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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- ing of the physiological alterations in critical illness and gen-
ations that affect the pharmacokinetics of antimicrobials. Al- eral pharmacokinetic principles of antimicrobials is impera-
though the pharmacokinetics of a number of antimicrobials tive for appropriate selection, dosing, and prediction of
have been studied in critically ill individuals, an understand- toxicity.
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
cessful treatment are common to both. Adequate em-
piric coverage of potential pathogens, effective drug
dosing, sufficient tissue penetration, suppression of re-
multiple organ dysfunction and, if left unabated, death. sistant organisms or superinfection, and avoidance of
Layered into the pathophysiology are preexisting toxicity are all significant factors that affect morbidity
chronic diseases that may also affect the interaction of and mortality due to infection in critically ill patients.
various organ systems. In this complex setting, the
pharmacokinetics of commonly used medications may BASICS OF PHARMACOKINETICS
be altered due to a range of factors including variable
gastrointestinal absorption, cardiac output, plasma In reviewing the pharmacokinetic parameters of a
protein binding, hepatic metabolism, or renal function. given agent, one commonly considers several different
As a result, the use of standard doses of medications aspects of a medication’s journey into, through, and out
may lead to therapeutic failure due to underdosing or, of the body. First is absorption. Orally or enterally ad-
conversely, toxic accumulation. The subject of the ministered medications must be well absorbed and
present review is the effect of critical illness on the achieve adequate serum concentrations to be used reli-
pharmacokinetics of antimicrobial agents and the im- ably in critically ill patients. Multiple factors specific
plications of such alterations on the treatment of infec- to critical illness and certain antimicrobials can de-
tions in the intensive care unit (ICU). Clinicians must crease absorption. Second is distribution. Tissue pene-
have a sound knowledge of the pharmacokinetic alter- tration is of paramount importance for successful treat-
ations encountered in the critically ill to ensure safe ment of infections in the critically ill, which often
and effective use of antimicrobials in this population. originate in lung, skin, and soft tissue. Third is metabo-
lism or biotransformation. While the therapeutic bene-
SIGNIFICANCE OF INFECTIONS IN THE ICU
To whom correspondence should be addressed: Aaron M. Cook,
Successful treatment of infections is of paramount PharmD, University of Kentucky Chandler Medical Center, 800
importance to the outcome of critically ill individuals. Rose St. C-117, Lexington, KY 40536-0293; e-mail: amcook0@
Community-acquired infection, such as sepsis or email.uky.edu.
pneumonia, is often the principal reason for critical ill- Aaron M. Cook, PharmD, clinical pharmacy specialist in Neurosur-
ness and admission to an ICU. As patients convalesce gery/Critical Care and adjunct assistant professor in Pharmacy,
in the ICU, the risk of acquiring a nosocomial infection University of Kentucky Chandler Medical Center, Lexington.
increases. Although the typical bacterial pathogens as- JOURNAL OF PHARMACY PRACTICE 2005. 18;2:75–83
sociated with community- and hospital-acquired in- © 2005 Sage Publications
fections are quite different, several principles of suc- DOI: 10.1177/0897190004273568
COOK

fit of many commonly used antimicrobials is not signif- liable absorption of medications from the GI tract
icantly affected by altered metabolism, there are including bioavailability, drug-drug interactions, GI
exceptions in which diminished metabolism could dysmotility, edema associated with fluid resuscitation,
have deleterious consequences. Last is elimination or and shunting of GI perfusion due to hypotension or
excretion. Elimination is governed by several systems vasoactive agents. All of these factors should be consid-
including pulmonary, renal, hepatic, lymphatic, and ered to ensure reliable enteral absorption of
gastrointestinal. Antimicrobials are typically most antimicrobials.
affected by changes in renal and hepatic elimination. Drug-nutrient and drug-drug interactions that alter
The pharmacokinetic alterations that are exhibited the absorption of antimicrobial agents can have a major
in critical illness are varied and are highly dependent impact on therapeutic response. Concomitant admin-
on the phase of illness. Very early in the course of criti- istration of ciprofloxacin with continuous enteral feed-
cal illness, patients may lack adequate cardiac output ings via nasogastric tube decreased ciprofloxacin bio-
and/or intravascular volume and thus exhibit poor end availability by a median of 44% (range, 31%-82%) in
organ perfusion (decreasing tissue perfusion and meta- one study of 12 critically ill individuals.7 This study
bolic and excretion capacity). After fluid resuscitation demonstrates the potential of concomitant enteral
and/or application of vasopressors/inotropes, patients feedings to chelate ciprofloxacin and diminish absorp-
often exhibit exaggerated end organ perfusion and in- tion. However, another study of 5 critically ill patients
creased tissue perfusion, metabolic capacity, and elim- with intra-abdominal infections demonstrated equiva-
ination. Later in the course of treatment, patients who lent area under the concentration-time curve (AUC;
do not clinically improve may ultimately develop pro- over 12 hours), despite continuous nasogastric or naso-
gressive or permanent organ dysfunction, causing me- duodenal enteral feedings.8 The variation in results of
tabolism and elimination to return to a state of dimin- these 2 studies may be due to the difference in enteral
ished activity. Variation in these phases of critical formulas used (administration rates, concentration of
illness should be considered when evaluating the cur- divalent cations), the route of administration (stomach
rently available literature investigating pharmacokin- or duodenum), and patient variability (wide range of
etic alterations of antimicrobials in the critically ill. creatinine clearances and weights). Similar results
Each study should be evaluated individually. The have been shown when combining ciprofloxacin with
reader is referred to several other excellent reviews re- antacids containing polyvalent cations (aluminum,
garding pharmacokinetics of antimicrobials and other magnesium, calcium) used for stress ulcer prevention.
medications in critically ill individuals.1-3 Other agents such as levofloxacin, linezolid, and fluco-
nazole are much more reliably absorbed, even in the
ABSORPTION presence of enteral feedings.9-11
Gastric dysmotility occurs often in critically ill pa-
The role of the gastrointestinal (GI) tract in critical tients. Catecholamines and overactivation of the sym-
illness has changed in recent years.4 In the past, many pathetic nervous system can cause impaired gastric
practitioners were content to bypass the GI tract as an emptying, likely by overriding vagal tone.12,13 Opioids
option for administering medications or nutrition. The are often used for sedation in critically ill patients. Di-
availability of parenteral nutrition, the presence of gas- minished GI motility is a common adverse effect of
tric dysmotility and subsequent relative lack of success these agents, particularly when used over long dura-
with nasogastric feeding, and the paucity of potent oral tions or at high doses. Vigorous fluid resuscitation may
antimicrobial agents rendered the use of the enteral result in edematous bowel and resulting diminished
route seemingly undesirable and unimportant.5 How- motility and absorptive capacity. Hyperglycemia has
ever, new information, techniques, and medications also been shown to decrease gastric emptying. Orally
are now available that have changed the way in which or enterally administered antimicrobials may exhibit
the GI tract is used in the critically ill. It is now evident erratic absorption in patients with gastric dysmotility
that enteral nutrition has many advantages over due to high gastric residual volumes and impaired gas-
parenteral nutrition and is well tolerated in most criti- tric emptying into the small intestine. Prokinetic
cally ill individuals.6 Increased comfort and success agents such as metoclopramide, erythromycin, or
with enteral nutrition has made the provision of early naloxone may be helpful in some patients to enhance
enteral access a common intervention. Thus, the op- gastric emptying.14-16 However, use of these agents to
portunity to initiate enteral administration of anti- increase absorption of antimicrobials is unproven. Tol-
microbials has become nearly universal in most ICUs. erance of enteral nutrition, gastric residual volume,
However, in critical illness, several factors affect the re- and overall clinical status should be considered before

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PHARMACOKINETIC ALTERATIONS OF ANTIMICROBIALS

administering antimicrobials orally or enterally in crit- Despite the potential for variable bioavailability of
ically ill patients. enterally administered antimicrobials, much of the
In the early stages of shock, the perfusion pressure of available clinical evidence supports the use of this
peripheral organs, such as the kidneys, GI tract, and route for critically ill patients. Many institutions have
liver, may be decreased as the body attempts to maxi- developed successful intravenous to oral (IV to PO)
mize oxygen delivery to “more essential” organs (the conversion programs, particularly for disease states
heart and brain). As a result, many critically ill individ- such as community-acquired pneumonia, to decrease
uals require vasopressors to maintain adequate organ length of stay and medication costs without adversely
perfusion pressure. Diminished blood flow to the GI affecting treatment outcomes.18,19 Most commonly,
tract may affect the absorption of antimicrobials. Al- agents such as azithromycin and levofloxacin are used.
though there is a wealth of evidence currently available A successful IV to PO conversion program will account
regarding the effects of vasopressors on splanchnic per- for the various factors that may alter absorption in criti-
fusion, the results of these studies vary widely and are cally ill patients, the patient’s clinical response, and
often contradictory. It appears that vasopressors such prudent antimicrobial selection to ensure optimal
as norepinephrine, dopamine, and vasopressin can de- treatment of the infection.
crease splanchnic perfusion. However, evidence also
exists to suggest that these agents may increase DISTRIBUTION
splanchnic perfusion. In all, the effects of vasopressors
are likely highly dependent on several factors includ- The systemic distribution of an antimicrobial is of-
ing the extent of vasodilatation, intravascular volume, ten an oversimplified phenomenon. A common model
cardiac output, and the dose of vasopressor used. Pa- used to describe distribution is the 2-compartment
tients with adequate intravascular volume, cardiac model, which involves addition of a drug to a central
output, and splanchnic vascular tone are likely to have compartment and distribution to a generic tissue com-
more reliable GI perfusion and absorption. partment. In reality, distribution of most antimicrobials
The absorption of several commonly used anti- during critical illness is not a uniform diffusion into a
microbial agents has been investigated in critically ill single tissue compartment. Rather, it is the combina-
patients. Rebuck et al reported the results of 10 criti- tion of many factors including the physiochemical
cally ill patients receiving levofloxacin (and no enteral characteristics of the agent, plasma protein binding, af-
nutrition).17 The levofloxacin peak serum concentra- finity for different tissue types (adipose, muscle, brain,
tion was significantly lower than with the same 500-mg etc), tissue perfusion, and the phase of critical illness.
dose given intravenously (7.3 mg/L vs 5.5 mg/L, P < A detailed description of distribution into the brain
.0001), but the AUC (62.4 mg•h/L vs 60.3mg•hr/L) and and central nervous system (CNS) is beyond the scope
absolute bioavailability (95%) were similar. The of the current review. The reader is referred elsewhere
pharmacokinetic parameters in critically ill patients af- in this supplement for a description of pharmaco-
ter oral dosing were also very similar to that seen with kinetic issues related to treating CNS infections.
oral dosing in healthy volunteers in a previous study. The systemic inflammatory response syndrome
Peak serum concentrations, AUC, and exudate concen- (SIRS) commonly manifest in critically ill patients is
trations of fluconazole were comparable in 9 GI surgery associated with an increase in extravascular fluid vol-
patients receiving 400 mg enterally (compared to 14 ume. This phenomenon, so-called “third spacing,” is
patients receiving 400 mg intravenously).10 Nine hospi- partially due to the release of cytokines as a result of
talized patients received linezolid 600 mg with enteral trauma, burns, or sepsis.20-22 Cytokines alter the normal
feedings, and although peak serum concentrations capillary permeability, allowing leakage of protein and
were less than when compared to intravenous dosing other oncotic molecules and obligatory fluid flux into
(17.27 mg/L vs 11.29 mg/L), the bioavailability was the extravascular space.23 In addition, hypoalbumin-
equivalent.11 The use of vasopressors is inconsistently emia is common in critical illness due to decreased
reported in all of these studies, so the effects of vaso- hepatic albumin synthesis and increased extravascular
active agents on absorption remain ill defined. How- deposition. The subsequent relative lack of colloid
ever, the results of these studies also suggest that levo- oncotic pressure in the intravascular space allows in-
floxacin, fluconazole, and linezolid are well absorbed, creased efflux of plasma volume into the interstitial
even in patients with potentially compromised GI space, causing edema. Vigorous fluid resuscitation can
function, and they appear to yield serum concentra- further contribute to peripheral and pulmonary edema
tions that are likely to be therapeutic. due to the high volume of fluid that is typically re-

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quired to maintain intravascular volume and organ sample collection, piperacillin dosing, and the loca-
perfusion. As a result, the volume of distribution of tion of the tissue sampled. However, the results
medications that are contained primarily within the highlight the importance of investigating tissue con-
intravascular space (aminoglycosides24,25) or that are centrations during critical illness rather than merely
highly plasma protein bound (ceftriaxone26) increases. extrapolating serum concentrations to approximate
Gentamicin volume of distribution was increased in a tissue distribution.
hyperdynamic septic group of subjects (0.48 L/kg) The tissue concentrations of imipenem appear to be
compared to controls (0.29 L/kg). 27 Similarly, reduced during critical illness.31 Six critically ill pa-
ceftriaxone also exhibits an elevated volume of distri- tients received standard doses of imipenem, each hav-
bution in critical illness (0.36 L/kg vs approximately ing end organ dysfunction (renal, hepatic, or respira-
0.173 L/kg in normal volunteers).26 Thus, the dose tory), and 4 patients required vasoactive agents to
required to achieve therapeutic serum concentrations maintain blood pressure. Despite similar serum AUC
may be greater in critically ill patients with SIRS and values obtained in healthy volunteers and critically ill
edema. patients, the muscle and subcutaneous concentrations
Hypoalbuminemia may also affect the tissue distri- of imipenem were markedly different. The serum to tis-
bution of antimicrobials by a separate mechanism. Un- sue AUC ratio was 2 for muscle and 2.3 for subcutane-
der normal circumstances, only the free (unbound) ous tissue in healthy volunteers. However, in critically
fraction of the drug is available to enter the interstitial ill individuals, this ratio increased to 9 and 7.1, respec-
space and interact with target tissue. However, this tively. Although the serum concentrations in critically
principle may not be entirely accurate in critical ill- ill individuals were above the typical MIC breakpoint
ness. Although total tissue drug concentrations may be for susceptible gram-negative bacteria (4 µg/mL) for ap-
elevated because of capillary permeability and third proximately 75% to 100% of the dosing interval, tissue
spacing, agents that are highly plasma protein bound concentrations exceeded 4 µg/mL in only 1 patient for
may exhibit increased binding in the interstitial space only a fraction of the dosing interval (30 minutes). Sim-
due to concomitant leakage of albumin.28 Thus, the to- ilar diminished tissue penetration of imipenem has
tal tissue concentrations are elevated, but an abnor- also been demonstrated in pancreatitis and pneumo-
mally high percentage of the interstitial drug is bound nia.32,33 Although considerable variability exists in
(pharmacologically inactive). these studies with regard to patient selection (severity
The general concepts described above may predict of illness, weight, renal function), the tissue type, and
the extent of tissue penetration for many antimicro- the method of measuring tissue concentrations, it is
bials. However, to further define the penetration of spe- apparent that the extent of imipenem tissue penetra-
cific agents in target tissues, techniques such as micro- tion is decreased in critical illness despite seemingly
dialysis, bronchial alveolar lavage (BAL), and tissue therapeutic serum concentrations.
excision have been increasingly used. These tech- In contrast to the variability with the above β-lactams,
niques not only demonstrate the tissue concentrations the fourth-generation cephalosporin cefepime has dem-
in relation to the serum concentration but also give in- onstrated consistent, extensive tissue penetration.
sight to the rate of elimination from the tissue and clini- Cefepime concentrations in lung parenchyma were
cal factors that may influence the accumulation of drug compared to serum concentrations obtained in 16 pa-
in the target tissue. tients undergoing surgery.34 Lung concentrations were
Variable tissue penetration has been reported for β- similar to serum at all time points and were above the
lactams such as piperacillin and imipenem. Pipera- MIC breakpoints of gram-negative pathogens for the
cillin skeletal muscle distribution was significantly majority of the dosing interval. Similar extensive pene-
lower in patients after aortic valve surgery than in tration was demonstrated when administering contin-
healthy volunteers (AUCtissue to AUCfree serum ratio of 0.27 uous infusion cefepime to critically ill patients with
vs 1.22, respectively). 29 However, piperacillin/ pneumonia. The mean epithelial lining fluid (ELF)
tazobactam lung distribution was more similar to se- cefepime concentration was 14.1 µg/mL (vs 13.5 µg/mL
rum in 5 critically ill patients with sepsis and pneumo- serum).35 Based on these results, it appears that
nia (AUCtissue to AUCfree serum ratio of 0.63), and tissue cefepime penetrates the lung tissue quite well, largely
concentrations were above the minimum inhibitory due to the fact that it is a zwitterion and rapidly pene-
concentration (MIC) of typical gram-negative patho- trates tissue without a lag time, allowing tissue concen-
gens for 2 to 6 hours of the dosing interval.30 The con- trations to mirror serum concentrations.
founding factors in these 2 reports are many, including The tissue penetration of aminoglycosides has also
the severity of illness of the patients, the method of been studied in critically ill individuals. Sixteen pa-

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tients receiving tobramycin (multiple daily dosing) for that fluoroquinolones tend to accumulate in high con-
pneumonia underwent a BAL after the systemic centrations in immune cells such as macrophages.46
tobramycin concentrations had reached steady state.36 For these infections, serum, and even tissue, concen-
The maximum ELF concentrations were 2.33 mg/L at trations may not be the best surrogate markers to pre-
30 minutes after the dose. The ELF to serum concentra- dict success.
tion ratio progressively increased throughout the dos- Vancomycin tissue penetration is relatively poor.
ing interval (from 0.3 to 1.53), indicating slower Concentrations of vancomycin below the typical MIC
tobramycin clearance from the tissue and the potential breakpoint for Staphylococcus aureus have been de-
for tobramycin accumulation in the alveoli after re- tected in the ELF of mechanically ventilated patients
peated dosing. It is unclear whether the higher serum within the first 24 hours of dosing. Physiochemically,
concentrations obtained with extended-interval dosing vancomycin is a large, polar molecule that does not
of aminoglycosides will achieve proportionally higher easily pass through lipid membranes. Although this
tissue concentrations. This is a particularly important may decrease the rate at which therapeutic tissue con-
piece of information because the MIC breakpoint for centrations are achieved, this fastidiousness may also
susceptibility of many nosocomial gram-negative impart the ability of vancomycin to persist in tissue
pathogens to tobramycin is ≤2 µg/mL (≤4 µg/mL for without reequilibrating back into the serum. In con-
Pseudomonas species). A peak concentration to MIC trast, the oxazolidinone linezolid penetrates lung tis-
ratio of 8 to 10 is generally thought to maximize bacteri- sue well.47 Despite this potential pharmacokinetic ad-
cidal activity of aminoglycosides.37 Such high concen- vantage, clinical superiority of linezolid over
trations of aminoglycosides are difficult to obtain in vancomycin has yet to be demonstrated in treating re-
most tissues because this class of agents tends to be ion- sistant gram-positive pneumonia.48
ized at human pH and therefore do not pass easily An often ignored factor associated with drug dispo-
through lipid membranes, relying primarily on porous sition is the presence of abnormally high fat mass. Obe-
membrane integrity, minimal bulk flow, and possibly sity is becoming more common in the general popula-
cation transport pumps to enter tissues. Despite appar- tion, with up to 25% of the general population in some
ent pharmacokinetic and pharmacodynamic short- states having a body mass index >30 kg/m2.49 The
comings, aminoglycosides continue to be used suc- pharmacokinetic alterations as a result of obesity are
cessfully (in combination with other active agents) for unknown for many of the antimicrobials used in criti-
severe infections. cally ill individuals. The interaction of physiologic
Fluoroquinolones are commonly suggested to have changes due to obesity and critical illness is also not
enhanced tissue penetration due to their relatively large well defined. Critically ill patients often lose lean body
volume of distribution in healthy volunteers and high mass due to protein catabolism or malnutrition and of-
lipophilicity in vivo.38,39 However, the volumes of dis- ten the calories supplied are converted to adipose tis-
tribution of levofloxacin (1.19 L/kg vs 0.94 L/kg nor- sue rather than muscle because of ongoing catabolic
mal)17,40 and ciprofloxacin (1.4 L/kg vs 2.4 L/kg processes.50 Thus, chronically critical ill individuals
normal)41,42 demonstrate marked variability in critical may have shifts in lean body mass and fat mass
illness. Skeletal muscle exposure of levofloxacin in throughout their stay in the ICU. In general, obesity
septic patients is comparable to that found in the serum may increase the volume of distribution for lipophilic
(AUCtissue to AUCfree serum ratio of 0.85).43 However, in an medications. Knowledge of the physiochemical char-
in vitro model using dynamic concentrations found in acteristics of individual medications can be helpful in
the skeletal muscle, levofloxacin did not adequately estimating whether a nonstandard dose is needed;
inhibit growth of Pseudomonas aeruginosa (MIC = 2 however, exceptions to the general rules above exist,
µg/mL) for nearly all patients. Higher doses of levo- and continued focused study on individual agents is
floxacin (≥750 mg) or combinations with other active needed to ensure safe and effective dosing recommen-
agents have been suggested to ensure therapeutic tis- dations are available for this population.51
sue concentrations.44 Ciprofloxacin concentrations in
burn eschar tissue were greater than that found in the METABOLISM
serum (Cmax = 4.9 µg/mL, AUC24-36 = 17.5 mg•h/L vs
eschar 18 µg/g), even though perfusion of eschar tends Hepatic biotransformation represents an important
to be lower than normal soft tissue.45 The persistence of step in the elimination of medications. Several factors
adequate concentrations may be due to decreased elim- including hepatic extraction ratio (first-pass effect),
ination from the target site. It is also important to re- metabolic capacity, and plasma protein binding may
member in the treatment of intracellular pathogens affect hepatic metabolism of antimicrobials. Changes

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in high-extraction medication clearance are primarily bound. This, in turn, causes a decrease in total serum
dependent on hepatic blood flow.52 The metabolism of concentrations due to increased metabolism and/or
the majority of commonly used antimicrobials is not volume of distribution. Theoretically, however, the to-
significantly affected by increases in hepatic blood tal drug exposure does not change because unbound
flow and thus is not subject to the first-pass effect to a concentrations equilibrate to baseline levels, free drug
high degree. Alternatively, significant decreases in concentrations remain constant, and thus tissue con-
hepatic blood flow as seen in acute shock may lead to centrations should not increase significantly.57,58 In
ischemia and hepatocyte death, which may diminish contrast, α-1 acid glycoprotein increases after injury
hepatic extraction. Low-extraction medication clear- and may decrease the fraction unbound (and, subse-
ance is typically dependent on the fraction of unbound quently, hepatic metabolism) of alkaline medications
drug in the serum and intrinsic clearance (metabolic such as clindamycin.59,60 Protein-binding alterations
capacity).52 The alterations seen in critical illness are should be considered in critically ill patients with
dependent on the extraction ratio of the antimicrobial, plasma protein changes, particularly in the setting of
the phase of critical illness (early, hyperdynamic vs treatment failure.
late, hypoperfusion), and the patient’s comorbidities The phase of critical illness may also affect overall
(congestive heart failure, cirrhosis). hepatic function and metabolic capacity. Early phases
Several commonly used antimicrobials, such as of critical illness associated with a hyperdynamic state,
erythromycin and ciprofloxacin, are low-extraction fluid resuscitation, and elevated cardiac output may
medications. Neither agent is highly protein bound, cause medications to be eliminated at a higher rate due
which minimizes the effect of changes in the fraction of to the augmented liver perfusion. Total serum concen-
unbound drug. However, both agents are extensively trations also may appear lower due to enhanced distri-
metabolized by the cytochrome P450 enzyme system. bution and an elevated free fraction. Later phases of
Inflammatory mediators such as tumor necrosis factor critical illness or low flow states such as congestive
and interleukin-6, among others, have the ability to in- heart failure exacerbation or unresuscitated shock may
hibit CYP450 enzymes.53 Thus, patients experiencing a be more associated with hepatic dysfunction and an
systemic inflammatory response such as after overall diminished ability of the liver to metabolize
cardiopulmonary bypass, multiple trauma, or severe medications and perform other normal, necessary
sepsis may have acutely diminished metabolic capac- functions due to hypoxia and hypoperfusion.
ity and elevated serum concentrations as a result. Al-
though the data demonstrating hepatic alterations in ELIMINATION
clearance are scarce for erythromycin and cipro-
floxacin, the potential increases in concentrations are Drug excretion is perhaps the most important
particularly worrisome for specific groups of patients, pharmacokinetic parameter related to the develop-
specifically, erythromycin and those at risk of cardiac ment or avoidance of toxicity. The kidneys are primar-
arrhythmia and ciprofloxacin and patients at risk for ily responsible for elimination of unchanged anti-
seizure.54,55 More commonly, however, these agents are microbials and hepatic metabolites. Renal excretion is
the enzyme inhibitors that reduce the clearance of the summation of glomerular filtration, tubular secre-
other medications used in the critically ill such as tion, and reabsorption. Variations in any of these func-
midazolam and methylprednisolone. Newer anti- tions, particularly filtration and secretion, can alter
microbials agents such as oxazolidinones, novel renal drug elimination.
fluoroquinolones, triazole antifungals, and ketolides Renal filtration and secretion are the primary modes
may also undergo hepatic biotransformation, and clini- of elimination for many of the commonly used anti-
cians should be aware of the potential for altered drug microbials in the ICU. Alterations in renal perfusion
metabolism in critical illness to avoid potential and function during critical illness are common and
toxicities. may cause wide variations in drug elimination. Early
Albumin also plays a role in the availability of a stages of sepsis, burn, head injury, and trauma are typi-
medication for biotransformation. Low-extraction cally characterized as “hyperdynamic” and are usually
medications may be affected by an altered unbound, or accompanied by increased cardiac output and an asso-
free, fraction. Albumin is often found in low concentra- ciated increase in glomerular filtration rate. Such pa-
tions in early critical illness and commonly binds tients may have higher dose requirements due to ele-
acidic drugs.56 Low serum concentrations of albumin, a vated clearance. The converse is true for patients in
negative acute phase reactant, allow a higher percent- shock who have not been adequately resuscitated,
age of highly protein-bound medications to be un- chronically critically ill individuals, those with con-

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gestive heart failure, or those in the late stages of sepsis the ICU because of the amount of antibiotics used in
or injury. Serum creatinine and calculated estimates of this area and the severity of illness of the patients. The
creatinine clearance are often unreliable due to presence of invasive devices such as endotracheal
changes in body composition, immobility, and rapid tubes, intravenous catheters, and urinary catheters also
muscle breakdown, such as with severe burns. The contributes to the development and persistence of re-
pharmacokinetic issues associated with antimicrobials sistant organisms by serving as a nidus for continued
in patients with renal failure and those undergoing growth and adherence. In addition, due to the poten-
hemodialysis are beyond the scope of this review, and tially increased volume and drug clearance associated
the reader is referred elsewhere in this supplement for with critical illness as described above, many critically
a description of issues related to renal dysfunction and ill individuals receiving antimicrobials may be under-
extracorporeal elimination of antimicrobials. dosed. Inadequate dosing and insufficient tissue pene-
The clinical application of these principles is tem- tration may lead to concentrations at the site of infec-
pered by contrary results. The systemic clearances of tion that are near or below the MIC of the pathogen,
renally eliminated agents such as meropenem, pipera- allowing unencumbered growth.
cillin, and levofloxacin were lower in critically ill pa- There appear to be pharmacodynamic targets that
tients than in normal volunteers.17,29,61 Aztreonam and are associated with maximal killing activity for agents
imipenem have exhibited similar clearance rates in that achieve concentrations above the MIC of the
critically ill individuals and normal volunteers.33 pathogen. For aminoglycosides, a peak concentration
Aminoglycosides have shown variable clearance in to MIC ratio of 8 to 10 appears to yield maximal bacteri-
critically ill patients, ranging from normal clearance cidal activity.37,68 Fluoroquinolone dosing appears to
rates to rapid clearance with a prolonged drug-free in- be optimized by obtaining an AUC/MIC ratio of ap-
terval after extended interval dosing.25,62,63 Vancomycin proximately 125, although precise targets likely vary
clearance was diminished in patients with sepsis but among drug-pathogen combinations.69 β-Lactams typi-
increased in those with burns.64,65 Uniquely, ciproflox- cally require a specific time of the concentration over
acin can be eliminated via compensatory trans- the MIC (T > MIC) to yield maximal effect.70 Pharma-
intestinal and biliary pathways in the presence of di- codynamic dosing strategies are becoming more com-
minished renal function in critically ill patients.66 The monly used to optimize the doses required to achieve
variability in the results of these studies may be attrib- these targets. Extended interval, or once-daily,
uted to the heterogeneous populations studied, aminoglycoside dosing is an example. By administer-
hydration status, and the phase of critical illness. In ing the total daily dose of aminoglycoside in 1 large
practice, most antimicrobials likely have large inter- dose, rather than in 3 smaller doses, a higher peak con-
individual variability and are dependent on the exis- centration (and higher peak to MIC ratio) is achieved.
tence of prior renal disease (eg, diabetes, hypertension) There also appears to be renewed interest in continu-
and current renal perfusion. Individualized therapeu- ous or prolonged infusions of antimicrobials that are
tic drug monitoring is advisable for those agents for dependent on achieving a goal T > MIC for optimal ac-
which it is feasible. tivity. A 3-hour infusion of meropenem increases the
Other common mechanisms of elimination include time over MIC as compared to the same dose given over
ester hydrolysis, lymphatic elimination, and entero- the standard half-hour infusion time.71 Continuous in-
hepatic recycling. Cholestasis is common in critically fusion vancomycin, cefepime, and piperacillin/
ill patients with sepsis, and impaired enterohepatic re- tazobactam appear to yield comparable time over MIC
cycling of medications may decrease the extent of elim- values to standard doses, which may allow for using
ination for antimicrobials such as nafcillin and ceftri- lower daily doses, decreased adverse effects, and
axone due to diminished biliary circulation. However, decreased drug costs.35,72,73
quantification of potential alterations in cholestatic
elimination is difficult and has not been adequately SUMMARY
investigated.
The pharmacokinetics of antimicrobials may be al-
THE LINK BETWEEN PHARMACOKINETICS tered in critically ill individuals for multiple reasons.
AND PHARMACODYNAMICS Preexisting diseases, the systemic inflammatory re-
sponse, the phase of critical illness, and iatrogenic fac-
Exposure of patients to antibiotics is a risk factor for tors such as fluid resuscitation and vasopressors can af-
developing infections due to resistant organisms.67 Ju- fect antimicrobial pharmacokinetics. Antimicrobial
dicious use of antibiotics is of particular importance in 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 chanically ventilated patients. Crit Care Med. 2002;30:1237-
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