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FLUOROQUINOLONES
While fluoroquinolones are considered concentration-
dependent antibiotics, the maximum dose that can be
safely administered is limited by dose-related central
nervous system toxicity, thus a Cmax/MIC of 10 to 12
cannot be achieved against many pathogens, and the time
that concentrations are maintained above the MIC must
be considered to maximize response. Therefore, in many
pharmacodynamic studies, the bactericidal effect has been
correlated with AUC/MIC (21). Against Gram-negative
bacteria, a total AUC/MIC≥125 is most often quoted as being
required for maximal effect, while Gram-positive bacteria,
such as Streptococcus pneumoniae, require a free AUC/
MIC≥30 (22,23). It is important to consider, however, which
fluoroquinolone was used in each pharmacodynamic study
since protein binding varies substantially across agents and
therefore, the total AUC/MIC targets may be different. In
a study of 74 patients receiving ciprofloxacin for serious
nosocomial infections predominantly due to Gram-negative
bacteria, a total AUC/MIC below 125 was associated with
a lower probability of clinical and microbiologic response
(22). Additionally, an AUC/MIC above 125 and above 250
were significantly associated with shorter median times
to eradication (AUC/MIC<125:32 days, 125-250:6.6 days,
>250:1.9 days, p< 0.005). Correcting for ciprofloxacin protein
binding of 40%, the ƒAUC/MIC threshold would be ~75. In
another study, a levofloxacin total drug AUC/MIC exposure
≥87 was prospectively determined to be predictive of
eradication in 47 patients with nosocomial pneumonia (24).
Correcting for levofloxacin protein binding, the ƒAUC/MIC
target would be ~65, a value quite similar to the exposure
required for ciprofloxacin against Gram-negative bacteria.
Although fluoroquinolones are widely prescribed antibiotics,
from a pharmacodynamic perspective, they are unable to
achieve optimal pharmacodynamic exposure at standard
dosages for not only bacteria considered resistant, but
also a number of bacteria that the microbiology laboratory
would classify as susceptible. This is a result of a higher
than acceptable breakpoint used to define susceptibility for
Gram-negatives (≤1mg/L for ciprofloxacin and ≤2mg/L for
levofloxacin). Pharmacodynamic simulation studies suggest
the proper breakpoints should be 0.25mg/L and 0.5mg/L,
respectively, which would significantly increase resistance
rates further at most hospitals, particularly against
P. aeruginosa (25). As a result, even aggressive regimens
such as ciprofloxacin 400mg every 8 hour and levofloxacin
750mg every 24 hour have achieved low probabilities of
attaining the required pharmacodynamic exposure against
Gram-negative bacteria. The empiric use of the antibiotics
as monotherapy for Gram-negative infections should be
discouraged unless MIC data suggests adequate exposure
is feasible.
GLYCOPEPTIDES (VANCOMYCIN)
Although vancomycin success for Gram-positive infections
has historically been thought to be associated with trough
values, and thus T> MIC, contemporary data suggests
that the AUC/MIC ratio best predicts outcomes for this
time-dependent antibiotic (26). Studies in patients with
pulmonary infections caused by S. aureus observed that
vancomycin response was associated with a total drug
AUC/MIC> 345, and microbiological eradication was
associated with an AUC/MIC >400. Alternative supportive
data are provided by studies suggesting that clinical
responses in S. aureus bacteremia were poor when the MIC
was >1mg/L; at this MIC, the standard vancomycin dose (1g
every 12 hours) does not attain these AUC/MIC exposures
in patients with normal renal function. A consensus
statement from the Infectious Diseases Society of America
(IDSA), Society of Infectious Diseases Pharmacists (SIDP),
and American Society of Health-Systems Pharmacist
(ASHP) recommended that a loading dose of vancomycin
be administered, particularly in critically ill patients,
followed by doses of 30mg/kg daily to achieve troughs of
15 to 20mg/L (26). However, in clinical scenarios where
the vancomycin MIC was 2mg/L without clinical response,
strong consideration for switching to an alternative
antibiotic was suggested. The challenge with optimizing
vancomycin based on the AUC/MIC ratio is 2 fold. First,
to estimate an accurate AUC, multiple concentrations
throughout the dosing interval are required; a trough alone
or peak alone strategy to estimate AUC underestimated
exposure by 23% and 14%, respectively (27). An approach
that uses a single trough value, or multiple (at least 2
samples over the dosing interval) concentrations, combined
with Bayesian estimation of the AUC was significantly
better at predicting the true AUC (~97% accurate). The
second challenge lies with the MIC test itself. The error in
accurate determination of the MIC is permitted to be 100%
in either direction, meaning that an MIC of 1mg/L is the
same as 0.5 and 2mg/L, thereby providing a 4 fold range in
potential exposures. A patient who achieves a 24 hour AUC
of 400mg*h/L infected with a bacteria reported as an MIC
of 1mg/L may actually have an AUC/MIC exposure between
200 and 800 based on variability of the MIC alone. As a
result, the IDSA MRSA guidelines emphasize assessment of
the patient response to therapy (28). Despite these well
documented challenges, vancomycin remains the gold
standard for the treatment of MRSA infections.
GLYCYLCYCLINES (TIGECYCLINE)
Tigecycline, the first member of the glycylcycline
antibiotic class, portrays time-dependent activity, and
the pharmacodynamic target most closely associated
[OPTIMIZING ANTIMICROBIAL PHARMACODYNAMICS: A GUIDE FOR YOUR STEWARDSHIP PROGRAM - Joseph L. Kuti, PharmD]