ANTIMICROBIAL CONCEPTS AND TIPS
Pharmacodynamics
Pharmacokinetics
versus pharmacodynamics
Pharmacokinetics mathematically
describe the relationship of antibiotic concentration to time. Terminology that is typically associated
with pharmacokinetics includes: absorption, distribution, metabolism,
elimination, half-life, volume of distribution, and area under the
concentration-time curve (AUC).
Pharmacodynamics describe the
relationship of antibiotic concentration to pharmacologic effect or
microorganism death. The three main
pharmacodynamic parameters that are used are the peak to MIC ratio (peak/MIC),
the AUC to MIC ratio (AUC/MIC), and the time the drug concentration remains
above the MIC (T>MIC).
Concentration
independent versus concentration dependent
Concentration independent (time
dependent) means that the rate and extent of microorganism killing remain
unchanged regardless of antimicrobial concentration. The pharmacodynamic parameter that is
most often predictive of outcome for concentration independent drugs is
T>MIC, although the AUC/MIC can be used because the AUC takes both the
antimicrobial concentration and time into account. Examples of concentration independent
antimicrobials include: beta-lactams, vancomycin, macrolides, aztreonam,
carbapenems, clindamycin, tetracyclines, quinupristin/dalfopristin,
flucytosine, and azole antifungals.
Concentration dependent (time
independent) means that the rate and extent of microorganism killing are a
function of the antimicrobial concentration (increase as the concentration
increases). The pharmacodynamic
parameter that is most often predictive of outcome for concentration dependent
drugs is peak/MIC, although the AUC/MIC can be used because the AUC takes both
the antimicrobial concentration and time into account. Examples of concentration dependent
antimicrobials include: fluoroquinolones, aminoglycosides, and amphotericin B.
Bacteriostatic
activity versus bactericidal activity
Bacteriostatic activity refers to
the inhibition of bacterial growth, while bactericidal activity refers to
killing the bacteria.
Minimum inhibitory
concentration (MIC)
– The MIC is defined as the lowest concentration of antibiotic that
completely inhibits growth of the specific organism being tested.
Minimum bactericidal
concentration (MBC)
– The MBC is defined as the lowest concentration of antibiotic at which
bacteria are killed.
Most of the available evidence supports the use of a
bactericidal agent when treating endocarditis or meningitis. However, data do not exist to support
this practice for other infectious diseases.
Pharmacodynamic properties do not remain constant for all
antimicrobials in a class for all microorganisms. In other words, if a drug is
concentration dependent and bactericidal against one organism, that does not
mean that it, or all the other drugs in its class, are concentration dependent
and bactericidal against all organisms.
However, because of a lack of data characterizing the pharmacodynamic
properties of various antimicrobials against several different organisms, we
usually lump antimicrobials into one category.
Vancomycin Dosing
Vancomycin is considered to be a concentration
independent or time dependent killer of bacteria. Therefore, increasing
antibiotic concentrations beyond the therapeutic threshold will not result in
faster killing or eliminate a larger portion of the bacterial population.
-
Use
Actual body weight (ABW)
-
Typical dose – 10 - 15 mg/kg
|
Estimated CrCl (mL/min) |
Initial Dosing Interval |
|
> 50 mL/min |
Q12H |
|
40-49 mL/min |
Q24H |
|
10-39 mL/min |
Q48H |
|
< 10 mL/min |
Q48-96H;As needed based on trough |
Vancomycin indications – Vancomycin is
NOT recommended for:
Routine surgical prophylaxis
Treatment of a single positive blood culture for
coagulase-negative staphylococci
Empiric therapy of a febrile neutropenic patient
where no evidence of gram-positive infection
exists
Continued empiric therapy if microbiologic
testing does not confirm an infection due to a beta-
lactam-resistant
organism
Selective gut decontamination
MRSA colonization
Primary therapy for pseudomembraneous colitis
Topical application or irrigation
Treatment of MSSA or other susceptible gram-positive infections in dialysis
patients
Prophylaxis in CAPD patients
Prophylaxis in low birth weight infants
Systemic or local prophylaxis for indwelling central or local catheters
Vancomycin levels ARE recommended in the following
settings:
Serious or life-threatening infections. TROUGH ONLY.
Patients receiving vancomycin/aminoglycoside or
vancomycin/amphotericin B
combination
therapy. TROUGH ONLY.
Anephric patients undergoing hemodialysis and receiving
infrequent doses of
vancomycin
for serious systemic infections. RANDOM TROUGH 4 hours after dialysis.
Patients receiving higher than usual doses of vancomycin
(adults: > 20 mg/kg/dose,
pediatrics: >
60 mg/kg/day). INITIAL PEAK &
TROUGH. Once therapeutic, do not repeat
levels if fluid
status and renal function are stable.
Patients with rapidly changing renal function (50%
increase/decrease or 0.5 mg/dl
increase/decrease in SCr over 24-48 hours). RANDOM TROUGH only.
Morbidly obese patients. TROUGH ONLY.
Reaffirm a seriously abnormal or unusual serum concentration
(i.e., line draws, inappropriate
times, etc.).
Neonates: a) determine a therapeutic level has been achieved
after culture results have been
reported and b)
monitor serum levels with prolonged therapy >10 days. INITIAL: PEAK
AND TROUGH;
TROUGH ONLY after therapeutic levels achieved for prolonged
administration
with stable renal function.
Patients receiving prolonged (>14 days) vancomycin
therapy. TROUGH ONLY.
Monitoring
is NOT recommended in the following settings:
Patients treated for less than five days.
Patients receiving oral vancomycin.
Patients with stable renal function who are treated for up
to 14 days for mild to moderate
infections.
Drug level recommendations
|
Drug |
|
Time to Obtain |
Therapeutic Range |
Hospital Cost |
|
Vancomycin * levels
not routinely recommended * |
Trough |
½
hour before infusion |
5-15
mcg/mL |
$9.71 |
|
Peak |
1 hour
after infusion |
25-40
mcg/mL |
$9.71 |
Aminoglycoside Dosing
Aminoglycosides are concentration dependent antibiotics,
meaning that as aminoglycoside concentration increases, the rate and extent of
bacterial killing increases. Presently, investigators suggest optimizing the
aminoglycoside peak serum concentration to bacterial MIC ratio (Peak/MIC) to a
value ≥ 10:1.
Aminoglycoside levels should be obtained according to the
following guidelines (not for extended interval/once daily dosing):
a.
Patient not responding to therapy as expected.
b. Suspected
toxicity (oto- or nephro-) or patient has a change in or impaired renal
function while on maintenance therapy.
c. Reaffirm
a seriously abnormal or unusual serum concentration (i.e., potential line
draws, inappropriate times, etc.)
d. To
determine that a therapeutic level has been achieved after culture results have
been reported and the decision to continue the aminoglycoside has been made.
e. Initial
dosage check for prophylactic or empiric therapy in neutropenic patients or
suspected Pseudomonas infections
(i.e., cystic fibrosis or ventilator-dependent patients).
f. Weekly
monitoring of prolonged therapy with aminoglycosides.
Desired Levels for Various
Infections
Cost to the institution for an aminoglycoside level
gentamicin à $10.43
tobramycin à $13.75
amikacin
à
$15.78
|
Desired Peak |
Desired Trough |
|
|
Gentamicin/
Tobramycin |
|
|
|
Synergy
(Gram-positives) |
3-5 |
<1 |
|
UTI,
endometriosis, pyelonephritis |
4-6 |
<1 |
|
Tissue
Infections, pneumonia, sepsis* |
6-8 |
<2 |
|
Cystic
Fibrosis |
10-12 |
<1 |
|
Amikacin |
|
|
|
Moderate
Infections |
15-25 |
<5 |
|
Severe
Infections |
25-40 |
<10 |
*For more
severe infections, such as pneumonia or sepsis, we usually recommend pushing the
peak more towards 8 mcg/mL due to penetration issues and better outcomes shown
with higher peaks.
Once Daily Dosing – The theories behind once
daily dosing (ODA) include:
a. Aminoglycosides
have concentration dependent activity.
The rate of bacterial killing increases as drug concentration is
increased. As stated previously,
investigators suggest optimizing the aminoglycoside peak serum concentration to
bacterial MIC ratio (Peak/MIC) to a value ≥ 10:1 to maximize bacterial
killing.
b. The
combination of a high peak and an “aminoglycoside-free” interval
will help to reduce the selection and the emergence of resistant organisms (by
eliminating the adaptive resistance phenomena), and minimize
aminoglycoside-associated toxicity.
c. A
high peak concentration of aminoglycosides leads to a longer duration of
post-antibiotic effect (PAE).
d. Exclusion criteria - pregnancy,
breastfeeding, burns (>20%), ascites, cystic fibrosis, cirrhosis, dialysis,
solid organ transplants, neutropenia, endocarditis, and CrCl < 20
mL/min. PLEASE NOTE: Once daily
dosing should be considered in all patients for which an aminoglycoside is
ordered for a suspected or documented Gram-negative rod infection, except for
those that meet the exclusion criteria.
ODA Dosing Guidelines
-
Use
Actual body weight (ABW)
-
If
patient is obese (>20% over ideal body weight - IBW) use dosing body weight
(DBW)
DBW
= IBW + [0.4 (ABW - IBW)]
-
Tobramycin/ gentamicin - dose at 4 to 7
mg/kg
-
Amikacin
– dose at 15 mg/kg
-
|
Estimated CrCl (mL/min) |
Initial Dosing Interval |
|
> 60 mL/min |
Q24H |
|
40-59 mL/min |
Q36H |
|
20-39 mL/min |
Q48H |
|
< 20 mL/min |
Not recommended |
ODA
Therapeutic Monitoring and Dose Adjustment
Levels should be obtained only in the following situations:
-
Random
serum level 10-12 hours after the start of the infusion of
the first dose to confirm appropriate serum level.
-
Confirm
an appropriate serum concentration after dosage adjustment.
-
Suspected
toxicity (oto- or nephro-) or when there is a change in or impaired renal
function while on maintenance therapy.
-
Reaffirm
a seriously abnormal or unusual serum concentration (i.e., potential line
draws, inappropriate times, etc.)
-
Weekly
monitoring of prolonged therapy with aminoglycosides
-
Dosage
adjustments should be made according to the Hartford Nomogram (see below).
-
Important Notes:
-
Because
the Hartford Nomogram was based on a dose of 7mg/kg, if a lower dose is being
used, the resultant level should be multiplied by a factor equal to 7 mg
divided by the dose used. Example:
If a patient is receiving 5mg/kg/day and the 10h post-dose level was 2 mcg/mL,
you would multiply the level by 1.4 (7/5) to give a level of 2.8 mcg/mL. This adjusted level is the one you would
plot on the
-
If
using amikacin, plot ½ of the serum concentration on the nomogram.
-
If
the level falls on the line, choose the longer interval for
administration.
-
If
the aminoglycoside level falls off the nomogram, traditional dosing should be
used.
Double coverage
Gram-negative Bacteria
The use of double coverage (two
antibiotics used to provide coverage for the same organism) relies on the
following principles: the combination provides a broad spectrum of coverage for
empiric treatment, before you know the identification and susceptibility of the
offending pathogen; the combination may provide additive or synergistic effects
against the pathogen; the combination of antibiotics may decrease or prevent
the emergence of resistant bacteria.
Inappropriate initial therapy has
been shown to cause increased morbidity and mortality, specifically related to
Gram-negative infections (usually Pseudomonas
and Acinetobacter spp.). Thus, double coverage serves the purpose
of providing broad spectrum initial empiric coverage. Of note, once culture identification and
susceptibilities have been reported, de-escalation is recommended. Once a causative pathogen is identified
and susceptibilities are reported, no evidence exists to support that
combination therapy is more effective than monotherapy.
Several studies have evaluated
various antibiotic combinations, usually a β-lactam and an aminoglycoside,
for the treatment of Gram-negative infections. Most of these studies have found no
differences between various regimens in terms of clinical and microbiologic
outcome as well as mortality rates.
Anaerobes
No data exist to support the use of
double coverage for anaerobic infections.