Page 814 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 61: Principles of Antimicrobial Therapy and the Clinical Pharmacology of Antimicrobial Drugs 545

predictors would be necessary for adequate eradication of the bacteria. parameter of interest is f T > MIC as described above. The changes in
5
These pharmacodynamic predictors include (1) the time that drug volume of distribution and clearance in critically ill patients can signifi-
concentrations remain above the MIC (T > MIC), (2) the ratio of the cantly affect the extent of f T > MIC for β-lactams. Volume of distri-
2,8
area under the plasma concentration-time curve (AUC) to the MIC bution is often increased as a result of capillary leak, positive-pressure
(AUC : MIC), (3) the ratio of the C max (peak concentration) to MIC ventilation, transfusions, and other interventions critically ill patients
(C max : MIC). Because the free-drug concentration is considered the may receive. With an increase in volume of distribution drug concentra-
5
biologically active component these parameters are often displayed as tions will be reduced. Since renal blood flow is often increased in patients
f T > MIC, fAUC : MIC, or fC max : MIC. with septic shock, renal clearance may also be elevated, contributing to
The percentage of the dosing interval that drug concentrations remain subtherapeutic levels of β-lactams. Although creatinine clearance is often
above the MIC is the driver of efficacy for a commonly administered calculated using equations such as Cockcroft-Gault, these may underes-
class of antibiotics known as β-lactams that is represented by the cepha- timate the clearance, in which case a creatinine clearance collection may
losporins, penicillins, and carbapenems. In situations where patients be more accurate. On the other hand, patients with renal dysfunction will
have a large volume of distribution or when the MIC of the organism is not clear the drug and therefore require fewer doses of antimicrobials due
high, larger doses may be necessary to achieve adequate concentrations. to an extended half-life. Overtly high concentrations of β-lactams can
While achieving the appropriate concentration is important, simply potentially lead to toxicities such as renal failure and seizures. Inadequate
administering larger doses is not adequate. The extent of bacterial dosing as a result of these pharmacokinetic changes can lead to untreated
eradication when using these drugs is time dependent and therefore infections, poor outcomes, a rise in resistant pathogens, and potential
maintaining that concentration is essential. Since many of these antimi- toxicities.
crobials have short half-lives, administering the dose more frequently Traditional dosing of β-lactams usually involves doses administered
is often necessary. Additionally, in the context of augmented renal over 30 minutes up to four times a day depending on the patient’s
function, patients may be clearing the drug much faster and therefore renal function. However, this dosing strategy may not achieve the ade-
will require the use of higher doses and more frequent dosing. Another quate f T > MIC targets necessary for bacterial killing. Since β-lactams
strategy is to administer the dose over a longer duration of time, com- display time-dependent killing administering the antimicrobial over
monly known as prolonged (administering each dose over 3-4 hours) or an extended period of time increases the fT > MIC and therefore the
continuous infusion (administering the entire daily dose as a 24-hour potential to optimize clinical and microbiological outcomes.
infusion). This dosing strategy has been shown to increase the f T > MIC
and therefore improve patient outcomes by increasing microbiological Penicillins: Piperacillin-tazobactam is an extended spectrum penicillin
and clinical success rates. It is important to note that these dosing with activity against Enterobacteriaceae, Pseudomonas aeruginosa, and
6,7
strategies can be challenging especially in critically ill patients receiv- many anaerobes. With broad gram-negative coverage it is often used
ing multiple medications where drug compatibility and limited venous empirically in patients with sepsis, ventilator-associated pneumonia,
access are present. Moreover, when considering these techniques, the and other serious infections. While dosing can vary based on indication and
stability profile of the antimicrobial in the chosen intravenous solution renal function, ICU patients typically receive 4.5 g every 6 hours due
should also be taken into account to ensure minimal loss of potency to the severity of their infections. Depending on the decline in renal
during the preparation and administration of therapy. function, the dosing interval should be further extended to every 8 or
AUC : MIC ratio has been shown to be the pharmacodynamic driver 12 hours. The volume of distribution and clearance of piperacillin in
of antimicrobials such as fluoroquinolones, vancomycin, azithromycin, ICU patients have been shown to be increased in previous pharmacoki-
9,10
linezolid, and daptomycin. The rate of killing by these antimicrobi- netic studies and therefore aggressive dosing is necessary. Given these
5
als is considered to be a hybrid of concentration and time; thus, this changes in pharmacokinetic parameters, fT > MIC can potentially be
pharmacodynamic parameter integrates the entire exposure profile. reduced, resulting in unsuccessful outcomes, especially for pathogens
Depending on the antimicrobial and the organism being treated a with high MICs. Penicillins typically require at least 50% fT > MIC to
specific AUC : MIC ratio is required to optimize antimicrobial killing. reach maximal bactericidal activity and this may not always be achieved
Unlike β-lactams, these antimicrobials may be dosed less frequently with conventional intermittent dosing. Administering larger doses as
because time of exposure in and of itself is less critical, however the previously studied with piperacillin-tazobactam will provide higher
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selection of the most appropriate dose is still paramount to ensure an overall exposures. Additionally, continuous infusion or extended infu-
adequate AUC (exposure) is being achieved. The goal of therapy is to sion administration are two ways to better optimize time-dependent
maximize the exposure of antimicrobial therapy. Aminoglycosides dis- antibiotics such as piperacillin-tazobactam. Continuous infusion dosing
play concentration-dependent killing and since this is the predominant of piperacillin-tazobactam can range from 9 to 18 g daily depending on
driver of efficacy they are dosed to achieve a targeted peak or maximum the type of infection, with higher doses used for bacteremia and pneumo-
concentration, based on the relationship of the MIC of the infecting nia, while lower doses are typically used for skin and skin structure infec-
organism (C : MIC). Similarly to β-lactams, since many of these anti- tions and community-acquired intra-abdominal infections. Extended
max
microbials are renally eliminated the overall exposures achieved is partly infusion dosing is usually administered as standard 3.375 or 4.5 g doses;
dependent on the patient’s renal function. Unlike the β-lactams, many of however, the duration of the infusion is extended to 3 to 4 hours. Monte
these antimicrobials (ie, vancomycin, aminoglycosides, daptomycin) are Carlo simulations have shown that using extended infusion dosing (ie,
associated with more significant toxicities such as nephrotoxicity, oto- 4-hour infusions every 8 hours) helps achieve the pharmacodynamic
12
toxicity, and rhabdomyolysis with supratherapeutic concentrations. Thus target at higher MICs versus intermittent dosing. This extended infu-
optimizing the toxicodynamic profile as well as the pharmacodynamic sion dosing strategy has been shown to decrease mortality and median
is a challenging aspect to dose optimization in the critically ill patient. length of stay in patients with APACHE II scores ≥17 in a retrospective
cohort study. Another study with continuous infusion piperacillin-
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ANTIMICROBIAL CLASSES tazobactam showed that fT > MIC was higher with continuous infusions
■ β-LACTAMS have shown favorable clinical outcomes especially in the critically ill
versus intermittent dosing (100% vs 62%, respectively). Other studies
13
β-Lactams are the most commonly prescribed class of antimicrobials population, including higher rate of clinical cure and lower mortality
with continuous or extended infusion piperacillin-tazobactam.
14-16
in the ICU. Typically, these drugs are hydrophilic and therefore have
8
a relatively low volume of distribution. Clearance of most antimicrobi- Carbapenems: With activity against a number of clinically significant
als in this class depends on the patient’s renal function. The extent of organisms such as P aeruginosa, Acinetobacter spp, and β-lactamase-
bacterial killing is time dependent and therefore the pharmacodynamic producing bacteria, carbapenems are often used in the ICU. 17,18

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