Diabetes Mellitus

Diabetes mellitus is an independent predictor for mucosal candidiasis, invasive candidiasis, and aspergillosis. Diabetic ketoacidosis has a strong association with rhinocerebral mucor (produced by Zygomycetes) and other atypical fungal infections, with hyperglycemia being the strongest predictor of candidemia after liver transplantation and cardiac bypass. It has been postulated that hyperglycemia produces several alterations in the normal host response to infection and in the fungus itself, increasing its virulence. Glycosylation of cell surface receptors facilitates fungal binding and subsequent internalization and apoptosis of the targeted cells. Glycosylation of opsonins renders them unable to recognize fungal antigens. Diabetic serum has diminished capacity to bind iron (therefore making it available to the pathogen). There is evidence that altered Th-1 lymphocyte recognition of fungal targets impairs the production of interferon-gamma (IFN-γ), and that Candida spp. overexpress a C₃-receptor–like protein that facilitates fungal adhesion to endothelium and mucosal surfaces. Dendritic cells and other antigen-presenting cells have been postulated as crucial in the induction of cell-mediated responses to fungi, and diabetic patient vaccination studies have showed an impaired antigen—T-cell interaction.

Neutropenia

There is a direct correlation between the degree of neutropenia and the risk for developing invasive fungal infections. Although a recent meta-analysis concluded that there is little benefit from prophylaxis or preemptive treatment in neutropenic cancer patients, this is a regular practice in the United States. Empirical antifungal therapy is the standard of care for febrile neutropenia patients after chemotherapy or bone marrow transplantation. When profound neutropenia exists, the risk for breakthrough candidemia (during antifungal therapy) is significantly higher, and the response to voriconazole (and likely other antifungals) is decreased. Novel therapies for the treatment of invasive fungal infections in neutropenic patients include granulocyte transfusions and infusion of IFN-γ.

Organ Transplantation and Immunosuppression

The two most common opportunistic fungal infections in transplant patients are caused by Candida spp. and Aspergillus spp., generally by the inhalation route (Aspergillus) or from gastrointestinal sources (Candida). Interestingly, the risk of fungal infection decreases six months after transplantation, unless a rejection episode requires intensification of the immunosuppression. In the solid organ transplant recipient, the graft itself is often affected. In liver transplantation, the risk of fungemia increases with the duration of the surgery and the number of transfusions. Other risk factors include the type of bile duct anastomosis (Roux-en-Y), the presence of tissue ischemia, infection with cytomegalovirus (CMV), and graft-versus-host disease. The most common place of occurrence for Aspergillus tracheobronchitis in lung transplant patients is at the bronchial anastomosis. Anastomotic colonization is both a risk factor for subsequent disruption or hemorrhage and a predictor for rejection and diminished graft survival. Surveillance bronchoscopies are recommended in this setting. Aspergillus is also the main organism responsible for fungemia after heart transplantation, and second only to CMV as the cause of pneumonia in the first month after operation.

Infectious complications are the main cause of morbidity and mortality in pancreas and kidney–pancreas transplantation. The most common organisms are gram-positive cocci, closely followed by gram-negative bacilli and Candida. Risk factors for fungal infections include bladder drainage (in cases of pancreas transplantation) and use of OKT-3 for rejection treatment. Kidney recipients, of all solid organ transplant recipients, have the lowest incidence of infectious complications. However, the risk is sufficiently high that all solid organ transplant recipients (kidney recipients included) receive fungal prophylaxis with fluconazole.

Solid and Hematological Malignant Tumors

Cancer patients are susceptible to opportunistic infections. Cancer and chemotherapy produce three types of immune dysfunction that render the patient vulnerable to opportunistic infections: neutropenia (see previously), deficits in lymphocyte cell-mediated immunity (e.g., Hodgkin disease and during corticosteroid treatment), and humoral immunodeficiency (e.g., multiple myeloma, Waldenström macroglobulinemia, and after splenectomy). The first two types are the most relevant in terms of fungal vulnerability. As many as one-third of the cases of febrile neutropenia after chemotherapy for malignant disease are due to invasive fungemia (see following treatment discussion). The type of lymphopenia is as important as the nadir of the lymphocyte count: Whereas Th-1 type responses (TNF-α, IFN-γ, and interleukin [IL]-12) confer protection against fungal infections, Th-2 (IL-4 and -10) responses are associated with progression of disease. Corticosteroids have anti-inflammatory properties, related to their inhibitory effects on the activation of various transcription factors, in particular NF-κB. In murine models, steroid treatment increases the production of IL-10 in response to a fungal insult, and decreased the recruitment of mononuclear cells to the site of infection. It does not, however, inhibit recruitment of neutrophils to sites of inflammation (IL-8-mediated).

Long-Term Use of Central Venous Catheters

Numerous studies have shown that many, if not most, episodes of candidemia are catheter-related; one of the largest prospective treatment studies of fungemia implicated a catheter 72% of the time. The isolation of C. parapsilosis from blood cultures is strongly associated with central venous catheter infection, parenteral nutrition, or prosthetic devices. The source of the fungal contaminants is different in neutropenic patients when compared with their non-neutropenic counterparts. In non-neutropenic subjects the most common portals of entry for catheter contamination (and subsequent infection) is the skin during catheter placement, manipulation of an indwelling catheter, and crossinfection among ICU patients attributed to hand carriage of microbial flora from health care workers. Other possible sources for primary catheter colonization include contaminated parenteral nutrition solution, multiple medication administration with repetitive violation of the sterile fluid path, and the presence of other medical devices. The secondary route of contamination for intravascular catheters and other foreign bodies in direct contact with the bloodstream (e.g., pacemakers, cardiac valves, orthopedic joint prostheses) is candidemia originating via translocation from the gastrointestinal tract. Endogenous flora are also the most common source in neutropenic and other immunosuppressed patients. Once the catheter becomes contaminated, a well-studied series of events takes place: The yeast adheres to the surface of the catheter and develops hyphal forms that integrate into a matrix of polysaccharides and proteins (biofilm) that increases in size and tridimensional complexity. This biofilm is the main reservoir for candidemia secondary to contaminated medical devices, as it sequesters the fungi from antimycotic medication and against the protective immune response.

In general, the removal of all central venous catheters is indicated following the diagnosis of systemic fungal infections and fungemia. Removal may not be necessary in neutropenic patients in whom the fungi originated from the GI tract. Antifungals in general are continued after the catheter is removed, and it is recommended that Candida ocular dissemination be ruled out (see following discussion of endophthalmitis).

Candida Colonization

The overgrowth and recovery of Candida spp. from multiple sites (without clinical symptoms of disease) has been linked to a high likelihood of invasive candidiasis, and the cumulative risk of death in these two conditions is similar. Risk factors for the development of Candida colonization include prior use of antibiotics or a bacterial infection prior to ICU admission, a prolonged stay in the ICU, and multiple gastrointestinal operations. The source of most of the outbreaks of systemic candidiasis in the context of colonization is frequently the gastrointestinal tract.

Because colonization with Candida spp. is not benign in the context of critical illness, it is desirable to identify and characterize patients further in terms of risk for invasive candidiasis. Screening techniques include routine surveillance cultures in ICU patients. The method proposed by Pittet et al., the colonization index, has been validated in surgical patients. A threshold index of 0.5 has been proposed for the initiation of empiric antifungal therapy in critically ill patients (see following treatment section), although some authorities suggest that the presence of multiple Candida isolates is an epiphenomenon.⁶

Use of Broad-Spectrum Antibiotics

The use of broad-spectrum antibiotics is one of the bestdocumented risk factors for fungal overgrowth and invasive infections, but the precise mechanism is not understood completely. In evaluating the effect of antibiotic use, one must consider first the complex interrelations between bacteria and fungi in human disease. At least three experimental models have been created to investigate and characterize possible interactions between bacterial and fungal pathogens. In murine models, ticarcillin-clavulanic acid and ceftriaxone (both of which have some antianaerobic therapy) are associated with substantial increases in colony counts of yeast flora of the gut. On the other hand, antibiotics with poor anaerobic activity are less likely to produce this effect (examples are ceftazidime and aztreonam). This observation was validated in a clinical review of the quantitative colonization of stool in immunocompromised patients treated with those antibiotics. However, this interaction between fungi overgrowth and anaerobic suppression is different from the well-studied model of Escherichia coli and Bacteroides fragilis in intra-abdominal abscess formation. The work of Sawyer et al. showed that C. albicans induces bacterial translocation into abscesses, but the relationship is one of direct competency, rather than synergy or cooperation.^7,8 This is different than the cooperation between C. albicans and Staphylococcus aureus, Serratia marcescens, and Enterococcus faecalis, where an amplification-type interaction has been documented. A number of immunomodulatory and immunosuppressive viruses have been shown to facilitate superinfections with opportunistic fungi, the most notable examples being CMV and human herpes virus (HHV)-6, because they induce the production of immunosuppressive cytokines. It seems that C. albicans thrives in situations where immunocompromise is present and adds virulence and mortality to existent bacterial infections in a species-specific manner. This hypothesis has been validated from clinical observations, where antifungal treatment adds little to the therapeutic effect of antibacterial agents alone. Thus, the use of antibiotics (three or more), especially those with anti-anaerobic properties, constitute a risk factor for fungal colonization and overgrowth, which in turn is a predictor for systemic fungal infections. The precise mechanism of action for this observation is unknown but is probably related to fungi-to-microbe competence and growth suppression. Candida may enhance the pathogenicity of certain bacteria, but not others, and this interaction remains to be elucidated.⁷

Duration of ICU Care and Invasive Mechanical Ventilation

Epidemiological observations correlating the duration of mechanical ventilation and the amount of intensive care required correlate with the occurrence of both systemic fungal infections and fungal colonization. Other factors involved in the pathogenesis and susceptibility of systemic candidiasis are total parenteral nutrition, use of H₂