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Ellie J. C. Goldstein, Section Editor
Antibiotic Dosing in Critically Ill Adult PatientsReceiving Continuous Renal Replacement Therapy
Robin L. Trotman,1 John C. Williamson,1 D. Matthew Shoemaker,2 and William L. Salzer2
1Department 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 phar-
macokinetics 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, ticarcillin–clavulanic acid, cefa-
zolin, cefotaxime, ceftriaxone, ceftazidime, cefepime, aztreonam, ciprofloxacin, levofloxacin, moxifloxacin, clindamycin, co-
listin, 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
mycin, meropenem, imipenem-cilastatin, nafcillin, ampicil-
used to treat critically ill patients with acute renal failure or
chronic renal failure. CRRT is better tolerated by hemodyn-
acid, cefazolin, cefotaxime, ceftriaxone, ceftazidime, cefepime,
amically unstable patients and is as effective at removing solutes
aztreonam, ciprofloxacin, levofloxacin, moxifloxacin, clin-
during a 24–48-h period as a single session of conventional
damycin, colistin, amikacin, gentamicin, tobramycin, flucon-
hemodialysis [1]. Solute removal is particularly relevant to an-
azole, itraconazole, voriconazole, amphotericin B (deoxycho-
timicrobial therapy, because many critically ill patients with
late and lipid formulations), and acyclovir. For drugs with no
acute renal failure have serious infections and require treatment
specific published data on dosing in patients receiving CRRT,
with ⭓1 antimicrobial. However, compared with data about
we used known chemical properties and other clinical data
antibiotic dosing in patients undergoing intermittent hemo-
(e.g., molecular weight, protein binding capacity, and removal
dialysis, there is a relative paucity of published data about an-
by intermittent hemodialysis) to make dosing recommen-
tibiotic dosing during CRRT in critically ill patients. In addi-
dations. The pharmacokinetic and pharmacodynamic prop-
tion, the rate of drug clearance during CRRT can be highly
erties of each antimicrobial and the typical susceptibilities of
variable in critically ill patients.
relevant pathogens were considered (table 1). In most cases,
We conducted a comprehensive review of Medline-refer-
the recommended "target" drug concentration corresponds to
enced literature to formulate dosing recommendations for the
the upper limit of the MIC range for susceptibility. The goal
following antibiotics frequently used to treat critically ill adult
of our dosing recommendations is to keep the concentration
patients undergoing CRRT: vancomycin, linezolid, dapto-
above the target MIC for an optimal proportion of the dosinginterval, reflecting known pharmacodynamic properties (time-
Received 21 January 2005; accepted 19 June 2005; electronically published 12 September
dependent vs. concentration-dependent killing), while mini-
Reprints or correspondence: Dr. Robin L. Trotman, Dept. of Internal Medicine, Section of
mizing toxicity due to unnecessarily high concentrations. How-
Infectious Diseases, Medical Center Blvd., Winston-Salem, NC 27157 (
[email protected]).
ever, these recommendations are meant to serve only as a guide
Clinical Infectious Diseases
until more data are available, and they should not replace sound
2005 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2005/4108-0013$15.00
clinical judgment. Recommended dosages are listed in table 2.
CLINICAL PRACTICE •
CID 2005:41 (15 October) • 1159
Pharmacokinetic and pharmacodynamic parameters of drugs used for treatment of crit-
ically ill adult patients receiving continuous renal replacement therapy.
or concentration-
dependent killing
NA, not applicable; PBC, protein-binding capacity.
a Data are for the parent compound.
b Denotes the highest MIC in the susceptible range for applicable pathogens, such as the b-lactam MIC for
Pseu-
c Trough concentrations of acyclovir are not routinely measured because this agent is phosphorylated into the active
form acyclovir triphosphate.
d The higher level is the recommended target trough concentration for
Candida species with an MIC in the dose-
dependent, susceptible range (fluconazole MIC, 16–32 mg/mL; itraconazole MIC, 0.25–0.5 mg/mL).
e The oral bioavailability of voriconazole is estimated to be 96%.
DESCRIPTION AND NOMENCLATURE OF CRRT
current dialysate flow, and drug removal depends on dialysateand blood flow rates. CVVHDF utilizes both diffusive and con-
Several methods of CRRT exist, and there is inconsistency in
vective solute transports and can require a large amount of
the literature regarding nomenclature. For this review, we will
fluid to replace losses during ultrafiltration [1–6].
use the following terms: continuous arteriovenous hemofiltra-
The pharmacokinetics of drug removal in critically ill pa-
tion (CAVH), continuous venovenous hemofiltration (CVVH),continuous arteriovenous hemodialysis (CAVHD), continuous
tients receiving CRRT is very complex, with multiple variables
venovenous hemodialysis (CVVHD), and continuous venov-
affecting clearance. These variables make generalized dosing
enous hemodialfiltration (CVVHDF). These are consistent with
recommendations difficult. Drug-protein complexes have a
the definitions established by an international conference on
larger molecular weight; therefore, antibiotics with low protein
CRRT [2]. The most common modalities currently used in
binding capacity in serum are removed by CRRT more readily.
intensive care units are CVVH, CVVHD, and CVVHDF [3].
Similarly, antibiotics that penetrate and bind to tissues have a
During CVVH, solute elimination is through convection,
larger volume of distribution, reducing the quantity removed
whereas CVVHD utilizes diffusion gradients through counter-
during CRRT. Sepsis itself increases the volume of distribution,
1160 •
CID 2005:41 (15 October) • CLINICAL PRACTICE
Antibiotic dosing in critically ill adult patients re-
moval in hemofiltration. Lastly, the membrane pore size is di-
ceiving continuous renal replacement therapy.
rectly proportional to the degree of drug removal by CRRT,often expressed as a sieving coefficient. Generally, biosynthetic
Dosage, by type of
membranes have larger pores, which allow removal of drugs
renal replacement therapy
with a larger molecular weight, unlike conventional filters.
These patient, drug, and mechanical variables significantly di-
Amphotericin B formulation
minish the utility of routine pharmacokinetic calculations for
0.4–1.0 mg/kg q24h
0.4–1 mg/kg q24h
determining antimicrobial dosing during CRRT [1, 4].
5–7.5 mg/kg q24h
5–7.5 mg/kg q24h
ANTIBIOTICS FOR DRUG-RESISTANT
The half-life of vancomycin increases signifi-
cantly 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
200–400 mg q12h
effectively remove vancomycin [7, 9–11]. Because of the pro-
longed half-life, the time to reach steady state will also be pro-
4 or 6 mg/kg q48h
4 or 6 mg/kg q48h
longed. Therefore, a vancomycin loading dose of 15–20 mg/kg
200–400 mg q24h
400–800 mg q24hc
is warranted. Vancomycin maintenance dosing for patients re-
ceiving CVVH varies from 500 mg q24h to 1500 mg q48h [7,
10]. For patients receiving CVVHD or CVVHDF, we recom-
mend a vancomycin maintenance dosage of 1–1.5 g q24h. Mon-
itoring of plasma vancomycin concentrations and subsequent
dose adjustments are recommended to achieve desired trough
Nafcillin or oxacillin
concentrations. A trough concentration of 5–10 mg/L is ade-
2.25–3.375 g q6h
quate for infections in which drug penetration is optimal, such
as skin and soft-tissue infections or uncomplicated bacteremia.
However, higher troughs (10–15 mg/L) are indicated for in-fections in which penetration is dependent on passive diffusion
All dosages are administered intravenously, unless otherwise
indicated. The recommendations assume an ultrafiltration rate of 1 L/h, a
of drug into an avascular part of the body, such as osteomyelitis,
dialysate flow rate of 1 L/h, and no residual renal function. CAVHD, contin-
endocarditis, or meningitis. Recent guidelines also recommend
uous arteriovenous hemodialysis; CVVH, continuous venovenous hemofil-tration; CVVHD, continuous venovenous hemodialysis; CVVHDF, continuous
higher troughs (15–20 mg/L) in the treatment of health care–
associated pneumonia, because of suboptimal penetration of
a Available commercially in a fixed ratio of 2 mg of ampicillin to 1 mg of
vancomycin into lung tissue [12].
b The switch from the intravenous to the oral formulation is possible when
Fifty percent of a linezolid dose is metabolized
in the liver to 2 inactive metabolites, and 30% of the dose is
c A dose of 800 mg is appropriate if the dialysate flow rate is 2 L/h and/
or if treating fungal species with relative azole resistance, such as
Candida
excreted in the urine as unchanged drug. There is no adjust-
ment recommended for patients with renal failure; however,
d Available commercially in a fixed ratio of 1 mg to 1 mg.
e
linezolid clearance is increased by 80% during intermittent he-
Recommended loading dose is 15–20 mg/kg of vancomycin and 500
mg of levofloxacin.
modialysis. There are very few data on linezolid clearance dur-
f Available commercially in a fixed ratio of 8 mg to 1 mg.
g
ing CRRT. On the basis of 4 studies [13–16], a linezolid dosage
Available commercially in a fixed ratio of 30 mg to 1 mg.
h The oral bioavailability of voriconazole is estimated to be 96%. Consider
of 600 mg q12h provides a serum trough concentration of 14
2 loading doses of 6 mg/kg po q12h. See Antifungals for details on contra-
mg/L, which is the upper limit of the MIC range for drug-
indications associated with the intravenous formulation in patients with renalfailure.
susceptible
Staphylococcus species [17]. The upper limit of theMIC range for drug-susceptible
Enterococcus and
Streptococcus
extends drug half-life, and alters the protein binding capacity
species is 2 mg/L [17]. Thus, no linezolid dosage adjustment
of many antimicrobials. CRRT mechanical factors may also
is recommended for patients receiving any form of CRRT; how-
affect drug clearance. Increasing the blood or dialysate flow rate
ever, in such patients, neither the disposition nor the clinical
can change the transmembrane pressure and increase drug
relevance of inactive linezolid metabolites are known. There-
clearance. The dialysate concentration may also affect drug re-
fore, the reader is cautioned to pay attention to hematopoietic
CLINICAL PRACTICE •
CID 2005:41 (15 October) • 1161
and neuropathic adverse effects when administering linezolid
receiving CRRT. On the basis of published data, piperacillin is
for extended periods to patients receiving CRRT [14].
cleared by all modalities of CRRT [31–34]. The tazobactam
Daptomycin is a relatively large molecule that
concentration has been shown to accumulate relative to the
is excreted primarily through the kidneys and requires dose
piperacillin concentration during CVVH [32, 33]. Thus, pi-
adjustment in patients with renal failure. There are no pub-
peracillin is the limiting factor to consider when choosing an
lished pharmacokinetic studies of daptomycin in patients re-
optimal dose. On the basis of results of 4 studies evaluating
ceiving CRRT. However, a study of daptomycin clearance in
piperacillin or the fixed combination of piperacillin-tazobactam
an in vitro model suggests that CVVHD does not remove a
in patients receiving CRRT [31–34], a dosage of 2 g/0.25 g q6h
significant amount of drug [18]. On the basis of these data and
piperacillin-tazobactam is expected to produce trough concen-
known chemical properties of daptomycin, the dose for patients
trations of these agents in excess of the MIC for most drug-
receiving CRRT should be the manufacturer-recommended
susceptible bacteria during the majority of the dosing interval.
dose for patients with a creatinine clearance rate of !30 mL/
For patients receiving CVVHD or CVVHDF, one should con-
min [19]. Care should be taken to monitor serum creatine
sider increasing the dose to 3 g/0.375 g piperacillin-tazobactam
phosphokinase levels at initiation of therapy and then weekly
if treating a relatively drug-resistant pathogen, such as
Pseu-
during receipt of daptomycin.
domonas aeruginosa (in which case piperacillin alone should beconsidered). Again, for patients with no residual renal function
who are undergoing CVVH and receiving prolonged therapywith piperacillin-tazobactam, it is not known whether tazo-
Imipenem is metabolized at the renal brush-
bactam accumulates. Moreover, the toxicities of tazobactam are
border membrane by the enzyme dehydropeptidase-I, which is
not known, and it has been recommended that alternating doses
inhibited by cilastatin. Seventy percent of the imipenem dose
of piperacillin alone in these patients may avoid the potential
is excreted unchanged in the urine when it is administered as
toxicity associated with tazobactam accumulation [32, 33].
a fixed dose combination with cilastatin. Imipenem and cilas-
Although few data exist with ampicillin-sulbactam and ticar-
tatin have similar pharmacokinetic properties in patients withnormal renal function; however, both drugs accumulate in pa-
cillin-clavulanate [35], extrapolations are possible between pi-
tients with renal insufficiency. Cilastatin may accumulate to a
peracillin-tazobactam and ampicillin-sulbactam. Piperacillin, ta-
greater extent, because nonrenal clearance of cilastatin accounts
zobactam, ampicillin, and sulbactam primarily are excreted by
for a lower percentage of its total clearance, compared with
the kidneys, and all 4 drugs accumulate in persons with renal
imipenem [20]. To maintain an imipenem trough concentra-
dysfunction. However, the ratio of b-lactam to b-lactamase in-
tion of ∼2 mg/L during CRRT, a dosage of 250 mg q6h or 500
hibitor is preserved in persons with varying degrees of renal
mg q8h is recommended [20–23]. A higher dosage (500 mg
insufficiency, because each pair has similar pharmacokinetics.
q6h) may be warranted in cases of relative resistance to imi-
This is not true for ticarcillin-clavulanate. Although ticarcillin
penem (MIC, ⭓4 mg/L) [23]. Cilastatin also accumulates in
will also accumulate with renal dysfunction, clavulanate is not
patients with hepatic dysfunction, and increasing the dosing
affected; it is metabolized by the liver. If the dosing interval is
interval may be needed to avoid potential unknown adverse
extended, only ticarcillin will remain in plasma at the end of the
effects of cilastatin accumulation.
interval [36]. For this reason, an interval 18 h is not recom-
In contrast to imipenem, meropenem does not require a
mended with ticarcillin-clavulanate during CRRT. Because
dehydropeptidase inhibitor. The meropenem MIC for most sus-
CVVHD and CVVHDF are more efficient at removing b-lactams
ceptible bacteria is ⭐4 mg/L. This represents an appropriate
such as ticarcillin, the dosing interval with these CRRT modalities
trough concentration for critically ill patients, especially when
should not exceed 6 h for ticarcillin-clavulanate.
the pathogen and MIC are not yet known [24, 25]. Many studies
Cephalosporins and aztreonam.
Cefazolin, cefotaxime,
have analyzed the pharmacokinetics of meropenem in patients
ceftriaxone, ceftazidime, cefepime, and aztreonam were in-
receiving CRRT [24–30]. There is significant variability in the
vestigated. With the exception of ceftriaxone, these b-lactams
data, owing to different equipment, flow rates, and treatment
are renally excreted and accumulate in persons with renal
goals. However, a meropenem dosage of 1 g q12h will produce
dysfunction. Because the rate of elimination is directly pro-
a trough concentration of ∼4 mg/L in most patients, regardless
portional to renal function, patients requiring intermittent
of CRRT modality. If the organism is found to be highly sus-
hemodialysis may receive doses much less often. In some
ceptible to meropenem, a lower dosage (500 mg q12h) may be
instances, 3 times weekly dosing after hemodialysis is ade-
quate. However, clearance by CRRT is greater for most of
Of the 3 b-lacta-
these agents, necessitating more-frequent dosing to maintain
mase–inhibitor combinations available commercially, only pi-
therapeutic concentrations greater than the MIC for an op-
peracillin-tazobactam has been extensively studied in patients
timal proportion of the dosing interval. Ceftriaxone is the
1162 •
CID 2005:41 (15 October) • CLINICAL PRACTICE
exception in this group of b-lactams, primarily because of its
MIC ratio in critically ill patients, including those who are
extensive protein-binding capacity, which prevents it from
receiving CAVHD [43, 51]. A ciprofloxacin dosage of 400 mg
being filtered, and its hepatic metabolism and biliary excre-
q.d. is recommended by the manufacturer for patients with a
tion. Ceftriaxone clearance in patients receiving CVVH has
creatinine clearance rate of ⭐30 mL/min. In critically ill patients
been shown to be equivalent to clearance in subjects with
receiving CRRT, a dosage of 600–800 mg per day may be more
normal renal function, and therefore, no dose adjustment is
likely to achieve an optimal AUC/MIC ratio, and for organisms
necessary for patients receiving CRRT [37, 38].
with a ciprofloxacin MIC of ⭓1 mg/mL, standard doses are less
The other cephalosporins and aztreonam are cleared at a rate
likely to achieve a target ratio. In addition, dose escalation may
equivalent to a creatinine clearance rate of 30–50 mL/min dur-
be warranted if ciprofloxacin is the only anti–gram-negative
ing CVVHD or CVVHDF, whereas the rate of clearance by
bacteria antibiotic prescribed, especially if the pathogen is
P.
CVVH is lower. If the goal in critically ill patients is to maintain
a therapeutic concentration for the entire dosing interval, a
Levofloxacin is excreted largely unchanged in the urine, and
normal, unadjusted dose may be required. This is the case with
significant dosage adjustments are necessary for patients with
cefepime. On the basis of 2 well-done studies involving critically
renal failure. Intermittent hemodialysis does not effectively re-
ill patients, a cefepime dosage of 1 g q12h is appropriate for
move levofloxacin, and therefore, supplemental doses are not
most patients receiving CVVH, and up to 2 g q12h is appro-
required after hemodialysis [40]. Levofloxacin is eliminated by
priate for patients receiving CVVHD or CVVHDF [39, 40].
CVVH and CVVHDF [48]. Malone et al. [44] found that a
Cefepime and ceftazidime pharmacokinetics are almost iden-
levofloxacin dosage of 250 mg q24h provided C
tical, and similar doses are advocated. Older recommendations
AUC /MIC values that were comparable to the values found
for CVVH dosing (1–2 g q24–48 h) are based on CAVH data
in patients with normal renal function after a dosage of 500
[41]. However, the current use of pump-driven systems pro-
mg q24h. Levofloxacin dosages of 250 mg q24h, after a 500-
vides more consistent blood flow and increases drug clearance.
mg loading dose, are appropriate for patients receiving CVVH,
It is not clear whether CAVH data can be extrapolated to
CVVHD, or CVVHDF [44, 48, 49].
CVVH, CVVHD, and CVVHDF. Three studies determined cef-
The pharmacokinetics of moxifloxacin have been recently
tazidime doses using newer CRRT modalities [5, 6, 42]. As with
studied in critically ill patients receiving CVVHDF [50]. These
cefepime and many other b-lactams, CVVHD removes cefta-
data, as well as known pharmacokinetics data, indicate no need
zidime more efficiently than does CVVH [6]. A ceftazidime
to adjust the moxifloxacin dosage for patients receiving CRRT.
dosage of 2 g q12h is needed to maintain concentrations abovethe MIC for most nosocomial gram-negative bacteria in crit-
ically ill patients receiving CVVHD and CVVHDF. Ceftazidime
Polymyxins have recently reemerged as therapeutic options for
1 g q12h is appropriate during CVVH. Studies have not been
multidrug-resistant gram-negative organisms, such as
P. aeru-
performed with cefazolin, cefotaxime, or aztreonam during
ginosa and
Acinetobacter species. Colistimethate sodium is the
CRRT. However, their pharmacokinetic and molecular prop-
parenteral formulation of colistin and is the product for which
erties are similar enough such that extrapolations are appro-
dosing recommendations are made. Colistin is a large cationic
priate. Dosing recommendations for these b-lactams are listed
molecule with a molecular weight of 1750 D, and it is tightly
bound to membrane lipids of cells in tissues throughout thebody [52]. These 2 properties suggest that the impact of CRRT
on colistin elimination is minimal. Colistin dosing should be
Few antibiotic classes have more data supporting the influence
based on the following 2 patient-specific factors: underlying
of pharmacodynamics on clinical outcomes than fluoroquin-
renal function and ideal body weight. No clinical data exist on
olones. The ratio of the area under the curve (AUC) to the
colistin dosing for patients receiving CRRT. On the basis of
MIC is a particularly predictive pharmacodynamic parameter
clinical experience and the pharmacokinetic properties of co-
[43], and most authorities recommend maximizing this ratio.
listin, we recommend using colistin at a dosage of 2.5 mg/kg
This is best accomplished by optimizing the dose, which may
q48h in patients undergoing CRRT.
be difficult in the critical care setting where fluoroquinolone
disposition may be altered and fluoroquinolone eliminationmay be reduced. The additional influence of CRRT makes dos-
Two pharmacokinetic parameters are essential predictors of
ing even more complex. Many studies have documented min-
aminoglycoside dosing. The volume of distribution can be used
imal effects of CRRT on fluoroquinolone elimination [44–50].
to predict the drug dose, and the elimination rate can be used
However, evidence exists that manufacturer-recommended
to predict the required dosing interval. The volume of distri-
dosing for ciprofloxacin will not always achieve a target AUC/
bution may be significantly larger in critically ill patients and
CLINICAL PRACTICE •
CID 2005:41 (15 October) • 1163
Aminoglycoside dosing recommendations for critically ill adults
receiving continuous renal replacement therapy.
Infection with gram-negative bacteria
Maintenance dosage
1 mg/kg q24–36h
2 mg/kg q24–48h
2 mg/kg q24–48h
7.5 mg/kg q24–48h
See Aminoglycosides for recommendations on monitoring drug levels. Target
peak and trough levels vary depending on the type of infection. Use calculated dosingbody weight for obese patients.
may result in subtherapeutic concentrations after an initial
dida species, routine antifungal susceptibilities are recom-
loading dose. CRRT itself may contribute to a larger volume
mended to direct antifungal choice and dosing [56]. Empirical
of distribution. However, CRRT offers some "control" in such
fluconazole should be administered at a daily dose of 800 mg
a dynamic state, and if the variables of CRRT are held constant,
for critically ill patients receiving CVVHD or CVVHDF with
aminoglycoside elimination is likely to be similarly constant.
a combined ultrafiltration and dialysate flow rate of 2 L/h and
Today's filters are capable of removing aminoglycosides at a
at a daily dose of 400 mg for patients receiving CVVH. The
rate equivalent to a creatinine clearance rate of 10–40 mL/min.
dose may be decreased to 400 mg (CVVHD and CVVHDF) or
This equates to an aminoglycoside half-life of 6–20 h. The
to 200 mg (CVVH) if the species is not
Candida krusei or
typical dosing interval with aminoglycosides will be ∼3 half-
Candida glabrata and the fluconazole MIC is ⭐8 mg/L.
lives; therefore, the typical dosing interval during CRRT will
Itraconazole and voriconazole are available in oral and par-
be 18–60 h. Indeed, most patients undergoing CRRT will re-
enteral formulations. The parenteral formulations are solubi-
quire an interval of 24, 36, or 48 h. The target peak concen-
lized in a cyclodextrin diluent, which is eliminated by the kid-
tration can also predict the dosing interval. If gentamicin is
neys and will accumulate in patients with renal insufficiency.
prescribed for synergy in the treatment of infection with gram-
The clinical significance of cyclodextrin accumulation in hu-
positive organisms, the target peak is 3–4 mg/mL. Only 2 half-
mans is not fully understood. Use of intravenous itraconazole
lives are required to reach a concentration of ⭐1 mg/mL, a
and voriconazole is not recommended for patients with cre-
typical trough level. If the target peak concentration is 8 mg/
atinine clearance rates of !30 and 50 mL/min, respectively, or
mL, it will take an additional half-life to get to 1 mg/mL. There-
for patients receiving any form of renal replacement therapy.
fore, the higher the target peak concentration, the longer the
Although oral formulations are not contraindicated, there are
required dosing interval. These principles are reflected in the
few data about triazole dosing for patients receiving CRRT [57].
dosing recommendations in table 3. However, monitoring ami-
On the basis of pharmacokinetics data, no dose reduction is
noglycoside concentrations is essential to determine the most
recommended for patients receiving CRRT.
appropriate dose. Performing first-dose pharmacokinetics may
Amphotericin B and its lipid preparations
be the quickest way to ensure adequate and safe dosing. To
have not been thoroughly investigated in critically ill patients
determine the most appropriate dose, the volume of distri-
receiving CRRT. However, case reports and small series have
bution and the elimination rate can be estimated by measuring
been performed [58–60]. Amphotericin B is a large molecule,
the peak concentration and a 24-h concentration. Even if first-
and when bound within a lipid structure, the product is even
dose pharmacokinetics analysis is not performed, determina-
larger. In addition, amphotericin B is extensively and rapidly
tion of the 24-h concentration is warranted to provide a mea-
distributed in tissues. On the basis of limited clinical data and
sure of elimination and the ultimate dosing interval.
the pharmacokinetics of amphotericin B, dose adjustments forCRRT are not recommended.
Unlike itraconazole and voriconazole, which are
metabolized, 80% of the fluconazole dose is eliminated un-
Acyclovir is eliminated by renal excretion and has a narrow
changed via the kidneys. Accumulation occurs in patients with
therapeutic index in patients with renal impairment. Its small
renal insufficiency, for whom a dose reduction is recommended.
molecular size, low protein-binding capacity, and water solu-
However, clearance of fluconazole by CVVHD and CVVHDF
bility make it readily removed by all types of dialysis. Generally,
in patients with renal insufficiency is significant and may be
acyclovir clearance during a 24-h period of CRRT is equivalent
equal to or greater than that for patients with normal renal
to a single session of intermittent hemodialysis [61–63]. Limited
function [53–55]. With the emergence of azole-resistant
Can-
pharmacokinetic data suggest that an acyclovir dosage of 5 mg/
1164 •
CID 2005:41 (15 October) • CLINICAL PRACTICE
kg iv q24h (based on ideal body weight) is adequate for most
ysis, or continuous venovenous hemofiltration in patients with acute
renal failure. Crit Care Med
2004; 32:2437–52.
infections, regardless of CRRT modality [61–63]. A dosage of
14. Brier ME, Stalker DJ, Aronoff GR, et al. Pharmacokinetics of linezolid
7.5 mg/kg iv q24h is appropriate for treatment of infections
in subjects with renal dysfunction. Antimicrob Agents Chemother
involving the CNS, such as herpes simplex virus encephalitis.
Subsequent acyclovir concentration monitoring should be per-
15. Pea F, Viale P, Lugano M, et al. Linezolid disposition after standard
dosages in critically ill patients undergoing continuous venovenous
formed when available.
hemofiltration: a report of 2 cases. Am J Kidney Dis
2004; 44:1097–102.
16. Kraft MD, Pasko DA, DePestel DD, Ellis JJ, Peloquin CA, Mueller BA.
Linezolid clearance during continuous venovenous hemodialfiltration:
a case report. Pharmacotherapy
2003; 23:1071–5.
These recommendations are based on very limited clinical data,
17. Zyvox (linezolid) [package insert]. New York, NY: Pfizer,
2005.
and in many cases, our dosing recommendations are extrap-
18. Churchwell MD, Pasko DA, Mueller BA. CVVHD transmembrane
clearance of daptomycin with two different hemodiafilters [abstract A-
olations from clinical experiences and known pharmacokinetic
22]. In: Program and abstracts of the 44th Interscience Conference on
and pharmacodynamic properties. More clinical data are
Antimicrobial Agents and Chemotherapy. Washington, DC: American
needed to support such extrapolations, and these recommen-
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Source: http://remi.uninet.edu/descarga/dosisabd.pdf
INTERNATIONAL JOURNAL OF DRUG DISCOVERY AND HERBAL RESEARCH (IJDDHR) ISSN: 2231-6078 5(1): Jan-March.: (2015), 826-835 The Curative Effect of Water Extracted From Pumpkin Seeds (Cucurbita Moschata) on Blood Lipid Level in Male Albino Mice Fed High Fat Diet Maraia, F. Elmhdwi1, Muftah A. Nasib2 and Idress Hamad Attitalla2
Road Traversability Analysis Using Network Properties of Roadmaps* Muhammad Mudassir Khan1, Haider Ali2, Karsten Berns3 and Abubakr Muhammad1 Abstract— Traversability analysis is an important aspect of its traversability which is sometimes not possible. To avoid autonomous navigation in robotics. In this paper, we relate traversing the terrain to find its traversability, exterioceptive