Clostridium difficile infection was confirmed by PCR, and at the time of diagnosis and initiation of therapy, the patient had normal renal function.
On day three, vancomycin was discontinued with gradual resolution of symptoms over the next 12 hours. The potential for absorption of oral vancomycin is not well described and is attributed to compromised intestinal epithelium allowing for increased drug absorption. Few studies suggested that oral vancomycin may result in therapeutic or even potentially toxic levels of serum vancomycin in patients with impaired renal function.
Ototoxicity may be a transient or permanent side effect of vancomycin therapy and is related to high serum levels. Symptoms usually resolve after decreasing the dose or cessation of vancomycin. The described case is unusual because despite normal renal function, the patient still developed ototoxicity, and systemic absorption of the drug was confirmed with a measurable vancomycin level approximately 24 hours after the drug was stopped.
This case reflects that some patients may be more susceptible to increased systemic absorption via the oral route, and the possibility for ototoxicity should be considered and discussed with patients while prescribing oral vancomycin. Clostridium difficile infection CDI has become an increasingly common infection with the widespread use of the antibiotic therapy [ 1 ]. It is the most common cause of nosocomial diarrhea, yet the incidence of CDI in the community is also on the rise [ 2 , 3 ].
Metronidazole is recommended for the treatment of patients with mild to moderate CDI and oral vancomycin for the treatment of patients with severe CDI and recurrent disease [ 2 ]. Oral vancomycin is predicted to be poorly absorbed from the gastrointestinal tract based on pharmacokinetic data [ 4 ]. However, prior reports have documented that oral vancomycin therapy may produce detectable serum concentrations in patients with severe colitis and renal failure [ 5 , 6 ]. There are no reports of ototoxicity as a complication following administration of oral vancomycin.
We report the first case of ototoxicity after administration of oral vancomycin in a patient with normal renal function. A year-old woman with history of hypertension and diabetes mellitus presented to the outpatient clinic with abdominal pain and diarrhea for two weeks. The patient was recently treated with clindamycin for sinusitis. On examination, the patient appeared comfortable, afebrile, and had normal vital signs. There was mild tenderness reported on abdominal palpation, and the remainder of the physical examination was unremarkable.
Clostridium difficile infection was confirmed by a positive stool toxin B PCR, and the patient was started on treatment with metronidazole. At the time of initiation of therapy, the patient had creatinine of 0. However, the reported symptoms persisted, and on day 5 of therapy, vancomycin was discontinued in the outpatient clinic. CDI is a well-established cause of nosocomial diarrhea in hospitals and long-term care facilities leading to a large burden of cost [ 1 ].
The epidemiology of C. In addition to an increasing incidence and virulence of infection, almost one fourth of patients have recurrent disease [ 7 ]. Vancomycin appears to be more efficacious than metronidazole for treatment of CDI [ 8 ]. Current treatment guidelines recommend use of oral vancomycin for severe disease and after the first recurrence of infection [ 2 ].
Poor absorption of oral vancomycin as predicted by pharmacokinetics forms the basis for use of oral vancomycin for colitis due to Clostridium difficile [ 5 ].
However, there are conflicting clinical data regarding the systemic absorption after oral administration. There are reported cases of detectable serum levels of vancomycin after oral administration in the setting of severe colitis and renal insufficiency [ 5 , 9 ]. In one series of 10 cases treated with oral vancomycin, 4 had detectable levels ranging 1.
Out of the 4 patients, 1 had renal insufficiency [ 10 ]. The observed risk factors for systemic exposure of the drug included ICU admission, over 10 days of therapy, presence of severe CDI, renal dysfunction, inflammatory conditions of the GI tract, and concomitant use of vancomycin retention enemas [ 6 ]. There are also reports indicating lack of systemic absorption of oral vancomycin [ 11 ]. In a recent pilot study including 8 children, 7 with inflammatory bowel disease and one with acute kidney injury, none had detectable levels of vancomycin after enteral administration [ 12 ].
Furthermore, despite the fact that renal excretion is the dominant route of vancomycin clearance, systemic absorption did not occur even in patients with renal insufficiency [ 13 ]. Transient or permanent ototoxicity has rarely been described as a side effect of vancomycin therapy and is related to high serum vancomycin levels [ 4 ]. Symptoms usually resolve after decrease in dose or cessation of vancomycin. There is no reported case of ototoxicity associated with use of oral vancomycin.
Our case is unusual because despite the absence of renal failure and other known risk factors for systemic exposure to vancomycin, the patient developed symptoms suggestive of ototoxicity. The patient was not concurrently taking other medications known to causing ototoxicity or with potential pharmacokinetic interactions with vancomycin.
Systemic absorption was confirmed by a measurable vancomycin level of 2. Due to the time lag in obtaining the drug level, the peak serum level of vancomycin could have been significantly higher than the measured level. Using the adverse drug reaction probability calculation method described by Naranjo et al. Our case reflects that ototoxicity due to vancomycin can develop after oral administration in the absence of renal impairment or other reported risk factors for systemic absorption.
The possibility of systemic absorption and possible ototoxicity should be considered and discussed with patients when prescribing oral vancomycin. The authors declare that there are no conflicts of interest regarding the publication of this paper.
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Journal overview. Academic Editor: Larry M. Received 10 Dec Accepted 01 Jun Medians and ranges were reported in figures. Median faecal concentrations of vancomycin were compared using the Mann-Whitney test.
Proportions were compared with the Pearson x 2 test or the Fisher exact test when numbers were small. A total of 19 patients were enrolled in the study. Four patients were subsequently excluded: two because they received vancomycin for only one day after recruitment, and two others who had less than 2 stool specimens collected during their hospital stay.
The final study sample included 15 patients nine women and six men with a median age of 63 range: years. Oral vancomycin was prescribed every six hours in all patients.
Five patients had their dosage modified during their hospital stay. No patient experienced a CDI relapse within 90 days of enrolment. Nine patients had a confirmed CDI three had a positive cytotoxicity assay, four had evidence of pseudomembranous colitis, and two had both while in the other six the diagnosis could not be confirmed.
Toxigenic cultures were positive only in patients in whom the diagnosis had been proven by other methods. Based on PCR ribotyping, none of the cultured strains corresponded to the hypervirulent strain ribotype Five were aged 60 years or more. We compared faecal levels of vancomycin in patients with or without CDI confirmation, and found no statistically significant differences at any day of therapy data not shown.
Additionally, baseline data were similar in both groups Table 1. Therefore, the rest of the analyses included all 15 patients, regardless of their CDI diagnosis. Day-to-day median faecal levels of vancomycin and ranges achieved according to dosage are illustrated in Figure 1. There were substantial variations between individual patients.
Higher doses of oral vancomycin mg or mg qid led to consistently higher faecal levels than the standard dose of mg qid Figure 1. Such differences were statistically significant from day 2 to day 4 inclusively. Median faecal vancomycin levels achieved with different oral vancomycin dosages. When no range is indicated, a single specimen was analyzed.
Median faecal vancomycin concentrations achieved in patients stratified according to their stool frequency. Three patients had their faecal levels measured after treatment completion. Serum samples were collected on day 1 and 3 after recruitment in 11 patients two did not consent to provide a blood sample and two others received IV vancomycin for some other reason and were excluded.
Serum concentrations ranged from 0 to 0. Many hospitals now reduce their acquisition costs by administering orally the generic formulation of intravenous vancomycin, which is fold cheaper. As could have been predicted from the product's limited absorption, faecal levels of vancomycin increased in proportion with the dosage administered.
For most of the duration of therapy, faecal levels achieved with the higher dosage are very unlikely to be more effective than those obtained with the standard mg qid dosage, which themselves were often times higher than the MIC 90 1. The faecal levels of vancomycin were influenced by stool frequency. Such findings are consistent with a higher output of loose stools resulting in some dilution of the vancomycin, but this would probably not be clinically relevant.
Therefore it seems to us, based on our data and published literature, that for most CDI patients the only rationale for giving a higher dosage would be as a loading dose or mg qid during the first hours, especially in patients with some ileus for whom the delivery of orally administered vancomycin might be delayed.
Beyond this initial period, there is little rationale for giving more than mg qid, unless the patient has very severe ileus: neither our study nor previous work specifically addressed this subpopulation of CDI cases. However, before modifying clinical practices, additional studies are required to evaluate lower dosages, in the hope that they would be as effective against C. These low serum levels are irrelevant with regard to potential nephrotoxicity or ototoxicity.
Only one published case reported a patient with significant systemic absorption and normal renal function but the patient suffered from severe graft-versus-host disease of the gastrointestinal tract [ 33 ]. Our study is the largest to quantify the systemic absorption of oral vancomycin.
Our study had limitations. Its small sample size limited its power to detect statistically significant differences between subgroups. Some of our patients were eventually proven not to have CDI. Since its main focus was on vancomycin pharmacokinetics, we elected to include all patients at the onset of their vancomycin prescription in order to have the most samples possible rather than wait for CDI confirmation.
In the absence of universally accepted criteria, we chose stool frequency to evaluate the impact of such a "diluting factor" on the faecal vancomycin levels but admittedly this is an imperfect measure of diarrhoea severity. Faecal levels of vancomycin are roughly proportional to the dosage administered and even in patients with high stool frequency are consistently to times higher than the MIC Patients given the standard mg qid dosage might have low faecal levels during the first 24 hours of treatment.
A loading dose of mg or mg qid during the first hours followed by the standard dosage should be evaluated in larger pharmacokinetics studies, since it might be less disruptive to the colonic flora and save unnecessary costs. J Antimicrob Chemother. N Engl J Med. Antimicrob Agents Chemother.
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Correspondence to Louis Valiquette. MG carried out the faecal assays and participated in the design of the study and coordination, performed the statistical analysis and helped to draft the manuscript. EHF performed faecal assay's validation. SS and LCF carried out the molecular analysis.
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