Background-Measurement of 6-thioguanine nucleotide concentrations may be useful for optimising treatment with azathioprine and 6-mercaptopurine. Methods-We conducted a study of 170 patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine to determine the relationship between 6-thioguanine nucleotide concentrations and both disease activity, as measured by the inflammatory bowel disease questionnaire (active disease <170, remission >170) and leucopenia. Blood was submitted for whole blood 6-thioguanine nucleotide concentration and leucocyte count. Results-Mean (SD) inflammatory bowel disease questionnaire score was 176 (32). There was no correlation between inflammatory bowel disease questionnaire scores and 6-thioguanine nucleotide concentrations (r s =−0.09, p=0.24). Median 6-thioguanine nucleotide concentrations in 56 patients with active disease and 114 patients in remission were similar (139 v 131 pmol/8×10 8 red blood cells; p=0.26). There was no correlation between 6-thioguanine nucleotide concentrations and leucocyte counts. Conclusions-In patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine, 6-thioguanine nucleotide concentrations did not correlate with disease activity, as measured by the inflammatory bowel disease questionnaire, or leucocyte count. These findings are discrepant with most previous studies, possibly due to selection of responding patients who tolerated the medications. A prospective, randomised, dose optimisation trial using 6-thioguanine nucleotide concentrations is warranted. (Gut 2001;49:665-670)

Aim-We evaluated the eVect of coadministration of sulphasalazine, mesalamine, and balsalazide on the pharmacokinetics and pharmacodynamics of azathioprine and 6-mercaptopurine. Methods-Thirty four patients with Crohn's disease receiving azathioprine or 6-mercaptopurine were enrolled in an eight week non-randomised parallel group drug interaction study and treated with mesalamine 4 g/day, sulphasalazine 4 g/day, or balsalazide 6.75 g/day. The primary outcome measure was the occurrence of clinically important leucopenia during the study, defined separately as total leucocyte counts <3.0 x 10 9 /l and <3.5×10 9 /l. Whole blood 6-thioguanine nucleotide concentrations were determined. Results-Three patients could not be evaluated for the primary outcome measure. In the remaining 31 patients, the frequency of total leucocyte counts <3.0 and <3.5 were: 1/10 and 5/10 in the mesalamine group; 1/11 and 6/11 in the sulphasalazine group; and 0/10 and 2/10 in the balsalazide group. There were significant increases in mean whole blood 6-thioguanine nucleotide concentrations from baseline at most time points in the mesalamine and sulphasalazine groups but not in the balsalazide group. Conclusions-In patients with Crohn's disease receiving azathioprine or 6-mercaptopurine, coadministration of mesalamine, sulphasalazine, and possibly balsalazide results in an increase in whole blood 6-thioguanine nucleotide concentrations and a high frequency of leucopenia. (Gut 2001;49:656-664)

Between July 1987 and January 1988, five patients dialyzed at a hemodialysis outpatient clinic developed systemic Mycobacterium chelonae abscessus (MCA) infections. Four of the five patients had arteriovenous graft infections, and two died during antimicrobial therapy. Case-patients were more likely than control-patients to have received high-flux dialysis during the 6 mo before their infection (100% vs. 30%, P = .009). MCA was cultured from the hose connected to a water spray device used for manual reprocessing of high-flux but not regular dialyzers. Renalin was the germicide used to manually disinfect dialyzers for reuse and was prepared at a concentration of 2.5%. Laboratory studies documented survival of MCA from two high-flux dialyzers that were reprocessed in a manner similar to that used in the clinic. Early diagnosis with complete rather than partial graft removal in combination with antimicrobial therapy is recommended for MCA graft infections. In addition, 2.5% Renalin did not appear to ensure complete killing of MCA in high-flux dialyzers that were manually reprocessed at this hemodialysis clinic.

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Mean corpuscular volume may correlate with erythrocyte 6-thioguanine nucleotide concentrations in patients treated with azathioprine and 6-mercaptourine. We conducted a study of 166 patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine to determine the relationship between mean corpuscular volume and erythrocyte 6-thioguanine nucleotide concentrations, disease activity as measured by the Inflammatory Bowel Disease Questionnaire (active disease <170, remission >170), and leukopenia. Blood was submitted for mean corpuscular volume, whole blood 6-thioguanine nucleotide concentration, and leukocyte count. The mean +/- SD mean corpuscular volume during treatment was 94.7 +/- 6.6 fL and the mean +/- SD change in mean corpuscular volume was 7.5 +/- 6.3 fL. There were significant correlations between mean corpuscular volume and erythrocyte 6-thioguanine nucleotide concentration (r(s) = 0.33, p < 0.001) and between change from baseline in mean corpuscular volume and erythrocyte 6-thioguanine nucleotide concentration (r(s) = 0.26, p = 0.001). There was no correlation between Inflammatory Bowel Disease Questionnaire scores and mean corpuscular volume values (r(s) = 0.01, p = 0.94). The mean corpuscular volume values in 55 patients with active disease and 111 patients in remission were similar (95.1 vs. 94.5 fL, p = 0.57). There was a weak negative correlation between the mean corpuscular volume and the leukocyte count, (r(s) = -0.18, p = 0.022). In patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine, mean corpuscular volume and change from baseline in mean corpuscular volume correlated with erythrocyte 6-thioguanine nucleotide concentrations and negatively with leukocyte counts, but did not correlate with disease activity as measured by the Inflammatory Bowel Disease Questionnaire. Measurement of mean corpuscular volume is a simple and inexpensive alternative to measurement of 6-thioguanine nucleotide concentrations in patients treated with azathioprine or 6-mercaptopurine.

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Seventeen cases of otitis media caused by Mycobacterium chelonae were detected among patients seen at a single ear-nose-and-throat (ENT) office (Office A) in Louisiana between May 5 and September 15, 1987. All the patients had a tympanotomy tube or tubes in place or had one or more tympanic-membrane perforations, with chronic otorrhea that was unresponsive to standard therapy with antimicrobial agents. Middle-ear exploration in six patients revealed abundant granulation tissue; multiple granulomas and acid-fast bacilli were demonstrated on a section of tissue from one patient with a nonhealing mastoidectomy incision. Thirteen of the 14 ear isolates obtained from patients seen in Office A had the same unusual pattern of high-level resistance to aminoglycosides. M. chelonae and other nontuberculous mycobacteria were recovered from several sources of water in Office A, as well as in another ENT office (Office B) in a neighboring city that was visited by the index patient. Only one additional case was detected in Office B during the same period. Otologic instruments in Office A were cleaned in an ultrasonic bath with tap water and a liquid detergent; the contents of the bath were changed only once weekly. Instruments in Office B were placed in boiling water between patient examinations. This outbreak establishes M. chelonae as an agent of otitis media and underscores the need for high-level disinfection or sterilization of ENT instruments between examinations to prevent the transmission of this organism to patients in the office setting.

Summary:Our aim was to report the clinical experience with combination treatment using tacrolimus and either azathioprine (AZA) or 6-mercaptopurine (6MP) in patients with Crohn's disease (CD) perianal fistulae. The medical records of all patients with Crohn's disease perianal fistulae seen at the Mayo Clinic from 1996-1998 who were treated with tacrolimus were reviewed. Clinical response was classified as: complete response, partial response, and nonresponse. Eleven patients were treated with oral tacrolimus for a mean duration of 22 weeks. The initial oral dose of tacrolimus ranged from 0.15 to 0.31 mg/kg/day. Azathioprine or 6MP was continued in combination with tacrolimus in seven patients and initiated simultaneously with tacrolimus in four patients. All patients improved clinically, seven had a complete response, and four had a partial response. The mean time to initial improvement was 2.4 weeks, and the mean time to complete response was 12.2 weeks. The most frequent adverse events were nausea, paresthesias, nephrotoxicity, and tremor. Patients with nephrotoxicity had a significantly higher mean initial tacrolimus dose (0.3 1 mg/kg/day) compared with patients who did not have nephrotoxicity (0.25 mgkg/day) (p = 0.035); however, there was not a statistically significant association between the starting dose or mean blood level and clinical response. Combination therapy with oral tacrolimus and AZA or 6MP may be effective treatment for CD perianal fistulae. Higher initial tacrolimus doses increase the risk of nephrotoxicity without improving clinical response.