inappropriate 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   conducted a prospective study in order to determine whether recommended -lactam regimens ensure appropriate phamacokinetic / pharmacodynamic exposure against pseudomonas aeruginosa in septic patients treated with continuous renal replacement therapy ( crrt ) . severe sepsis and septic shock cause significant morbidity and mortality . early appropriate empiric broad - spectrum antibiotics and advanced resuscitation therapy acute kidney injury requiring renal replacement therapy occurs in 5% to 6% of critical patients . 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 affected by crrt and may be altered by acute renal failure and critical illness . recommendations for patients who have chronic renal failure and who are undergoing intermittent hemodialysis are not appropriate for the critically ill , because of differences in the mode of renal replacement therapy and in pharmacokinetics . the 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 ) . many studies that focus on calculating the dosing regimen in critical patients fail to consider basic pharmaco - kinetic parameters like volume of distribution ( vd ) , protein binding , weight , residual renal function , hepatic function , mode of crrt , membrane and surface area , sieving coefficient , effluent and dialysate rate , blood flow rate , and severity of illness . these assume either that measurement of antibiotic concentrations is widely available or that the sieving coefficient 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 . crrt is sometimes initiated early in septic patients without unduly impaired renal function to facilitate water balance control . in these circumstances , 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 drug clearance may actually increase in patients with acute renal failure , so hepatic function should also be considered . the modality and dosage of crrt in critical patients vary widely both between and within studies . likewise , a patient may undergo different modalities , blood and ultrafiltration flows may vary , and the prescribed dose could differ from the current dose . changes in crrt modality , blood flow , ultrafiltration rate , or location of fluid replacement require dose adjustments , and interrupting crrt because of multiple filter clotting or for surgical or image procedures may affect plasma drug removal . moreover , recent modifications to crrt , including high - volume hemofiltration , high - adsorption hemofiltration , high - cutoff membranes , and hybrid systems like coupled plasma filtration absorbance , increase -lactam elimination . -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 filtration . their effectiveness depends on how long the serum concentration exceeds a threshold ( four to five times the minimum inhibitory concentration ( mic ) ) . depending on the target organism and the choice of -lactams , the serum concentration should exceed the threshold during 40% to 100% of the dosing interval . this is particularly important for life - threatening pathogens potentially resistant to multiple antibiotics as intermittent dosing may allow drug concentrations to fall below the mic . continuous or extended infusion could maximize the pharmacodynamics of -lactams . finally , tissue concentrations differ from plasma concentrations and vary among antibiotics . 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 . by determining serum concentrations of -lactam antibiotics in patients with sepsis and renal failure under crrt , these authors confirmed that antibiotic dosage is often insufficient in this setting . these findings are clinically relevant : the authors recommend not reducing the dose of -lactams during the first 48 hours and monitoring pharmaco - kinetics thereafter . more studies like this are needed to evaluate the appropriate dosage of other antibiotics in patients with acute renal failure and severe sepsis . crrt : continuous renal replacement therapy ; mic : minimum inhibitory concentration ; vd : volume of distribution .
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 .