4. Empiric Therapy
Often microbiologic diagnosis is not
known
Decision regarding optimal empiric
treatment based on:
host factors
microbial factors
geographic factors
antimicrobial factors
5. 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?
7. 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?
8. 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
10. Renal/Hepatic Impairment
Implications for treatment:
Dose adjusting for renal impairment
Avoiding nephrotoxic drugs
Avoiding hepatotoxic drugs
Implications for monitoring:
If unavoidable
ensure good hyrdration
Monitor renal and liver function
11. Presence of Prostheses
Implications 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. Ethnicity
Consider diseases endemic in country
of origin:
Ex: TB in patients from TB endemic areas
as well as aboriginal patients
Ex: Stronglyoides in patients from tropical
countries
13. 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
14. Pregnancy
Issues of antibiotic use in pregnancy
have to be considered
Risks of transmission to baby:
HIV
GBS
HSV
Syphilis
16. Probable Organisms
Have to know most likely organisms for
various common infections:
CAP
Cellulitis
Intra-abdominal infections
Endocarditis
17. 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
18. Natural History
Rapidly fatal vs slow growing:
Ex: Meningococcemia – can be rapidly
fatal
Ex: TB meningitis often more indolent
course
HIV
Hep C
19. 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
20. Antimicrobial Factors
Site of infection
Route of Administration
Bactericidal vs Bacteristatic
Combination vs single therapy
21. Site of Infection
Susceptibility testing is geared to attainable
serum levels
Does not account for host factors or
conditions that alter antimicrobial access
Ex: 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
22. Route of Administration
Many options exist:
Enteral
Parenteral
Small particle aerosol
Intrathecal
Topical
23. Enteral Administration
Must know oral bioavailability
Must be resistant to breakdown by
gastric juices
Some drugs must be given with buffer
Some require acidity for absorption
Other drugs cannot be given in high
enough doses orally
24. 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
25. 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
26. Adjunctive Approaches
Shock and Sepsis: supportive care with fluids,
possibly steroids
Bacterial meningitis: steroids
Drainage and Debridement of abscesses
Removal of prosthetic materials
Correction of trace nutrient deficiencies
Correction of protein calorie malnutrition
Assisted organ function with ventilator,
dialysis, vasopressors/ionotropes
27. Monitoring Response to
Therapy
Certain amount of gestalt
Monitor infectious parameters: fever,
WBC, ESR etc.
Knowledge of natural history
Imaging
Repeat cultures useful in endocarditis,
complicated UTI (ie normally sterile
areas)
28. Duration of Therapy
Very few studies to establish minimum
durations of therapy
Ex. Viridans strep endocarditis:
5 days therapy: 80% failure
10 days: 50%
20 days: 2%
Duration usually based on anecdote
Most uncomplicated bacterial infections can
be treated for –14 days
4-6 weeks for endocarditis, osteo,
6-12 months: Mycobacterial diseases,
29. Pharmacoeconomics
Cost of illness includes:
Medications
Provider visits
Administration of medications
Loss of productivity
Cost is a tertiary consideration after
effectiveness and safety
34. Penicillinase Resistant
Penicillins
Protoype: Cloxacillin
Covers:
Staph spp including MSSA, 2/3 of Staph epi
Strep spp
No coverage for enterococcus
No coverage for gram negative
organisms or anaerobes
37. 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
39. 2nd Generation
Prototype: Cefuoxime
Covers:
Gram positives (Staph, Strep)
H influenza
M catarrhalis
Cefoxitin:
Some serratia coverage
Anaerobic activity
Used for intra-abdominal infection and PID
40. 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
41. 4th Generation
Prototype: Cefepime
Coverage:
Maintainsgram positive activity (Strep)
Psuedomonas
Lower potential for resistance
Cefixime – oral version
Good against gram negatives and Strep
No pseudomonal activity
42. Carbapenems
Imipenem, Meropenem, Ertapenem
Imipenem/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
43. Monobactam
Prototype: Aztreonam
AerobicGNB
Pseudomonas
No gram positive or anaerobic coverage
Similar spectrum to aminoglycosides
without renal toxicity
Cross reactivity to penicillin is rare but
increases with ceftazidime
46. Fluoroquinolones
Includes:
Ciprofloxacin
Ofloxacin
Levofloxacin
Gatifloxicin
Moxifloxacin
Mechanism of Action:
DNA gyrase inhibitors
Toxicity:
GI symptoms
47. 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
48. 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
50. Macrolides
Includes:
Erythromycin
Clarithromycin
Azithromycin
Mechanism of Action:
Binds to ribosomal subunit
Blocks protein synthesis
Toxicity:
GI upset (especially with erythromycin)
51. Erthromycin
Active against Strep spp
Also effective against:
Legionella
Mycoplasma
Campylobacter
Chlamydia
N gonohhrea
Poor for H influenza
Used infrequently due to GI upset
52. Clarithromycin
Active against:
Strep including pneumoniae
Moraxella, Legionella, Chlamydia
Atypical mycobacteria
More active against H influenza
Used in combination against H pylori
Less GI side effects
53. Azithromycin
Active against:
Mycoplasma, Legionella, Chlamydia
H influenza
Strep spp
Long half life
5 day course is adequate
Less GI side effects
54. 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
55. 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
56. 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
57. 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
61. 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)
63. 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