Vancomycin Serum Trough Concentrations Research Articles

Nephrotoxicity of Vancomycin and Teicoplanin Alone and in Combination with an Aminoglycoside

Background and Purpose: Vancomycin and teicoplanin are considered first line medications for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections but these agents are also associated with the side-effect of nephrotoxicity. This study investigated the association between treatment with vancomycin monotherapy, teicoplanin monotherapy and combinations of these drugs with aminoglycoside antibiotics, and the occurrence of nephrotoxicity. Methods: Patients treated with vancomycin or teicoplanin, either alone or in combination with an aminoglycoside antibiotic from June to December 2003 were included. Data analyzed included age, gender, renal function (before and after drug administration), days of antibiotics administration, location of infection, other antibiotics used in combination factors affecting renal function. Results: A total of 96 patients, comprising 50 males and 46 females, with a mean age of 67.97±13.43 years were included. Multivariate logistic regression analysis revealed no association between treatment with vancomycin or teicoplanin and gender, chronic renal function impairment, dialysis treatment, diabetes, hypertension, mean age, combination with an aminoglycoside, or treatment in the ICU. Among the 28 courses of vancomycin treatment for which there were adequate serum concentration monitoring data, 16 (57.1%) courses resulted in high trough vancomycin concentration, 8 (28.6%) courses were in the normal range, and 4 (14.3%) courses were low trough concentration. Vancomycin trough serum concentrations were significantly higher in ICU patients (p=0.003). Conclusion: There was no significant difference (p＞0.05) in nephrotoxicity among patients treated with vancomycin or teicoplanin alone or in combination with an aminoglycoside. Vancomycin trough serum concentrations were highest in critically ill patients. Additional serum concentration monitoring in ICU patients was therefore advised after the use of vancomycin, in order to make necessary dosage adjustment. This can avoid unnecessary drug expenditure and reduce the likelihood of side-effects.

Clinical Application and Evaluation of Vancomycin Dosing in Adults

Objective: To evaluate the accuracy of a vancomycin dosing method (study method) in estimating volume of distribution (Vd) and clearance of vancomycin (Clvanco) and the frequency with which it would provide serum vancomycin concentrations (SVCs) within a specified range compared with other published methods. Methods: One hundred and seven patients with 108 pairs of SVCs were used to calculate patient-specific Vd and Clvanco. Based on these patient-specific Vd and Clvanco values, the predictive ability of the estimated parameters from the study dosing method (Vd [L] = 0.17 [age] + 0.22 [actual body weight] + 15; Clvanco = creatinine clearance) was evaluated against three previously published pharmacokinetic dosing methods, using predictive performance analysis (precision and bias). Furthermore, the patient-specific pharmacokinetic parameters were used to simulate steady-state peak and trough SVCs, using first-order pharmacokinetic equations from doses derived from the study method, the three different pharmacokinetic methods, and two other published dosing schemes. The frequency with which each method would have achieved target peak and trough SVCs was determined. Results: The study method was found to be more precise and less biased (p < 0.05) than comparative methods in predicting vancomycin Vd and Clvanco. The study method also resulted in a higher frequency of steady-state peak and trough SVCs within the target range specified. Conclusions: The study method presented here provided a reliable estimation of vancomycin pharmacokinetic parameters that was easily applied to various patient populations to individualize vancomycin dosing, and frequently yielded SVCs within a predictable and desired range.

Impact of Monitoring Vancomycin Peak and Trough Concentrations versus Trough Concentrations Alone on Dose Adjustments: An Outcomes Analysis

Objective: To determine whether monitoring both steady-state peak and trough serum vancomycin concentrations or steady-state trough serum vancomycin concentrations alone resulted in differences between two groups of patients in terms of dose adjustment, clinical outcome, and toxicity. Design: The study was a retrospective chart review of patients treated with vancomycin during two time periods. Group 1 represented patients hospitalized between July 1, 1996, and January 31, 1997. These patients routinely had vancomycin peak and trough concentrations measured. Group 2 represented patients hospitalized from July 1, 1997, to January 31, 1998, who were monitored with trough vancomycin concentrations only. Setting: A university teaching hospital. Patients: Adults at least 18 years of age who received a constant dose of intravenous vancomycin for at least three consecutive days were eligible for inclusion in the study. Patients were selected from lists generated by the Microbiology Department. The lists contained vancomycin serum concentrations measured during those time frames. Main Outcome Measures: The main outcome measure was to assess whether dose adjustments by prescribers were influenced by both vancomycin peak and trough concentrations or by the trough concentration alone. Results: Forty-nine and 37 patients met the criteria for inclusion into group 1 and group 2, respectively. The mean duration of therapy in group 1 (15 ± 10 d) was not statistically different from that of group 2 (14 ± 12 d). Patients in both groups received a mean daily vancomycin dose of approximately 1,500 mg. In analyzing treatment decisions, trough concentration was the only significant factor influencing a change in total daily dose of vancomycin (p = 0.038). Furthermore, although the method of vancomycin serum concentration monitoring varied between the two groups, the mean clinical outcome parameters were comparable. Conclusions: Prescribers tended to adjust vancomycin regimens based only on trough serum concentrations; monitoring peak serum vancomycin concentrations did not enhance patient care. Mean outcome parameters in the two groups were comparable.

Vancomycin population pharmacokinetics in neonates.

Recently the value of vancomycin therapeutic drug monitoring, as well as the required therapeutic range, has been subject of debate, resulting in new recommendations. This study was performed to incorporate these new insights in an up-to-date dosing scheme for neonates of various gestational ages. In this retrospective study with prospective validation, 108 newborns with suspected central line-related septicemia during the first month of life received 30 mg/kg/day vancomycin divided into two doses regardless of gestational or postconceptional age. Trough and peak vancomycin serum concentrations were determined before and after the third dose. Vancomycin data were analyzed according to a one-compartment open model with use of NONMEM population pharmacokinetic software. Model parameters were evaluated and then used to simulate vancomycin dosing for different dose and dose interval combinations. Targets were a trough concentration between 5 and 15 mg/L and a peak below 40 mg/L. In the prospective study, the optimal scheme was tested in 22 patients. Of the 108 patients, 34.3% of measured trough concentrations and 17.6% of peak concentrations were outside the desired therapeutic range. The model that best fitted the data included clearance and volume per kilogram and was independent of gestational age. Simulation of various dosing schemes showed that a dosing schedule of 30 mg/kg/day, irrespective of gestational age, in three doses was optimal, and this scheme was prospectively tested. Mean trough concentrations before the second dose were 8.2 +/- 2.2 mg/L versus a predicted trough of 8.9 +/- 2.5 mg/L. No peak levels higher than 40 mg/L were found. The use of the proposed schedule leads to adequate vancomycin trough serum concentrations, and there is no need for routine monitoring of peak serum concentrations.

Vancomycin dosage requirements among pediatric intensive care unit patients with normal renal function

Purpose: The purpose of this study was to determine a vancomycin dosage regimen among pediatric intensive care unit (PICU) patients with normal renal function resulting in desired peak and trough serum concentration and to determine the predictability of vancomycin peak concentrations based on reported trough concentrations. Materials and Methods: The medical records of all PICU patients who received vancomycin over a 12-month period were identified through a hospital computer search and were obtained from the hospital's Department of Medical Records. Demographic and laboratory data as well as the patient's vancomycin dosing history were recorded. Patients who lacked appropriately timed vancomycin peak and trough concentrations or who exhibited renal dysfunction were excluded from the study population. The optimal vancomycin dose and the predictability of peak concentrations based on trough concentrations were assessed. Results: A total of 135 patients were identified as having received vancomycin therapy during their PICU hospitalization between June 1997 and June 1998. Fifty-nine patients were excluded due to renal dysfunction or inappropriate vancomycin concentrations resulting in 76 patients representing our study population. The initial mean dose of vancomycin was 47 mg/kg/day resulting in a mean peak and trough serum concentration of 19 and 6 μg/mL, respectively. A mean of 2.2 (range, 1 to 5) and 2.1 (range, 1 to 5) peak and trough serum concentrations were reported for each patient, respectively. A mean of 1.1 (range, 0 to 4) dosing changes per patient was noted resulting in a final mean dose of 60 mg/kg/day corresponding to a mean peak and trough serum concentration of 26 and 8 μg/mL, respectively. A vancomycin trough concentration >5 μg/mL was highly predictive for a corresponding peak concentration >20 μg/mL ( P > .0001). Eighty percent of the trough concentrations <5 μg/mL were associated with peak concentrations <20 μg/mL, whereas 81% of trough concentrations > 5 μg/mL were associated with corresponding peak concentrations >20 μg/mL. Conclusions: PICU patients required higher doses of vancomycin than are typically prescribed to achieve conventionally accepted peak and trough vancomycin serum concentrations. In the absence of renal impairment, we recommend an initial dosage regimen of 60 mg/kg/day divided every 8 hours. Vancomycin trough concentrations are highly predictive of corresponding peak concentrations and therefore may negate the need to obtain routine peak concentrations. Copyright © 2000 by W.B. Saunders Company

Optimisation of Vancomycin Regimen in Neutropenic Haematological Patients with Normal Renal Function

Objective: To assess the appropriateness, on a pharmacokinetic basis, of a twice-daily regimen of vancomycin 1g in neutropenic patients with normal renal function, a regimen frequently used in the empirical treatment of this patient group. The study also used a Bayesian pharmacokinetic approach to predict vancomycin concentrations in order to determine the optimal dosage frequency of the drug (two or four daily doses) in this population. Patients and Methods: Data were collected retrospectively as part of routine therapeutic drug monitoring (TDM) of vancomycin in 16 adult neutropenic patients. TDM of vancomycin peak (Cmax) and trough (Cmin) serum concentrations was performed after twice daily administration of vancomycin lg as a 1-hour intravenous infusion for 48 hours. According to TDM results (Cmin≥7 or <7 mg/L), the vancomycin regimen was individualised (total daily dose split into two or four divided doses) by means of a Bayesian-based pharmacokinetic computer programme. TDM was then repeated on day 7. Optimal Cmin were defined as with the range of 7 to 10 mg/L. Results: On day 3 of therapy, nine patients had subtherapeutic Cmin (3.97 ± 0.59 mg/L; range 2.98 to 4.95 mg/L) according to ahigh estimated creatinine clearance (CLcr 1.79 ± 0.49 ml/kg/min; range 1.39 to 2.79 ml/kg/min), and another three patients had Cmin <7 mg/L. On day 7, higher vancomycin Cmin were achieved (8.92 ± 2.87 mg/L) in the 12 patients in whom their total daily dose was split into four (Cmin were optimal in nine and supratherapeutic in three patients), despite no major differences in the total daily dosage of vancomycin (29.77 ± 5.89 vs 30.85 ± 6.68 mg/kg; p = 0.79) and CLcr (1.63 ± 0.43 vs 1.90 ± 0.45 ml/kg/min; p = 0.19) versus day 3. Dose-normalised results suggested large interindividual pharmacokinetic variability. Conclusion: Since the volume of distribution and/or clearance of vancomycin can be increased in patients with haematological malignancies and normal renal function, increasing the number of daily doses from two to four (with the same total daily dose) may increase t > MIC, an important determinant of vancomycin efficacy. However, because of interpatient variability, TDM of vancomycin is strongly recommended to individualise therapy in this subpopulation.

Association of Serum Vancomycin Concentration with Renal Dysfunction

Objective: To evaluate the association of vancomycin-related renal dysfunction with age; serum vancomycin trough concentration; baseline serum creatinine concentration; duration of vancomycin treatment; comorbid medical conditions of congestive heart failure, chronic renal failure, diabetes mellitus, and hepatic cirrhosis; and the concurrent use of drugs that can cause impairment of renal function. Design: A retrospective analysis of medical records of hospitalized patients who received intravenous vancomycin was conducted. Setting: This study was conducted in a 125-bed, tertiary care, government teaching hospital. Methods: Data were collected on 122 men, ranging in age from 41 to 95 years, who received vancomycin during a five-year period starting in 1991. Vancomycin-related renal dysfunction, defined as an increase of ≥0.5 mg/dL in serum creatinine concentration from the baseline value, was examined for an association with age; baseline serum creatinine concentration; duration of vancomycin treatment; serum vancomycin trough concentrations &gt;15 μg/mL; and comorbid conditions of congestive heart failure, chronic renal failure, diabetes mellitus, and hepatic cirrhosis. The concurrent use of aminoglycosides, amphotericin B, diuretics, angiotensin-converting enzyme (ACE) inhibitors, Cimetidine, and intravenously administered contrast medium was also analyzed. Results: Stepwise logistic regression and odds ratio analyses failed to identify an association between vancomycin-related renal dysfunction and any factor examined except concurrent use of diuretics and ACE inhibitors. Conclusions: Patients receiving intravenous vancomycin concurrently with diuretics or ACE inhibitors have a higher risk of renal impairment. No incident of renal dysfunction was attributed to vancomycin alone.

Vancomycin pharmacokinetics and dosing in premature neonates.

We prospectively studied the pharmacokinetic parameters of vancomycin in premature neonates given vancomycin according to a dosage protocol developed in our neonatal unit. Study infants were administered vancomycin according to four postconceptional age (PCA) groups: (0) 18 mg/kg every 36 h for PCA < 27 weeks; (I) 16 mg/kg every 24 h for PCA 27-30 weeks; (II) 18 mg/kg every 18 h for PCA 31-36 weeks; and (III) 15 mg/kg every 12 h for PCA > or = 37 weeks. Pharmacokinetic parameters were calculated from peak and trough serum vancomycin concentrations at steady state. Results in 44 infants (PCA, 27-44 weeks) showed that our dosage regimen achieved target peak serum vancomycin concentrations in 64% of neonates in Groups I-III, although it tended to undershoot the target trough concentrations. Volume of distribution (Vd), normalized for body weight, remained constant throughout the PCA range, with a mean value of 0.56 L/kg, whereas absolute clearance (r = 0.81) and normalized clearance (r = 0.48) increased with PCA (p < 0.005). The increase in clearance with PCA is associated with a greater elimination rate constant and shorter half-life. Vancomycin therapy can be initiated in a standard fashion according to our protocol or by individualizing the dosage regimen based on a Vd of 0.56 L/kg and clearance estimated from the infant's body weight and PCA groups.

Influence of malignancy on the pharmacokinetics of vancomycin in infants and children.

This prospective, controlled study evaluates the influence of malignancy on the pharmacokinetics and dosage requirements of vancomycin in 33 infants and children with cancer (age 5.72 +/- 4.11 years, mean +/- SD) compared with 31 patients without cancer (age 4.18 +/- 5.10 years) using a two-compartment Bayesian pharmacokinetic program. Patients in the malignancy group required a vancomycin dosage regimen of 71.5 +/- 13.9 mg/kg/day to attain a mean peak serum vancomycin concentration (SVC) of 22.38 +/- 4.54 mg/liter and a mean trough SVC of 6.84 +/- 2.78 mg/liter. Patients without cancer in the control group required a mean vancomycin dosage regimen of 50.2 +/- 13.0 mg/kg/day to attain a mean peak SVC of 21.70 +/- 6.70 mg/liter and a mean trough SVC of 8.05 +/- 3.01 mg/liter. Comparative analysis of pharmacokinetic data revealed an increase in vancomycin clearance (0.149 +/- 0.028 liter/hour/kg) in the malignancy group as compared with that (0.114 +/- 0.031 liter/hour/kg) in the control group. There were no significant differences with respect to the mean values of volume of distribution between two groups (0.638 +/- 0.079 liter/kg vs. 0.618 +/- 0.102 liter/kg). Analysis of the predictive performance of the Bayesian program indicated that final sets of peak and trough SVCs were predicted with minimal bias and accurate precision in both study groups. This study showed that the presence of malignancy in infants and children increased vancomycin clearance resulting in larger dosage requirements.

A prospective study of vancomycin pharmacokinetics and dosage requirements in pediatric cancer patients.

Pharmacokinetics of vancomycin and dosage requirements were evaluated prospectively in 28 pediatric cancer patients 9 months to 13 years of age. The predictive performance of a two-compartment Bayesian forecasting program was also evaluated. A mean (+/- SD) daily dosage of 75 +/- 22 mg/kg/day was necessary to attain a mean peak serum vancomycin concentration (SVC) of 23.1 +/- 5.8 mg/liter and a mean trough SVC of 6.2 +/- 2.3 mg/liter. Mean vancomycin clearance, volume of distribution and serum half-life were 0.153 +/- 0.033 liter/hour/kg, 0.63 +/- 0.08 liter/kg and 2.95 +/- 0.48 hours. Final peak SVCs, which reflected the last dosage regimens received, were predicted with minimal bias (mean prediction error, -1.2 mg/liter) and accurate precision (root mean-squared prediction error, 2.0 mg/liter) whereas trough SVCs were predicted with even smaller bias (mean prediction error, -0.1 mg/liter) and greater precision (root mean-squared prediction error, 0.8 mg/liter). This study showed that pediatric cancer patients with normal renal function required vancomycin dosage regimens substantially greater than the standard 40 mg/kg/day to attain the desired SVCs.

Comparison of Vancomycin Pharmacokinetics in Hospitalized Elderly and Young Patients Using a Bayesian Forecaster

Limited data have been published that compare the pharmacokinetic parameters of vancomycin in elderly versus young patients. This study was designed to assess vancomycin pharmacokinetics in 148 elderly (> or = 60 years of age) and 140 young (18-59 years of age) hospitalized infected patients. Serum vancomycin concentrations were determined using fluorescence polarization immunoassay. Serum concentration-versus-time data were fitted to a two-compartment Bayesian forecasting program. Elderly versus young vancomycin pharmacokinetic parameters derived were as follows (patients with serum creatinine < or = 1.5 mg/dL); mean +/- standard deviation terminal disposition half-life (t1/2) of 17.8 +/- 11.8 versus 7.5 +/- 6.7 hours, respectively, P < .05; volume of distribution (Vz) of 74.2 +/- 32.3 versus 67.0 +/- 30.7 L, respectively, P = .16; and total body clearance (CL) of 0.71 +/- 0.41 versus 1.22 +/- 0.50 mL/min/kg, respectively, P < .05. Comparing subjects with normal serum creatinine values (< or = 1.5 mg/dL), the elderly required smaller daily doses as compared with the young group to maintain target peak and trough vancomycin serum concentrations (18.2 +/- 5.8 verus 25.2 +/- 7.8 mg/kg/day, P < .05). Stepwise multiple regression models for the pharmacokinetic parameters were developed to assess the predictive power of age, controlling for the effects of gender, total body weight, serum creatinine, and creatinine clearance. Age was consistently an independent and significant predictor of t1/2, Vz, and CL. These data demonstrate that elderly patients exhibit significant differences in vancomycin pharmacokinetic parameters compared with young patients and constitute a patient population in need of individualized vancomycin dosing due to substantial heterogeneity in physiologic and pharmacokinetic parameters.

Risk of nephrotoxicity with combination vancomycin-aminoglycoside antibiotic therapy.

One hundred five patients receiving concurrent aminoglycoside and vancomycin therapy of at least 5 days' duration were retrospectively reviewed for development of nephrotoxicity. All had their vancomycin and aminoglycoside serum concentrations controlled by a clinical pharmacokinetics service. Nephrotoxicity occurred in 28 (27%) of the patients. Twenty-two of the 28 had other factors that are known to contribute to renal failure (amphotericin B therapy, sepsis, liver disease, obstructive uropathy, pancreatitis, anesthesia). The remaining six developed nephrotoxicity without other known contributing factors. Logistic regression analysis revealed associations between nephrotoxicity and age, sex, aminoglycoside trough and vancomycin peak and trough serum concentrations, length of aminoglycoside and vancomycin therapy, concurrent amphotericin B therapy, liver disease, neutropenia, and peritonitis (p less than 0.05). In addition to factors previously reported, this study found that neutropenia and peritonitis are associated with an increased risk of nephrotoxicity. Patients with one or more risk factors warrant close monitoring of renal function as well as vancomycin and aminoglycoside serum concentrations.

Nephrotoxicity of vancomycin, alone and with an aminoglycoside

The incidence of nephrotoxicity in patients receiving vancomycin alone or in combination with an aminoglycoside was prospectively evaluated. A total of 231 courses of antibiotic therapy in 224 patients were consecutively monitored over 28-month period. One hundred and sixty-eight patients received vancomycin alone, 63 patients received vancomycin with an aminoglycoside, and 103 patients received gentamicin. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dl or a 50% increase above baseline, whichever was greater. Eight patients (5%) receiving vancomycin alone, 14 patients (22%) receiving vancomycin with an aminoglycoside, and 11 patients (11%) receiving gentamicin alone were found to have nephrotoxicity. Factors found to be associated with increased risk of nephrotoxicity in patients receiving vancomycin were concurrent therapy with an aminoglycoside, length of treatment with vancomycin (greater than 21 days), and vancomycin trough serum concentration (greater than 10 mg/l). Although the incidence of vancomycin nephrotoxicity is low, patients receiving vancomycin therapy with the above risk factors should be closely monitored.

Evaluation of a Bayesian method for predicting vancomycin dosing.

The purpose of this study is to evaluate the performance of a vancomycin dosing program in predicting dosages necessary to achieve desired serum vancomycin concentrations in a relatively large patient population. With the completion of initial performance evaluation, revised pharmacokinetic parameter estimates derived in the initial evaluation are used to reevaluate program performance. The program uses population estimates of vancomycin's volume of distribution (Vd) and clearance (Cl) to initially predict dosing, then individualizes those estimates by a Bayesian algorithm (iterations) which uses dosing and the resulting serum vancomycin concentration data. Use of the Bayesian forecaster with one iteration significantly increases the calculated Cl value as compared with population estimates; two and three iterations significantly increase both Vd and Cl when compared with population estimates. Absolute values of the predicted minus observed peak serum vancomycin concentrations (accuracy) are 17.7 +/- 14.0, 6.1 +/- 3.6, and 3.4 +/- 2.1 mg/L for dosing using population estimates, Bayesian with one iteration, and Bayesian with two iterations, respectively. Similarly, accuracy of predictions for trough concentrations is 13.8 +/- 12.4, 3.5 +/- 3.2, and 3.2 +/- 2.6 mg/L for each method, respectively. Bias of dosing predictions in achieving desired peak and trough serum vancomycin concentrations is also significantly reduced by using the Bayesian algorithm. Use of the mean Vd and Cl values from three iterations as the starting parameters in a new group of 12 patients significantly improves program performance when compared with use of initial population parameters. Time of sampling for peak serum concentrations has no effect on program performance. In patients with impaired renal function, use of population estimates resulted in less accurate dosing prediction, but this less accurate performance was not observed with use of the Bayesian forecaster. These data demonstrate the accuracy and lack of bias in individualized dosing predictions using the Bayesian dosing method and the ability of revised pharmacokinetic parameter estimates to improve performance.

Vancomycin ototoxicity and nephrotoxicity. A review.

Vancomycin has been in clinical use as a potent antistaphylococcal antibiotic for over 30 years. Most reports of ototoxicity and nephrotoxicity have been associated with early, relatively impure, formulations of vancomycin. This paper reviews the literature concerning vancomycin ototoxocity and nephrotoxicity and the evidence for their correlation with the therapeutic serum concentration range. There have been 28 reports of vancomycin-associated ototoxicity published in the medical literature since 1958. It remains unclear whether any diminution in hearing is permanent or reversible. Few patients in the literature had follow-up audiometry and the hearing impairment tends to be at higher frequencies. Several authors reported peak serum vancomycin concentrations, but the exact time these were drawn with respect to the last dose is mostly unclear. In other reports, the 'peak' concentrations noted 3 to 6 hours after the last dose are probably indicative of much higher concentrations because of vancomycin's rapid phase of distribution. More than half the 57 cases of reported nephrotoxicity due to vancomycin occurred within the first 6 years of the drug's use. Many of these patients also had pre-existing renal dysfunction or were concomitantly receiving other nephrotoxic agents. It is unclear whether the coadministration of aminoglycosides produces a synergistic toxicity. The exact incidence of nephrotoxicity is uncertain, but is probably less with the current, relatively pure, product. The correlation of nephrotoxicity with certain serum vancomycin concentrations remains to be clarified. Other aspects also require clarification, such as when to draw samples to determine peak serum concentrations and whether or not routine measurements are necessary at all. In the absence of better guidelines, efforts should be made to tailor individual patient's regimens to produce peak and trough serum vancomycin concentrations to within the widely accepted ranges of 30 to 40 and 5 to 10 mg/L, respectively. In addition, the concomitant use of other potentially nephrotoxic and ototoxic agents should be avoided.

Relationship of serum antibiotic concentrations to nephrotoxicity in cancer patients receiving concurrent aminoglycoside and vancomycin therapy

Methicillin-resistant coagulase-negative staphylococci have become increasingly responsible for febrile episodes in cancer patients, often necessitating the addition of vancomycin to an aminoglycoside-containing broad-spectrum antibiotic regimen. A total of 229 courses of antibiotic therapy in 229 patients were evaluated for nephrotoxicity associated with the administration of an aminoglycoside and/or vancomycin. The incidence of nephrotoxicity observed in patients administered an aminoglycoside (Group A) was 18 percent; vancomycin (Group B) 15 percent; and an aminoglycoside concurrently with vancomycin (Group C) 15 percent. The following pharmacokinetic/dosing factors were significantly associated with increased nephrotoxicity in the groups: baseline serum creatinine level, mean daily dose during the first three days of therapy (Group B), and elevated serum trough aminoglycoside or vancomycin concentrations (2 μg/ml or more or 10 μg/ml or more, respectively). No cumulative nephrotoxicity was demonstrated with the concurrent administration of vancomycin and an aminoglycoside. A higher incidence of nephrotoxicity was seen in Group C (42 percent) and Group B (27 percent) patients, in whom trough serum vancomycin concentrations were 10 μg/ml or more.

Evaluation of a new vancomycin dosing method.

Thirty-one patients who were prescribed vancomycin therapy at our institution since January 1, 1986, were dosed using the guidelines as described by Lake and Peterson. Peak and trough vancomycin serum concentrations were measured at steady state: 24 (77%) peak serum concentrations were within the range of 20-30 mg/L, and 24 (77%) trough serum concentrations were within the range of 5-10 mg/L. We have found that the method of Lake and Peterson is satisfactory for initiating vancomycin therapy in most patients. Some, however, may not achieve optimal serum concentrations using these guidelines alone, and their regimens may have to be adjusted based upon actual serum concentration data.

Pharmacokinetics of vancomycin: observations in 28 patients and dosage recommendations.

Studies of the pharmacokinetics of vancomycin were conducted in a group of 28 patients with serious staphylococcal infection. Serum specimens were collected before and on 11 occasions after vancomycin administration. Serum concentration time data were fitted to a biexponential equation, using nonlinear regression analysis. A prolonged distribution phase with a half-life of 0.5 +/- 0.3 h (standard deviation) and a central component volume of 9.0 +/- 4.0 liters were demonstrated. Wide interpatient variation was observed in the terminal half-life which ranged from 3 to 13 h (mean, 6 h) and in the distribution volume which ranged from 14 to 111 liters (mean, 39 liters). A correlation of 0.45 (Pearson product moment correlation coefficient) was found between vancomycin clearance and creatinine clearance. Multiple regression analyses demonstrated that 50% of the variance (R2) in the terminal half-life and vancomycin clearance could be explained on the basis of renal function, volume of distribution, age, weight, and sex. These observations suggest that adults with normal renal function should receive an initial dosage of 6.5 to 8 mg of vancomycin per kg intravenously over 1 h every 6 to 12 h. After 24 h, and through the period of therapy, trough and peak serum vancomycin concentrations should be monitored, and the dose and dosage interval should be changed to produce the desired peak (30 to 40 micrograms/ml) and trough (5 to 10 micrograms/ml) levels.