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Susceptibility to infections in persons with diabetes mellitus

Susceptibility to infections in persons with diabetes mellitus

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2021. | This topic last updated: Mar 03, 2020.

INTRODUCTION — It is widely accepted by both the medical profession and the general public that diabetics have an increased propensity to develop infections. Although several epidemiologic studies have shown that diabetics receive treatment for infections more often than non-diabetics, the magnitude of the effect of diabetes on the risk of infection remains an active research question.

Host- and organism-specific factors that may explain why people with DM are more susceptible to particular infections will be reviewed here. The clinical features, diagnosis, and treatment of specific infections that appear either to be more prevalent in diabetics or to have unique features when they occur in diabetics are discussed separately. These infections include:

●Foot infections (see "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities")

●Urinary tract infections, including fungal infections (see "Emphysematous urinary tract infections")

●Superficial fungal infections, such as oral candidiasis, onychomycosis, and intertrigo (see "Esophageal candidiasis in adults" and "Onychomycosis: Epidemiology, clinical features, and diagnosis" and "Intertrigo")

●Mucormycosis (see "Mucormycosis (zygomycosis)")

●Malignant external otitis (see "Malignant (necrotizing) external otitis")

●Emphysematous cholecystitis (see "Acute calculous cholecystitis: Clinical features and diagnosis")

●Pyomyositis, which is a primary bacterial infection of skeletal muscle characterized by the formation of one or more intramuscular abscesses (see "Pyomyositis")

●Necrotizing fasciitis, usually due to mixed aerobic and anaerobic infection (see "Necrotizing soft tissue infections")

RISK OF INFECTION — Most studies support an increased risk of infection among patients with diabetes mellitus compared with the general population, although the magnitude of this risk is uncertain [1-7]. As examples:

●In a matched cohort study using a Canadian electronic medical record-based surveillance system, the odds of any infection were higher among 1779 patients with diabetes (22 percent on insulin) compared with 11,066 matched controls, after controlling for potential confounders (adjusted odds ratio 1.21, 95% CI 1.07-1.37) [1]. In particular, diabetes mellitus was associated with skin and soft tissue infections followed by genitourinary, gastrointestinal, and respiratory infections; there was no association with head and neck, musculoskeletal, and viral infections.

●In another retrospective cohort study using a large primary care database in England, the incidence rate ratio (IRR) for any infection was higher among 5863 patients with type 1 diabetes mellitus (IRR 1.66, 95% CI 1.59-1.74) and 96,930 with type 2 diabetes mellitus (1.47, 95% CI 1.46-1.49) compared with age, sex, and practice-matched controls (n = 11,696 for type 1 and n = 191,822 for type 2) [2]. The IRRs for type 1 diabetes mellitus were highest for bone and joint infections, endocarditis, meningitis, and sepsis. The IRRs for type 2 diabetes mellitus were highest for bone and joint infections, candidiasis, sepsis, and cellulitis.

●One study from the Netherlands assessed the number of infections in treated type 2 diabetics cared for in a general practice during a two-year period [4]. Four hundred and fifty-eight infections occurred in 193 patients for a mean of 2.4 infections per patient (± 1.9).

Most, but not all studies suggest that the risk of infection in diabetes mellitus is associated with hyperglycemia or lack of diabetes mellitus control [4,8,9]. In particular, diabetes mellitus and postoperative hyperglycemia have been strongly associated with surgical site infections (SSIs) [9-14]. As an example, in a multivariable logistic regression analysis of 49,817 patients undergoing major vascular surgery, diabetes mellitus was significantly associated with SSI (OR 1.3, 95% CI 1.2-1.4) [14]. Additionally, in a study involving 1561 patients undergoing general and vascular surgery, postoperative hyperglycemia was the sole independent risk factor for SSI among general surgery patients after multivariate adjustment for other factors, such as age, emergency status, American Society of Anesthesiologists preoperative classification score, and operative time [13]. There appeared to be a linear relationship between the degree of elevation in postoperative glucose concentrations and the risk of an SSI. The study's retrospective design, the absence of postoperative glucose level measurements on approximately a quarter of the patients, and the lack of association between hyperglycemia and SSI among vascular surgery patients lower confidence in the results. However, they are generally consistent with other observational data, including a prospective study of 1000 patients undergoing cardiothoracic surgical procedures, in whom increasing levels of postoperative hyperglycemia (in patients with or without diabetes mellitus) were increasingly associated with risk of SSI [10].

Accordingly, several studies have suggested that improved glucose control during the operative and perioperative period can reduce the risk of postoperative infections following cardiac surgery [15,16]. In a meta-analysis of four randomized trials plus six cohort studies, glycemic control with a continuous insulin infusion to maintain glucose levels ≤200 mg/dL lowered SSI rates following cardiac surgery compared with subcutaneous insulin [16]. (See "Perioperative management of blood glucose in adults with diabetes mellitus", section on 'Glucose management'.)

It is likely that the association between diabetes mellitus and SSIs is related to the deleterious effect of hyperglycemia on chemotaxis, phagocytosis, and adherence of granulocytes. (See "Risk factors for impaired wound healing and wound complications", section on 'Diabetes'.)

Diabetes mellitus has also been associated with worse outcomes with infections such as bacteremia and endocarditis [17-19].

HOST FACTORS — Host-specific factors that are thought to predispose diabetic patients to infection include the following:

●Hyperglycemia-related impairment of the immune response

●Vascular insufficiency

●Sensory peripheral neuropathy

●Autonomic neuropathy

●Skin and mucosal colonization with pathogens such as Staphylococcus aureus and Candida species

Hyperglycemia-related impairment of immune response — Neutrophil chemotaxis and adherence to vascular endothelium, phagocytosis, intracellular bactericidal activity, opsonization, and cell-mediated immunity are all depressed in diabetics with hyperglycemia [20-22]. Investigations to identify the mechanisms of immune impairment have noted the following findings:

●Release of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1-beta from lipopolysaccharide-stimulated macrophages is reduced in diabetic mice compared with control mice [23].

●The level of macrophage inflammatory protein 2, a mediator of lung neutrophil recruitment, is significantly decreased in diabetic compared with control mice [24]. The deficiency causes a delay in neutrophil recruitment in the lungs.

●Hyperglycemia impairs opsonophagocytosis by diverting nicotinamide adenine dinucleotide phosphate from superoxide production into the aldose reductase-dependent polyol pathway [25].

●Diabetic mice with a bacterial infection of the scalp had greater than twofold induction of genes that directly or indirectly induce apoptosis compared with normoglycemic controls [26]. Blocking apoptosis allows for a significant improvement in wound healing and bone growth.

●Methylglyoxal-glycation, which is a major pathway of glycemic damage in diabetics, inhibits production of IL-10 from myeloid cells as well as interferon-gamma and TNF-alpha from T cells; it also reduces major histocompatibility complex class I expression on the surface of myeloid cells [27].

●High glucose concentrations competitively inhibit binding of oligosaccharides by C-type lectin; such binding is necessary for many functions of the immune system [28].

There has been substantial interest in studying the effects of glucose control in critically ill nondiabetic patients. This is discussed in detail separately. (See "Glycemic control and intensive insulin therapy in critical illness".)

Vascular insufficiency — Vascular disease is common in diabetes. When present, vascular insufficiency may result in local tissue ischemia that in turn enhances the growth of microaerophilic and anaerobic organisms while simultaneously depressing the oxygen-dependent bactericidal functions of leukocytes. Vascular disease related to diabetes may also impair the local inflammatory response and the absorption of antibiotics.

Sensory peripheral neuropathy — Minor local trauma in patients with diabetes-associated peripheral neuropathy may result in skin ulcers, which, in turn, lead to diabetic foot infections. Skin lesions in such patients are often either unnoticed or ignored until infection occurs.

Autonomic neuropathy — Patients with diabetes-associated autonomic neuropathy may develop urinary retention and stasis that, in turn, predispose them to develop urinary tract infections.

Increased skin and mucosal colonization — Patients with diabetes, particularly those who inject insulin daily, often have asymptomatic nasal and skin colonization with S. aureus. Furthermore, according to an analysis of data from the National Health and Nutrition Examination Survey (NHANES) collected between 2001 and 2002, diabetic patients who are colonized with S. aureus are more likely to have a methicillin-resistant S. aureus isolate than a susceptible one (odds ratio 2.6, 95% CI 1.1-6.1) [29]. Colonization may predispose to cutaneous or incisional staphylococcal infections as well as transient bacteremia, which may then result in infection at distant sites such as damaged muscle.

Mucosal colonization with Candida albicans is also common. Women with diabetes who have poor glycemic control are more prone to vulvovaginal candidiasis than euglycemic women [30,31]. In particular, women with type 2 diabetes appear prone to non-albicans Candida species [32]. (See "Candida vulvovaginitis: Clinical manifestations and diagnosis", section on 'Risk factors'.)

ORGANISM-SPECIFIC FACTORS — There are several organism-specific factors that predispose diabetics to infection.

Candida albicans — Glucose-inducible proteins promote adhesion of Candida albicans to buccal or vaginal epithelium. This adhesion, in turn, impairs phagocytosis, giving the organism an advantage over the host [22].

Rhizopus species — Ketone reductases allow Rhizopus spp, which cause mucormycosis, to thrive in high glucose, acidic conditions typically present in diabetic patients with ketoacidosis [33]. (See "Mucormycosis (zygomycosis)".)

Burkholderia pseudomallei — Diabetes is strongly associated with the risk of acquiring melioidosis in endemic areas. It is the single most common risk factor in patients who develop this infection. One of multiple reasons for this propensity is the fact that macrophage killing of Burkholderia pseudomallei is impaired in diabetic patients [34]. Drugs such as glyburide are associated with reduced mortality in patients with melioidosis, and glyburide reduces bacterial dissemination of B. pseudomallei in an experimental mouse model [35-37]. (See "Melioidosis: Epidemiology, clinical manifestations, and diagnosis" and "Melioidosis: Treatment and prevention".)

Uropathogenic Escherichia coli — Advanced glycation end products (AGEs) accumulate in diabetics over time. In a mouse model, AGEs enhance the binding of uropathogenic Escherichia coli isolates to the bladder urothelium, possibly increasing the susceptibility of diabetics to lower urinary tract infections with this organism [38].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topic (see "Patient education: Diabetes and infections (The Basics)")

SUMMARY

●It is widely accepted that diabetics have an increased propensity to develop infections. Despite a number of both systemic and local host factors that can contribute to infections, whether diabetics truly are at greater risk for infection and the magnitude of the effect of diabetes on the risk of infection remain active questions. (See 'Introduction' above.)

●Most studies indicate that patients with diabetes mellitus have a higher risk of infection compared with the general population. In particular, an association between diabetes mellitus (particularly with postoperative hyperglycemia) and surgical site infection (SSI) is relatively well established.

●Host-specific factors that are thought to predispose diabetic patients to infection include the following:

•Hyperglycemia-related impairment of the immune response

•Vascular insufficiency

•Sensory peripheral neuropathy

•Autonomic neuropathy

•Skin and mucosal colonization with pathogens such as Staphylococcus aureus and Candida species (see 'Host factors' above)

●Neutrophil chemotaxis and adherence to vascular endothelium, phagocytosis, intracellular bactericidal activity, opsonization, and cell-mediated immunity are all depressed in diabetics with hyperglycemia. (See 'Hyperglycemia-related impairment of immune response' above.)

●Vascular disease is common in diabetes. When present, vascular insufficiency may result in local tissue ischemia that, in turn, enhances the growth of microaerophilic and anaerobic organisms while simultaneously depressing the oxygen-dependent bactericidal functions of leukocytes. Vascular disease related to diabetes may also impair the local inflammatory response and the absorption of antibiotics. (See 'Vascular insufficiency' above.)

●Minor local trauma in patients with diabetes-associated peripheral neuropathy may result in skin ulcers, which, in turn, lead to diabetic foot infections. Skin lesions in such patient are often either unnoticed or ignored until infection occurs. (See 'Sensory peripheral neuropathy' above.)

●Patients with diabetes-associated autonomic neuropathy may develop urinary retention and stasis that, in turn, predispose them to develop urinary tract infections. (See 'Autonomic neuropathy' above.)

●Patients with diabetes, particularly those who inject insulin daily, often have asymptomatic nasal and skin colonization with S. aureus. Furthermore, diabetic patients who are colonized with S. aureus are more likely to have a methicillin-resistant S. aureus isolate than a susceptible one. Colonization may predispose diabetic patients to cutaneous or incisional staphylococcal infections as well as transient bacteremia, which may then result in infection at distant sites such as damaged muscle. (See 'Increased skin and mucosal colonization' above.)

●Women with diabetes who have poor glycemic control are more prone to vulvovaginal candidiasis than euglycemic women. (See 'Increased skin and mucosal colonization' above.)

●There are several organism-specific factors that predispose diabetics to infection:

•Glucose-inducible proteins promote adhesion of Candida albicans to buccal or vaginal epithelium. This adhesion, in turn, impairs phagocytosis, giving the organism an advantage over the host.

•Ketone reductases allow Rhizopus spp, which cause mucormycosis, to thrive in high glucose, acidic conditions typically present in diabetic patients with ketoacidosis. (See 'Organism-specific factors' above.)

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diabetes mellitus
2021/05/04 02:25