Appropriate antibiotic dosing in severe sepsis and acute renal failure: factors to consider

Severe sepsis and septic shock cause considerable morbidity and mortality. Early appropriate empiric broad-spectrum antibiotics and advanced resuscitation therapy are the cornerstones of treatment for these conditions. In prescribing an antibiotic regimen in septic patients with acute renal failure treated with continuous renal replacement therapy, several factors should be considered: pharmacokinetics, weight, residual renal function, hepatic function, mode of renal replacement therapy (membrane and surface area, sieving coefficient, effluent and dialysate rate, and blood flow rate), severity of illness, microorganism, minimum inhibitory concentration, and others. Studies that determine the serum antibiotic concentrations are very useful in establishing the correct dosage in critical patients.

Ina ppropriate antimicrobial therapy refers not only to an unsuitable drug choice in terms of spectrum of activity but also to an inadequate dosing regimen. With this in mind, Seyler and colleagues [1] conducted a prospective study in order to determine whether recommended βlactam regimens ensure appro priate phamacokinetic/ pharma co dynamic exposure against Pseudomonas aerugi nosa in septic patients treated with continuous renal replacement therapy (CRRT).
Severe sepsis and septic shock cause signifi cant morbidity and mortality. Early appropriate empiric broadspectrum antibiotics and advanced resuscitation therapy are the cornerstones of treatment for these condi tions [2]. Acute kidney injury requiring renal replace ment therapy occurs in 5% to 6% of critical patients. Th ese patients use signifi cant resources and up to 60% die from their injuries [3]. Optimized antibiotic dosing may help reduce this burden; however, data to guide dosing in patients with severe sepsis/septic shock and multiple organ dysfunction under CRRT are scant. Antibiotic dosing in these conditions is complicated, and incorrect dosage may result in drug toxicity or treatment failure and resistance.
Antibacterial pharmacokinetics are aff ected by CRRT and may be altered by acute renal failure and critical illness [4]. Recommendations for patients who have chronic renal failure and who are undergoing intermittent hemodialysis are not appropriate for the critically ill, because of diff erences in the mode of renal replacement therapy and in pharmacokinetics [5]. Th e optimal dose of antibiotics is usually based on theoretical considerations derived from data from non-critical patients (healthy individuals or those with chronic renal failure with dosage adjustment based on creatinine clearance) [6]. Many studies that focus on calculating the dosing regimen in critical patients fail to consider basic pharmacokinetic parameters like volume of distribution (Vd), protein binding, weight, residual renal function, hepatic function, mode of CRRT, membrane and surface area, sieving coeffi cient, effl uent and dialysate rate, blood fl ow rate, and severity of illness. Various dose adjustment equations have been proposed for critical patients requiring CRRT. Th ese assume either that measurement of antibiotic concentrations is widely available or that the sieving coeffi cient can be accurately estimated from data on protein binding obtained from non-critical patients. Only unbound antibiotic is pharmacologically active, but serum protein levels in critical patients vary considerably, so the proportion of unbound drug is unpredictable [7,8].
CRRT is sometimes initiated early in septic patients without unduly impaired renal function to facilitate water balance control. In these circumstances, the creatinine clearance can be substantially maintained [9,10]. If we add the clearance of the extracorporeal circuit, the dose must be adjusted to avoid underdosage. Critical patients can have hepatic dysfunction but hepatic

Abstract
Severe sepsis and septic shock cause considerable morbidity and mortality. Early appropriate empiric broad-spectrum antibiotics and advanced resuscitation therapy are the cornerstones of treatment for these conditions. In prescribing an antibiotic regimen in septic patients with acute renal failure treated with continuous renal replacement therapy, several factors should be considered: pharmacokinetics, weight, residual renal function, hepatic function, mode of renal replacement therapy (membrane and surface area, sieving coeffi cient, effl uent and dialysate rate, and blood fl ow rate), severity of illness, microorganism, minimum inhibitory concentration, and others. Studies that determine the serum antibiotic concentrations are very useful in establishing the correct dosage in critical patients. drug clearance may actually increase in patients with acute renal failure, so hepatic function should also be considered [11].
Th e modality and dosage of CRRT in critical patients vary widely both between and within studies. Likewise, a patient may undergo diff erent modalities, blood and ultra fi ltration fl ows may vary, and the prescribed dose could diff er from the current dose. Changes in CRRT modality, blood fl ow, ultrafi ltration rate, or location of fl uid replacement require dose adjustments, and interrupting CRRT because of multiple fi lter clotting or for surgical or image procedures may aff ect plasma drug removal. Adsorption of antibiotics on the fi lter may also result in drug elimination. Th e clinical importance of βlactam adsorption is unknown. Moreover, recent modifications to CRRT, including high-volume hemofi ltration, high-adsorption hemofi ltration, high-cutoff membranes, and hybrid systems like coupled plasma fi ltration absorbance, increase β-lactam elimination [12].
β-lactams have low molecular weights, low Vd (0.3 to 0.4 L/kg), and relatively low protein binding (10% to 68%). Nearly all are excreted primarily unchanged via glomerular fi ltration. Th us, hemofi ltration removes β-lactams, so CRRT requires dosage adjustments. β-lactams have timedependent bactericidal activity and a slow continuous bactericidal eff ect. Th eir eff ectiveness depends on how long the serum concentration exceeds a threshold (four to fi ve times the minimum inhibitory concentration (MIC)). Depending on the target organism and the choice of β-lactams, the serum concentration should exceed the threshold during 40% to 100% of the dosing interval. Th is is particularly important for life-threatening pathogens potentially resistant to multiple antibiotics as intermittent dosing may allow drug concentrations to fall below the MIC [13]. Continuous or extended infusion could maximize the pharmacodynamics of β-lactams [14]. Finally, tissue concentrations diff er from plasma concentrations and vary among antibiotics [15].
Given the number of variables to consider for antibiotic prescription in critical patients undergoing CRRT and the deleterious impact of underdosage, data from real patients are important. Studies should focus on infections with high intensive care unit incidence caused by germs with high multi-antibiotic resistance, as in the article by Seyler and colleagues [1]. By determining serum concentrations of β-lactam antibiotics in patients with sepsis and renal failure under CRRT, these authors confi rmed that antibiotic dosage is often insuffi cient in this setting. Th ese fi ndings are clinically relevant: the authors recommend not reducing the dose of β-lactams during the fi rst 48 hours and monitoring pharmacokinetics thereafter. More studies like this are needed to evaluate the appropriate dosage of other antibiotics in patients with acute renal failure and severe sepsis.