The Effect of Renal Replacement Therapy and Antibiotic Dose on Antibiotic Concentrations in Critically Ill Patients: Data From the Multinational Sampling Antibiotics in Renal Replacement Therapy Study.

BACKGROUND: The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. METHODS: We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. RESULTS: We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4-8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35-65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P < .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9-18.8), piperacillin was 78.6 mg/L (49.5-127.3), tazobactam was 9.5 mg/L (6.3-14.2), and vancomycin was 14.3 mg/L (11.6-21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. CONCLUSIONS: In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.

Can we use an ex vivo continuous hemofiltration model to describe the adsorption and elimination of meropenem and piperacillin?

OBJECTIVES: To determine the adsorption and elimination characteristics of meropenem and piperacillin during simulated continuous renal replacement therapy (CRRT), and to compare the observed data from this ex vivo study with previous data from clinical studies. METHOD: This was an experimental study utilizing a modified CRRT circuit and polysulfone membrane (1.2 m2), circulated with a blood-crystalloid mixture. Adsorption onto the CRRT circuit was tested over a 4-h period, and clearance was assessed separately using variable continuous hemofiltration settings. RESULTS: A rapid 9% reduction in circulating meropenem and piperacillin concentrations was observed at approximately 0.5 and 1.0 h for each antibiotic, respectively. The post-dilution setting was associated with a significantly higher sieving coefficient (Sc) and filter clearance (CLfilter) (mean ± SD) (Sc 1.14 ± 0.10 versus 1.06 ± 0.04; CLfilter 19.05 ± 1.63 versus 17.59 ± 0.62 ml/min, P values < 0.05) for meropenem. No significant differences were observed for piperacillin pharmacokinetics. Clinically comparable Sc data were observed between data obtained from the ex vivo study and data from previous clinical studies, for both antibiotics. CONCLUSIONS: Meropenem and piperacillin appear to be rapidly adsorbed into the CRRT circuit, and the delivery site of fluid replacement significantly influences meropenem pharmacokinetics. However, these findings are likely to be clinically insignificant and not affect dosing requirements. This ex vivo method could be a surrogate for future clinical pharmacokinetic studies of CRRT. Further research is required to explore the applicability of the ex vivo method to further characterize antibiotic pharmacokinetics during CRRT.

Pharmacokinetics of piperacillin in critically ill patients receiving continuous venovenous haemofiltration: A randomised controlled trial of continuous infusion versus intermittent bolus administration.

Here we describe the pharmacokinetics of piperacillin administered by continuous infusion (CI) versus intermittent bolus (IB) dosing in critically ill patients receiving continuous venovenous haemofiltration (CVVH) and compare the frequency of pharmacodynamic/pharmacokinetic (PK/PD) target attainment with each dosing strategy. This was a prospective pharmacokinetic trial in 16 critically ill patients with severe sepsis or septic shock undergoing CVVH and randomised to receive either CI or IB administration of a standard daily dose of piperacillin/tazobactam (11.25g/day on Day 1 followed by 9g/day). Serial blood samples were measured on two occasions. Piperacillin pharmacokinetics were calculated using a non-compartmental approach. Blood concentrations were compared with established PK/PD targets. On occasion 1 (Days 1-3 of therapy), IB administration resulted in significantly higher piperacillin peak concentrations (169 vs. 89mg/L; P=0.002), whereas significantly higher steady-state concentrations were observed in CI patients (83 vs. 57mg/L; P=0.04). Total clearance and clearance not mediated by CVVH were significantly higher with CI administration [median (interquartile range), 1.0 (0.7-1.1) and 0.8 (0.6-1.0)mL/kg/min; P=0.001 and 0.001, respectively]. The estimated unbound piperacillin concentrations were four times above the target susceptibility breakpoint (16mg/L) for the entire dosing interval (100%fT>4xMIC) in 87.5% of patients receiving CI administration (sampling occasion 1), compared with 62.5% of IB patients achieving the desired target (50%fT>4xMIC). Compared with IB dosing, and despite similar CVVH settings, CI administration of piperacillin results in a pharmacokinetic profile that may optimise outcomes for less susceptible pathogens.

How can we ensure effective antibiotic dosing in critically ill patients receiving different types of renal replacement therapy?

Determining appropriate antibiotic dosing for critically ill patients receiving renal replacement therapy (RRT) is complex. Worldwide unstandardized and heterogeneous prescribing of RRT as well as altered patient physiology and pathogen susceptibility all cause drug disposition to be much different to that seen in non-critically ill patients. Significant changes to pharmacokinetic parameters, including volume of distribution and clearance, could be expected, in particular, for antibiotics that are hydrophilic with low plasma protein binding and that are usually primarily eliminated by the renal system. Antibiotic clearance is likely to be significantly increased when higher RRT intensities are used. The combined effect of these factors that alter antibiotic disposition is that non-standard dosing strategies should be considered to achieve therapeutic exposure. In particular, an aggressive early approach to dosing should be considered and this may include administration of a 'loading dose', to rapidly achieve therapeutic concentrations and maximally reduce the inoculum of the pathogen. This approach is particularly important given the pharmacokinetic changes in the critically ill as well as the increased likelihood of less susceptible pathogens. Dose individualization that applies knowledge of the RRT and patient factors causing altered pharmacokinetics remains the key approach for ensuring effective antibiotic therapy for these patients. Where possible, therapeutic drug monitoring should also be used to ensure more accurate therapy. A lack of pharmacokinetic data for antibiotics during the prolonged intermittent RRT and intermittent hemodialysis currently limits evidence-based antibiotic dose recommendations for these patients.

Interethnic differences in pharmacokinetics of antibacterials.

BACKGROUND: Optimal antibacterial dosing is imperative for maximising clinical outcome. Many factors can contribute to changes in the pharmacokinetics of antibacterials to the extent where dose adjustment may be needed. In acute illness, substantial changes in important pharmacokinetic parameters such as volume of distribution and clearance can occur for certain antibacterials. The possibility of interethnic pharmacokinetic differences can further complicate attempts to design an appropriate dosing regimen. Factors of ethnicity, such as genetics, body size and fat distribution, contribute to differences in absorption, distribution, metabolism and elimination of drugs. Despite extensive previous work on the altered pharmacokinetics of antibacterials in some patient groups such as the critically ill, knowledge of interethnic pharmacokinetic differences for antibacterials is limited. OBJECTIVES: This systematic review aims to describe any pharmacokinetic differences in antibacterials between different ethnic groups, and discuss their probable mechanisms as well as any clinical implications. METHODS: We performed a structured literature review to identify and describe available data of the interethnic differences in the pharmacokinetics of antibacterials. RESULTS: We found 50 articles that met our inclusion criteria and only six of these compared antibacterial pharmacokinetics between different ethnicities within the same study. Overall, there was limited evidence available. We found that interethnic pharmacokinetic differences are negligible for carbapenems, most ß-lactams, aminoglycosides, glycopeptides, most fluoroquinolones, linezolid and daptomycin, whereas significant difference is likely for ciprofloxacin, macrolides, clindamycin, tinidazole and some cephalosporins. In general, subjects of Asian ethnicity achieve drug exposures up to two to threefold greater than Caucasian counterparts for these antibacterials. This difference is caused by a comparatively lower volume of distribution and/or drug clearance. CONCLUSION: Interethnic pharmacokinetic differences of antibacterials are likely; however, the clinical relevance of these differences is unknown and warrants further research.

Pharmacokinetics of meropenem in critically ill patients receiving continuous venovenous haemofiltration: a randomised controlled trial of continuous infusion versus intermittent bolus administration.

The objective of this study was to describe the pharmacokinetics of meropenem, administered by continuous infusion (CI) or intermittent bolus (IB), in critically ill patients receiving continuous venovenous haemofiltration (CVVH) and to evaluate the frequency of pharmacokinetic/pharmacodynamic target attainment with each dosing strategy. This was a prospective, randomised controlled trial in critically ill patients receiving CVVH and administered meropenem by CI or IB. Serial meropenem concentrations in plasma and ultrafiltrate were measured after administration of a standard total daily dose (4 g/day on Day 1, followed by 3g/day thereafter) on two occasions during antibiotic therapy. Meropenem pharmacokinetic parameters were calculated using a non-compartmental approach. Sixteen critically ill patients receiving CVVH concurrently treated with meropenem were randomised to CI (n = 8) or IB dosing (n = 8). IB administration resulted in higher maximum concentrations (C(max)) [64.7 (58.9-80.3) and 64.8 (48.5-81.8) mg/L, respectively] on both sampling occasions compared with CI (P < 0.01 and P = 0.04, respectively). CI resulted in a higher meropenem steady-state concentration (Css) on occasion 1 [26.0 (24.5-41.6) mg/L] compared with the minimum concentration (C(min)) observed for IB patients [17.0 (15.7-19.8)mg/L; P < 0.01]. CVVH contributed to ca. 50% of meropenem total clearance in these patients. The administered meropenem doses resulted in plasma drug concentrations that were >4× the targeted susceptibility breakpoint (2mg/L) for 100% of the dosing interval, for both groups, on both occasions. CI could be an alternative to IB for meropenem administration in critically ill patients receiving CVVH.

A national survey of renal replacement therapy prescribing practice for acute kidney injury in Malaysian intensive care units.

OBJECTIVES: To describe renal replacement therapy (RRT) prescribing practices in Malaysian intensive care units (ICU), and compare this with previously published data from other regions. METHOD: A survey was sent to physicians responsible for prescribing RRT in major ICU throughout Malaysia. The questionnaire sought information on the physicians' background, and detailed information regarding RRT settings. RESULTS: Nineteen physicians from 24 sites throughout Malaysia responded to the survey (response rate 79.2%). Sixteen respondents were intensivists (84%), 2 were anaesthetists (11%) and one was a nephrologist (5%). The majority (58%) used continuous venovenous haemofiltration (CVVH) as the treatment of choice for acute kidney injury (AKI) in critically ill patients. RRT prescription was predominantly practitioner-dependent (63%), while 37% reported use of a dedicated protocol. The mean blood flow rate and effluent flow rate used for continuous RRT (CRRT) were 188.9 ± 28.9 mL/min and 30.6 ± 4.7 mL/kg/h respectively. Replacement fluid solutions containing both lactate and bicarbonate were commonly used during CRRT, applied both pre- and post-dilution. CONCLUSION: CRRT was the first-choice modality used to treat AKI in critically ill patients. CVVH was the most common CRRT technique used, while other RRT modalities were used less frequently. Overall, RRT practices were similar to those observed in other regions, although the modality and settings used were slightly different, likely due to local availability.

The impact of variation in renal replacement therapy settings on piperacillin, meropenem, and vancomycin drug clearance in the critically ill: an analysis of published literature and dosing regimens*.

OBJECTIVES: To describe the effect of different renal replacement therapy modalities and settings on the clearance of meropenem, piperacillin, and vancomycin in critically ill patients and to evaluate the frequency with which current dosing regimens achieve therapeutic concentrations. DESIGN: Regression analyses of published pharmacokinetic data. SETTING: Pubmed was searched for relevant articles published between 1952 and 2013. SUBJECTS: Original research articles describing the pharmacokinetics of meropenem, piperacillin, and vancomycin in critically ill patients receiving renal replacement therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data from 30 studies were analyzed. The mean age of the patient groups involved in studies of meropenem, piperacillin, and vancomycin were 55.3, 60.3, and 56.9 years, respectively. The mean blood and effluent flow rates used for each antibiotic were 151.3 and 33.8 mL/min, 131.8 and 27.3 mL/min, and 189.3 and 35.6 mL/min, respectively, in continuous renal replacement therapy studies. Correlations existed between effluent flow rate in continuous renal replacement therapy and extracorporeal clearance for meropenem (rs = 0.43; p = 0.12), piperacillin (rs = 0.77; p = 0.10), and vancomycin (rs = 0.90; p = 0.08). Current dosing regimens achieved target concentrations for meropenem (89%), piperacillin (83%), and vancomycin (60%) against susceptible pathogens. CONCLUSIONS: Effluent flow rate appears to be a reliable predictor of antibiotic clearance in critically ill patients despite significantly altered pharmacokinetics in these patients. Higher dosing regimens maybe required in critically ill patients receiving renal replacement therapy, in the presence of high effluent flow rates and/or the presence of poorly susceptible pathogens, particularly for vancomycin.

Improving antibiotic dosing in special situations in the ICU: burns, renal replacement therapy and extracorporeal membrane oxygenation.

PURPOSE OF REVIEW: Antibiotic dosing for critically ill patients that is derived from other patient groups is likely to be suboptimal because of significant antibiotic pharmacokinetic changes, particularly in terms of drug volume of distribution and clearance. Organ support techniques including renal replacement therapy (RRT) and extracorporeal membrane oxygenation (ECMO) increase the pharmacokinetic variability. This article reviews the recently published antibiotic pharmacokinetic data associated with burns patients, those receiving continuous RRT (CRRT), sustained low-efficiency dialysis (SLED) and ECMO. RECENT FINDINGS: These groups develop increases in volume of distribution that necessitate the use of higher initial doses to rapidly achieve therapeutic antibiotic concentrations. Burns patients have supranormal drug clearances requiring more frequent administration of antibiotics. Patients receiving CRRT or SLED have variable drug clearances related to different equipment and RRT settings at different institutions. ECMO presents a different challenge because there is such a dearth of data with higher than standard doses potentially required, even in the presence of end-organ failure. SUMMARY: In the context of such variable pharmacokinetics, a guideline approach to dosing remains elusive because of insufficient available data and, therefore, use of therapeutic drug monitoring should be considered advantageous where possible.