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Is antimicrobial underexposure due to glomerular hyperfiltration a possible cause of increased mortality rate from bacterial infections in critically ill patients?

We read with interest the study of Fuster-Lluch et al (1) suggesting that glomerular hyperfiltration (GHF) is a relatively frequent occurrence among critically ill patients admitted to the intensive care unit. From this study, it appears that on the day of admission more than one-sixth of patients exhibited GHF (16/89, 17.9%), irrespective of the reason for admission (postoperative, multiple trauma or medical pathology). Additionally, several patients with normal glomerular filtration rate at the time of admission developed GHF during the first week. This fact was attributed to a hyperdynamic state leading to an enhanced renal perfusion (2,3), as suggested by the trend toward higher diastolic blood pressure observed in GHF patients (1).

As correctly pointed out by the same authors, GHF may significantly increase renal clearance of some drugs, so that we fully agree with their conclusions about the specific risk of drug underdosing in GHF patients and with their suggestions to support further studies to better define the clinical impact of this.

However, what we are particularly concerned about is the potential role that GHF may have in increasing mortality rate from bacterial infections in critically ill patients treated with standard dosages of renally excreted antimicrobials. Of note, it should not be overlooked that most of the antibacterial agents used to treat life-threatening bacterial infections in critically ill patients, namely beta-lactams, glycopeptides, aminoglycosides and levofloxacin, are hydrophilic or moderately liphophilic drugs which are almost completely cleared as unchanged moiety by the renal route (2). This means that marked underexposure at the infection site may be expected in GHF patients whenever standard dosages of these drugs are used, as recently shown for example with piperacillin (4) and this may obviously favour treatment failure.

A recently published study which assessed the mortality risk according to glomerular filtration rate estimates (eGFR) among 33,386 community patients aged 50 and over collected by family doctors during 2000 in Hull and East Yorkshire, UK, offers interesting insights on this topic (5). The hazard ratio of dying (adjusted for age and gender) in relation to eGFR exhibited a 'U' shaped curve, since both low eGFR (<30 ml/min/1.73 [m.sup.2]) and high eGFR (120 to 150 ml/min/1.73 [m.sup.2]) were equally predictive (hazard ratio 2.60 and 2.63, respectively) of increased mortality compared to patients with eGFR of 60 to 89 ml/min/1.73 [m.sup.2]. Interestingly, when looking at immediate causes of death of those patients who died in hospital (n=2887), the percentage of high eGFR patients dying from infectious and parasitic diseases was almost double that of patients with all other eGFR bands (about 10 % for eGFR of 120 to 150 ml/min/1.73 [m.sup.2] vs less than 5% each for eGFR of 90 to 119, 60 to 89, 30 to 59, <30 ml/min/1.73 [m.sup.2]). Although these findings may occur for several reasons and although it is known that eGFR does not always correlate well with measured GFR, it may be speculatively suggested that the increased mortality rate for infection of the high eGFR patients could be related also to drug underexposure as a consequence of increased renal excretion of antimicrobials.

Prospective studies are required to better define the clinical relevance that GHF may have in increasing failure rate when treating bacterial infections in critically ill patients with standard dosages of renally excreted antimicrobials. Meanwhile, intensive care unit physicians must be aware of the need for a daily reassessment of antimicrobial regimens according to a daily measure of creatinine clearance to optimise efficacy in patients with severe sepsis, as suggested by the Surviving Sepsis Campaign guidelines (6), keeping in mind that the assessment of renal function must not only identify patients with renal impairment, but also identify those with GHF for whom higher dosages of renally excreted antimicrobials may be indicated.

References

(1.) Fuster-Lluch O, Geronimo-Pardo M, Peyro-Garcia R, Lizan-Garcia M. Glomerular hyperfiltration and albuminuria in critically ill patients. Anaesth Intensive Care 2008; 36:674-680.

(2.) Pea F, Viale P, Furlanut M. Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet 2005; 44:1009-1034.

(3.) Pea F, Pavan F, Furlanut M. Clinical relevance of pharmacokinetics and pharmacodynamics in cardiac critical care patients. Clin Pharmacokinet 2008; 47:449-462.

(4.) Conil JM, Georges B, Mimoz O, Dieye E, Ruiz S, Cougot P et al. Influence of renal function on trough serum concentrations of piperacillin in intensive care unit patients. Intensive Care Med 2006; 32:2063-2066.

(5.) Cox HJ, Bhandari S, Rigby AS, Kilpatrick ES. Mortality at low and high estimated glomerular filtration rate values: a 'U' shaped curve. Nephron Clin Pract 2008; 110:c67-72.

(6.) Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 2008; 34:17-60.

F. PEA

M. FURLANUT

P. VIALE

Udine, Italy
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Title Annotation:Correspondence
Author:Pea, F.; Furlanut, M.; Viale, P.
Publication:Anaesthesia and Intensive Care
Article Type:Report
Geographic Code:4EUIT
Date:Mar 1, 2009
Words:835
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