Stanford Antimicrobial Safety and Sustainability Program

Approval date: 5/2021

Stanford Health Care PIRRT Antimicrobial Dosing Resource

Background:
Prolonged intermittent renal replacement therapy (PIRRT) is a hybrid renal replacement strategy that is used for
critically ill patients with acute kidney injury. Similar to CRRT, it is a temporary modality used in the setting of
hemodynamic instability; however, it is run over a fraction of 24-hour period (i.e. 6-18 hours). Similar to iHD, this form
of renal replacement is often provided multiple times a week. Advantages of PIRRT over CRRT include earlier patient
mobilization and greater flexibility for procedures during the day.

PIRRT antimicrobial dosing differs from CRRT dosing, as there are PK phases (intra-dialytic and inter-dialytic
phases). For dialyzable drugs, the half-life of the drug will be shorter in the intra-dialytic phase compared to the inter-
dialytic phase. This must be considered when dosing antimicrobials and extrapolating all CRRT antimicrobial dosing
regimens to patients undergoing PIRRT is not appropriate.

How to use this resource:

While there are multiple benefits to PIRRT, there is limited clinical data to inform antimicrobial dosing. This dosing
resource was developed with limited published data available. PIRRT settings may vary among centers. Use caution
when extrapolating these guidelines to each patient. Refer to the appendix for an in-depth summary of each dosing
recommendation. If there are significant toxicity or efficacy concerns when treating patients, consider an infectious
diseases consultation or contacting an infectious diseases pharmacist.

Stanford PIRRT Practice (may be variable):

Traditional run time: ~12 hours (shorter depending on patient tolerability)
Blood flow rate: 150-300ml/min
Dialysate flow rate (for 12-hour PIRRT session): 20-25ml/kg/hr
Effluent rate (depending on fluid balance goal): ~20-25ml/kg/hr

Recommended PIRRT Timing of dose

Antimicrobial Comments
dose
It is not recommended to dose
Amphotericin No renal dose adjustment or dose timing recommendations adjust amphotericin for patients
undergoing RRT.
Ampicillin/ No specific Based on a PK case study of 12
3 g IV every 8 hours recommendations critically ill patients.
Sulbactam
Based on the results of a PK
Caspofungin study, in which the effects of RRT
No renal dose adjustment or dose timing recommendations
on caspofungin were negligible.
No specific Informed by multiple studies,
2 g load then 1 g (EI) IV every 8
Cefepime recommendation including case reports and a
hours
Monte Carlo Simulation.
No specific Informed by multiple studies,
2 g load then 1 g IV every 8
Ceftazidime recommendations including case reports and a
hours
Monte Carlo Simulation.
Non-HAP/VAP indication: 750
mg IV every 8 hours No specific
Ceftolozane/ recommendations Based on the results of a case
Tazobactam report.
HAP/VAP: 1500 mg IV every 8
hours
Based on the results of a case
Ceftriaxone No renal dose adjustment or dose timing recommendations
report.
 Stanford Antimicrobial Safety and Sustainability Program
Approval date: 5/2021

Dose should be
400 mg IV every 12 hours or administered following
Ciprofloxacin Based on the results of a Monte
500 mg PO every 12 hours
cessation of PIRRT Carlo Simulation

Skin/Soft tissue: 4 mg/kg IV

every 24 hours Dose should be
administered following Based on the results of a
Daptomycin prospective, single dose PK
Bacteremia/Endovascular/E. cessation of PIRRT
faecium infections: study.
6-8 mg/kg IV every 24 hours
Based on the results of a
One dose should be prospective open label study and
Ertapenem 500 mg IV every 12 hours administered following
Monte Carlo Simulation. 1-gram
cessation of PIRRT
daily dosing has also been
studied.
Pseudomonas: 750 mg load
then 500 mg IV every 24 hours Dose should be
administered following Based on the results of a Monte
Levofloxacin Carlo Simulation.
Non-Pseudomonas: 750 mg cessation of PIRRT
load then 250 mg IV every 24
hours
Based on the results of a PK
One dose should be study. Consider an alternative
No renal dose adjustment administered following
Linezolid agent for treatment durations > 14
recommended cessation of PIRRT days or closely monitor for
toxicity.
One dose should be
administered following Informed by multiple studies,
Meropenem 1 g (EI) IV every 12 hours including case reports and a
cessation of PIRRT
Monte Carlo Simulation.

General: 3.375 (EI) IV every 8

hours Informed by multiple studies,
Piperacillin/ No specific including case reports and a
Tazobactam Severe/sepsis/CF/nosocomial recommendations Monte Carlo Simulation.
PNA: 4.5 g (EI) IV every 8 hours

Abbreviations: PIRRT = prolonged intermittent renal replacement therapy, EI = extended interval, IV = intravenous, CF = cystic fibrosis

Formulas for dosing weights:

Ideal body weight IBW (male) = 50kg + (2.3 x height in inches > 60 inches)
Ideal body weight IBW (female) = 45kg + (2.3 x height in inches > 60 inches)
Adjusted Body Weight ABW (kg) = IBW + 0.4 (TBW – IBW)
 Stanford Antimicrobial Safety and Sustainability Program
Approval date: 5/2021

Appendix:

Antimicrobial Summary of the data and clinical trial characteristics

There is no published information on PIRRT dosing [2]. It is recommended not to dose adjust
amphotericin for patients undergoing CRRT.
Amphotericin
Concentration time profiles of amphotericin B lipid complex are similar on and off CVVH, suggesting
standard doses can be administered during RRT. [8]
This recommendation was made based on a PK case study of 12 critically ill patients with anuric AKI.
Pharmacokinetics after a single dose of ampicillin/sulbactam (2 g/1 g) given over 30 minutes was
obtained in 12 patients. Dialysis was started approximately 3 hours after the end of the infusion. The
authors used an HD system (Genius batch dialysis system) and ran it for an extended period, which
they termed extended dialysis (ED). The average dialysis time during the study was 442±77 minutes
(7.3hrs) and mean blood and counter current dialysate flow was 162±6 ml/min. 87% of ampicillin and
Ampicillin/
93% of sulbactam was removed by a single ED session. Ampicillin/sulbactam concentrations exceeded
Sulbactam
MIC90 values of Enterobacteriaceae, such as E. coli or K. pneumoniae (MIC90 ≤2.0 mg/L) or E.
faecalis (MIC90=2.0 mg/L), only for 8 hours (approximately 30% of the dosing interval for patients on
intermittent hemodialysis) after start of infusion. The authors concluded that at least 3 gram every 12-
hour dosing should be utilized. Because the run time in this study was less than what we do at SHC
and concentrations were only above the MIC90 of key pathogens for 30% of the dosing interval, 3-
gram every 8-hour dosing is reasonable at SHC. [3]
Caspofungin In a PK analysis, the effects of RRT on caspofungin elimination appeared to be negligible. [4]
The recommendation was made based on the results of multiple studies.

In one case report, PIRRT was ran as a 7-hour treatment in the haemodiafiltration mode with a blood
flow rate of 200 mL/minute, dialysate flow rate of 240 mL/minute, and an approximate ultrafiltration rate
of 233 mL/hour. During the PIRRT sampling period, the patient was prescribed cefepime 2 g every 12
hours administered over 30 minutes. Cefepime concentrations during the sampling were at least 29-
fold higher than the breakpoint MIC of P. aeruginosa (0.001 mg/L) and E. Coli (1 mg/L). The authors
concluded that cefepime 2 gram every 12 hours during PIRRT days was a reasonable dosing regimen
than those undergoing PIRRT, although they did not utilize EI. [1]

In another Monte Carlo Simulation study, four different prolonged intermittent renal replacement
Cefepime therapy settings commonly used in practice were simulated: 8 hours a day (ultrafiltration rate/dialysate
flow rate of 5 L/h) or 10 hours a day (ultrafiltration rate/dialysate flow rate of 4 L/h) of hemofiltration
(HF) or hemodialysis (HD). Blood flow rate was fixed at 300 mL/min for all settings. The PTA was
calculated using the antibiotic's PD target during the first 48 hours of therapy. Optimal doses were
defined as the smallest daily dose achieving ≥90% PTA to treat Pseudomonas aeruginosa in all PIRRT
effluent and duration combinations. MCS of cefepime 1‐2 g every 12 hours did not meet the goal of
90% PTA. Cefepime 1 g every 6 hours after a 2 g loading dose was the regimen with the lowest daily
dose that reached the PTA goal, which was the dose recommended by the authors. Of note, 1 gram
every 8 hours as an EI was not tested but 1 gram every 8 hours over 30 minutes had a <80% PTA. The
PTA was lower when beta‐lactams were administrated concomitantly with PIRRT initiation (T0)
compared with when started as late as possible after the drug dose. [5]
This recommendation was made based on a Monte Carlo Simulation study. In the study, four different
prolonged intermittent renal replacement therapy settings commonly used in practice were simulated: 8
hours a day (ultrafiltration rate/dialysate flow rate of 5 L/h) or 10 hours a day (ultrafiltration
rate/dialysate flow rate of 4 L/h) of hemofiltration (HF) or hemodialysis (HD). Blood flow rate was fixed
at 300 mL/min for all settings. The PTA was calculated using the antibiotic's PD target during the first
48 hours of therapy. Optimal doses were defined as the smallest daily dose achieving ≥90% PTA to
Ceftazidime treat Pseudomonas aeruginosa in all PIRRT effluent and duration combinations. Ceftazidime 1 g every
8 hours reached PTA targets in >90% of virtual patients. [5]

Another study showed a PTA of 98% for the pharmacodynamic target of 50% fT≥1 × MIC, with
ceftazidime 1 g every 8 hours in 16 critically ill patients receiving sustained low efficiency dialysis
(SLED). Residual diuresis was 0 (0–90) mL/day and SLED was performed with a mean (SD) blood and
dialysate flow of 264 mL/min (40) and a mean ultrafiltration of 540 mL/h (164) over 299 (68) min. [6]
 Stanford Antimicrobial Safety and Sustainability Program
Approval date: 5/2021

This recommendation was made from the results of a single case report. The patient was a 55 y/o
critically ill patient with MDR-PSA from sternal wound. PIRRT x 7.5 hours, blood flow 200ml/min,
dialysate 200ml/min, UFR 250ml/h. Ceftolozane/tazobactam load of 750mg x1 over 90
Ceftolazone/
minutes followed by 150mg q8h on non-PIRRT days and 750mg during and immediately after
Tazobactam
PIRRT. Ceftolozane MIC was at least 2x higher than P.aeruginosa MIC of 4 mg/L throughout sampling
period and >4 for tazobactam. The authors recommended a dose of 750 mg every 8 hours for non-
HAP/VAP indications. [7]
This recommendation was based on the results of a case study of one patient. the PIRRT blood flow
rate was 200ml/min, the dialysate flow rate was 200ml/min, and the UFR was 250ml/h. PIRRT was ran
Ceftriaxone for 10 hours/day. Ceftriaxone 2g was given over 30 mins and serial blood samples were taken to
measure unbound drug. This dosing regimen resulted in plasma concentrations >1 mg/L (breakpoint
for Enterobacteriacae) the entire dosing interval while undergoing PIRRT without notable toxicity. [8]
In a Monte Carlo Simulation, it was found that ciprofloxacin and levofloxacin cannot be recommended
as empiric monotherapy for serious gram-negative infections in patients receiving PIRRT due to
suboptimal efficacy. However, this was based on old fluoroquinolone breakpoints for Pseudomonas of
Ciprofloxacin
1/2 for ciprofloxacin and levofloxacin respectively. These breakpoints have since been revised to 0.5/1
for Pseudomonas and 0.25/0.5 for Enterobacterales. The ciprofloxacin regimen of 400 mg IV every 12
hours met ~90% PTA for a breakpoint of 0.5 for Pseudomonas and Enterobacterales. [12]
This recommendation was based on the results of a prospective, single dose PK study of 10 patients in
an ICU receiving daptomycin 6mg/kg 8 hours before extended dialysis (blood & dialysate 160ml/min x
Daptomycin 8 hours). Serial blood samples were taken, and 23.3% of drug was removed after one dialysis session.
The study concluded a daily dose of 6 mg/kg daptomycin is necessary in this population to avoid under
dosing. Also, of note, the earlier the dialysis with respect to drug administration, the lower the AUC0–inf
and the higher the resulting total body clearance. [9]
This recommendation was based on the results of a prospective open label study and Monte Carlo
Simulation.

In a single center, prospective, open label study of 6 ICU patients with ARF receiving extended dialysis
patients were treated with ertapenem 1g. Blood & dialysate flow rates were ran at 160ml/h x 8 hour.
Serial plasma samples were taken. A single dose of 1g over 30 mins exceeded MIC90 of 2mg/L for
>20h of the 24h dosing interval. The authors proposed a 1-gram daily dose but did not comment on
toxicity. [10]

In a Monte Carlo Simulation to determine initial dose of carbapenems for critically ill patients receiving
Ertapenem PIRRT, optimum doses of doripenem, meropenem, imipenem, and ertapenem were all studied.
Infusion times were 0.5 hour (ertapenem, imipenem ≤ 500 mg, and meropenem) or 1 hour (doripenem
and imipenem > 500 mg). MCS of 5000 patients evaluated multiple regimens in 4 different PIRRT
effluent/duration combinations (4 L/h × 10 hours or 5 L/h × 8 hours in hemodialysis or hemofiltration)
occurring at the beginning or 14–16 hours after drug infusion. Blood flow rate was 300 mL/min in all
PIRRT settings. The PTA was calculated using ≥40% free serum concentrations above 4x the MIC for
the first 48 hours. Optimal doses were defined as the smallest daily dose achieving ≥90% PTA in all
PIRRT combinations. Ertapenem 500 mg followed by 500 mg post‐PIRRT was optimal at the MIC of 1
mg/L for Streptococcus pneumoniae. The authors concluded that ertapenem 500 mg initially followed
by 500 mg post‐PIRRT is recommended empirically to achieve optimal exposures in critically ill patients
receiving daily 8‐ to 10‐hours of PIRRT. [11]
n a Monte Carlo Simulation, it was found that ciprofloxacin and levofloxacin cannot be recommended as
empiric monotherapy for serious gram-negative infections in patients receiving PIRRT due to suboptimal
efficacy. However, this was based on old fluoroquinolone breakpoints for Pseudomonas of 1/2 for
ciprofloxacin and levofloxacin respectively. These breakpoints have since been revised to 0.5/1 for
Levofloxacin
Pseudomonas and 0.25/0.5 for Enterobacterales. The levofloxacin regimen of 750 mg LD, then 500 mg
q24h post-PIRRT, successfully met ~90 % PTA for the new Pseudomonas breakpoint of 1 and a 750 mg
LD, then 250 mg q24h post-PIRRT dose met ~90% PTA for a breakpoint of 0.5 for Enterobacterales.
[12]
This recommendation was based on a prospective, single dose PK study. All patients were in the ICU
and received 600 mg of intravenous linezolid before starting renal replacement therapy, which
consisted of intermittent hemodialysis lasting 3-4 hrs in eight patients, sustained low-efficiency dialysis
lasting 8 hrs in five patients, and continuous venovenous hemofiltration lasting 10.5–12 hrs in two
Linezolid
patients. Serum concentrations were measured. Mean drug removal was 193.7 mg with HD (32.3% of
the dose administered), 205 mg with SLED (33.9%), and 74.8 mg and 105 mg with a CVVH session of
10.5 and 12 hrs, respectively (12.4 and 17.5%). Levels dropped at the end to <4 mg/dL (MIC90 for
Staphylococcus aureus) in three of five patients on SLED. The authors concluded that one should give
 Stanford Antimicrobial Safety and Sustainability Program
Approval date: 5/2021

the antibiotic dose at the end of an intermittent RRT session to ensure adequate drug levels and
close monitoring of serum drug levels could allow further dose adjustments as needed. [13]
In a Monte Carlo Simulation to determine initial dose of carbapenems for critically ill patients receiving
PIRRT, optimum doses of doripenem, meropenem, imipenem, and ertapenem were all studied.
Infusion times were 0.5 hour (ertapenem, imipenem ≤ 500 mg, and meropenem) or 1 hour (doripenem
and imipenem > 500 mg). MCS of 5000 patients evaluated multiple regimens in 4 different PIRRT
effluent/duration combinations (4 L/h × 10 hours or 5 L/h × 8 hours in hemodialysis or hemofiltration)
occurring at the beginning or 14–16 hours after drug infusion. Blood flow rate was 300 mL/min in all
PIRRT settings. The PTA was calculated using ≥40% free serum concentrations above 4x the MIC for
Meropenem the first 48 hours. Optimal doses were defined as the smallest daily dose achieving ≥90% PTA in all
PIRRT combinations. Optimal initial dosing regimens using the smallest daily doses was meropenem 1
g every 12 hour. [11]

There was also a prospective clinical PK study of 10 SICU patients on EDD, with an average clearance
time of 8h using high-flux dialyzer with mean blood and dialysate flow each 160ml/min. Serial plasma
meropenem concentrations obtained. Patients were given meropenem 1g over 30 mins, 6 hours before
EDD was started & found fraction of drug removed was 18%. [14]
This recommendation was informed by multiple studies, including case reports and a Monte Carlo
Simulation.

In the MCS, four different prolonged intermittent renal replacement therapy settings commonly used in
practice were simulated: 8 hours a day (ultrafiltration rate/dialysate flow rate of 5 L/h) or 10 hours a day
(ultrafiltration rate/dialysate flow rate of 4 L/h) of hemofiltration (HF) or hemodialysis (HD). Blood flow
rate was fixed at 300 mL/min for all settings. The PTA was calculated using the antibiotic's PD target
Piperacillin/ during the first 48 hours of therapy. Optimal doses were defined as the smallest daily dose achieving
Tazobactam ≥90% PTA to treat Pseudomonas aeruginosa in all PIRRT effluent and duration combinations. [5]

Prospective study of 6 anuric critically ill patients on SLED x 6-8h. (12L/h blood flow & dialysate). Pts
received piperacillin/tazobactam 4.5g over 30 mins and serial blood samples taken. 58% removed by
SLED. [15]

Prospective population PK study using MCS of 34 adult ICU patients receiving SLED x8 hours (Blood
flow 200ml/min, dialysate 300ml/min). Target of 50% fT>MIC, 3.375g q8h appropriate for organisms
with MIC < 16mg/L. [16]

References:
1. Xu JH, Cheng V, Rawlins M, et al. Pharmacokinetics of Amoxicillin and Cefepime During Prolonged Intermittent Renal Replacement
Therapy: A Case Report. EMJ Nephrol.2020;8[1]:78-83.
2. Brown P, Battistella M. Principles of Drug Dosing in Sustained Low Efficiency Dialysis (SLED) and Review of Antimicrobial Dosing
Literature. Pharmacy (Basel). 2020 Mar 9;8(1):33. doi: 10.3390/pharmacy8010033. PMID: 32182835; PMCID: PMC7151685.
3. Lorenzen JM, Broll M, Kaever V, et al. Pharmacokinetics of ampicillin/sulbactam in critically ill patients with acute kidney injury undergoing
extended dialysis. Clin J Am Soc Nephrol. 2012;7:385-90. Epub 2012/01/10. doi 10.2215/CJN.05690611
4. Weiler S, Seger C, Pfisterer H, Stienecke E, et al. Pharmacokinetics of caspofungin in critically ill patients on continuous renal replacement
therapy. Antimicrob Agents Chemother 57:4053–4057. doi:10.1128/AAC.00335-13
5. Jang, JM, Mueller BA, et al; A Monte Carlo Simulation Approach for Beta-Lactam Dosing in Critically Ill Patients Receiving Prolonged
Intermittent Renal Replacement Therapy. The Journal of Clinical Pharmacology. 2018 Oct; 58(10):1254-1265.
6. Konig C, Braune S, Roberts JA, et al. Population pharmacokinetics and dosing simulations of ceftazidime in critically ill patients receiving
sustained low‐efficiency dialysis. J Antimicrob Chemother. 2017;72(5):1433–1440.
7. Rawlins M, Cheng V, Raby E, Dyer J, Regli A, Ingram P, McWhinney BC, Ungerer JPJ, Roberts JA. Pharmacokinetics of Ceftolozone-
Tazobactam during Prolonged Intermittent Renal Replacement Therapy. Chemotherapy. 2018;63(4):203-206. doi:
10.1159/000493196. Epub 2018 Oct 10. PMID: 30304718.
8. Chang T, Cheng V, Rawlins M, et al. Pharmacokinetics of Ceftriaxone During prolonged Intermittent Renal Replacement Therapy In a
Patient with Child-Pugh B Cirrhosis and Ascites. EMJ Nephrol. 2020;8[1]:54-58
9. Kielstein JT, Eugbers C, Bode-Boeger SM, et al. Dosing of daptomycin in intensive care unit patients with acute kidney injury undergoing
extended dialysis--a pharmacokinetic study. Nephrol Dial Transplant 2010;25:1537-41. Epub 2009/12/25. doi 10.1093/ndt/gfp704
10. Burkhardt O, Hafer C, Langhoff A, et al. Pharmacokinetics of ertapenem in critically ill patients with acute renal failure undergoing extended
daily dialysis. Nephrol Dial Transplant. 2009; 24:267–271
11. Lewis SJ, Kays MB, and Mueller BA. Use of Monte Carlo Simulations to Determine Optimal Carbapenem Dosing in Critically Ill patients
Receiving Prolonged Intermittent Renal Replacement Therapy. The Journal of Clinical Pharmacology. 2016;56(10): 1277-1287.
12. Lewis, SJ Mueller, BA, et al. In silico trials using Monte Carlo simulation to evaluate ciprofloxacin and levofloxacin dosing in critically ill
patients receiving prolonged intermittent renal replacement therapy. Renal Replacement Therapy. (2016) 2:45.
13. Fiaccadori E, Maggiore U, Rotelli C, et al. Removal of linezolid by conventional intermittent hemodialysis, sustained low-efficiency dialysis,
or continuousvenovenous hemofiltration in patients with acute renal failure. Crit Care Med. 2004;32:2437-2442.
14. Kielstein JT, Czock D, Schopke T, et al. Pharmacokinetics and Total Elimination of meropenem and vancomycin in Intensive Care Unit
Patients Undergoing Extended Daily Dialysis. Critical Care Medicine. 2006;34:51-56.
 Stanford Antimicrobial Safety and Sustainability Program
Approval date: 5/2021

15. Sinnollareddy MG, Roberts MS, Lipman J, Peake SL, Roberts JA. Pharmacokinetics of piperacillin in critically ill patients with acute kidney
injury receiving sustained low-efficiency diafiltration. J AntimicrobChemother. 2018;73:1647-1650. doi:10.1093/jac/dky057
16. Kanji S, Roberts JA. Piperacillin population pharmacokinetics in critically ill adults during sustained low-efficiency dialysis. Annals of
Pharmacotherapy. 2018;52(10):95-973.
17. Bellmann R, Egger P, Djanani A, Wiedermann CJ. Pharmacokinetics of amphotericin B lipid complex in critically ill patients on continuous
veno-venous haemofiltration. Int J Antimicrob Agents. 2004; 23:80-83.

1. Document Information
a. Original Author/Date: Emily Fox, PharmD and Miranda Wong, PharmD 1/2021
2. Gatekeeper: Antimicrobial Stewardship Program
3. Review and Renewal Requirement
a. This document will be reviewed every three years and as required by change of law or
practice
4. Approvals
a. Antimicrobial Subcommittee: 5/2021
b. P&T: 5/2021