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Antimicrobial Agents and Chemotherapy, November 2004, p. 4427-4429, Vol. 48, No. 11
0066-4804/04/$08.00+0 DOI: 10.1128/AAC.48.11.4427-4429.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.
Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center,1 Albert Einstein College of Medicine, Bronx, New York2
Received 24 March 2004/ Returned for modification 28 April 2004/ Accepted 11 July 2004
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5 days of a therapy of 1 g every 12 h. |
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Yet recent data from prospective murine models have confirmed that subcutaneous vancomycin administration is a risk factor for the persistence of high-density vanB VRE intestinal colonization (6). Subcutaneously administered vancomycin maintained levels of colonization density as high as those seen with oral vancomycin and higher than those achieved with expanded-spectrum cephalosporin antibiotics. Limited data also suggest that i.v. vancomycin monotherapy may increase the density of human VRE rectal colonization (5). At our own institution, a cross-sectional study of the prevalence of vanA VRE rectal colonization identified a significant difference in prevalence between those patients receiving i.v. vancomycin for <5 days and those receiving it for 5 days, 28 and 64% (P < 0.001), respectively (4). This temporal variation in VRE rectal colonization prevalence was not present in patients who were administered i.v. antibiotics other than vancomycin or in patients who received no antibiotics, despite comparable lengths of stay. These studies suggested the hypothesis that biliary excretion of i.v. vancomycin occurred and that it was potentially related to duration of therapy. Our investigation sought to evaluate both possibilities.
Study patients were enrolled from among all patients who had newly initiated i.v. vancomycin therapy. Patients with a calculated creatinine clearance of <50 ml/min or evidence of active bowel pathology, including diarrhea, inflammation, and malignancy, were excluded. Thirty-one hospitalized patients were enrolled. Twenty patients provided single or multiple stool samples according to two protocols: all samples were acquired <5 days into therapy or all were acquired after 5 days of therapy. Serial stool samples were collected from seven patients, both before and after day 5 of therapy. Any guaiac-positive stool sample or any sample potentially contaminated with urine was excluded. Five patients receiving doses of 1 g q24h provided nine stool samples. Twenty-six patients receiving 1 g ql2h provided 54 stool samples (inclusive of all seven patients with serial stool sample collections). Bile samples were obtained from two additional patients receiving i.v. vancomycin who had undergone external biliary stenting. One patient receiving doses of 1 g q12h was sampled on days 7 and 9 of therapy, and a second patient receiving 1 g q24h was sampled on days 17, 20, and 23 of therapy.
Twenty-two patients received only i.v. vancomycin therapy, three received i.v. vancomycin and gentamicin, and six received i.v. vancomycin in combination with other antibiotics. Most patients were monitored for serum drug levels, and although serum sample testing could not be reliably arranged to coincide with timing of stool or bile sampling, there was no evidence that measured values in serum exceeded the upper limit of the therapeutic range for any patient.
Bile and stool samples were assayed for vancomycin concentrations with an AxSym II fluorescence polarization immunoassay. The serum assay protocol was modified for stool samples to include an extraction of the sample in dilute ammonia to prevent nonspecific binding of vancomycin to protein in the stool. The modified assay was calibrated by comparing vancomycin-spiked stool samples of known concentration to corresponding known concentrations of vancomycin in water. There was excellent correlation across a range of values from >2 to 62.5 µg/ml, and the assay was sensitive to within 2 µg of vancomycin per ml. Levels of <2 µg/ml were considered negative and were included as a level of 0 µg/ml for the calculation of mean concentrations.
For each sample, 1 g of stool was vortexed in 3 ml of dilute ammonia solution and then centrifuged to remove particulate matter. One-hundred-fifty-microliter aliquots of the supernatant were assayed; 150-µl aliquots of bile were directly assayed.
Results for the 46 stool samples analyzed from 23 patients receiving doses of 1 g of vancomycin q12h are summarized in Table 1. Results for the nine stool samples from patients receiving 1 g q24h are summarized in Table 2.
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3.9 µg/ml. Among patients receiving 5 days of therapy, 26 of 28 samples (92.9%) had detectable levels of vancomycin that ranged from 3.3 to 94.8 µg/ml, with 28.6% of samples containing vancomycin concentrations of >10 µg/ml. The proportion of positive cases and the mean measured vancomycin concentration were significantly higher among samples obtained from patients who had received 5 days of therapy than among those who had received <5 days of therapy (92.9% versus 19.2% and 12.1 µg/ml versus 0.7 µg/ml [P < 0.005]). Samples from the seven patients with serial stool samples were all negative before day 5 and had measurable levels of vancomycin on or after day 5 (range, 3.0 to 20.8 µg/ml; mean, 7.6 µg/ml; 71.4% of samples had >5.05 µg/ml). Among patients receiving doses of 1 g q24h, only one sample, obtained on the seventh day of therapy, was positive at 8.8 µg of vancomycin per ml.
All bile samples had detectable levels of vancomycin. The patient receiving doses of 1 g ql2h had vancomycin concentrations of 8.2 and 10.9 µg/ml on days 7 and 9 of therapy, respectively. The patient receiving doses of 1 g q24h had 11.4, 10.8, and 12.5 µg of vancomycin per ml in bile on days 17, 20, and 23 of therapy, respectively.
The results demonstrate that biliary excretion of vancomycin can occur during i.v. administration of the drug and can result in detectable levels of vancomycin in stool. The influence of stool vancomycin on VRE rectal colonization at the concentrations we report remains largely uninvestigated. Evidence supporting the clinical significance of our results includes (i) a single prior study which documented the elimination of Clostridium species and the elimination or reduction of vancomycin-sensitive Enterococcus faecalis concentrations with stool vancomycin concentrations of 0 to 110 µg/ml and (ii) limited data suggesting that i.v. vancomycin monotherapy can increase human VRE rectal colonization density (5, 7). These studies suggest that the concentrations of vancomycin in stool samples reported in this investigation are capable of disruption of the natural bowel anaerobic flora (a process linked with the establishment of VRE colonization) and possibly enrichment of existing VRE in the bowel. Further research into the microbiological impact of low concentrations of vancomycin in stools is required, but the present findings are suggestive of a mechanism by which i.v. vancomycin therapy could influence VRE rectal colonization.
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