CRRT Antibiotic Dosing
CRRT Antibiotic Dosing
CRRT Antibiotic Dosing
CLINICAL PRACTICE
Ellie J. C. Goldstein, Section Editor
Department of Internal Medicine, Section of Infectious Diseases, Wake Forest University Health Sciences, Winston-Salem, North Carolina;
and 2Department of Internal Medicine, Division of Infectious Diseases, University of Missouri Health Science Center, Columbia, Missouri
Continuous renal replacement therapy (CRRT) is now commonly used as a means of support for critically ill patients with
renal failure. No recent comprehensive guidelines exist that provide antibiotic dosing recommendations for adult patients
receiving CRRT. Doses used in intermittent hemodialysis cannot be directly applied to these patients, and antibiotic pharmacokinetics are different than those in patients with normal renal function. We reviewed the literature for studies involving
the following antibiotics frequently used to treat critically ill adult patients receiving CRRT: vancomycin, linezolid, daptomycin,
meropenem, imipenem-cilastatin, nafcillin, ampicillin-sulbactam, piperacillin-tazobactam, ticarcillinclavulanic acid, cefazolin, cefotaxime, ceftriaxone, ceftazidime, cefepime, aztreonam, ciprofloxacin, levofloxacin, moxifloxacin, clindamycin, colistin, amikacin, gentamicin, tobramycin, fluconazole, itraconazole, voriconazole, amphotericin B (deoxycholate and lipid
formulations), and acyclovir. We used these data, as well as clinical experience, to make recommendations for antibiotic
dosing in critically ill patients receiving CRRT.
Continuous renal replacement therapy (CRRT) is frequently
used to treat critically ill patients with acute renal failure or
chronic renal failure. CRRT is better tolerated by hemodynamically unstable patients and is as effective at removing solutes
during a 2448-h period as a single session of conventional
hemodialysis [1]. Solute removal is particularly relevant to antimicrobial therapy, because many critically ill patients with
acute renal failure have serious infections and require treatment
with 1 antimicrobial. However, compared with data about
antibiotic dosing in patients undergoing intermittent hemodialysis, there is a relative paucity of published data about antibiotic dosing during CRRT in critically ill patients. In addition, the rate of drug clearance during CRRT can be highly
variable in critically ill patients.
We conducted a comprehensive review of Medline-referenced literature to formulate dosing recommendations for the
following antibiotics frequently used to treat critically ill adult
patients undergoing CRRT: vancomycin, linezolid, daptoReceived 21 January 2005; accepted 19 June 2005; electronically published 12 September
2005.
Reprints or correspondence: Dr. Robin L. Trotman, Dept. of Internal Medicine, Section of
Infectious Diseases, Medical Center Blvd., Winston-Salem, NC 27157 ([email protected]).
Clinical Infectious Diseases 2005; 41:115966
2005 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2005/4108-0013$15.00
Table 1. Pharmacokinetic and pharmacodynamic parameters of drugs used for treatment of critically ill adult patients receiving continuous renal replacement therapy.
PBC,
%
Primary
route of
a
elimination
Volume of
distribution,
L/kg
Half-life
for normal
renal
function, h
Time-dependent
or concentrationdependent killing
Target
trough level,
b
mg/L
Acyclovir
Ampicillin
Aztreonam
15
28
56
Renal
Renal
Renal
0.6
0.29
0.2
24
1.2
1.72.9
Time
Time
Time
NAc
8
8
Cefepime
Cefotaxime
Ceftazidime
16
2738
21
Renal
Renal
Renal
0.25
0.150.55
0.23
2.1
1
1.6
Time
Time
Time
8
8
8
Ceftriaxone
Cilastatin
Ciprofloxacin
Clavulanate
90
40
40
30
Hepatic
Renal
Renal
Hepatic
0.15
0.20
1.8
0.3
8
1
4.1
1
Time
NA
Concentration
NA
8
NA
1
NA
Clindamycin
Colistin
Daptomycin
Fluconazole
6095
55
92
12
Hepatic
Renal
Renal
Renal
0.61.2
0.34
0.13
0.65
3
2
8
30
Time
Concentration
Concentration
Time
2
4
4
816d
Imipenem
Itraconazole
20
99
Renal
Hepatic
0.23
10
1
21
Time
Time
4
0.1250.25d
2438
31
2
50
16
2023
4565
38
55
Renal
Hepatic
Renal
Hepatic
Renal
Renal
Renal
Renal
Renal
1.09
0.6
0.25
1.72.7
0.18
0.180.33
0.17
0.250.5
0.7
Concentration
Time
Time
Concentration
Time
NA
Time
Time
Time
2
4
4
2
16
4
16
14
10
58
Hepatic
4.6
Drug
Levofloxacin
Linezolid
Meropenem
Moxifloxacin
Piperacillin
Tazobactam
Ticarcillin
Sulbactam
Vancomycin
Voriconazolee
NOTE.
78
4.85.4
1
12
1
1
1.2
1
6
12
Time
0.5
Table 2. Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy.
Dosage, by type of
renal replacement therapy
Drug
CVVH
CVVHD or CVVHDF
Amphotericin B formulation
Deoxycholate
Lipid complex
35 mg/kg q24h
35 mg/kg q24h
Liposomal
35 mg/kg q24h
35 mg/kg q24h
Ampicillin-sulbactam
3 g q12h
3 g q8h
Aztreonam
12 g q12h
2 g q12h
Cefazolin
12 g q12h
2 g q12h
Cefepime
12 g q12h
2 g q12h
Acyclovir
a
Cefotaxime
12 g q12h
2 g q12h
Ceftazidime
12 g q12h
2 g q12h
Ceftriaxone
2 g q1224h
2 g q1224h
Clindamycin
600900 mg q8h
600900 mg q8h
Ciprofloxacin
200 mg q12h
200400 mg q12h
Colistin
4 or 6 mg/kg q48h
4 or 6 mg/kg q48h
200400 mg q24h
400800 mg q24h
250 mg q6h or
500 mg q8h
250 mg q6h,
500 mg q8h, or
500 mg q6h
Daptomycin
b
Fluconazole
Imipenem-cilastatin
Levofloxacin
Linezolid
250 mg q24h
250 mg q24h
600 mg q12h
600 mg q12h
Meropenem
1 g q12h
1 g q12h
Moxifloxacin
400 mg q24h
400 mg q24h
2 g q46h
2 g q46h
2.25 g q6h
2.253.375 g q6h
Nafcillin or oxacillin
f
Piperacillin-tazobactam
g
Ticarcillin-clavulanate
2 g q68h
Vancomycin
1 g q48h
h
Voriconazole
4 mg/kg po q12h
3.1 g q6h
1 g q24h
moval in hemofiltration. Lastly, the membrane pore size is directly proportional to the degree of drug removal by CRRT,
often expressed as a sieving coefficient. Generally, biosynthetic
membranes have larger pores, which allow removal of drugs
with a larger molecular weight, unlike conventional filters.
These patient, drug, and mechanical variables significantly diminish the utility of routine pharmacokinetic calculations for
determining antimicrobial dosing during CRRT [1, 4].
4 mg/kg po q12h
Vancomycin. The half-life of vancomycin increases significantly in patients with renal insufficiency [7, 8]. It is a middle
molecular weight antibiotic, and although compounds of this
size are poorly removed by intermittent hemodialysis, they are
removed by CRRT [7, 9]. CVVH, CVVHD, and CVVHDF all
effectively remove vancomycin [7, 911]. Because of the prolonged half-life, the time to reach steady state will also be prolonged. Therefore, a vancomycin loading dose of 1520 mg/kg
is warranted. Vancomycin maintenance dosing for patients receiving CVVH varies from 500 mg q24h to 1500 mg q48h [7,
10]. For patients receiving CVVHD or CVVHDF, we recommend a vancomycin maintenance dosage of 11.5 g q24h. Monitoring of plasma vancomycin concentrations and subsequent
dose adjustments are recommended to achieve desired trough
concentrations. A trough concentration of 510 mg/L is adequate for infections in which drug penetration is optimal, such
as skin and soft-tissue infections or uncomplicated bacteremia.
However, higher troughs (1015 mg/L) are indicated for infections in which penetration is dependent on passive diffusion
of drug into an avascular part of the body, such as osteomyelitis,
endocarditis, or meningitis. Recent guidelines also recommend
higher troughs (1520 mg/L) in the treatment of health care
associated pneumonia, because of suboptimal penetration of
vancomycin into lung tissue [12].
Linezolid. Fifty percent of a linezolid dose is metabolized
in the liver to 2 inactive metabolites, and 30% of the dose is
excreted in the urine as unchanged drug. There is no adjustment recommended for patients with renal failure; however,
linezolid clearance is increased by 80% during intermittent hemodialysis. There are very few data on linezolid clearance during CRRT. On the basis of 4 studies [1316], a linezolid dosage
of 600 mg q12h provides a serum trough concentration of 14
mg/L, which is the upper limit of the MIC range for drugsusceptible Staphylococcus species [17]. The upper limit of the
MIC range for drug-susceptible Enterococcus and Streptococcus
species is 2 mg/L [17]. Thus, no linezolid dosage adjustment
is recommended for patients receiving any form of CRRT; however, in such patients, neither the disposition nor the clinical
relevance of inactive linezolid metabolites are known. Therefore, the reader is cautioned to pay attention to hematopoietic
CLINICAL PRACTICE CID 2005:41 (15 October) 1161
Aminoglycoside
Gram-positive
synergy, dosage
Loading dose
Gentamicin
Tobramycin
1 mg/kg q2436h
Not applicable
3 mg/kg
3 mg/kg
Not applicable
10 mg/kg
Amikacin
Maintenance dosage
2 mg/kg q2448h
2 mg/kg q2448h
7.5 mg/kg q2448h
dida species, routine antifungal susceptibilities are recommended to direct antifungal choice and dosing [56]. Empirical
fluconazole should be administered at a daily dose of 800 mg
for critically ill patients receiving CVVHD or CVVHDF with
a combined ultrafiltration and dialysate flow rate of 2 L/h and
at a daily dose of 400 mg for patients receiving CVVH. The
dose may be decreased to 400 mg (CVVHD and CVVHDF) or
to 200 mg (CVVH) if the species is not Candida krusei or
Candida glabrata and the fluconazole MIC is 8 mg/L.
Itraconazole and voriconazole are available in oral and parenteral formulations. The parenteral formulations are solubilized in a cyclodextrin diluent, which is eliminated by the kidneys and will accumulate in patients with renal insufficiency.
The clinical significance of cyclodextrin accumulation in humans is not fully understood. Use of intravenous itraconazole
and voriconazole is not recommended for patients with creatinine clearance rates of !30 and 50 mL/min, respectively, or
for patients receiving any form of renal replacement therapy.
Although oral formulations are not contraindicated, there are
few data about triazole dosing for patients receiving CRRT [57].
On the basis of pharmacokinetics data, no dose reduction is
recommended for patients receiving CRRT.
Amphotericin B. Amphotericin B and its lipid preparations
have not been thoroughly investigated in critically ill patients
receiving CRRT. However, case reports and small series have
been performed [5860]. Amphotericin B is a large molecule,
and when bound within a lipid structure, the product is even
larger. In addition, amphotericin B is extensively and rapidly
distributed in tissues. On the basis of limited clinical data and
the pharmacokinetics of amphotericin B, dose adjustments for
CRRT are not recommended.
ANTIFUNGALS
Triazoles. Unlike itraconazole and voriconazole, which are
metabolized, 80% of the fluconazole dose is eliminated unchanged via the kidneys. Accumulation occurs in patients with
renal insufficiency, for whom a dose reduction is recommended.
However, clearance of fluconazole by CVVHD and CVVHDF
in patients with renal insufficiency is significant and may be
equal to or greater than that for patients with normal renal
function [5355]. With the emergence of azole-resistant Can1164 CID 2005:41 (15 October) CLINICAL PRACTICE
ACYCLOVIR
Acyclovir is eliminated by renal excretion and has a narrow
therapeutic index in patients with renal impairment. Its small
molecular size, low protein-binding capacity, and water solubility make it readily removed by all types of dialysis. Generally,
acyclovir clearance during a 24-h period of CRRT is equivalent
to a single session of intermittent hemodialysis [6163]. Limited
pharmacokinetic data suggest that an acyclovir dosage of 5 mg/
14.
15.
16.
CONCLUSIONS
These recommendations are based on very limited clinical data,
and in many cases, our dosing recommendations are extrapolations from clinical experiences and known pharmacokinetic
and pharmacodynamic properties. More clinical data are
needed to support such extrapolations, and these recommendations should not supercede sound clinical judgment.
17.
18.
19.
20.
Acknowledgments
We thank Dr. Kevin High for help with preparation of the manuscript.
Potential conflicts of interest. R.L.T. has been a member of the speakers bureau for Pfizer Pharmaceuticals, and J.C.W. has received research
funding from Elan Pharmaceuticals. D.M.S. and W.S.: no conflicts.
21.
22.
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