review article infections in diabetes: a reviewijdonline.com/issues/4_new.pdf · 2019-12-01 ·...

11Int J Diab. July-December 2019: 11-18

ABSTRACTEpidemiological data indicates that diabetics are more prone to infections due to impaired immune response including defects in neutrophil chemotaxis as well as release of tumor necrosis factor–alpha and IL-1. Skin and mucosal colonization, vasculopathy and neuropathy increase the predisposition. There is increased incidence of common infections including UTI and respiratory infections. Other infections which are more specific in diabetics include malignant necrotozing otitis externa, rhinocerebral mucormycosis, emphysematous cholecystitis and pyelonephritis, diabetic foot infection, necrotizing fasciitis and Fournier’s gangrene. Since delay in diagnosis of these conditions is associated with very high morbidity and mortality, it is essential for endocrinologists to be familiar with the clinical presentation of these infections. It is a team approach for management and involvement of a surgeon and a critical care/infectious diseases specialist is important.Keywords: Infections in diabetes, malignant otitis externa, rhinocerebral mucormycosis, emphysematous cholecystitis, emphysematous pyelonephyritis, diabetic foot, necrotizing fasciitis, Fournier’s gangrene.

INTRODUCTIONDiabetes mellitus increases the susceptibility to develop infections in patients. Epidemiological data confirms that diabetics are more likely to be treated for infective pathologies than non-diabetic patients. There is higher propensity for superficial and systemic fungal infections, foot infections, urinary tract infections, pyomyositis and necrotizing fasciitis, emphysematous cholecystitis, malignant otitis externa. A retrospective cohort study by Carey IM, et al. compared 102,493 primary care diabetic patients with 203,518 control subjects without diabetes. Compared to controls, diabetics had higher rates of all infections, with the highest incidence rate ratio (IRR) seen for bone and joint infections, sepsis and cellulitis. IRRs for infection-related hospitalizations were 3.71 (95% CI, 3.27-4.21) for T1DM and 1.88 (95% CI-1.83-1.92) for T2DM. The authors estimated that 6% of infection-related hospitalizations and 12% of infection-related deaths were attributable to diabetes. Type 1 diabetics were more prone to serious infections compared to type 2 diabetics.1

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Infections in Diabetes: A ReviewMonica MahajanMedical DirectorDepartment of Internal Medicine Max HealthcareMax Multi-speciality Hospitals, Panchsheel Park and Lajpat Nagar, New Delhi, India

Review Article

To cite: Mahajan M. Infections in Diabetes: A Review. Int J Diab 2019;11-18

Received on: 10/10/2019

Accepted on: 17/10/2019

Address for CorrespondenceMonica MahajanMedical Director, Max Multi-speciality Hospitals Panchsheel Park and Lajpat Nagar New Delhi, [email protected]

In a meta-analysis by Boreland L, et al., the effective-ness of tight glycemic control with a continuous insulin infusion during the peri-operative period in cardiac surgery patients reduced the incidence of surgical site infections compared with standard diabetes management2 (odd ratio 0.35, 95% CI, 0.25-0.49, p <0.00001). There are a number of host and organism specific factors predisposing diabetics to infections.

HOST FACTORS PREDISPOSING TO INFECTIONS

Impaired ImmunityUncontrolled blood sugar causes defects in immune response mechanisms including neutrophil chemotaxis

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Monica Mahajan

and adherence to endothelial surface, opsonization, phagocytosis and cell-mediated immunity. There is reduction in release of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1-beta, macrophage inflammatory protein-2, interferon-gamma and MHC class I expression on surface of myeloid cells. Hyperglycemia diverts NADPH from superoxide production into aldose reductase-dependent polyol pathway leading to impairment of opsono-phagocytosis. There is decreased production of growth factors and angiogenic response causing delayed wound healing.

Skin and Mucosal ColonizationDiabetics have increased colonization of skin and mucosal sites by S. aureus and Candida species. Majority of patients are asymptomatic but are more prone to cutaneous and deep seated infections as well as bloodstream infections. Vulvovaginal candidiasis is more frequent in uncontrolled diabetics compared to well controlled diabetic women.

Vasculopathy and Peripheral Vascular DiseaseAtherosclerosis develops early in diabetics. Vascular insufficiency in diabetics results in the following:• Local tissue ischemia resulting in proliferation of

pathogenic organisms• Suppressed leucocyte activity at site of infection• Impaired inflammatory response• Reduced action of antimicrobials at the site of

infection

NeuropathyTraumatic skin lesions lead to deeper and more devastating diabetic foot infections since there is impaired pain perception due to peripheral neuropathy and patient does not realise there is an injury. Autonomic neuropathy related bladder involvement predisposes to UTI. Autonomic neuropathy also causes dryness and fissuring of skin due to loss of sweating.

ORGANISM SPECIFIC FACTORS PREDISPOSING TO INFECTIONSAdvanced glycation end products (AGEs) enhance binding of E. coli to bladder urothelium increasing the chances of a urine infection. Hyperglycemia promotes adhesion of Candida to oral and vaginal mucosa and

interferes with phagocytosis. Mucorales grow well in an acidic, high glucose environment due to presence of an enzyme called ketone reductase. Mucormycosis is more frequent in diabetic ketoacidosis. Melioidosis is an infection caused by Burkholderia pseudomallei. Diabetics have impaired macrophage phagocytic activity making her more prone to melioidosis.

INFECTIONS IN DIABETES MELLITUS (FLOw CHART 1)• Common infections with increased incidence in

diabetes mellitus• Specific infections predominantly in diabetes mellitus

Specific Infections in Diabetics

Malignant (Necrotizing) External OtitisMalignant otitis externa is a necrotizing infection of the external auditory canal and skull base caused by Pseudomonas aeruginosa. Other organisms that have been implicated are S.aureus, Proteus mirabilis, Klebsiella oxytoca, Aspergillus species and Candida species. Majority of the patients are geriatric diabetics. Aural exposure to water contaminated with Pseudomonas may result in the infection. Isolation of Pseudomonas from the external auditory canal is always considered pathological. Patients present with excruciating pain and ear discharge which is unresponsive to topical medication.

Flow chart 1: Classification of infections in diabetes mellitus

Infections in Diabetes: A Review


Physical examination reveals granulation tissue at the Santorini’s fissures (bone-cartilage junction). Disease progression results in osteomyelitis of the skull base and temporo-mandibular joint, cranial nerve palsies, meningitis and dural sinus thrombophlebitis. Diagnosis is based on clinical examination, high ESR/CRP and imaging modalities including CT, MRI or gallium single photon emission computerized tomography (SPECT ) scans. It shows bony erosion and soft tissue involvement. Culture isolates Pseudomonas. Differential diagnosis includes squamous cell carcinoma of the temporal bone. The mainstay of treatment includes semi-synthetic penicillins, carbapenems, cephalosporins and fluoro-quinolone anti-pseudomonal antibiotics. These include piperacillin-tazobactam, ceftazidime, cefepime, ciprofloxacin and levofloxacin. Voriconazole or liposomal amphotericin B are used for fungal malignant otitis externa.3

DIABETIC FOOT INFECTIONS (FIG. 1)The pathogenesis of diabetic foot infections includes multiple risk factors including hyperglycemia, neuropathy and vasculopathy. There is a reduced perception of pain and temperature, foot deformities and soft tissue pressure damage along with impaired sweating resulting in dry fissured skin. Micro-organisms gain easy entry through the unhealthy skin. Diminished blood supply delays wound healing. Hyperglycemia interferes with immune defence mechanisms.

Superficial infections are caused by aerobic gram positive cocci including Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pyogenes and coagulase-negative staphylococci. Deeper infections are polymicrobial and caused by enterococci, Enterobacteriaceae, P.aeruginosa and anaerobes. Anaerobes including Bacteroides species and Clostridium species produce necrosis with gangrene, Methicillin resistant staphylococcus aureus (MRSA) and vancomycin-intermediate S. aureus infect patients with previous hospitalization or prolonged antibiotic use. The risks increasing pseudomonas infection include foot soaking and exposure to water. ESBLs are common in hospitalized catheterized patients. An analysis of records of 447 hospitalized Indian patients with diabetic foot ulcers found that 66% were polymicrobial, 23% were monomicrobial and 11% were sterile. Contrary to western data, gram negative bacteria were more prevalent.4

The infection may be localized to the site of trauma, spread to contiguous structures or bloodstream. All the classical signs of inflammation-erythema, warmth, swelling, tenderness, induration-may or may not be manifest in the presence of severe ischemia or sensory neuropathy. Necrotizing infections are accompanied with formation of bullae, purulent discharge and soft tissue gas. Gangrene and tissue necrosis are ominous signs. Septicemia results in fever, chills and hypotension. Osteomyelitis should be suspected in a non-healing ulcer overlying bony prominences which is not improving despite off-loading and antimicrobials. Features favoring diagnosis of osteomyelitis include:• Grossly visible bone or ability to probe to bone• Ulcer size larger than 2 cm2

• Ulcer duration >1-2 weeks• ESR >70 mm/h5

X-ray features include bone erosion, periosteal reaction, mixed lucency, soft tissue swelling and gas, sclerosis, foreign body and bony deformity. MRI is more sensitive in delineating extent of involvement and bone marrow edema. Examination should include evaluation for neuropathy and vascular insufficiency by NCV and doppler studies respectively before any surgical intervention is planned. Microbial growth on a culture may be a true pathogen or a colonizer. Post-debridement tissue specimen, curettage from ulcer base or aspirate from an abscess bone biopsy should be cultured both aerobically and anaerobically.

Fig. 1: Diabetic foot with secondary infection in a patient with established axonal neuropathy and vascular insufficiency


Monica Mahajan

Wound management includes dressings and off-loading of pressure. Broad spectrum antibiotics may be required for long periods.Vancomycin, linezolid or daptomycin are active against MRSA. Anti-pseudomonal antibiotics include cephalosporins, carbapenems and quinolones. Surgical management includes debridement, resection of callus and nonviable tissue, re-vascularization or amputation. Surgery maybe required for primary closure of wound or correcting the mechanics of the foot. Adjunctive therapies include application of vacuum assisted wound closure (VAC) G-CSF and hyperbaric oxygen. Diabetic foot infections are classified as:• Uninfected-no signs of inflammation• Mild-superficial infection limited to skin and sub-

cutaneous tissue, erythema ≤2 cm around the ulcer• Moderate-deeper or more extensive cellulitis extend-

ing >2 cm and involving the deeper tissues, tendons and muscles, joint or bone

• Severe-infection causing systemic signs or metabolic instability.

Management involves a multi-disciplinary approach to improve prognosis. A good glycemic control and focus on nutrition is imperative. Differential diagnoses include acute Charcot arthropathy, trauma, venous stasis and thrombosis.

EMPHYSEMATOUS CHOLECYSTITISEmphysematous cholecystitis is a surgical emergency with a high mortality rate of 15-25%. This form of acute cholecystitis is caused by gas forming organisms including Clostridium welchii, E. coli and Klebsiella species. Other organisms include Staphylococci, Streptococci and Pseudomonas. Gas maybe present in the wall or lumen of gallbladder or in the biliary ducts. It is associated with high incidence of gangrene and perforation. Other complications include peri-cholecystic abscess and biliary peritonitis. Incidence is higher in elderly, males and 2/3rd of patients are diabetics.6 Majority of the patients have cholelithiasis but the condition may be associated with acalculus cholecystitis too. Histopathology of the specimen may show endarteritis obliterans. Other pathogenesis that have been proposed include vascular compromise of the cystic artery, immune defects, torsion of gallbladder. Patients present with fever, nausea, vomiting and right upper quadrant pain. Abdominal wall crepitus may be rarely elicited but it may aid in diagnosis.

Radiographs demonstrate intramural gas due to gas-forming organisms. Ultrasound may misinterpret air in gallbladder wall as overlying bowel gas. In case a patient has both emphysematous cholecystitis and emphysematous pyelonephritis, suspect hematogenous seeding of bacteria. Antibiotic regimen should include drugs against Clostridium including clindamycin or metronidazole. Laparoscopic cholecystectomy may be attempted but may need to be converted to open cholecystectomy.

EMPHYSEMATOUS URINARY TRACT INFECTIONS (FIG. 2)Urinary infections caused by gas forming organisms may result in cystitis, pyelitis, or pyelonephritis. Majority of cases are caused by E. coli or Klebsiella pneumoniae. The predisposing factors are diabetes and urinary tract obstruction. Most of the infections occur in elderly women. The clinical presentation includes fever, dysuria and frequency/urgency of urine. These feature may be indistinguishable from acute pyelonephritis and the diagnosis is mainly based on imaging of the urinary tract. Pneumaturia may be noted on catheterization. A CT scan maybe diagnostic (Table 1). Emphysematous cystitis is managed with bladder irrigation and parenteral antibiotics.

RHINOCEREBRAL MUCORMYCOSIS36% to 88% of cases of mucormycosis occur in diabetics. It maybe the initial manifestation of diabetic

Fig. 2: Emphysematous pyelonephritis in a 70 years old uncontrolled diabetic patient



Table 1CT scan based classification and management of emphysematous pyelonephritis

Class Involvement Management Class I Gas in the collecting system only/emphysematous

pyelitisAntibiotics alone

Class II Gas in renal parenchyma without extension into extra renal space

Percutaneous catheter drainage, antibiotics and relieve obstruction if present

Class III A Extension of gas to perinephric space between renal capsule and renal fascia

Percutaneous catheter drainage, antibiotics, relieve obstruction and early nephrectomy if war-ranted. Risk factors include thrombocytopenia, acute kidney injury and shock

Class III B Extension of gas to pararenal space, beyond renal fascia

As in Class III A

Class IV Bilateral emphysematous pyelonephritis or solitary kidney with emphysematous pyelonephritis

Bilateral percutaneous catheter drainage and relieve obstruction

ketoacidosis in a previously undiagnosed diabetic. An acidic pH increases the free iron concentration in serum. This promotes the growth of the fungus. Rhizopus grows well in acidic environment rich in glucose due to the presence of an enzyme ketone reductase. Rhino-orbital-cerebral mucormycosis develops due to germination of the inhaled sporangiospores in the paranasal sinuses. There is invasion of the surrounding structures including the orbit, palate and brain. The symptoms include fever, nasal stuffiness, retro-orbital pain, diplopia, headache and altered sensorium. There is presence of a black eschar on the nasal mucosa or palate. The involved tissue looks violaceous-black. There is destruction of facial tissue, ophthalmoplegia, endophthalmitis, cavernous sinus or internal carotid artery thrombosis. It is rapidly fatal if untreated. Imaging studies and nasal endoscopy are diagnostic. Amphotericin B is the drug of choice whereas posaconazole and isavuconazole are used as salvage therapy. Mucorales are resistant to conventional antifungals including fluconazole, flucytosine, voriconazole and echinocandins.

NECROTIZING FASCIITIS (FIGS 3 AND 4)Necrotizing fasciitis or necrotizing erysipelas was first described by Hippocrates in 500 BC. Diabetic patients are more prone to a fulminant necrotizing infection of the deeper soft tissue, subcutaneous fat and muscle fascia. The initial appearance of the overlying skin maybe normal leading to a misdiagnosis. In later stages, the skin gets necrosed.

Fig. 3: Gas and fluid collection under the gluteus maximus in a case of necrotizing fasciitis

Fig. 4: Fungal necrotizing Fasciitis of the entire abdominal wall


Monica Mahajan

The hallmark of necrotizing fasciitis is intense pain and tenderness over the involved skin and underlying muscle mimicking a ruptured muscle. The systemic features like fever, myalgia and malaise develop later. Destruction of subcutaneous nerves may cause anesthesia of the involved area. Physical examination findings include edema beyond the area of erythema, crepitus and skin vesicles. The subcutaneous tissue gives a wooden hardened feel. The gold standard diagnostic criteria is an incisional biopsy of fascia under local anesthesia performed bed side with diathermy. There is a ‘dishwater fluid’ or foul discharge, necrosis and lack of pus. There is no role of culturing skin blisters. Histopathology reveals adipocyte necrosis, and necrosis of vessel walls with very few inflammatory cells.7 Table 2 shows microbial classification of necrotizing fasciitis. Differential diagnoses include cellulitis, myonecrosis, lymphedema, non-infectious/eosinophilic fasciitis, phlegmasia cerulea dolens and myxedema. The treatment requires a coordinated effort between the physician and the surgeon. Early extensive debridement is the cornerstone of management. Antimicrobials include carbapenems, cephalosporins, clindamycin, aminoglycosides, tigecycline and/or antifungals. Some studies have shown a role of hyperbaric oxygen therapy and IVIG.

FOURNIER’S GANGRENE (FIGS 5A AND B)Fournier’s gangrene, named after the French venereologist Alfred Fournier, is a polymicrobial necrotizing fasciitis involving the external genitalia, perineum and perianal areas. The most frequent

Table 2Microbial classification of necrotizing fasciitis

Type Etiology Organism(s) FeaturesType I Polymicrobial/synergistic Mixed anaerobes and aerobes Often derived from bowel flora;

indolent course. More in DM, CKD, Bowel perforation, surgery

Type II Monomicrobial Group A beta-hemolytic Streptococcus(GAS), Staph aureus, Gas gangrene

Skin or throat derived; highly ag-gressive.Nosocomial, athletes, trauma

Type III Gram negative, often marine related organisms

Vibrio species mainly Commoner in Asia, contaminated seafood ingestion or contamination of wound by sea water

Type IV Fungal Candida or Zygomycetes Very aggressive especially in im-munocompromised

underlying risk factors are diabetes, alcoholism and urogenital trauma. Trauma maybe accidental, surgical or intentional following body piercing, instrumentation, foreign body or implants. Diabetes is present in upto 70% of cases. The infection spreads along the anatomical fascial planes but spares the deeper muscles. It is important for the surgeon performing the debridement to be familiar with the various fascial planes including the Camper fascia, Scarpa fascia, Colles fascia and Dartos fascia. Necrotizing fasciitis may spread to involve the abdominal wall and chest wall up to the clavicles. Thrombosis of the deep circumflex iliac arteries and external and internal pudendal arteries causes skin necrosis. Obliterative endarteritis ensues. The urethra, testes and spermatic cord are usually spared due to several fascial layers surrounding them which are separate from the Dartos fascia. Moreover, the testicular arteries arise directly from aorta. Infection may spread at a massive pace of even 2-3 cm per hour.

Predisposing Factors for Fournier’s Gangrene8

• Urethral, penile, scrotal or testicular injury• Instrumentation including catheterization, catheter

removal and chronic indwelling catheters• Penile implants• Post-coital injury• Ischiorectal abscess• Perianal abscess• Carcinoma colon• Hemorrhoidectomy• Insect bite• Vasectomy• Circumcision



Figs 5A and B: (A) Extensive debridement in a case of Fournier’s; (B) Complete reconstruction and temporary diversion colostomy in the same case

The FDA identified 55 unique cases of Fournier’s gangrene in patients receiving SGLT2 inhibitors between 1 March 2013 and 31 January 2019. The patients ranged in age from 33 to 87 years; 39 were men, and 16 were women. Time to onset after initiation of SGLT2-inhibitor therapy ranged from 5 days to 49 months.9

Clinical features include scrotal pain and swelling, blistering, ulceration and foul smelling discharge. Plain films, retrograde urethrograms, ultrasound, CT and MRI aid in diagnosis. This is a life-threatening condition requiring early surgical intervention. Patient may require extensive excision of necrotic tissue, suprapubic cystostomy, urinary or fecal diversion and complex closure procedures. The exposed testes maybe re-implanted in an abdominal pouch. Hyperbaric oxygen therapy may improve outcome. Extensive disease and septicemia are associated with very high mortality.

PREVENTION OF INFECTIONS IN DIABETES10

• Maintenance of good glycemic control• Foot care

• Immunization � Influenza vaccine � Pneumococcal vaccine � Hepatitis B vaccine in unvaccinated individuals � Tetanus and diphtheria vaccine � Zoster vaccine

• While administering antibiotics, consider potential toxicity and impact of gastropathy on oral absorption.

It is important to incorporate management practises to prevent, identify and to treat life-threatening infections while handling diabetic patients. It requires a dedicated team approach. Immunization should be an integral part of patient’s prescription. Prevention is always better than cure.

REFERENCES 1. Carey IM, Critchley JA, DeWilde S, et al. Risk of Infection

in Type 1 and Type 2 Diabetes Compared With the General Population: A Matched Cohort Study. Diabetes Care. 2018;41(3):513-21.

2. Boreland L, Scott-Hudson M, Hetherington K, et al. The effectiveness of tight glycemic control on decreasing surgical site infections and readmission rates in adult patients with diabetes undergoing cardiac surgery: A systematic review. Heart Lung. 2015;44(5):430-40.

BA


Monica Mahajan

3. Carlton DA, Perez EE, Smouha EE. Malignant external otitis: The shifting treatment paradigm. Am J Otolaryngol. 2018; 39(1):41-5.

4. Ramakant P, Verma AK, Misra R, et al. Changing microbiological profile of pathogenic bacteria in diabetic foot infections: time for a rethink on which empirical therapy to choose? Diabetologia. 2011;54(1):58-64.

5. Butalia S, Palda VA, Sargeant RJ, et al. Does this patient with diabetes have osteomyelitis of the lower extremity? JAMA. 2008; 299:806.

6. Garcia-Sancho Tellez L, Rodriguez-Montes JA, Fernandez de Lis S, et al. Acute emphysematous cholecystitis. Report of twenty cases. Hepatogastroenterology. 1999; 46(28):2144-8.

7. Wong CH, Chang HC, Pasupathy S, et al. Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality. J Bone Joint Surg Am. 2003; 85(8):1454-60.

8. Eke N. Fournier’s gangrene: a review of 1726 cases. Br J Surg. 2000; 87(6):718-28.

9. Bersoff-Matcha SJ, Chamberlain C, Cao C, et al. Fournier Gangrene Associated With Sodium-Glucose Co-transporter-2 Inhibitors: A Review of Spontaneous Post-marketing Cases. Ann Intern Med. 2019; 170:764.

10. Joshi N, Mahajan M. Infections and diabetes. In: Pickup JC, Williams G, Publ (Eds). Textbook of Diabetes. Blackwell Publishing. 3rd edition; 2003. pp. 40.1-40.16.

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