Prescribing in the critically ill patient can be a challenge due to a number of factors impacting on pharmacology:
- variable enteral absorption and interaction with enteral feed
- less protein binding in hypoalbuminaemic states
- extravascular volume expansion with fluid loading and capillary leak can alter the volume of distribution
- altered hepatic metabolism of drugs
- impaired renal excretion
- accumulation of toxic metabolites
- removal by renal replacement therapy
- interaction with other drugs
There’s another factor to bear in mind, though, which has been recently highlighted in the context of antibiotic prescription: that of Augmented Renal Clearance (ARC).
Some ICU patients have supraphysiologic renal function. Several studies have demonstrated significant numbers of ICU patients with higher than normal creatinine clearance. This is thought to be due to varying combinations of the following factors:
- Low systemic vascular resistance and increased cardiac output leading to increased renal blood flow
- Above factors enhanced by aggressive fluid and vasoactive therapy in pursuit of haemodynamic targets
- These lead to increase delivery of solute to the kidneys and increased clearance
This can have implications for prescribing: the serum creatinine will not identify these patients, but it is possible that ARC will result in less effective therapy for a given dose of a renally-excreted drug, for example beta-lactam antibiotics.
An editorial by critical care physician Dr Andrew Shorr highlights the inadequacy of basing prescribing recommendations on data from the ex-vivo interaction between drug and pathogen:
‘To believe that all patients will respond in the same fashion and with the same trajectory is to become handcuffed by the median response noted in clinical trials……….The central fallacy of the bug-drug approach is that it misses the key role of the host.’
Sub-therapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations
Chest. 2011 Dec 22. [Epub ahead of print] Free Full Text
Antibiotics in the critically ill: the bug, drug, host triad
Chest. 2012 Jul 1;142(1):8-10 Free Full Text
Should prophylactic antibiotics be given to burns patients? A systematic review of 17 trials concludes they may reduce all-cause mortality when given for 4-14 days after admission; there was a reduction in pneumonia with systemic prophylaxis and a reduction in wound infections with perioperative prophylaxis. However the overall methodological quality of the trials was poor and in three trials, resistance to the antibiotic used for prophylaxis significantly increased. The authors consequently do not recommend prophylaxis for patients with severe burns other than perioperatively.
Take home message: not needed as part of critical care resuscitation
Prophylactic antibiotics for burns patients: systematic review and meta-analysis
BMJ. 2010 Feb 15;340:c241
A retrospective review of appropriate vs inappropriate antimicrobial therapy was undertaken in over four thousand septic shock patients from multiple centres. In terms of definitions, the authors state:
“Appropriate antimicrobial therapy was considered to have been initiated if an antimicrobial with in vitro activity appropriate for the isolated pathogen or pathogens (or in the case of culture-negative septic shock, an antimicrobial or antimicrobial agent concordant with accepted international norms for empiric therapy and modified to local flora) was either the first new antimicrobial agent with which therapy was started after the onset of recurrent or persistent hypotension or was initiated within 6 h of the administration of the first new antimicrobial agent. Otherwise, inappropriate therapy was considered to have been initiated.”
The results are striking: survival rates after appropriate and inappropriate initial therapy were 52.0% and 10.3%, respectively (odds ratio [OR], 9.45; 95% CI, 7.74 to 11.54; p < 0.0001).
A multivariable logistic regression analysis of possible factors that may affect outcome showed the appropriateness of the initial antimicrobial therapy remained most strongly associated with outcome (OR, 8.99; 95% CI, 6.60 to 12.23; p < 0.0001) among all the risk factors assessed.
Initiation of Inappropriate Antimicrobial Therapy Results in a Fivefold Reduction of Survival in Human Septic Shock
Chest. 2009 Nov;136(5):1237-48
N.B. This work was done by the same authors who brought us the study that showed the earlier antibiotics were given to hypotensive septic patients, the better the outcome:
Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34:1589-1596
In a multicentre study in France, adult patients expected to stay in the intensive care unit for more than 3 days who had suspected bacterial infections were randomised to have antibiotics started or stopped based on predefined cut-off ranges of procalcitonin concentrations (n=307 patients) or to receive antibiotics according to present guidelines (control, n=314). Patients in the procalcitonin group had significantly more days without antibiotics than did those in the control group (14∙3 days [SD 9·1] vs 11∙6 days [SD 8∙2]; absolute difference 2∙7 days, 95% CI 1∙4 to 4∙1, p<0∙0001) without a difference in 28-day or 60-day mortality or ICU length of stay. An editorial points out that as an open-label trial, a treatment bias might have occurred because physicians were aware that their patients had had procalcitonin measurements taken, raising the question as to whether the procalcitonin concentrations themselves or simply the act of measuring procalcitonin led to the recorded reduction in antibiotic use.
The study used the following guidelines for starting, continuing, or stopping of antibiotics according to procalcitonin concentrations:
Guidelines for starting of antibiotics – Excludes situations requiring immediate antibiotic treatment (eg, septic shock, purulent meningitis)
- Concentration <0·25 μg/L – Antibiotics strongly discouraged
- Concentration ≥0·25 and <0·5 μg/L – Antibiotics discouraged
- Concentration ≥0·5 and <1 μg/L – Antibiotics encouraged
- Concentration ≥1 μg/L – Antibiotics strongly encouraged
If blood sample taken for calculation of procalcitonin concentration at early stage of episode, obtain a second procalcitonin concentration 6–12 h later
Guidelines for continuing or stopping of antibiotics
- Concentration <0·25 μg/L – Stopping of antibiotics strongly encouraged
- Decrease by ≥80% from peak concentration, or concentration ≥0·25 and <0·5 μg/L – Stopping of antibiotics encouraged
- Decrease by <80% from peak concentration, and concentration ≥0·5 μg/L – Continuing of antibiotics encouraged
- Increase of concentration compared with peak concentration and concentration ≥0·5 μg/L – Changing of antibiotics strongly encouraged
Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial
Lancet. 2010 Feb 6;375(9713):463-74