Antibiotic Choices
OutlineGeneral Considerations:   Host Factors   Geographic Considerations   Microbial Factors   Antimicrobial Factors ...
OutlineReview of antibiotic classes:    Beta-lactams    Macrolides    Fluoroquinolones    Aminoglycosides    Lincosam...
Empiric TherapyOften microbiologic diagnosis is notknownDecision regarding optimal empirictreatment based on:  host facto...
Empiric Therapy17 yr old previously healthy man with 2 dayhx of fever, sore throat, cough.    Diagnostic possibilities?  ...
Host FactorsAgeImmune adequacyUnderlying diseasesRenal/hepatic impairmentPresence of prosthetic materialsEthnicityPregnancy
AgeCan help to narrow the diagnosis withcertain infections: Ex:   Meningitis:           What bugs would you consider in ...
Immune AdequacyImmune status important clue:     Ex: Asplenic patients: at risk for encapsulated bacterial      infection...
Underlying DiseaseDiabetesTransplantHIVCancerRenal impairmentAutoimmune diseases
Renal/Hepatic ImpairmentImplications for treatment: Dose  adjusting for renal impairment Avoiding nephrotoxic drugs Avo...
Presence of ProsthesesImplications for diagnosis: What   bug is more pathogenic with artificial  joints/valves?Implicatio...
EthnicityConsider diseases endemic in countryof origin: Ex: TB in patients from TB endemic areas  as well as aboriginal p...
Geographic FactorsNeed to know common microbialcauses of infection in your area:    Ex:MRSA: 40% of S. aureus isolates in...
PregnancyIssues of antibiotic use in pregnancyhave to be consideredRisks of transmission to baby:    HIV    GBS    HSV ...
Microbial FactorsProbable organismsProbable susceptibility patternsNatural history of infectionsLikelihood of obtaining go...
Probable OrganismsHave to know most likely organisms forvarious common infections: CAP Cellulitis Intra-abdominal   inf...
Microbial SusceptibilitiesKnow general microbial susceptibilities aswell as those which are geographicalyspecific: S pneu...
Natural HistoryRapidly fatal vs slow growing: Ex: Meningococcemia – can be rapidly  fatal Ex: TB meningitis often more i...
Likelihood of Obtaining     Microbiologic DataMay be difficult to get specimen: Ex:   brain abscessIf patient has been on...
Antimicrobial FactorsSite of infectionRoute of AdministrationBactericidal vs BacteristaticCombination vs single therapy
Site of InfectionSusceptibility testing is geared to attainableserum levelsDoes not account for host factors orconditions ...
Route of AdministrationMany options exist: Enteral Parenteral Small  particle aerosol Intrathecal Topical
Enteral AdministrationMust know oral bioavailabilityMust be resistant to breakdown bygastric juices Some drugs must be gi...
Bactericidal vs BacteristaticCidal: B-lactams, aminoglycosides,quinolonesStatic: tetracyclines. Macrolides,lincosamidesBut...
Combination TherapyThree main reasons:    Broader coverage: may be necessary for empiric     treatment of certain infecti...
Adjunctive ApproachesShock and Sepsis: supportive care with fluids,possibly steroidsBacterial meningitis: steroidsDrainage...
Monitoring Response to          TherapyCertain amount of gestaltMonitor infectious parameters: fever,WBC, ESR etc.Knowledg...
Duration of TherapyVery few studies to establish minimumdurations of therapyEx. Viridans strep endocarditis:    5 days th...
PharmacoeconomicsCost of illness includes:    Medications    Provider visits    Administration of medications    Loss ...
Antibiotics: drugs for bugs
Beta LactamsIncludes:      Penicillins, cephalosporins, carbapenems, monobactamsMechanism of Action:      Inhibits cell ...
Beta-LactamsNatural Penicillins:      Pen G, Pen V, benzathine penicillinSpectrum of activity:    Viridans group strep, ...
AminopenicillinsPrototypes: Ampicillin, AmoxicillinCovers:    Strepspp    Does not cover enterococcusSpectrum extended t...
Penicillinase Resistant         PenicillinsProtoype: CloxacillinCovers:    Staph spp including MSSA, 2/3 of Staph epi   ...
CarboxypenicillinsPrototype: TicarcillinCovers:    Covers   Stenotrophomonas, PseudomonasProblems with hypernatremia,hypo...
UreidopenicillinsPrototype: PiperacillinCovers    Strep spp (less than earlier generations)    Enterococcus    Anaerobi...
CephalosporinsDivided into 4 generationsIncreasing gram negative coverage withless gram positive coverage withincreasing g...
1st GenerationPrototype: CefazolinCovers:    Staph   spp (MSSA)    Strep spp    E. coli, Klebsiella, Proteus mirabilisN...
2nd GenerationPrototype: CefuoximeCovers:    Gram   positives (Staph, Strep)    H influenza    M catarrhalisCefoxitin: ...
3rd GenerationDivided into two main groups:   Ceftazidime:             Pseudomonas             Good gram negative cover...
4th GenerationPrototype: CefepimeCoverage:    Maintainsgram positive activity (Strep)    Psuedomonas    Lower potential...
CarbapenemsImipenem, Meropenem, ErtapenemImipenem/Meropenem:    Staph (MSSA), Strep    Anaerobic activity    Gram negat...
MonobactamPrototype: Aztreonam AerobicGNB Pseudomonas No gram positive or anaerobic coverageSimilar spectrum to aminogl...
AminoglycosidesIncludes:    Gentamycin    Tobramycin    Amikacin    StreptomycinMOA:    binds to 30S/50S ribosomal su...
AminoglycosidesCovers:   Aerobic GNB including pseudomonas   Mycobacteria   Brucella, Franscicella   Nocardia   Syner...
FluoroquinolonesIncludes:    Ciprofloxacin    Ofloxacin    Levofloxacin    Gatifloxicin    MoxifloxacinMechanism of A...
FluoroquinolonesAll cover:    Mycoplasma, Legionella, Chlamydia    Francisella, Rickettsia, Bartonella    Atypical myco...
FluoroquinolonesOfloxacin:    Better gram positive coverage (Strep but min staph     coverage)    No pseudomonas activit...
FluoroquinolonesMoxifloxacin:    Activity           against Strep and Staph    Anaerobic coverage    No pseudomonas act...
MacrolidesIncludes:    Erythromycin    Clarithromycin    AzithromycinMechanism of Action:    Binds to ribosomal subuni...
ErthromycinActive against Strep sppAlso effective against:    Legionella    Mycoplasma    Campylobacter    Chlamydia  ...
ClarithromycinActive against:    Strep including pneumoniae    Moraxella, Legionella, Chlamydia    Atypical mycobacteri...
AzithromycinActive against:    Mycoplasma,   Legionella, Chlamydia   H  influenza    Strep sppLong half life5 day cours...
ClindamycinMechanism of Action:      Blocks protein synthesis by binding to ribosomal subunitsToxicity:    Rash    GI s...
MetronidazoleMechanism not well understoodCovers:    Most anaerobes except Peptostreptococci,     Actinmycetes, Propriono...
TetracyclinesIncludes:    Tetracycline    Doxycycline    MinocyclineMechanism of Action:    Binds to 30S ribosomal sub...
TetracyclinesSpectrum includes unusual organisms    Rickettsia    Chlamydia    Mycoplasma    Vibrio cholera    Brucel...
GlycopeptidesPrototype: VancomycinMechanism of Action:    Inhibits   cell wall synthesisToxicity:    Ototoxicity        ...
GlycopeptidesCoverage:    Gram  positives: Staph (incl. MRSA), strep,     enterococcus    Gram positive anaerobes    Ex...
Sulfa drugsIncludes: TMP/SMXMechanism of Action:    Folate   reductase inhibitorToxicity:    Hypersensitivity           ...
SulfaCoverage:    Strep, Staph    H influenza    L monocytogenes    Many GNG (E coli, Klebsiella)    PCP    Nocardia...
ChloramphenicolBroad spectrum activity:    GPC, GNB    Menigitis organisms    Rickettsia spp    No activity against Kl...
LinezolidMechanism of Action:      Binds to ribosomal subunit inhibiting protein synthesisOral drugActive against:    VR...
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Antibiotic choices

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Antibiotic choices

  1. 1. Antibiotic Choices
  2. 2. OutlineGeneral Considerations:  Host Factors  Geographic Considerations  Microbial Factors  Antimicrobial Factors  Adjunctive Approaches  Pharmacoeconomics
  3. 3. OutlineReview of antibiotic classes:  Beta-lactams  Macrolides  Fluoroquinolones  Aminoglycosides  Lincosamides  Tetracyclines  Others: vancomycin, metronidazole, chloramphenicol, linezolid
  4. 4. Empiric TherapyOften microbiologic diagnosis is notknownDecision regarding optimal empirictreatment based on: host factors microbial factors geographic factors antimicrobial factors
  5. 5. Empiric Therapy17 yr old previously healthy man with 2 dayhx of fever, sore throat, cough.  Diagnostic possibilities?  Can he wait or should be be treated?  What would you treat him with?17 yr old with HIV and 2 day hx of fever, sorethroat, cough.  Diagnostic possibilities?  Can he wait or should he be treated?  What should he be treated with?
  6. 6. Host FactorsAgeImmune adequacyUnderlying diseasesRenal/hepatic impairmentPresence of prosthetic materialsEthnicityPregnancy
  7. 7. AgeCan help to narrow the diagnosis withcertain infections: Ex: Meningitis:  What bugs would you consider in neonate? In adult? Ex: EBV infection  In what age group would you consider this diagnosis? Ex: UTI:  How does age affect your interpretation of laboratory results?
  8. 8. Immune AdequacyImmune status important clue:  Ex: Asplenic patients: at risk for encapsulated bacterial infections  Ex: HIV/AIDS patients: at risk for variety of opportunistic infections  Ex: Transplant patients: at risk for a variety of infections depending on timeline etc.Previous use of antibiotics: Prolonged broad spectrum Diarrhea
  9. 9. Underlying DiseaseDiabetesTransplantHIVCancerRenal impairmentAutoimmune diseases
  10. 10. Renal/Hepatic ImpairmentImplications for treatment: Dose adjusting for renal impairment Avoiding nephrotoxic drugs Avoiding hepatotoxic drugsImplications for monitoring: If unavoidable  ensure good hyrdration  Monitor renal and liver function
  11. 11. Presence of ProsthesesImplications for diagnosis: What bug is more pathogenic with artificial joints/valves?Implications for Treatment: Infected hardware needs to be removed Addition of rifampin in certain situations (effective in treatment of prosthetic infections)
  12. 12. EthnicityConsider diseases endemic in countryof origin: Ex: TB in patients from TB endemic areas as well as aboriginal patients Ex: Stronglyoides in patients from tropical countries
  13. 13. Geographic FactorsNeed to know common microbialcauses of infection in your area:  Ex:MRSA: 40% of S. aureus isolates in US but only 3% of isolates in CanadaConsider patient ethnicityTravel history is important:  Ex:fever in traveller returning from Sudan vs fever in person who has never left Edmonton
  14. 14. PregnancyIssues of antibiotic use in pregnancyhave to be consideredRisks of transmission to baby:  HIV  GBS  HSV  Syphilis
  15. 15. Microbial FactorsProbable organismsProbable susceptibility patternsNatural history of infectionsLikelihood of obtaining goodmicrobiologic dataSite of Infection
  16. 16. Probable OrganismsHave to know most likely organisms forvarious common infections: CAP Cellulitis Intra-abdominal infections Endocarditis
  17. 17. Microbial SusceptibilitiesKnow general microbial susceptibilities aswell as those which are geographicalyspecific: S pneumoniae: 15% resistant to erythromycin, 3% to penicillin P. aeruginosa: 30-40% resistant to ciprofloxacin, 20-25% to ceftazidime MRSA: account for 3-4% of S aureus isolates*For Capital Health Region for 2004
  18. 18. Natural HistoryRapidly fatal vs slow growing: Ex: Meningococcemia – can be rapidly fatal Ex: TB meningitis often more indolent courseHIVHep C
  19. 19. Likelihood of Obtaining Microbiologic DataMay be difficult to get specimen: Ex: brain abscessIf patient has been on antibiotics, it willaffect culture results
  20. 20. Antimicrobial FactorsSite of infectionRoute of AdministrationBactericidal vs BacteristaticCombination vs single therapy
  21. 21. Site of InfectionSusceptibility testing is geared to attainableserum levelsDoes not account for host factors orconditions that alter antimicrobial accessEx: diffusion into CSF is limited in many drugsEx: abscesses:  Difficult to penetrate abscess wall  High bacterial burden  Low pH and low oxygen tension can affect antibiotic activity
  22. 22. Route of AdministrationMany options exist: Enteral Parenteral Small particle aerosol Intrathecal Topical
  23. 23. Enteral AdministrationMust know oral bioavailabilityMust be resistant to breakdown bygastric juices Some drugs must be given with buffer Some require acidity for absorptionOther drugs cannot be given in highenough doses orally
  24. 24. Bactericidal vs BacteristaticCidal: B-lactams, aminoglycosides,quinolonesStatic: tetracyclines. Macrolides,lincosamidesBut there are exceptions:  Chloramphenicol thought to be bacteriostatic is cidal in H influenza, S pneumonia, N. menigitidis
  25. 25. Combination TherapyThree main reasons:  Broader coverage: may be necessary for empiric treatment of certain infections. Ex. Intra-abdominal sepsis  Synergistic activity: eg amp + gent for serious enterococcal infections  Prevent resistance: eg TBDisadvantages:  antagonism – theoretically should avoid combining bacteriostatic and bactericidal agents  Potential for increased toxicity
  26. 26. Adjunctive ApproachesShock and Sepsis: supportive care with fluids,possibly steroidsBacterial meningitis: steroidsDrainage and Debridement of abscessesRemoval of prosthetic materialsCorrection of trace nutrient deficienciesCorrection of protein calorie malnutritionAssisted organ function with ventilator,dialysis, vasopressors/ionotropes
  27. 27. Monitoring Response to TherapyCertain amount of gestaltMonitor infectious parameters: fever,WBC, ESR etc.Knowledge of natural historyImagingRepeat cultures useful in endocarditis,complicated UTI (ie normally sterileareas)
  28. 28. Duration of TherapyVery few studies to establish minimumdurations of therapyEx. Viridans strep endocarditis:  5 days therapy: 80% failure  10 days: 50%  20 days: 2%Duration usually based on anecdoteMost uncomplicated bacterial infections canbe treated for –14 days4-6 weeks for endocarditis, osteo,6-12 months: Mycobacterial diseases,
  29. 29. PharmacoeconomicsCost of illness includes:  Medications  Provider visits  Administration of medications  Loss of productivityCost is a tertiary consideration aftereffectiveness and safety
  30. 30. Antibiotics: drugs for bugs
  31. 31. Beta LactamsIncludes:  Penicillins, cephalosporins, carbapenems, monobactamsMechanism of Action:  Inhibits cell wall synthesis by binding to PBP and preventing formation of peptidoglycan cross linkageToxicity:  Hypersensitivity reaction  10-20% X-reactivity with carbapenems  10% x-reactivity with 1st generation cephalosporins  1% x-reactivity with 3rd generation cephalosporins
  32. 32. Beta-LactamsNatural Penicillins:  Pen G, Pen V, benzathine penicillinSpectrum of activity:  Viridans group strep, B-hemolytic strep, many Strep pneumoniae  Most N. menigiditis  Staph spp  Oral anaerobes  L monocytogenes, Pasteurella multocida, Treponema pallidum, Actinmyces israelii  enterococcus (1/3) pen sensitive
  33. 33. AminopenicillinsPrototypes: Ampicillin, AmoxicillinCovers:  Strepspp  Does not cover enterococcusSpectrum extended to include someGNB:  E. coli, Proteus mirabilis, Salmonella spp, Shigella, Moraxella, Hemophilus spp
  34. 34. Penicillinase Resistant PenicillinsProtoype: CloxacillinCovers:  Staph spp including MSSA, 2/3 of Staph epi  Strep sppNo coverage for enterococcusNo coverage for gram negativeorganisms or anaerobes
  35. 35. CarboxypenicillinsPrototype: TicarcillinCovers:  Covers Stenotrophomonas, PseudomonasProblems with hypernatremia,hypokalemia, platelet dysfunction
  36. 36. UreidopenicillinsPrototype: PiperacillinCovers  Strep spp (less than earlier generations)  Enterococcus  Anaerobic organisms  Pseudomonas  Broad Gram negative coverage Iftazobactam added – increases Staph coverage and anaerobic coverage
  37. 37. CephalosporinsDivided into 4 generationsIncreasing gram negative coverage withless gram positive coverage withincreasing generationsEnterococci are not covered by any ofgenerations
  38. 38. 1st GenerationPrototype: CefazolinCovers:  Staph spp (MSSA)  Strep spp  E. coli, Klebsiella, Proteus mirabilisNo anaerobic activity
  39. 39. 2nd GenerationPrototype: CefuoximeCovers:  Gram positives (Staph, Strep)  H influenza  M catarrhalisCefoxitin:  Some serratia coverage  Anaerobic activity  Used for intra-abdominal infection and PID
  40. 40. 3rd GenerationDivided into two main groups: Ceftazidime:  Pseudomonas  Good gram negative coverage  Lose gram positive coverage (poor against Strep)  Ceftriaxone/cefotaxime:  Reasonable Strep coverage, poor Staph coverage  Good gram negative coverage  Little anti-pseudomonal activity  Little anaerobic activity  Good CSF penetration  Toxicity includes biliary sludge
  41. 41. 4th GenerationPrototype: CefepimeCoverage:  Maintainsgram positive activity (Strep)  Psuedomonas  Lower potential for resistanceCefixime – oral version  Good against gram negatives and Strep  No pseudomonal activity
  42. 42. CarbapenemsImipenem, Meropenem, ErtapenemImipenem/Meropenem:  Staph (MSSA), Strep  Anaerobic activity  Gram negatives (Legionella, Chlamydia, Mycoplasma, B cepacia, Stenotrophomonas)  Pseudomonas  Enterococcus faecalis but not faeciumErtapenem  Allows once a day dosing  Does not cover pseudomonas
  43. 43. MonobactamPrototype: Aztreonam AerobicGNB Pseudomonas No gram positive or anaerobic coverageSimilar spectrum to aminoglycosideswithout renal toxicityCross reactivity to penicillin is rare butincreases with ceftazidime
  44. 44. AminoglycosidesIncludes:  Gentamycin  Tobramycin  Amikacin  StreptomycinMOA:  binds to 30S/50S ribosomal subunit  inhibit protein synthesisToxicity:  CN VIII - irreversible  Renal toxicity – reversible  Rarely hypersensitivity reactions
  45. 45. AminoglycosidesCovers:  Aerobic GNB including pseudomonas  Mycobacteria  Brucella, Franscicella  Nocardia  Synergy with B-lactams (Enterococci, Staphylococci)
  46. 46. FluoroquinolonesIncludes:  Ciprofloxacin  Ofloxacin  Levofloxacin  Gatifloxicin  MoxifloxacinMechanism of Action:  DNA gyrase inhibitorsToxicity:  GI symptoms
  47. 47. FluoroquinolonesAll cover:  Mycoplasma, Legionella, Chlamydia  Francisella, Rickettsia, Bartonella  Atypical mycobacteriaCipro:  Good gram negative coverage  Poor gram positive coverage  N gonorrhea, H influenza  Good for UTI, infectious diarrhea  In combination for pseudomonas
  48. 48. FluoroquinolonesOfloxacin:  Better gram positive coverage (Strep but min staph coverage)  No pseudomonas activityLevofloxacin:  L-entomer of ofloxacin so identical coverage  Used for LRTIGatifloxacin:  Increased activity against strep  No pseudomonas activity
  49. 49. FluoroquinolonesMoxifloxacin:  Activity against Strep and Staph  Anaerobic coverage  No pseudomonas activity
  50. 50. MacrolidesIncludes:  Erythromycin  Clarithromycin  AzithromycinMechanism of Action:  Binds to ribosomal subunit  Blocks protein synthesisToxicity:  GI upset (especially with erythromycin)
  51. 51. ErthromycinActive against Strep sppAlso effective against:  Legionella  Mycoplasma  Campylobacter  Chlamydia  N gonohhreaPoor for H influenzaUsed infrequently due to GI upset
  52. 52. ClarithromycinActive against:  Strep including pneumoniae  Moraxella, Legionella, Chlamydia  Atypical mycobacteria  More active against H influenzaUsed in combination against H pyloriLess GI side effects
  53. 53. AzithromycinActive against:  Mycoplasma, Legionella, Chlamydia H influenza  Strep sppLong half life5 day course is adequateLess GI side effects
  54. 54. ClindamycinMechanism of Action:  Blocks protein synthesis by binding to ribosomal subunitsToxicity:  Rash  GI symptoms  C diff colitis seen in 1-10%No gram negative or enterococcus coverageCovers Staph spp (MSSA), Strep spp andanaerobes
  55. 55. MetronidazoleMechanism not well understoodCovers:  Most anaerobes except Peptostreptococci, Actinmycetes, Proprionobacterium acnes  Parasitic protozoa: Giardia lamblia, E. histolyticaToxicity:  Neutropenia  Disulfuram reaction  Potentiation of warfarin
  56. 56. TetracyclinesIncludes:  Tetracycline  Doxycycline  MinocyclineMechanism of Action:  Binds to 30S ribosomal subunit  Blocks protein synthesisToxicity:  Rash, Photosensitivity, impairs bone growth and stains teeth of children, increased uremia
  57. 57. TetracyclinesSpectrum includes unusual organisms  Rickettsia  Chlamydia  Mycoplasma  Vibrio cholera  Brucella  Borreila burgdorferiiMinocycline:  Active against stenotrophomonas and P acnes  May be active against MRSADoxycycline:  Used for prophylaxis against Plasmodium spp
  58. 58. GlycopeptidesPrototype: VancomycinMechanism of Action:  Inhibits cell wall synthesisToxicity:  Ototoxicity – rare  Can induce histamine release – red man syndrome
  59. 59. GlycopeptidesCoverage:  Gram positives: Staph (incl. MRSA), strep, enterococcus  Gram positive anaerobes  Exceptions: VRE, Leuconostoc, LactobacillisInferior to beta-lactams in terms of curerates for beta-lactam sensitiveorganisms
  60. 60. Sulfa drugsIncludes: TMP/SMXMechanism of Action:  Folate reductase inhibitorToxicity:  Hypersensitivity reactions  Thrombocytopenia  rash
  61. 61. SulfaCoverage:  Strep, Staph  H influenza  L monocytogenes  Many GNG (E coli, Klebsiella)  PCP  Nocardia  Isospora belliBecause of frequent allergic rxns, only usedin special circumstances (eg PCPpneumonia)
  62. 62. ChloramphenicolBroad spectrum activity:  GPC, GNB  Menigitis organisms  Rickettsia spp  No activity against Klesiella, Eterobacter, Serratia, Proteus, PseudomonasToxicity:  Dose related marrow toxicity  Idiosyncratic aplastic anemia  Gray syndrome – abdominal distention, cyanosis, vasomotor collapse (seen in liver failure pts)
  63. 63. LinezolidMechanism of Action:  Binds to ribosomal subunit inhibiting protein synthesisOral drugActive against:  VRE, MRSA  EnterococcusNo activity against gram negativesVery expensive ($140/day) and currently notcovered
  64. 64. Questions

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