Download CLINICAL ASPECTS OF FUNGAL INFECTIONS IN DIABETES

Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 70 No. 4 pp. 587ñ596, 2013
ISSN 0001-6837
Polish Pharmaceutical Society
REVIEW
CLINICAL ASPECTS OF FUNGAL INFECTIONS IN DIABETES
ANNA PORADZKA1, MARIUSZ JASIK2*, WALDEMAR KARNAFEL2 and PIOTR FIEDOR3
Student Scientific Organisation APEX of Department of General and Transplantation Surgery,
Medical University of Warsaw, Nowogrodzka 59, 02-006 Warszawa, Poland
2
Department of Gastroenterology and Metabolic Diseases, Medical University of Warsaw,
Banacha 1a, 02-097 Warszawa, Poland
3
Department of General and Transplantation Surgery, Transplantation Institute,
Medical University of Warsaw, Nowogrodzka 59, 02-006 Warszawa, Poland
1
Abstract: Diabetes mellitus is one of the main risk factors of fungal infections of oral cavity, lower part of gastrointestinal tract, skin, foot, urogenital system and blood. Mycosis is a serious diagnostic and therapeutic problem and cause of mortality in diabetes. Fungal infections are also an important problem among hemodialysis
patients with diabetes or diabetic patients after pancreas or kidney transplantation This work briefly describes
the etiology, symptoms, diagnosis and ways of prophylaxis and treatment of mycosis in diabetic population.
There is also emphasized the great connection between effective treatment of mycosis and glycemic control.
Keywords: diabetes, fungal infections, antifungal treatment
centration of glucose in blood and saliva which can
be treated as a nutrients for fungi (4). The significant
role plays promoting an exaggerated inflammatory
response to the periodontal microflora (5). There is
also a relationship between the presence of removable prostheses or cigarette smoking and higher rate
of fungal infections by diabetics (6).
Oral candidiasis include, excepting pseudomembranous candidiasis, also: median rhomboid
glossitis, athrophic glossitis, denture stomatitis and
angular cheilitis (7).
The diagnosis includes examination of the
mouth followed by culturing a swab from the affected area (labial and buccal mucosa, hard and soft
palate, tongue periodontal tissues or oropharynx)
and sensitivity testing (1, 8).
On the surface of oral cavity occur white
patches. The tongue might be bright red. Other
symptom can be burning sensation in the mouth or
dysphagia (1). Usually, the disease can be also
asymptomatic (9).
Untreated candidiasis can lead to serious, even
fatal, complications or cause chronic hyperplastic
candidiasis, known as candidal leukoplakia (1, 10).
It is also worth mentioning that periodontal
infections can adversely affect glycemic control,
Diabetes mellitus is a major risk factor for
mycotic infections. The fungal infections are difficult diagnostic and therapeutic problems, serious
cause of morbidity or mortality in diabetes. The particularly difficult problem makes up mycosis among
hemodialysis patients with diabetes and in posttransplant diabetes after kidney transplantation.
Also, the main risk factor for fungal infections is
diabetes with a pre-existing kidney graft in pancreas
transplant recipients. Early diagnosis and effective
treatment plays an important role in proceeding to
the therapy of mycotic infections.
Diagnostic and therapeutic problems of mycosis
in diabetes
Oral cavity
Diabetes mellitus is a predisposing factor of
oral candidiasis (opportunistic infection caused by
overgrowth of commensal of the mouth - Candida
species e.g., the most prevalent Candida albicans),
especially of pseudomembranous candidiasis (1, 2).
Also non-albicans species (Pichia, Trichosporon,
Geotichum) can be identified in the oral cavity of
patient with poorly controlled diabetes, being prone
to frequent and severe fungal infections (3, 4). The
poor glycemic control is associated with a high con-
* Corresponding author: e-mail: [email protected]
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increasing serum glucose level, in people with diabetes (8).
The incidence of infections can be reduced by
appropriate prophylaxis. Very important is patient
education, avoiding tobacco use, proper glycemic
control and oral hygiene (11). Significant is rinsing
the mouth with the topical antifungal, coating the
whole mucosa with the medicine and holding in the
mouth for a few minutes, after removing the dentures (1). The patient should soak the denture in
0.1% hypochlorite solution or chlorhexidine solution to eliminate the fungi. White vinegar (diluted 1
: 20) can be used twice a week instead of it (12, 13).
The first line treatment is topical antifungal therapy
ñ polyene antibiotics: nystatin and amphotericin,
eventually imidazoles. Topical therapy is advised
also to patients with need of systemic treatment
(intolerance or resistance to local application),
because of possibility of reducing dose and duration
of systemic preparations, to achieve reduction of
adverse effects and drug interactions. Nystatin and
amphotericin are not absorbed from the gastrointestinal tract (1).
Modern medicaments ñ polyene antibiotics
alert cell membrane permeability and azoles are
inhibitors of fungal synthesizing enzymes of ergosterol (1). Recommended drugs include: nystatin,
amphotericin and miconazole. First line treatment in
patients without dentures is amphotericin alone
(lozenges 10 mg or suspension 100 mg/mL, four
times a day after meals), or if patient is wearing dentures ñ amphotericin with nystatin (available as
ointment (100,000 U/g, oral suspension 100,000
units/mL or pastilles (100,000 IU)) or miconazoles
(oral gel 20 mg/mL, after meals). The managing
takes three weeks. If the therapy is ineffective, the
medications should be replaced. The lozanges of
amphotericin are contraindicated in diabetics
because of high sugar content. For that reason also
nystatin oral rinse and clotrimazole troches should
be avoided by diabetes. As alternative, fluonazole
(100 mg/day) and itraconazole (200 mg/day) can be
prescribed (1, 12-14). In diabetic patients the modifications to insulin doses are needed for a period of
oral infection to avoid infection related hyperglycemia (7). The side effects of nystatin and imidazole are: nausea, vomiting, and diarrhoea. The alternative in these cases can be clotrimazole and ketoconazole, which are applied in local form.
Nowadays, the most important problem is raising
drug resistance. Sensitivity test results can help in
choice of the most effective treatment, however, the
mostly common reason of poor response to the
antibiotic is non-compliance (1, 3, 7, 12).
Lower part of gastrointestinal tract
The intestinal tract is an important reservoir for
many nosocominal organisms e.g., Candida species
(15). At the present time, only few studies show evidence that diabetes mellitus is a risk factor for intestinal Candida colonization (9, 16). It has been
demonstrated that the frequent of colonization by
moulds and yeast-like fungi in the intestine of children with diabetes mellitus is higher than in healthy
children. There was a relationship between rate of
colonization and HbA1c level. Other studies showed
the presence of Candida albicans strains in diabeticís stool (9).
Skin and its appendages
Diabetes mellitus is strongly associated with
the development of fungal infections and dermatoses connected with skin manifestations. Two
third of diabetic subjects have increased frequency
of infections caused by Candida or dermatophytes
(tinea pedis and onychomycosis) during the course
of the disease process (17-20). Dermatologic problems occur more often in patients with type 2 diabetes mellitus, by whom infectious involvement of
the skin is more often (autoimmune skin lesions are
more common in type 1 diabetes) (21). The most
frequent fungal diseases are: tinea pedis (interdigitalis), onychomycosis, candidal intertrigo and candidal vaginitis (22, 23).
Skin colonization and the development of several skin manifestations in patients with poor
glycemic control and elevated glycosylated hemoglobin, who have abnormal carbohydrate metabolism, relative insulin availability, neuron degeneration, deranged collagen production, microvascular
complications and impaired wound healing, seems to
be related to a multitude of skin disorders (17-19, 21,
22). In addition, the prevalence of cutaneous disease
have relation to number of risk factors including age,
male gender, family history of onychomycosis and
intake of immunosuppressive agents (17, 20).
Candida infections can be first presenting sign
of undiagnosed diabetes mellitus (6, 17). Fungal
infections in diabetes can provide a portal of entry
into the circulation for bacterial pathogens (17).
All infections should be mycologically proven
(19).
By Candida spp. the medication of choice are
topical antifungal creams with nystatin, clotrimazole
or econazole. If topical treatment is ineffective, oral
management with fluconazole is the second line treatment (17). Very important is predicting microvascular complications. and the tight control of blood glucose (19, 21). Traditional antibiotic - griseofulvin
Clinical aspects of fungal infections in diabetes
activity is limited to dermatophytes and is ineffective.
The newer management strategy includes: itraconazole, terbinafine and fluconazole. Ketoconazole is
used only in local form, because of hepatotoxicity
effect. Itraconasole is administering at a dose of 200
mg/d for three months or as pulse therapy with 400
mg/d in two daily doses of 200 mg for one week per
month for three or four months (20, 24-26).
The regiment of drugs depends on culture identification, affected part of body, seriousness of
infection, earlier management and immune situation
of the patient (24). Routinely, azoles, terbinafine are
prescribed. Terbinafine (inhibitor of fungal squalene
epoxidase) cream and sertaconazole cream is the
recommended first line treatment for superficial skin
infections. Onychomycosis is an indication for systemic antimycotics (for example terbinafine 250
mg/d for 2-12 weeks). The systemic treatment is
connected with adverse effects: nausea, abdominal
pain, vomiting, diarrhea, dizziness, rash and pruritus
(24, 25). In patients with mucormycosis, amphotericin B with debridement is used (21).
Patients with diabetes are at increased risk of
mycological infection known as toenail onychomycosis. Gender, age and severe nail changes play role
in the infections development (17, 27).
Onychodystrophy of several finger nails is a dermatophyte infection caused by three classes of
fungi: dermatophytes (Trichophyton sp. e.g., T. gallinae (zoophilic dermatophyte) (28, 29), Fusarium
solani (16)), yeast (e.g., Candida albicans) or nondermatophyte molds (30).
Dystrophic nails look thick, brittle and discolored, often with a yellow shade. The nail plate may
be separated from the nail bed (onycholysis).
Characteristic is paronychial inflammation of the
nail edge surrounding skin. The most severe clinical
manifestation of the disease is total dystrophic onychomycosis. Nails can be very painful and make
walking difficult (30).
Culture test of samples collected from the nail
plate or subungual debris, KOH-prepared direct
microscopy and histopathological examination can
verify clinical suspicion of the mycological infection (28, 30-32).
Untreated fusarial onychomycosis leads to
serious consequences (33). Vascular insufficiency,
impaired wound healing, and compromised
immunologic state predispose to secondary fungal
and bacterial infections (paronychia, cellulitis) (29).
Diabetic patients with peripheral neuropathy and
sharp edged nails are more likely to cause abrasion
injuries, what affect in decreased quality of life and
is a risk factor for other foot disorders and limb
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amputation (17, 29, 30). Erosion of the nail bed and
hyponychium can progress osteomyelitis of underlying bone (30).
For diabetic patients possible managing
options are: topical therapy, systemic therapy, combination therapy, and nail removal. Well tolerated
and effective are oral antifungal agents: itraconazole
and terbinafine in treating onychomycosis caused by
dermatophytes and traconazole by molds infections.
The systemic treating can cause side effects and
drug interactions, especially in diabetic patients.
Griseofungin (500-1000 mg daily) has a lot of disadvantages: narrow spectrum, poor efficacy, inconsistent bioavailability and significant adverse
effects. The newer drug are: itraconazole (200 mg
twice daily for 1 week each month, duration: 12
weeks) and terbinafine (250 mg, duration: 12
weeks). They can be used in continuous or pulse
therapy. The possible adverse effects are: gastrointestinal disturbances, dizziness, skin rash, pruritis,
and headache. The agents may cause drug interactions (they are competitive inhibitors of the
cytochrome P-450 3A4 isozyme).(17, 29-31, 34)
According to some authors fluconazole (150-300
mg weekly, duration: 6-18 months) can be effective
in therapy of onychomycosis caused by dermatophytes and molds (17, 29-31).
In case, when oral medications are contraindicated, the topical therapy (ciclopirox 8% solution) is
available, well tolerated and effective treatment
option, with a good penetration of the nail matrix.
The adverse event is mild erythema. The medicine
should be applicated once daily for up to 6 months
(17, 29-31, 34).
Diabetic foot
Fungal foot infection (FFI) is diabetic dermopathy which includes the most frequent mycological infections in the form of both tinea pedis
(skin infection) and onychomycosis (nail infection)
(35, 36). FFI occurs in one-thirds of patients (37)
and increases the risk of developing diabetic foot
syndrome - a major reason of disability and mortality in diabetic subjects, particularly men (29, 34, 35,
38). The most common pathogens are: yeast and
dermatophytes and the most frequent dermatophyte
is Trichophyton rubrum (39, 40).
Food disorders (non healing ulcers and other
lesions) appears to be secondary to multiple factors,
including diabetes-inducted impairments in circulation and peripheral neuropathy, retinopathy, obesity
and duration of diabetes. This situation, together
with poor nail grooming, serve as an entry portal for
infectious organisms (29, 34, 37, 39, 40).
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Sharp, infected nails can injure or even pierce
the skin. Fissures in the plantar or interdigital skin
can become an entry side for bacteria, especially cellulitis infection (39, 41). Diabetics with FFI demonstrate decreases of bodily pain, impairment of mental
health, self-esteem and social functioning, enhancing
patients quality of life and often leading to social isolation (34, 38). Sometimes, it can be difficult to note
and recognize foot disorders because of decrease of
sensation what can result in deep infection. The
potential implication is a higher rate of gangrene,
diabetic ulcers and an increased incidence of lower
extremity amputation (35, 39, 41, 42).
Clinical symptoms of onychomycosis include
onycholysis, hyperkeratosis, brittleness, paronychial
inflammation, and color change (29).
The diagnosis should be confirmed by fungal
culturing, direct microscopy or histopathologic
examination (29, 34, 38).
Regression and recurrence of illness is characterized for treatment of fungal infections. To
improve the efficacy of management there is a need
of appropriate antifungal therapy containing the use
of oral antifungal agents, topical therapy and
mechanical intervention. Grizeofulvin is connected
with number of adverse effects and modest efficacy.
More effective and safe are itraconazole, terbinafine
and fluconazole (29, 34, 36, 38). Preferred and
effective is topical therapy (ciclopirox) characterized by lower potential for adverse effects and drug
interactions but also by poor penetration and minimal efficacy. But in the cases, when lunula is
already affected, the topical therapy is not sufficient
and systemic agents must be prescribed. The therapy can be improved by using a combination of topical and systemic agents (29, 36, 37). The significant
role plays also prevention through inspection,
hygiene, appropriate foot wear, skin care with
creams or lotions containing 10% urea (39).
Urogenital system
Candida microorganisms are responsible for
vulvovaginal candidosis (VVC) (even 25% of vulvovaginal infections). Predominant yeast are
Candida albicans, Candida glabrata and Candida
tropicalis (43, 44). The incidence of infection affects
70-75% of women. The prevalence is higher in the
sexually active, young women.(44-46) Women with
uncontrolled, severe type 2 diabetes are more prone
to be infected.(45, 47-49) Antibiotic use, hyperglycemia, diabetes type and HbA1c level are recognized as a cause of VVC (48, 50, 51).
Women carry candida organisms in the vagina
without symptoms or signs of vaginitis, because of
balance between pathological effects and vaginal
defense factors (45, 52). To the source of infection
belongs: intestinal reservoir, sexual transmission
and vaginal relapse (persisting) (45).
Identification of the type of infection and classification of its degree of severity can assist in the
selection of appropriate therapy. Microscopic examination of vaginal secretion and culturing confirm
the diagnosis. There is a possibility of use of PCR
detection test. In women and adolescent girls with
recurrent VVC is a glucose tolerance test recommended (45, 53, 54).
VVC can be asymptomatic or can clinically
manifest with: acute pruritus, cottage-cheese-like
vaginal discharge, vaginal soreness, irritation, vulvar
burning, dyspareunia, external dysuria, slight odor,
erythema and swelling of the labia and vulva (45).
There is the need for effective antifungal treatment with topical azoles or oral ones e.g., itraconazole, miconazole, elotrimazole, butoconazole or fluconazole (44, 45, 53). Oral drugs are more frequently associated with systemic toxicity and drug interactions (55). The response to single dose of fluconazole is reduced by diabetics (53). Important is also
restricting dietary intake of sugar (45). In otherwise
healthy women, treatment with an antifungal in not
advised (45, 48).
Itraconazole has good efficacy and safety with
C. albicans and other Candida species. Acute vulvovaginitis can be treated by using itraconazole (capsules 400 mg, single-dose: 200 mg in the morning
and 200 mg in the evening) (44). In the case of limited response, the managing should be prolonged to
5-7 days. The common side effect is burning sensation (45).
In recurrent vulvovaginal candidosis the induction course of azole (ketoconazole 100 mg daily,
clotrimazole 500 mg in suppositories, fluconazole
150 mg daily) is continued to the time, when patient
is asymptomatic and culture negative. It can take 714 days. The self-diagnosis and the early initiation
of empiric topical therapy (500 mg clotrimazole
intravaginaly). Beside of side effects (gastrointestinal, hepatotoxicity of ketoconazole), the drug interaction with hypoglycemic agents can be essential in
diabetic population (45, 55).
Only 33% of diabetic women with vulvovaginitis candidiasis achieve the success in treating
with fluconazole (single dose 150 mg). It is associated with high prevalence of C. glabrata in diabetic
population (43, 45, 56). Relatively good efficacy
follows boric acid (vaginal suppositories, 600 mg
daily, duration: 7-14 days). It is well-tolerated.
Possible adverse events are: burning sensation and
Clinical aspects of fungal infections in diabetes
vestibular erythema. The action way of boracid is
unknown, but presumably it destroys the cell wall of
fungi (43, 46, 49). If there is no response to boric
acid, the use of 17% flucytosine or flucytosine with
amphotericin B (topical intervaginal cream, duration: 2 weeks) is successful. But the treatment
should be not too long because of possibility of
resistance. Intravaginal use of flucytosine donít
show side effects in comparison with oral or parenteral form (gastrointestinal and bone marrow toxicity) (43, 45).
Rosenstock et al. reported that diabetic patients
achieve better glycemic control with low rate of
hypoglycemia, after adding canagliflozin (inhibitor
of subtype 2 sodium-glucose transport protein,
which increases urinary glucose excretion) to metformin therapy. The disadvantage of canagliflozin is
higher rate of genital infections (57). The treatment
cause the higher incidence of vulvovaginal adverse
events in diabetic females (58). The other study
showed that there is no influence on urinary tract
infections (59).
Specific fungal infections
Mucormycosis, considering to be the most
invasive fungal infection, shows increased number
of saprophytic members of the Mucorales. There is
significant link between initiated airborne infection
of upper and lower respiratory tract and the clinical
development of sinusitis, rhinocerebral mucormycosis, pulmonary infection or even liver and brain
mucormycosis. Its incidence is closely correlated to
diabetic ketoacidosis, neutropenia, protein-calorie
malnutrition, and iron overload (60-62). The disease
can be fatal (61).
Clinical manifestations include: facial pain or
headache and fever. In orbital form orbital cellulosis, extraocular muscle paresis, periorbital edema,
proptosis, chemosis and blindness are commonly
found and in cerebral form the common signs are:
formation of abscesses and necrosis of the frontal
lobes. Black, nectotic eschar can be found on the
palate or in the nasal mucosa (21, 60). Facial numbness is frequent and results from infarctions of sensory nerves such as branches of the fifth cranial
nerve (21).
The diagnosis contain: culturing, histological
examination and MRI (60, 61).
Mucormycosis should be treated aggressively
by surgical debridement (often repeated every day)
combined with administration of intravenous amphotericin B (1 mg/kg daily, 1.5 mg/kg daily by incidence of aggressive infection and 0.8-1 mg/kg daily
after stabilization of health state). The common
591
adverse event is nephrotoxicity. In resistant patients
and in cases of nephrotoxicity amphotericin B lipid
complex (3 mg/kg daily) should be prescribed.
Efficiency of azoles (itraconazole, fluconazole) is
not documented. The protocols with additional regiment of rifampicin or tetracycline arenít recommended because of lack of study. Diabetic ketoacidosis should by immediately corrected (60, 61).
Diabetic individuals are more likely to be
infected with angio-invasive, saprophyte, opportunistic fungal zygomatoses. By diabetics the
rhinocerebral form is especially of high prevalence.
The lung and cutaneous involvement are less frequent.(63, 64) The incidence of mucormycosis is
decreasing (65).
Predisposing factors include: phagocytic dysfunction due to neutrophenia, ketoacidosis, neutrophil dysfunction during diabetes and low serum
pH, which reduce the activity of inflammatory
response against Rhizopus (63).
The episode of sinusitis not responding to
short-term antibacterial therapy should be considered as a zygomatosis. Characteristic for infected
tissues is necrosis (63). If the disease concerns
lungs, characteristic are: acute pneumonia, fever,
cough and pleuric pain (64).
Pathological examination and culturing should
be performed to obtain appropriate diagnosis (63, 64).
The mortality of diabetic patients with
zygomycosis is 44%. Aggressive surgical treatment
can decrease death rate. Management strategies
includes high-dose amphotericin B (5-6 mg/kg
daily) or posaconasole. Posaconasole has low efficiency, high risk of drug interactions and must be
given peroral. These are the reasons, why it shouldnít be prescribed as first-line therapy. New antifungal drugs are not active against zygomatosis. There
is also need to control glycemia and acidosis (63).
Statins show the activity against a range of
Zygomycetes molds (65).
Coccidiodomycosis is a fungal infection
caused by Coccidioides species. The relation of
coccidioidomycosis and glycemia is significant,
and thatís why this infection affects patients with
diabetes mellitus. The measurement of serum glucose in persons with coccidioidomycosis is recommended to identify patients with increased risk of
severe, complicated infection. The symptoms of
infection disappear spontaneously without medical
treatment (66).
Futhermore, high-risk diabetic patients are
considered to represent predisposing factors, such as
suppression of neutrophil activity, for aspergillosis:
cerebral, sino-orbital and pulmonary (67-70).
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ANNA PORADZKA et al.
Fungemia
The occurrence of the invasive candidiasis like
candidemia, representing high mortality rate and the
need of long treatment, has been increasing recently
(71, 72). It is a common medical condition in
patients with immunosuppressive therapy for organ
transplantation, chemotherapy for malignancy or
after surgery treatment. Candidemia incidence is
statistically correlated with hyperglycemia. Severe
hyperglycemia is considered as important risk factor
of serious consequences: increased morbidity, worst
clinical course, longer hospital stay, late complications and mortality (71, 73-77). This invasive mucosis is due to opportunistic fungal pathogens: yeasts
(e.g., Candida albicans), molds (e.g., Aspergillus
fumigates) and a broad list of other fungi. In diabetic population non-albicans Candida is prominent
cause of candidemia. Up to 30% of all patients with
candidemia are diabetic individuals (78, 79).
Proliferation of fungi in deep tissues and
organs is associated with disruption of this barrier
due to peripheral vascular disease, neuropathy,
insulin injections, surgery, or insertion of intravascular catheter (78).
Diagnosis depends upon clinical suspicion,
isolating and identification of the infecting
pathogens by culturing and histopathology (72, 74).
For patients from high risk groups prophylactic
antifungal therapy and strict glycemia control are
extremely important (78). Recommended, first-line
treatment is administration of amphotericin B.
Undergoing surgical debridement and eradicating
therapy with alternative antifungal agents is preferred in case of nonsusceptible to standard azole or
polyene therapy (72).
C. glabrata infections demonstrate a high rate
of fluconazole resistance. In such cases, the results
can be greatly improved by using of amphotericin B
or flucytosine. The most proper management for
opportunistic yeast-like fungi (e.g., Trichosporon
spp.) is amphotericin B, fluconazole or both of
them. In infections caused by Geotrichum or
Rhodotorula, amphotericin B, flucytosine or fluconazole are mainly used (72, 74).
The recent study have shown the benefit from
anidulafungin treatment of candidemia or invasive
candidiosis in critically ill patients with fluconazole
resistance (200 mg on the first day and than 100 mg
daily, duration: 10-42 days, intravenous) (80).
Mycosis among hemodialysis patients with diabetes
Hemodialysis patients and diabetics are both at
increased risk of developing onychomycosis. Dialysis
duration and presence of diabetes mellitus are independent predisposing factors. The uremic patients
with hemodialysis suffer more often from dystrophic
nail changes and onychomycosis. Nail diseases in this
disease affect 71.4% of patients. The most frequent
occurring change is half and half nails. Absence of
lunula is also common. Secondary to hypochromic
anemia or chronic renal failure brittle nails are
observed. The prevalence of it is also increased
among immunocompromised patients like diabetics
(81, 82). Patients with continuous ambulatory peritoneal dialysis with previous bacterial peritonitis and
antibiotic management demonstrate an increased
propensity to develop fungal peritonitis (83).
There is a pressing need to take care of
hemodialysis, diabetic patients nails and foot.
Hemodialysis diabetics should be especially carefully examined for onychomycosis, because of dangerous, serious implications such as erysipelas or
amputation (81).
Post-transplant diabetes after kidney transplantation
Systemic infectious diseases are the important
cause of morbidity and mortality in renal transplant
recipients. Systemic fungal infections occurs in 114% after kidney transplantation and the incidence
of invasive fungal infections is informed even to
1.5%. Recipients are especially prone to Candida
spp. (fungemia, catheter and urinary tract),
Aspergillus spp. (lungs and central nervous system),
Cryptococcus neoformans (lungs and central nervous system) and Zygomatosis infections as a consequence of immunosuppressive therapy. Patients
with anti-rejection therapy or/and diabetes mellitus
are showing an increased propensity to develop fungal infection (84-88). Also skin infections (e.g., candidal infections, dermatomycoses, onychomycoses)
take place more frequently by renal transplant recipients, especially prone were diabetics (89). Early
diagnosis combined with appropriate therapy may
prevent local spread and potential systemic dissemination (84, 87, 90).
New onset diabetes after transplantation
(NODAT), called also post-transplant diabetes mellitus (PTDM) has a high incidence after kidney
transplantation. Risk factors of PTDM are immunosuppression scheme (high doses of tacrolimus and
corticosteroid), age, ethnicity, overweight, obesity,
hepatitis C infection and cytomegalovirus infection.
The prevalence of this complication after solid
organ transplant is evaluated from 2 to 53%, and
after kidney transplantation 4-25%. PDTA is an
independent predictor associated with serious com-
Clinical aspects of fungal infections in diabetes
plications like infections, cardiovascular disease,
chronic transplant dysfunction and worst graft survival (91-94).
Diagnostic procedures include conventional
fungal laboratory diagnosis, enzymatic activity
tests, serologic tests, molecular diagnosis of samples
from recipients who are highly predisposed to
mycotic infections (84, 95).
The prophylaxis of fungal infections in renal
transplant recipients isnít recommended. The widely used fluconazole prophylaxis is associated with
negative selection of resistant strains. The empirical
treatment should be administer in the event of invasive fungal infection clinical suspicion. The drugs of
choice are: amphotericin B, lisosomal amphotericin
B, itraconazole, voriconazole, posaconazole or
caspofungin. After the results of microbiologic
examination are known, the choice of proper management should be arranged individually and
depends on sensitivity examination, minimal
inhibitory concentration and clinical state of the
patient. The high rate of drug resistance is observed,
especially to azole agents (fluconazole). The use of
echinocandins can be considered (84, 85).
Pancreas transplant recipients
Patients after solid organ transplantation,
including simultaneous pancreas-kidney transplantation (SPKT) which improves long-term survival of
insulin-dependent diabetes mellitus, are predisposed
to develop fungal infection. The most frequent
pathogens responsible for colonization and infection
are: Candida and Cryptococcus neoformans. That is
one of most frequent causes of prolonged hospitalization, higher morbidity and mortality rate. To minimize the risk of this important complication, fluconazole (C. albicans), voriconazole (non-albicans
species), flucitozine or amphotericin B (e.g.,
mucormycosis) can be used. The removal of the
transplanted organ may be necessary if antimycotic
treatment is unsuccessful (96-99). The use of
amphotericin B causes adverse events (renal and
bone marrow toxicity), which could be reduced with
antihistamine and anti-inflammatory prophylaxis.
Saline administration or use of lipid form of amphotericin B can reduce renal toxicity. Using of amphotericin B combined with cyclosporine can lead to
acute renal failure. The interaction with the P450
enzyme system must be considered by fluconazole
(100, 101).
Morbidity and mortality in pancreas transplant
recipients remain high mainly owing of infection,
especially fungal one with 6-38% rate. Causes connected with fungal transmission are undetectable or
593
link to the donor organ or bloodstream, but donorrelated transmission occurs infrequently. Most of
infections occur up to six months after surgery.
Bladder drainage, accumulation of pancreatic fluid
in the peritoneal cavity, vascular graft thrombosis,
preoperative peritoneal dialysis, pancreatitis after
reperfusion, retransplantation, preexisting renal
graft and use of immunossuppresion, type and duration of diabetes mellitus are factors which predispose transplant patients to developing fungal diseases. The most frequent are: predominating
Candida (risk rate > 45%), Aspergillus and
Coccoidoidomycosis or more rare Mucormycosis.
The typical infection are: superficial, deep wound,
intraabdominal or urinary tract infection, peritonitis
or fungemia. This complications impact significantly risk of graft loss (the function continued in only
22%, graft pancreatectomy takes place in > 78% and
mortality rate is 20%) (99-108).
The proper diagnostic tools are: culture and
serology examination, antigen detection, nucleic acid
detection, antibody detection, histopathology and
radiology (100). Transplant donors control would
reduce the risk of infection transmission (109).
To eradicate fungi and increase graft survival
amphotericin B and azoles (fluconazole = 4 weeks)
are recommended (95, 102, 104). In high risk groups
prophylaxis with fluconazole should be considered.
It has been reported to be effective and well tolerated. The difficulties due to nonalbicans Candida
species, which can be fluconazole resistant, are possible. In this cases other azoles, lipid form of
amphotericin B or echinocandins should be prescribed (102, 107, 110)..
CONCLUSION
Particular attention must be given to patients
with diabetes mellitus because of high incidence of
fungal infections in this population. Also the diabetic patients during hemodialysis and after pancreas or
kidney transplantation are more prone to fungal
infections. The prevalence of mycosis in diabetics is
a serious mortality cause. The problem may be minimalized by proper use of prophylaxis and regular
communication with patient. The restricted sensitivity to popular agents, e.g., fluconazole, should be
always considered. To avoid treatment-resistance
every case of mycosis must be precisely diagnosed.
The acquaintance with fungi strain, its drug sensitivity and minimal inhibitory concentration can
allow to arrange the best agent, dose and length of
management and greatly improve the success in
treatment.
594
ANNA PORADZKA et al.
Statement
The authors declare that there in no conflict of
interest.
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Received: 04. 09. 2012