Invasive fungal infections are major sources of morbidity and mortality among critically ill patients in surgical ICU and have emerged as an important public health problem especially in third-world nations. Over the last decade, fungal sepsis has continued to increase rapidly despite the use of antifungal agents and mortality remains high due to delays in proper diagnosis and administration of appropriate antifungal therapy (Meerssemann et al 2004). The majority of nosocomial fungal infections are due to Candida species. Candida are frequent commensal yeasts of the human gastrointestinal, respiratory, reproductive tracts and the skin. Candida colonization is an important prerequisite to invasive disease and sepsis. A significant proportion of invasive candidiasis occurs in the surgical ICU and rates of Candida colonization increase with length of stay and is exacerbated in critically ill patients with impaired host defenses (Hajjeh et al 2004). The transition of Candida from a harmless commensal fungus to an invasive opportunistic pathogen requires the disruption of anatomical barriers and translocation of pathogen to circulation (Spellberg 2008). Candida systemic infection is associated with several risk factors including broad-spectrum antibiotics, corticosteroids, central venous lines, malnutrition, hemodialysis, mechanical ventilation, renal failure, and venous/urinary catheterization, which are fairly common following major surgery (Bendel et al 2002). Candidemia in surgical patients in the ICU may also occur through the horizontal transmission of Candida by hospital staff through the insertion of central venous or urinary catheters. Significant efforts must be made to develop proper risk stratification strategies to guide antifungal therapy and reduce candidemia-related mortalities in resource-poor nations in an efficient and cost-effective manner.
The diagnosis of severe candidiasis in the third world is frequently based on overall clinical status with few laboratory tests, which are done using cultures of sputum, blood, urine, or stool. However, the reliance on laboratory tests to confirm a diagnosis of invasion can be time consuming and misleading. In fact, approximately only half of patients with invasive candidiasis have positive blood cultures (Solomkin et al 1982). This may be due to difficulty of Candida to grow in culture or by interference from a coincident bacterial infection from the patient. This has significant implications in resource-poor countries as sample cultures are usually the only means of confirming a candidemia diagnosis. Using nonculture markers of candidiasis, such as serum (1,3)-β-ᴅ-glucan (BG) (polysaccharide cell wall components), ᴅ-aribinitol, enolase, and mannan, can be used for a more definitive confirmation of candidemia. For example, serum BG levels exceeding 60 pg/ml positively identifies 80% of patients with invasive fungal disease (Ostrosky-Zeichner et al 2005). Using non-culture diagnostic tools are promising in terms of rapidly identifying candidemia in resource-limited settings. More experimental methods of detecting candidemia from patient samples include using Candida species specific polymerase chain reaction (PCR) or peptide nucleic acid-fluorescence in situ hybridization (PNA-FISH) (McMullan et al 2008). PNA-FISH can be performed on Candida blood culture growths and provide rapid determination of species infection and facilitate specific antifungal treatment selection. Although the latter two diagnostic tools still require cultures, they are promising bench-to-bedside tools that will facilitate early detection of invasive candidiasis. Promoting the use of standard and experimental diagnostic aids in resource-poor countries can be more cost-effective as early detection and preventative measures will decrease length of ICU stay.
The concept of early presumptive therapy (EPT) is a strategy that can be used to assess the risk of developing invasive candidemia and the treatment of high-risk patients who exhibit signs and symptoms of the disease even in the absence of positive cultures. Critically ill surgical patients at risk for Candida colonization have an increased risk of developing invasive disease and prevention of colonization improves patient outcomes. However, not all cases of colonization results in invasive candidiasis. Therefore, clinical evaluation becomes a critical and cost-effective strategy in resource-limited settings to assess patients who would benefit from EPT before invasive candidemia development. Unfortunately, there are no established diagnostic tests that reliably distinguish infection from colonization. The overgrowth and invasion of Candida in the gastrointestinal tract corresponds with colonization of other multiple sites. Candiduria, presence and increased growth of Candida in the bladder, can be used as an indicator of disseminated candidiasis, where the presence of candidemia without candiduria is very unlikely (Stone et al 1974). A positive test result for candiduria can be used as a risk factor to initiate prophylaxis with antifungal agents. An important idea to consider is that the urinary system is not the only colonization site that can lead to invasive disease. Investigation into Candida colonization of multiple sites, such as peritoneal cavity or respiratory tract, can provide an indication of high-risk of invasive/disseminated disease for the initiation of EPT. Thereby, early therapy with low doses of antifungal agent(s) may prevent subsequent severe disseminated candidemia and will be more resource-effective in poor nations.
The main intervention for established fungal infections in the ICU involves antifungal therapy. Current key antifungal agents include amphotericin B (AmpB), fluconazole, voriconazole, and the echinocandins. Other agents can include lipid-amphotericin B formulations and 5-flucytosine, however, in resource-limited settings, usually only AmpB and fluconazole are available. When selecting an antifungal therapy, we must consider the drug's activity, toxicity, pharmacological kinetic and dynamic attributes, multi-drug interactions, possibility of resistance development, and affordability. Particularly for critically ill patients in resource-limited settings, these choices become vitally important and new strategies must be adopted to improve survival.
AmpB is widely used against invasive fungal infections due to their broad activity spectrum, clinical efficacy, availability and affordability. However, AmpB is associated with considerable nephrotoxicty and high doses are unsuitable for post-operative patients, especially during renal failure and hemodialysis. Lipid-AmpB formulations which have lower toxic effects may be used but this represents a higher cost per treatment and may not be the most viable option in poor countries. An alternate treatment involves AmpB and fluconazole combination therapy. This allows using lower doses of AmpB in combination with a safer, affordable and effective antifungal to reduce toxicity in critically ill patients with invasive candidiasis. Fluconazole dosage can be adjusted for patients with renal dysfunction and undergoing hemodialysis. However, fluconazole is not without its own caveats. Certain species of Candida (glabrata and krusei) have acquired fluconazole resistance. Although these species comprise less than one-third of all Candida, it raises the emerging issue and need for new therapies especially in resource-poor nations.
Voriconazole is commonly used for invasive aspergillosis but is effective for patients with invasive candidiasis (Kullberg et al 2005). Voriconazole is active against a wide spectrum of fungi and is commonly used against Candida that have gained resistance to fluconazole. Critically ill patients can have variability in drug bioavailability dependant on route of administration and it is generally advisable to administer initial therapy intravenously. However, intravenous voriconazole requires cyclodextrin, which is highly nephrotoxic thereby limiting its use in critically ill patients. Furthermore, unlike the benefits from AmpB, voriconazole and fluconazole combination therapy may lead to azole resistance and adverse drug-drug interactions.
The echinocandins are an increasingly used first-line therapy for critically ill patients with invasive candidiasis in the ICU of developed countries (Sobel et al 2007). Several properties make echinocandins attractive for treatment of invasive fungal infections: broad activity spectrum against Candida, lack of azole cross-resistance which allows the use of combination therapies, high clinical efficacy and low risk for adverse drug-drug interactions. Echinocandins are mainly metabolized by the liver and is unaffected by renal dysfunction. However, echinocandins confer a higher cost and is not readily available in developing nations.
Inappropriate antibiotic treatments and antibiotic misuse have been a major contributing factor in the emergence of resistance bacteria. Furthermore, inappropriate antibiotic treatment is one of the major contributing factors in the development of invasive candidemia in critically ill surgical patients. Antibacterial agents lead to the suppression of commensal intestinal flora, which can inhibit Candida growth and prevent its adherence to mucosal cells (Stone et al 1974). Critically ill surgical patients are prone to measures that can disrupt the normal intestinal barrier such as physical disruption of anatomical barriers due to surgery, intestinal ischemia, bowel obstruction, immunosuppression, and malnutrition. An immunosuppressed state can lead to an increased risk of invasion by low virulent pathogens such as Candida. The gut-associated lymphoid tissue (GALT) in the human gastrointestinal tract is a mucosal innate defense system that protects against invasion by pathogens. Host defenses in the GALT have been associated with innate phagocytic cells, which protect against dissemination, mediated by a specific γδ-T cell subset population, which prevent colonization of pathogens (Hajjeh et al 2004). Immunosuppression is a common measure following surgery and increases the patient's risk of developing invasive fungal disease. Malnutrition is another major concern for patients in third-world countries and can alter the commensal intestinal flora into a state that promotes Candida overgrowth and colonization. The implementation of a pro-biotic nutrition plan for all patients following surgical procedures could limit the risk of developing disseminated candiasis and replace the commensal microbes responsible for the inhibition of Candida growth and colonization.
A final concern to address in terms of public health is the development and spread of nosocomial candidemia. Candida colonization of hospital workers' hands may facilitate horizontal transmission of the pathogen particularly if they are involved in post-surgical care of the patients. For instance, the handling of central venous or urinary catheters by a nurse carrying Candida can serve as an increased risk for candidemia in surgical patients and this risk may only be elevated with prolonged stays in the ICU. This problem is especially relevant in resource-poor nations as poor sanitation habits and lack of proper health care techniques due to perhaps the disruption of resources through military conflict, lack of sanitary food/water, or overcrowding in hospitals can lead to increased risks of nosocomial infections. The education of third-world health care workers on the subject and establishing the practice of hygiene techniques will dramatically reduce the risk of nosocomial infections (including fungal infections) in the ICU. Perhaps health care workers can be instructed to wear personal protective equipment (gloves, face mask, etc) when administering care, discontinue the reuse of catheter tubes to cut costs, and not to overcrowd critically ill patients in the ICU. Adoption of simple sanitation practices will work to greatly reduce transmission of nosocomial fungal infections.
The incidences of candidemia in surgical patients in resource-poor nations is increasing at an alarming rate given the difficulty in diagnosis, emerging antifungal resistance, and the high mortality and morbidity that is associated with invasive candidiasis. Further research that aims at understanding the epidemiology of invasive fungal infections can provide insights into the development of risk stratification strategies to minimize disease in critically ill surgical patients in the ICU. A more stringent clinical assessment of critically ill surgical patients must be adopted to identify fungal infections, even in moderately ill patients who are still at risk of developing invasive, disseminated fungal infections. Clinical thresholds must prophylaxis and initiation of antifungal treatment must be lowered, since traditional methods of multiple blood cultures or positive biopsies before treatment are too late to prevent serious illness and death. More research is needed to develop diagnostic tools that can distinguish between infection from colonization and invasion. New intervention strategies must be adopted where the misuse of antibiotics are limited and more definitive laboratory tests used to identify Candida species infection to initiate the surgical patient on EPT using low doses of minimally less toxic antifungals to prevent life-threatening invasive disease. A novel idea involves the ability to alter the gastrointestinal microbiome to facilitate an environment that restricts growth and colonization of Candida. Overall, the best intervention strategies for invasive candidiasis in surgical patients in resource-limited settings would involve early detection of invasive fungal infections, prevention of its spread in the ICU, and prophylactic/pre-emptive therapy that would be more efficient and resource-effective by decreasing the need for costly higher efficacy antifungals, risk of antifungal resistance and length of ICU stay.
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