Vancomycin Dosing in Patients on Intermittent HemodialysisStefaan J. Vandecasteele and An S. De VrieseDepartment of Nephrology and Infectious Diseases, AZ Sint-Jan Brugge-Oostende AV, Brugge, BelgiumABSTRACTVancomycin has been a cornerstone antibiotic for the treat- inﬂuenced by the timing of administration (during or after dial-ment of severe gram-positive infections in dialysis patients for ysis), the type of ﬁlter used, and the duration of dialysis. Actualdecades. Whereas subtherapeutic vancomycin levels convey a body weight, the interdialytic interval, and residual renal func-risk of treatment failure and the further emergence of resistance tion are also considerations. As in patients with normal kidneyin staphylococci, supratherapeutic vancomycin levels are asso- function, a weight-based loading dose of 20–25 mg ⁄ kg shouldciated with a dose-related incremental risk for nephrotoxicity be used in dialysis patients. While most ﬁxed-dose maintenanceand ototoxicity. Consequently, a narrow therapeutic range regimens fail to reach target levels in the majority of hemodial-with a trough-level target between 15 and 20 lg ⁄ ml is recom- ysis patients, straightforward evidence on optimal maintenancemended. Vancomycin dosing in hemodialysis patients is mainly dosing is lacking. Vancomycin is a bacteriocidal glycopeptide antibiotic mortality in this population (7,8). Septicemia in thisproduced by Streptomyces orientalis that was introduced population, often vascular access-related, is responsiblein clinical practice in 1956 to treat infections caused by for three quarters of the infectious mortality (7,8).penicillinase-producing Staphylococcus aureus (1). Gram-positive organisms cause 58–99% of tunneledVancomycin is active against the vast majority of gram- catheter-related bloodstream infections and 70–93% ofpositive organisms, with the notable exception of arteriovenous ﬁstula- or graft-related bloodstream infec-vancomycin-resistant enterococci (VRE) and the occa- tions in hemodialysis patients (7). In hemodialysissional strains of vancomycin-resistant Staphylococcus patients, S. aureus is the single leading pathogen,aureus (VRSA) (2). Vancomycin inhibits the synthesis of accounting for 27–39% of all bacteremias, which arethe cell wall in gram-positive bacteria by the formation complicated in almost half of the cases (7,8). Hemodialy-of a stable complex with murein pentapeptides, thus pre- sis patients have a 100-fold higher risk for invasiveventing further peptidoglycan formation (3). Although MRSA infections than the general population (45.2 ⁄vancomycin is a bacteriocidal antibiotic, its killing effect 1000 vs. 0.2–0.4 ⁄ 1000 in the United States in 2005) (9).is slow, and further negatively affected by stationary These epidemiological data and the suitable pharma-growth phase, bioﬁlm formation, anaerobic growth con- cokinetic characteristics of vancomycin have fostered itsditions, and large bacterial inoculates (1,4,5). Early use in dialysis patients for decades (3). Vancomycinbatches of vancomycin contained many impurities, lead- is, however, frequently prescribed inappropriatelying to a signiﬁcant toxicity and the nickname Mississippi in hemodialysis patients, mainly for the treatment of b-mud (1,6). lactam-sensitive organisms (10,11). Several lines of The launching of penicillinase-resistant anti- evidence point toward a superiority of b-lactam antibiot-staphylococcal penicillins and ﬁrst-generation cephalo- ics over vancomycin in the treatment of severe methicil-sporins in the beginning of the 1960s pushed vancomycin lin-susceptible S. aureus infections, by virtue of theirinto the background (6). Since the early 1980s, methicil- more rapid killing curve and higher intrinsic efﬁcacy (8).lin-resistant Staphylococcus aureus (MRSA) dispersed For methicillin-susceptible S. aureus bacteremia inworldwide throughout hospitals and subsequently also hemodialysis patients, both a higher recurrence rate (12)in the community, fueling a rapid increase in vancomy- and lower cure rate (13) were observed with vancomycincin use (1,2,6). versus cefazolin (8). Infection is the second leading cause of death in The ongoing emergence of staphylococcal strains withhemodialysis patients, accounting for 12–36% of the reduced susceptibility for vancomycin has resulted in considerable changes in the dosing guidelines for thisAddress correspondence to: Stefaan J. Vandecasteele, drug with suggested target trough levels of 15–20 lg ⁄ mlMD, PhD, Department of Nephrology and Infectious (3,4). Little information exists on the achievability ofdiseases, AZ Sint-Jan Brugge-Oostende AV, Ruddershove these guidelines in hemodialysis patients. The current10, 8000 Brugge, Belgium, Tel.: +3250452200, Fax: review aims to develop a practical dosing guidance for+3250452299, or e-mail: Stefaan.Vandecasteele@azsintjan.be. hemodialysis patients, based on the scarce availableSeminars in Dialysis—Vol 24, No 1 (January–February) 2011pp. 50–55 evidence and the general and hemodialysis-speciﬁcDOI: 10.1111/j.1525-139X.2010.00803.x pharmacokinetic (PK) and pharmacodynamic (PD)ª 2011 Wiley Periodicals, Inc. properties of vancomycin. 50
VANCOMYCIN DOSING IN HEMODIALYSIS 51 PK ⁄ PD of Vancomycin morbidity, mortality, and health care expenses (8). Within the group of susceptible S. aureus, the propor- Vancomycin has no appreciable oral absorption and tion of staphylococci with an MIC for vancomycinshould be administered intravenously (1). It is highly sol- between 1 and 2 lg ⁄ ml is steadily increasing, indicatinguble in water and compatible with most widely used a further shift to the right of the MIC (8,21). Staphylo-solvents such as dextran and sodium chloride in which it cocci with a MIC between 1 and 2 lg ⁄ ml impart amay remain stable for several days at room temperature higher risk for treatment failure than more susceptible(1). Vancomycin is almost exclusively cleared via the kid- species (3,8,21).ney. In patients with a normal renal function, 80–90%of the dose is excreted unchanged in the urine within24 hours (3,4). After injection, vancomycin has a com- Therapeutic Monitoring of Vancomycinplex concentration–time proﬁle, with a half-life of6–12 hours in patients with normal renal function and The American Society of Health-System Pharmacists,of 100–200 hours in anuric patients (1,3–5). Vancomy- the Infectious Diseases Society of America, and the Soci-cin clearance correlates linearly with the creatinine clear- ety of Infectious Diseases Pharmacists published a con-ance (CrCl) and glomerular ﬁltration (1,14–18). sensus review on the therapeutic monitoring of A small fraction of vancomycin is cleared extrarenal- vancomycin in 2009 (4). The activity of vancomycinly, possibly by hepatic conjugation. This leads to the for- against staphylococcal species is best predicted by themation of vancomycin crystalline degeneration products 24-hour area under the concentration curve over the(19). These products accumulate in patients with end- MIC (AUC ⁄ MIC or AUIC) and not by the time thatstage renal disease (ESRD) and cross-react with some the concentration curve is above the MIC (T>MIC), asolder, polyclonal ﬂuorescence polarizations assays, lead- previously assumed (5). An AUIC of >400 and >850ing to an overestimation by up to 40% of the vancomy- correlate with clinical and microbiological cure, respec-cin levels in these cases (10,19). tively (4,23). The volume of distribution of vancomycin is about Consequently, an AUC ⁄ MIC ‡ 400 is recommended0.4–1 L ⁄ kg in normal patients and 0.72–0.9 L ⁄ kg in as the therapeutic target for invasive S. aureus infectionspatients with ESRD; protein binding is 50–55% in nor- (4). When for example, 1 g of vancomycin is given twicemal patients and 20% in ESRD patients (1,4,5,14,15). daily to a patient with a normal kidney function and aThe volume of distribution is slightly higher in obese body weight of 80 kg, an AUIC of approximately 250patients (20). Tissue penetration of vancomycin is vari- will be reached (4). It is therefore apparent that anable, but often poor (4). Penetrations of 41–51% in lung, AUC ⁄ MIC of ‡400 needed for clinical cure is difﬁcult to17% in ventilated lung, 0–18% in uninﬂamed and obtain in many patients, especially when strains with a36–48% in inﬂamed meninges and 10–30% in, respec- MIC ‡ 2 lg ⁄ ml are involved (4). The target AUC ⁄ MICtively, diabetic and normal skin and soft tissues have of >850 required for microbiological cure appearsbeen reported (1,4,5). In S. aureus, vancomycin has a unachievable in the majority of patients (4).limited postantibiotic effect of 0.2–2 hours (5). Obtaining the multiple serum vancomycin concentra- tions required to calculate the AUC ⁄ MIC is not practi- cal for routine use. Consequently, the trough serumThe Waning Susceptibility of Staphylococci for concentration is used as a surrogate marker for the Vancomycin AUC and is recommended as both the most accurate and practical method of therapeutic drug monitoring for In 2006, the Clinical and Laboratory Standard Insti- vancomycin (4). Troughs should be obtained just beforetute established breakpoints for vancomycin for the next dose in steady-state conditions; this is after theS. aureus. A minimal inhibitory concentration (MIC) £ fourth dose in patients with a normal renal function2 lg ⁄ ml is deﬁned as susceptible, a MIC of 4–8 lg ⁄ ml as (4).This strategy is obviously not valid in hemodialysisintermediary susceptible (referred to as vancomycin- patients. In all patients at risk for nephrotoxicity, ‘‘moreintermediary S. aureus or VISA) and a MIC ‡ 16 lg ⁄ ml frequent’’ trough-level monitoring tailored to theas resistant (referred to as vancomycin-resistant patients individual characteristics is recommended (3,4).S. aureus or VRSA) (21). Only a few cases of VRSA have Clear guidance on timing and frequency of trough-levelbeen reported, but almost half of them occurred in monitoring in patients on hemodialysis is lacking (3,4).patients with chronic kidney disease (22). VRSA have Trough-level monitoring just before each dialysis sessionacquired the vanA gene from vancomycin-resistant with subsequent dose adaptation at the end of the sameenterococci, leading to altered peptidoglycan precursors dialysis session seems the most appropriate (15). Whenand high-level vancomycin resistance with MIC > this it not feasible for logistic reasons, trough levels of512 lg ⁄ ml (22). VISA arise from progressive and unu- the previous dialysis session may be helpful.sual thickening of the staphylococcal cell wall (21). Up to 11% of apparently vancomycin-susceptibleMRSA strains contain subpopulations that are only A Narrow Therapeutic Range: Trough Levelsintermediary susceptible to vancomycin and that are eas- of 15–20 lg ⁄ mlily missed in the routine laboratory (21). These strainsare referred as heterogeneous VISA or hVISA (21). Both On the one hand, subtherapeutic vancomycin concen-VISA and hVISA are clearly associated with increased trations should be avoided for reasons of efﬁcacy (3,4).
52 Vandecasteele and De VrieseThe steadily decreasing susceptibility of S. aureus to TABLE 2. Proposed dose guidance for vancomycin in hemodialysisvancomycin and the accompanying risk for treatment patientsfailure with low serum vancomycin concentrations were Vancomycin dosing in hemodialysis patientsdiscussed in the previous sections. Additionally, thereseems to be a causal link between (prolonged) low serum Monitoring Trough-level monitoring beforevancomycin concentrations and the emergence of each dialysis session Target trough levels 15–20 lg ⁄ mlhVISA and VISA (24). Consequently, vancomycin >20 lg ⁄ ml: incremental risk fortrough concentrations should always be maintained nephro- and ototoxicityabove 10 lg ⁄ ml, and preferably above 15 lg ⁄ ml, espe- <15 lg ⁄ ml: incremental risk forcially in pathogens with a MIC > 1 lg ⁄ ml, to generate treatment failure and resistancethe AUC ⁄ MIC target of >400 (4). For complicated Infusion rate 15 mg ⁄ minute, with end of infusionS. aureus infections such as bacteremia, osteomyelitis, at the end ofand meningitis, trough concentrations of 15–20 lg ⁄ ml dialysis sessionare strongly recommended (4). Loading dose 20–25 mg ⁄ kg actual (dry) On the other hand, supratherapeutic vancomycin con- body weight Maintenance dose No good data; ﬁxed doses arecentrations carry a substantial and incremental risk of inappropriatenephrotoxicity (3) and ototoxicity (25). A considerable Probably guided by troughdecrease in CrCl has been reported in 17–55% of the levels, interdialytic elapse, actualpatients in whom trough levels of ‡15 lg ⁄ ml were body weight, residual renal functionobtained (3). This risk was commensurate with total Maximal dose 4 g, also in extreme obesityvancomycin dose and further enhanced by the presence Timing of administration Intradialytic administration isof chronic kidney disease and coadministration of more convenientother nephrotoxic agents such as aminoglycosides (3). than postdialytic administration,Consequently, vancomycin may affect residual kidney dose is 13–34% higher than with post-HD dosingfunction in hemodialysis patients. Vancomycin-inducedhigh-frequency hearing loss has been reported in up to12% of the patients treated with this drug, especially inthe elderly (25). 1486 Da (3,15,26). A study of 409 vancomycin trough levels in dialysis patients counterintuitively demon- PK ⁄ PD of Vancomycin in Hemodialysis strated only a minor inﬂuence of body weight, duration Patients of dialysis, blood ﬂow rate, and dialysate ﬂow rate on vancomycin removal (27). The main PK/PD characteristics of vancomycin in Low-ﬂux membranes remove vancomycin poorlyhemodialysis patients are summarized in Table 1. Dose (15,26). Consequently, once-weekly dosing schedulesguidance for vancomycin in hemodialysis patients is were frequently used with these membranes (15,26). Insummarized in Table 2. contrast, high-ﬂux membranes are characterized by extraction rates as high as 30–46% of the dose adminis- tered (15,26,28–31). One study found an extraction rateVancomycin Clearance of 30 ± 7% during a 3-hour dialysis session and of Extracorporeal removal of vancomycin is favored by 38 ± 8% during a 4-hour dialysis session (32).its moderate volume of distribution and low protein Although data are conﬂicting, dialytic removal of vanco-binding, and hampered by its high molecular weight of mycin has been reported to correlate with Kt ⁄ V (33,34). Such a correlation would not be expected to be very strong given vancomycin’s ‘‘middle molecule’’ character- istics.TABLE 1. PK and PD parameters of vancomycin in hemodialysis Differences in vancomycin clearance between the patients various synthetic high-ﬂux dialysis membranes, if any,Administration IV do not appear to be clinically relevant (28,32,33,35).T1 ⁄ 2 100–200 hours in anuric patients One study did not ﬁnd signiﬁcant differences inVd 0.72–0.9 ⁄ kg vancomycin clearance between high-permeabilityProtein binding 20% polyethersulphone, middle-low-permeability polyether-Vancomycin clearance Correlates linearly with ClCrPostantibiotic effect 0.2–2 hours (Staphylococcus aureus) sulphone and polyacrylonitrile membranes (33). AsExtraction rate 30–46% (with high-ﬂux membranes) reviewed previously, ﬁlter reuse slightly decreases Increases with dialysis duration, kt ⁄ V vancomycin clearance (10), a ﬁnding of unclear clini- Decreases slightly with ﬁlter reuse cal importance (10).Rebound 16–36%; maximal 3–6 hours after dialysisPK ⁄ PD parameter AUC ⁄ MIC During the 3–6 hours following dialysis, blood con- >400 for clinical cure centrations of vancomycin rebound by 16–36%, reﬂect- >850 for microbiological cure ing a redistribution phase (15,33). Consequently, Vd, volume of distribution; T1 ⁄ 2, half-life; AUC ⁄ MIC, area under estimates of vancomycin removal based on an immedi-the (concentration) curve ⁄ minimal inhibitory concentration; PD, phar- ate postdialysis serum level will overestimate its dialyticmacodynamic; PK, pharmacokinetic. clearance (15).
VANCOMYCIN DOSING IN HEMODIALYSIS 53 (15.1–20 lg ⁄ ml), 69–75% of the doses were subthera-Vancomycin Dosing in Hemodialysis Patients: peutic, and 5–8% supratherapeutic (27). In another trial,Loading Dose a maintenance dose of 500 mg given at the end of the A weight-based loading dose of 20 mg ⁄ kg dry body- dialysis session produced a trough level ofweight given after dialysis is superior to a ﬁxed dose of 17 ± 8 lg ⁄ ml, but details on the proportion of patients1 g in reaching the target levels (28). At 48 hours, mean reaching the target trough levels of 15–20 lg ⁄ ml weretrough levels were 18.3 and 12.3 lg ⁄ ml, respectively, lacking (14).with 7% and 30% of the patients not reaching a trough An inﬂuence of the ABW on vancomycin mainte-level >10 lg ⁄ ml (28). A weight-based loading dose of nance doses in hemodialysis patients may be expected,25 mg ⁄ kg dry body weight given during the end of the but the extent of this inﬂuence remains unclear.dialysis session with a maximal infusion rate of 1 g ⁄ h It appears non sequitur to administer the same mainte-has also been suggested, but supporting data are feeble nance dose before a 2- and 3-day interdialytic interval.(30). However, no studies have examined the size of the Using ﬁxed doses for vancomycin treatment in vancomycin supplement to be given before the longerhemodialysis patients appears especially problematic in ‘‘weekend’’ interdialytic interval.patients with high body mass index (10). Several stud-ies conducted in patients with normal renal function Timing of Vancomycin Administration: Duringdemonstrate that even in the (morbidly) obese, initial or After Dialysis?vancomycin dose should be based on actual bodyweight (ABW) and not on ideal body weight (IBW) Rapid infusion of vancomycin may cause generalized(36–38). As vancomycin loading doses are largely inde- histamine release, causing the ‘‘red man’’ syndrome.pendent of renal function, it is likely that an ABW- Guidelines therefore recommend a maximal infusionbased loading dose should also be used in dialysis rate of 15 mg ⁄ minute (4). Consequently, intradialyticpatients (3,28). Given the longer administration time administration of vancomycin is more convenient thanrequired for higher doses and the consequent greater postdialytic administration in this often ambulatorydialytic loss, slightly higher doses may be required in population.the morbidly obese. Data on the inﬂuence of edema When vancomycin is administered during the lastare lacking. Guidelines propose a maximal daily dose hour of dialysis instead of after dialysis, elimination ofof 4 g in patients with normal kidney function (4). 13–50% of the dose has been reported (10,31,39). ThisThere are no data on acceptable maximal doses in should be borne in mind when deciding on the mode ofextreme obesity. It seems reasonable to extend this administration. One study compared the infusion ofupper limit to the obese population, as well as to 15 mg ⁄ kg after dialysis, 15 mg ⁄ kg during the last hourhemodialysis patients. of dialysis, and 30 mg ⁄ kg during the last 2 hours of dial- ysis (31). Average trough levels were 23.8, 17.9, and 29.7 lg ⁄ ml at day 3 and 14.9, 10.5, and 19.0 lg ⁄ ml atVancomycin Dosing in Hemodialysis Patients: day 5 (31).Maintenance Dose Data on maintenance doses in hemodialysis Alternative Intermittent Dialysis Modespatients are equivocal. When vancomycin was admin-istered once weekly in a dose of 20 mg ⁄ kg using No experimental data exist on the dosing of vancomy-high-ﬂux ﬁlters, 84% and 28% of the patients had a cin in short-daily and nocturnal hemodialysis (40).trough level of respectively <10 and <5 lg ⁄ ml after Mathematical modeling, abusively assuming T>MIC1 week (28). as the principal PK ⁄ PD parameter, predicted that identi- Recalculation of the data from this paper reveals that cal doses as used in conventional thrice weekly dialysiswith a ﬁxed dose of 500 mg administered after each should be given after each daily dialysis (40). A removaldialysis session, 40.8% of the trough levels were lower rate for vancomycin of 36% over an 8-hour dialysis ses-than 15 lg ⁄ ml, 31% were above 20 lg ⁄ ml, and only sion has been reported in sustained low-efﬁciency dialy-28% were in the currently recommended range of sis (SLED) (41).15–20 lg ⁄ ml (28). When a similar schedule was adminis-tered during the last hour of dialysis rather than after the Residual Renal Functiondialysis session, 2% of the patients had supratherapeutictrough levels (>20 lg ⁄ ml), 86% had subtherapeutic The impact of residual renal function (RRF) ontrough levels (47% between 10 and 15 lg ⁄ ml, 37% vancomycin dosing in hemodialysis patients has notbetween 5 and 10 lg ⁄ ml, and 2% <5 lg ⁄ ml), and only been studied. The vast majority of papers on this topic12% of the patients had trough levels in the target range have excluded patients with relevant RRF (10,27,28,32).of 15–20 lg ⁄ ml (32). Based on the linear relation between CrCl and vancomy- In an algorithm using a 1000 mg loading dose fol- cin clearance, Pallotta and Manley calculated thatlowed by a maintenance dose of 1000 mg if trough levels trough levels at 48 hours may be 40% lower in patientswere <8 lg ⁄ ml, 500 mg if trough levels were with a residual CrCl of 15 ml ⁄ minute than in anuric8–15.9 lg ⁄ ml, and no supplement if trough levels were patients (10). In clinical practice, however, it remains‡16 lg ⁄ ml, only 20–23% of the doses were appropriate unclear whether and to which extent RRF should be
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