Antibiotic choices

1. Antibiotic Choices

2. Outline
General Considerations:
Host Factors
Geographic Considerations
Microbial Factors
Antimicrobial Factors
Adjunctive Approaches
Pharmacoeconomics

3. Outline
Review of antibiotic classes:
Beta-lactams
Macrolides
Fluoroquinolones
Aminoglycosides
Lincosamides
Tetracyclines
Others: vancomycin, metronidazole,
chloramphenicol, linezolid

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?

6. Host Factors
Age
Immune adequacy
Underlying diseases
Renal/hepatic impairment
Presence of prosthetic materials
Ethnicity
Pregnancy

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

9. Underlying Disease
Diabetes
Transplant
HIV
Cancer
Renal impairment
Autoimmune diseases

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

15. Microbial Factors
Probable organisms
Probable susceptibility patterns
Natural history of infections
Likelihood of obtaining good
microbiologic data
Site of Infection

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,
endemic mycoses

29. Pharmacoeconomics
Cost of illness includes:
Medications
Provider visits
Administration of medications
Loss of productivity
Cost is a tertiary consideration after
effectiveness and safety

30. Antibiotics: drugs for bugs

31. 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 1
st
generation cephalosporins
1% x-reactivity with 3
rd
generation cephalosporins

32. 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

33. Aminopenicillins
Prototypes: Ampicillin, Amoxicillin
Covers:
Strep spp
Does not cover enterococcus
Spectrum extended to include some
GNB:
E. coli, Proteus mirabilis, Salmonella spp,
Shigella, Moraxella, Hemophilus spp

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

35. Carboxypenicillins
Prototype: Ticarcillin
Covers:
Covers Stenotrophomonas, Pseudomonas
Problems with hypernatremia,
hypokalemia, platelet dysfunction

36. Ureidopenicillins
Prototype: Piperacillin
Covers
Strep spp (less than earlier generations)
Enterococcus
Anaerobic organisms
Pseudomonas
Broad Gram negative coverage
If tazobactam added – increases Staph
coverage and anaerobic coverage

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

38. 1
st
Generation
Prototype: Cefazolin
Covers:
Staph spp (MSSA)
Strep spp
E. coli, Klebsiella, Proteus mirabilis
No anaerobic activity

39. 2
nd
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. 3
rd
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. 4
th
Generation
Prototype: Cefepime
Coverage:
Maintains gram 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
Aerobic GNB
Pseudomonas
No gram positive or anaerobic coverage
Similar spectrum to aminoglycosides
without renal toxicity
Cross reactivity to penicillin is rare but
increases with ceftazidime

44. 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

45. Aminoglycosides
Covers:
Aerobic GNB including pseudomonas
Mycobacteria
Brucella, Franscicella
Nocardia
Synergy with B-lactams (Enterococci,
Staphylococci)

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

49. Fluoroquinolones
Moxifloxacin:
Activity against Strep and Staph
Anaerobic coverage
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

58. Glycopeptides
Prototype: Vancomycin
Mechanism of Action:
Inhibits cell wall synthesis
Toxicity:
Ototoxicity – rare
Can induce histamine release – red man
syndrome

59. Glycopeptides
Coverage:
Gram positives: Staph (incl. MRSA), strep,
enterococcus
Gram positive anaerobes
Exceptions: VRE, Leuconostoc, Lactobacillis
Inferior to beta-lactams in terms of cure
rates for beta-lactam sensitive
organisms

60. Sulfa drugs
Includes: TMP/SMX
Mechanism of Action:
Folate reductase inhibitor
Toxicity:
Hypersensitivity reactions
Thrombocytopenia
rash

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)

62. 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)

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

64. Questions