George R. Bailie

Vancomycin Ototoxicity and Nephrotoxicity A Review

SummaryVancomycin 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 otoxocity 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.

Intravenous or Intraperitoneal Vancomycin for the Treatment of Continuous Ambulatory Peritoneal Dialysis Associated Gram-Positive Peritonitis?

A clinical and pharmacokinetic study was carried out to determine whether an intraperitoneal (IP) loading dose of vancomycin was as effective as an intravenous (IV) load in the treatment of continuous ambulatory peritoneal dialysis (CAPD)-associated gram-positive peritonitis. Each patient continued a 14-day treatment on IP maintenance doses. All cases of peritonitis (10 in each group) were eradicated. Side effects occurred in 3 patients following IV vancomycin and in none following IP vancomycin. Serum and peritoneal vancomycin concentrations equilibrated fully and rapidly with each route. It is concluded that an IP loading dose of vancomycin, followed by IP maintenance doses, is as effective as and produces fewer side effects than an IV loading dose in the treatment of CAPD peritonitis.

Clearance from dialysate and equilibration of intraperitoneal vancomycin in continuous ambulatory peritoneal dialysis.

SummaryThis article reports on a study of the disposition of loading doses (1g and 15 mg/kg) of vancomycin given intraperitoneally to 6 patients on continuous ambulatory peritoneal dialysis with Gram-positive peritonitis. Dialysate samples were collected every 30 minutes during the first dwell, and serum samples were collected after the first 5 exchanges and after 7 or 14 days. The dialysate concentration/time data were fitted to a monoexponential curve for 4 patients and to a biexponential curve for 2 others. Dialysis clearance was 0.73 ± 0.04 L/h (1g dose) and 0.70 ± 0.23 L/h (15 mg/kg dose). Total body clearance was 0.51 ± 0.36 L/h. Serum concentrations reached 14 to 18 mg/L (15 mg/kg dose) and 6.75 to 24 mg/L (1g dose) at the end of the first dwell. The half-life of equilibration of vancomycin across the peritoneal membrane was 2.5 ± 2.3 hours. Intraperitoneal loading doses of vancomycin produce concomitant serum concentrations in excess of the minimum inhibitory concentrations for susceptible organisms. Administration on a milligram per kilogram basis produces more consistent serum concentrations than using a standard loading dose which is not based on bodyweight.

Bioavailability of Bumetanide in Grossly Oedematous Patients

SummaryA pharmacokinetic study was undertaken to determine the bioavailability of bumetanide in grossly oedematous patients. Six nephrotic patients were administered bumetanide 2mg orally (as tablets) and intravenously as single doses, in a randomised fashion. Serum bumetanide concentration-time profiles were characterised. Data were fitted to a 2-compartment model (5 patients) and a 3-compartment model (1 patient). Analysis of the areas under the curves showed a bioavailability of 0.84 ± 0.2, which is similar to that in normal individuals. It is suggested that the bioavailability of oral bumetanide in oedematous patients is not altered significantly and that the apparent resistance to diuretics in such patients may be due to another cause.

Failure of intraarticular ceftazidime in a patient with Pseudomonas aeruginosa septic arthritis.

This report describes a patient with Pseudomonas aeruginosa septic arthritis who received ceftazidime by the intravenous and intraarticular routes. Concentrations of ceftazidime in the synovial fluid following both routes of administration were measured and found to be above the minimum inhibitory concentration. Despite this the organism was not eradicated. We were unable to find other literature describing the disposition of ceftazidime in synovial fluid and therefore this single-patient study provides novel information. We were unable to account for the apparent failure of therapy.

Imipenem/cilastatin efficacy evaluated

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