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This online tutorial series "Quality Improvement: Tool Time" reinforces practical application of tools and competencies acquired during the live activity. Each Tool is a combination of faculty commentary on essentials in clinical practice, links to relevant scientific publications, and a printable handout that will serve as a reminder. Please select the topic:
  1. Ensuring Quality of Care 
    2.              
  2. Optimizing Vancomycin for MRSA Infections
    3.       
  3. Selecting Appropriate Therapy for ESBL- and KPC-Producers
    4.       
  4. Dosing Strategies for MDR P. aeruginosa/A. baumannii Infections
    5.       
  5. Adjusting Antimicrobial Regimens for Efficacy and Safety
    6.       

Adjusting Antimicrobial Regimens for Efficacy and Safety

Applying Culture Results to Adjust Treatment: De-escalation of Therapy

De-escalation of therapy reduces the unnecessary use of antimicrobials and has the potential to decrease the risk of development of resistance without affecting clinical outcomes. More research is needed to arrive at the optimal approach for de-escalation of therapy.

The Table on the right can serve as a useful guide in adopting a strategy for de-escalation.[1] Adjustments should be made based on the individual patient characteristics and specific conditions at each institution.
Strategy for de-escalation: A guide [1]
  1. Obtain microbiologic samples as soon as an infection is suspected
  2. Begin empiric therapy based on patient risk factors for multidrug-resistant pathogens and local susceptibility patterns
  3. Evaluate and de-escalate once culture results and susceptibility profiles are obtained
Individualizing Antimicrobial Dosing According to Patient Factors
Pharmacokinetics of antimicrobials can vary significantly based on patient factors—age, weight, and severity of illness, among others. Dose adjustment for patients with renal impairment is an established practice. However, pharmacists must also consider other patient factors when deciding on an optimal dose to ensure effectiveness while minimizing the risk for adverse events.

Weight


Severity of Illness

Research has demonstrated that doses of some antimicrobial agents may need to be increased in obese patients to achieve effective concentrations at the site of infection. A study of obese patients treated with 600 mg of linezolid for cellulitis found that drug concentrations were diminished in obese patients compared to healthy volunteers.[2]

Though some antimicrobials use weight-based dosing, such as vancomycin and the aminoglycosides, the question that follows is—are there limits on the maximum dose when treating obese or morbidly obese patients?

Studies are needed to gain a better understanding of the pharmacokinetics of other antimicrobials in obese patients to ensure effective and safe doses are administered.

In addition to weight, the severity of illness can impact antimicrobial pharmacokinetics. One study compared the pharmacokinetics of intravenous levofloxacin in critically ill patients versus healthy volunteers (Table).[3] The results revealed significantly higher drug exposure in critically ill patients, potentially increasing the risk of adverse events, and supporting the need for dose adjustment in these patients.

Variable Critically
III
Patients
(N=26) 		Healthy
Volunteers
(N=10) 		P
Values
Cmax (mg/L) 7.5 6.4 .0008
Cmin (mg/L) 1.0 0.6 .0006
AUC0-24
(mg.h/L) 		66.1 54.6 .042
Half-life (h) 8.0 7.0 .021
In the absence of clinical data that clearly demonstrate how patient factors can impact pharmacokinetics of certain antimicrobials, pharmacists must work together with other team members to ensure that appropriate and safe dosing of drugs is administered to their patients.

References

  1. Kollef MH, Micek ST. Strategies to prevent antimicrobial resistance in the intensive care unit. Crit Care Med. 2005;33:1845-1853. Click here for abstract
  2. Stein GE, Schooley SL, Peloquin CA, et al. Pharmacokinetics and pharmacodynamics of linezolid in obese patients with cellulitis. Ann Pharmacother. 2005;39:427-432. Click here for abstract
  3. Rebuck JA, Fish DN, Abraham E. Pharmacokinetics of intravenous and oral levofloxacin in critically ill adults in a medical intensive care unit. Pharmacotherapy. 2002;22:1216-1225. Click here for abstract


Suggested Reading
Faulkner CM, Cox HL, Williamson JC. Unique aspects of antimicrobial use in older adults. Clin Infect Dis. 2005;40:997-1004. Click here for complete article
This article reviews complications of prescribing antimicrobials for elderly patients. Polypharmacy, a common issue due to the presence of comorbidities, increases the risk of drug–drug interactions. Adverse events are more common. The physiological changes associated with advanced age can alter drug pharmacokinetics. Accurate estimates of renal function cannot be made with standard methods.

Herring AR, Williamson JC. Principles of antimicrobial use in older adults. Clin Geriatr Med. 2007;23:481-497. Click here for abstract
This review describes how some of the fundamental principles of antimicrobial therapy can change when treating elderly patients—selection of empiric therapy, risk stratification for severe or atypical infections, potential drug–drug interactions related to polypharmacy, and age-related impact on pharmacokinetic parameters. The authors emphasize a greater need to include elderly patients in clinical trials to assess differences in efficacy and safety of antimicrobials.

Hibbard ML, Kopelman TR, O’Neill PJ, et al. Empiric, broad-spectrum antibiotic therapy with an aggressive de-escalation strategy does not induce gram-negative pathogen resistance in ventilator-associated pneumonia. Surg Infect (Larchmt). 2010;11:427-432. Click here for abstract
This retrospective study evaluated changes in susceptibilities of gram-negative bacteria at one institution that implemented an aggressive policy of de-escalation of therapy following empiric broad-spectrum coverage for VAP. There was no evidence for increased resistance following this strategy and the authors concluded that de-escalation of therapy is a valid practice.

Pai MP, Bearden DT. Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy. 2007;27:1081-1091. Click here for abstract
This article explores the effects of obesity on antimicrobial disposition and pharmacokinetics. The authors review the available clinical data, which historically have focused on antimicrobials requiring therapeutic drug monitoring, such as vancomycin and aminoglycosides. The authors conclude that additional studies are needed to establish dosing recommendations in obese patients.