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Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults

Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults
Authors:
Richard H Drew, PharmD, MS, FCCP, FIDP
George Sakoulas, MD
Section Editor:
David C Hooper, MD
Deputy Editor:
Elinor L Baron, MD, DTMH
Literature review current through: Nov 2021. | This topic last updated: Jun 30, 2021.

INTRODUCTION — Vancomycin is a glycopeptide antibiotic administered intravenously for treatment of patients with suspected or proven invasive gram-positive infections, including methicillin-resistant Staphylococcus aureus (MRSA).

Appropriate dosing and administration of vancomycin requires consideration of the pathogen and its susceptibility, type and severity of infection, patient weight, and kidney function [1-5]. The optimal approach to vancomycin dosing and monitoring for invasive MRSA infections is a subject of ongoing controversy and study. Challenges include how best to optimize clinical efficacy (particularly in the setting of emerging resistance) while minimizing toxicity (primarily nephrotoxicity) [6-9].

Issues related to parenteral vancomycin dosing and serum concentration monitoring in adult patients will be reviewed here, including guidelines on therapeutic monitoring published in 2020 by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Disease Society, and the Society of Infectious Disease Pharmacists [1], and by the Canadian Agency for Drugs and Technologies in Health [10].

Issues related to vancomycin hypersensitivity are discussed separately. (See "Vancomycin hypersensitivity".)

GENERAL PHARMACOLOGY PRINCIPLES

Tissue penetration — Following intravenous administration, vancomycin is distributed widely to various tissues and body fluids, with a volume of distribution ranging from 0.4 to 1 L/kg [11]. Penetration of vancomycin varies by site and concomitant disease state. For example, limited cerebrospinal fluid penetration may be enhanced by the presence of inflamed meninges. Penetration of vancomycin into soft tissue may be impaired in patients with diabetes [12]. Vancomycin penetration into lung tissue is limited, relative to that of simultaneous serum concentration. The ratio of lung tissue to serum concentration is about 0.25 [13].

Drug clearance — The primary route of vancomycin elimination is via renal excretion of unchanged drug. While the rate of elimination is directly related to creatinine clearance [2], accurate estimates of drug clearance based on equations estimating kidney function (notably glomerular filtration rate and/or creatinine clearance) are difficult. Among the adult patients with altered vancomycin clearance are those with critical illness, burns, those receiving renal replacement therapy, and older adults [14].

Pharmacokinetic/pharmacodynamic target — In vitro and in vivo assessments of pharmacokinetic/pharmacodynamic (PK/PD) models demonstrate that bactericidal activity (ie, a 1- to 2-log reduction in bacterial inoculum in animal models) may be achieved when the vancomycin area under the 24-hour time-concentration curve to minimum inhibitory concentration determined by broth microdilution (AUC/MICBMD) ratio approximates or exceeds 400 mg ▪ hour/L [1,15-17]. In general, the MICBMD tends to be 1.5- to 2-fold lower than the MIC determined by Etest (MICEtest). In addition, in vitro data suggest that an AUC <400 mg ▪ hour/L potentiates the emergence of methicillin-resistant S. aureus (MRSA) resistance and vancomycin-intermediate S. aureus strains. Issues related to achieving the efficacy target are discussed below. (See 'Severe S. aureus infection' below.)

For treatment of severe, invasive infection due to S. aureus, the optimal PK/PD efficacy target is considered to be an AUC/MICBMD ratio of 400 to 600 mg ▪ hour/L. This target is based on available data for isolates with an MICBMD of 1 mcg/mL.

The target range is derived largely from observational studies of patients with MRSA bacteremia. Among the limitations of such studies is that most used simple vancomycin clearance formulas (based on daily vancomycin dose and estimated kidney function) to determine AUC values. In general, such formulas overestimate vancomycin clearance (by 40 to 50 percent), providing imprecise estimates of the AUC [1,18-20].

Limited data suggest that higher AUC/MICBMD targets (>600 mg ▪ hour/L) may be required in patients with endocarditis due to MRSA [21]. However, such targets are controversial because their attainment is not always associated with successful clinical outcome and their use is associated with increased risk of nephrotoxicity [22]. (See 'Severe S. aureus infection' below.)

In patients with infection due to S. aureus isolates with MICBMD ≥2 mcg/mL, clinical failure of vancomycin has been observed [23-26]. For such isolates, an AUC/MICBMD of ≥400 mg ▪ hour/L is not reliably achievable with conventional dosing methods in patients with normal kidney function [27]. In such cases alternatives to vancomycin therapy should be considered [1]. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia", section on 'Borderline vancomycin susceptibility'.)

Infusion rate — Vancomycin should be diluted to a concentration of no more than 5 mg/mL and infused at a rate of 10 to 15 mg/minute (ie, 1000 mg over ≥1 hour). For patients who develop infusion reaction (histamine-mediated flushing during or immediately following infusion of vancomycin), a slower infusion rate or reduction in dose is warranted. (See 'Rash' below.)

APPROACH TO DOSING AND MONITORING — Vancomycin pharmacokinetic parameters vary substantially among individual patients. Therefore, individualization of the dosing regimen (independent of method) and frequent reassessment are needed to optimize drug efficacy, minimize toxicity, and minimize emergence of resistance.

Severe S. aureus infection — Severe S. aureus infections include (but are not limited to) bacteremia, endocarditis, osteomyelitis, prosthetic joint infection, pneumonia warranting hospitalization, or infection causing critical illness (table 1).

The approach to use of vancomycin for management of severe S. aureus infections is based largely from studies of methicillin-resistant S. aureus (MRSA) bacteremia in adults, with limited data for pneumonia and infective endocarditis. These findings are extrapolated to management of osteomyelitis and infections of the central nervous system. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia" and "Antimicrobial therapy of left-sided native valve endocarditis" and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults".)

Selecting a dosing/monitoring method

Intermittent versus continuous infusion — Vancomycin may be administered via intermittent infusion (II) or continuous infusion (CI). In general, II is the most common approach. However, CI may be an advantageous alternative in certain circumstances. (See 'Intermittent infusion' below and 'Continuous infusion' below.)

Potential settings for CI include patients with critical illness (particularly those on continuous renal replacement therapy) and patients receiving outpatient antimicrobial therapy [1] (see 'Continuous renal replacement' below). Potential advantages of CI include rapid pharmacokinetic (PK) target attainment, less variability in steady-state concentration, ease of serum drug concentration monitoring (given less dependence on sampling time or multiple concentrations to calculate area under the 24-hour time-concentration curve [AUC]), and lower potential risk of nephrotoxicity [28-34]. Disadvantages include the need for a dedicated intravenous line or compatibility with other agents administered through the same line.

Data comparing intermittent with continuous vancomycin administration are limited. Thus far, it is not possible to draw definitive conclusions regarding comparative efficacy or safety of CI versus II, given differences in study design, control and/or accounting for confounders, and lack of adequate statistic power.

AUC versus trough-guided serum concentration monitoring — For patients with severe S. aureus infection receiving vancomycin via II, there are two methods of determining maintenance dosing: area under the 24-hour time-concentration curve (AUC)- and trough-guided dosing. The optimal approach to vancomycin serum concentration monitoring for management invasive MRSA infections is a subject of ongoing study [6-9].

For treatment of patients with severe MRSA infection and stable kidney function, we favor AUC-guided dosing over trough-guided dosing, to target optimal vancomycin exposure and reduce the risk of vancomycin-induced nephrotoxicity; this approach is in keeping with the 2020 guidelines published by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Disease Society, and the Society of Infectious Disease Pharmacists [1] and the Canadian Agency for Drugs and Technologies in Health [10]. However, thus far data are lacking to establish the superiority of this approach for treatment outcomes [20].

Given the increasing availability and experience with the use of AUC calculators (including Bayesian and non-Bayesian tools), we favor AUC-guided monitoring in patients with severe S. aureus infection and stable kidney function; this approach requires involvement of a pharmacist. If AUC-guided monitoring (with AUC calculator and pharmacist involvement) is not feasible, trough-guided monitoring is warranted.

Implementation issues associated with AUC-guided monitoring include the need for staff education, protocol development, software acquisition, and workflow integration for health care workers, laboratory personnel, and pharmacists. Despite its challenges, this approach to AUC estimation has been successfully adopted by some hospitals in the United States.

AUC-guided dosing should not be used among patients for which data supporting this approach are sparse; these categories include patients with unstable kidney function, patients on renal replacement therapy, patients with nonsevere infections (such as skin and skin structure or urinary tract infection) or non-MRSA infections, and patients with central nervous system infections (ie, meningitis and ventriculitis):

Management of patients with unstable kidney function is discussed below. (See 'Patients with unstable kidney function' below and 'Trough-guided intermittent dosing' below.)

Management of patients on renal replacement therapy is discussed below. (See 'Patients on renal replacement therapy' below.)

Management of patients with nonsevere or non-S. aureus infections is discussed below. (See 'Nonsevere or non-S. aureus infection' below.)

Management of patients with central nervous system infections is discussed separately. (See "Initial therapy and prognosis of bacterial meningitis in adults".)

For patients with MRSA infection with MICBMD ≥2 mcg/mL, alternative therapeutic agents should be considered, since AUC-guided dosing assumes a minimum inhibitory concentration determined by broth microdilution (MICBMD) of 1 mcg/mL to achieve AUC/MICBMD targets. This is discussed further separately. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia", section on 'Borderline vancomycin susceptibility' and "Staphylococcus aureus bacteremia with reduced susceptibility to vancomycin".)

Data to support use of trough-guided dosing for optimizing drug efficacy are sparse. In one systematic review including more than 2000 patients with invasive MRSA infection, no difference in all-cause mortality was observed between patients with trough concentrations of <15 mcg/mL versus ≥15 mcg/mL [35]. Similarly, another meta-analysis including more than 1600 patients with S. aureus bacteremia noted no correlation between trough concentrations >15 mcg/mL and rates of treatment failure, persistent bacteremia, or mortality [36].

As discussed above, vancomycin activity is best predicted by the ratio of the AUC/MIC. The AUC represents the integrated quantity of cumulative drug exposure (ie, the serum drug concentration-time curve over a defined interval). Traditionally, given the cumbersome nature of AUC estimation in a clinical context, trough-guided dosing (maintaining trough concentrations between 15 and 20 mcg/mL) has been used a surrogate marker for the AUC. However, since a trough measurement represents a single exposure point at the end of the dosing interval, a wide range of concentration-time profiles may be associated with a particular trough [6,35-40]. (See 'Pharmacokinetic/pharmacodynamic target' above.)

Use of trough-guided dosing may be associated with higher likelihood of acute kidney injury than AUC-guided dosing. Among adults with normal kidney function managed with Bayesian software to achieve AUC of ≥400, approximately 60 percent are expected to have a vancomycin trough concentration below the traditional minimum target of 15 mg/L, reducing the likelihood of nephrotoxicity [40]. While AUCs of ≥400 mg ▪ hour/L are usually obtained in patients with steady-state troughs of 15 to 20 mg/L [27,41], such troughs are rarely needed to achieve this AUC target and may exceed the upper AUC target of 600 [42]. (See 'Acute kidney injury' below.)

In a retrospective study comparing the incidence of nephrotoxicity with AUC-guided dosing versus trough monitoring among 1,280 patients on vancomycin, use of AUC-guided dosing was associated with a lower likelihood of acute kidney injury (AKI; odds ratio 0.52, 95% CI 0.34-0.80) [43]. Similarly, in a prospective study including 252 patients on vancomycin monitored via troughs of 10 to 20 mg/L or Bayesian-estimated AUC values of ≥400 mg ▪ hour/L, the likelihood of nephrotoxicity was 8 percent versus 0 to 2 percent, respectively [18]. Among patients with AKI, the median vancomycin trough concentration was 15.7 mg/L and the median AUC was 625 mg ▪ hour/L. Among patients without AKI, the median vancomycin trough concentration was 8.7 mg/L and the median AUC was 423 mg ▪ hour/L.

Intermittent infusion — The approach to II for nonobese patients with stable kidney function is described below. The approach to II requires special consideration in the following patient populations:

Patients with obesity (see 'Patients with obesity' below)

Patients on renal replacement therapy (see 'Patients on renal replacement therapy' below)

Patients with unstable kidney function (see 'Patients with unstable kidney function' below)

Loading dose — We give a loading dose for patients with known or suspected severe S. aureus infection [1]. Use of a loading dose in such patients reduces the likelihood of suboptimal initial vancomycin exposure. (See 'Severe S. aureus infection' above.)

We administer a vancomycin loading dose of 20 to 35 mg/kg, based on actual body weight, rounded to the nearest 250 mg increment and not exceeding 3000 mg [1]. Within this range, we use a higher dose for critically ill patients and a lower dose for patients undergoing renal replacement therapy, patients with obesity, and patients receiving vancomycin via CI. (See 'Critical illness' below and 'Patients on renal replacement therapy' below and 'Patients with obesity' below and 'Continuous infusion' below.)

Data on use of vancomycin loading dose are limited, due to small size, heterogenous populations, and variable dosing practices [44-47]. In one trial including 99 adults presenting to the emergency department with an indication for vancomycin, patients were randomly assigned to receive an initial loading dose (30 mg/kg) or a standard dose (15 mg/kg) [45]. A vancomycin trough of 15 to 20 mg/L was achieved more frequently among patients who received a loading dose than those who received a standard dose (34 versus 3 percent). The study was not powered to detect a difference in other outcomes including mortality or nephrotoxicity.

Initial maintenance dose/interval — The initial maintenance dose consists of approximately 15 to 20 mg/kg actual body weight (rounded to the nearest 250 mg). The dosing interval may be determined by either a nomogram (table 2) or utilizing first-order equations based on estimates of creatinine clearance using the Cockcroft-Gault equation (calculator 1). As an example, a 70 kg patient with normal renal function would receive a dose of 1000 mg to 1250 mg IV every 8 to 12 hours.  

In settings where AUC-guided dosing is possible, the anticipated AUC, peak concentration, and trough concentration can be estimated prior to administration. Thereafter, adjustments are made based on AUC-guided or trough-guided serum concentration monitoring to establish the subsequent maintenance dose and interval.

In general, for most patients with normal kidney function, vancomycin dosing consists of approximately 15 to 20 mg/kg/dose (based on actual body weight rounded to the nearest 250 mg) every 8 to 12 hours.

Subsequent maintenance dose/interval

AUC-guided intermittent dosing — For patients with severe S. aureus infection and stable kidney function, we favor area under the 24-hour time-concentration curve (AUC)-guided dosing (when available) to target optimal vancomycin exposure and reduce the risk of vancomycin-induced nephrotoxicity [1]. (See 'AUC versus trough-guided serum concentration monitoring' above.)

For patients with serious MRSA infections (assuming a vancomycin MICBMD of 1 mcg/mL), a vancomycin AUC of 400 to 600 mg ▪ hour/L should be targeted.

Methods for AUC determination and subsequent determination of the dose and interval include:

Use of an AUC calculator (preferred method) − The preferred approach to AUC-guided dosing involves the use of an AUC calculator (Bayesian or non-Bayesian), together with an individual patient's vancomycin serum concentrations, to calculate an individualized dosing regimen [48]. This is most often performed by a pharmacist (either outside or integrated within the electronic medical record).

Following administration of the loading dose (see 'Loading dose' above) and the initial maintenance dose (see 'Initial maintenance dose/interval' above), two serum vancomycin concentrations are collected within the first 24 to 48 hours: a peak (at one to two hours after infusion) and a trough (at end of the dosing interval, prior to the next dose) [38,49-51]. While a single trough concentration may be sufficient, further study of this approach is needed [40].

The approach to dose adjustments to achieve the target AUC depends on the type of calculator used.

Use of this approach requires a hospital or health care system to purchase software, provide pharmacist training, and ensure adequate staffing to make daily dose adjustments for individual patients.

Data evaluating use of Bayesian software for AUC-guided monitoring are limited. In one observational study including 123 adults with MRSA bacteremia in which Bayesian methods were used to estimate the daily AUC, the risk of failure (30-day mortality, bacteremia ≥7 days, or recurrent infection) was lowest when the day 1 AUC/MICBMD ratio exceeded 521 (relative risk [RR] 0.66, 95% CI 0.32-1.33) and the day 2 AUC/MICBMD ratio exceeded 650 mg ▪ hour/L (RR 0.59, 95% CI 0.29-1.22) [52].

Use of first-order pharmacokinetic equations − An alternative method consists of AUC estimation via first-order PK equations [38,49]. Use of spreadsheet software programmed with the appropriate equations has been described to facilitate such a practice.

Following administration of the loading dose (see 'Loading dose' above) and the initial maintenance dose (see 'Initial maintenance dose/interval' above), two serum vancomycin concentrations are collected, preferably near steady-state (eg, the fourth dose): a trough before the fourth dose and a peak (at one to two hours after infusion of the fourth dose) [38,53].

After estimating the AUC utilizing serum concentration data, the total daily dose may be revised accordingly to produce proportional changes in the observed AUC [54,55]. However, this approach only provides a snapshot of the AUC for the sampling period. In addition, for patients who receive multiple dosing regimens within a 24-hour period, it is difficult to estimate the vancomycin AUC with this approach.

Trough-guided intermittent dosing — Trough-guided dosing is warranted for management of patients with severe S. aureus infection who require vancomycin therapy in the following circumstances:

Settings where it is not feasible to perform AUC-guided dosing, including where individualized pharmacist involvement may not be available

Patients with unstable kidney function

Patients with central nervous system infection (eg, meningitis or ventriculitis), given limited data to support use of AUC-guided dosing in these circumstances

Following administration of the loading dose (see 'Loading dose' above) and the initial maintenance dose (see 'Initial maintenance dose/interval' above), vancomycin serum concentration monitoring is performed.

In the setting of stable kidney function (and in the absence of significant renal dysfunction), steady-state vancomycin serum trough concentrations should be collected prior to the fourth dose following the most recent dose adjustment, within 30 minutes prior to infusion [56]. Dose adjustments should be guided by vancomycin troughs (target 15 to 20 mcg/mL for severe infection), based on careful interpretation of concentration timing, clinical response, tolerability, stability of kidney function, and plans for continued therapy (including need for outpatient antibiotic therapy).

In general, for most patients with normal kidney function, vancomycin dosing consists of approximately 15 to 20 mg/kg/dose (based on actual body weight rounded to the nearest 250 mg) every 8 to 12 hours, not to exceed single doses of 2000 mg unless measured serum trough concentrations are below target concentrations. In the setting of rapid renal clearance (such as in burn patients or in younger patients with normal kidney function), administration of vancomycin every 8 hours may be required to achieve target troughs.

Subsequent monitoring — Once the maintenance dose has been established (regardless of the method; eg, AUC-guided or trough-guided dosing), continued serum vancomycin and creatinine concentrations should be monitored at least weekly in the following circumstances [57,58]:

Patients receiving vancomycin beyond the initial empiric stage (eg, longer than 48 to 72 hours)

Patients at increased risk of nephrotoxicity, such as those with underlying renal dysfunction and use of concomitant nephrotoxic medications

Patients with fluctuating kidney function, fluctuating fluid balance, hemodynamic instability, critical illness, morbid obesity, or receiving renal replacement therapy

In general, adjustment of the dose (with no adjustment of the dosing interval) will result in proportional change in the serum concentration (assuming drug clearance is in steady state). Therefore, changes in the total daily dose will result in proportional changes in AUC. Each change in the individual dose will alter both peak and trough concentrations proportionately.

Adjustment of the dosing interval does not result in proportional change in the trough concentration. The predicted effect of such adjustment requires a calculation. Pharmacists are able to assist in such calculations and to optimize vancomycin dosing for individual patients.

Following dose adjustment, repeat vancomycin serum concentrations should be measured prior to the fourth dose following the adjustment (in the setting of stable kidney function).

Continuous infusion — Most studies of CI used loading doses of 15 to 20 mg/kg, followed by total daily doses of 30 to 40 mg/kg (up to 60 mg/kg) to achieve a target steady-state concentration of 20 to 25 mcg/mL [59]. The desired drug exposure may be achieved by changing the rate of infusion. Use of CI facilitates AUC calculation (eg, a single steady-state concentration multiplied by a factor of 24). However, use of AUC targets in the setting of CI has not been validated.

Nonsevere or non-S. aureus infection — The optimal method of dosing and AUC target for nonsevere or non-S. aureus infections is not well established; pending further study, we favor trough-guided dosing. While some hospitals may use AUC-guided monitoring for such patients, the optimal AUC target for nonsevere or non-S. aureus infections is not well established.

For patients receiving vancomycin for treatment of nonsevere infection (such as uncomplicated skin and soft tissue infection) who are not on renal replacement therapy, we do not favor routine use of a loading dose (since early therapeutic vancomycin concentrations are not as critical as in patients with severe S. aureus infection).

For patients with normal renal function, vancomycin dosing consists of approximately 15 to 20 mg/kg/dose (based on actual body weight rounded to the nearest 250 mg) every 8 to 12 hours, not to exceed single doses of 2000 mg.

The initial maintenance dose may also be determined using a nomogram (table 2) including the actual body weight and creatinine clearance (estimated using the Cockcroft-Gault equation (calculator 1)). For patients who will continue vancomycin for ≥3 days, we favor trough-based maintenance dose adjustments with target trough concentrations of 10 to 15 mcg/mL. For patients who receive vancomycin for <3 days (in the setting of stable kidney function and absence of other risk factors for altered vancomycin kinetics), vancomycin concentration monitoring is often omitted; the value of such monitoring prior to achieving steady state (usually around treatment day 2 to 3) is uncertain.

Once the maintenance dose has been established, vancomycin serum concentration monitoring is performed as described above. (See 'Subsequent monitoring' above.)

For patients with severe infections due to pathogens other than S. aureus, data regarding the relationship between vancomycin exposure and clinical efficacy are sparse. The approach to vancomycin dosing for treatment of infectious endocarditis is addressed in consensus guidelines and is discussed separately. (See "Antimicrobial therapy of left-sided native valve endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis".)

SPECIAL POPULATIONS

Patients with obesity — Obesity (defined as a body mass index of ≥30 kg/m2) may be associated with an increased risk of vancomycin-induced nephrotoxicity, due to supratherapeutic exposure resulting from dosing calculated using actual body weight [60,61].

Studies evaluating vancomycin kinetics in patients with obesity have reported mathematical relationships between patient-specific parameters (sex, body weight, and serum creatinine) and vancomycin clearance [11,62]. Such estimates are useful in both area under the 24-hour time-concentration curve (AUC)- and trough-guided strategies to determine initial maintenance doses and dosing interval.

The decision to administer a vancomycin loading dose should be guided by infection severity (and therefore urgency to achieve a targeted concentration). If a loading dose is indicated, we administer 20 to 25 mg/kg (rounded to the nearest 250 mg with a maximum of 3000 mg) [62]. Within this range, we use a higher dose for critically ill patients.

The approach to determination of a maintenance dose for patients with obesity is similar to the approach for nonobese patients. (See 'Subsequent maintenance dose/interval' above.)

In general, for most patients with obesity and normal kidney function, vancomycin dosing consists of approximately 30 to 45 mg/kg per day (based on actual body weight) in two or three divided doses [63]. In general, the total daily dose should not exceed 4500 mg/day unless justified by serum concentration monitoring [1,62].

Patients on renal replacement therapy — Significant alterations in vancomycin distribution and elimination can occur in patients receiving renal replacement therapy. Consideration must be given to time between the prior vancomycin dose and dialysis, intradialytic or postdialysis administration, method of dialysis (and associated dialyzer permeability), and dialysis frequency.

We give a loading dose for patients on receiving renal replacement therapy (regardless of the pathogen or severity of infection), to optimize the potential for early achievement of therapeutic concentrations. Data on use of a loading dose for patients on renal replacement are limited to modeling studies to evaluate the optimal approach to achieving target troughs [64-66].

Data for AUC-guided dosing in patients requiring renal replacement therapy are limited. In one report, predialysis serum concentrations ranging between 10 to 20 mcg/mL (a common target in this population) resulted in suboptimal AUC exposures in many patients (range 250 to 450 mg ▪ hour/L) [67]. Therefore, further study is needed to optimize AUC-guided dosing strategies in this population.

Intermittent hemodialysis — Vancomycin dosing requirements in patients requiring chronic intermittent hemodialysis is dependent largely on the dialyzer permeability. High-flux intermittent (three- to four-hour sessions performed three times weekly) hemodialysis is commonly used for patients requiring chronic hemodialysis and is the most efficient at vancomycin drug removal. A three to four hour dialysis session using a high-flux membrane can reduce predialysis serum concentrations of vancomycin by up to 50 percent.

Vancomycin dosing should be based on actual body weight at the time of drug administration [1]. A dosing strategy for such patients (loading dose followed by maintenance dosing, as described in the 2020 vancomycin dosing guidelines) is as follows [1]:

For patients receiving vancomycin after dialysis, the initial (loading) dose consists of 25 mg/kg, followed by a maintenance dose (given after subsequent dialysis sessions) of 10 mg/kg (high dialyzer permeability) or 7.5 mg/kg (low dialyzer permeability). The loading dose may be reduced (to 20 to 25 mg/kg) if the next dialysis session is anticipated within 24 hours.

For patients receiving intradialytic vancomycin, the approach depends on the dialyzer permeability. In the setting of high dialyzer permeability (ie, high-flux dialyzer), the initial (loading) dose consists of 35 mg/kg followed by a maintenance dose of 10 to 15 mg/kg. In the setting of low dialyzer permeability (ie, low-flux dialyzer), the loading dose consists of 30 mg/kg, followed by an initial maintenance dose of 7.5 to 10 mg/kg [1]. Doses are rounded to the nearest 250 mg.

Maintenance dosing is most often administered during the final hour of the dialysis session to expedite discharge from the dialysis unit. Approximately 20 to 40 percent of a vancomycin dose administered during dialysis is removed [68,69].

Predialysis serum concentration monitoring facilities the determination of subsequent vancomycin doses while avoiding postdialysis rebound concentrations, which can occur up to three to six hours after a session [70]. After the initial maintenance dose is calculated, subsequent maintenance doses are determined based on serum concentrations obtained immediately prior to dialysis [71]. Predialysis serum concentration monitoring should be performed for two dialysis sessions following an initial maintenance regimen, for any maintenance dose modifications, and then at least weekly thereafter. Dose adjustments should be made as summarized in the table (table 3).

In the typical three times-weekly hemodialysis schedule, a dose increase of 25 percent is usually needed for the three-day interdialytic period to maintain sufficient vancomycin concentrations on the third day [64,65,72].

Intermittent hemodialysis may be utilized more frequently (up to daily) at slower blood and dialysate flow rates and longer durations (such as 6 to 12 hours per day) in attempts to facilitate outpatient dialysis and/or minimize the undesirable hemodynamic effects. Since the time to the next hemodialysis session is reduced (relative to traditional intermittent hemodialysis of three times weekly), a reduced loading dose of 20 mg/kg can be administered in such settings. Maintenance doses depend on timing of administration but up to 15 mg/kg can be administered initially if given within the final 60 to 90 minutes of the dialysis session [1]. Serum concentration monitoring predialysis should be conducted as described above to determine dose adjustments.

Peritoneal dialysis — For patients on peritoneal dialysis requiring systemic administration of vancomycin for treatment of infection outside the peritoneal cavity, an intravenous loading dose of 20 to 25 mg/kg (rounded to the nearest 250 mg increment) should be administered. A vancomycin serum concentration should be obtained approximately 48 to 72 hours after the loading dose, and subsequent doses (15 to 20 mg/kg intravenously) should be administered based on attainment of goal serum concentrations.

Patients with peritonitis may best be treated via intraperitoneal administration of vancomycin. This is discussed further separately. (See "Microbiology and therapy of peritonitis in peritoneal dialysis".)

Continuous renal replacement — In patients receiving continuous renal replacement therapy (CRRT), vancomycin clearance is relatively constant over the dosing interval and is closely related to the rate of ultrafiltrate/dialysate flow. Such patients may receive intermittent or continuous infusions (CIs) of vancomycin.

For patients receiving CRRT at conventional effluent rates (20 to 25 mL/kg/hour) managed with intermittent dosing, the vancomycin loading dose consists of 20 to 25 mg/kg (actual body weight), followed by an initial maintenance dose of 7.5 to 10 mg/kg every 12 hours [1].

Subsequent maintenance dosing should be based on serum concentration monitoring conducted within the first 24 hours to ensure the AUC target is met [73]. The optimal pharmacokinetic targets among patients receiving CRRT are uncertain; studies validating the AUC goal of 400 to 600 mg ▪ hour/L used in other settings have not been conducted in this population. Nonetheless, the maintenance doses described above aim to reach this AUC target. (See 'AUC-guided intermittent dosing' above.)

In patients with fluid overload, the need for dosing reductions should be anticipated as the volume status normalizes.

CIs of vancomycin may be useful in patients receiving CRRT. Issues related to CI of vancomycin are discussed above [74,75]. (See 'Continuous infusion' above.)

Patients with unstable kidney function — Patients with unstable kidney function (either worsening or improving) are perhaps the most challenging population for determination of an optimal vancomycin dosing schedule, due to fluctuations in drug distribution and elimination.

For such patients, a strategy referred to as "dose per concentration" is employed. Target serum concentrations consist of 15 to 20 mcg/mL for severe infection and 10 to 15 mcg/mL for nonsevere infection.

For patients with severe S. aureus infection, a loading dose of 20 to 25 mg/kg may given. For patients with nonsevere or non-S. aureus infection, the initial dose is administered as outlined in the nomogram (table 2).

Following the initial/loading dose, a serum vancomycin concentration is obtained at 12 to 24 hours. If the concentration is above the target concentration, a repeat concentration is obtained the following day; once the concentration is at or below the target concentration, a repeat dose (15 to 20 mg/kg rounded to the nearest 250 mg increment) is administered. If the concentration is below the target concentration, a repeat dose (15 to 20 mg/kg rounded to the nearest 250 mg increment) is administered. Therefore, the frequency of drug administration is guided by repeated serum concentration monitoring.

Critical illness — Among patients with critical illness, increases in the volume of distribution (and the resulting increase in clearance) have been described [76]. In such patients, higher vancomycin loading doses (25 to 30 mg/kg) may be required to achieve optimal vancomycin exposure.

ADVERSE EFFECTS — Adverse effects of parenteral vancomycin include rash (due to infusion reaction or true vancomycin sensitivity), infusion-related reactions, nephrotoxicity, and ototoxicity. (See "Vancomycin hypersensitivity".)

Infusion reaction

Phlebitis — Intravenous administration of vancomycin has been associated with low rates of infusion-site phlebitis, given its acidic pH. Administration of vancomycin via central venous access may minimize such reactions but is not required. Additional strategies that may reduce the likelihood of phlebitis include reducing the infusion rate, diluting the drug in higher volumes of fluid, and the use of continuous infusion [77].

Rash — Vancomycin-induced infusion reaction associated with rash (formerly termed ‘Red man syndrome’) is a histamine-mediated reaction observed during or immediately following vancomycin infusion [78]. Dermatologic findings may include erythema that can be confluent or blotchy, typically involving the head and neck but also the trunk, extremities, and palms or soles or urticaria that can be localized or diffuse.

The reaction may be reduced or eliminated by avoiding excessive vancomycin doses, prolonging the infusion time (eg, administering the drug at a rate of no more than 500 mg/hour), and administration of antihistamines (prior to or during infusion) [79]. Some patients require an even slower infusion rate or continuous infusion dosing [80].

Issues related to infusion reaction and vancomycin hypersensitivity reactions are discussed further separately. (See "Vancomycin hypersensitivity", section on 'Vancomycin infusion reaction'.)

Acute kidney injury — Acute kidney injury (AKI) is an important adverse effect of vancomycin. The mechanism of vancomycin nephrotoxicity involves apoptosis induced by accumulation of drug in proximal tubular epithelial cells.

Factors influencing risk of AKI include dose, host-related factors (increased weight, pre-existing renal dysfunction, and critical illness), and concurrent administration of nephrotoxic agents (such as aminoglycosides, loop diuretics, amphotericin B, intravenous contrast dye, and vasopressors) [81,82].

Most studies define vancomycin-associated AKI as an increase in the serum creatinine concentration by ≥0.5 mg/dL, an increase in serum creatinine by 50 percent from baseline in consecutive daily readings, or a decrease in calculated creatinine clearance by 50 percent from baseline on two consecutive days, in the absence of an alternative explanation [1]. A more sensitive threshold, an increase in serum creatinine of ≥0.3 mg/dL over a 48-hour period, has also been proposed as an indicator of vancomycin-associated AKI [83,84].

The incidence of vancomycin-associated AKI is variable. In one meta-analysis including 15 studies, the prevalence of vancomycin-associated AKI ranged from 5 to 43 percent [84-88]. Similarly, in another meta-analysis including 13 studies (randomized trials and cohort studies) comparing patients treated with vancomycin with patients treated with a nonglycopeptide antibiotic, the relative risk of AKI with vancomycin was 2.45 (95% CI 1.69-3.55) [89]. Most episodes of AKI developed between 4 and 17 days after initiation of therapy.

Impact of dose — Several retrospective studies have attempted to quantify the relationship between vancomycin exposure and likelihood of AKI [90,91]. The available data suggest that the risk of AKI increases as a function of the vancomycin trough concentration, especially when the trough is maintained within the 15 to 20 mg/L [25,81,84,90,92] range generally targeted for severe infections. Similarly, data suggest that the risk of AKI increases as the area under the 24-hour time-concentration curve (AUC) increases, especially when the daily AUC exceeds 650 to 1300 [1,40,91]. In one study including 166 patients treated with vancomycin, the likelihood of AKI was 2.5-fold greater among patients with AUC values above 1300 compared with patients with lower values (30.8 versus 13.1 percent) [90]. Similarly, in a prospective study of patients with methicillin-resistant S. aureus bacteremia, AKI increased along the day 2 AUC continuum in a stepwise manner, and patients with day 2 AUC values ≥793 were at the greatest risk for AKI [20].

Coadministration with other drugs — Coadministration of vancomycin with other nephrotoxic agents is associated with increased risk of AKI; these include loop diuretics, amphotericin B, intravenous contrast dye, vasopressors, and select beta-lactams (notably piperacillin-tazobactam and flucloxacillin) [81,82,93]. In addition, nephrotoxicity associated with coadministration of vancomycin and an aminoglycoside is well established; the incidence of acute renal failure in this setting may be as high as 20 to 30 percent [85,88,94].

For patients who require treatment with vancomycin as well as beta-lactam agent (eg, with activity gram-negative pathogens), we suggest selection of a hydrophilic agent (such as a cephalosporin) rather than a hydrophobic agent, to reduce the likelihood of nephrotoxicity. If anaerobic coverage is needed, metronidazole can be added to the regimen.

The above approach is based on data demonstrating an increased incidence of nephrotoxicity associated with coadministration of vancomycin and beta-lactams. One review suggested increased nephrotoxicity potential for hydrophobic beta-lactams (eg, piperacillin, antistaphylococcal beta-lactams) as opposed to hydrophilic beta-lactams (most cephalosporins, ampicillin) [95]. An increased incidence of nephrotoxicity associated with coadministration of vancomycin and piperacillin-tazobactam has been well-described; in some studies, an odds ratio of AKI associated with coadministration of these drugs (relative to vancomycin monotherapy and coadministration with other beta-lactams, notably cefepime) is up to 3.5 [96-108]. Studies evaluating combination therapy with vancomycin and cephalosporins suggest low potential for nephrotoxicity; however, they are limited by retrospective design, small sample size, and suboptimal assessment for nephrotoxicity [109-112].

Management — It can be difficult to distinguish between drug-induced AKI and other causes of AKI including acute interstitial nephritis. Development of AKI in the setting of vancomycin therapy should prompt discontinuation of the drug.

Data regarding timeframe for recovery from vancomycin-induced AKI are confounded by presence of additional risk factors for AKI. In one review, improvement or resolution was noted in approximately three-quarters of patients [113].

Ototoxicity — Ototoxicity has been observed in association with vancomycin administration; ototoxicity attributable to vancomycin should prompt discontinuation of the drug [114,115]. Potential risk factors for vancomycin-induced ototoxicity include pre-existing hearing abnormalities and underlying renal dysfunction [94,116,117].

Ototoxicity associated with vancomycin is more common in older patients. In one report including 89 patients who underwent audiograms after an average of 27 days of vancomycin administration, high-frequency hearing loss was observed among patients >53 years of age in 19 percent of cases; no hearing loss was observed among patients <53 years of age [115]. Another study including 130 newborns who received vancomycin and were followed with audiology screening demonstrated no association between vancomycin and ototoxicity [118].

In the absence of tinnitus or ataxia, clinical detection of vancomycin ototoxicity is challenging; in the absence of audiometric testing, high-frequency hearing loss may not be detected and when it occurs, reversibility is unknown. In addition, older adults at greatest risk often suffer high-frequency hearing loss in the absence of vancomycin therapy.

Data regarding the natural history of vancomycin-induced ototoxicity are limited; it is generally considered reversible in most cases [116].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of Staphylococcus aureus infection".)

SUMMARY AND RECOMMENDATIONS

The approach to vancomycin dosing in adults depends on the pathogen, the type and severity of infection, and patient factors including weight and kidney function (table 1). Vancomycin is usually administered intermittently; in certain circumstances, continuous infusion may be a useful alternative. (See 'Introduction' above and 'Intermittent infusion' above and 'Continuous infusion' above.)

For patients with known or suspected severe Staphylococcus aureus infection (including bacteremia, endocarditis, osteomyelitis, prosthetic joint infection, pneumonia warranting hospitalization, infection involving the central nervous system, and/or critical illness) and stable kidney function, our approach to vancomycin dosing is as follows (see 'Severe S. aureus infection' above):

We suggest administration of a loading dose (Grade 2C), to reduce the likelihood of suboptimal initial vancomycin exposure. We give a loading dose of 20 to 35 mg/kg (based on actual body weight). (See 'Loading dose' above.)

The initial maintenance dose consists of 15 to 20 mg/kg actual body weight (rounded to the nearest 250 mg); the dosing interval is determined by a nomogram (table 2). In general, for most patients with normal kidney function, vancomycin dosing consists of approximately 15 to 20 mg/kg/dose (based on actual body weight rounded to the nearest 250 mg) every 8 to 12 hours. (See 'Initial maintenance dose/interval' above.)

For subsequent maintenance dosing in patients with stable kidney function, we suggest area under the 24-hour time-concentration curve (AUC)-guided dosing if such an option is available (rather than trough-guided dosing) (Grade 2C), to target optimal vancomycin exposure and reduce the risk of vancomycin-induced nephrotoxicity. This approach requires the assistance of a pharmacist. The optimal pharmacokinetic/pharmacodynamic efficacy target is considered to be an AUC/minimum inhibitory concentration determined by broth microdilution ratio of 400 to 600 mg ▪ hour/L. (See 'Subsequent maintenance dose/interval' above and 'Pharmacokinetic/pharmacodynamic target' above.)

-The AUC-guided regimen is established using an AUC calculator (Bayesian or non-Bayesian) together with two serum vancomycin concentrations collected within the first 24 to 48 hours.

-If an AUC calculator is not available, the subsequent regimen is calculated using first-order pharmacokinetic equations and two serum vancomycin concentrations collected near steady-state. (See 'AUC-guided intermittent dosing' above.)

-The approach to dose adjustments to achieve the target AUC depends on the type of calculator used.

For patients with unstable kidney function (either worsening or improving) and in settings where it is not feasible to perform AUC-guided dosing, trough-guided dosing is warranted. After the loading dose, the initial maintenance dose is determined using a nomogram (table 2). Thereafter, the subsequent regimen is guided by a serum vancomycin trough concentration collected near steady state (target 15 to 20 mcg/mL). (See 'Trough-guided intermittent dosing' above.)

For patients with nonsevere S. aureus infection (such as uncomplicated skin and soft tissue infection), our approach to vancomycin dosing is as follows (see 'Nonsevere or non-S. aureus infection' above):

We suggest not administering loading dose (Grade 2C), since early therapeutic vancomycin concentrations are not as critical in patients with nonsevere infection. The initial dose may be determined using a nomogram (table 2) including the actual body weight and creatinine clearance (estimated using the Cockcroft-Gault equation (calculator 1)). Thereafter, for patients who will continue vancomycin for ≥3 days, the subsequent regimen is guided by a serum vancomycin trough concentration collected at steady state (target 10 to 15 mcg/mL).

For patients with severe infections due to pathogens other than S. aureus, data regarding the relationship between vancomycin exposure and clinical efficacy are sparse. The approach to vancomycin dosing for treatment of infectious endocarditis is addressed in consensus guidelines; this is discussed separately. (See 'Nonsevere or non-S. aureus infection' above and "Antimicrobial therapy of left-sided native valve endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis".)

For patients on renal replacement therapy, we suggest use of a loading dose (Grade 2C). The initial regimen depends on the timing of vancomycin administration and the dialyzer permeability. Subsequent maintenance doses are determined based on serum concentrations obtained immediately prior to dialysis (table 3). (See 'Patients on renal replacement therapy' above.)

Adverse effects of parenteral vancomycin include rash (due to infusion reaction or true vancomycin sensitivity), infusion-related reactions, nephrotoxicity, and ototoxicity. For patients who require coadministration of vancomycin with a beta-lactam agent, we suggest selecting a hydrophilic agent (such as a cephalosporin) rather than a hydrophobic agent (such as piperacillin) (Grade 2C), to minimize the risk of nephrotoxicity. (See 'Adverse effects' above.)

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  104. Hammond DA, Smith MN, Painter JT, et al. Comparative Incidence of Acute Kidney Injury in Critically Ill Patients Receiving Vancomycin with Concomitant Piperacillin-Tazobactam or Cefepime: A Retrospective Cohort Study. Pharmacotherapy 2016; 36:463.
  105. Karino S, Kaye KS, Navalkele B, et al. Epidemiology of Acute Kidney Injury among Patients Receiving Concomitant Vancomycin and Piperacillin-Tazobactam: Opportunities for Antimicrobial Stewardship. Antimicrob Agents Chemother 2016; 60:3743.
  106. Rutter WC, Burgess DR, Talbert JC, Burgess DS. Acute kidney injury in patients treated with vancomycin and piperacillin-tazobactam: A retrospective cohort analysis. J Hosp Med 2017; 12:77.
  107. Downes KJ, Cowden C, Laskin BL, et al. Association of Acute Kidney Injury With Concomitant Vancomycin and Piperacillin/Tazobactam Treatment Among Hospitalized Children. JAMA Pediatr 2017; 171:e173219.
  108. Robertson AD, Li C, Hammond DA, Dickey TA. Incidence of Acute Kidney Injury Among Patients Receiving the Combination of Vancomycin with Piperacillin-Tazobactam or Meropenem. Pharmacotherapy 2018; 38:1184.
  109. Trinh TD, Zasowski EJ, Lagnf AM, et al. Combination Vancomycin/Cefazolin (VAN/CFZ) for Methicillin-Resistant Staphylococcus aureus (MRSA) Bloodstream Infections (BSI). Open Forum Infect Dis 2017; 4:S281.
  110. Zasowski EJ, Trinh TD, Atwan SM, et al. The Impact of Concomitant Empiric Cefepime on Patient Outcomes of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections Treated With Vancomycin. Open Forum Infect Dis 2019; 6:ofz077.
  111. Dilworth TJ, Ibrahim O, Hall P, et al. β-Lactams enhance vancomycin activity against methicillin-resistant Staphylococcus aureus bacteremia compared to vancomycin alone. Antimicrob Agents Chemother 2014; 58:102.
  112. Alosaimy S, Sabagha NL, Lagnf AM, et al. Monotherapy with Vancomycin or Daptomycin versus Combination Therapy with β-Lactams in the Treatment of Methicillin-Resistant Staphylococcus Aureus Bloodstream Infections: A Retrospective Cohort Analysis. Infect Dis Ther 2020; 9:325.
  113. Filippone EJ, Kraft WK, Farber JL. The Nephrotoxicity of Vancomycin. Clin Pharmacol Ther 2017; 102:459.
  114. Klibanov OM, Filicko JE, DeSimone JA Jr, Tice DS. Sensorineural hearing loss associated with intrathecal vancomycin. Ann Pharmacother 2003; 37:61.
  115. Forouzesh A, Moise PA, Sakoulas G. Vancomycin ototoxicity: a reevaluation in an era of increasing doses. Antimicrob Agents Chemother 2009; 53:483.
  116. Brummett RE. Ototoxicity of vancomycin and analogues. Otolaryngol Clin North Am 1993; 26:821.
  117. Brummett RE, Fox KE, Jacobs F, et al. Augmented gentamicin ototoxicity induced by vancomycin in guinea pigs. Arch Otolaryngol Head Neck Surg 1990; 116:61.
  118. de Hoog M, van Zanten BA, Hop WC, et al. Newborn hearing screening: tobramycin and vancomycin are not risk factors for hearing loss. J Pediatr 2003; 142:41.
Topic 484 Version 50.0

References

1 : Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists.

2 : Pharmacokinetics of vancomycin in patients with various degrees of renal function.

3 : Vancomycin therapy in patients with impaired renal function: a nomogram for dosage.

4 : A simplified dosing method for initiating vancomycin therapy.

5 : An updated comparison of drug dosing methods. Part IV: Vancomycin.

6 : Vancomycin Area Under the Curve-Guided Dosing and Monitoring for Adult and Pediatric Patients With Suspected or Documented Serious Methicillin-Resistant Staphylococcus aureus Infections: Putting the Safety of Our Patients First.

7 : Should Therapeutic Drug Monitoring Based on the Vancomycin Area Under the Concentration-Time Curve Be Standard for Serious Methicillin-Resistant Staphylococcus aureus Infections?-No.

8 : Vancomycin Advanced Therapeutic Drug Monitoring: Exercise in Futility or Virtuous Endeavor to Improve Drug Efficacy and Safety?

9 : 60 Plus Years Later and We Are Still Trying to Learn How to Dose Vancomycin.

10 : 60 Plus Years Later and We Are Still Trying to Learn How to Dose Vancomycin.

11 : Vancomycin pharmacokinetics in patients with various degrees of renal function.

12 : Impaired target site penetration of vancomycin in diabetic patients following cardiac surgery.

13 : Penetration of vancomycin into human lung tissue.

14 : A Larger Dose of Vancomycin Is Required in Adult Neurosurgical Intensive Care Unit Patients Due to Augmented Clearance.

15 : Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections.

16 : Impact of area under the concentration-time curve to minimum inhibitory concentration ratio on vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus bacteraemia.

17 : Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets.

18 : Prospective Trial on the Use of Trough Concentration versus Area under the Curve To Determine Therapeutic Vancomycin Dosing.

19 : Identification of Vancomycin Exposure-Toxicity Thresholds in Hospitalized Patients Receiving Intravenous Vancomycin.

20 : The Emperor's New Clothes: PRospective Observational Evaluation of the Association Between Initial VancomycIn Exposure and Failure Rates Among ADult HospitalizEd Patients With Methicillin-resistant Staphylococcus aureus Bloodstream Infections (PROVIDE).

21 : Association between vancomycin day 1 exposure profile and outcomes among patients with methicillin-resistant Staphylococcus aureus infective endocarditis.

22 : Predictors of mortality for methicillin-resistant Staphylococcus aureus health-care-associated pneumonia: specific evaluation of vancomycin pharmacokinetic indices.

23 : Vancomycin in vitro bactericidal activity and its relationship to efficacy in clearance of methicillin-resistant Staphylococcus aureus bacteremia.

24 : Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia.

25 : High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity.

26 : Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin.

27 : Point: Vancomycin is not obsolete for the treatment of infection caused by methicillin-resistant Staphylococcus aureus.

28 : Continuous versus intermittent infusion of vancomycin in severe Staphylococcal infections: prospective multicenter randomized study.

29 : Serum vancomycin levels resulting from continuous or intermittent infusion in critically ill burn patients with or without continuous renal replacement therapy.

30 : Continuous intravenous administration of vancomycin in medical intensive care unit patients.

31 : Vancomycin-associated nephrotoxicity in the critically ill: a retrospective multivariate regression analysis*.

32 : High dose vancomycin for osteomyelitis: continuous vs. intermittent infusion.

33 : Nephrotoxicity of continuous versus intermittent infusion of vancomycin in outpatient parenteral antimicrobial therapy.

34 : Efficacy of continuous infusion of vancomycin for the outpatient treatment of methicillin-resistant Staphylococcus aureus infections.

35 : Association of vancomycin serum concentrations with efficacy in patients with MRSA infections: a systematic review and meta-analysis.

36 : Vancomycin Trough Concentration as a Predictor of Clinical Outcomes in Patients with Staphylococcus aureus Bacteremia: A Meta-analysis of Observational Studies.

37 : Vancomycin: we can't get there from here.

38 : Innovative approaches to optimizing the delivery of vancomycin in individual patients.

39 : Evaluation of Vancomycin Prediction Methods Based on Estimated Creatinine Clearance or Trough Levels.

40 : Are vancomycin trough concentrations adequate for optimal dosing?

41 : Vancomycin AUC/MIC ratio and 30-day mortality in patients with Staphylococcus aureus bacteremia.

42 : Vancomycin Area Under the Curve Simplified.

43 : A Quasi-Experiment To Study the Impact of Vancomycin Area under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity.

44 : Vancomycin loading doses: a systematic review.

45 : A randomized trial of loading vancomycin in the emergency department.

46 : High Single-dose Vancomycin Loading Is Not Associated With Increased Nephrotoxicity in Emergency Department Sepsis Patients.

47 : Simple approach to improving vancomycin dosing in intensive care: a standardised loading dose results in earlier therapeutic levels.

48 : Benchmarking therapeutic drug monitoring software: a review of available computer tools.

49 : Making the change to area under the curve-based vancomycin dosing.

50 : Vancomycin Area Under the Curve Dosing and Monitoring at an Academic Medical Center: Transition Strategies and Lessons Learned.

51 : Review and Validation of Bayesian Dose-Optimizing Software and Equations for Calculation of the Vancomycin Area Under the Curve in Critically Ill Patients.

52 : Vancomycin exposure in patients with methicillin-resistant Staphylococcus aureus bloodstream infections: how much is enough?

53 : A suggested approach to once-daily aminoglycoside dosing.

54 : The pharmacokinetic and pharmacodynamic properties of vancomycin.

55 : Vancomycin: a review of population pharmacokinetic analyses.

56 : Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.

57 : Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility.

58 : Monitoring serum vancomycin levels: climbing the mountain because it is there?

59 : Review of continuous-infusion vancomycin.

60 : Review of continuous-infusion vancomycin.

61 : Evaluation of a vancomycin dosing nomogram in obese patients weighing at least 100 kilograms.

62 : Dosing vancomycin in the super obese: less is more.

63 : Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists.

64 : Weight-based loading of vancomycin in patients on hemodialysis.

65 : Implementation of a dose calculator for vancomycin to achieve target trough levels of 15-20 microg/mL in persons undergoing hemodialysis.

66 : Vancomycin pharmacokinetics and pharmacodynamics during short daily hemodialysis.

67 : Vancomycin pharmacokinetics and pharmacodynamics during short daily hemodialysis.

68 : CAHP-210 dialyzer influence on intra-dialytic vancomycin removal.

69 : Removal of vancomycin administered during dialysis by a high-flux dialyzer.

70 : Post-Dialysis Parenteral Antimicrobial Therapy in Patients Receiving Intermittent High-Flux Hemodialysis.

71 : Vancomycin dosing in high flux hemodialysis: a limited-sampling algorithm.

72 : Vancomycin dosing and monitoring for patients with end-stage renal disease receiving intermittent hemodialysis.

73 : Vancomycin clearance during continuous venovenous haemofiltration in critically ill patients.

74 : Prospective evaluation of a continuous infusion vancomycin dosing nomogram in critically ill patients undergoing continuous venovenous haemofiltration.

75 : Continuous infusion of vancomycin in septic patients receiving continuous renal replacement therapy.

76 : Vancomycin Area under the Curve and Pharmacokinetic Parameters during the First 24 Hours of Treatment in Critically Ill Patients using Bayesian Forecasting.

77 : Influence of vancomycin infusion methods on endothelial cell toxicity.

78 : Vancomycin Infusion Reaction - Moving beyond "Red Man Syndrome".

79 : Red man syndrome.

80 : Vancomycin skin tests and prediction of "red man syndrome" in healthy volunteers.

81 : Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity.

82 : Vancomycin-associated renal dysfunction: where are we now?

83 : A Comparison of Traditional and Novel Definitions (RIFLE, AKIN, and KDIGO) of Acute Kidney Injury for the Prediction of Outcomes in Acute Decompensated Heart Failure.

84 : Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter.

85 : Vancomycin and the kidney.

86 : Vancomycin ototoxicity and nephrotoxicity. A review.

87 : Mild nephrotoxicity associated with vancomycin use.

88 : Nephrotoxicity of vancomycin, alone and with an aminoglycoside.

89 : Vancomycin and the Risk of AKI: A Systematic Review and Meta-Analysis.

90 : Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients.

91 : Is peak concentration needed in therapeutic drug monitoring of vancomycin? A pharmacokinetic-pharmacodynamic analysis in patients with methicillin-resistant staphylococcus aureus pneumonia.

92 : A retrospective analysis of possible renal toxicity associated with vancomycin in patients with health care-associated methicillin-resistant Staphylococcus aureus pneumonia.

93 : Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcalβ-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial.

94 : Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity.

95 : Organic anion transporter 3 interacts selectively with lipophilicβ-lactam antibiotics.

96 : Piperacillin-Tazobactam Added to Vancomycin Increases Risk for Acute Kidney Injury: Fact or Fiction?

97 : Systematic Review and Meta-Analysis of Acute Kidney Injury Associated with Concomitant Vancomycin and Piperacillin/tazobactam.

98 : Risk of Acute Kidney Injury in Patients on Concomitant Vancomycin and Piperacillin-Tazobactam Compared to Those on Vancomycin and Cefepime.

99 : Is the Combination of Piperacillin-Tazobactam and Vancomycin Associated with Development of Acute Kidney Injury? A Meta-analysis.

100 : Nephrotoxicity during Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime.

101 : Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with and without concomitant piperacillin-tazobactam.

102 : Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin-tazobactam or cefepime.

103 : Vancomycin-associated nephrotoxicity in adult medicine patients: incidence, outcomes, and risk factors.

104 : Comparative Incidence of Acute Kidney Injury in Critically Ill Patients Receiving Vancomycin with Concomitant Piperacillin-Tazobactam or Cefepime: A Retrospective Cohort Study.

105 : Epidemiology of Acute Kidney Injury among Patients Receiving Concomitant Vancomycin and Piperacillin-Tazobactam: Opportunities for Antimicrobial Stewardship.

106 : Acute kidney injury in patients treated with vancomycin and piperacillin-tazobactam: A retrospective cohort analysis.

107 : Association of Acute Kidney Injury With Concomitant Vancomycin and Piperacillin/Tazobactam Treatment Among Hospitalized Children.

108 : Incidence of Acute Kidney Injury Among Patients Receiving the Combination of Vancomycin with Piperacillin-Tazobactam or Meropenem.

109 : Combination Vancomycin/Cefazolin (VAN/CFZ) for Methicillin-Resistant Staphylococcus aureus (MRSA) Bloodstream Infections (BSI)

110 : The Impact of Concomitant Empiric Cefepime on Patient Outcomes of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections Treated With Vancomycin.

111 : β-Lactams enhance vancomycin activity against methicillin-resistant Staphylococcus aureus bacteremia compared to vancomycin alone.

112 : Monotherapy with Vancomycin or Daptomycin versus Combination Therapy withβ-Lactams in the Treatment of Methicillin-Resistant Staphylococcus Aureus Bloodstream Infections: A Retrospective Cohort Analysis.

113 : The Nephrotoxicity of Vancomycin.

114 : Sensorineural hearing loss associated with intrathecal vancomycin.

115 : Vancomycin ototoxicity: a reevaluation in an era of increasing doses.

116 : Ototoxicity of vancomycin and analogues.

117 : Augmented gentamicin ototoxicity induced by vancomycin in guinea pigs.

118 : Newborn hearing screening: tobramycin and vancomycin are not risk factors for hearing loss.