Antibiotic dosing recommendations in critically ill patients receiving new innovative kidney replacement therapy.

BACKGROUND: The Tablo Hemodialysis System is a new innovative kidney replacement therapy (KRT) providing a range of options for critically ill patients with acute kidney injury. The use of various effluent rate and treatment durations/frequencies may clear antibiotics differently than traditional KRT. This Monte Carlo Simulation (MCS) study was to develop antibiotic doses likely to attain therapeutic targets for various KRT combinations. METHODS: Published body weights and pharmacokinetic parameter estimates were used to predict drug exposure for cefepime, ceftazidime, imipenem, meropenem and piperacillin/tazobactam in virtual critically ill patients receiving five KRT regimens. Standard free ß-lactam plasma concentration time above minimum inhibitory concentration targets (40-60%fT> MIC and 40-60%fT> MICx4) were used as efficacy targets. MCS assessed the probability of target attainment (PTA) and likelihood of toxicity for various antibiotic dosing strategies. The smallest doses attaining PTA ≥ 90% during 1-week of therapy were considered optimal. RESULTS: MCS determined ß-lactam doses achieving ∼90% PTA in all KRT options. KRT characteristics influenced antibiotic dosing. Cefepime and piperacillin/tazobactam regimens designed for rigorous efficacy targets were likely to exceed toxicity thresholds. CONCLUSION: The flexibility offered by new KRT systems can influence ß-lactam antibiotic dosing, but doses can be devised to meet therapeutic targets. Further clinical validations are warranted.

Vancomycin and daptomycin dosing recommendations in patients receiving home hemodialysis using Monte Carlo simulation.

BACKGROUND: Few drug dosing recommendations for patients receiving home hemodialysis (HHD) have been published which has hindered the adoption of HHD. HHD regimens vary widely and differ considerably from conventional, thrice weekly, in-center hemodialysis in terms of treatment frequency, duration and blood and dialysate flow rates. Consequently, vancomycin and daptomycin clearances in HHD are also likely to be different, consequently HHD dosing regimens must be developed to ensure efficacy and minimize toxicity when these antibiotics are used. Many HHD regimens are used clinically, this study modeled ten common HHD regimens and determined optimal vancomycin and daptomycin dosing for each HHD regimen. METHODS: Monte Carlo simulations using pharmacokinetic data derived from the literature and demographic data from a large HHD program treating patients with end stage kidney disease were incorporated into a one-compartment pharmacokinetic model. Virtual vancomycin and daptomycin doses were administered post-HHD and drug exposures were determined in 5,000 virtual patients receiving ten different HHD regimens. Serum concentration monitoring with subsequent dose changes was incorporated into the vancomycin models. Pharmacodynamic target attainment rates were determined for each studied dose. The lowest possible doses that met predefined targets in virtual patients were chosen as optimal doses. RESULTS: HHD frequency, total dialysate volumes and HHD durations influenced drug exposure and led to different dosing regimens to meet targets. Antibiotic dosing regimens were identified that could meet targets for 3- and 7-h HHD regimens occurring every other day or 4-5 days/week. HHD regimens with 3-day interdialytic periods required higher doses prior to the 3-day period. The addition of vancomycin serum concentration monitoring allowed for calculation of necessary dosing changes which increased the number of virtual subjects meeting pharmacodynamic targets. CONCLUSIONS: Doses of vancomycin and daptomycin that will meet desired pharmacodynamic targets in HHD are dependent on patient and HHD-specific factors. Doses used in conventional thrice weekly hemodialysis are unlikely to meet treatment goals. The antibiotic regimens paired with the HHD parameters studied in this analysis are likely to meet goals but require clinical validation.

Telavancin pharmacokinetics in patients with chronic kidney disease receiving haemodialysis.

BACKGROUND: Telavancin is a lipoglycopeptide antibiotic with limited pharmacokinetic data to guide drug dosing in patients receiving haemodialysis. OBJECTIVES: This study characterized telavancin pharmacokinetics in patients receiving haemodialysis. PATIENTS AND METHODS: This was a Phase IV, prospective, open-label, single-centre, crossover pharmacokinetic study (ClinicalTrials.gov: NCT02392208). Eight subjects with end-stage kidney disease requiring maintenance haemodialysis (mean ±â€ŠSD: 47 ±â€Š20 years, 69.5 ±â€Š17.1 kg) received 5 mg/kg telavancin IV 3 h before starting a 3.5 hour haemodialysis treatment with a high-permeability haemodialyser (haemodialysis period). After a 14 day washout period, a second 5 mg/kg dose was administered post-haemodialysis (control period). Telavancin plasma concentrations were measured over a 2 day period after each dose and non-compartmental pharmacokinetic analyses were performed. RESULTS: The geometric mean (GM) of telavancin overall clearance was 11.2 mL/h/kg (intrinsic clearance and dialytic clearance) in the haemodialysis period and 5.9 mL/h/kg (off-haemodialysis clearance) in the control period [GM ratio (GMR) = 1.89; 90% CI: 1.70-2.10; P < 0.01]. The GM t½ was 13.1 h when haemodialysis occurred 3 h post-dosing in the haemodialysis period but extended to 20.9 h with post-haemodialysis dosing in the control period (GMR = 0.63; 90% CI: 0.54-0.73; P < 0.01). The GM of telavancin plasma concentrations removed by haemodialysis was 27.7%. The GMR of peak plasma concentration and volume of distribution of the haemodialysis period and the control period were 0.88 (90% CI: 0.79-0.98; P = 0.08) and 1.17 (90% CI: 1.05-1.30; P = 0.048), respectively. CONCLUSIONS: Haemodialysis with high-permeability haemodialysers removes telavancin considerably (∼⅓ of body load). Telavancin 5 mg/kg every 48 h post-haemodialysis dosing is recommended, but dose adjustments may be warranted if haemodialysis starts within 3 h of telavancin administration.

Therapeutic Monitoring of Vancomycin for Serious Methicillin-resistant Staphylococcus aureus Infections: A Revised Consensus Guideline and Review by the American Society of Health-system Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists.

Recent clinical data on vancomycin pharmacokinetics and pharmacodynamics suggest a reevaluation of current dosing and monitoring recommendations. The previous 2009 vancomycin consensus guidelines recommend trough monitoring as a surrogate marker for the target area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC). However, recent data suggest that trough monitoring is associated with higher nephrotoxicity. This document is an executive summary of the new vancomycin consensus guidelines for vancomycin dosing and monitoring. It was developed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. These consensus guidelines recommend an AUC/MIC ratio of 400-600 mg*hour/L (assuming a broth microdilution MIC of 1 mg/L) to achieve clinical efficacy and ensure safety for patients being treated for serious methicillin-resistant Staphylococcus aureus infections.

Renal Dosing of Antibiotics: Are We Jumping the Gun?

Antibiotic renal dose adjustments are determined in patients with stable chronic kidney disease and may not translate to patients in late-phase trials and practice. Ceftolozane/tazobactam, ceftazidime/avibactam, and telavancin all carry precautionary statements for reduced clinical response in patients with baseline creatinine clearance of 30-50 mL/min, potentially due to unnecessary dose reduction in the setting of acute kidney injury (AKI). In this review, we discuss the regulatory landscape for antibiotics eliminated by the kidney and highlight the importance of the first 48 hours of therapy. Using a clinical database, we identified AKI on admission in a substantial proportion of patients with pneumonia (27.1%), intraabdominal (19.5%), urinary tract (20.0%), or skin and skin structure infections (9.7%) that resolved by 48 hours in 57.2% of cases. We suggest that deferred renal dose reduction of wide therapeutic index antibiotics could improve outcomes in patients with infectious diseases.

Antibiotic Exposure Profiles in Trials Comparing Intensity of Continuous Renal Replacement Therapy.

OBJECTIVES: To determine whether the probability of target attainment over 72 hours of initial therapy with beta-lactam (cefepime, ceftazidime, piperacillin/tazobactam) and carbapenem (imipenem, meropenem) antibiotics were substantially influenced between intensive and less-intensive continuous renal replacement therapy groups in the Acute Renal Failure Trial Network trial and The RENAL Replacement Therapy Study trial. DESIGN: The probability of target attainment was calculated using pharmacodynamic targets of percentage of time that free serum concentrations (fT): 1) were above the target organism's minimum inhibitory concentration (≥ fT > 1 × minimum inhibitory concentration); 2) were above four times the minimum inhibitory concentration (≥ % fT > 4 × minimum inhibitory concentration); and 3) were always above the minimum inhibitory concentration (≥ 100% fT > minimum inhibitory concentration) for the first 72 hours of antibiotic therapy. Demographic data and effluent rates from the Acute Renal Failure Trial Network and RENAL Replacement Therapy Study trials were used. Optimal doses were defined as the dose achieving greater than or equal to 90% probability of target attainment. SETTING: Monte Carlo simulations using demographic data from Acute Renal Failure Trial Network and RENAL Replacement Therapy Study trials. PATIENTS: Virtual critically ill patients requiring continuous renal replacement therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The pharmacodynamic target of fT greater than 1 × minimum inhibitory concentration led to similarly high rates of predicted response with antibiotic doses often used in continuous renal replacement therapy. Achieving 100% fT greater than minimum inhibitory concentration is a more stringent benchmark compared with T greater than 4 × minimum inhibitory concentration with standard antibiotic dosing. The intensity of effluent flow rates (less intensive vs intensive) did not substantially influence the probability of target attainment of antibiotic dosing regimens regardless of pharmacodynamic target. CONCLUSIONS: Antibiotic pharmacodynamic target attainment rates likely were not meaningfully different in the low- and high-intensity treatment arms of the Acute Renal Failure Trial Network and RENAL Replacement Therapy Study Investigators trials.

Single dose oral ranolazine pharmacokinetics in patients receiving maintenance hemodialysis.

PURPOSE: Ranolazine is a novel anti-angina treatment approved in the United States for chronic stable angina. Ranolazine pharmacokinetics have not been studied previously in patients who receive maintenance hemodialysis. This study describes the pharmacokinetics of ranolazine and three major metabolites (CVT-2738, CVT-2512, CVT-2514) in patients receiving thrice weekly hemodialysis. METHODS: Eight participants receiving maintenance hemodialysis completed this prospective, open-label study (study identifier NCT01435174 at Clinicaltrials.gov). Three participants received a single tablet of ranolazine 500 mg (followed by an interim analysis), and five received 2 tablets of ranolazine 500 mg. Blood samples were collected over 65 h to determine the pharmacokinetic characteristics during and between hemodialysis sessions. Non-compartmental analysis was used to determine the individual pharmacokinetic parameters. RESULTS: Ranolazine off-hemodialysis elimination phase half-lives were 3.6 and 3.9 h for 500 mg and 1000 mg doses, respectively. The time to maximum concentration ranged from 2 to 18 hours and the average maximum concentration was 0.65 ± 0.27 mcg/mL and 1.18 ± 0.48 mcg/mL for ranolazine 500 mg and 1000 mg dose, respectively. The mean hemodialysis percent reduction ratio for the ranolazine 500 mg dose was 52.3 ± 8.1% and for the ranolazine 1000 mg dose was 69.2 ± 37.6%. CONCLUSIONS: Data on ranolazine dosing in patients receiving maintenance hemodialysis is almost non-existent. Given the extent of pharmacokinetic variability observed with the 500 mg and 1000 mg oral doses of ranolazine, neither can be recommended as a starting dose in patients receiving maintenance hemodialysis. Guided by the information gained form this study about the extent of hemodialytic drug clearance, further multi-dose clinical trials of ranolazine are needed to optimize therapeutic outcomes in this patient population.

Influence of hemodialysis on regadenoson clearance in an in vitro hemodialysis model.

BACKGROUND: Regadenoson is a novel pharmacological stress agent whose disposition during hemodialysis is not known. The purpose of this study was to determine the clearance of regadenoson under varying dialytic conditions using an in vitro hemodialysis model. METHODS AND RESULTS: Whole human blood was used to analyze the effect of hemodialysis on the clearance of regadenoson. Regadenoson transmembrane clearance (CLD) was assessed for both a standard permeability and a high permeability polysulfone hemodialyzer with blood/dialysate flow rates of 300/600 and 400/800 mL/min. A two-tailed, paired Student's t test was used to compare regadenoson CLD between hemodialyzer types and flow rates. The mean ± SD regadenoson CLD values ranged between 62.5 ± 11.8 and 89.1 ± 24.0 mL/min for all dialytic conditions. There was no significant difference in regadenoson CLD between hemodialyzer types and flow rates (p > .05). CONCLUSIONS: Hemodialysis enhances the clearance of regadenoson independent of hemodialyzer permeability and blood/dialysate flow rate. This clearance is modest relative to total body clearance and is unlikely to produce a clinically significant outcome.

Prevention of hypophosphatemia during continuous renal replacement therapy-An overlooked problem.

Hypophosphatemia is a common and potentially serious complication occurring during continuous renal replacement therapy (CRRT). Phosphate supplementation is required in the vast majority of patients undergoing CRRT, particularly beyond the first 48 hours. Supplementation can be provided either as a standalone oral or parenteral treatment or as an additive to CRRT solutions. Each approach has advantages and disadvantages, and clinicians must weigh the individual factors most relevant in their practice setting. Currently there are no consensus protocols for phosphate replacement in CRRT, and many centers replete phosphate in response to hypophosphatemia as opposed to pre-emptively. Repletion protocols have also been challenged in recent years by shortages in injectable phosphate solutions. More recently a commercially available phosphate-containing CRRT solution was approved in the United States, but there has been limited clinical experience with this product. In this review, we present recommendations for phosphate repletion in CRRT to prevent hypophosphatemia, and describe our experience using phosphate-containing CRRT solutions.

Ex vivo Rezafungin Adsorption and Clearance During Continuous Renal Replacement Therapy.

BACKGROUND/AIMS: To determine adsorption and transmembrane clearances (CLTM) of rezafungin, a novel long-acting echinocandin, in continuous venovenous hemofiltration (CVVH). METHODS: A validated ex vivo bovine blood CVVH model using polysulfone and AN69 hemodiafilters was used to evaluate urea and rezafungin CLTM at 3 different ultrafiltrate flow rates. Rezafungin adsorption to the CRRT apparatus was determined for each hemodiafilter. RESULTS: The sieving coefficient (SC) from CVVH with 3 different ultrafiltrate flow rates was 0 for both HF1400 and Multiflow-150 hemodiafilters, while urea SC was approximately 1 at all flow rates. Hemodiafilter type and ultrafiltrate flow rate did not influence CLTM. Rezafungin adsorption to the CVVH apparatus was not observed for either hemodiafilter. CONCLUSION: Rezafungin is not removed by CVVH by membrane adsorption or via CLTM. Ultrafiltrate flow rates and hemodiafilter types are unlikely to influence rezafungin CLTM. No dosage adjustment of rezafungin is likely required for critically ill patients receiving CVVH.

Acetaminophen clearance during ex vivo continuous renal replacement therapies.

Intravenous acetaminophen is an adjuvant to opioid use in critically ill and surgical patients requiring continuous renal replacement therapy (CRRT). The objective of this study was to determine the ex vivo transmembrane clearance of intravenous acetaminophen during continuous hemofiltration and hemodialysis. Transmembrane clearance was assessed using a validated ex vivo bovine blood model for CRRT using an F8 or HF1400 hemodiafilter. Ultrafiltrate and dialysate flow rates were 1, 2, and 3 L/h. Urea and acetaminophen clearances were calculated and compared. Acetaminophen was readily cleared by continuous hemofiltration with both hemodiafilters. Acetaminophen clearance rates were 92-98% of ultrafiltrate production rates. Similarly, dialytic acetaminophen clearances approximated dialysate flow rates for both hemodiafilters. Acetaminophen is readily cleared by CRRT. Patients receiving CRRT and acetaminophen may require increased doses for adequate pain control.

Ex vivo Ceftolozane/Tazobactam Clearance during Continuous Renal Replacement Therapy.

BACKGROUND/AIMS: To determine ceftolozane/tazobactam transmembrane clearances (CLTM) in continuous hemofiltration (CHF) and continuous hemodialysis (CHD) and to determine optimal ceftolozane/tazobactam dosing regimens for patients receiving continuous renal replacement therapy (CRRT). METHOD: Validated, ex vivo CHF and CHD bovine blood models using polysulfone (HF1400) and AN69 (Multiflow 150-M) hemofilters were used to evaluate adsorption and CLTM at different effluent flow rates. Monte Carlo simulations (MCS) using pharmacokinetic parameters from published studies and CLTM from this study were used to generate ceftolozane/tazobactam dosing for patients receiving CRRT. RESULTS: CHF and CHD CLTM did not differ at equivalent effluent rates. CLTM approximated effluent flow rates. No adsorption of ceftolozane/tazobactam occurred for either hemofilter. Effluent flow was the most important determinant of MCS-derived doses. CONCLUSION: CRRT clearances of ceftolozane/tazobactam depended on effluent flow rates but not hemofilter types. MCS-derived ceftolozane/tazobactam doses of 750 (500/250)-1,500 (1,000/500) mg every 8 h met pharmacodynamic targets for virtual patients receiving CRRT at contemporary effluent rates.

Dose Timing of Aminoglycosides in Hemodialysis Patients: A Pharmacology View.

Aminoglycosides for patients undergoing intermittent hemodialysis (IHD) have traditionally been dosed at half the normal dose administered at the end of a hemodialysis session. Several investigations have suggested that administering higher doses preceding or with the initiation of dialysis would more readily optimize pharmacodynamic parameters. However, the selection of an optimal aminoglycoside dosing strategy in patients receiving IHD is complex and requires consideration of numerous factors, precluding a singular approach. By reviewing aminoglycoside pharmacokinetics, pharmacodynamics, risks for toxicity and resistance development, and practical considerations, we derive indication- and setting- specific recommendations. We identify some areas (definitive therapy of gram-negative infections in patients receiving predictable hemodialysis sessions, for example) where dosing preceding or with the initiation of dialysis is optimal and feasible, and others (gram-positive synergy, unstable patients with poor/unpredictable vascular access) where postdialysis dosing remains preferred. Finally, given the dearth of data exploring the pharmacodynamics and clinical outcomes of IHD patients receiving aminoglycoside therapy, we identify several key questions in need of investigation.

We Underdose Antibiotics in Patients on CRRT.

Appropriate antibiotic dosing in critically ill, infected, patients receiving continuous renal replacement therapy (CRRT) is crucial to improve patient outcomes. Severe sepsis and septic shock result in changes in pharmacokinetic parameters, including increased volume of distribution, hypoalbuminemia, and changes in renal and nonrenal clearances. The lack of CRRT standardization, nonrecognition of how CRRT variability affects antibiotic removal, fear of antibiotic toxicity, and limited drug dosing resources all contribute to suboptimal antibiotic therapy. Even when antibiotic CRRT pharmacokinetic studies are available, they are often based on old CRRT methodologies that do not exist in contemporary CRRT practice, resulting in unhelpful/inaccurate dosing recommendations. Application of these older doses in Monte Carlo simulation studies reveals that many of the recommended dosing regimens will never attain pharmacodynamic targets. In this review, using cefepime as an example, we illustrate whether clinicians are likely to achieve pharmacokinetic/pharmacodynamic targets when the recommended dosing regimens are prescribed in this patient population. We encourage clinicians to aggressively dose antibiotics with large loading dose and higher maintenance doses to reach the targets.

Antibiotic Dosing in Patients With Acute Kidney Injury: "Enough But Not Too Much".

Increasing evidence suggests that antibiotic dosing in critically ill patients with acute kidney injury (AKI) often does not achieve pharmacodynamic goals, and the continued high mortality rate due to infectious causes appears to confirm these findings. Although there are compelling reasons why clinicians should use more aggressive antibiotic dosing, particularly in patients receiving aggressive renal replacement therapies, concerns for toxicity associated with higher doses are real. The presence of multisystem organ failure and polypharmacy predispose these patients to drug toxicity. This article examines the pharmacokinetic and pharmacodynamic consequences of critical illness, AKI, and renal replacement therapy and describes potential solutions to help clinicians give "enough but not too much" in these very complicated patients.

Fluconazole dosing predictions in critically-ill patients receiving prolonged intermittent renal replacement therapy: a Monte Carlo simulation approach.

Fluconazole is a renally-eliminated antifungal commonly used to treat Candida species infections. In critically-ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic (PK) data are available to guide fluconazole dosing. We used previously-published fluconazole clearance data and PK data of critically-ill patients with acute kidney injury to develop a PK model with the goal of determining a therapeutic dosing regimen for critically-ill patients receiving PIRRT. Monte Carlo simulations were performed to create a virtual cohort of patients receiving different fluconazole dosing regimens. Plasma drug concentration-time profiles were evaluated on the probability of attaining a mean 24-hour area under the drug concentration-time curve to minimum inhibitory concentration ratio (AUC24h : MIC) of 100 during the initial 48 hours of antifungal therapy. At the susceptibility breakpoint of Candida albicans (2 mg/L), 93 - 96% of simulated subjects receiving PIRRT attained the pharmacodynamic target with a fluconazole 800-mg loading dose plus 400 mg twice daily (q12h or pre and post PIRRT) regimen. Monte Carlo simulations of a PK model of PIRRT provided a basis for the development of an informed fluconazole dosing recommendation when PK data was limited. This finding should be validated in the clinical setting.

Tedizolid Adsorption and Transmembrane Clearance during in vitro Continuous Renal Replacement Therapy.

BACKGROUND/AIMS: To study transmembrane clearance (CLTM) and adsorption of tedizolid, a novel oxazolidinone antibiotic, in continuous hemofiltration (CVVH) and continuous hemodialysis (CVVHD). METHODS: In vitro CVVH/CVVHD models with polysulfone and AN69 hemodiafilters were used. Tedizolid CLTM during CVVH/CVVHD was assessed at various ultrafiltrate (Quf) and dialysate rates (Qd). Tedizolid adsorption was tested in a recirculating CVVH model over 4 h. RESULTS: In CVVH, CLTM did not differ between filter types. In CVVHD, tedizolid CLTM was significantly higher with the polysulfone hemodiafilter at Qd 6 l/h (p < 0.02). Tedizolid exhibited irreversible adsorption to the CRRT apparatus and bound significantly higher to the polysulfone hemodiafilter. CONCLUSION: Tedizolid's CLTM is dependent on Qd, Quf, and hemodiafilter type. At conventional CRRT rates, tedizolid CLTM appears modest relative to total body clearance and is unlikely to require dose adjustments. CRRT adsorption in the clinical setting is likely less than what we observed in this in vitro, continuously recirculating blood model.

Pharmacokinetics of ertapenem in critically ill patients receiving continuous venovenous hemodialysis or hemodiafiltration.

This study characterizes the pharmacokinetics of ertapenem, a carbapenem antibiotic, in critically ill adult subjects receiving continuous renal replacement therapy (CRRT). Eight critically ill patients with suspected/known Gram-negative infections receiving continuous venovenous hemodialysis (CVVHD) or continuous venovenous hemodiafiltration (CVVHDF) and ertapenem were enrolled. One gram of ertapenem was infused over 30 min. Predialyzer blood samples were drawn with the first dose of ertapenem from the hemodialysis tubing at time zero, 30 min, and 1, 2, 4, 8, 12, 18, and 24 h after the start of the ertapenem infusion. Effluent was collected at the same time points. Ertapenem total serum, unbound serum, and effluent concentrations from all eight subjects were used simultaneously to perform a population compartmental pharmacokinetic modeling procedure using NONMEM. Monte Carlo simulations were performed to evaluate the ability of several ertapenem dosing regimens (500 mg once daily, 750 mg once daily, 500 mg twice daily, and 1,000 mg once daily) to obtain effective unbound serum concentrations above 0.5, 1, and 2 µg/ml. For our simulated patients, all regimens produced unbound ertapenem concentrations above 2 µg/ml for 40% of the dosing interval for at least 96% of simulated patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00877370.).

Antibiotic dosing in critically ill patients receiving CRRT: underdosing is overprevalent.

Published CRRT drug dosing algorithms and other dosing guidelines appear to result in underdosed antibiotics, leading to failure to attain pharmacodynamic targets. High mortality rates persist with inadequate antibiotic therapy as the most important risk factor for death. Reasons for unintended antibiotic underdosing in patients receiving CRRT are many. Underdosing may result from lack of the recognition that better hepatic function in AKI patients yields higher nonrenal antibiotic clearance compared to ESRD patients. Other factors include the variability in body size and fluid composition of patients, the serious consequence of delayed achievement of antibiotic pharmacodynamic targets in septic patients, potential subtherapeutic antibiotic concentrations at the infection site, and the influence of RRT intensity on antibiotic concentrations. Too often, clinicians weigh the benefits of overcautious antibiotic dosing to avoid antibiotic toxicity too heavily against the benefits of rapid attainment of therapeutic antibiotic concentrations in critically ill patients receiving CRRT. We urge clinicians to prescribe antibiotics aggressively for these vulnerable patients.