Invasive Candidiasis Deep Tissue Infection: Case

Report and Literature Review

Introduction

Invasive fungal diseases are important causes of morbidity and mortality. Candida spp. are
opportunistic pathogens of the endogenous flora, which may cause (serious) infections or ‘candidiasis’ (also
called candidosis). ‘Superficial’ candidiasis (e.g. vaginal and oropharyngeal candidiasis) is considered the
most prevalent fungal infection, although it does not compromise survival. Nevertheless, Candida spp. may
also cause life-threatening infections, the so-called ‘invasive candidiasis’, by invading the bloodstream
(candidemia) and/or deep-seated organs. Despite its severity, little is known about deep-seated candidiasis,
although its occurrence is closely related to that of candidemia. The host factor is paramount in the
development of both candidemia and deep-seated candidiasis, since it mainly occurs in highly debilitated
patients.1 As a result of the wide disease spectrum related to Candida infection in humans, invasive
candidiasis described in this article includes candidemia, deep tissue infection and disseminated candidiasis.
This definition is adapted from the consensus of the Invasive Fungal Infections Cooperative Group (IFICG)
of the European Organization for Research and Treatment of Cancer (EORTC) and the Mycoses Study
Group (MSG) of the National Institute of Allergy and Infectious Diseases (NIAID), and was originally
applied to immunocompromised patients. Consequently, invasive candidiasis is generally found in severely
ill patients, such as patients in the intensive care unit [ICU] or immunocompromised patients.2

Case Report

A 61 year-old male patient, coming to the ER with left hip complaints of pain with pain scale 8.
Complaints have been felt for 10 days. In addition to complaining about the waist pain, the patient also
complained of dizziness and swollen left leg. Patients have a history of hypertension and gout arthritis. In
these patients performed several investigations such as limb ultrasound, lumbar MRI, complete blood
examination, CRP and Femafactor examination, and vertebral biopsy. On blood examination found levels
of hemoglobin 12.8 gr / dL, leukocyte number 15.280 thousand / mmk. In the blood chemistry examination
found creatinine 1.31 mg / dL. In the microbiological examination with pod specimen from vertebral
biopsy, Candida sp 2+, leukocyte 2+ was found.

Risk factors

There are many risk factors for candidal colonization and infection including: host barrier
disruption (e.g., major burn), acute or chronic graft versus host disease particularly with gut involvement,
antibiotics, neutropenia, cancer, invasive procedures, ICU admission, steroids and hyperglycemia, severe
catabolism secondary to injury, total parenteral nutrition (TPN), mechanical ventilation, prolonged
hospitalization, malnutrition, multiple medical co-morbidities and stress ulcer prophylaxis. Some risk
factors facilitate Candida colonization (e.g., steroids), others contribute to tissue or bloodstream invasion
(e.g., intravascular catheters), while others impair host defenses. In patients with candidemia, 84–90% of
colonizing and infecting strains are identical, with the time from colonization to infection typically brief.
In burn patients, prior Candida species colonization typically precedes systemic candidiasis.3
Pathogenesis

As a commensal, Candida resides in yeast form and multiplies by budding into blastospores, but
during weakened immunity of the host it transforms into the hyphal form as the start of pathogenesis. In
vivo study has revealed that change in pH, oxygen, carbon dioxide, or glucose concentration in host tissue
triggers this transition. Filamentous forms are more adhesive due to increased expression of adhesins on
the surface, and also secretion of a higher amount of hydrolytic enzyme enhances the invasiveness.
Moreover, the pathogenic stage has to resist recognition by the immune system or damaging macrophages
and neutrophils. This interaction with host tissue in favor of Candida results in deep tissue penetration and
the establishment of infections. It is speculated that host (tissue environment and immune system) alone
determines the balance between commensalism and pathogenicity. The work of several researchers has
shown that certain genes such as pHregulated PHR1 and PHR2, genes encoding secreted aspartyl
proteinases (SAPs 1–9), and genes encoding phospholipases (PHL A–D) are expressed differentially in
specific tissues at different stages of infections. Expression or modulation of these genes on the same
mucosal surfaces only during transition from the commensal to the parasitic stage reflects a weakness in
the immune system responsible for this shift. Candida survives and proliferates as commensal in
competition with other microbial flora and is affected by epithelial cell proliferation and the immune
system. Proliferation of epithelial cells constitutively forces Candida to attempt deeper invasion into tissues.
Prolonged antibiotic therapy provides more available nutrients and space for Candida to multiply as other
commensal microbial flora are diminished. Immune suppression in HIV patients and inhibition of epithelial
cell proliferation such as in cancer therapy changes the tissue environment in terms of pH, osmolarity, and
oxidative stress. This changed condition is perceived by the candidal cell and subsequently down- or up-
regulation of certain genes provokes Candida to switch over from commensal to opportunistic
pathogens.4,5,8

Deep Tissue Infection6,7,8

1. Gastro intestinal tract [GIT], liver, spleen and peritoneum. Deep tissue candidiasis may have
originated from fungal translocation across an intact bowel wall, which is facilitated by the
decreased intestinal mucosal barrier function patients. GIT involvement is invariably present in
leukaemia patients and is therefore one of the major sources of infection including hepatosplenic
involvement. Deep tissue candidiasis may present as hepatosplenic (or chronic disseminated)
candidiasis, which rarely occurs in non-neutropenic patients. These patients usually have a
disturbed liver function and experience fever not responding to antibacterial treatment. Candida
peritonitis is most often secondary to bowel perforation e.g. following surgery, trauma, or
peritoneal dialysis, which is often polymicrobial.
2. Trachea and Lung Fungal pneumonia is an uncommon entity, but important differences exist
between infections caused by mold and yeasts: yeast will rarely cause pneumonia. Candida
pneumonia is thus an extremely rare disorder, occurring primarily as a result of haematogeneous
dissemination. However, Candida spp. are often isolated from the tracheal aspirates of
mechanically ventilated patients (~25%), which reflects the colonization of the bronchial tree.
Antifungal therapy should therefore not be prescribed based on isolation of Candida spp. from
respiratory specimens. Because lung biopsies can often not be performed in critically ill patients,
 and yeast infections do not have typical features on computerised tomography, ante-mortem
diagnosis remains difficult.
3. Urinary tract. Candida is isolated from the urine mainly in patients with bladder catheterisation,
most often representing colonization. There is however, no reliable method to differentiate
colonization from infection. High colony counts (> 10.000 cfu/ml) have been associated with
infection in patients without indwelling catheter. Pyuria may be a sign of cystitis or pyelonephritis,
but it can also be caused either by bacteria or mucosal trauma by catheterisation. Candidiasis can
be ruled out in the absence of pyuria and low colony counts. Patients with candiduria are frequently
colonized at other body sites, increasing the risk of developing candidemia. Candiduria is
associated with an overall mortality rate of up to 50% and should rather be considered as an
epiphenomenon or marker of severity.
4. Cardiovascular candidiasis. Because of the small size of the lesions, the heart compromised by
candidiasis may manifest subtle alterations in its function, and therefore most Candida myocarditis
is clinically undetectable. Endocarditis and pericarditis are less common, but morbidity and
mortality are disastrous. Candida endocarditis has become a threat in patients after cardiac surgery
particularly when prosthetic valves have been inserted, and is also encountered in drug addicts and
in patients with long-term venous catheters . Complications of Candida endocarditis include
embolisms, congestive heart failure and sepsis. The valvular vegetations tend to be bulkier than
those caused by bacteria. In any of these circumstances, Candida may evoke little or no
inflammatory reaction or may induce a suppurative response. Arterial emboli from Candida
endocarditis are generally larger than from bacterial infection, and consequently, larger vessels are
involved in the embolisation with subsequent infarction often seen in the spleen, kidneys, brain and
lower extremities.
5. Central Nervous System [CNS]. Neonates are the group most at risk for Candida meningitis, but it
has also been reported among other patient groups (e.g. HIV) as an occasional manifestation of
disseminated candidiasis, after neurosurgery and surgery in the oral cavity. Cerebral involvement
with Candida spp. is often not recognized until autopsy examination, due to the typically severe
underlying primary disease and the small and focal nature of the parenchymal CNS lesions in
candidiasis. Nevertheless, it is the most common cerebral mycosis found post-mortem, surpassing
cryptococcosis which is clinically most frequently recognized.
6. Eye deep tissue candidiasis of the eye can be present as chorioretinitis and endophthalmitis, and is
usually of endogenous origin. Chorioretinitis is, by definition, confined to the choroid and retina
but may evolve to endophthalmitis, in which the vitreous cavity is also affected. Of all cases of
endophthalmitis, only 2-15% are endogenous, although most cases of endogenous endophthalmitis
are caused by Candida spp., followed by Aspergillus spp..
7. Endocrine organs. Haematogenous Candida lesions can be found in the endocrine organs at
autopsy. The thyroid and adrenals especially may be involved but these lesions are not often
clinically significant. Since most patients with fungal thyroiditis had disseminated fungal infection
with delay in diagnosis and treatment, the described overall mortality was high.
8. Osteo-articular Candidiasis in bone and cartilage is uncommon in clinical practice and literature,
and may be present as e.g. osteomyelitis, septic arthritis, spondylodiscitis and infected joint
prostheses. These infections are usually hematogenously spread, or related to surgery. Because
presenting features are often nonspecific, osteo-articular candidiasis can be difficult to recognize
in the early stages, and therefore adequate treatment is often delayed.
Osteo-articular Candidiasis9,10

Reports of Candida osteomyelitis did not begin to rise until the 1970s. It is a rare disease, but with
the increased prevalence of factors predisposing to invasive candidiasis, Candida osteomyelitis is emerging
more frequently in select populations. This condition is associated with significant morbidity, particularly
when diagnosis is delayed because of late recognition of Candida spp as potential bone pathogens.
Osteomyelitis with Candida and other fungal species may occur in patients who have severely compromized
host-defense mechanisms or who are receiving longstanding intravenous therapy or central parenteral
nutrition. Osteomyelitis due to Candida species can occur following either hematogenous dissemination or
direct traumatic inoculation. Limited data are available regarding the incidence of candidal osteomyelitis.
This entity has been reported in organ transplant patients, in bone marror transplant recipients, intravenous
drug addicts, and severely ill patients with multiorgan failure. The pathogenesis in all instances is similar.
A breach in the normal mucocutaneous barrier in a patient on antibiotics or immunosuppression becomes
a portal of entry for Candida and, following an episode of fungemia, Candida can localize in any deep
tissue. The patient reported here had a past history of nonrheumathoid arthritis, had neither used steroids,
cytostatic drugs nor received antibiotic treatment. The pathogenesis of her disease cannot be explained by
any of these mechanisms.

The most common presenting complaint is localized pain. Pain frequently occurs without
constitutional symptoms; less than half of reported cases demonstrated fever or elevated sedimentation
rates. The vertebrae , followed by the sternum, are the sites most commonly affected after an episode of
candidemia. When the sternum is involved, draining sinus tracts are commonly seen. One such case of C
albicans sternal osteomyelitis in a patient who had undergone coronary artery bypass graft surgery 1 year
prior was characterized by multiple draining sinus tracts along the midline incision extending to the anterior
mediastinum and destroying the manubrium and upper sternum.

Candida infection develops as a manifestation of systemic candidemia in most cases. Factors that
predispose to systemic infection with this agent include immunosuppression during the course of anti-
cancer therapy, organ transplantation, parenteral hyperalimentation, indwelling arterial/venous catheters,
intravenous drug addiction, diabetes, broad-spectrum antibiotic therapy, HIV infection, corticosteroid
therapy, and myeloperoxidase deficiency. Direct implantation of Candida is a very rare cause. The usual
species involved is Candida albicans, although examples of infection with C. tropicalis, C. paratropicalis,
and C. guilliermondii have been reported.

The most common presenting complaint is localized pain. Pain frequently occurs without
constitutional symptoms; less than half of reported cases demonstrated fever or elevated sedimentation
rates. The vertebrae, followed by the sternum, are the sites most commonly affected after an episode of
candidemia. When the sternum is involved, draining sinus tracts are commonly seen. One such case of C
albicans sternal osteomyelitis in a patient who had undergone coronary artery bypass graft surgery 1 year
prior was characterized by multiple draining sinus tracts along the midline incision extending to the anterior
mediastinum and destroying the manubrium and upper sternum.

The diagnosis of candida osteomyelitis or septic arthritis is not easy to establish. Blood cultures are
frequently negative, as only 30% to 50% of persons who have disseminated candidiasis have positive blood
cultures. There are few characteristic clinical or radiologic features to suggest a fungal origin of bone
destruction or joint invasion. A high index of suspicion must be maintained in the appropriate host or in
those who have bone or joint infections unresponsive to antibiotic therapy. Appropriate cultures may yield
results in a timely fashion.

Radiographic findings associated with candida vertebral osteomyelitis are indistinguishable from
those found with bacterial infection. They include destruction of the superior plate of one vertebral body
and the inferior plate of the adjoining body, along with narrowing of the respective disc space. CT and MRI
may be useful to delineate cord compression, paraspinal abscess, and the degree of disc space or vertebral
body involvement. Bone or gallium scans may be helpful in diagnosing the presence of spinal osteomyelitis,
but culture of biopsy tissue is needed to identify the causative microorganisms. In cases of sternal
osteomyelitis, percutaneous needle biopsy has been efficacious in establishing the diagnosis. Osteomyelitis
of the long bones may reveal demineralization and a mottled trabecular pattern.

Involvement of unsual sites can sometimes create problems in diagnosis. Needle biopsy is an
extremely useful diagnostic procedure with a yield of results that are 25-100% positive. Open biopsy is
indicated as the ultimate dianostic procedure.

Treatment is based on antifungal chemotherapy with or without surgical debridement; amphotericin

B is considered the drug of choice. There is no evidence that flucytosine in combination with amphotericin
B is more effective than amphotericin B alone in the treatment of Candida osteomyelitis. The use of
flucytosine alone cannot be recommended since resistant strains emerge rapidly during treatment. Some
investigators recommend an amphotericin B dose of 1-1,5 g.

If standard antifungal treatment with intravenous amphotericin B cannot be followed or fails, the
choice of other drugs (eg, azoles) should be based on susceptibility testing, although clinical correlation
data are lacking. Successful treatment of candida infections has been noted with drugs that were observed
to be resistant in vitro. The newer azoles such as fluconazole, itraconazole, voriconazole, and posaconazole
may be potential alternative agents and are associated with less toxicity. In one report, C albicans knee
arthritis in a person who was immunocompetent was successfully treated with joint aspiration and lavage
and 200 to 400 mg of fluconazole daily for 3 months. Prolonged maintenance treatment with fluconazole
for up to 2 years has been reported. There are limited data on the use of caspofungin in the treatment of
candida arthritis and osteomyelitis.

Antifungal susceptibility testing may help in deciding which drug to use, but the interpretation of
results should be made with caution. How long the treatment sholud continue has not yet been established.
According to some authors, patients sholud be treated for two to four weeks after resolution of clinical signs
and symptoms of infection and when there is microbiological evidence of eradication of the infection.

Investigators have measured serum and joint fluid levels of amphotericin B in patients who have
candida arthritis, and have found that levels vary from 20% to more than 100% of the serum concentration.
These variations notwithstanding, the joint-fluid drug levels are felt to be sufficient to inhibit fungal growth.
Joint-fluid drug levels of fluconazole have been reported to approximate those in plasma.

There is controversy over the usefulness of intra-articular amphotericin as an adjunct in infections

limited to the joint capsule. Surgery, including synovectomy combined with arthrodesis, has been required
for successful management in some joint infection cases. Vertebral osteomyelitis may require surgical
stabilization and decompression, but in cases without neurologic compromise, medical treatment alone has
been successful.

Antifungal susceptibility testing may help in deciding which drug to use, but the interpretation of
results should be made with caution. How long the treatment sholud continue has not yet been established.
According to some authors, patients sholud be treated for two to four weeks after resolution of clinical signs
and symptoms of infection and when there is microbiological evidence of eradication of the infection.

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