Page 817 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

548 PART 5: Infectious Disorders

■ GLYCOPEPTIDES TABLE 61-1 Summary of Antimicrobial Classes and Pharmacodynamic Targets

Vancomycin is often one of the first antimicrobials patients receive and Best Correlated With Efficacy
is typically used as empiric therapy for suspected MRSA infections. The Antimicrobial Bacterial Killing PD Parameter
current dosing recommendations are 15 to 20 mg/kg every 8 to 12 hours
for patients with normal renal function. Loading doses of 25 to 30 mg/kg Penicillins Time dependent fT > MIC 50%
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are recommended for patients with serious infections to help obtain Cephalosporins Time dependent fT > MIC 50%-70%
target trough concentrations quicker. In critically ill patients, increased Carbapenems Time dependent fT > MIC 40%
volume of distribution can lead to suboptimal exposure of vancomycin.
Oftentimes, it can take several days for patients to have appropriate Aminoglycoside Concentration dependent C : MIC ≥10
max
trough concentrations and in the context of critically ill patients this can Glycopeptides Concentration dependent AUC : MIC >400
be even more challenging. Guidelines for vancomycin therapeutic drug Lipopeptides Concentration dependent AUC : MIC
monitoring recommend monitoring trough levels with a goal trough
of 15 to 20 µg/mL. The pharmacodynamic parameter that has been Oxazolidinone Concentration dependent AUC : MIC 80-100
associated with successful organism eradication in animal models is an Polymyxins Concentration dependent fAUC : MIC 12-15
AUC : MIC ratio of ≥400. However, the ability to obtain this ratio in Glycylcyclines Concentration dependent AUC : MIC
patients with the current dosing recommendations is highly dependent
on the MIC of the pathogen. Generally speaking, current dosing recom- Fluoroquinolones Concentration dependent AUC : MIC >100 (gram-
mendations will not achieve the targeted AUC : MIC ratio of 400 when negative)
the MIC of the infecting organism is >1 µg/mL. Therefore, S aureus AUC : MIC 30-50 (gram-positive)
isolates with vancomycin MIC of 2 µg/mL will not be adequately treated
despite being reported as susceptible based on current breakpoint high bronchopulmonary concentrations, linezolid is a viable treatment
information. A number of studies have associated clinical failure and alternative for patients that may be intolerant or are not able to optimize
mortality with higher vancomycin MICs. Unfortunately, administer- vancomycin exposures due to altered pharmacokinetics or in patients
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ing larger doses is not always an option due to the high incidence of who are infected with staphylococci with MICs >1 µg/mL.
nephrotoxicity. Although vancomycin has been used for many years,
there are still significant challenges in treating patients effectively with ■ GLYCYLCYCLINES
this antimicrobial.
Similar to vancomycin, the optimization of the pharmacodynamics Tigecycline is an intravenous glycylcycline with a very broad spectrum
of teicoplanin is increasingly difficult in the context of elevated MICs. of activity including MRSA, VRE, Enterobacteriaceae (including those
Recently published literature showed poorer clinical and microbiologi- producing extended spectrum β-lactamases), Acinetobacter spp, as well as
cal outcomes with higher teicoplanin MICs in patients with pneumonia a number of anaerobic organisms and is often used for intra-abdominal
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and bacteremia. 40,41 Alternative agents to teicoplanin should be consid- infections, pneumonia, and skin and skin structure infections. Although
ered in patients with high MICs, enhanced clearance, or in the setting the antimicrobial spectrum of activity is relatively broad, tigecycline does
of renal dysfunction that would make optimal glycopeptide exposures not have activity against P aeruginosa and therefore is not typically used
difficult to achieve. empirically in the critical care setting. Tigecycline is dosed with a 100-mg
loading dose, followed by 50 mg every 12 hours and dose adjustments
■ OXAZOLIDINONES for renal dysfunction are not required. The primary route of elimina-
tion is via biliary excretion and therefore patients with severe hepatic
Linezolid, an oxazolidinone antimicrobial, is a newer antimicrobial impairment would require a decreased maintenance dose of 25 mg every
most often used for infections caused by MRSA or vancomycin-resistant 12 hours. Because tigecycline has a long half-life (approximately 40 hours)
enterococci. Standard dosing is 600 mg every 12 hours and does not and therefore exhibits a prolonged post- antibiotic effect, the pharma-
require dose modifications based on renal or hepatic function. Linezolid codynamic parameter that best correlates with efficacy is AUC : MIC
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is available in intravenous and oral formulations with an oral bioavailabil- ratio. Due to its larger volume of distribution, tigecycline distributes
ity of 100%. An AUC : MIC target of 80 to 100 is the pharmacodynamic extensively into human tissues. Pharmacokinetic studies have shown that
target associated with efficacy and is obtained with standard dosing concentrations in epithelial lining fluid and alveolar cells are significantly
against susceptible organisms with MICs up to 4 µg/mL (Table 61-1). higher than those found in serum. A previous phase 3 study comparing
42
Linezolid has been studied in patients with ventilator-associated pneu- tigecycline at the approved dose compared with imipenem/cilastatin for
monia and was found to penetrate into tissues well with adequate concen- the treatment of ventilator-associated pneumonia showed lower cure
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trations in epithelial lining fluid. Another study showed a higher clinical rates in patients treated with tigecycline (47.9% vs 70.1%). However, a
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response in patients treated with linezolid compared with vancomycin recent study evaluated higher doses of tigecycline, 75 mg every 12 hours
for nosocomial pneumonia caused by MRSA. Although some studies and 100 mg every 12 hours, for the treatment of hospital-acquired pneu-
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suggest a shorter half-life and larger volume of distribution in critically ill monia. A higher clinical response was seen with doses of 100 mg every
patients, these changes do not seem significant enough to greatly impact 12 hours supporting the need for higher exposure. Lastly, tigecycline
overall exposure. Additionally, dosing in the obese population has been should not be used to treat bacteremia as there are concerns regarding
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previously studied and showed that adequate exposures were achieved in inadequate serum concentrations. 52
this study was conducted in healthy volunteers who are physiologically ■ LIPOPEPTIDES
populations up to approximately 150 kg. It should be noted, however, that
different than critically ill patients. While generally well tolerated, line- Daptomycin is a lipopeptide with bactericidal activity against many
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zolid can cause myelosuppression. However, this is typically seen with gram-positive organisms including MRSA and vancomycin-resistant S
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an extended duration of therapy (>14 days) and is reversible. Due to this aureus (VRSA). It is most often used for serious S aureus infections such
adverse effect, a complete blood count should be monitored periodically. as bacteremia, endocarditis, and skin and skin structure infections.
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Additionally, because linezolid has weak monoamine oxidase inhibi- Dosing of daptomycin typically depends on the type of infection with
tory activity, the use of concomitant monoamine oxidase inhibitors and lower doses of 4mg/kg per day used for skin infections. While the
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selective serotonin reuptake inhibitors should be cautioned for the risk approved dose is 6 mg/kg, as a result of the pharmacokinetic linearity,
of potential serotonin syndrome. As a result of its predictable pharma- safety, and frequent use of this agent for patients failing medical manage-
cokinetic profile, lack of dosage adjustment in the renally impaired and ment for bacteremia and endocarditis, many experts recommend doses

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