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Diabetes Mellitus and Infectious Diseases: Controlling Chronic Hyperglycemia

Introduction

As the incidence of diabetes mellitus continues to rise, common focus areas for diabetes control are blood glucose levels, diet, and exercise. Addressing and controlling these factors as well as other factors associated with diabetes are essential for a better quality of life; however, awareness of an increased risk of infections is also warranted in diabetes patients with chronic hyperglycemia.

The immune system is comprised of two subcategories: innate immunity and adaptive immunity. Innate immunity, the first line of defense, is activated when a pathogen initially presents itself. This portion of immunity is inherited at birth and is not specific in its mechanism of defense. In addition, it serves the overall immune system by alerting specific cells of pathogen invasion to activate the adaptive immune system. The innate immune system has physical and chemical mechanisms of response. These include but are not limited to sneezing, coughing, sweating, maintenance of normal body temperature, and gram-positive normal flora on the skin.

Adaptive immunity is a very specific aspect of a properly functioning immune system that provides protection against previous infections experienced by the host. These responses are mediated by lymphocytes, which consist of natural killer (NK) cells, B cells and T cells. Vaccinations and exposure to pathogens benefit the adaptive immune system by establishing immunologic memory. In the event of another attack by the same foreign organism, the adaptive immune system is able to provide a more efficient response.

Complications of Chronic Hyperglycemia

Patients with uncontrolled diabetes are considered immunosuppressed due to the negative effects of elevated blood sugars on the immune system. Hyperglycemia impairs overall immunity through different mechanisms. Chronic hyperglycemia in diabetes patients can lead to acidosis, which limits the activity of the immune system. The effects of these changes are reversible upon treatment of acidosis and hyperglycemia.

Chronic hyperglycemia slows perfusion through blood vessels, causing nerve damage as time progresses. The skin, one of the key barriers in innate immunity, is no longer competent, yielding protection against trauma and inflammation. Because of impaired nerves in the skin, the host may not notice trauma to the skin until an infection is present. As a result, skin and soft tissue infections are prominent in diabetes patients with chronic hyperglycemia. Along with poor management of blood glucose, cellulitis and diabetic foot ulcers could heal slower than desired and transition to more severe conditions such as osteomyelitis. Such conditions must be treated promptly and correctly with antimicrobial therapy and other appropriate supplements of care (i.e. wound care and debridements). Damaged nerves are not only noted in the skin, but in other areas of the body such as the urinary tract. With damage to the nerves in the urinary tract, urine retention will breed urinary tract infections.

Although the most common infections in diabetes patients involve the skin and urinary tract, more severe infections may arise if blood sugars are not controlled. High glucose levels limit and deregulate neutrophil synthesis, which is essential in the immune system to attack a foreign object. Cytosolic calcium in polymorphonuclear leukocytes (PMNs) increases in the presence of hyperglycemia and is inversely proportional to the occurrence of phagocytosis in patients with type II diabetes. High levels of cytosolic calcium inhibit the synthesis of adenosine triphosphate (ATP), which is essential for phagocytosis. The ability of PMN leukocytes to mobilize to the site of infection and stimulate of apoptosis is negatively impacted as well.

If the pathogen is able to invade the host without the assistance of the innate immune system, an increased risk of infection is expected. Hyperglycemia causes other undesirable changes in the function of the immune system such as decreased complement response, leukocyte adherence and bactericidal activity.

Infections

Bacteria’s ability to thrive in the presence of elevated blood sugars activates the immune response to combat such infections. In addition, a hyperglycemic state negatively affects the body’s ability to respond to antimicrobial therapy. Common bacterial infections include gram negative organisms such as Pseudomonas aeruginosa, Klebsiella pneumonia, and E. coli. Gram-positive organisms, such as Staphylococcus & Streptococcus are common, also. Anaerobic organisms may be present as well due to decreased blood and oxygen perfusion throughout the blood vessels for the synthesis of leukocytes. Other infections include fungal infections such as Candida, and viral infections.

 

Condition
Etiology
Source
Signs & Symptoms
Complications
Antimicrobial Treatment
 
 
Comments
Malignant Otitis Externa
Inflammation and damage at the base of the skull due to an untreated outer ear infection P. aeruginosa – most common organism Yellow-green drainage from the ear

Odor
Fever

Deep inner ear pain

Spread of infection throughout the bodyReoccuring infection

Brain and/or nerve damage

Osteomyelitis of temporal bone

Cipro(Ciprofloxacin)

750 mg every 12 hours, oral route OR 400 mg every 12 hours, intravenous route

Zosyn
(Piperacillin/Tazobactam)

4g to 6 g every 4 to 6 hours, intravenous route

Timentin (Ticarcillin/Clavulanate Potassium)

3 g every 4 hours, intravenous route

Fortaz

(Ceftazidime)

2 g every 12 hours, intravenous route

Maxipime
(Cefepime)

2 g every 12 hours, intravenous route

In severe cases, Primaxin (Imipenem/cilastin) may be used due to its pseudomonal coverage.

In addition, aminoglycosides (i.e. gentamicin) in combination with antimicrobials with pseudomonal converage may be used.

Ciprofloxacin resistant strands of pseudomonas does not increase morbidity or mortality.

Rhinocerebral Mucormycosis
Initially presents itself as an acute sinus infection.Caused by the Inhalation of fungal spores which can move quickly to the brain if not treated promptly. Saprophytic aerobic fungi found in soil and bread mold. Headache, N/V, fever and lethargy

Inflammation

Facial: Weakness, numbness & pain

Nasal:

Pale or gray

Necrotizing (black) areas in face

Pus drainage

Ocular: Fixed pupil

Nystagmus
Blindness

Nerves:

Altered mental status

Dizziness & unsteady gait

Negative effects of the following cranial nerves: II, III, IV, V, VI, & VII

Cerebral edema

Failure of prompt treatment may progress condition to a coma or stroke First-line therapy:

Debridement

Amphotericin B (weight based dose)

Alternative therapy:

Noxafil (Posaconazole)

400 mg twice daily, oral route (suspension)

Nephrotoxicity

(associated with Amphotericin B; consider lipid based formulation)

Achievement of steady state with posaconazole occurs in 1 week; should not be considered as initial therapy.

While providing antifugal treatment, underlying cause of the compromised immune system must be addressed (i.e. hyperglycemia)

Duration of treatment is dependent on patient’s response to therapy.

Emphysematous Cholecystitis
Discovery of gas in gallbladder lumen, wall or surrounding tissuesGallstones = ~50% of all cases Polymicrobial infection: gram positive, gram negative, and anaerobes Right upper quadrant pain not related to physical activity; may radiate

Fever

Absent bowel sounds

Perforated gallbladder

Septic shock

Broad spectrum antibiotics:

Example(s):
Zosyn
Unasyn
Primaxin
Antimicrobial combinations may be used and should possess gram positive, pseudomonal, and anaerobic coverage.

Urinary Tract Infection/ Pyelonephritis
Bacteria in the urinary tract/ Upper urinary tract infection affecting the kidneys

Gram-negative organismsE. Coli,

 P. mirabilis,

P. aeruginosa, etc.

Yeast

In some cases, polymicrobial infection is present

Dysuria

Flank pain

Abdominal discomfort

Toxic fever

Chills

Dry mucous membranes

Tachycardia
Fluoroquinolones

Cipro

(Ciprofloxacin)

500 mg twice daily, oral route

Levaquin (Levofloxacin) 750 mg daily, oral route

If oral route is intolerable, consider the following options of therapy:

Cipro or Levaquin IV

Zosyn

(Piperacillin – tazobactam)

3.375 mg every 6 hours, intravenous route

Primaxin

(Imipenem-Cilastin)

500 mg every 6 hours, intravenous route

Merrem
(Meropenem)

1 g every 8 hours, intravenous route

Ampicilin 1-2 g every 6 hours + Gentamicin 2mg/kg/dose every 8 hours, intravenous route

Longer duration of therapy(7-14 days)

Levaquin = 5 days of therapy

Second line therapy:

Fortaz

(Ceftazidime)

500 mg every 8-12 hours, intravenous route for 10 days

Maxipime

(Cefepime) 2 g every 12 hours, intravenous route for 10 days

Bactrim DS/Septra DS may be considered

Bullous Diabeticorum
Unknown
N/A
Blisters
Development of osteomyelitis

Amputation
N/A
Spontaneous healing in 2- 6 weeks
SSTI
Inflammation or wounds
Gram-positive
MRSA

Polymicrobial infection

Inflammation or wounds that fail to heal properly Development into more severe conditions such as osteomyelitis or necrotizing faciitis MSSA SSTIs:

Nafcillin
Oxacillin
Dicloxacillin
Cefazolin

CA-MRSA SSTIs:

Vancomycin

Zyvox
(Linezolid)

600 mg every 12 hours, intravenous or oral route

Cleocin (Clindamycin)

600 mg/kg every 8 hours, intravenous route OR 300-450 mg three times daily, oral route

Cubicin (Daptomycin)

4 mg/kg every day, intravenous route

Doxycycline

100 mg twice daily, oral route

Bactrim
(TMP-SMZ)

1-2 double strength tablets twice daily, oral route

De-escalate antimicrobial when appropriate.

Vancomycin trough ranges:

10-15 mg/L for minor infections

15-20 mg/L for severe infections

Diabetic Foot Infections
Lack of blood flow due to chronic hyperglycemia, peripheral vascular disease, and neuropathy

Polymicrobial infection

Polymicrobial infection including S. aureus, Streptococci, & P. aeruginosa
Tachycardia
Hypotension
Pain
Fever
Chills

Purulent discharge

Erythema

Osetomyelitis

Necrotizing faciitis

Amputation
Mild:
Dicloxacillin

Keflex

(Cephalexin)

Levaquin (Levofloxacin)

Augmentin

(Amoxicillin/ clavulanate)

Doxycycline

Bactrim DS

(TMP-SMZ)

Moderate- Severe:

Levaquin

(Levofloxacin)

Rocephin (Ceftriaxone)

Unasyn
(Ampicillin-Sulbactam)
Avelox
(Moxifloxacin)
Invanz
(Ertapenem)
Tygacil
(Tygecycline)

Levaquin or Cipro + Clindamycin

Vancomycin
Zosyn
(Piperacillin-tazobactam)
Cubicin
(Daptomycin)
Fortaz
(Ceftazidime)
Maxipime
(Cefepime)
Wound care & debridement play a major role in the healing process of these infections.

De-escalate antimicrobial therapy when appropriate.

Vancomycin trough range:

15-20 mg/L

Osteomyelitis
Untreated infection that has spread to the bone S. aureusGram-negative bacill

Polymicrobial infection

Localized painTenderness in infected area

Swelling, fever

Erythema

Amputation
Sepsis
Augmentin
 875 mg twice daily, oral route
Zosyn

3.375 g every 6 hours, intravenous route

 Unasyn

3 g every 6 hours, intravenous route

 Timentin

3.1 g every 6 hours, intravenous route

Clindamycin600 mg every 6 hours, intravenous route or oral route + Cipro 750 mg oral route OR 400 mg every 12 hours, intravenous route OR Levaquin750 mg daily, oral route + Vancomycin 15mg/kg every 12 hours, intravenous route if MRSA is suspected or confirmed.

Wound care & debridement play a major role in the healing process of these infections.

Treatment should be a minimum of 6 weeks.

Vancomycin trough range:

15-20 mg/L

Necrotizing Faciitis
Lethal infection due to untreated wound Polymicrobial infection including anaerobes Skin necrosis

Blisters

Gas in soft tissue

Spread of necrotic tissue inspite of antibiotics

Amputation
Sepsis
Anti-pseudomonal fluoroquinolone i.e. Cipro

Zosyn

4.5 grams every 6 hours, intravenous route

Clindamycin 600-600 mg every 8 hours, intravenous route

Vancomycin 15-20 mg/kg every 12 hours, intravenous route

Primaxin 1 g every 6-8 hours, intravenous route

Merrem (Meropenem)

1g every 8 hours, intravenous route

Fortaz

2 g every 6 hours, intravenous route + Flagyl 500 mg every 6 hours, intravenous route OR Clindamycin (see dose above)

Aminoglycosides

Wound care & debridement play a major role in the healing process of these infections.

Combination therapy may be used to effectively treat infection.

Vancomycin trough range:

15-20 mg/L

Conclusion

Preventing the development of diabetic complications such as infections, kidney failure, and amputations involves proper glycemic control. Addressing different aspects of diabetes control aid in the reduction of infection susceptibility. Literature suggests maintaining blood glucose levels below 200 mg/dL. Glucose levels above 200 mg/dL are expected to pose an increased risk of infections. To assist in the maintenance of proper perfusion through blood vessels, adherence to standard of care is vital. Standard of care includes maintaining HbA1c < 7%, blood pressure <130/80 mmHg, proper control of cholesterol levels and vaccination use (i.e. annual influenza vaccination). Patients should also have annual foot exams and should inspect their feet daily in between exams. To prevent dryness, patients should ensure that their feet are moisturized. Walking barefoot or wearing uncomfortable shoes is not advised. Women with diabetes have a higher risk of experiencing yeast and urinary tract infections. Therefore, they are encouraged to have annual physicals and report any signs or symptoms of such infections. Proper wiping techniques during restroom use are wiping from front to back to prevent the transmission of bacteria to the vaginal area. Voiding after sexual intercourse is also encouraged. Adherence to the previously mentioned tips allows both the patient and the health care provider to take charge of this disease in the pursuit of improving the patient’s quality of life.

References
  1. Butler, K, and D Joffe, eds. “Complications and Co-morbidities Slides.” Diabetes In Control. Diabetes In Control, 30 2012. Web. 28 Nov 2012. <http://www.diabetesincontrol.com/articles/homerun-slides?series=Mastery-Series>.medscape
  2. Clement, Stephen, Susan Braithwaite, et al. “Management of Diabetes and Hyperglycemia in Hospitals.” Diabetes Care. 27.2 (2004): 553-91. Web. 28 Nov. 2012. <http://care.diabetesjournals.org/content/27/2/553.full.pdf html>.
  3. Hooton, Thomas, Suzanne Bradley, et al. “Oxford Journals: Clinical Infectious Diseases- Urinary Catheter Guidelines.” Oxford Journals: Clinical Infectious Diseases- Urinary Catheter Guidelines. (2010): 625-63. Web. 28 Nov. 2012. <http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/Comp UTI.pdf>.
  4. Khardori R. “Infections in patients with diabetes mellitus.” Medscape reference. WebMD 2011.
  5. Lipsky, Benjamin, Anthony Berendt, et al. “Oxford Journals: Clinical Infectious Diseases – IDSA Guideline for Diabetic Foot Infections.” Oxford Journals: Clinical Infectious Diseases – IDSA Guideline for Diabetic Foot Infections. (2012): 132-73. Web. 28 Nov. 2012. <http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/2012 Diabetic Foot Infections Guideline.pdf>.
  6. Stevens, Dennis, Alan Bisno, et al. “Oxford Journals: Clinical Infectious Diseases – Guidelines for Skin and Soft-Tissue Infections.” Oxford Journals: Clinical Infectious Diseases – Guidelines for Skin and Soft-Tissue Infections. (2005): 1373-1406. Web. 28 Nov. 2012. <http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/Skin and Soft Tissue.pdf>.

— Kristin Robinson, PharmD Candidate FAMU College of Pharmacy