use of antibiotics in the intensive care unit

IntensIve care

Use of antibiotics in the intensive care unitstuart Dickson

Abstractthe incidence of sepsis is rising both as a reason for initial admission to

the intensive care unit and as a complication of the healthcare provided.

recognition of the sepsis syndrome and subsequent identification and

control of its source are important steps in the management of critically

ill patients with infection. administering the appropriate dose of the

correct antibiotic at the optimal time is the key to using antibiotics effec-

tively in the intensive care unit. Given the rising incidence of antibiotic-

resistant pathogens it is incumbent upon clinicians to use antibiotics

effectively and appropriately for the benefit of the individual patient and

the intensive care unit population as a whole.

Keywords antibiotic therapy; continuous infusion; critically ill; intensive

care; pharmacodynamics; pharmacokinetics

Empirical antibiotic therapy

In a recent large multicentre European study,1 the incidence of sepsis in patients admitted to the intensive care unit was 24.7%. A further 12.7% of patients developed healthcare-associated infection as a complication of their admission to critical care. Critically ill patients with manifestations of sepsis, severe sep-sis or septic shock warrant urgent broad spectrum antibiotic therapy. The mortality of patients with septic shock who do not receive appropriately selected antibiotic therapy increases by the hour. Patients should receive parenteral antibiotic therapy within the first hour of the recognition of severe sepsis.2 A number of factors should be taken into consideration in the selection of the appropriate antibiotic regimen (Table 1).

Once an antibiotic regimen has been selected, the clinician must prescribe the appropriate dose and dosing interval. Know-ledge of the pharmacokinetics and pharmacodynamics of anti-microbials in the critically ill is important in this respect.

Pharmacokinetics

Pharmacokinetics refers to aspects of drug handling in the body such as absorption, bioavailability, distribution, protein bind-ing, metabolism and elimination. Absorption of drugs using

Stuart Dickson, MRCP, is Consultant in Acute Medicine and Intensive

Care at Derriford Hospital, Plymouth, UK. He qualified from the

University of Edinburgh and trained in Infectious Diseases in London

and in Intensive Care Medicine in south-west England, UK. Conflicts of

interest: none declared.

anaestHesIa anD IntensIve care MeDIcIne 10:4 16

the enteral route is unpredictable in the critically ill. Antibiotic therapy should always be initiated parenterally in seriously ill patients. In critically ill patients the volume of distribution of drugs including antimicrobial agents is significantly increased. This means that drugs with a large volume of distribution (e.g. aminoglycosides) will require a higher loading dose in order to reach the desired serum concentration. This principle is not affected by factors such as hepatic or renal impairment, which, if present, may reduce the elimination of the antibiotic. Alteration of the dosing interval or the maintenance dose of the prescribed antimicrobial agent is required to prevent accumulation of the antibiotic and associated toxicities.

Many antimicrobial agents are excreted primarily via the kidneys:• penicillins – ampicillin, amoxicillin, flucloxacillin, piperacillin• cephalosporins – cefuroxime, cefotaxime, ceftazidime• carbapenems – imipenem, meropenem• glycopeptides – vancomycin, teicoplanin• aminoglycosides – gentamicin, amikacin• fluoroquinolones – ciprofloxacin, levofloxacin

after reading this article, you should be able to:

• list five factors that must be considered when selecting

empirical antibiotic therapy

• describe three pharmacodynamic relationships that influence

the efficacy of different antibiotics

• name three antibiotic classes that demonstrate concentration-

dependent killing.

Learning objectives

Clinical factors to be considered in the choice of empirical antibiotic therapy

• the clinical syndrome presenting (e.g. pneumonia, urinary

tract sepsis)

• Possible pathogens causing the clinical syndrome

• community-acquired infection or healthcare-associated

infection

• Local patterns of resistance

• History of recent foreign travel and potential acquisition of

resistant pathogens

• Prevalence of multidrug-resistant pathogens in the local

community/healthcare institutions (e.g. methicillin-resistant

Staphylococcus aureus (Mrsa), extended spectrum beta-

lactamase (esBL)-containing enterobacteriaceae)

• antibiotic penetration at the anatomical site of infection

• recent antibiotic therapy

• Known allergies to antibiotics

• Oral versus parenteral administration

• renal function

• Hepatic function

• Local antibiotic formulary

Table 1

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IntensIve care

• fluconazole• colistin• daptomycin.

In the presence of renal impairment, adjustment of main-tenance doses may be required. Estimates of creatinine clearance derived from equations (e.g. Cockcroft and Gault) are used in clinical practice to guide antimicrobial dosing.

The dosing of antimicrobial therapy in patients receiving continuous venovenous haemofiltration (CVVH) is complex. In patients undergoing CVVH, there is increased clearance of anti-biotics with low protein-binding capacity and smaller volumes of distribution. The issue is further complicated given that these parameters are also altered by the critical illness itself. Technical factors such as blood flow rates, transmembrane pressures and the porosity of the membrane used may also enhance clearance of antimicrobials. Antibiotic dosing in patients undergoing renal replacement therapy is complex and ideally requires advice from a specialist pharmacist.

Liver disease is often associated with hypoalbuminaemia, which may significantly affect antibiotics with high protein bind-ing. Other agents may undergo significant metabolism in the liver via a number of different enzyme systems. There is no way of quantifying hepatic function in clinical practice; therefore, spe-cialist advice should be sought in guiding antibiotic dose modifi-cation in patients with liver disease. Antimicrobial agents which are principally excreted by the liver include:• ceftriaxone• linezolid• clindamycin• moxifloxacin• itraconazole• voriconazole.

Antimicrobial agents with high lipid permeability (e.g. tetra-cyclines, macrolides, rifampicin) are effective agents in the treat-ment of infections associated with intracellular pathogens (e.g. Mycoplasma, Legionella, Chlamydia, mycobacteria).

The measurement of serum drug levels may be useful in guid-ing antibiotic dosing in circumstances in which the therapeutic range is known (e.g. vancomycin, aminoglycosides). However, clinicians should be aware that serum concentrations of anti-biotics measured in vitro do not necessarily reflect the concentra-tions present in vivo at the site of the infection. For example, if vancomycin is used in the treatment of pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA), the rela-tively poor penetration of vancomycin into infected lung tissue at serum trough concentrations of 5–10 mg/l may contribute to therapeutic failure. It has been suggested that vancomycin serum trough concentrations of 15–20 mg/l may be more efficacious.

Pharmacodynamics

Pharmacodynamics is related to the antimicrobial activity of the drug at its site of action and its function over time (Figure 1). The minimum inhibitory concentration (MIC) of a bacterial isolate for a particular antimicrobial is an important concept in understanding the pharmacodynamics of antibiotic therapy. Peak antibiotic concentrations of at least four times the MIC are required to ensure maximal bacterial killing. There are a number of relationships involving the MIC which have been shown to be


important in establishing the efficacy of different antimicrobial agents3:• AUC/MIC – the ratio of the area under the serum concentration

time curve (AUC) to the MIC• Cmax/MIC – the ratio of the peak serum antibiotic concentration

to the MIC• time > MIC – the proportion of time (over 24 hours) that the

serum antibiotic concentration is greater than the MIC.The efficacy of concentration-dependent antibiotics (e.g.

aminoglycosides, fluoroquinolones, metronidazole, colistin, dap-tomycin) are associated with high AUC/MIC and/or Cmax/MIC ratios. Concentration-dependent antibiotics are associated with persistent suppression of bacterial growth as concentrations of the antibiotic fall. This post-antibiotic effect is seen more often in Gram-positive infections than in those caused by Enterobac-teriaceae. The peak concentration of the antibiotic obtained at the site of actual infection is a key consideration in prescribing concentration-dependent antibiotics.

The antibiotics which demonstrate time-dependent killing (e.g. penicillins, cephalosporins, carbapenems, clindamycin, azoles, linezolid, vancomycin) have no significant post-antibiotic effect. The optimal antibiotic effect is achieved when the antibi-otic concentration at the site of the infection is greater than the MIC of the bacterial population for a sufficient duration. Antimi-crobial agents with short half-lives (e.g. benzylpenicillin) should be administered frequently to optimize efficacy.

Continuous antibiotic infusions

Attempts have been made to optimize the activity of time- dependent antibiotic agents in the management of critically ill patients by administering continuous infusions of antibiotics. Although studies have demonstrated more rapid attainment and maintenance of the desired antibiotic concentration with contin-uous antibiotic infusions than with intermittent bolus regimens, this has not yet been translated into improved clinical outcomes.4

Se

rum

an

tib

ioti

c co

nce

ntr

ati

on

Antibiotic–time concentration curve

Time (hours)

Maximum serum

concentration (Cmax)

Area under the time–concentration

curve (AUC)

Minimum inhibitory

concentration (MIC)

Figure 1

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IntensIve care

Critics suggest that the increased volume of distribution and vari-able drug elimination encountered in critically ill patients man-dates the need for therapeutic drug monitoring (a service which is not routinely available in clinical practice for most antimicrobial agents) in order to use continuous antibiotic infusions optimally. Further clinical trials detailing both pharmacodynamic data and clinical outcomes are required before continuous infusions of time-dependent antibiotics can be introduced into routine critical care practice.

Antibiotics: a valuable resource

The appropriate use of antimicrobial agents in healthcare insti-tutions is important if the emergence of increasingly resistant microorganisms is to be controlled. This is particularly true in the intensive care unit. While the use of broad-spectrum empiri-cal antibiotic therapy in the management of critically ill septic patients is entirely appropriate, this must be balanced by sound clinical judgement that seeks to limit the overuse of antimicro-bials in the intensive care unit. The overuse of antimicrobial agents contributes directly to the selection pressure that results in the emergence of resistant pathogens.5

Although initiating antimicrobial therapy in the critically ill unstable patient is entirely appropriate, it may be equally appropriate to delay the initiation of antimicrobials in patients who are suspected of developing an infection but who are clini-cally stable. Such patients should be monitored closely pending results of microbiological investigations. This strategy allows for the appropriate use of targeted narrow-spectrum antimicrobial therapy, and so avoids unnecessary empirical use of agents with a broader spectrum.

In patients who have commenced empirical broad-spectrum antimicrobial therapy, the results of microbiological investiga-tions should prompt a re-evaluation of therapy. If the cultures are


negative and the patient has clinically improved, early cessation of antimicrobial therapy should be considered. If the cultures are positive, then the use of narrower-spectrum antimicrobial agents should be encouraged wherever possible. Patients who receive a prolonged course of broad-spectrum antimicrobials are at increased risk of later infective episodes caused by resistant pathogens.

The development of local antimicrobial guidance for clinicians initiating empirical antibiotic therapy not only serves to guide the clinician in making the appropriate antibiotic choice but also serves to restrict the inappropriate use of broader-spectrum antimicrobial agents. ◆

REFEREnCEs

1 vincent JL, sakr Y, sprung cL, et al. sepsis in european intensive care

units: results of the sOaP study. Crit Care Med 2006; 34: 344–53.

2 Dellinger rP, Levy MM, carlet JM, et al. surviving sepsis campaign:

international guidelines for management of severe sepsis and septic

shock 2008. Crit Care Med 2008; 36: 296–327.

3 estes D. review of pharmacokinetics and pharmacodynamics of

antimicrobial agents. Mayo Clin Proc 1998; 73: 1114–22.

4 Leone M, Martin c. How to break the vicious circle of antibiotic

resistances? Curr Opin Crit Care 2008; 14: 587–92.

5 roberts Ja, Lipmana J, Blotd s, et al. Better outcomes through

continuous infusion of time-dependent antibiotics to critically ill

patients? Curr Opin Crit Care 2008; 14: 390–6.

FURThER REAding

trotman rL, Williamson Jc, shoemaker M, et al. antibiotic dosing in

critically ill adult patients receiving continuous renal replacement

therapy. Clin Infect Dis 2005; 41: 1159–66.

1 © 2009 elsevier Ltd. all rights reserved.

use of antibiotics in the intensive care unit

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