Gail Itokazu, Pharm.D.
Spring 1998

General Principles - Infectious Diseases

  1. Objectives
  2. Pharmacologic Principles
  3. Antimicrobial Use
  4. Summary: Antibiotic Selection

Required Reading

  1. Barriere SL. Selection of Antimicrobial Regimens. In Pharmacotherapy: A Pathophysiologic Approach. DiPiro JT, et al, eds. Elsevier, NY, 3rd Edition, 1997. Chapter 98, pp 1953-67.

Optional Readings

The following readings are not required, but may enhance your understanding of the material in this section.

1. Hessen MT, Kaye D. Principles of selection and use of antibacterial agents. Infectious Disease Clinics of North America 1995; 9:531-45.

2. Reese RE, Betts RF. Antibiotic use. In: Reese RE, Betts RF (eds), A Practical Approach to Infectious Diseases. (4th edition). Boston: Little Brown and Company, 1996. Pp. 1059-1097.

Goal: Understand the principles of antimicrobial therapy and processes involved in selecting antimicrobial therapy.

Objectives:

  1. List 3 indications for antibiotics.
  2. Discuss the value of a gram stain.
  3. Discuss the difference between MIC and MBC.
  4. Discuss the situations in which drugs with bactericidal activity is preferable to bacteriostatic activity.
  5. Discuss the factors that limit the delivery of active drug to the site of infection.
  6. Define the post-antibiotic effect and concentration-dependent killing.
  7. Discuss how the post-antibiotic effect and concentration-dependent killing influences the dosing regimen of antibiotics.
  8. Describe the difference between additive, synergistic, indifferent, and antagonistic antibacterial activity.
  9. List 5 reasons for using a combination of antimicrobial drugs.
  10. Know the difference between colonization, contamination, self-limiting infection, and infection.
  11. Discuss the factors that need to be considered when selecting antimicrobial therapies.
  12. List 4 reasons for failure of antimicrobial therapy.

I. PHARMACOLOGIC PRINCIPLES

A. Pharmacokinetics

1. absorption of antimicrobials

2. distribution (delivery) of antibiotic to site of infection; blood, CNS, bone, urine, brain, eye, etc

Factors Limiting Delivery of Active Drug to Site of Infection

  1. protein binding - limits distribution of drug from vascular to extravascular site of infection
  2. local environment at infection site

increased pH - abscess, lung >>reduces activity of aminoglycosides

anaerobic site -aminoglycosides --> penetration into bacterial cells depends on an oxygen dependent reaction

proteins - enzymes, eg., beta-lactamases inactivate beta-lactams; bind to antibiotics

3. elimination/metabolism

renal - determine creatinine clearance -->

adjust dosage regimen for renally eliminated drugs

hemodialysis, peritoneal dialysis

hepatic - general recommendations available

B. Pharmacodynamics

1. Bacteriostatic vs Bactericidal

MIC (minimum inhibitory concentration)

several times the MIC, though sub-inhibitory concentrations may enhance phagocytosis, decrease bacterial adherence, etc.

MBC (minimum bactericidal concentration)

preferable in situations when normal host defenses are absent:

febrile neutropenic pts, endocarditis, meningitis, brain abscess, osteomyelitis caused by staphylococci

2. Post-antibiotic effect (aminoglycoside, quinolone)

persistent suppression of an organism’s growth despite drug concentrations below the MIC

with respect to the dosing regimen, drugs with a post-antibiotic effect would theoretically still be effective when given less frequently (more convenient)

3. Concentration-dependent killing (aminoglycoside, quinolone)

higher antibiotic concentrations relative to MIC of bug ---> greater rate and extent of bacterial killing

with respect to the dosing regimen, drugs with concentration-dependent killing would theoretically be more effective if higher peak levels are achieved (higher peak:MIC ratio)

4. Concentration-independent killing (beta-lactams, vancomycin)

antibiotic concentrations must always be maintained above the MIC of the bug for antibacterial activity

5. Antibiotic combinations

additive antibacterial activity: (1 + 1 = 2)

synergistic " " : (1 + 1 = 4)

indifferent " " : (1 + 1 = 1)

antagonistic " " : (1 + 1 = 0)

Rationale for Antibiotic Combinations

1. synergy

use drugs with different sites of action (cell wall active drug enhancing the penetration of intracellularly acting drug)

Pseudomonas aeruginosa, Enterococci, Staphylococcus aureus, Cryptococcus

2. prevention of emergence of resistance (tuberculosis)

3. polymicrobial infections

4. initial therapy, particularly in immunocompromised or seriously ill patient

5. minimize drug toxicity

combinations of lower doses of drugs active against the organism (cryptococcal meningitis)

II. ANTIMICROBIAL USE

A. DETERMINE NEED FOR ANTIBIOTICS

Not All Positive Cultures Require Treatment with Antibiotics

  1. Colonization vs
  2. Contaminant vs
  3. Self-limiting infection vs
  4. Infection

a. clinical/laboratory/radiologic findings

b. culture data - organism, WBCs vs epithelial cells on gram stain

eg: Staphylococcus epidermidis --> normal skin flora ---> likely contaminant if only 1 of 2 sets of blood cultures are positive and patient has no clinical/lab findings of infection

B. INDICATIONS FOR ANTIBIOTICS

  1. Documented infection - organism and site of infection known
  2. Prevention of infection - eg., surgical wound
  3. Empiric Therapy - unknown organism, site may also be unknown

antibiotic selected on basis of literature demonstrating the usual pathogens for each infection

most likely pathogen --> drug choice

eg: intravenous drug user, heart murmur --> Staphylococcus aureus endocarditis --> anti-staphylococcal drug

C. DETERMINING THE MOST LIKELY PATHOGEN

  1. Focal findings - urinary tract, respiratory tract, intra-abdominal, skin, etc.
  2. gram stain - provides early information on organism morphology, presence/absence of WBCs
  3. patient data - age, prior antibiotics, prior culture data
  4. setting - community vs hospital acquired (hospital infections associated with more resistant pathogens)

D. WHAT IS THE BEST ANTIBIOTIC FOR THE PATIENT?

1. Patient variables

a.Allergies

b.abnormal organ function (renal, hepatic, bone marrow, etc)- consider adverse effects of antibiotics

- consider need for bactericidal vs bacteriostatic agents

- consider concurrent medications and potential drug interactions

c. severity of illness

2. Antibiotic variables

a. Efficacy for infection of interest

1. antibiotic penetration

2. reduced antibacterial activity at site of infection

b. Side effects

c. Frequency of administration (compliance)

d. Available dosage forms (IV, PO, etc) for desired route of administration

e. Cost

D. MODIFICATION OF THERAPY

1. culture results

2. susceptibility to antibiotics

In-vitro vs in-vivo efficacy (limitations)

shigella - in-vitro susceptibility to amoxicillin, cephalosporins but not clinically effective

E. DURATION OF THERAPY

Variable, depends in part on the site and severity of infection, clinical response to therapy, host factors.

F. MONITORING EFFICACY/SAFETY OF THERAPY

1. clinical improvement

2. serum bactericidal titers - measures killing capacity of the patient's serum to the infecting organism; not routinely done in hospitals as test is not standardized, leading to variable results from different labs

3. antibiotic levels - aminoglycosides, vancomycin, flucytosine

G. REASONS FOR ANTIBIOTIC FAILURE

  1. Drug Selection – inability to achieve adequate drug concentrations at the site of infection (e.g., pharmacokinetic issues such as poor absorption or distribution to the site of infection or rapid drug elimination; inactivation of drug at the site of infection).
  2. Host Factors – immunocompromised patients (e.g, granulocytopenic patients, AIDS patients).
  3. Need for surgical intervention (e.g., abscess, necrotic tissue).
  4. Microbial resistance prior to starting therapy or emerging during therapy.
  5. Wrong diagnosis (e.g., patient may not have an infectious process).
  6. Errors in microbial susceptibility testing.

SUMMARY: ANTIBIOTIC SELECTION

likely bug(s) --> drug choice

1. Clinical presentation

a. site of infection - likely bug(s)

b. medical/surgical history

1. compromised versus immunocompromised patient

2. underlying conditions

3. recent antimicrobial therapy (selects for resistant bugs)

4. renal/hepatic function

5. allergies

6. concurrent medications - drug interactions

7. setting where infection was acquired

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