antibiotic choices
TRANSCRIPT
Antibiotic Choices
Outline
General Considerations:Host FactorsGeographic ConsiderationsMicrobial FactorsAntimicrobial FactorsAdjunctive ApproachesPharmacoeconomics
Outline
Review of antibiotic classes:Beta-lactamsMacrolidesFluoroquinolonesAminoglycosidesLincosamidesTetracyclinesOthers: vancomycin, metronidazole,
chloramphenicol, linezolid
Empiric Therapy
Often microbiologic diagnosis is not knownDecision regarding optimal empiric treatment based on: host factorsmicrobial factorsgeographic factorsantimicrobial factors
Empiric Therapy
17 yr old previously healthy man with 2 day hx 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, sore throat, cough.
Diagnostic possibilities? Can he wait or should he be treated? What should he be treated with?
Host Factors
Age
Immune adequacy
Underlying diseases
Renal/hepatic impairment
Presence of prosthetic materials
Ethnicity
Pregnancy
Age
Can help to narrow the diagnosis with certain 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?
Immune Adequacy
Immune 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
Underlying Disease
Diabetes
Transplant
HIV
Cancer
Renal impairment
Autoimmune diseases
Renal/Hepatic Impairment
Implications for treatment:Dose adjusting for renal impairmentAvoiding nephrotoxic drugsAvoiding hepatotoxic drugs
Implications for monitoring: If unavoidable
ensure good hyrdrationMonitor renal and liver function
Presence of Prostheses
Implications for diagnosis:What bug is more pathogenic with artificial
joints/valves?
Implications for Treatment: Infected hardware needs to be removedAddition of rifampin in certain situations
(effective in treatment of prosthetic infections)
Ethnicity
Consider diseases endemic in country of origin:Ex: TB in patients from TB endemic areas
as well as aboriginal patientsEx: Stronglyoides in patients from tropical
countries
Geographic Factors
Need to know common microbial causes of infection in your area:
Ex: MRSA: 40% of S. aureus isolates in US but only 3% of isolates in Canada
Consider patient ethnicity
Travel history is important:Ex: fever in traveller returning from Sudan vs
fever in person who has never left Edmonton
Pregnancy
Issues of antibiotic use in pregnancy have to be considered
Risks of transmission to baby:HIVGBSHSVSyphilis
Microbial Factors
Probable organisms
Probable susceptibility patterns
Natural history of infections
Likelihood of obtaining good microbiologic data
Site of Infection
Probable Organisms
Have to know most likely organisms for various common infections:CAPCellulitis Intra-abdominal infectionsEndocarditis
Microbial Susceptibilities
Know general microbial susceptibilities as well as those which are geographicaly specific: 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
Natural History
Rapidly fatal vs slow growing:Ex: Meningococcemia – can be rapidly
fatal Ex: TB meningitis often more indolent
course
HIV
Hep C
Likelihood of Obtaining Microbiologic Data
May be difficult to get specimen: Ex: brain abscess
If patient has been on antibiotics, it will affect culture results
Antimicrobial Factors
Site of infection
Route of Administration
Bactericidal vs Bacteristatic
Combination vs single therapy
Site of Infection
Susceptibility testing is geared to attainable serum levelsDoes not account for host factors or conditions that alter antimicrobial accessEx: diffusion into CSF is limited in many drugs Ex: abscesses:
Difficult to penetrate abscess wall High bacterial burden Low pH and low oxygen tension can affect antibiotic
activity
Route of Administration
Many options exist:EnteralParenteralSmall particle aerosol IntrathecalTopical
Enteral Administration
Must know oral bioavailability
Must be resistant to breakdown by gastric juicesSome drugs must be given with bufferSome require acidity for absorption
Other drugs cannot be given in high enough doses orally
Bactericidal vs Bacteristatic
Cidal: B-lactams, aminoglycosides, quinolones
Static: tetracyclines. Macrolides, lincosamides
But there are exceptions:Chloramphenicol thought to be bacteriostatic is
cidal in H influenza, S pneumonia, N. menigitidis
Combination Therapy
Three 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 TB
Disadvantages: antagonism – theoretically should avoid combining
bacteriostatic and bactericidal agents Potential for increased toxicity
Adjunctive Approaches
Shock 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
Monitoring Response to Therapy
Certain amount of gestaltMonitor infectious parameters: fever, WBC, ESR etc.Knowledge of natural historyImagingRepeat cultures useful in endocarditis, complicated UTI (ie normally sterile areas)
Duration of Therapy
Very few studies to establish minimum durations of therapyEx. Viridans strep endocarditis:
5 days therapy: 80% failure 10 days: 50% 20 days: 2%
Duration usually based on anecdoteMost uncomplicated bacterial infections can be treated for –14 days4-6 weeks for endocarditis, osteo, 6-12 months: Mycobacterial diseases, endemic mycoses
Pharmacoeconomics
Cost of illness includes:MedicationsProvider visitsAdministration of medicationsLoss of productivity
Cost is a tertiary consideration after effectiveness and safety
Antibiotics: drugs for bugs
Beta Lactams
Includes: Penicillins, cephalosporins, carbapenems, monobactams
Mechanism of Action: Inhibits cell wall synthesis by binding to PBP and
preventing formation of peptidoglycan cross linkage
Toxicity: Hypersensitivity reaction 10-20% X-reactivity with carbapenems 10% x-reactivity with 1st generation cephalosporins 1% x-reactivity with 3rd generation cephalosporins
Beta-Lactams
Natural Penicillins: Pen G, Pen V, benzathine penicillin
Spectrum 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
Aminopenicillins
Prototypes: Ampicillin, Amoxicillin
Covers:Strep sppDoes not cover enterococcus
Spectrum extended to include some GNB:
E. coli, Proteus mirabilis, Salmonella spp, Shigella, Moraxella, Hemophilus spp
Penicillinase Resistant Penicillins
Protoype: Cloxacillin
Covers:Staph spp including MSSA, 2/3 of Staph epiStrep spp
No coverage for enterococcus
No coverage for gram negative organisms or anaerobes
Carboxypenicillins
Prototype: Ticarcillin
Covers:Covers Stenotrophomonas, Pseudomonas
Problems with hypernatremia, hypokalemia, platelet dysfunction
Ureidopenicillins
Prototype: PiperacillinCovers
Strep spp (less than earlier generations)EnterococcusAnaerobic organismsPseudomonasBroad Gram negative coverage
If tazobactam added – increases Staph coverage and anaerobic coverage
Cephalosporins
Divided into 4 generations
Increasing gram negative coverage with less gram positive coverage with increasing generations
Enterococci are not covered by any of generations
1st Generation
Prototype: Cefazolin
Covers:Staph spp (MSSA)Strep sppE. coli, Klebsiella, Proteus mirabilis
No anaerobic activity
2nd Generation
Prototype: CefuoximeCovers:
Gram positives (Staph, Strep)H influenzaM catarrhalis
Cefoxitin:Some serratia coverageAnaerobic activityUsed for intra-abdominal infection and PID
3rd Generation
Divided 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
4th Generation
Prototype: Cefepime
Coverage:Maintains gram positive activity (Strep)PsuedomonasLower potential for resistance
Cefixime – oral version Good against gram negatives and StrepNo pseudomonal activity
Carbapenems
Imipenem, Meropenem, ErtapenemImipenem/Meropenem:
Staph (MSSA), Strep Anaerobic activity Gram negatives (Legionella, Chlamydia, Mycoplasma, B
cepacia, Stenotrophomonas) Pseudomonas Enterococcus faecalis but not faecium
Ertapenem Allows once a day dosing Does not cover pseudomonas
Monobactam
Prototype: AztreonamAerobic GNBPseudomonasNo gram positive or anaerobic coverage
Similar spectrum to aminoglycosides without renal toxicityCross reactivity to penicillin is rare but increases with ceftazidime
Aminoglycosides
Includes: Gentamycin Tobramycin Amikacin Streptomycin
MOA: binds to 30S/50S ribosomal subunit inhibit protein synthesis
Toxicity: CN VIII - irreversible Renal toxicity – reversible Rarely hypersensitivity reactions
Aminoglycosides
Covers:Aerobic GNB including pseudomonasMycobacteria Brucella, FranscicellaNocardiaSynergy with B-lactams (Enterococci,
Staphylococci)
Fluoroquinolones
Includes: Ciprofloxacin Ofloxacin Levofloxacin Gatifloxicin Moxifloxacin
Mechanism of Action: DNA gyrase inhibitors
Toxicity: GI symptoms
Fluoroquinolones
All cover: Mycoplasma, Legionella, Chlamydia Francisella, Rickettsia, Bartonella Atypical mycobacteria
Cipro: Good gram negative coverage Poor gram positive coverage N gonorrhea, H influenza Good for UTI, infectious diarrhea In combination for pseudomonas
Fluoroquinolones
Ofloxacin: Better gram positive coverage (Strep but min staph
coverage) No pseudomonas activity
Levofloxacin: L-entomer of ofloxacin so identical coverage Used for LRTI
Gatifloxacin: Increased activity against strep No pseudomonas activity
Fluoroquinolones
Moxifloxacin:Activity against Strep and StaphAnaerobic coverageNo pseudomonas activity
Macrolides
Includes:ErythromycinClarithromycinAzithromycin
Mechanism of Action: Binds to ribosomal subunit Blocks protein synthesis
Toxicity: GI upset (especially with erythromycin)
Erthromycin
Active against Strep spp
Also effective against: Legionella Mycoplasma Campylobacter Chlamydia N gonohhrea
Poor for H influenza
Used infrequently due to GI upset
Clarithromycin
Active against:Strep including pneumoniaeMoraxella, Legionella, ChlamydiaAtypical mycobacteriaMore active against H influenza
Used in combination against H pylori
Less GI side effects
Azithromycin
Active against:Mycoplasma, Legionella, ChlamydiaH influenzaStrep spp
Long half life
5 day course is adequate
Less GI side effects
Clindamycin
Mechanism of Action: Blocks protein synthesis by binding to ribosomal subunits
Toxicity: Rash GI symptoms C diff colitis seen in 1-10%
No gram negative or enterococcus coverage
Covers Staph spp (MSSA), Strep spp and anaerobes
Metronidazole
Mechanism not well understood
Covers: Most anaerobes except Peptostreptococci,
Actinmycetes, Proprionobacterium acnes Parasitic protozoa: Giardia lamblia, E. histolytica
Toxicity: Neutropenia Disulfuram reaction Potentiation of warfarin
Tetracyclines
Includes: Tetracycline Doxycycline Minocycline
Mechanism of Action: Binds to 30S ribosomal subunit Blocks protein synthesis
Toxicity: Rash, Photosensitivity, impairs bone growth and stains
teeth of children, increased uremia
Tetracyclines
Spectrum includes unusual organisms Rickettsia Chlamydia Mycoplasma Vibrio cholera Brucella Borreila burgdorferii
Minocycline: Active against stenotrophomonas and P acnes May be active against MRSA
Doxycycline: Used for prophylaxis against Plasmodium spp
Glycopeptides
Prototype: Vancomycin
Mechanism of Action: Inhibits cell wall synthesis
Toxicity:Ototoxicity – rareCan induce histamine release – red man
syndrome
Glycopeptides
Coverage:Gram positives: Staph (incl. MRSA), strep,
enterococcusGram positive anaerobesExceptions: VRE, Leuconostoc, Lactobacillis
Inferior to beta-lactams in terms of cure rates for beta-lactam sensitive organisms
Sulfa drugs
Includes: TMP/SMX
Mechanism of Action:Folate reductase inhibitor
Toxicity:Hypersensitivity reactionsThrombocytopenia rash
Sulfa
Coverage: Strep, Staph H influenza L monocytogenes Many GNG (E coli, Klebsiella) PCP Nocardia Isospora belli
Because of frequent allergic rxns, only used in special circumstances (eg PCP pneumonia)
Chloramphenicol
Broad spectrum activity: GPC, GNB Menigitis organisms Rickettsia spp No activity against Klesiella, Eterobacter, Serratia,
Proteus, Pseudomonas
Toxicity: Dose related marrow toxicity Idiosyncratic aplastic anemia Gray syndrome – abdominal distention, cyanosis,
vasomotor collapse (seen in liver failure pts)
Linezolid
Mechanism of Action: Binds to ribosomal subunit inhibiting protein synthesis
Oral drug
Active against: VRE, MRSA Enterococcus
No activity against gram negatives
Very expensive ($140/day) and currently not covered
Questions