Urinary Tract Infections and Diabetes Mellitus

People with diabetes are at a greater risk of many infections. This includes infections of the urinary tract, respiratory tract, skin and soft tissues. Infections are a significant cause of morbidity and mortality in this population. While the reasons for this elevated risk are complex, impaired innate and adaptive immune responses within the hyperglycaemic environment are thought to be important factors.

Poor glycaemic control is associated with a higher risk of infection. One large cohort study found that, for most infection types, the rate of infections rose steadily with increasing HbA_1c. This was particularly true for patients with a HbA_1c ≥ 11%. Chronic complications of diabetes, such as neuropathy, can also predispose to infections.

The urinary tract is one of the most common sites of bacterial infections in people with diabetes. While the frequency of urinary tract infections (UTIs) is increased, this population is also likely to experience a worse prognosis. They are more likely to require hospitalisation for their UTI, and serious complications are more common.

Emphysematous pyelonephritis

Emphysematous pyelonephritis (EPN) is one of the most serious types of UTI. Although this is an uncommon condition, it is highly associated with diabetes, with around 95% of cases occurring in patients with uncontrolled diabetes mellitus.

Emphysematous pyelonephritis is an acute necrotising infection of the renal parenchyma and surrounding tissues. It is caused by bacteria that are able to ferment glucose to produce carbon dioxide. Potential causative pathogens include Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. In almost 70% of cases, E. coli is isolated on urine or pus cultures.

If not diagnosed early, this condition can be life-threatening, with mortality mostly related to septic complications. Patients may initially present with non-specific symptoms, although the clinical triad of fever, flank pain and nausea is typically seen. In severe cases, altered consciousness and shock may be apparent. Predictors of poor prognosis include thrombocytopenia, azotaemia, and high urinary red blood cell counts. Diagnosis is supported by imaging of the abdomen and pelvis, which will show the presence of intra-renal gas.

Initial treatment includes broad-spectrum antibiotics, fluid and electrolyte resuscitation, acid-base balance, percutaneous catheter drainage, and rapid glycaemic control. Empiric antibiotic therapy should target gram-negative bacteria while also considering local resistance patterns and individual patient factors. Third or fourth-generation cephalosporins or carbapenems may be considered. Factors that may favour the use of a carbapenem include hospitalisation with antibiotic use within the previous 12 months, the need for emergency haemodialysis, or the presence of disseminated intravascular coagulation. One study demonstrated that these factors had a significant correlation with cephalosporin resistance.

While emphysematous pyelonephritis is rare, it should be considered in patients with diabetes who present with pyelonephritis. Early recognition and initiation of appropriate therapy are essential to minimise mortality and potentially reduce the need for nephrectomy.

Sodium-glucose cotransporter-2 inhibitors

While diabetes itself is a risk factor for UTIs, one class of medications used to treat diabetes has been suggested to increase this risk even further. Concerns were raised about sodium-glucose cotransporter-2 (SGLT2) inhibitors and their potential to increase the risk of urinary tract and genital infections. This is related to the way in which they reduce blood glucose levels. As they work to inhibit glucose reabsorption in the proximal tubules, glucose levels in the urine are elevated. The resulting glycosuria is hypothesised to enhance bacterial growth within the urogenital environment.

Dapagliflozin and empagliflozin are SGLT2 inhibitors. They are available as single-ingredient preparations and fixed-dose combinations with metformin or linagliptin.

While urogenital infections have been reported in association with these medicines, data from large randomised clinical trials and real-world population-based studies suggest that they may not increase the risk of UTIs. One meta-analysis demonstrated that while SGLT2 inhibitors may increase the risk of genital infections, the class is not generally associated with an increased risk of UTI. However, dapagliflozin was associated with an increased risk of UTI compared to placebo when given at a dose of 10mg daily (RR 1.33, 95% CI 1.10–1.61), but not at 5mg daily. This elevated risk was not seen with empagliflozin at any dose nor with dapagliflozin when compared to active comparators.

This lack of observed UTI risk despite the favourable conditions these medicines provide for bacterial growth could be related to their diuretic effect. Therefore, the UTI risk profile may be different for patients with abnormal urinary flow.

Pathogens

Urinary tract infections occurring in people with diabetes are more likely to be caused by resistant pathogens. This includes extended-spectrum β-lactamase-positive Enterobacteriaceae, fluoroquinolone-resistant uropathogens, carbapenem-resistant Enterobacteriaceae, and vancomycin-resistant Enterococci.

The increased incidence of resistant infections in this group could be related to a general increased consumption of antibiotics for UTIs and other infections. This highlights the importance of antimicrobial stewardship initiatives to ensure that antimicrobial use is optimal in this group. For example, asymptomatic bacteriuria is more common in people with diabetes. However, this should not be treated with antibiotics unless the patient is pregnant or undergoing certain elective urological procedures. In other cases, the evidence suggests that treatment of asymptomatic bacteriuria does not reduce the incidence of symptomatic UTI or long-term complications and may increase the risk of resistant infections.

Type 2 diabetes is also a risk factor for fungal UTIs, typically with Candida spp. Fluconazole is often the agent of choice for the treatment of fungal UTIs. It has high oral bioavailability, a long half-life, and achieves adequate levels in the urine. Fluconazole is active against C. albicans and the most common non-albicans Candida species. Higher doses are typically required for infections caused by C. glabrata (recently renamed Nakaseomyces glabrata). The most recent AURA report (Antimicrobial Use and Resistance in Australia Surveillance System) finds that azole resistance among this species is 8.6% and may be increasing. Amphotericin B is a potential alternative where resistant yeasts are involved. However, liposomal formulations of amphotericin B do not achieve high urinary concentrations. Therefore, they are not suitable for lower UTIs.

Prevention

Optimal control of diabetes is essential to minimise the risk of infections as well as other diabetes complications. The Royal Australian College of General Practitioners (RACGP) make the following recommendations for the optimal management of type 2 diabetes:

• Eat according to the Australian dietary guidelines; individual dietary review is recommended if cardiovascular disease is present;
• Weight loss, if appropriate;
• At least 30 minutes of moderate physical exercise on most days (total ≥150 minutes/week);
• Cease smoking, where relevant;
• Limit alcohol intake to ≤2 standard drinks per day;
• Aim for 6–8 mmol/L fasting and 8–10 mmol/L postprandial blood glucose levels
• HbA_1c goals should be individualised, but a general goal would be ≤7% (6.5–7.5%) or ≤53 mmol/mol (48–58 mmol/mol);
• Address cardiovascular risk factors, as appropriate (i.e. blood pressure, blood lipids, etc.); and
• Consider vaccination, e.g. against seasonal influenza and pneumococcal disease.

Other preventative measures that may be considered to reduce the risk of UTIs include adequate hydration, avoidance of constipation, and attention to hygiene.