 38. Vancomycin:Spectrum Gram-positive bacteria  Methicillin-Susceptible AND Methicillin-Resistant S. aureus and coagulase-negative staphylococci  Streptococcus pneumoniae (including PRSP), viridans streptococcus, Group streptococcus  Enterococcus sp.  Corynebacterium, Bacillus. Listeria, Actinomyces  Clostridium sp. (including C. difficile), Peptococcus, Peptostreptococcus No activity against gram-negative aerobes or anaerobes
  • 39. Vancomycin Clinical Uses • Infections due to MRSA • Serious gram-positive infections in β-lactam allergic patients • Oral vancomycin for refractory C. difficile colitis
  • 40. Vancomycin: Adverse Effects• Red-Man Syndrome  flushing, pruritus, erythematous rash on face and upper torso  related to RATE of intravenous infusion; should be infused over at least 60 minutes  resolves spontaneously after discontinuation  may lengthen infusion (over 2 to 3 hours) or pretreat with antihistamines in some cases• Nephrotoxicity and Ototoxicity  rare with monotherapy, more common when administered with other nephro- or ototoxins  risk factors include renal impairment, prolonged therapy, high doses, ? high serum concentrations, other toxic meds• Dermatologic - rash• Hematologic - neutropenia and thrombocytopenia with prolonged therapy• Thrombophlebitis
  • 41. Clindamycin• Inhibits protein synthesis by binding exclusively to the 50S ribosomal subunit• bacteriostatic activity, but may be bactericidal at high concentrations against very susceptible organisms Dosing  IV 600 - 900 mg q 8 h  Oral 300 – 450 mg q 6 h
  • 42. Clindamycin: Spectrum Gram-Positive Aerobes • Methicillin-susceptible Staphylococcus aureus (MSSA only) • Streptococcus pneumoniae (only PSSP) – resistance is developing • Group and viridans streptococci• Anaerobes• Other Bacteria – Pneumocystis carinii, Toxoplasmosis gondii, Malaria
  • 43. Clindamycin: Pharmacology• Absorption• Rapidly and completely absorbed (F = 90%); food with minimal effect on absorption• Distribution• Good serum concentrations with PO or IV• Good tissue penetration including bone• minimal CSF penetration
  • 44. Clindamycin: Adverse Effects• Gastrointestinal – 3 to 4 %  Nausea, vomiting, diarrhea, dyspepsia• C. difficile colitis – one of worst offenders  Mild to severe diarrhea  Requires treatment with metronidazole• Hepatotoxicity - rare  Elevated transaminases• Allergy - rare
  • 45. Metronidazole• Mechanism of Action  Ultimately inhibits DNA synthesis concentration-dependent bactericidal activity
  • 46. Metronidazole: Adverse Effects• Gastrointestinal  Nausea, vomiting, stomatitis, metallic taste• CNS – most serious  Peripheral neuropathy, seizures, encephalopathy  Use with caution in pts with CNS disorders• Mutagenicity, carcinogenicity  Avoid during pregnancy and breastfeeding
  • 47. Metronidazole -Drug Interactions Drug Interaction Warfarin* ↑ anticoagulant effect Alcohol* Disulfuram reaction Phenytoin ↑ phenytoin concentrations Lithium ↑ lithium concentrations Phenobarbital ↓ metronidazole concentrations Rifampin ↓ metronidazole concentrations
  • 48. Colistin Nephrotoxic :  Toxic ATN  Correlate with accumalative dose  Onset at first 4 days  Process will go on until 1-2 wks  Recover within 3-9 wks  Neuromuscular blockade, CNS SE
  • 49. TYGACIL® (tigecycline) Mechanism - inhibiting protein synthesis Board spectrum, (ไม่ cover Pseudomonas) limit used only to treat infections proven or strongly suspected to be caused by susceptible bacteria. SE  เหมือน tetracycline อื่น  Anaphylaxis/anaphylactoid reactions  Fetal harm, tooth discoloration  hepatic dysfunction and hepatic failure have been reported  Acute pancreatitis have been reported
  • 50. Teicoplanin, Targocid Glycopeptide antibiotics ADR – same as vancomycin in lower incidience alternative agent in subjects experiencing severe RMS due to vancomycin Dosing  Loading 400 mg i.v. injection q 12 hrs *3 doses  Maintenance dose: 400 mg IV or IM OD
  • 51. Fosfomycin - phosphonic acid cell-wall inhibitor , Bactericidal little cross-resistance, cross SE Spectrum  MRSA  Enterobacteriaceae  Enterococci  ? A.baumannii MDR Dose  4-6 กรัมต่อวัน อาจจะเพิ่มได้ถง 4-8 กรัมต่อครั้ง วัน ึ ละ 3 ครั้ง สำาหรับการรักษาบริเวณที่ยาทั่วไปเข้าถึง ยาก หรือ เป็นเชือที่มีค่า MIC สูง ้
  • 52. Mechanisms of antibiotic resistance1. Enzymatic inhibition 1.1 Inactivation: b-lactams (b-lactamases) 1.2 Modification: aminoglycosides (AG-modifying enz)2. Target alteration or overproduction2.1 Alteration • Ribosome: macrolides, lincosamides • Enzymes: b-lactams (PRSP, MRSA),quinolones, rifampin, sulfa, TMP2.2 Overproduction: sulfa, TMP; glycopeptides (VISA)3. Decreased uptake 3.1 Impermeability: imipenem (Opr-D def.) 3.2 Active efflux pump: tetracycline, b-lactams, quinolones4. Bypass pathway(s): sulfa, trimethoprim
  • 53. = antibiotic 2. Target alteration 3.1 Impermeability1.1 Enzymatic inactivation D B 3.2 Efflux.2 Enzymatic modification A B C pump 4. Bypass pathway
  • 54. Types of antibiotic resistanceI. Intrinsic (primary) resistance • Chromosomal change •Micro-evolutionary change (antigenic drift): point mutation •Macro-evolutionary change (antigenic shift): inversions, duplications etcII. Extrinsic (secondary, acquired) resistance • Plasmids: transformation (Tf), transduction (Td), conjugation (Cj) • Transposons/integrons: Tf, Td or Cj • Bacteriophages: Td • Genomic islands: Td • Naked foreign DNA: Tf
  • 55. Gram-positive PRSP MRSA VISA, VRSA VRE MLS-R-GAS• Target • Target • Target • Target • Target• Chr • Tn/Pl (VISA) • Plasmid/Tn • Efflux • Target (VRSA) • Chr/Tn/Pl • Pl/Tn • Enz. Inacti- vation Gram-negative • Chr. or Plb-lactamase- Quinolone-R Efflux-mediated producing organisms • Target (Chr) • Chr > Pl • ESBL • Efflux (Chr >Pl) • AmpC • Carbapenemases
  • 56. Naked foreign DNA Nucleus TransformationTrans Chromosomeduction Plasmid Bacterial cell (+) Conjugation Bacterial cell (-)
  • 57. Chromosome 1. Plasmid mutation, inversion 4. GI att I 2. Transposonint I gene cassette 3. Integron Nucleus Bacteria