Reduction of susceptibility to azoles and 5-fluorocytosine and growth acceleration in Candida albicans in glucosuria.

Diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia and glucosuria, and is a risk factor for Candida infections. To reveal the potential effects of glucosuria on Candida spp., we investigated their growth and antifungal susceptibilities in normal human urine to which glucose was added. The viable cell numbers of Candida spp. were more than 10 fold higher in the urine added 3000 mg/dL glucose than in plain urine. In antifungal susceptibility, more than 80% of Candida albicans clinical isolates increased minimum inhibitory concentrations of azoles and 5-fluorocytosine with the addition of glucose, and exceeded their breakpoints. In most of the C. albicans clinical isolates, the mRNA expression of the azole resistance genes ERG11, CDR1, CDR2, and MDR1 in the presence of glucose in urine. These observations provide valuable information about the clinical course and therapeutic effects of azoles against C. albicans infections in patients with diabetes mellitus and hyperglucosuria.

Effect of SGLT2 inhibitors in a murine model of urinary tract infection with Candida albicans.

AIMS: Urinary tract infection (UTI) is a common clinical problem in diabetic patients; however, the relationship between UTI and glucosuria remains uncertain. To investigate the relationship, we examined the effect of glucosuria induced by sodium glucose cotransporter 2 (SGLT2) inhibitors on the progression of UTI in mice. METHODS: From 1 day before transurethral inoculation with Candida albicans, female mice were treated orally once a day with an SGLT2 inhibitor in different treatment regimens: (i) dapagliflozin at 10 mg/kg for 2, 3 or 7 days, (ii) dapagliflozin at 0.1, 1 or 10 mg/kg for 3 days and (iii) dapagliflozin, canagliflozin or tofogliflozin at 10 mg/kg for 3 days. To evaluate the ascending UTI, the kidneys were removed 6 days after the inoculation, and the number of viable C. albicans cells in kidney was measured as colony-forming units (CFU). RESULTS: In mice treated with dapagliflozin, the number of C. albicans CFU in kidney increased in accordance with both treatment duration and dose. The number of CFU significantly increased when mice were treated with 10 mg/kg dapagliflozin or canagliflozin but not tofogliflozin. With dapagliflozin and canagliflozin, urine glucose concentration (UGC) significantly increased up to 24 h after drug administration; with tofogliflozin, UGC significantly increased only up to 12 h after drug administration. CONCLUSIONS: Our data indicate that increased susceptibility to UTI is associated with a persistent increase in UGC.

Effects of the antifungal agent itraconazole on proliferative changes of the forestomach mucosa in alloxan-induced diabetic rats.

Alloxan-induced diabetic rats frequently exhibit proliferative lesions of squamous hyperplasia accompanied by chronic inflammation and Candida albicans infection in the forestomach, and some lesions progress to squamous cell carcinoma (SCC). Candida infection causes not only hyperplastic changes with inflammation but might also lead to SCC in human oral mucosa. Thus, the present study was conducted to examine the effects of the antifungal agent itraconazole (ITCZ) on proliferative and inflammatory changes of the forestomach in alloxan-induced diabetic WBN/Kob rats. Diabetes was induced by alloxan at fifteen weeks of age. Rats were allocated to three groups at forty-five weeks of age and were given ITCZ by gavage 0 (vehicle control), 5, and 10 mg/kg/day for four weeks, and they were sacrificed at the sixty-fifth week of age. Mucosal hyperplastic changes were consistently accompanied by inflammation and Candida infections in the 0 mg/kg group. These lesions were reduced by ITCZ (0 mg/kg; 100%, 5 mg/kg; 53.5%, 10 mg/kg; 61.5%). Squamous cell carcinoma was detected in three rats from the 0 mg/kg, but only one rat from the 10 mg/kg dose groups in this study. Itraconazole reduced the degree of mucosal hyperplasia, inflammatory changes, and Candida infection. Therefore, C. albicans infection was an important factor in pathogenesis of mucosal proliferation and inflammation.

The influence of glucose added urine on the in vitro antimicrobial activity of various antibiotics.

BACKGROUND & OBJECTIVE: Factors associated with the medium, including calcium and magnesium ion concentration and pH have been shown to affect the results of susceptibility testing but very little is known about glycosuria and the effect of glucose on the antimicrobial effect of antibiotics. In this study we assessed the influence of glucose added urine on the in vitro activities of various antibiotics by the microbroth dilution method. METHODS: Sixteen Escherichia coli isolates from patients with urinary infections were used in this study. Nine antibiotics were tested for their antimicrobial activity. Minimum inhibitory concentrations (MICs) were performed by the microbroth dilution method parallel in Mueller Hinton broth and glucose added urine. RESULTS: MICs of nearly all antibiotics were higher in glucose added urine than MICs in broth. MIC(90) against ampicillin was 32-fold higher in glucose added urine than MIC(90) in broth. MIC(90)s against ampicillin-sulbactam, cephalothin, cefuroxime, ceftriaxone and ciprofloxacin in glucose added urine were significantly (P<0.05) higher than MIC(90) in broth. Equal MIC(90) in glucose added urine and broth were obtained for amikacin, sulphamethoxazole and trimethoprime. INTERPRETATION & CONCLUSION: Our findings demonstrated that MICs of antibiotics are influenced by the glucose added urine.

Effect of glucose and pH on uropathogenic and non-uropathogenic Escherichia coli: studies with urine from diabetic and non-diabetic individuals.

It is generally assumed that one of the reasons why diabetics are more susceptible to urinary tract infections than non-diabetics is their 'sweet urine'. However, very little information is available on this subject. Therefore, the growth rates of different Escherichia coli strains were studied in human urine with and without added glucose and with and without a constant pH, and compared with their growth rates in Mueller-Hinton broth (MHB). Eight isolates were used (three from blood cultures from urosepsis patients, two urinary isolates, two faecal isolates and one laboratory strain K12). All isolates grew better in MHB than in urine, but with the exception of the laboratory strain, they had the same growth rate in urine. No significant difference was found between the growth rate in urine from diabetics without glucosuria and that in urine from non-diabetics. The addition of glucose (up to a concentration of 1000 mg/dl) to urine and MHB enhanced the growth rate of all isolates. However, very high concentrations of glucose (up to 10000 mg/dl) in urine and MHB caused a decrease in bacterial growth rate when the urinary pH was not kept constant. The stationary phase was reached later and the final bacterial yield was greater when the urine was made less acidic. As the uropathogenic strains did not grow better in urine than the other isolates, it may be concluded that better growth in urine is not one of the causes of the greater virulence of these strains.

[A diabetic patient with cystitis emphysematosa]. / Een diabetespatiënt met cystitis emphysematosa.

In a woman aged 80 years arriving in the Emergency Room with progressive malaise, anorexia and somnolence, a large resistance was found in the lower abdomen, which proved to be due to cystitis emphysematosa. The patient was known to suffer from non-insulin dependent diabetes mellitus. Imaging revealed a large accumulation of gas in the urinary bladder, which was treated successfully with catheterization and antibiotics. Cystitis emphysematosa is a rare condition, characterized by collection of gas in the bladder and bladder wall and brought about by gas-forming micro-organisms that decompose glucose. In patients with diabetes mellitus optimal regulation of the blood glucose levels, with a view to preventing glycosuria, is a condition of speedy recovery. Although cases with a fatal outcome have been reported, the prognosis in general is favourable.