PHARMACOKINETIC ALTERATIONS OF ANTIMICROBIALS
COOK
10.1177/0897190004273568
Pharmacokinetic Alterations
of Antimicrobials in the Critically Ill
Aaron M. Cook, PharmD
Critical illness is accompanied by multiple physiologic alter-
ations that affect the pharmacokinetics of antimicrobials. Al-
though the pharmacokinetics of a number of antimicrobials
have been studied in critically ill individuals, an understand-
KEY WORDS: Pharmacokinetics, antimicrobials, critical illness, adult.
C RITICAL ILLNESS IS OFTEN CAUSED by a sys-
temic inflammatory reaction due to trauma, acute
organ failure, thrombosis, or infection that results in
multiple organ dysfunction and, if left unabated, death.
Layered into the pathophysiology are preexisting
chronic diseases that may also affect the interaction of
various organ systems. In this complex setting, the
pharmacokinetics of commonly used medications may
be altered due to a range of factors including variable
gastrointestinal absorption, cardiac output, plasma
protein binding, hepatic metabolism, or renal function.
As a result, the use of standard doses of medications
may lead to therapeutic failure due to underdosing or,
conversely, toxic accumulation. The subject of the
present review is the effect of critical illness on the
pharmacokinetics of antimicrobial agents and the im-
plications of such alterations on the treatment of infec-
tions in the intensive care unit (ICU). Clinicians must
have a sound knowledge of the pharmacokinetic alter-
ations encountered in the critically ill to ensure safe
and effective use of antimicrobials in this population.
SIGNIFICANCE OF INFECTIONS IN THE ICU
Successful treatment of infections is of paramount
importance to the outcome of critically ill individuals.
Community-acquired infection, such as sepsis or
pneumonia, is often the principal reason for critical ill-
ness and admission to an ICU. As patients convalesce
in the ICU, the risk of acquiring a nosocomial infection
increases. Although the typical bacterial pathogens as-
sociated with community- and hospital-acquired in-
fections are quite different, several principles of suc-
ing of the physiological alterations in critical illness and gen-
eral pharmacokinetic principles of antimicrobials is impera-
tive for appropriate selection, dosing, and prediction of
toxicity.
cessful treatment are common to both. Adequate em-
piric coverage of potential pathogens, effective drug
dosing, sufficient tissue penetration, suppression of re-
sistant organisms or superinfection, and avoidance of
toxicity are all significant factors that affect morbidity
and mortality due to infection in critically ill patients.
BASICS OF PHARMACOKINETICS
In reviewing the pharmacokinetic parameters of a
given agent, one commonly considers several different
aspects of a medication’s journey into, through, and out
of the body. First is absorption. Orally or enterally ad-
ministered medications must be well absorbed and
achieve adequate serum concentrations to be used reli-
ably in critically ill patients. Multiple factors specific
to critical illness and certain antimicrobials can de-
crease absorption. Second is distribution. Tissue pene-
tration is of paramount importance for successful treat-
ment of infections in the critically ill, which often
originate in lung, skin, and soft tissue. Third is metabo-
lism or biotransformation. While the therapeutic bene-
To whom correspondence should be addressed: Aaron M. Cook,
PharmD, University of Kentucky Chandler Medical Center, 800
Rose St. C-117, Lexington, KY 40536-0293; e-mail: amcook0@
email.uky.edu.
Aaron M. Cook, PharmD, clinical pharmacy specialist in Neurosur-
gery/Critical Care and adjunct assistant professor in Pharmacy,
University of Kentucky Chandler Medical Center, Lexington.
JOURNAL OF PHARMACY PRACTICE 2005. 18;2:75–83
© 2005 Sage Publications
DOI: 10.1177/0897190004273568
 COOK
fit of many commonly used antimicrobials is not signif-
icantly affected by altered metabolism, there are
exceptions in which diminished metabolism could
have deleterious consequences. Last is elimination or
excretion. Elimination is governed by several systems
including pulmonary, renal, hepatic, lymphatic, and
gastrointestinal. Antimicrobials are typically most
affected by changes in renal and hepatic elimination.
The pharmacokinetic alterations that are exhibited
in critical illness are varied and are highly dependent
on the phase of illness. Very early in the course of criti-
cal illness, patients may lack adequate cardiac output
and/or intravascular volume and thus exhibit poor end
organ perfusion (decreasing tissue perfusion and meta-
bolic and excretion capacity). After fluid resuscitation
and/or application of vasopressors/inotropes, patients
often exhibit exaggerated end organ perfusion and in-
creased tissue perfusion, metabolic capacity, and elim-
ination. Later in the course of treatment, patients who
do not clinically improve may ultimately develop pro-
gressive or permanent organ dysfunction, causing me-
tabolism and elimination to return to a state of dimin-
ished activity. Variation in these phases of critical
illness should be considered when evaluating the cur-
rently available literature investigating pharmacokin-
etic alterations of antimicrobials in the critically ill.
Each study should be evaluated individually. The
reader is referred to several other excellent reviews re-
garding pharmacokinetics of antimicrobials and other
medications in critically ill individuals.1-3
ABSORPTION
The role of the gastrointestinal (GI) tract in critical
illness has changed in recent years.4 In the past, many
practitioners were content to bypass the GI tract as an
option for administering medications or nutrition. The
availability of parenteral nutrition, the presence of gas-
tric dysmotility and subsequent relative lack of success
with nasogastric feeding, and the paucity of potent oral
antimicrobial agents rendered the use of the enteral
route seemingly undesirable and unimportant.5 How-
ever, new information, techniques, and medications
are now available that have changed the way in which
the GI tract is used in the critically ill. It is now evident
that enteral nutrition has many advantages over
parenteral nutrition and is well tolerated in most criti-
cally ill individuals.6 Increased comfort and success
with enteral nutrition has made the provision of early
enteral access a common intervention. Thus, the op-
portunity to initiate enteral administration of anti-
microbials has become nearly universal in most ICUs.
However, in critical illness, several factors affect the re-
76 • JOURNAL OF PHARMACY PRACTICE 2005(18.2)
liable absorption of medications from the GI tract
including bioavailability, drug-drug interactions, GI
dysmotility, edema associated with fluid resuscitation,
and shunting of GI perfusion due to hypotension or
vasoactive agents. All of these factors should be consid-
ered to ensure reliable enteral absorption of
antimicrobials.
Drug-nutrient and drug-drug interactions that alter
the absorption of antimicrobial agents can have a major
impact on therapeutic response. Concomitant admin-
istration of ciprofloxacin with continuous enteral feed-
ings via nasogastric tube decreased ciprofloxacin bio-
availability by a median of 44% (range, 31%-82%) in
one study of 12 critically ill individuals.7 This study
demonstrates the potential of concomitant enteral
feedings to chelate ciprofloxacin and diminish absorp-
tion. However, another study of 5 critically ill patients
with intra-abdominal infections demonstrated equiva-
lent area under the concentration-time curve (AUC;
over 12 hours), despite continuous nasogastric or naso-
duodenal enteral feedings.8 The variation in results of
these 2 studies may be due to the difference in enteral
formulas used (administration rates, concentration of
divalent cations), the route of administration (stomach
or duodenum), and patient variability (wide range of
creatinine clearances and weights). Similar results
have been shown when combining ciprofloxacin with
antacids containing polyvalent cations (aluminum,
magnesium, calcium) used for stress ulcer prevention.
Other agents such as levofloxacin, linezolid, and fluco-
nazole are much more reliably absorbed, even in the
presence of enteral feedings.9-11
Gastric dysmotility occurs often in critically ill pa-
tients. Catecholamines and overactivation of the sym-
pathetic nervous system can cause impaired gastric
emptying, likely by overriding vagal tone.12,13 Opioids
are often used for sedation in critically ill patients. Di-
minished GI motility is a common adverse effect of
these agents, particularly when used over long dura-
tions or at high doses. Vigorous fluid resuscitation may
result in edematous bowel and resulting diminished
motility and absorptive capacity. Hyperglycemia has
also been shown to decrease gastric emptying. Orally
or enterally administered antimicrobials may exhibit
erratic absorption in patients with gastric dysmotility
due to high gastric residual volumes and impaired gas-
tric emptying into the small intestine. Prokinetic
agents such as metoclopramide, erythromycin, or
naloxone may be helpful in some patients to enhance
gastric emptying.14-16 However, use of these agents to
increase absorption of antimicrobials is unproven. Tol-
erance of enteral nutrition, gastric residual volume,
and overall clinical status should be considered before
 PHARMACOKINETIC ALTERATIONS OF ANTIMICROBIALS
administering antimicrobials orally or enterally in crit-
ically ill patients.
In the early stages of shock, the perfusion pressure of
peripheral organs, such as the kidneys, GI tract, and
liver, may be decreased as the body attempts to maxi-
mize oxygen delivery to “more essential” organs (the
heart and brain). As a result, many critically ill individ-
uals require vasopressors to maintain adequate organ
perfusion pressure. Diminished blood flow to the GI
tract may affect the absorption of antimicrobials. Al-
though there is a wealth of evidence currently available
regarding the effects of vasopressors on splanchnic per-
fusion, the results of these studies vary widely and are
often contradictory. It appears that vasopressors such
as norepinephrine, dopamine, and vasopressin can de-
crease splanchnic perfusion. However, evidence also
exists to suggest that these agents may increase
splanchnic perfusion. In all, the effects of vasopressors
are likely highly dependent on several factors includ-
ing the extent of vasodilatation, intravascular volume,
cardiac output, and the dose of vasopressor used. Pa-
tients with adequate intravascular volume, cardiac
output, and splanchnic vascular tone are likely to have
more reliable GI perfusion and absorption.
The absorption of several commonly used anti-
microbial agents has been investigated in critically ill
patients. Rebuck et al reported the results of 10 criti-
cally ill patients receiving levofloxacin (and no enteral
nutrition).17 The levofloxacin peak serum concentra-
tion was significantly lower than with the same 500-mg
dose given intravenously (7.3 mg/L vs 5.5 mg/L, P <
.0001), but the AUC (62.4 mg•h/L vs 60.3mg•hr/L) and
absolute bioavailability (95%) were similar. The
pharmacokinetic parameters in critically ill patients af-
ter oral dosing were also very similar to that seen with
oral dosing in healthy volunteers in a previous study.
Peak serum concentrations, AUC, and exudate concen-
trations of fluconazole were comparable in 9 GI surgery
patients receiving 400 mg enterally (compared to 14
patients receiving 400 mg intravenously).10 Nine hospi-
talized patients received linezolid 600 mg with enteral
feedings, and although peak serum concentrations
were less than when compared to intravenous dosing
(17.27 mg/L vs 11.29 mg/L), the bioavailability was
equivalent.11 The use of vasopressors is inconsistently
reported in all of these studies, so the effects of vaso-
active agents on absorption remain ill defined. How-
ever, the results of these studies also suggest that levo-
floxacin, fluconazole, and linezolid are well absorbed,
even in patients with potentially compromised GI
function, and they appear to yield serum concentra-
tions that are likely to be therapeutic.
Despite the potential for variable bioavailability of
enterally administered antimicrobials, much of the
available clinical evidence supports the use of this
route for critically ill patients. Many institutions have
developed successful intravenous to oral (IV to PO)
conversion programs, particularly for disease states
such as community-acquired pneumonia, to decrease
length of stay and medication costs without adversely
affecting treatment outcomes.18,19 Most commonly,
agents such as azithromycin and levofloxacin are used.
A successful IV to PO conversion program will account
for the various factors that may alter absorption in criti-
cally ill patients, the patient’s clinical response, and
prudent antimicrobial selection to ensure optimal
treatment of the infection.
DISTRIBUTION
The systemic distribution of an antimicrobial is of-
ten an oversimplified phenomenon. A common model
used to describe distribution is the 2-compartment
model, which involves addition of a drug to a central
compartment and distribution to a generic tissue com-
partment. In reality, distribution of most antimicrobials
during critical illness is not a uniform diffusion into a
single tissue compartment. Rather, it is the combina-
tion of many factors including the physiochemical
characteristics of the agent, plasma protein binding, af-
finity for different tissue types (adipose, muscle, brain,
etc), tissue perfusion, and the phase of critical illness.
A detailed description of distribution into the brain
and central nervous system (CNS) is beyond the scope
of the current review. The reader is referred elsewhere
in this supplement for a description of pharmaco-
kinetic issues related to treating CNS infections.
The systemic inflammatory response syndrome
(SIRS) commonly manifest in critically ill patients is
associated with an increase in extravascular fluid vol-
ume. This phenomenon, so-called “third spacing,” is
partially due to the release of cytokines as a result of
trauma, burns, or sepsis.20-22 Cytokines alter the normal
capillary permeability, allowing leakage of protein and
other oncotic molecules and obligatory fluid flux into
the extravascular space.23 In addition, hypoalbumin-
emia is common in critical illness due to decreased
hepatic albumin synthesis and increased extravascular
deposition. The subsequent relative lack of colloid
oncotic pressure in the intravascular space allows in-
creased efflux of plasma volume into the interstitial
space, causing edema. Vigorous fluid resuscitation can
further contribute to peripheral and pulmonary edema
due to the high volume of fluid that is typically re-
JOURNAL OF PHARMACY PRACTICE 2005(18.2) • 77
 COOK
quired to maintain intravascular volume and organ
perfusion. As a result, the volume of distribution of
medications that are contained primarily within the
intravascular space (aminoglycosides24,25) or that are
highly plasma protein bound (ceftriaxone26) increases.
Gentamicin volume of distribution was increased in a
hyperdynamic septic group of subjects (0.48 L/kg)
compared to controls (0.29 L/kg). 27 Similarly,
ceftriaxone also exhibits an elevated volume of distri-
bution in critical illness (0.36 L/kg vs approximately
0.173 L/kg in normal volunteers).26 Thus, the dose
required to achieve therapeutic serum concentrations
may be greater in critically ill patients with SIRS and
edema.
Hypoalbuminemia may also affect the tissue distri-
bution of antimicrobials by a separate mechanism. Un-
der normal circumstances, only the free (unbound)
fraction of the drug is available to enter the interstitial
space and interact with target tissue. However, this
principle may not be entirely accurate in critical ill-
ness. Although total tissue drug concentrations may be
elevated because of capillary permeability and third
spacing, agents that are highly plasma protein bound
may exhibit increased binding in the interstitial space
due to concomitant leakage of albumin.28 Thus, the to-
tal tissue concentrations are elevated, but an abnor-
mally high percentage of the interstitial drug is bound
(pharmacologically inactive).
The general concepts described above may predict
the extent of tissue penetration for many antimicro-
bials. However, to further define the penetration of spe-
cific agents in target tissues, techniques such as micro-
dialysis, bronchial alveolar lavage (BAL), and tissue
excision have been increasingly used. These tech-
niques not only demonstrate the tissue concentrations
in relation to the serum concentration but also give in-
sight to the rate of elimination from the tissue and clini-
cal factors that may influence the accumulation of drug
in the target tissue.
Variable tissue penetration has been reported for β-
lactams such as piperacillin and imipenem. Pipera-
cillin skeletal muscle distribution was significantly
lower in patients after aortic valve surgery than in
healthy volunteers (AUCtissue to AUCfree serum ratio of 0.27
vs 1.22, respectively). 29 However, piperacillin/
tazobactam lung distribution was more similar to se-
rum in 5 critically ill patients with sepsis and pneumo-
nia (AUCtissue to AUCfree serum ratio of 0.63), and tissue
concentrations were above the minimum inhibitory
concentration (MIC) of typical gram-negative patho-
gens for 2 to 6 hours of the dosing interval.30 The con-
founding factors in these 2 reports are many, including
the severity of illness of the patients, the method of
78 • JOURNAL OF PHARMACY PRACTICE 2005(18.2)
sample collection, piperacillin dosing, and the loca-
tion of the tissue sampled. However, the results
highlight the importance of investigating tissue con-
centrations during critical illness rather than merely
extrapolating serum concentrations to approximate
tissue distribution.
The tissue concentrations of imipenem appear to be
reduced during critical illness.31 Six critically ill pa-
tients received standard doses of imipenem, each hav-
ing end organ dysfunction (renal, hepatic, or respira-
tory), and 4 patients required vasoactive agents to
maintain blood pressure. Despite similar serum AUC
values obtained in healthy volunteers and critically ill
patients, the muscle and subcutaneous concentrations
of imipenem were markedly different. The serum to tis-
sue AUC ratio was 2 for muscle and 2.3 for subcutane-
ous tissue in healthy volunteers. However, in critically
ill individuals, this ratio increased to 9 and 7.1, respec-
tively. Although the serum concentrations in critically
ill individuals were above the typical MIC breakpoint
for susceptible gram-negative bacteria (4 µg/mL) for ap-
proximately 75% to 100% of the dosing interval, tissue
concentrations exceeded 4 µg/mL in only 1 patient for
only a fraction of the dosing interval (30 minutes). Sim-
ilar diminished tissue penetration of imipenem has
also been demonstrated in pancreatitis and pneumo-
nia.32,33 Although considerable variability exists in
these studies with regard to patient selection (severity
of illness, weight, renal function), the tissue type, and
the method of measuring tissue concentrations, it is
apparent that the extent of imipenem tissue penetra-
tion is decreased in critical illness despite seemingly
therapeutic serum concentrations.
In contrast to the variability with the above β-lactams,
the fourth-generation cephalosporin cefepime has dem-
onstrated consistent, extensive tissue penetration.
Cefepime concentrations in lung parenchyma were
compared to serum concentrations obtained in 16 pa-
tients undergoing surgery.34 Lung concentrations were
similar to serum at all time points and were above the
MIC breakpoints of gram-negative pathogens for the
majority of the dosing interval. Similar extensive pene-
tration was demonstrated when administering contin-
uous infusion cefepime to critically ill patients with
pneumonia. The mean epithelial lining fluid (ELF)
cefepime concentration was 14.1 µg/mL (vs 13.5 µg/mL
serum).35 Based on these results, it appears that
cefepime penetrates the lung tissue quite well, largely
due to the fact that it is a zwitterion and rapidly pene-
trates tissue without a lag time, allowing tissue concen-
trations to mirror serum concentrations.
The tissue penetration of aminoglycosides has also
been studied in critically ill individuals. Sixteen pa-
 PHARMACOKINETIC ALTERATIONS OF ANTIMICROBIALS
tients receiving tobramycin (multiple daily dosing) for
pneumonia underwent a BAL after the systemic
tobramycin concentrations had reached steady state.36
The maximum ELF concentrations were 2.33 mg/L at
30 minutes after the dose. The ELF to serum concentra-
tion ratio progressively increased throughout the dos-
ing interval (from 0.3 to 1.53), indicating slower
tobramycin clearance from the tissue and the potential
for tobramycin accumulation in the alveoli after re-
peated dosing. It is unclear whether the higher serum
concentrations obtained with extended-interval dosing
of aminoglycosides will achieve proportionally higher
tissue concentrations. This is a particularly important
piece of information because the MIC breakpoint for
susceptibility of many nosocomial gram-negative
pathogens to tobramycin is ≤2 µg/mL (≤4 µg/mL for
Pseudomonas species). A peak concentration to MIC
ratio of 8 to 10 is generally thought to maximize bacteri-
cidal activity of aminoglycosides.37 Such high concen-
trations of aminoglycosides are difficult to obtain in
most tissues because this class of agents tends to be ion-
ized at human pH and therefore do not pass easily
through lipid membranes, relying primarily on porous
membrane integrity, minimal bulk flow, and possibly
cation transport pumps to enter tissues. Despite appar-
ent pharmacokinetic and pharmacodynamic short-
comings, aminoglycosides continue to be used suc-
cessfully (in combination with other active agents) for
severe infections.
Fluoroquinolones are commonly suggested to have
enhanced tissue penetration due to their relatively large
volume of distribution in healthy volunteers and high
lipophilicity in vivo.38,39 However, the volumes of dis-
tribution of levofloxacin (1.19 L/kg vs 0.94 L/kg nor-
mal)17,40 and ciprofloxacin (1.4 L/kg vs 2.4 L/kg
normal)41,42 demonstrate marked variability in critical
illness. Skeletal muscle exposure of levofloxacin in
septic patients is comparable to that found in the serum
(AUCtissue to AUCfree serum ratio of 0.85).43 However, in an
in vitro model using dynamic concentrations found in
the skeletal muscle, levofloxacin did not adequately
inhibit growth of Pseudomonas aeruginosa (MIC = 2
µg/mL) for nearly all patients. Higher doses of levo-
floxacin (≥750 mg) or combinations with other active
agents have been suggested to ensure therapeutic tis-
sue concentrations.44 Ciprofloxacin concentrations in
burn eschar tissue were greater than that found in the
serum (Cmax = 4.9 µg/mL, AUC24-36 = 17.5 mg•h/L vs
eschar 18 µg/g), even though perfusion of eschar tends
to be lower than normal soft tissue.45 The persistence of
adequate concentrations may be due to decreased elim-
ination from the target site. It is also important to re-
member in the treatment of intracellular pathogens
that fluoroquinolones tend to accumulate in high con-
centrations in immune cells such as macrophages.46
For these infections, serum, and even tissue, concen-
trations may not be the best surrogate markers to pre-
dict success.
Vancomycin tissue penetration is relatively poor.
Concentrations of vancomycin below the typical MIC
breakpoint for Staphylococcus aureus have been de-
tected in the ELF of mechanically ventilated patients
within the first 24 hours of dosing. Physiochemically,
vancomycin is a large, polar molecule that does not
easily pass through lipid membranes. Although this
may decrease the rate at which therapeutic tissue con-
centrations are achieved, this fastidiousness may also
impart the ability of vancomycin to persist in tissue
without reequilibrating back into the serum. In con-
trast, the oxazolidinone linezolid penetrates lung tis-
sue well.47 Despite this potential pharmacokinetic ad-
vantage, clinical superiority of linezolid over
vancomycin has yet to be demonstrated in treating re-
sistant gram-positive pneumonia.48
An often ignored factor associated with drug dispo-
sition is the presence of abnormally high fat mass. Obe-
sity is becoming more common in the general popula-
tion, with up to 25% of the general population in some
states having a body mass index >30 kg/m2.49 The
pharmacokinetic alterations as a result of obesity are
unknown for many of the antimicrobials used in criti-
cally ill individuals. The interaction of physiologic
changes due to obesity and critical illness is also not
well defined. Critically ill patients often lose lean body
mass due to protein catabolism or malnutrition and of-
ten the calories supplied are converted to adipose tis-
sue rather than muscle because of ongoing catabolic
processes.50 Thus, chronically critical ill individuals
may have shifts in lean body mass and fat mass
throughout their stay in the ICU. In general, obesity
may increase the volume of distribution for lipophilic
medications. Knowledge of the physiochemical char-
acteristics of individual medications can be helpful in
estimating whether a nonstandard dose is needed;
however, exceptions to the general rules above exist,
and continued focused study on individual agents is
needed to ensure safe and effective dosing recommen-
dations are available for this population.51
METABOLISM
Hepatic biotransformation represents an important
step in the elimination of medications. Several factors
including hepatic extraction ratio (first-pass effect),
metabolic capacity, and plasma protein binding may
affect hepatic metabolism of antimicrobials. Changes
JOURNAL OF PHARMACY PRACTICE 2005(18.2) • 79
 COOK
in high-extraction medication clearance are primarily
dependent on hepatic blood flow.52 The metabolism of
the majority of commonly used antimicrobials is not
significantly affected by increases in hepatic blood
flow and thus is not subject to the first-pass effect to a
high degree. Alternatively, significant decreases in
hepatic blood flow as seen in acute shock may lead to
ischemia and hepatocyte death, which may diminish
hepatic extraction. Low-extraction medication clear-
ance is typically dependent on the fraction of unbound
drug in the serum and intrinsic clearance (metabolic
capacity).52 The alterations seen in critical illness are
dependent on the extraction ratio of the antimicrobial,
the phase of critical illness (early, hyperdynamic vs
late, hypoperfusion), and the patient’s comorbidities
(congestive heart failure, cirrhosis).
Several commonly used antimicrobials, such as
erythromycin and ciprofloxacin, are low-extraction
medications. Neither agent is highly protein bound,
which minimizes the effect of changes in the fraction of
unbound drug. However, both agents are extensively
metabolized by the cytochrome P450 enzyme system.
Inflammatory mediators such as tumor necrosis factor
and interleukin-6, among others, have the ability to in-
hibit CYP450 enzymes.53 Thus, patients experiencing a
systemic inflammatory response such as after
cardiopulmonary bypass, multiple trauma, or severe
sepsis may have acutely diminished metabolic capac-
ity and elevated serum concentrations as a result. Al-
though the data demonstrating hepatic alterations in
clearance are scarce for erythromycin and cipro-
floxacin, the potential increases in concentrations are
particularly worrisome for specific groups of patients,
specifically, erythromycin and those at risk of cardiac
arrhythmia and ciprofloxacin and patients at risk for
seizure.54,55 More commonly, however, these agents are
the enzyme inhibitors that reduce the clearance of
other medications used in the critically ill such as
midazolam and methylprednisolone. Newer anti-
microbials agents such as oxazolidinones, novel
fluoroquinolones, triazole antifungals, and ketolides
may also undergo hepatic biotransformation, and clini-
cians should be aware of the potential for altered drug
metabolism in critical illness to avoid potential
toxicities.
Albumin also plays a role in the availability of a
medication for biotransformation. Low-extraction
medications may be affected by an altered unbound, or
free, fraction. Albumin is often found in low concentra-
tions in early critical illness and commonly binds
acidic drugs.56 Low serum concentrations of albumin, a
negative acute phase reactant, allow a higher percent-
age of highly protein-bound medications to be un-
80 • JOURNAL OF PHARMACY PRACTICE 2005(18.2)
bound. This, in turn, causes a decrease in total serum
concentrations due to increased metabolism and/or
volume of distribution. Theoretically, however, the to-
tal drug exposure does not change because unbound
concentrations equilibrate to baseline levels, free drug
concentrations remain constant, and thus tissue con-
centrations should not increase significantly.57,58 In
contrast, α-1 acid glycoprotein increases after injury
and may decrease the fraction unbound (and, subse-
quently, hepatic metabolism) of alkaline medications
such as clindamycin.59,60 Protein-binding alterations
should be considered in critically ill patients with
plasma protein changes, particularly in the setting of
treatment failure.
The phase of critical illness may also affect overall
hepatic function and metabolic capacity. Early phases
of critical illness associated with a hyperdynamic state,
fluid resuscitation, and elevated cardiac output may
cause medications to be eliminated at a higher rate due
to the augmented liver perfusion. Total serum concen-
trations also may appear lower due to enhanced distri-
bution and an elevated free fraction. Later phases of
critical illness or low flow states such as congestive
heart failure exacerbation or unresuscitated shock may
be more associated with hepatic dysfunction and an
overall diminished ability of the liver to metabolize
medications and perform other normal, necessary
functions due to hypoxia and hypoperfusion.
ELIMINATION
Drug excretion is perhaps the most important
pharmacokinetic parameter related to the develop-
ment or avoidance of toxicity. The kidneys are primar-
ily responsible for elimination of unchanged anti-
microbials and hepatic metabolites. Renal excretion is
the summation of glomerular filtration, tubular secre-
tion, and reabsorption. Variations in any of these func-
tions, particularly filtration and secretion, can alter
renal drug elimination.
Renal filtration and secretion are the primary modes
of elimination for many of the commonly used anti-
microbials in the ICU. Alterations in renal perfusion
and function during critical illness are common and
may cause wide variations in drug elimination. Early
stages of sepsis, burn, head injury, and trauma are typi-
cally characterized as “hyperdynamic” and are usually
accompanied by increased cardiac output and an asso-
ciated increase in glomerular filtration rate. Such pa-
tients may have higher dose requirements due to ele-
vated clearance. The converse is true for patients in
shock who have not been adequately resuscitated,
chronically critically ill individuals, those with con-
 PHARMACOKINETIC ALTERATIONS OF ANTIMICROBIALS
gestive heart failure, or those in the late stages of sepsis
or injury. Serum creatinine and calculated estimates of
creatinine clearance are often unreliable due to
changes in body composition, immobility, and rapid
muscle breakdown, such as with severe burns. The
pharmacokinetic issues associated with antimicrobials
in patients with renal failure and those undergoing
hemodialysis are beyond the scope of this review, and
the reader is referred elsewhere in this supplement for
a description of issues related to renal dysfunction and
extracorporeal elimination of antimicrobials.
The clinical application of these principles is tem-
pered by contrary results. The systemic clearances of
renally eliminated agents such as meropenem, pipera-
cillin, and levofloxacin were lower in critically ill pa-
tients than in normal volunteers.17,29,61 Aztreonam and
imipenem have exhibited similar clearance rates in
critically ill individuals and normal volunteers.33
Aminoglycosides have shown variable clearance in
critically ill patients, ranging from normal clearance
rates to rapid clearance with a prolonged drug-free in-
terval after extended interval dosing.25,62,63 Vancomycin
clearance was diminished in patients with sepsis but
increased in those with burns.64,65 Uniquely, ciproflox-
acin can be eliminated via compensatory trans-
intestinal and biliary pathways in the presence of di-
minished renal function in critically ill patients.66 The
variability in the results of these studies may be attrib-
uted to the heterogeneous populations studied,
hydration status, and the phase of critical illness. In
practice, most antimicrobials likely have large inter-
individual variability and are dependent on the exis-
tence of prior renal disease (eg, diabetes, hypertension)
and current renal perfusion. Individualized therapeu-
tic drug monitoring is advisable for those agents for
which it is feasible.
Other common mechanisms of elimination include
ester hydrolysis, lymphatic elimination, and entero-
hepatic recycling. Cholestasis is common in critically
ill patients with sepsis, and impaired enterohepatic re-
cycling of medications may decrease the extent of elim-
ination for antimicrobials such as nafcillin and ceftri-
axone due to diminished biliary circulation. However,
quantification of potential alterations in cholestatic
elimination is difficult and has not been adequately
investigated.
THE LINK BETWEEN PHARMACOKINETICS
AND PHARMACODYNAMICS
Exposure of patients to antibiotics is a risk factor for
developing infections due to resistant organisms.67 Ju-
dicious use of antibiotics is of particular importance in
the ICU because of the amount of antibiotics used in
this area and the severity of illness of the patients. The
presence of invasive devices such as endotracheal
tubes, intravenous catheters, and urinary catheters also
contributes to the development and persistence of re-
sistant organisms by serving as a nidus for continued
growth and adherence. In addition, due to the poten-
tially increased volume and drug clearance associated
with critical illness as described above, many critically
ill individuals receiving antimicrobials may be under-
dosed. Inadequate dosing and insufficient tissue pene-
tration may lead to concentrations at the site of infec-
tion that are near or below the MIC of the pathogen,
allowing unencumbered growth.
There appear to be pharmacodynamic targets that
are associated with maximal killing activity for agents
that achieve concentrations above the MIC of the
pathogen. For aminoglycosides, a peak concentration
to MIC ratio of 8 to 10 appears to yield maximal bacteri-
cidal activity.37,68 Fluoroquinolone dosing appears to
be optimized by obtaining an AUC/MIC ratio of ap-
proximately 125, although precise targets likely vary
among drug-pathogen combinations.69 β-Lactams typi-
cally require a specific time of the concentration over
the MIC (T > MIC) to yield maximal effect.70 Pharma-
codynamic dosing strategies are becoming more com-
monly used to optimize the doses required to achieve
these targets. Extended interval, or once-daily,
aminoglycoside dosing is an example. By administer-
ing the total daily dose of aminoglycoside in 1 large
dose, rather than in 3 smaller doses, a higher peak con-
centration (and higher peak to MIC ratio) is achieved.
There also appears to be renewed interest in continu-
ous or prolonged infusions of antimicrobials that are
dependent on achieving a goal T > MIC for optimal ac-
tivity. A 3-hour infusion of meropenem increases the
time over MIC as compared to the same dose given over
the standard half-hour infusion time.71 Continuous in-
fusion vancomycin, cefepime, and piperacillin/
tazobactam appear to yield comparable time over MIC
values to standard doses, which may allow for using
lower daily doses, decreased adverse effects, and
decreased drug costs.35,72,73
SUMMARY
The pharmacokinetics of antimicrobials may be al-
tered in critically ill individuals for multiple reasons.
Preexisting diseases, the systemic inflammatory re-
sponse, the phase of critical illness, and iatrogenic fac-
tors such as fluid resuscitation and vasopressors can af-
fect antimicrobial pharmacokinetics. Antimicrobial
use in this population is an ongoing challenge for clini-
JOURNAL OF PHARMACY PRACTICE 2005(18.2) • 81
 COOK
cians in their effort to balance optimal drug delivery to
the infection site and to avoid toxicity. Continued work
in this area is necessary, particularly with optimizing
tissue penetration and antimicrobial delivery to the in-
fection site and in developing a system to help stan-
dardize patient populations to ease comparisons from
one study to another. Clinicians should be mindful of
potential pharmacokinetic alterations of antimicro-
bials in the critically ill and consider alternative agents
or dosing strategies when necessary.
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