1. Vancomycin Dosing in Patients on Intermittent
Hemodialysis
Stefaan J. Vandecasteele and An S. De Vriese
Department of Nephrology and Infectious Diseases, AZ Sint-Jan Brugge-Oostende AV, Brugge, Belgium
ABSTRACT
Vancomycin 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. Actual
decades. 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 kidney
in staphylococci, supratherapeutic vancomycin levels are asso- function, a weight-based loading dose of 20–25 mg ⁄ kg should
ciated with a dose-related incremental risk for nephrotoxicity be used in dialysis patients. While most fixed-dose maintenance
and 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 maintenance
mended. Vancomycin dosing in hemodialysis patients is mainly dosing is lacking.
Vancomycin is a bacteriocidal glycopeptide antibiotic mortality in this population (7,8). Septicemia in this
produced by Streptomyces orientalis that was introduced population, often vascular access-related, is responsible
in 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 tunneled
Vancomycin is active against the vast majority of gram- catheter-related bloodstream infections and 70–93% of
positive 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 hemodialysis
sional 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 are
the 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 invasive
venting 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 its
ditions, and large bacterial inoculates (1,4,5). Early use in dialysis patients for decades (3). Vancomycin
batches of vancomycin contained many impurities, lead- is, however, frequently prescribed inappropriately
ing 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 their
into 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 in
worldwide 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 vancomycin
cin use (1,2,6). versus cefazolin (8).
Infection is the second leading cause of death in The ongoing emergence of staphylococcal strains with
hemodialysis patients, accounting for 12–36% of the reduced susceptibility for vancomycin has resulted in
considerable changes in the dosing guidelines for this
Address correspondence to: Stefaan J. Vandecasteele, drug with suggested target trough levels of 15–20 lg ⁄ ml
MD, PhD, Department of Nephrology and Infectious (3,4). Little information exists on the achievability of
diseases, AZ Sint-Jan Brugge-Oostende AV, Ruddershove these guidelines in hemodialysis patients. The current
10, 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 available
Seminars in Dialysis—Vol 24, No 1 (January–February) 2011
pp. 50–55
evidence and the general and hemodialysis-specific
DOI: 10.1111/j.1525-139X.2010.00803.x pharmacokinetic (PK) and pharmacodynamic (PD)
ª 2011 Wiley Periodicals, Inc. properties of vancomycin.
50

2. 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 vancomycin
should be administered intravenously (1). It is highly sol- between 1 and 2 lg ⁄ ml is steadily increasing, indicating
uble 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 a
may 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 within
24 hours (3,4). After injection, vancomycin has a com- Therapeutic Monitoring of Vancomycin
plex concentration–time profile, with a half-life of
6–12 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 vancomycin
ly, possibly by hepatic conjugation. This leads to the for- against staphylococcal species is best predicted by the
mation 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 that
stage renal disease (ESRD) and cross-react with some the concentration curve is above the MIC (T>MIC), as
older, polyclonal fluorescence polarizations assays, lead- previously assumed (5). An AUIC of >400 and >850
ing 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 recommended
0.4–1 L ⁄ kg in normal patients and 0.72–0.9 L ⁄ kg in as the therapeutic target for invasive S. aureus infections
patients with ESRD; protein binding is 50–55% in nor- (4). When for example, 1 g of vancomycin is given twice
mal patients and 20% in ESRD patients (1,4,5,14,15). daily to a patient with a normal kidney function and a
The volume of distribution is slightly higher in obese body weight of 80 kg, an AUIC of approximately 250
patients (20). Tissue penetration of vancomycin is vari- will be reached (4). It is therefore apparent that an
able, but often poor (4). Penetrations of 41–51% in lung, AUC ⁄ MIC of ‡400 needed for clinical cure is difficult to
17% in ventilated lung, 0–18% in uninflamed and obtain in many patients, especially when strains with a
36–48% in inflamed meninges and 10–30% in, respec- MIC ‡ 2 lg ⁄ ml are involved (4). The target AUC ⁄ MIC
tively, diabetic and normal skin and soft tissues have of >850 required for microbiological cure appears
been 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 serum
The 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 before
tute established breakpoints for vancomycin for the next dose in steady-state conditions; this is after the
S. aureus. A minimal inhibitory concentration (MIC) £ fourth dose in patients with a normal renal function
2 lg ⁄ ml is defined as susceptible, a MIC of 4–8 lg ⁄ ml as (4).This strategy is obviously not valid in hemodialysis
intermediary susceptible (referred to as vancomycin- patients. In all patients at risk for nephrotoxicity, ‘‘more
intermediary S. aureus or VISA) and a MIC ‡ 16 lg ⁄ ml frequent’’ trough-level monitoring tailored to the
as 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-level
been 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 session
acquired the vanA gene from vancomycin-resistant with subsequent dose adaptation at the end of the same
enterococci, leading to altered peptidoglycan precursors dialysis session seems the most appropriate (15). When
and high-level vancomycin resistance with MIC > this it not feasible for logistic reasons, trough levels of
512 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-susceptible
MRSA strains contain subpopulations that are only A Narrow Therapeutic Range: Trough Levels
intermediary susceptible to vancomycin and that are eas- of 15–20 lg ⁄ ml
ily missed in the routine laboratory (21). These strains
are 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).

3. 52 Vandecasteele and De Vriese
The steadily decreasing susceptibility of S. aureus to TABLE 2. Proposed dose guidance for vancomycin in hemodialysis
vancomycin and the accompanying risk for treatment patients
failure with low serum vancomycin concentrations were Vancomycin dosing in hemodialysis patients
discussed in the previous sections. Additionally, there
seems to be a causal link between (prolonged) low serum Monitoring Trough-level monitoring before
vancomycin concentrations and the emergence of each dialysis session
Target trough levels 15–20 lg ⁄ ml
hVISA and VISA (24). Consequently, vancomycin >20 lg ⁄ ml: incremental risk for
trough concentrations should always be maintained nephro- and ototoxicity
above 10 lg ⁄ ml, and preferably above 15 lg ⁄ ml, espe- <15 lg ⁄ ml: incremental risk for
cially in pathogens with a MIC > 1 lg ⁄ ml, to generate treatment failure
and resistance
the AUC ⁄ MIC target of >400 (4). For complicated Infusion rate 15 mg ⁄ minute, with end of infusion
S. aureus infections such as bacteremia, osteomyelitis, at the end of
and meningitis, trough concentrations of 15–20 lg ⁄ ml dialysis session
are 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 are
centrations carry a substantial and incremental risk of inappropriate
nephrotoxicity (3) and ototoxicity (25). A considerable Probably guided by trough
decrease in CrCl has been reported in 17–55% of the levels, interdialytic elapse, actual
patients in whom trough levels of ‡15 lg ⁄ ml were body weight, residual
renal function
obtained (3). This risk was commensurate with total Maximal dose 4 g, also in extreme obesity
vancomycin dose and further enhanced by the presence Timing of administration Intradialytic administration is
of chronic kidney disease and coadministration of more convenient
other nephrotoxic agents such as aminoglycosides (3). than postdialytic administration,
Consequently, vancomycin may affect residual kidney dose is 13–34% higher than
with post-HD dosing
function in hemodialysis patients. Vancomycin-induced
high-frequency hearing loss has been reported in up to
12% of the patients treated with this drug, especially in
the 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 poorly
hemodialysis patients are summarized in Table 1. Dose (15,26). Consequently, once-weekly dosing schedules
guidance for vancomycin in hemodialysis patients is were frequently used with these membranes (15,26). In
summarized 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 rate
Vancomycin 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 in
Vd 0.72–0.9 ⁄ kg vancomycin clearance between high-permeability
Protein binding 20% polyethersulphone, middle-low-permeability polyether-
Vancomycin clearance Correlates linearly with ClCr
Postantibiotic effect 0.2–2 hours (Staphylococcus aureus) sulphone and polyacrylonitrile membranes (33). As
Extraction 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 dialysis
PK ⁄ 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 dialytic
macodynamic; PK, pharmacokinetic. clearance (15).

4. 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 of
weight given after dialysis is superior to a fixed dose of 17 ± 8 lg ⁄ ml, but details on the proportion of patients
1 g in reaching the target levels (28). At 48 hours, mean reaching the target trough levels of 15–20 lg ⁄ ml were
trough 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 longer
hemodialysis 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: During
demonstrate that even in the (morbidly) obese, initial
or After Dialysis?
vancomycin dose should be based on actual body
weight (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 infusion
based loading dose should also be used in dialysis rate of 15 mg ⁄ minute (4). Consequently, intradialytic
patients (3,28). Given the longer administration time administration of vancomycin is more convenient than
required for higher doses and the consequent greater postdialytic administration in this often ambulatory
dialytic loss, slightly higher doses may be required in population.
the morbidly obese. Data on the influence of edema When vancomycin is administered during the last
are lacking. Guidelines propose a maximal daily dose hour of dialysis instead of after dialysis, elimination of
of 4 g in patients with normal kidney function (4). 13–50% of the dose has been reported (10,31,39). This
There are no data on acceptable maximal doses in should be borne in mind when deciding on the mode of
extreme obesity. It seems reasonable to extend this administration. One study compared the infusion of
upper limit to the obese population, as well as to 15 mg ⁄ kg after dialysis, 15 mg ⁄ kg during the last hour
hemodialysis 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 at
Vancomycin Dosing in Hemodialysis Patients:
day 5 (31).
Maintenance Dose
Data on maintenance doses in hemodialysis
Alternative Intermittent Dialysis Modes
patients 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>MIC
1 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 dialysis
with a fixed dose of 500 mg administered after each should be given after each daily dialysis (40). A removal
dialysis 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 Function
dialysis session, 2% of the patients had supratherapeutic
trough levels (>20 lg ⁄ ml), 86% had subtherapeutic The impact of residual renal function (RRF) on
trough levels (47% between 10 and 15 lg ⁄ ml, 37% vancomycin dosing in hemodialysis patients has not
between 5 and 10 lg ⁄ ml, and 2% <5 lg ⁄ ml), and only been studied. The vast majority of papers on this topic
12% 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 that
lowed by a maintenance dose of 1000 mg if trough levels trough levels at 48 hours may be 40% lower in patients
were <8 lg ⁄ ml, 500 mg if trough levels were with a residual CrCl of 15 ml ⁄ minute than in anuric
8–15.9 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

5. 54 Vandecasteele and De Vriese
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