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
Even if Viagra is not needed, it is possible that the doctor will be able to determine the etiology of erectile dysfunction and prescribe appropriate treatmen viagra australia it doesn't pay to forget about sexual activeness even at the first sings of malfunction.
Remi.uninet.eduEllie 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 . 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@example.com).
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 . 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 .
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 .
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 . 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 . 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 .
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 . 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 . 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 , 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 . 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) . 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 . 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 . Levofloxacin is eliminated by priate for patients receiving CVVHD or CVVHDF [39, 40].
CVVH and CVVHDF . Malone et al.  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 . 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 . 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 . 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 . 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- , 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 . 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 .
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- Society for Microbiology, 2004:5.
19. Cubicin (daptomycin) [package insert]. Lexington, MA: Cubist Phar- dations should not supercede sound clinical judgment.
20. Mueller BA, Scarim SK, Macias WL. Comparison of imipenem phar- macokinetics in patients with acute or chronic renal failure treated
with continuous hemofiltration. Am J Kidney Dis 1993; 21:172–9.
We thank Dr. Kevin High for help with preparation of the manuscript.
21. Tegeder I, Bremer F, Oelkers R, et al. Pharmacokinetics of imipenem- Potential conflicts of interest.
R.L.T. has been a member of the speak- cilastatin in critically ill patients undergoing continuous venovenous ers' bureau for Pfizer Pharmaceuticals, and J.C.W. has received research hemofiltration. Antimicrob Agents Chemother 1997; 41:2640–5.
funding from Elan Pharmaceuticals. D.M.S. and W.S.: no conflicts.
22. Hashimoto S, Honda M, Yamaguchi M, Sekimoto M, Tanaka Y. Phar- macokinetics of imipenem and cilastatin during continuous hemodi- alysis in patients who are critically ill. ASAIO J 1997; 43:84–8.
23. Fish DN, Teitelbaum I, Abraham E. Pharmacokinetics and pharma- 1. Joy M, Matzke G, Armstrong D, Marx M, Zarowitz B. A primer on codynamics of imipenem during continuous renal replacement therapy continuous renal replacement therapy for critically ill patients. Ann in critically ill patients. Antimicrob Agents Chemother 2005; 49:2421–8.
Pharmacother 1998; 32:362–75.
24. Giles LJ, Jennings AC, Thomson AH, Creed G, Beale RJ, McLuckie A.
2. Bellomo R, Ronco C, Mehta RL. Nomenclature for continuous renal Pharmacokinetics of meropenem in intensive care units receiving con- replacement therapies. Am J Kidney Dis 1996; 28(Suppl 3):S2–7.
tinuous veno-venous hemofiltration or hemidialfiltration. Crit Care 3. Cotterill S. Antimicrobial prescribing in patients on haemofiltration.
Med 2000; 28:632–7.
J Antimicrob Chemother 1995; 36:773–80.
25. Valtonen M, Tiula E, Backman JT, Neuvonen PJ. Elimination of mer- 4. Joos B, Schmidli M, Keusch G. Pharmacokinetics of antimicrobial openem during continuous veno-venous haemofiltration in patients agents in anuric patients during continuous venovenous haemifiltra- with acute renal failure. J Antimicrob Chemother 2000; 45:701–4.
tion. Nephrol Dial Transplant 1996; 11:1582–5.
26. Tegeder I, Neumann F, Bremer F, Brune K, Lotsch J, Geisslinger G.
5. Traunmuller F, Schenk P, Mittermeyer C, Thalhammer-Scherrer R, Pharmacokinetics of meropenem in critically ill patients with acute Ratheiser K, Thalhammer F. Clearance of ceftazidime during contin- renal failure undergoing continuous venovenous hemofiltration. Clin uous venovenous haemofiltration in critically ill patients. J Antimicrob Pharmacol Ther 1999; 65:50–7.
Chemother 2002; 49:129–34.
27. Thalhammer F, Schenk P, Burgmann H, et al. Single-dose pharma- 6. Matzke GR, Frye RF, Joy MS, Palevsky PM. Determinants of ceftazi- cokinetics of meropenem during continuous venovenous hemofiltra- dime clearance by continuous venovenous hemofiltration and contin- tion. Antimicrob Agents Chemother 1998; 42:2417–20.
uous venovenous hemodialysis. Antimicrob Agents Chemother 2000;
28. Ververs T, van Dijk A, Vinks SA, et al. Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous 7. Joy MS, Matzke GR, Frye RF, Palevsky PM. Determinants of vanco- venovenous hemofiltration. Crit Care Med 2000; 28:3412–6.
mycin clearance by continuous venovenous hemofiltration and con- 29. Kruger WA, Schroeder TH, Hutchison M, et al. Pharmacokinetics of tinuous venovenous hemodialysis. Am J Kidney Dis 1998; 31:1019–27.
meropenem in critically ill patients with acute renal failure treated by 8. Matzke GR, Zhanel GG, Guay DR. Clinical pharmacokinetics of van- continuous hemodialfiltration. Antimicrob Agents Chemother 1998;
comycin. Clin Pharmacokinet 1986; 11:257–82.
9. DelDot ME, Lipman J, Tett SE. Vancomycin pharmacokinetics in crit- ically ill patients receiving continuous hemodialfiltration. Br J Clin 30. Robatel C, Decosterd A, Biollaz J, Schaller MD, Buclin T. Pharma- Pharmacol 2004; 58:259–68.
cokinetics and dosage adaption of meropenem during continuous ven- 10. Boereboom FT, Ververs FF, Blankestijn PJ, Savelkoul TJ, van Dijk A.
ovenous hemodialfiltration in critically ill patients. J Clin Pharmacol Vancomycin clearance during continuous venovenous haemofiltration in critically ill patients. Intensive Care Med 1999; 25:1100–4.
31. Mueller SC, Majcher-Peszynska J, Hickstein H, et al. Pharmacokinetics 11. Santre C, Leroy O, Simon M, et al. Pharmacokinetics of vancomycin of piperacillin-tazobactam in anuric intensive care patients during con- during continuous hemodialfiltration. Intensive Care Med 1993; 19:
tinuous venovenous hemodialysis. Antimicrob Agents Chemother 12. American Thoracic Society, Infectious Diseases Society of America.
32. Valtonen M, Tiula E, Takkunem O, Backman JT, Neuvonen PJ. Elim- Guidelines for the management of adults with hospital-acquired, ven- ination of piperacillin/tazobactam combination during continuous tilator-associated, and healthcare-associated pneumonia. Am J Respir venovenous haemofiltration and haemodialfiltration in patients with Crit Care Med 2005; 171:388–416.
acute renal failure. J Antimicrob Chemother 2001; 48:881–5.
13. Fiaccadori E, Maggiore U, Rotelli C, et al. Removal of linezolid by 33. van der Werf TS, Mulder PO, Zijlstra JG, Uges DR, Stegman CA.
conventional intermittent hemodialysis, sustained low-efficiency dial- Pharmacokinetics of piperacillin and tazobactam in critically ill patients CLINICAL PRACTICE • CID 2005:41 (15 October) • 1165
with renal failure, treated with continuous veno-venous hemofiltration mofiltration in critically ill patients. J Antimicrob Chemother 2001;
(CVVH). Intensive Care Med 1997; 23:873–7.
34. Cappellier G, Cornette C, Boillot A, et al. Removal of piperacillin in 49. Hansen E, Bucher M, Jakob W, Lemberger P, Kees F. Pharmacokinetics critically ill patients undergoing continuous venovenous hemofiltra- of levofloxacin during continuous veno-venous hemofiltration. Inten- tion. Crit Care Med 1998; 26:88–91.
sive Care Med 2001; 27:371–5.
35. Rhode B, Werner U, Hickstein H, Ehmcke H, Drewelow B. Pharma- 50. Fuhrmann V, Schenk P, Jaeger W, Ahmed S, Thalhammer F. Phar- cokinetics of mezlocillin and sulbactam under continuous veno-venous macokinetics of moxifloxacin in patients undergoing continuous ven- hemodialysis (CVVHD) in intensive care patients with acute renal ovenous haemodiafiltration. J Antimicrob Chemother 2004; 54:780–4.
failure. Eur J Clin Pharmacol 1997; 53:111–5.
51. Fish DN, Bainbridge JL, Peloquin CA. Variable disposition of cipro- 36. Hardin TC, Butler SC, Ross S, Wakeford JH, Jorgensen JH. Comparison floxacin in critically ill patients undergoing continuous arteriovenous of ampicillin-sulbactam and ticarcillin-clavulanic acid in patients with hemodiafiltration. Pharmacotherapy 1995; 15:236–45.
chronic renal failure: effects of differential pharmacokinetics on serum 52. Falagas ME, Kasiakou SK. Colistin: the revival of polymyxins for the bactericidal activity. Pharmacotherapy 1994; 14:147–52.
management of multidrug-resistant gram-negative bacterial infections.
37. Kroh UF, Lennartz H, Edwards D, Stoeckel K. Pharmacokinetics of Clin Infect Dis 2005; 40:1333–41.
ceftriaxone in patients undergoing continuous veno-venous hemofil- 53. Pittrow L, Penk A. Dosage adjustment of fluconazole during contin- tration. J Clin Pharmacol 1996; 36:1114–9.
uous renal replacement therapy (CAVH, CVVH, CAVHD, CVVHD).
38. Matzke GR, Frye RF, Joy MS, Palevsky PM. Determinants of ceftriaxone Mycoses 1999; 42:17–9.
clearance by continuous venovenous hemofiltration and hemodialysis.
54. Valtonen M, Tiula E, Neuvonen PJ. Effects of continuous venovenous Pharmacotherapy 2000; 20:635–43.
haemofiltration and haemodialfiltration on the elimination of flucon- 39. Malone RS, Fish DN, Abraham E, Teitelbaum I. Pharmacokinetics of azole in patients with acute renal failure. J Antimicrob Chemother cefepime during continuous renal replacement therapy in critically ill patients. Antimicrob Agents Chemother 2001; 45:3148–55.
55. Muhl E, Martens T, Iven H, Rob P, Bruch HP. Influence of continuous 40. Allaouchiche B, Breilh D, Jaumain H, Gaillard B, Renard S, Saux M- veno-venous haemodialfiltration and continuous veno-venous hae- C. Pharmacokinetics of cefepime during continuous venovenous he- mofiltration on the pharmacokinetics of fluconazole. Eur J Clin Phar- modialfiltration. Antimicrob Agents Chemother 1997; 41:2424–7.
macol 2000; 56:671–8.
41. Davies SP, Lacey LF, Kox WJ, Brown EA. Pharmacokinetics of cefu- 56. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of can- roxime and ceftazidime in patients with acute renal failure treated by didiasis. Clin Infect Dis 2004; 38:161–89.
continuous arteriovenous haemodialysis. Nephrol Dial Transplant 57. Robatel C, Rusca M, Padoin C, Marchetti O, Liaudet L, Buclin T.
Disposition of voriconazole during continuous veno-venous haemo- 42. Sato T, Okamoto K, Kitaura M, Kukita I, Kikuta K, Hamaguchi M.
dialfiltration (CVVHDF) in a single patient. J Antimicrob Chemother The pharmacokinetics of ceftazidime during hemodialfiltration in crit- ically ill patients. Artif Organs 1999; 23:143–5.
58. Bellmann R, Egger P, Djanani A, Wiedermann CJ. Pharmacokinetics 43. Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag of amphotericin B lipid complex in critically ill patients on continuous JJ. Pharmacodynamics of intravenous ciprofloxacin in seriously ill pa- veno-venous haemofiltration. Int J Antimicrob Agents 2004; 23:80–3.
tients. Antimicrob Agents Chemother 1993; 37:1073–81.
59. Bellmann R, Egger P, Gritsch W, et al. Amphotericin B lipid formu- 44. Malone RS, Fish DN, Abraham E, Teitelbaum I. Pharmacokinetics of lations in critically ill patients on continuous veno-venous haemofil- levofloxacin and ciprofloxacin during continuous renal replacement tration. J Antimicrob Chemother 2003; 51:671–81.
therapy in critically ill patients. Antimicrob Agents Chemother 2001;
60. Tomlin M, Priestly GS. Elimination of liposomal amphotericin B by hemodialfiltration. Intensive Care Med 1995; 21:699–700.
45. Davies SP, Azadian BS, Kox WJ, Brown EA. Pharmacokinetics of cip- 61. Boulieu R, Bastien O, Gaillard S, Flamens C. Pharmacokinetics of rofloxacin and vancomycin in patients with acute renal failure treated acyclovir in patients undergoing continuous venovenous hemodialysis.
by continuous haemodialysis. Nephrol Dial Transplant 1992; 7:848–54.
Ther Drug Monit 1997; 19:701–4.
46. Wallis SC, Mullany DV, Lipman J, Rickard CM, Daley PJ. Pharma- 62. Bleyzac N, Barou P, Massenavette B, et al. Assessment of acyclovir cokinetics of ciprofloxacin in ICU patients on continuous veno-venous intraindividual pharmacokinetic variability during continuous hemo- haemodialfiltration. Intensive Care Med 2001; 27:665–72.
filtration, continuous hemodialfiltration, and continuous hemodialysis.
47. Fish DN, Chow AT. The clinical pharmacokinetics of levofloxacin. Clin Ther Drug Monit 1999; 21:520–5.
Pharmacokinet 1997; 32:101–19.
63. Khajehdehi P, Jamal JA, Bastani B. Removal of acyclovir during con- 48. Traunmuller F, Thalhammer-Scherrer R, Locker GJ, et al. Single-dose tinuous veno-venous hemodialysis and hemodiafiltration with high- pharmacokinetics of levofloxacin during continuous veno-venous hae- efficiency membranes. Clin Nephrol 2000; 54:351–5.
1166 • CID 2005:41 (15 October) • CLINICAL PRACTICE
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