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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Candida infections in surgical intensive care unit patients

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Service des Soins Intensifs Medico-Chirurgeaux, Erasmus University, Bruxelles, Belgium

Introduction

Infections with fungal pathogens, of which Candida species predominate, are an important cause of morbidity and mortality among the critically ill. The vast majority of these infections are nosocomial in nature, acquired during the patient's hospital admission, and the incidence of such infections appears to be increasing. There are many possible explanations for this including the fact that older, more debilitated patients who previously would never have survived to develop a nosocomial infection are being treated. The number of immunocompromised patients, at greater risk of fungal infection, treated on our intensive care units (ICUs) has increased considerably. The widespread use of invasive monitoring and therapeutic equipment also increases the risk of fungal colonization and infection. Finally, broad spectrum antibiotic use suppresses normal intestinal bacterial flora encouraging the proliferation of Candida within the gastrointestinal tract, a precondition for systemic infection. An acute awareness of the increasing incidence of Candida as a pathogen and of the associated morbidity and mortality is necessary.

In this chapter we will review the epidemiology, diagnosis, and recommended treatment regimens for Candida infections.

Epidemiology and pathogenesis

Candida albicans is present as part of the normal microflora of the gastrointestinal tract or oropharynx in many individuals. Alterations in host defense whether caused by underlying disease such as diabetes mellitus, prolonged ICU stay, or other factors, can result in an overgrowth of Candida, termed colonization. Antibiotic administration can also provoke colonization by eliminating the normal bacterial microflora of the gut, and allowing the proliferation of Candida. Such colonization, while not life-threatening itself, may progress to severe and fatal systemic infection in the susceptible critically ill patient. Translocation of the fungus across the gastrointestinal mucosa into the bloodstream is probably the most common mechanism by which colonization becomes systemic infection. Abnormal mucosal function and limited mucosal integrity in the critically ill patient encourage this process.

Risk factors for developing systemic candidiasis include increasing age, history of diabetes mellitus, length of ICU stay, length of mechanical ventilatory support, presence of central vascular catheters, severity of underlying disease, and prolonged use of antibiotics or total parenteral nutrition (table I).

Table I. Common risk factors which have been identified in clinical trials as being associated with the development of candidemia.

Table I

Common risk factors which have been identified in clinical trials as being associated with the development of candidemia.

Several studies have indicated the possible role of cross-infection between patients and staff in the transmission of Candida infection. Infection control procedures such as hand-washing must therefore be closely observed.

Fungal colonization is frequent among the critically ill, affecting as many as 64% of ICU patients. Although the incidence of systemic invasive mycosis is much less common (2% of patients) it is associated with a high mortality, prolonged ICU and hospital stays, and increased costs. Crude mortality rates of 26–56% have been reported, and attributable mortality rates of 22–38%. Candida species are implicated in 72–78% of these fungal infections.

Candida albicans remains the most commonly observed member of the Candida family although Candida glabrata, krusei and parapsilosis are being increasingly seen. Overall there has been an increase worldwide in the rate of nosocomial fungal infection with most marked increases occurring in surgical patients.

Diagnosis

Clinical signs of Candida infection are those of infection in general, such as fever, leukocytosis, … and are non-specific.

The diagnosis of systemic candidal infection relies primarily on the presence of positive blood cultures, although systemic infection is not always associated with candidemia.

Positive cultures of urine may indicate a primary, isolated urine infection with Candida but should raise the possibility of renal involvement in disseminated disease. The presence of Candida endophthalmitis is indicative of advanced disseminated candidiasis but is relatively rare, occurring in 9–15% of patients with systemic Candida infection. Other signs of disseminated infection include skin lesions and septic arthritis but these are encountered even more rarely. Antibody detection is an unreliable means of diagnosis as healthy individuals may have detectable fungal antibody. Antigen and metabolite detection also have limitations. The use of new molecular diagnostic tests, such as polymerase chain reaction techniques, may provide a more accurate means of early diagnosis, and further our understanding of the epidemiology, including means of transmission, of Candida infection.

Therapy

Early reluctance to treat the presence of fungal organisms which were believed to be relatively benign, has been replaced by a much more aggressive approach as we have come to realize the high mortality associated with systemic fungal infection, and as newer, effective anti-fungal agents with limited toxicity have been developed. There are two main anti-fungal agents which have been employed: The polyene, amphotericin B, and the triazole, fluconazole.

Amphotericin B

Clinically used for over 30 years, this polyene compound has a broad antifungal spectrum, including most species of Candida. An interaction between the drug and ergosterol present on the fungal cell membrane produces a hole in the fungal membrane and leakage of cellular contents. However, human cells also contain sterols and toxicity, particularly renal tubular damage occurs relatively frequently and may limit use. Recommended doses range from 0.3–0.7 mg/kg/day. Formulations in which amphotericin is combined with liposomes were developed to reduce nephrotoxicity but they are considerably more expensive. A clinical trial comparing a lipid emulsion formulation with standard amphotericin B showed similar efficacy with reduced toxicity in the lipid formulation group, although this group did develop a significant thrombocytopenia, not associated with active bleeding. Further studies on these formulations are clearly indicated. Amphotericin B has been used in combination with flucytosine, to extend the anti-fungal spectrum. However, flucytosine is associated with considerable toxicity of its own and is excreted almost exclusively by the kidney, which can result in increased toxicity in patients with reduced renal function due to the amphotericin. If this combination is used, flucytosine levels should be closely monitored.

Fluconazole

This newer drug, developed in the mid 1980s, acts by inhibiting fungal cytochrome P450 enzymes and hence blocks sterol biosynthesis. It is available in both oral and intravenous preparations. Some resistance to fluconazole has been reported and certain species, notably C. krusei and C. glabrata are less sensitive to fluconazole. The recommended dose ranges from 100–400 mg/day although there is some evidence that higher doses may be more effective.

Treatment with amphotericin and fluconazole have been compared in several clinical trials. Results from these trials suggest little difference in eradication rates or outcome between the two drugs, but all studies report significantly less toxicity with fluconazole.

In view of the lower toxicity and similar efficacy, fluconazole is now the preferred drug for systemic Candida infection, although in patients with infection due to C. krusei or C. glabrata amphotericin B may still be preferred.

The combination of amphotericin with fluconazole has been suggested but no clinical results of the use of this strategy are available. Other therapeutic options are being developed including new triazoles, such as voriconazole, and echinocandins, but these remain experimental at present.

With the difficulties in diagnosis of Candida infection, knowing when to initiate treatment can be a problem, although several studies have indicated that early treatment is associated with improved survival. Positive blood cultures alone are not a reliable indication of systemic infection, and early presumptive therapy should be considered in patients at high risk of developing candidal infection.

A recent consensus conference supports treatment in all patients with a single positive blood culture for Candida. Guidelines published by the British Society for Antimicrobial Chemotherapy suggest that preemptive anti-fungal therapy be initiated in at risk patients with a single positive blood culture, patients in whom Candida is isolated from any sterile body site (except urine), patients with positive yeast microscopy in a sterile specimen, and at risk patients with histological evidence of yeast in tissue.

Anti-fungal prophylaxis is not currently recommended in all patients although certain groups, for example liver transplant recipients, may benefit from this approach. Prophylaxis with liposomal amphotericin has been shown to be effective in reducing the incidence of invasive candidal infections in liver transplant recipients when compared with placebo. Similarly, prophylaxis with fluconazole has been shown to be of benefit in patients undergoing bone marrow transplant. More studies are needed to further identify which patients will benefit from anti-fungal prophylaxis and which drug at what dose is most appropriate. Anti-fungal prophylaxis in all surgical patients is clearly not indicated and carries the risk of encouraging the development of drug resistance, already being seen for some species.

Conclusion

The increasingly important role of fungal agents in the pathogenesis of nosocomial infections and the associated high mortality rates demand that we develop an aggressive approach to the prevention and diagnosis of fungal infection among the critically ill population. Despite a general paucity of studies providing level I evidence, recommendations and guidelines regarding the management of patients with systemic candidal infection have been made (table II). Early preemptive therapy is recommended in some patients and prophylaxis may be of benefit in carefully selected groups. The efficacy of fluconazole combined with its low toxicity make it an attractive first-line agent in many fungal infections, although amphotericin remains the drug of choice in known less susceptible Candida species. With the changing pattern of systemic candidal infections and emerging resistance, treatment decisions must take into account local fungal epidemiology and resistance patterns.

Table II. Guidelines for treatment of systemic candidal infections from the British Society for Antimicrobial Chemotherapy Working Party (1994) and the International Consensus Conference for the Management and Prevention of Severe Candidal Infections (1997).

Table II

Guidelines for treatment of systemic candidal infections from the British Society for Antimicrobial Chemotherapy Working Party (1994) and the International Consensus Conference for the Management and Prevention of Severe Candidal Infections (1997).

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Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6999
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