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Antimicrobial therapy

Antimicrobial therapy. Prof Ivo Ivić. Bacterial sensitivity to specific antibiotic. Determinants MIC- minimal inhibitory concentration (inhibit, but does not kill bacteria) disables visible bacterial growth in liquid media (12h) allows growth after inoculation on solid media

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Antimicrobial therapy

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  1. Antimicrobial therapy Prof Ivo Ivić

  2. Bacterial sensitivity to specific antibiotic Determinants • MIC- minimal inhibitory concentration (inhibit, but does not kill bacteria) • disables visible bacterial growth in liquid media (12h) • allows growth after inoculation on solid media • MBC- minimal bactericidal concentrations • kills all bacteria • no growth after inoculation on solid media

  3. Requirements for treatment success(using conventional dosage of antibiotic) The lower the MIC, the better the therapy Amount of antibiotic above MIC The greater the AUC, the better the therapy Time above MIC • to achieve serum antibiotic concentrations above MIC • to maintain this concentrations for enough long period after adminstration

  4. Bacterial sensitivity to specific antibiotic – antibiogram • Sensitive • low MIC values for specific antibiotic • conventional dosage = high probability of cure • Resistant • high MIC values for specific antibiotic • therapeutic concentrations not achieveable by conventional or increased dosage

  5. Bacterial sensitivity to specific antibiotic – antibiogram Example Str.pneumoniaeintermediatedlypenicillinsensitive Pneumonia: treatment success with increased dosage Meningitis: tretment failure even with increaed dosage • Intermediate sensitivity • MIC values increased (but not high) • possibility of treatment failure • Increased dosage = sometimes provides therapeutic success

  6. Recoveryfrombacterialinfection:relationshipbetweenantibioticandneutrophilsRecoveryfrombacterialinfection:relationshipbetweenantibioticandneutrophils • Antibiotic: • reduces number of bacteria • facilitate clearing of bacteria by neutrophils • At level of 102-103bacteria/g of tissue • Neutrophil clean bacteria without help of antibiotic • Usualy, this point is achieved after 5 days of therapy

  7. Makingdecision for antibotictherapy

  8. Presenceofbacterialinfection? yes no Determineprobable site of infection ObservecloselyObtaincultures Obtaincultures includingblood Patientsworsens Beginempirictherapy Streamlineantibiotic: - narrowestspectrum - fewest drug possible At day 3 Chek cultureand Gram stains Negative, or Colonisation

  9. Makingdecision for antibiotictherapy: Checklist Assess the of possibility of bacterial infection Assess site of infection/pahtogen(s) involved Assess antibotic susceptibility of presumed pathogen Check data about previous antibiotic therapy/resistence Check important predisposing host factors After 3 days select drug with the narrowest antibacterial spectrum

  10. Rationalselectionofantibiotics Questions to beanswered • How broad is antibacterialspectrumofchoosenantibiotic? • Wethertheantibiotic(s)is -cidal or -static? • What are theantibotics major toxicities? • How is the drug metabolisedandeliminated? Isthereneed for dosignadjustment? • What is the price of the antibioticselected?

  11. Antibacterial spectrum of some antibiotic groups

  12. antibiotics

  13. Antibiotic groups: • -lactams • Aminoglycosides • Glycopeptides • Macrolides • Ketolides • Lincosamides • Tetracyclines • Chloramphaenicol • Quinolones • Oxazolidines • Streptogramins • Daptomycin • Metrondiaziol • Sulfonamides • Trimetoprim • Colistin

  14. β-LACTAM ANTIBIOTICS R1side chain: -anibacterialproperties R2side chain: -pharmacocinetics -methabolism R1 R2

  15. Carbapenems Monobactams Clavulanic acid Penicillins Cephalosporins

  16. Antibacterialmechanismofβ-lactams • Inactivation of cell wall enzymes (PBP-s) • Cessation of cell wall sythesis • during active cell growth and divison • Cell lysis = bactericidal effect • antagonised by bacteriostatic agents

  17. Bacterialresistencemechanisms • Destruction of β-lactam ring by β-lactameses • penicilinases, cefalosporinases, ESBL, karbapenemases • Modification of PBP-s • lowered affinity for specific β-lactam antibiotic • preserved cell wall syntheis

  18. Hipersensitivity to β-lactamantibiotics   • The most commontoxicity • Immediateor Delayed • Anaphylactic (IgEmediated) • Urticaria, angioedemaQuincke • Asthmaticattac • Anaphylacticshock • Non-anaphylactic • Maculopapularrash

  19. Hipersenitivity:Penicillins vs Cephaloporins • Penicillins • 1-10 % allergic reactions • 1-7% cross-reactity to cephalosporins • Cephalosporins • 1- 3% allergic reactions • rarely anaphylactic

  20. A practicalapproachincaseofpencillinallergy • Anaphylactic • all β-lactams should be avoides • or desensitizationshould be carried out • Non-anaphylactic • another group of β-lactams is allowed

  21. Other -lactam adverse reactions • Imipenem: siezures • in patients with renal dysfunction • less frequent with other karbapenems • Ceftriaxon: aseptic inflammation of gallbladder • drug crystalisation in gallbladder • Cephalosporins + aminoglycosides: nephrotoxicity • Clostridium difficile diarrhoea

  22. Penicillins

  23. Penicillins • Natural penicilins • Aminopenicilins • Penicillaze-resistentpencillins (anti-staphylococcal) • Carboxypencillinsandureidopencillins (anti-pseudomonal)

  24. 1.Natural penicilins (PCN) • Narrow spectrum • S.pygenes, S. viridans, S.pneumoniae, Neisseria meningitidis • Anaerobic mouth flora • Clostridium perfrigens, C.tetani, Leptosipra • Short half-life: dosage 3-6 times/day • Renal excretion: dose adjustment with renal funciton Preparations • i.v. : PCN G • i.m.: prokain PCN G, benzatin PCN G • p.o.: PCN V-K

  25. 2. Aminopenicillins (iv, im, po) 2a. Amoxycillin , Ampicillin • Moderatespectrum: • Gram-positive: Streptococci., Enterococci, Lysteria • Gram-negative: E.coli, Salmonella, Haemophilusinfluenzae (if-lactamasesensitive) • Short half life • Renalexcretion (unchanged)

  26. 2b. Amoxycillin-clavulanate , Ampicilin-sulbactame • Broader spectrum with addition of: • Meticillin sensitive Staphylococcus aureus (MSSA) • -lactamese producing gram-negative bacteria: • Moraxella catarrhalis, • H.influenzae, • Enterobacteriaceae.

  27. 3. Penicillase-resistantpenicillins (iv, po)(meticillinsensitivity) Cloxacillin and Dicloxacillin • Very narrow spectrum- • Indication: MSSA, S.pyogenes (cellulitis) • Ineffective against anerobes and enterobacteriaceae • Short half-life • Hepatal elimination (bile excretion)

  28. Carboxypenicillins and Ureidopenicillins (iv)(tikarcillin) (piperacilin) • Activityaganist: • Gram-negative bactera • Anaerobes (+ B.fragilis) • MSSA Intrabdominalinfections VAP Mixed soft tissueinfections • Rezisten to -lactamase of gram-negative bacteria: • Pseudomonas, other enterobacteriaceae Nowdays market- only with -lactamase inhibitors: • Tikarcilin-clavulanate • Piperacilin-tazobactam

  29. cephalosporins

  30. 1st generation cephalosporins • Activity: • Streptoccci, MSSA, oral cavity anaerobes • some CA gram negative bacilli (E.coli) • Ineffective against • MRSA, penicillin-resitant S.pneumoniae • H.influenzae • Renal excretion • Do not pass blood-brain barrier • Good for soft tissue infections

  31. 2nd generation cephalosporins • Similar to 1st generation, wider gram neg.activity • H.influenzae, Neisseria sp, Moraxella catarrhalis • Renal excretion • Indications • Uncomplicated UTI, otitis media • Soft tissue infection, pelvic inflammatory disease • Oral preparation (cefuroxim-axetil): • low serum levels • expensive

  32. 3rd generation cephalosporins Activity • Excellentagainstgram negative bacteria • Nessseriasp, H.influenzae, M.catarrhalis • Enterobacteriaceae • Ceftazidim: theonlyactiveagainstPs.aeruginosa • Excelentagainstgram positivecoccci • S.pyogenes, S.viridans, otherstreptococci • S.pneumoniae (includingmoderately PCN resistantstrains) • PooragainstS.aureusandhigly PCN resistantS.pneumoniae

  33. 3rd generation cephalosporins • Ceftriaxon- long half life: 1-2 doses/day • Others: 3-4 doses/day • All cross blood brain barrier • Excretion • Renal: for most members • Ceftriaxone: hepatal (gallbladder crystals!) • Indications: • CA pneumonia and meningitis • UTI and abdominal infections CA: CommunityAcquired

  34. 3rd generation cephalosporins ORAL • Cefexime • Cefpodoxime proxetil PARENTERAL (iv, im) • Cefotaxime • Ceftriaxone • Ceftazidime

  35. 4th generation cephalosporins(cefexime) • Resistant to ESBL • Wide antibacterial spectrum • Similar to 3rd gen.cephalosporins plus: Ps.aeruginosa and MSSA (but not MRSA!) Indicatons • Nosocomial infections (iv)

  36. 5th generation cephalosporins(ceftaroline) • Antibacterial spectrum • Similar to 3.gen.cephalosprins(ceftriaxon) plus: MRSA and VISA (vancomyin intermdately restant SA) • Indications • CA pneumonia • Complicated soft tissue infections

  37. Carbapenems

  38. Carbapenems Very wide antibacterialspectrum • Gram negative bacteria, including: • ESBL producingstrains • P.aeruginosa(withexceptionofertapenem) • Gram positivebacteria, including: • MSSA (but not MRSA) • Anaerobes

  39. Carbapenems • Carbapenems • Imipenem-cilastatin • Etrapenem(1dose/day, inactiveagainstP.aeruginosa) • Meropenem • Doripenem • Indications (pending results of the microbiology) • Severely ill patients with nosocomial infection • Severe mixed infections

  40. aminoglycosides

  41. Aminoglycosides • Derived form Streptomyces bacteria • Bactericidal, but inactive low pH medium • Post-antibotic effec: • Short exposure to antibiotic Prolonged suspension of bacterial growth (despite falling of antibiotic level below MIC) • The higer dose, the longer post-antibiotic effect • 1 dose/day possible

  42. Aminoglycosides Activity • Excellent against gram-negative bacteria • Sinergy with penicillins for: • S.viridans, Enterococcus, P.aeruginosa • But not as monotherapy for them • Renal excretion • Deceased creatinin clearance Dose adjustment

  43. Aminoglycosides Toxicity • Nephrotoxicity (usualy reversible) • Ototxycity (usualy ireverible) • Avoid aminoglicosides in: • Eldery patients • Renal disease • Patients wit liver disase • Dehidration and hypotension • Combination with cephalosporins, vankomycin, clindamycin, fursemid • Monitoring of serum levels is reccommended

  44. Aminoglycosides (iv, im) • Gentamicin • Amikacin • Netilmicin • Tobramicin (topical th- eyeinfections) • Streptomycin (tularemia, plague, tb)

  45. Vancomycin Teicoplanin glycopeptides

  46. Glycopeptides • Inhibt cell wall sythesis (peptidoglycan)- bactericial • Long half life, postantibiotic effect • 1-2 dose/day • Do not cross blood-brain barrier • Activity • Gram positive cocci • SA, S.pneumoniae, Enterococcus, etc. • Renal excretion • Deceased creatinin clearance Dose adjustment

  47. Glycopeptides Limitedtherapeuticindications • MR staphylococci (MRSA and koagulasa neg.) • PCN highly resistant S.peumoniae • Enterocci in patients with PNC allergy • Clostridum difficile diarrhoea iresponsive to metronidazol (oral therapy)

  48. MacrolidesandKetolides

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