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550 PART 5: Infectious Disorders

Piperacillin/tazobactam has also been studied in critically ill patients Current guidelines for developing an ASP recommend two strategies.
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receiving CRRT and generally it is recommended that a dose of 4.5 g First, prospectively auditing antimicrobial use within an institution and
every 8 hours should be used, although some studies have suggested that providing feedback to prescribers can help reduce misuse of antimi-
even doses of 4.5 g every 6 hours lead to subtherapeutic fT > MIC against crobials. Prospective auditing and interventions by infectious diseases
pathogens with MIC of greater than 32 µg/mL. Unfortunately, the risk pharmacist and physicians have been shown to decrease the unnecessary
of subtherapeutic concentrations versus drug accumulation should be use of broad-spectrum antibiotics, decrease rates of C difficile infections,
considered for each patient. Of note, the risk of drug accumulation is less and have contributed to substantial cost savings. Additionally, restric-
when using polysulfone hemofilters compared with acrylonitrile. tion of certain antimicrobials can also help reduce inappropriate use and
Cephalosporins are also easily removed by CRRT. Cefepime and ceftazi- decrease overall costs. Limiting the prescribing of certain antimicrobials
dime both have relatively low protein binding, a low volume of distribution, to only an infectious diseases service can help ensure more appropriate
and a shorter half-life. Pharmacokinetics studies with both compounds use of the agent.
show that a significant portion of the drug is removed via extracorporeal When implementing new initiatives, it is important to understand
clearance. 67,68 Typical dosing for ceftazidime includes 0.25 g every 12 hours the concerns of all personnel involved. For example, extended infusions
to 0.75 g every 12 hours. Dosing for cefepime is 1 to 2 g every 12 hours. Both of β-lactams would likely be viewed as an inconvenience from a nurs-
of these dosing regimens can be increased when using high ultrafiltration ing perspective. However, educating them of the benefits to the patient
rates and when infections are more serious. As a result of the potential for and the improved clinical outcomes can outweigh these perceived
inadequate exposures due to dosage reductions in the context of pharmaco- inconveniences. Educating staff can help increase the acceptance of a
kinetic alterations and higher MICs of β-lactams for patients in the ICU on stewardship program and all the changes associated with it. Developing
CRRT, standard (ie, nonrenal adjusted) doses are advocated. 24,69 clinical pathways to treat specific infections such as ventilator-associated
Vancomycin has been shown to be removed significantly with both pneumonia allows an institution to use local susceptibility to data
CVVH and CVVHDF, however this varies depending on the ultrafiltra- to optimize antimicrobial regimens. The implementation of clinical
tion rates. Generally, a loading dose of 15 mg/kg should be adminis- pathways has been utilized in many institutions and can help reduce
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tered, followed by 0.5 g every 12 hours with frequent therapeutic drug mortality, length of stay and improve outcomes. 24,73 Once culture results
monitoring to ensure adequate exposures. are available, antibiotic therapy should be de-escalated to target the
Fluoroquinolones are lipophilic antimicrobials with a relatively high infecting pathogen. De-escalation can reduce cost and more impor-
volume of distribution. Ciprofloxacin and levofloxacin are both renally tantly decrease unnecessary antimicrobial exposure. Also, antimicrobial
eliminated. However, it has been observed that ciprofloxacin is not 9dosing should be individualized for the patient based on characteristics
significantly removed with CRRT and typical dosing recommenda- such as renal function, weight, causative organism, and site of infection.
tions are 400 mg every 8 to 12 hours for these patients. Levofloxacin Additionally, pharmacokinetic and pharmacodynamic considerations
is different in that it is significantly removed by CRRT and clearance regarding administration of antimicrobials such as prolonged or con-
depends on the patient’s residual renal function and the flow rates tinuous infusion of β-lactams or once daily administration of aminogly-
applied. Generally, a loading dose of 500 mg and a maintenance dose cosides should be appropriately implemented.
of 250 mg every 24 hours is recommended for most patients. However The outcomes of an ASP should be measured to determine the
maintenance doses can be increased to 500 mg every 24 hours for high impact on antimicrobial use, resistance patters, clinical outcomes, and
flow rates to ensure adequate AUC exposures. costs. Additionally, measuring outcomes serves as a continuous quality
Dosing in the presence of CRRT remains a significant challenge improvement process. Understanding the outcomes of an ASP can help
as there are many variable factors that can affect the antimicrobial determine where improvements are still needed and what is successful.
exposure. Ideally, drug levels should be monitored closely. The MIC of As a result of the complexity of managing infection in the critically ill
the infecting pathogen should also be considered to determine if goal patient, great care should be given to implement an antimicrobial regi-
pharmacodynamic targets are likely being achieved with the regimen men early in the course of infection based on the suspected pathogen
administered. and local susceptibility profiles. The application of pharmacodynamic
principles may further assist with dose optimization and the improve-
ment of clinical and microbiologic outcomes. The overlay of good stew-
ANTIMICROBIAL STEWARDSHIP ardship practices should further assist the process of improving quality

Antimicrobial resistance continues to increase and is associated with care while minimizing the unwanted consequences of antimicrobial use
increased length of hospital stay, hospital cost, and mortality. 71,72 Overuse such as resistance in the target pathogen or the development of cata-
and misuse of antimicrobials have been linked to a rise in resistant strophic super infections such as Clostridium difficile.
pathogens, which can often be easily transmitted throughout a hospital.
Implementation of an antimicrobial stewardship program (ASP) has
been shown to improve patient outcomes and decrease health care costs KEY REFERENCES
by selecting the most appropriate antibiotic, duration, dose, and route of • Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases
administration for the patient. The goal in implementing an ASP is to Society of America and the Society for Healthcare Epidemiology
improve patient care and ensure successful outcomes. An ASP should of America guidelines for developing an institutional program to
consist of a multidisciplinary team of at least an infectious diseases enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:159-177.
physician and a clinical pharmacist with infectious diseases training.
The addition of a clinical microbiologist who can provide surveillance • Katsios CM, Burry L, Nelson S, et al. An antimicrobial stewardship
data on antimicrobial resistance, an infection control professional, program improves antimicrobial treatment by culture site and the
hospital epidemiologist, and an information system specialist would be quality of antimicrobial prescribing in critically ill patients. Crit
optimal. The focus of the ASP should be on treating bacteria that are Care. 2012;16(6):R216.
increasingly prevalent within the hospitals and are associated with a • Nicasio AM, Eagye KJ, Nicolau DP, et al. Pharmacodynamic-based
high level of resistance, such as ESBL-producing Enterobacteriaceae, and clinical pathway for empiric antibiotic choice in patients with
minimizing adverse effects from antimicrobial use such as Clostridium ventilator-associated pneumonia. J Crit Care. 2010;25(1):69-77.
difficile infections. Additionally, the focus should be on disease-based • Nicolau DP. Optimizing outcomes with antimicrobial ther-
management rather than simply antibiotic management as antimicrobial apy through pharmacodynamic profiling. J Infect Chemother.
acquisition cost is a relatively small component when considering the 2003;9:292-296.
cost of care for a patient with poor outcomes. 73

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