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Acs0819 Fungal Infection

This document discusses fungal infections in surgical patients and provides guidance on evaluating and managing patients at risk of Candida infection. Key points: - Fungal infections are an important cause of morbidity/mortality in surgical settings, especially in critically ill, transplant, and neonatal patients. - Colonization is distinguished from infection, though colonization is a risk factor. Diagnosis of infection considers culture results and clinical signs/symptoms. - A diagnostic algorithm is provided to guide evaluation and treatment based on risk factors, culture results, and clinical presentation. Empiric antifungal therapy and source control are recommended for higher-risk situations.

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© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 1 19 FUNGAL INFECTION Pamela A. Lipsett, M.D., F.A.C.S., F.C.C.M. Approach to the Surgical Patient at Risk for Candidiasis Fungal infections remain an important cause of morbidity and may experience Candida colonization at a single site. 2-7 The colo- mortality in surgical settings, with critically ill patients, transplant nization index (the number of sites tested divided by the number patients, and sick neonates all being especially vulnerable. Over of sites colonized) and the corrected colonization index (the num- the past few decades, technological and scientific advancements ber of sites tested divided by the number of sites showing heavy have improved physicians’ ability to sustain life in critically ill growth) have been proposed as criteria for selecting a high-risk patients; developments in chemotherapeutics and immune-based patient population to be considered for possible early preemptive therapies have yielded increased survival for many cancer patients; or therapeutic intervention.3,8,9 When test results from multiple organ transplantation has evolved dramatically; and the use of sites show no evidence of fungal colonization, it is almost certain invasive therapies (e.g., ventricular assist devices) has increased that no fungal infection is present.3,6,9 markedly. With these changes has come an increase in the inci- dence of serious Candida infections,1 as well as an increase in the Infection incidence of the less common (but nonetheless potentially fatal) At a basic level, fungal invasion or infection might be defined as noncandidal infections caused by Aspergillus and the Zygomycetes isolation of a fungal pathogen from a patient with signs and symp- Mucor and Rhizopus. toms of an infection. As applied to fungal pathogens, however, this Despite the significant progress in the supportive and intensive definition is an oversimplification. Clinicians relying on such a care of patients at risk, the development of a number of new and simplified definition would be prone to mistake some instances of useful antifungal agents in the past decade, and the noteworthy fungal colonization for cases of true fungal infection. A degree of improvements in therapeutic approaches to fungal infections, consensus has been reached regarding what constitutes a fungal physicians’ ability to diagnose these infections in a timely fashion infection in a neutropenic patient,10 but to date, no such consen- remains limited, and patient outcomes remain poor. Antifungal sus has been achieved as to what constitutes fungal infection in a prophylaxis has emerged as a potential means of reducing the nonimmunocompromised patient.2,8,11-18 occurrence of serious fungal infections. In patient populations esti- Given that it is not possible to establish a definitive diagnosis of mated to be at high risk for acquiring a fungal infection, antifun- fungal infection in all cases, it is often reasonable to express the gal prophylaxis has reduced infection rates by about 50%; howev- diagnosis in terms of the degree of certainty about the presence of er, it has not been shown to improve mortality significantly. infection. Fungal infections can thus be classified as definite or This chapter outlines an approach to the workup and manage- probable.10 In brief, a definite fungal infection is present when ment of the nonneutropenic surgical patient with a suspected can- deep tissue invasion is seen on a biopsy or culture from a sterile didal infection, taking into account epidemiology, risk factors, site in conjunction with clinical or radiologic abnormalities.10 diagnostic evaluation, and therapy. Noncandidal infections (asper- Unfortunately, there is currently no agreement as to what signs gillosis and zygomycosis) are considered as well. and symptoms constitute a probable or possible fungal infection in a nonneutropenic patient.16-18 Definition and Classification TYPES OF FUNGAL INFECTION FUNGAL COLONIZATION VERSUS FUNGAL INFECTION Candidemia A positive blood culture has traditionally been the gold standard Colonization for the diagnosis of candidemia and is now universally accepted as Fungal pathogens can be isolated under a number of clinical establishing the presence of a fungal infection.16,17 Because blood- conditions. 2-7 Isolation of a fungal pathogen in the absence of any borne Candida can originate from a variety of different sites— signs or symptoms of clinical infection is termed colonization. including deep-seated infections (via hematogenous spread), Fungal colonization, by itself, does not suffice to define fungal catheter-related infections, and the gastrointestinal tract (via infection, but it remains an important risk factor for future inva- translocation), to name but a few—it is imperative that clinicians sive fungal infection. It is believed that once colonization has evaluating candidemic patients search carefully for all potential occurred, Candida pathogens can gain access to the bloodstream sources of infection. The search should include assessment of via three major routes: through the GI tract mucosal barrier, from intravascular catheter sites, evaluation for peripheral septic throm- an intravascular catheter, and from a localized source of fungal bophlebitis, and examination of the abdomen as a possible site of infection. 2-7 A prolonged stay in an intensive care unit is associat- infection. Because metastatic infection may develop from can- ed with an increased risk of fungal infection. Depending on the didemia, new sources of fungal pathogens (e.g., endophthalmitis, patient population and the rigor and thoroughness with which infective endocardititis, hepatosplenic candidiasis, and arthritis) sites are cultured, as many as 50% to 80% of critically ill patients may arise over time.16,17
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 2 Identify patient at risk for Candida infection Major risk factors include • Previous bacterial infection and therapy with multiple antibiotics. • Isolation of Candida from ≥ 2 sites. • Disruption of the intestinal mucosal barrier (total parenteral nutrition, severe diarrhea, colitis, major operation, trauma, or extensive burns). • Immunosuppression (neutropenia, cancer, organ transplantation, hemodialysis, or extensive burns). Other risk factors include • Central venous catheters • Urinary catheters • Prematurity • Neonates • Heroin addiction. Initiate measures to diagnose candidiasis Look for findings that may signal hematogenous candidiasis: • Endophthalmitis • Suppurative thrombophlebitis • High-grade candiduria without instrumentation of the bladder or the renal pelvis. Obtain cultures of sputum, oropharynx, stool, urine, drain sites, and blood. Obtain 2 sets of blood cultures daily for 2 days (or longer if the patient remains febrile). Consider serologic tests and histologic analyses (see text). Look for findings that may signal hematogenous candidiasis: • Endophthalmitis • Suppurative thrombophlebitis • High-grade candiduria without instrumentation of the bladder or the renal pelvis. Exclude other possible causes of persistent fever. Blood cultures are positive for Candida, or clinical or laboratory signal of potential hematogenous candidiasis is present Patient is hemodynamically stable, does not have high-grade candidemia, and does not appear to have organ infection Remove all venous catheters (preferred). or Leave venous catheter in place initially, and consider removal if clinical condition deteriorates or does not improve after 2 days of therapy. Patient is infected or colonized by C. albicans, Patient is infected or colonized by C. tropicalis, C. parapsilosis, or other germ C. krusei, C. glabrata, or C. lusitaniae tube–positive candidal organism Give an echinocandin (e.g., caspofungin, Give fluconazole, 6 mg/kg/day I.V. for 2–3 days, 70 mg I.V., loading dose, followed by 50 then, if possible, switch to 400 mg/day p.o. mg/day I.V.). Treat for 7–10 days (patient should be free of Treat for 5–7 days (patient should be signs and symptoms of infection for 5 days free of signs and symptoms of infection before treatment is ended). for 5 days before treatment is ended).
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 3 Approach to the Surgical Patient at Risk for Candidiasis Blood cultures are negative for Candida, and no Blood cultures are negative for Candida, clinical or laboratory signal of potential hematogenous no clinical or laboratory signal of potential candidiasis is present, but Candida is isolated hematogenous candidiasis is found, and from ≥ 2 remote sites (≥ 1 site for C. tropicalis) Candida is isolated from ≤ 1 remote site (0 sites for C. tropicalis) Consider fluconazole, 400 mg/day I.V. for 2–3 days, then 400 mg/day p.o. If decolonization is required when a Continue surveillance cultures weekly. resistant species is present, consider an alternative agent, such as an echinocandin or amphotericin B, 0.5 mg/kg/day. (Consider adding flucytosine, 25 mg/kg/day p.o. in 2 divided doses, for C. glabrata and C. lusitaniae.) Continue treatment for as long as patient remains critically ill. Patient is hemodynamically unstable, has high-grade candidemia, or shows evidence of organ infection Remove all venous catheters. Treat any associated syndromes of hematogenous candidiasis (e.g., endophthalmitis, pericarditis, suppurative thrombophlebitis, endocarditis). Patient is infected or colonized by C. albicans, Patient is infected or colonized by C. tropicalis, C. parapsilosis, or other germ tube–positive C. krusei, C. glabrata, or C. lusitaniae candidal organism Give an echinocandin, or give amphotericin B, Give fluconazole, 800 mg/day I.V. (Consider adding 0.7–1.0 mg/kg/day I.V. (Consider adding flucytosine, 25 mg/kg/day p.o. in 2 divided doses.) flucytosine, 25 mg/kg/day p.o. in 2 divided Treat for 10–14 days after disappearance of all signs and doses. Also consider adding G-CSF, 300 g/day.) symptoms of infection. Treat for 10–14 days after disappearance of all signs and symptoms of infection.
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 4 A positive blood culture is an indication for initiation of anti- 9.2% of all bloodstream infections diagnosed in the surgical ICUs, fungal therapy.16,17 However, systemic Candida infection may be and more than half of the isolates were non-albicans species. present even in the absence of a positive blood culture. Blood cul- The morbidity and mortality associated with fungal infections tures have a 50% false-negative rate and may take as long as 4 are considerable.27-30 Between 1980 and 1997, multiple-cause days to yield results. Accordingly, clinicians should not assume mortality from mycoses in the United States rose from 1,557 that the absence of a positive blood culture or tissue biopsy means deaths to 6,534 (most of which were associated with Candida, that a fungal infection is not present; nearly 44% of patients with Aspergillus, and Cryptococcus species).27 Two case-control studies a negative blood culture have evidence of disseminated fungal performed at a single institution 15 years apart revealed no infection at autopsy.19 Increasingly, candidal invasion is being improvement in the mortality attributable to candidemia: the observed on autopsy specimens in cases where the diagnosis had attributable mortality was 38% in the earlier study (1983–1986)31 not been clinically suspected.20 and 49% in the later one (1997–2001).32 Moreover, fungal infections place a substantial economic bur- Disseminated Candidiasis den on the health care system.28-31,33 In one study, costs were, on Patients in whom several noncontiguous organs are infected by average, $41,000 (in 1993 dollars) higher for high-risk ICU pa- Candida species are considered to have a disseminated infection tients than for low-risk ICU patients.30 In a large European study, acquired through hematogenous spread. To establish the diagno- patients with Candida infection stayed longer both in the ICU sis, the organism must be identified by means of histologic analy- (12.7 days) and in the hospital (15.5 days), and the direct costs sis, culture of tissue samples obtained from at least one internal associated with their care were higher by almost 16,000 euros.30 In organ, or both, and there should be radiographic, pathologic, or an earlier study from my institution (Johns Hopkins Hospital), the culture-derived evidence of infection in at least one other organ. attributable increase in the cost of ICU care for surgical patients The presence of candidemia in association with Candida skin with fungal infections was $21,590 (in 1996 dollars).29 lesions or of endophthalmitis in a setting consistent with a diag- IDENTIFICATION OF AT-RISK nosis of Candida infection is also diagnostic of disseminated can- SURGICAL PATIENTS didiasis.17 Hepatosplenic candidiasis is a more chronic form of disseminated Candida infection that typically develops in neu- The risk factors associated tropenic cancer patients.17 with the acquisition of fungal infections have been well defined [see Table 1].2,11-14,34,35 Epidemiology and Risk Factors General factors contributing to both the risk of incurring a fun- MAGNITUDE OF THE PROBLEM IN SURGICAL PATIENTS gal infection and the outcome to be expected after such an infec- Hospital-acquired, invasive Candida infections have become tion include disruption of cutaneous or mucosal barriers, defects increasingly common causes of morbidity and mortality in hospi- in the number and function of neutrophils or in cell-mediated talized patients. Between 1979 and 2000, the incidence of immunity, metabolic derangements (as seen in preoperative and Candida bloodstream infections increased by 207%.1,21,22 Data postoperative patients), and extreme youth or advanced age (see from the National Nosocomial Infections Surveillance System above). In an effort to create a rule for identifying a patient pop- (NNIS) indicated that in the period from 1989 to 1998, C. albi- ulation with at least a 10% risk of fungal infection, a database of cans was the seventh most common cause of nosocomial infection 2,890 patients who had stayed in an ICU for more than 4 days in the ICU setting, accounting for 4.9% of bloodstream infections was subjected to retrospective review and statistical modeling.14 and 4.8% of surgical site infections.23 Data from another nation- The best rule the authors were able to formulate included either al surveillance study, Surveillance and Control of Pathogens of the use of a systemic antibiotic or the presence of an intravenous Epidemiological Importance (SCOPE), indicated that in the peri- central line, along with any two of the following: total parenteral od from 1995 to 2002, Candida species, as a group, were the nutrition, any dialysis, surgery, pancreatitis, or immunosuppres- fourth most common cause of nosocomial bloodstream infection sive agents. This rule captured 34% of patients with fungal infec- (after coagulase-negative staphylococci, Staphylococcus aureus, and tions. More important, it had a high negative predictive value and enterococci).24 In ICU patients, Candida species were the third could be used to help exclude fungal infection as a likely possibil- most common cause of nosocomial bloodstream infection. ity. Several other authors have attempted to predict a high-risk Between 1995 and 2002, the percentage of bloodstream isolates patient population, but to date, these models have not been used accounted for by Candida species rose from 8% to 12%. successfully in published papers or clinical trials and thus have not Population-based studies have identified certain demographic entered clinical practice.8,15 groups that appear to be at special risk for invasive Candida infec- Of surgical patients, those in the ICU, those who have sus- tion.1,25 One such group consists of patients at the extremes of age, tained trauma or burns, and those who have received solid organ with neonates being one of the most rapidly growing at-risk transplants (liver, pancreas, and small bowel transplant recipients, groups. Race appears to play a role as well. In one study, the inci- in particular) appear to be at higher risk for invasive fungal infec- dence of fungal infections in neonates younger than 30 days was tion. The incidence of invasive Candida infection in liver trans- reported to be 466/100,000 (960/100,000 in black neonates and plant patients ranges from 1.3% to 15% for those receiving anti- 238/100,000 in white neonates).25 Surgical patients are also at par- fungal prophylaxis36-38 and may be as high as 23% for those not ticular risk for fungal infection: more than 50% of all fungal infec- receiving prophylaxis.39 In pancreas transplant recipients, the inci- tions occur in this patient population.24 In the National dence of invasive fungal infection is approximately 9%40; in small Epidemiology of Mycosis Survey (NEMIS), 42 Candida blood- bowel transplant recipients, it may be as high as 59%.41 Longer stream infections were identified in 4,276 patients admitted to six stays in the ICU, GI surgery, and the presence of invasive central surgical ICUs between 1993 and 1995, for an incidence of 9.8 venous lines appear to impart special risk to surgical patients.3,26,42 such infections per 1,000 admissions.26 Candida species caused One of the most important steps in treating fungal infection is rec-
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 5 Table 1 Clinical Presentation and Diagnostic Methods for Common Fungal Infections 147 Host Fungus Major Clinical Presentations Diagnostic Methods Normal host Aspergillus Allergic bronchopulmonary Serum IgE, precipitins Blastomyces Acute pneumonitis: chronic lung or skin Culture, tissue Candida Vaginitis, thrush, candidemia, I.V. catheter Culture/smear Coccidioides Acute pneumonitis, chronic cavitary, pulmonary nodule Precipitins, complement fixation, culture Cryptococcus Pulmonary, meningitis Culture, latex agglutination Histoplasma Acute pulmonary, progressive dissemination in infants and elderly, Culture, antigen detection chronic cavitary in chronic airway obstruction Compromised host Diabetes mellitus Candida Disseminated, pyelonephritis, vaginitis Culture/smear C. glabrata Pyelonephritis Culture Zygomycetes (Mucor, Rhizopus) Rhinocerebral, paranasal, pulmonary, gastrointestinal, cutaneous Culture, tissue Malignancy or corticosteroids Aspergillus Invasive/lung, sinuses, disseminated Culture, tissue Candida Fungemia, acute and chronic disseminated candidiasis Culture, tissue Coccidioides Disseminated Culture, precipitins, complement fixation Cryptococcus Pulmonary, meningeal, disseminated Culture, latex agglutination, India ink preparation Dematiaceous fungi Lung, sinuses, brain, disseminated Culture, tissue Fusarium Lung, sinuses, cellulitis at site of onychomycosis, disseminated Culture, tissue Histoplasma Progressive disseminated Culture, antigen detection C. glabrata Disseminated Culture, tissue Trichosporon Disseminated Culture, tissue Zygomycetes (Mucor, Rhizopus) Rhinocerebral, paranasal, pulmonary, gastrointestinal, cutaneous, Culture, tissue disseminated Extensive surgery and previous antibiotic therapy Candida Vaginitis, thrush, esophagitis, disseminated Culture, tissue C. glabrata Disseminated Culture ognizing that a particular patient is at risk for this condition.16-18 As absence of bladder instrumentation may each provide special clues noted [see Definition and Classification, Fungal Colonization ver- suggesting an increased risk for fungal infection. A careful eye sus Fungal Infection, above], fungal colonization is certainly an examination to identify the presence of candidal infection should important risk factor for invasive fungal infection.2-7 be performed while the results of cultures of various sites are being Whereas most fungal infections probably originate from endoge- awaited [see Investigative Studies, Culture, below], and a repeat nous sources, some undoubtedly originate from interactions with examination should be performed after therapy for proven can- patients’ external environments—in particular, from interactions didemia. Candidal endophthalmitis may remain asymptomatic with health care workers.43-47 Cross-infection with Candida via until late in the course of infection.17,18,50,51 hand transmission has been described in several studies.43-47 In one The presence of peripheral suppurative phlebitis that fails to yield study, 6% of nurses’ hand cultures contained fungal pathogens, bacteria or does not respond to antibacterial agents may be an early with which 2 of 57 patients with candidemia could be linked by clue to the presence of hematogenous candidiasis. Gentle squeezing means of DNA fingerprinting.48 In another, nail contamination in of the venous catheter exit site may express pus that yields Candida the operating room was linked to an outbreak of C. tropi- species on a smear or culture. Surgical excision of the infected vein calis–infected sternal wounds.47 Parenteral nutrition has also been usually reveals Candida infection in its lumen.17,18,50,52 identified as a potential source of contamination with Candida.49 The presence of high-grade candiduria in surgical patients who have not undergone instrumentation of the renal pelvis or the bladder suggests hematogenous candidiasis and should prompt a Clinical Evaluation workup for this infection. In this setting, candiduria may result Patients with candidemia or from seeding or filtering through the kidney.17,18,50,53-58 disseminated candidiasis can Fever is sometimes the only sign of infection; however, it may present with a wide variety of be absent in infected patients who are receiving corticosteroids. clinical signs and symp- Because fungal pathogens interact with the Toll-like receptors toms.11,17,18,50 Identification of (TLRs), just as bacterial pathogens do, patients with fungal high-risk patients is probably the infections may present with the systemic inflammatory response single most important step in syndrome (SIRS) or septic shock. Accordingly, the diagnosis establishing the diagnosis of candidiasis.8,14,15,17,18,36,50 Although should be seriously considered in high-risk patients who are per- they are not very common presenting signs or symptoms, candidal sistently febrile. Because of the high mortality associated with endophthalmitis, suppurative phlebitis, and candiduria in the fungal infection, empirical antifungal therapy is recommended
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 6 Table 2 Antimicrobial Agents of Choice for Candidal Infections* Infection Agent of Choice Alternative Agents Comments Hematogenous Candidemia and acute dis- Fluconazole, or echinocandin, Lipid formulations of ampho- Fluconazole should be given for C. albicans; if a fluconazole- seminated candidiasis or amphotericin B ± flucytosine tericin B resistant species is known to be present or azole use has been prolonged, one of the echinocandins should be select- ed; amphotericin B should be selected in unusual cases when Candida is not the infecting pathogen; a two-drug regi- men can be given to hemodynamically unstable patients with persistent high-grade fungemia Candida endophthalmitis Fluconazole Amphotericin B + flucytosine; Patients with vitral involvement require vitrectomy in addition to voriconazole; caspofungin antifungal therapy Suppurative phlebitis Fluconazole + flucytosine Amphotericin B + flucytosine The central venous catheter should be removed and the infect- ed vein excised Endocarditis Amphotericin B + flucytosine Fluconazole + caspofungin Surgical replacement or repair of valves is essential to prevent death from embolization or cardiac failure; oral fluconazole should be given after successful completion of a prolonged course of amphotericin B therapy; there is anecdotal evi- dence that fluconazole and caspofungin can be beneficial Pericarditis Amphotericin B Fluconazole — Prosthetic device–related Fluconazole or amphotericin B — Removal of device is required for successful therapy infection Arthritis Fluconazole — — Osteomyelitis Amphotericin B Fluconazole Surgical drainage of pus is required Meningitis Amphotericin B + flucytosine Fluconazole + flucytosine — Nonhematogenous Oropharyngeal Otherwise normal host Nystatin Ketoconazole, fluconazole, — clotrimazole troches Patients at risk for hema- Fluconazole Ketoconazole — togenous infection (e.g., cancer patients, surgical patients) Deep candidiasis Esophagitis and GI Fluconazole Echinocandin; amphotericin B Amphotericin B should be reserved for cases of failure of flu- candidiasis conazole therapy without endoscopic evidence of other causes of disease Peritonitis and intra- Fluconazole Echinocandin; amphotericin B — abdominal Wound Fluconazole Amphotericin B Antifungal therapy should be given to patients who do not respond to antibacterial therapy Urinary tract Cystitis Fluconazole Amphotericin B Fluconazole is preferable because of its high drug concentra- tion in urine and because it is better tolerated; echinocandins Pyelitis appear to yield low urinary tract concentrations Without papillitis Fluconazole — With papillitis Fluconazole + flucytosine Amphotericin B — Pyelonephritis Fluconazole + flucytosine Amphotericin B — *Therapy is individualized on the basis of the patient's clinical condition and the infecting species. for early treatment of a clinical occult infection or for prevention inexpensive test is the germ tube test, which can distinguish C. albi- of a new infection. cans (positive result) from other Candida species. More than 90% of C.albicans isolates produce germ tubes when incubated in serum for 2 to 3 hours at 37° C. Several commercial products are now Investigative Studies available to aid in the rapid identification of Candida species.59,60 Positive cultures from nonsterile sites (sputum, urine, and wound CULTURE drainage) must be interpreted with caution because of the frequent The workup of a surgical patient with suspected hematogenous occurrence of Candida as a normal commensal of humans. Such candidiasis begins with a complete set of cultures of sputum, cultures are useful mainly as an indication of colonization and, con- oropharynx, stool, urine, all drain sites, and blood [see Table 2]. sequently, of the risk of infection in the appropriate setting. Candidiasis rarely develops in patients whose cultures show no evi- ANTIBODY DETECTION, ANTIGEN DETECTION, POLYMERASE dence of Candida at any site.6,7,43 Obtaining more than six sets of CHAIN REACTION, AND METABOLITE ASSAY blood cultures has little value, and there is no evidence to support obtaining arterial cultures. Once a blood culture has turned posi- Many published papers and commercial products have touted tive for Candida, the species must be rapidly identified so that the the benefits of various auxiliary serologic tests in the identification correct antifungal agent can be selected for treatment. A rapid and of patients with fungal infection. At present, however, assays for
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 7 fungal wall elements (mannan), D-arabinitol (a cell membrane Management of Candidemia metabolite), or enolase (cell cytoplasm) appear to be of limited and Acute Disseminated value, as do polymerase chain reaction (PCR)–based assays.50,59-67 Candidiasis These tests have mixed sensitivities and specificities that prohibit Patients who have Candida their widespread application. A 2005 study evaluated the assay for infections can now be treated (1→3)-β-D-glucan, an important constituent of fungal cell walls with any of a number of anti- that is absent from bacterial cell walls.59 At a cutoff value of 60 fungal agents, including pg/ml, the assay had a sensitivity of 69.9% and a specificity of amphotericin B, the azoles (flu- 87.1%, with a positive predictive value of 83.8% and a negative conazole, itraconazole, voriconazole, and posaconazole), flucyto- predictive value of 75.1%. At a cutoff value of 80 pg/ml, it had a sine, the lipid amphotericin products (see below), and the sensitivity of 64.4% and a specificity of 92.4%, with a positive pre- echinocandins (caspofungin, micafungin, and anidulafungin) [see dictive value of 89% and a negative predictive value of 73%. Of Table 3].68-79 Randomized, controlled trials designed to determine the 107 patients with proven candidiasis, 81.3% showed positive noninferiority have demonstrated that several agents—namely, flu- results at a cutoff value of 60 pg/ml, and 77.6% showed positive conazole, itraconazole, voriconazole, caspofungin, and micafun- results at a cutoff value of 80 pg/ml.This screening test may be of gin—can be considered not inferior to the previous standard ther- some use in following high-risk patients, especially when per- apy—namely, amphotericin B or lipid formulations thereof.68-78 formed serially. Because of the emergence of non-albicans species as significant pathogens, it is vital that surgeons be aware of the variety of HISTOLOGIC ANALYSIS Candida species that may be encountered and the relevant drug Analysis of fungal smears is a relatively insensitive method of sensitivities.80-83 Most C. albicans isolates are sensitive to all of the diagnosing candidiasis and other fungal infections in otherwise currently available agents, but some low-level resistance has been sterile sites (e.g., joint fluid, peritoneal fluid, vitreous humor, or reported, especially with previous long-term exposure to azoles at cerebrospinal fluid).67 Centrifugation of these fluids and examina- low dosages.80-83 C. glabrata may be resistant to fluconazole or tion of the sediment may improve the diagnostic yield.50 require some modification of the dosage; C. krusei is resistant to Conventional fungal stains, such as hematoxylin-eosin, periodic fluconazole; and C. lusitaniae may be resistant to amphotericin acid–Schiff (PAS), and Gomori methenamine-silver (GMS), are B.80-83 The selection of the initial antifungal agent to be used is useful. The most sensitive stain is calcofluor white, but unfortu- based on estimation of the likelihood of infection, assessment of nately, it requires fluorescent microscopy. Deep tissue biopsy pro- the probable sensitivity or resistance of the fungal species, consid- vides a definitive diagnosis of candidiasis. eration of specific patient risk factors (e.g., renal or hepatic insuf- Table 3 Antifungal Chemotherapy68-79 Route of Drug Indications Major Side Effects Administration Hematogenous and deep-seated candidiasis; aspergillosis; blastomy- Anemia, headache, chills, fever, nausea, renal dysfunc- Amphotericin B I.V., intrathecal cosis; coccidioidomycosis; histoplasmosis; cryptococcosis tion, hypotension, tachypnea, hypokalemia, phlebitis Clotrimazole Oropharyngeal candidiasis Oral — Candidiasis (bloodstream infection, endocarditis, urinary tract infec- Leukopenia, thrombocytopenia, liver dysfunction, Flucytosine Oral diarrhea tion); cryptococcosis Oropharyngeal and esophageal candidiasis; hematogenous candidal Fluconazole infection; other candidal infections (e.g., urinary tract infection, peri- Oral, I.V. Nausea and vomiting, skin rash, liver dysfunction tonitis); meningeal coccidioidomycosis; cryptococcosis Itraconazole Histoplasmosis; blastomycosis; aspergillosis Oral Nausea, vomiting, liver dysfunction Candidiasis (chronic mucocutaneous candidiasis or oropharyngeal Ketoconazole candidiasis); candiduria; blastomycosis; coccidioidomycosis; histo- Oral Hepatotoxicity, nausea or vomiting, occasional suppres- plasmosis; chromomycosis; paracoccidioidomycosis sion of adrenal function Aspergillosis (invasive); candidiasis (chronic mucocutaneous candidia- Photophobia, visual hallucinations, photosensitivity/rash, Voriconazole sis or oropharyngeal candidiasis) and hematogenous candidal infec- Oral, I.V. drug interactions, hepatotoxicity, nausea and vomiting, tion; candiduria; Fusarium or Scedosporium infection fever Abdominal pain, nausea or vomiting, diarrhea, drug inter- Posaconazole Disseminated candidiasis; prophylaxis of aspergillosis or oropharyn- Oral actions, prolonged QT interval, hyperbilirubinemia, he- geal canidiasis in immunocompromised patients. patotoxicity, occasional suppression of adrenal function Candidiasis (chronic mucocutaneous candidiasis or oropharyngeal Caspofungin candidiasis); hematogenous candidal infection; aspergillosis I.V. Rash, pruritus, nausea, vomiting, thrombophlebitis, (refractory) headache, fever, increased liver enzymes Micafungin Candidiasis (chronic mucocutaneous candidiasis or oropharyngeal I.V. Rash, pruritus, nausea, vomiting, diarrhea, throm- candidiasis); candidiasis prophylaxis; stem cell transplantation bophlebitis, headache, fever, increased liver enzymes Candidiasis (chronic mucocutaneous candidiasis or oropharyngeal Hypokalemia, diarrhea Anidulafungin I.V. candidiasis); hematogenous candidal infection
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 8 ficiency), and determination of whether the patient should receive ness analysis, both amphotericin B deoxycholate and its lipid the agent orally or intravenously.68-79 In addition, selection of the products provided fewer discounted lives saved than either flu- best antifungal agent for a specific at-risk or infected patient is conazole or caspofungin did (according to the data available at the facilitated and enhanced by familiarity with the typical pathogens time of publication).89 in the local community. At present, there are no evidence-based guidelines concerning Several oral and intravenous azoles are available for clinical the optimal duration of therapy.17,18 This decision should be based use.17,18,69,72,74-77 Clotrimazole and miconazole are not suitable for in part on the severity of the patient’s illness, as well as on his or systemic therapy. Ketaconazole has very poor and erratic GI her immune constitution. In general, therapy should be continued absorption and thus is not used for systemic therapy. Itraconazole for at least 14 days after the last positive cultures and the resolu- also has very erratic GI absorption and therefore should not be tion of all signs and symptoms of infection in the most seriously ill used for systemic therapy either.17,18 A single trial conducted in a patients. Shorter courses of therapy may be appropriate in careful- pediatric population found that itraconazole at a dosage of 10 ly selected patient populations without signs of hemodynamic mg/kg/day orally was clinically similar to fluconazole at a dosage of instability or evidence of distant metastatic infection. 200 mg/day orally for treatment of candidemia.84 The I.V. agent CATHETER MANAGEMENT fluconazole is a well-tolerated triazole that shows good activity in candidemic patients. Individual clinical trials involving nonneu- The fundamental controversy about whether central venous tropenic patients with candidemia, as well as a meta-analysis of access lines should be removed when identified in patients with these trials, indicate that amphotericin deoxycholate and flucona- candidemia stems from the multiple routes by which infection zole yield similar outcomes in terms of overall mortality, attribut- occurs in different patient populations.91-94 When the GI tract is able mortality, and clinical and microbiologic response but differ the source of candidemia (as in cancer patients with mucositis),95 in terms of toxicity, with fluconazole appearing to be less toxic.85- catheter removal is unlikely to yield any significant benefit. On the 88 Thus, it is reasonable to use fluconazole to treat patients with other hand, when an I.V. catheter is a source of ongoing can- candidemia. didemia, there is some evidence to suggest that removal of the The 2004 treatment guidelines published by the Infectious catheter may shorten the time to blood clearance and perhaps Disease Society of America suggest that physicians may choose even improve overall survival. In a study examining catheter among three alternatives for primary treatment of candidemia in exchange in patients without cancer, replacement of all vascular nonneutropenic adult patients: (1) amphotericin B deoxycholate catheters shortened the duration of candidemia from 5.6 days to (0.6 to 1.0 mg/kg/day, or one of the lipid formulations); (2) flu- 2.6 days.91 The current state of knowledge regarding the impor- conazole (400 to 800 mg orally or I.V.); and (3) caspofungin tance of biofilm, the penetration of antifungal agents, and the (loading dose of 70 mg I.V., followed by 50 mg/day I.V. or, if the attachment of new pathogens tends to favor removal of catheters patient has severe obstructive hepatic disease, 35 mg/day I.V.).17 If to the extent possible after candidemia. Given the available data, the species is known or believed to be C. albicans, fluconazole physicians should consider removing all intravascular catheters (loading dose of 12 mg/kg I.V., followed by I.V. infusion of 6 from inpatients who have candidemia with persistent fever, persis- mg/kg/day) is appropriate. Fluconazole has excellent oral bioavail- tent or high-grade fungemia, or C. parapsilosis infection (which is ability and frequently can be delivered orally after the first few more likely to be catheter related than infection with another days. Dose adjustments must be considered if renal insufficiency Candida species would be). is present. 17,18,69,72,74-77 If the patient has received long-term azole IMMUNOTHERAPY therapy, is known to be colonized with C. glabrata or C. krusei, or both, then one of the echinocandins—either caspofungin (loading Despite the availability of newer antifungal agents, treatment dose of 70 mg I.V., followed by 50 mg/day I.V.) or micafungin failures remain significant problems. Physicians’ familiarity with (100 mg/day I.V.)—should be administered.68,71,73,78,89 If the the roles of both innate and acquired immunity in the acquisition species then proves sensitive to fluconazole, this agent may then be and resolution of fungal infections has grown substantially over the given orally to continue therapy. Although clinical trials have past several years.96 The development of adjunctive immunother- shown voriconazole (6 mg/kg I.V. every 12 hours for the first 24 apies based on an understanding of the host immune response has hours, then 3 mg/kg I.V. every 12 hours, p.o. switch 200 mg every led to preliminary trials with cytokines such as interferon gamma 12 hours) to be an acceptable agent for treating candidemia,90 and granulocyte colony-stimulating factor (G-CSF),97 as well as there are many drug interactions and side effects of which the with granulocyte transfusion.98 Although these trials have demon- physician must be aware when using this drug. In particular, strated safety and (perhaps) proof of principle, they do not support patients who have undergone transplantation and those with HIV clinical use of these agents, especially in nonneutropenic patients. infections are very likely to be taking agents that interact with Active investigation into the TLR-mediated pathogen recognition voriconazole. and signal transduction pathway and the means by which Candida The current role of amphotericin B in the treatment of can- evades the TLR-mediated host immune response may lead to new didemia is limited by its toxicity [see Systemic Antifungal Agents, immunotherapies in the future. Because both persons at risk and Amphotericin B, below]. The lipid-associated formulations of host risk factors are identifiable, host vaccination remains a prime amphotericin B are less nephrotoxic than the parent compound.61 focus of investigation into prevention.96 Three such formulations are available: (1) amphotericin B lipid ANTIFUNGAL PROPHYLAXIS complex (Abelcet), (2) amphotericin B colloidal dispersion (Amphocil, Amphotec), and (3) liposomal amphotericin B The use of antifungal prophylaxis remains a controversial (AmBisome). A prospective, randomized trial found Abelcet to be topic,3,99-108 though four recent meta-analyses109-112 and a as efficacious as conventional amphotericin B for treating hema- Cochrane review111 have all concluded that prophylactic adminis- togenous candidiasis.62 If, however, the patient is known to have a tration of antifungal agents to high-risk critically ill or surgical Candida infection, the infection can and should be treated with patients reduces the incidence of invasive fungal infection but has one of the agents previously mentioned. In a 2005 cost-effective- no proven effect on mortality. These analyses illustrate the prob-
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 9 a b c Figure 1 Candida endophthalmitis is common in patients with persistent fungemia. On funduscopy, a charac- teristic white, cotton-wool–like exudate can be seen (a). Cut section of an eye shows Candida retinitis (b). A microscopic view of Candida chorioretinitis is also provided (c).146 lems inherent in attempting to combine data from small trials that The data do not yet support widespread or routine use of anti- employed different agents (ketoconazole and fluconazole) at dif- fungal prophylaxis. Accordingly, it is worthwhile to formulate ferent dosages in different at-risk patient populations. Perhaps the some general conclusions regarding which patients should receive most difficult issue in determining whether antifungal prophylax- antifungal prophylaxis and which agent should be used. It is rea- is should be employed involves the lack of a consensus on how sonable to consider antifungal prophylaxis in patients similar to fungal infection should be defined. Without a well-understood those in the aforementioned studies (see above), including organ end point, it is impossible to decide whether a therapy should be transplant patients3,17,109-112 and patients enrolled in referenced widely applied. clinical trials. In most of these patient populations, fluconazole is To date, there have been eight major studies of antifungal pro- the most appropriate agent for prevention of Candida infection: it phylaxis that are applicable to the critically ill surgical patient pop- has few side effects, it can be administered orally, and out of the ulation.3,102-108 The three largest of these are of particular rele- agents that have been well studied, it is the most reasonably vance. In one study, a large number of liver transplant recipients priced. In view of the increasing reports of resistance, however, the were randomly assigned to receive either placebo or fluconazole use of fluconazole should not be extended to additional patient for a period of 10 weeks (during which administration switched populations, especially those who are less ill and certainly those from I.V. to oral).105 Definitions of fungal infections included both who are at less risk. The key question in making the decision for deep and superficial infections.The authors documented a signif- or against antifungal prophylaxis should be whether the benefits icant decrease in fungal colonization and fungal infection (both achievable in the patient population being considered for prophy- superficial and deep) in the fluconazole group but reported no sig- laxis are significant enough to outweigh the cost and the risk of nificant difference in mortality between groups. Although hepato- eventual (and even expedited) resistance developing with exces- toxicity was absent in the fluconazole group, neurologic toxicity sive use. was higher than in the placebo group, presumably as a conse- ORGAN INFECTIONS quence of increases in cyclosporine levels, which must be adjust- ed in patients receiving prophylactic fluconazole. In a large study that enrolled 220 patients in the medical or sur- Candidal Endophthalmitis gical ICU on or after their third day in the unit, prophylaxis with The diagnosis of candidal endophthalmitis usually implies fluconazole, 100 mg I.V., was compared with placebo.108 The hematogenous spread to multiple organs and the need for sys- patients enrolled in this trial were critically ill, were receiving res- temic antifungal therapy. Identification of eye involvement early in piratory support from a mechanical ventilator, and were undergo- therapy is crucial for preserving visual acuity [see Figure 1].51 ing selective decontamination of the GI tract. Candidemia was Patients who have only chorioretinitis respond better to drug ther- virtually eliminated in the fluconazole group. In addition, the inci- apy alone than patients who show vitreal involvement. Treatment dence of invasive candidal infection was lower in this group (3.9% depends on achieving an adequate concentration of an agent versus 8.9%), and fungal colonization was both less frequent and effective against the fungal pathogen within the vitreous compart- less intense. ment.51 Because antifungal drugs do not penetrate the vitreous Finally, in a single-institution, randomized, double-blind, place- body as well as they do the other ocular compartments,113 patients bo-controlled trial that compared enteral fluconazole (800 mg with vitreal involvement require early vitrectomy in addition to loading dose, followed by 400 mg/day) with placebo for preven- antifungal therapy. tion of fungal infections in high-risk critically ill surgical patients, Fluconazole is currently the drug of choice because of its the authors reported that fluconazole prophylaxis yielded a two- proven efficacy and its higher concentration (20% to 70% of the to threefold reduction in fungal infection but had no effect on corresponding plasma level) in ocular tissue, including the vitre- mortality.3 Using a strict case definition that did not include fun- ous body.51,114 Accordingly, I recommend 800 mg/day of flucona- gal colonization, the intent-to-treat analysis demonstrated 20 zole until a major response is observed, at which time it may be patients with fungal infections (15.3%) in the placebo group and possible to reduce the dose to 400 mg/day. Many other Candida 11 such patients (8.5%), including four with infections that were and non-Candida fungal species may also cause endophthalmitis, unknown at enrollment, in the fluconazole group. The number and in such cases, fluconazole may not provide effective coverage. needed to treat (i.e., the number of patients who would have to If the infecting organism (especially C. krusei) is potentially resis- receive antifungal prophylaxis for a single fungal infection to be tant to fluconazole, the recommended therapy is amphotericin B prevented) was 14.5, a low number that suggests a highly signifi- (0.7 to 1.0 mg/kg/day I.V.), preferably in conjunction with flucy- cant effect. tosine.115 Intravitreal injection of amphotericin B is recommend-
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 10 ed for vitreal infections. Both voriconazole and caspofungin have Successful treatment of fungal arthritis with fluconazole has had limited success in patients with more resistant infections.51 been reported in several cases.122 I recommend giving fluconazole The optimal duration of therapy for endogenous endoph- at a dosage of 400 to 800 mg/day for 6 to 12 months; others sug- thalmitis is unknown. Ophthalmologic consultation is critical in gest giving amphotericin B first for 1 to 2 weeks, then switching to establishing the diagnosis, assessing the patient’s response to ther- fluconazole.17 Fluconazole can be used for short-term therapy, apy, detecting complications, and determining whether early vit- either alone or in combination with surgery, as well as for long- rectomy is indicated to prevent loss of sight.116 term suppressive therapy in patients who are at risk for recurrence or who cannot undergo surgical debridement. In general, surgical Suppurative Thrombophlebitis, Endocarditis, and Pericarditis resection of the involved joint is required. A rare but serious consequence of hematogenous candidemia is Except for sternal infections complicating median sternotomy, suppurative thrombophlebitis, which results from infection of a most cases of candidal osteomyelitis develop through hematoge- vessel traumatized by prolonged catheterization. Endothelial dis- nous spread. Vertebral body involvement is common. Back pain ruption exposes the basement membrane and leads to thrombus and fever may be followed by radiculopathy. Surgical drainage of formation and propagation. Suppurative thrombophlebitis is par- all purulent collections is essential for a good response; however, ticularly serious because intravascular infection results in a persis- surgical debridement of bony lesions may not be needed. tent high-density fungemia. Management of this disease consists Although amphotericin B has been the standard drug of choice for of high-dose antifungal therapy, removal of the central venous candidal osteomyelitis, fluconazole may be considered as an alter- catheter, and excision of the infected vein (when possible).52,117 native. Amphotericin B should not be used for mediastinal irriga- Typically, blood cultures remain positive for several days; some- tion after drainage and debridement of a mediastinal infection, times, they remain positive for as long as 3 to 4 weeks despite because there is a high probability of chemical mediastinitis. appropriate antifungal therapy, if the infected vein is not excised. Fungal infections account for between 1% and 10% of all Meningitis pathogens isolated from patients with infective endocarditis.17 In Candidal meningitis may follow hematogenous spread, or it patients with prosthetic valves, the rate at which fungi are isolated may be a complication of neurosurgery or the implantation of ven- may be as high as 10%. The overall outcome of candidal infective triculoperitoneal shunts. In neonates, Candida infection may be endocarditis is grim, carrying a reported mortality of up to 80%, present without previous surgery and without previously docu- especially when complicated by congestive heart failure and persis- mented fungemia, but often, an intravascular catheter is pre- tent fungemia.118 Embolic phenomena are more commonly associ- sent.123 The infection is insidious and sometimes goes undiag- ated with fungal endocarditis than with the nonfungal variety. nosed. Most patients with candidal meningitis have recently Candidal endocarditis is very difficult to treat. A 2005 review received antibacterial agents, and half have previously had bacter- found that patients with candidal endocarditis who underwent ial meningitis. The overall mortality is around 10%. adjunctive surgery had a lower reported mortality.118 Thus, surgi- The standard therapeutic regimen for candidal meningitis con- cal replacement or repair of valves is required to prevent death sists of amphotericin B with flucytosine. As an alternative, a com- from embolization or cardiac failure in patients with complicated bination of high-dose fluconazole (800 mg/day) and flucytosine (50 prosthetic valve endocarditis. Amphotericin B, with or without mg/kg/day) may be considered; this is a particularly attractive flucytosine, has been the therapy of choice; however, neither the approach because of the high CSF concentrations achieved with optimal dosage nor the optimal duration of therapy has been both agents. Removal of the infected shunts, as well as the intravas- determined. There is some anecdotal information suggesting that cular catheter, is recommended when possible.17,123 The duration fluconazole, with or without caspofungin, may be successfully of treatment should be based on the patient’s clinical response and employed in this setting, primarily as long-term suppressive ther- the culture results. In general, prolonged treatment (more than 4 apy after the initial administration of amphotericin B.119 Because weeks beyond the resolution of symptoms) is suggested. of the high risk of late relapse, long-term maintenance therapy with oral fluconazole should be considered in patients unwilling or Pneumonia unable to undergo surgical treatment. True candidal pneumonia is rare, but it can occur through Candidal pericarditis is a very rare complication of hematoge- hematogenous dissemination into the lung as one of many sites of nous candidiasis. The surgical patients at risk for purulent peri- infection.17,124,125 Oropharyngeal aspiration of oral and upper tra- carditis caused by Candida are those who have undergone a car- cheal organisms does not typically cause pneumonia.The value of diac operation, those who have a malignancy and whose host deep tracheal suction or even bronchoalveolar lavage in defining defenses are impaired, and those who have a debilitating chronic this disease should be questioned. Histopathologic confirmation is disease.120 Patients should be treated with surgical drainage or recommended.17 Laryngeal infection should be considered; some debridement and with high-dose amphotericin B or fluconazole. case reports suggest that it can be rapidly progressive. Arthritis and Osteomyelitis Candidal joint infections can develop via hematogenous spread Management of Nonhematogenous Candidiasis as a consequence of inadvertent direct inoculation during joint pro- SUPERFICIAL INFECTION cedures or intra-articular injection of corticosteroids. Such infec- tions typically involve a single joint (most frequently the knee or the Oral candidiasis (thrush) appears as a whitish, patchy hip) and tend to occur in patients with rheumatoid arthritis or pros- pseudomembrane covering an inflamed oropharynx; it common- thetic joint devices.121 Local symptoms (i.e., pain on weight bear- ly involves the tongue, the hard and soft palates, and the tonsillar ing or on full extension) may be present. Diagnosis is best achieved pillars. Controlled trials have shown nystatin suspension, oral by visualizing the organisms or growing them from the joint fluid. amphotericin B, clotrimazole troches, oral ketoconazole, flucona- Early diagnosis and systemic antifungal therapy are vital for pre- zole, and itraconazole to be efficacious for eradicating the clinical venting destruction of the cartilage or loosening of the prosthesis. symptoms of oral candidiasis.17
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 11 Nystatin should be given as a 10 to 30 ml suspension five times daily, and the patient should be instructed to swish it around the mouth before swallowing; alternatively, the patient may take one or two troches five times daily. Clotrimazole is given five times daily in the form of a 10 mg troche that should be held in the mouth until dissolved. In surgical patients at risk for hematoge- nous infection, systemic therapy with ketoconazole (200 to 400 mg once daily), itraconazole (200 mg/day), or fluconazole (100 mg once daily) is preferred.17 Antifungal therapy should be administered for 7 to 14 days. Ketoconazole and itraconazole are slightly less effective than fluconazole because of variable GI absorption. Repeated episodes of oral candidiasis are common. DEEP CANDIDIASIS Esophagitis and Gastrointestinal Candidiasis Superficial candidiasis involving only mucosal surfaces used to be a common finding at autopsy in surgical patients who had had Figure 2 Superficial candidiasis may be found at all levels of the a protracted hospital stay characterized by recurrent sepsis. Such GI tract. Here, the esophagus of a patient found at autopsy to have lesions may arise at any site in the GI tract but appear most com- disseminated candidiasis shows disrupted epithelium, submucosal monly in the esophagus and the small bowel; in some cases, they inflammation, and the presence of yeast in the submucosa. progress to hematogenous infection [see Figure 2]. In a minority of patients, the pathology of candidal infection of the lower GI tract may change from diarrhea without demonstra- Such infections are often located in the abdomen, the liver, the bil- ble tissue invasion to direct penetration into the submucosa, iary tree, the pancreas, or the peritoneal cavity. Percutaneous which eventually leads to pseudomembranous enterocolitis. drainage can play an important role in the management of these Direct vascular invasion through the bowel wall may occur in difficult problems; however, one retrospective review of percuta- immunosuppressed patients; these patients may exhibit extensive neous drainage of fungal collections in the abdomen or thorax involvement of the GI tract from mouth to anus. Nonneutropenic suggested that clinical failures occur more often when complex surgical patients may exhibit more localized GI involvement. fluid collections are visible radiographically, when patients have a The preferred therapy for esophageal candidiasis consists of flu- history of malignancy, and when patients are critically ill.127 conazole (100 mg/day orally) or itraconazole (200 mg/day) for 14 Patients with peritonitis and intra-abdominal abscesses should to 21 days.17 In patients who remain symptomatic after 7 days of receive systemic antifungal therapy, usually in combination with therapy, endoscopy is indicated to rule out other causes of antibacterial therapy (given that these infections are almost always esophagitis. If endoscopy proves that esophagitis is being caused polymicrobial in origin). The risk of dissemination is increased by candidal infection, low-dose amphotericin B (0.4 mg/kg/day) both by the recurrence of intra-abdominal infection and by the may be administered. Alternatively, caspofungin or voriconazole presence of extensive areas of communication between the may be given,17 though it should be kept in mind that voricona- abdominal cavity and the external environment via either fistulas zole causes more adverse events without being more efficacious. or drain tracts. Because fluconazole is very safe and is capable of Therapy for esophageal candidiasis should be continued for at reaching high concentrations in peritoneal fluid, it is useful in the least 4 days after symptoms resolve; immunosuppressed patients management of candidal peritonitis and should be considered the generally require more extended therapy to prevent relapse. agent of choice in cases where the pathogens are susceptible to Because stool cultures do not differentiate between coloniza- it.107 Fluconazole should be given at a dosage similar to that tion and infection, candidiasis in the lower GI tract is usually a employed in treating systemic disease (loading dose of 12 mg/kg postmortem diagnosis; hence, there are no reliable criteria govern- I.V., followed by 6 mg/kg/day I.V.), with a 50% dosage reduction ing when and how to treat this condition. It has been reported, in cases of renal impairment.When pathogens are resistant to flu- however, that patients who have diarrhea that can only have been conazole, caspofungin and voriconazole at systemic dosages are caused by heavy colonization with Candida species may respond acceptable alternatives.17 dramatically to 2 to 4 days of nystatin therapy. On rare occasions, candidal peritonitis occurs after long-term ambulatory peritoneal dialysis. This infection is not clinically dis- Peritonitis and Intra-abdominal Abscess tinguishable from bacterial peritonitis. In such cases, the infection Perhaps the most controversial issue in the management of tends to remain localized and to manifest with low-grade fever and Candida infectious syndromes in surgical patients is the question abdominal pain and tenderness.The peritoneal dialysate is usual- of whether specific systemic therapy is required to eradicate the ly cloudy and contains more than 100 neutrophils/mm3. Therapy infection within intra-abdominal abscesses, peritoneal fluid, or fis- consists of systemic antifungal therapy and removal of the peri- tula drainage.17 Candida is frequently cultured from intra-abdom- toneal catheter. The abdominal pain caused by the addition of inal infectious foci but should be considered a serious threat only amphotericin B to the dialysate has raised concern that chemical in high-risk patients.126 Four risk factors for intra-abdominal can- peritonitis might give rise to adhesions and thus impair the effica- didiasis have been identified: (1) gastrointestinal perforations, cy of dialysis. Accordingly, this agent should not be used for peri- especially in the upper GI tract, (2) anastomotic leakage, (3) toneal irrigation. Immediate removal of the peritoneal catheter has surgery for acute pancreatitis, and (4) splenectomy.107,126 In been recommended. Fluconazole should be considered as the patients with a localized fungal infection necessitating drainage, agent of choice and should be given for 1 to 14 days. A new there is no replacement for adequate drainage and debridement. catheter should not be placed for 4 to 6 weeks. In centers with a
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 12 high rate of fungal peritonitis secondary to peritoneal dialysis, nys- Hematogenous infections of the kidneys leading to multiple tatin prophylaxis may be considered. A prospective, randomized renal abscesses are treated as instances of hematogenous candidi- study of patients on continuous ambulatory dialysis found that asis. However, because both fluconazole and flucytosine are well Candida peritonitis was successfully prevented with oral nystatin tolerated, have good tissue diffusion, and are excreted in the urine (tablets containing 500,000 units given four times a day).128 in high concentrations, it is reasonable to assume that the combi- Occasionally, Candida species may cause cholangitis, biliary nation of these two agents represents the therapy of choice for tract disease, pancreatic abscess, or liver abscess. This problem is such infections. increasingly found in cancer patients with percutaneously placed GENITAL CANDIDIASIS drainage catheters. Such patients must be given systemic therapy if there is any clinical evidence of infection (e.g., candidemia), and Fungal vulvovaginitis is a common problem in women and is the drainage catheter must be changed. Diverticulitis complicated often associated with antibiotic therapy and poor glucose control. by candidal pylephlebitis has also been reported. It may be divided into simple and complex forms, with more than 90% of women having the simple form and the remaining 10% Wound Infections experiencing recurrent symptoms. The diagnosis is based on the Diagnosis and treatment of candidal wound infections are prob- clinical findings and on the presence of pseudohyphae on a fungal lematic. Recovery of Candida species from drains and wounds does smear. not necessarily mean that this organism is causing tissue infection; Antifungal agents, including oral azoles (fluconazole, 150 mg in however, isolation of Candida or demonstration of invasive forms a single dose; ketoconazole, 400 mg/day for 5 days; or itraconazole, on biopsies at reoperation would suggest that invasive infection is 200 mg in a single dose) and topical medications (suppositories, present. Antifungal therapy should be administered to patients creams, and vaginal tablets), are effective against more than 90% of with demonstrated invasive infection and possibly to those in uncomplicated infections. However, women who have experienced whom antibacterial therapy has failed and Candida has been iso- four or more episodes of vulvovaginal candidiasis during a 12- lated. If a deep sternal wound culture is obtained and is positive month period and those who have sustained acute severe attacks of for Candida after coronary bypass surgery, antifungal agents candidal vaginitis are less likely to respond to conventional therapy. should be given to prevent the establishment of candidal osteo- Preventive measures include control of host factors such as dia- myelitis of the sternum. betes mellitus, antifungal prophylaxis during the course of antibiot- ic therapy and under other high-risk conditions, and avoidance of CANDIDURIA systemic corticosteroids, oral contraceptives, and antibiotics if pos- Candida is either the most common or the second most com- sible. Therapy with oral fluconazole, itraconazole, or ketoconazole mon pathogen isolated from the urine in surgical ICU patients. should be provided for approximately 14 days to ensure clinical The term urinary candidiasis refers to an ill-defined group of syn- remission and negative fungal cultures, followed by a maintenance dromes, many of which probably represent colonization rather regimen of fluconazole (150 mg once weekly for 6 months). than infection. Thus, the actual importance and meaning of can- Recurrence of vulvovaginal candidiasis is common, arising in 30% diduria are controversial.53-58 Candiduria is very common in hos- to 40% of patients after cessation of the maintenance regimen.130 pitalized patients who have had urinary catheters in place for more than 14 days.58 In this setting, it is more likely to reflect coloniza- tion than infection. In ICU patients, however, the significance of Management of Other Fungal Infections candiduria is less clear-cut: it may represent either upper tract dis- ASPERGILLOSIS ease or hematogenous disease and filtration of the pathogens into the urine.129 Increasing concentrations of Candida in the urine, Aspergillosis, a rare infection in general surgical patients, is now, especially after a catheter exchange and particularly in a critically unfortunately, becoming increasingly common in certain subpop- ill surgical patient with known risk factors, should raise concerns ulations, such as patients who experience marked immunosup- about possible upper-tract or disseminated disease. pression after undergoing chemotherapy with cytotoxic agents, Besides simple colonization, the spectrum of candidal urinary those being given adrenal corticosteroids, and those who have tract infection includes cystitis, pyelitis (i.e., infection of the renal recently received antirejection therapy.82 Most cases of nosocomi- pelvis), fungus ball of the ureter, and renal abscesses.The diagno- al aspergillosis are acquired via airborne transmission. Colonization sis of cystitis is based on the presence of symptoms of cystitis, dif- of the respiratory tract is followed by invasive disease if the predis- fuse erythema or fungal plaques on cystoscopy, candiduria, and posing factors are present. Sources of airborne fungi in microepi- pyuria. Candida cystitis warrants therapy. If a triple-lumen catheter demics frequently are associated with construction within the hos- is in place, bladder irrigation with amphotericin B (50 mg/L/day pital or at adjacent sites. Other modes of transmission have also for 2 days) may be tried. Fluconazole (200 mg once daily) is a been reported for aspergillosis, including foreign bodies, catheters, more attractive approach because of the convenience, the lower and bandages. cost, and the very high drug concentrations achieved in the Acute invasive pulmonary aspergillosis is the most common urine.54 Flucytosine is excreted in the urine in high concentrations form of Aspergillus infection in immunocompromised surgical and may be particularly useful against C. glabrata infection. patients.82 The organisms tend to invade blood vessels and cause Management of pyelitis depends on whether the renal papillae thrombosis and infarction of the surrounding tissues. The infec- are invaded or the ureter is obstructed with a fungus ball. Patients tion may manifest itself in the form of acute vascular events such with no papillitis and an open ureter usually respond to irrigation as pulmonary embolisms or, more rarely, myocardial infarction, with amphotericin B through a ureteral or percutaneous catheter. cerebral hemorrhage, or Budd-Chiari syndrome. Pulmonary If papillitis is present, systemic antifungal therapy with fluconazole Aspergillus infections include necrotizing bronchopneumonia (400 mg/day) is recommended. If fungus balls are present, surgi- and hemorrhagic pulmonary infarction, each accounting for cal removal should be considered in addition to treatment with about one third of these infections. Pulmonary aspergillosis may antifungal agents.54 extend to contiguous organs or be disseminated. The rhinocere-
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 13 Table 4 Characteristics of Currently Available Azoles*68-79 Ketoconazole Fluconazole Itraconazole Voriconazole Posaconazole Spectrum Narrow Expanded Expanded Expanded Expanded Route(s) of administration Oral Oral, I.V. Oral Oral, I.V. Oral Erratic, requires gastric Erratic, requires gastric Bioavailability Excellent Excellent With meals acidity acidity Dose dependent, Plasma half-life (hr) 6–9 30 20–40 19–35 nonlinear Hepatotoxicity Occasional Occasional Occasional Occasional Occasional GI intolerance Frequent Occasional Occasional Occasional Occasional CSF penetration No Yes No Yes — Renal excretion No Yes No Yes No Interaction with other drugs Frequent Occasional Frequent Very frequent Very frequent *Intravenous miconazole is also available but offers no advantage over the currently available azoles. bral form of aspergillosis occurs less often than the pulmonary pulmonary, GI, cutaneous, or (very rarely) disseminated. Any form. It originates in the sinuses and progresses through soft tis- patient with a necrotic lesion on the skin, soft, hard palate or nose sues, cartilage, and bone, causing lesions in the palate and the should be considered to have an angioinvasive mold infection nose. Occasionally, the infection progresses through the base of until emergency biopsy proves otherwise. the skull and involves the brain. Appropriate management of zygomycosis consists of extensive Diagnosis of Aspergillus infection is difficult. Computed tomog- surgical debridement of infected areas, rapid correction of the raphy can be diagnostic131 and often allows early recognition of underlying disease, and administration of an appropriate antifun- aspergillosis. In one study that used CT scans as a means of inves- gal agent. One of the lipid amphotericin products should be the tigation, the mean time to diagnosis of invasive pulmonary first-line therapeutic agent, with high-dose amphotericin B deoxy- aspergillosis fell from 7 days to less than 2 days, and this reduction cholate a second choice. was associated with a decrease in mortality. CT may also be com- EMERGING PATHOGENS bined with detection of Aspergillus antigen (galactomannan), an approach that shows promise for early diagnosis of invasive pul- Fusarium and Scedosporium species are increasingly common monary aspergillosis.132 Often, however, diagnosis of Aspergillus causes of infections in surgical patients, especially in recipients of infection depends on identifying the organism in culture or histo- stem cell or organ transplants.82,134 Most cases of Scedosporium pathologic specimens.82 Recovery of Aspergillus species from the infection present as disseminated disease; skin lesions are com- respiratory tract culture of a surgical patient should be considered mon, and the lungs and the CNS are frequently involved. to represent contamination or colonization unless the patient is Surgeons may be tempted to use amphotericin B to treat these symptomatic and severely immunosuppressed. unusual molds, but voriconazole has been shown to yield better All of the antifungal agents currently used for primary treat- outcomes with both Fusarium and Scedosporium. ment of Aspergillus are associated with relatively high incidences Many other mold species are also emerging as significant of treatment failures and fairly poor outcomes. At present, pathogens. In an at-risk patient, recovery of any fungus from any voriconazole (at the dosage previously described [see site should prompt an evaluation by an infectious disease special- Management of Candidemia and Acute Disseminated ist to determine the clinical significance of the isolate. Candidiasis, above]) is the treatment of choice, with lipid amphotericin B formulations as secondary agents. In some insti- tutions, combination therapy with an echinocandin is occasion- Systemic Antifungal Agents ally employed as an alternative. AMPHOTERICIN B ZYGOMYCOSIS (MUCOR AND RHIZOPUS) Amphotericin B was the first systemic antifungal agent and has Some of the most rapidly advancing forms of angioinvasive fun- historically been considered the gold standard for antifungal ther- gal infection are caused by the Zygomycetes Mucor and apy. Today, however, its usefulness in daily practice is substantial- Rhizopus.133 The reservoir, the mode of transmission, the patho- ly less than it once was, primarily because of the proliferation of genesis, and the clinical presentations are similar to those of many alternative agents that are less toxic (but that also may pos- Aspergillus species. Zygomycosis is being seen with increasing fre- sess a more limited spectrum of activity) [see Table 4].17,135,136 quency in stem cell transplant recipients who have been receiving Amphotericin B is lipophilic and binds avidly to ergosterol, the voriconazole prophylaxis. In surgical patients, the major risk fac- principal sterol in the fungal cytoplasmic membrane.This binding tors include diabetic ketoacidosis, immunosuppression after cyto- disrupts the integrity of the membrane, resulting in leakage of toxic chemotherapy, adrenal corticosteroid therapy, organ trans- intracellular contents and cell death. The clinical effectiveness of plantation, skin damage (e.g., from adhesive tape, an arm board, amphotericin B against fungi is believed to be attributable to the or severe burns), iron overload, and a prolonged postoperative drug’s stronger affinity for ergosterol (found in fungal cell mem- stay.133 Zygomycotic infections may be rhinocerebral, paranasal, branes) than for cholesterol (the principal sterol found in mam-
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 14 malian cell membranes). Another proposed mechanism of action liposomal amphotericin B (AmBisome) is the one that is best tol- is oxidation-dependent amphotericin B–induced stimulation of erated. It should be noted that all of these formulations do still macrophages.99 Most of the fungal species that cause human have some negative effect on renal function. infections are susceptible to amphotericin B. FLUCYTOSINE Because amphotericin B is lipophilic, it must be complexed with a bile salt (deoxycholate) to be able to stay in solution. Flucytosine can be useful for the treatment of hematogenous Unfortunately, about 20% of patients receiving amphotericin B candidiasis. When used as a single agent, however, it is associated deoxycholate experience an acute infusion-related reaction con- with a high failure rate and secondary emergence of resistance. sisting of fever, hypotension, and tachycardia.135 Premedication Accordingly, flucytosine is usually employed in combination ther- with acetaminophen may blunt this response; if it does not, pre- apy, typically to treat Cryptococcus infections. Its major toxic effect medication with hydrocortisone (25 to 50 mg I.V.) or meperi- is marrow suppression, especially when it is given at the prescribed dine (25 to 50 mg I.V.) is recommended. Hypotension, hyper- dosage (i.e., 37.5 mg/kg every 6 hours). tension, hypothermia, and bradycardia have also been reported Administration of flucytosine at a dosage of 25 mg/kg/day every as infusion-related toxic effects of amphotericin B deoxycholate. 12 hours will often yield effective serum peak and trough levels. Ventricular arrhythmias have been associated with rapid infusion Peak serum concentrations should be monitored and the dosage of amphotericin B deoxycholate and with administration of this adjusted so as to maintain a peak level of about 25 μg/ml. agent to patients with severe hypokalemia or renal failure. Flucytosine penetrates well into the eye and the CNS and thus Through inhibition of erythropoietic production secondary to may be used as a component of combination therapy for candidal nephrotoxicity, amphotericin B suppresses the production of red endophthalmitis, meningitis, and endocarditis. It is removed by blood cells, causing a normocytic, normochromic anemia. As a hemodialysis and peritoneal dialysis. Patients undergoing result of renal tubular loss, acidosis, hypokalemia, and hypomag- hemodialysis should receive a 37.5 mg/kg dose of flucytosine after nesia are common. The need to replace lost electrolytes should each dialysis session unless their initial peak serum concentration be expected. Patients should be kept well hydrated. is higher than 25 μg/ml or their postdialysis concentration is high- Common practice is to give a 1 mg test dose and observe the er than 10 μg/ml. Patients undergoing peritoneal dialysis should patient for 1 hour in the hope of identifying patients at risk for receive a single 37.5 mg/kg dose daily. severe acute reactions.The full dose of the drug (0.6 to 1 mg/kg/ FLUCONAZOLE day) is then infused over a period of 4 to 6 hours, though there is evidence to suggest that much shorter infusion times (e.g., 1 The mechanism of action of fluconazole is preferential inhibi- hour in patients with adequate cardiopulmonary and renal func- tion of cytochrome P-450 enzymes in fungal organisms. Several tion) may be acceptable.The total dose depends on the extent of Candida species, including C. tropicalis, are susceptible to this the infection and the patient’s condition. Patients must be mon- agent; however, C. krusei is highly resistant. C. glabrata may be sus- itored carefully during the first day of therapy. The infusion ceptible, resistant, or susceptible–dose dependent (S-DD) (i.e., should be discontinued if the patient becomes hemodynamical- exhibiting dose-dependent sensitivity).81 Because fluconazole is ly unstable. relatively nontoxic at its recommended dosage, larger doses (up to If acute reactions limit the amount of drug that can be infused, 1,600 mg) may be given to achieve the higher minimum inhibito- patients are premedicated with hydrocortisone (25 to 50 mg I.V.), ry concentrations (MICs) required to treat S-DD C. glabrata (16 either alone or in combination with meperidine (25 to 50 mg I.V.), to 32 μg/ml, compared with less than 8 μg/ml for susceptible 30 minutes before amphotericin B infusion is begun. strains). Fluconazole is not clinically active against Aspergillus Renal toxicity and hypokalemia are the primary toxicities of species. amphotericin B [see Table 3]. Amphotericin B–induced nephrotox- Fluconazole is available in both oral forms (pill and suspension) icity may be glomerular (characterized by a decrease in glomeru- and an I.V. form. In any form, it is rapidly and almost completely lar filtration rate and renal blood flow) or tubular (with urinary absorbed from the GI tract: serum concentrations achieved after casts, hypokalemia, hypomagnesemia, renal tubular acidosis, and oral administration are almost identical to those achieved after I.V. nephrocalcinosis).100 All of these abnormalities occur to varying infusion. This high degree of GI absorption, which is not affected degrees in almost all patients receiving the drug. In most patients, by gastric acidity or the presence of food, is a major advantage that renal dysfunction gradually resolves after discontinuance of thera- fluconazole has over ketoconazole. An initial loading dose that is py. Amphotericin B nephrotoxicity may be minimized by refrain- twice the usual daily dose is recommended. Fluconazole is distrib- ing from using it with other agents that exert synergistic nephro- uted evenly in body tissues, penetrates into the vitreous humor toxic effects135 (e.g., aminoglycosides, vancomycin, cisplatin, and and the aqueous humor of the eye, and crosses the blood-brain cyclosporine) and by providing sodium suplementation. Sodium barrier. It is excreted largely unchanged in the urine and under- supplementation consists of I.V. infusion of 500 ml of 0.9% saline goes only minimal metabolism in the liver. Consequently, dosage solution 30 minutes before the administration of amphotericin B, schedules must be adjusted in patients with renal impairment. followed by a second infusion of the same amount of saline after Hemodialysis substantially reduces serum concentrations of flu- the amphotericin B infusion is completed. conazole, and peritoneal dialysis also appears to remove the drug. To minimize synergistic nephrotoxicity when amphotericin B is A standard dose should be given after each course of dialysis. used in conjunction with other nephrotoxic agents, use of one of The toxic effects of fluconazole are similar to those of other the less nephrotoxic lipid formulations of amphotericin B—such azoles, including nausea and vomiting (in about 2% of patients), as amphotericin B lipid complex (Abelcet), amphotericin B col- headache, fatigue, abdominal pain, and diarrhea68-78; exfoliative loidal dispersion (Amphocil, Amphotec), or liposomal ampho- dermatitis also occurs, but very rarely. Transient abnormalities of tericin B (AmBisome)—may be indicated.136 These preparations liver function are observed in approximately 3% of patients who differ from each other with respect to the amount of amphotericin receive fluconazole. Fatal hepatic necrosis was reported to have B present and the type of lipid used, as well as with respect to their developed in two patients who were receiving fluconazole, but it physical forms, pharmacokinetics, and toxicities. Of the three, was unclear whether the drug played a causal role. Fluconazole
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 15 does not induce adrenal suppression. On occasion, fluconazole cytopenia, and abdominal pain occasionally occur. As a conse- administration may lead to prolongation of the QT interval. quence of hepatic metabolism, posaconazole has been associated Because fluconazole interacts with warfarin, phenytoin, and with elevated liver enzyme levels, hyperbilirubinemia, and hepato- cyclosporine when given in a daily dose of 200 mg or higher, cellular damage. Liver function test results should be monitored serum concentrations of these agents should be monitored when at baseline and throughout the course of posaconazole therapy. they are used in conjunction with fluconazole. Prolongation of the QT interval and adrenal insufficiency may also be seen with administration of this agent. ITRACONAZOLE Because posaconazole is an inhibitor of cytochrome P-450 Itraconazole is a synthetic triazole that is similar to other imida- 34A, it may be expected to increase the plasma concentrations of zoles (e.g., ketaconazole). Its mechanism of action involves inhibi- drugs metabolized via this pathway.Various drug interactions may tion of cytochrome P-450 and prevention of ergosterol synthesis occur, and it frequently proves necessary to adjust the dosages of in fungal cell membranes. Itraconazole is active against Aspergillus other agents being given simultaneously with posaconazole. The species and several of the endemic fungi (Histoplasma, Crypto- adult dosage for posaconazole is 200 mg three times daily, taken coccus, and Coccidioides, to name a few). It is available in two oral with a full meal or a liquid nutritional supplement.138 The use of forms: a capsule (100 mg) and a suspension (10 mg/ml). The this agent in pregnant patients is not recommended. bioavailability of the capsule is approximately 55%. Absorption is KETOCONAZOLE enhanced by the presence of food in the stomach but is signifi- cantly reduced by the presence of antacids or H2-receptor block- Ketoconazole is effective against yeast infections of the skin and ers. The bioavailability of the suspension is higher; this formula- the mucous membranes; however, it should not be used to treat tion should be given on an empty stomach. In some patient pop- hematogenous candidiasis. Ketoconazole is not available in an I.V. ulations, however, GI absorption of itraconazole is erratic, and form, and the serum levels it is capable of reaching depend large- oral administration might be ineffective. In such cases, I.V. infu- ly on gastric acidity [see Table 4]. The same adverse events and sion should be considered. drug-drug interactions observed with itraconazole occur with Itraconazole is metabolized to a large degree in the liver, and ketoconazole. this process yields an active metabolite, hydroxyitraconazole. ECHINOCANDINS (CASPOFUNGIN, MICAFUNGIN, Accordingly, the dosage must be adjusted in patients with hepatic ANIDULAFUNGIN) failure; however, the pharmacokinetics of itraconazole are not affected by renal impairment or hemodialysis. Serum concentra- The echinocandins are lipopeptides that have been syntheti- tions of digoxin may increase when this agent is given with itra- cally modified from the fermentation broths of various fungi.68- conazole,104 and the metabolism of itraconazole may be accelerat- 70,73,78 They act by weakening the fungal cell wall. More specif- ed when drugs that induce hepatic enzymes are given simultane- ically, they bind to (1→3)-β-D-glucan synthase, thereby block- ously.84,104 Serum concentrations of itraconazole should therefore ing synthesis of (1→3)-β-D-glucan, a substance that, along with be measured in patients with invasive infections. Itraconazole is a chitin, provides shape and integrity to the fungal cell wall. The potent inhibitor of cytochrome P-450 34A and may increase the plasma concentrations of drugs metabolized via this pathway. Itraconazole is generally well tolerated in dosages as high as 400 a mg/day.The most common side effects are nausea, vomiting, diar- rhea, and abdominal discomfort. Headaches, rash, pruritus, and dizziness occasionally occur. At higher doses, a mineralocorticoid excess syndrome (characterized by hypokalemia, hypertension, and edema) has been described, and hypokalemia develops in as many as 6% of patients who take 400 mg/day for several months.104 The Federal Drug Administration (FDA) has issued a black box warning against the use of itraconazole in patients with congestive heart failure and those at risk for drug-drug interac- b c d tions. Because itraconazole may be teratogenic, it should be avoided in pregnant patients as well. Itraconazole is currently approved only for treating blastomycosis, histoplasmosis, and aspergillosis, but it is also effective for treating candidiasis and cryptococcosis. POSACONAZOLE Posaconazole, the newest of the triazoles, also prevents synthe- sis of ergosterol by inhibiting lanosterol 14-α-demethylase. It is Figure 3 Candida takes several forms as it grows. A blastospore highly selective for fungal cytochrome P-450 systems, but unlike is a unicellular form (a). Blastospores divide by budding, a other azoles, it is not extensively metabolized by cytochrome P- process in which new cellular material grows from a site on the 450 enzymes.137 Posaconazole is active against Candida and blastospore (b). Nuclear division then occurs, and a septum forms Aspergillus species, as well as against Cryptococcus, Fusarium, the between the two new cells. A hypha is a long tube of several cells Zygomycetes, and filamentous fungi. divided by septa (c). A mycelium is a cellular aggregate that Like the other azoles, posaconazole is well tolerated even with includes a hypha and its branches (d). A pseudohypha differs long-term administration.137 The most common side effects are from a true hypha in that it is composed of morphologically dis- fever, nausea, vomiting, diarrhea, and headaches. Rash, thrombo- tinct, elongated blastospores.
© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 16 resulting loss of fungal cell wall integrity leads to osmotic lysis nonenzymatic peptide hydrolysis and N-acetylation to yield two of the cell. inactive metabolites. Micafungin is metabolized into three metabo- The echinocandins, as a class, are active against Candida lites71; cytochrome P-450 3A plays a minor role in this process. species, including C. krusei and C. glabrata.68-70,73,78 In addition, Anidulafungin undergoes spontaneous degradation into an inactive they are active against Aspergillus species, including A. fumigatus,A. open ring peptide; no hepatic metabolism has been observed. flavus, and A. terres; in this setting, they show some synergism with Both caspofungin and micafungin have been shown to be not itraconazole and voriconazole. None of the echinocandins are inferior to lipid formulations of amphotericin B for the treatment active against Cryptococcus, and none should be used for this indi- of invasive candidiasis. In addition, they have been found to have cation. The emerging fungi Fusarium, Rhizopus, Mucor, fewer adverse effects, especially those effects that would necessitate Scedosporium, and Pseudallescheria boydii are all resistant to each of discontinuance of therapy (e.g., renal toxicity). One study has the echinocandins. found anidulafungin to be superior to fluconazole.139 All of the echinocandins are available solely as I.V. formulations. Overall, the echinocandins are well tolerated. They are all asso- Caspofungin is given in a loading dose of 70 mg I.V., followed by ciated with essentially the same set of adverse effects, which on the infusion of 50 mg/day.70 Anidulafungin is given in a 200 mg loading whole are not serious. Phlebitis, fever, nausea and vomiting are dose on day 1, followed by infusion of 100 mg/day.79 Micafungin among the most commonly reported adverse effects. does not require a loading dose and is given at a dosage of 100 Thrombocytopenia, hypokalemia, and abnormal liver function mg/day.71 Caspofungin is slowly metabolized in the liver through test results are occasionally reported. Discussion Pathogenesis of Candida Infection eral pathways.The first such pathway is phagocytosis. Ingestion by For Candida to move from commensal to pathogen, it must phagocytes brings Candida into an intracellular position, and the invade either epithelial or endothelial cells. Even when this organ- leuckocytes then move across the endothelial cell lining and into ism causes superficial disease, it is capable of eluding detection by the bloodstream. Candida species have indeed been observed the immune system. One way in which Candida avoids recogni- within circulating leukocytes; however, the observation that fungal tion is to assume an intraepithelial position. A key virulence factor infections are common in neutropenic patients argues that a for C. albicans is its ability to change from a blastospore to a fila- mechanism other than phagocytosis must also play a major role. mentous hyphal form, and vice versa [see Figure 3]. Most of the The second pathway is passage of Candida pathogens between evidence suggests that invasive disease is caused by the hyphal endothelial cells and thence into the bloodstream.The fenestrated form, given that hyphae are found within cells140 and blastospores endothelium in the kidney is one site at which this process might on the epithelial surface or between cells (see below). Candida can occur. The final pathway is endocytosis by the endothelial cells gain entry to epithelial cells either through production of lytic themselves.The process of endocytosis requires intact endothelial enzymes141 or through endocytosis.142 The lytic enzymes pro- cell microfilaments and microtubules and is in part governed by duced include secreted aspartyl proteinases (SAPs), which are tyrosine phosphorylation of endothelial cell proteins. Both killed believed to digest the epithelial cell surface and thereby give and live Candida are ingested by this mechanism. In vitro studies Candida access to the interior of the cell. Mutated forms of SAPs have shpown that Candida hyphae induce their own endocytosis and substances that inhibit SAPs can reduce the ability of Candida by expressing the invasinlike protein Als3, which binds to N-cad- to enter epithelial cells. Hyphal forms of Candida have a greater herin on the cell surface.144 This binding then induces phosphory- capacity for inducing endocytosis than blastospores do, which lation,145 causing rearrangement of the microfilaments to produce suggests that the hyphae express invasinlike molecules on their cell pseudopods and initiate endocytosis. surfaces143; however, the exact identities of these molecules are not It should be kept in mind that this is a highly simplified expla- yet known. nation and does not detail the many unknown specifics of the cel- In susceptible patients, Candida species can enter the blood- lular processes involved. How Candida blastospores like those stream either through translocation across the GI mucosa or via seen with C. glabrata gain access to the bloodstream is currently an intravascular catheter.This invasion occurs through three gen- unknown.
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Acs0819 Fungal Infection

  • 1.
    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 1 19 FUNGAL INFECTION Pamela A. Lipsett, M.D., F.A.C.S., F.C.C.M. Approach to the Surgical Patient at Risk for Candidiasis Fungal infections remain an important cause of morbidity and may experience Candida colonization at a single site. 2-7 The colo- mortality in surgical settings, with critically ill patients, transplant nization index (the number of sites tested divided by the number patients, and sick neonates all being especially vulnerable. Over of sites colonized) and the corrected colonization index (the num- the past few decades, technological and scientific advancements ber of sites tested divided by the number of sites showing heavy have improved physicians’ ability to sustain life in critically ill growth) have been proposed as criteria for selecting a high-risk patients; developments in chemotherapeutics and immune-based patient population to be considered for possible early preemptive therapies have yielded increased survival for many cancer patients; or therapeutic intervention.3,8,9 When test results from multiple organ transplantation has evolved dramatically; and the use of sites show no evidence of fungal colonization, it is almost certain invasive therapies (e.g., ventricular assist devices) has increased that no fungal infection is present.3,6,9 markedly. With these changes has come an increase in the inci- dence of serious Candida infections,1 as well as an increase in the Infection incidence of the less common (but nonetheless potentially fatal) At a basic level, fungal invasion or infection might be defined as noncandidal infections caused by Aspergillus and the Zygomycetes isolation of a fungal pathogen from a patient with signs and symp- Mucor and Rhizopus. toms of an infection. As applied to fungal pathogens, however, this Despite the significant progress in the supportive and intensive definition is an oversimplification. Clinicians relying on such a care of patients at risk, the development of a number of new and simplified definition would be prone to mistake some instances of useful antifungal agents in the past decade, and the noteworthy fungal colonization for cases of true fungal infection. A degree of improvements in therapeutic approaches to fungal infections, consensus has been reached regarding what constitutes a fungal physicians’ ability to diagnose these infections in a timely fashion infection in a neutropenic patient,10 but to date, no such consen- remains limited, and patient outcomes remain poor. Antifungal sus has been achieved as to what constitutes fungal infection in a prophylaxis has emerged as a potential means of reducing the nonimmunocompromised patient.2,8,11-18 occurrence of serious fungal infections. In patient populations esti- Given that it is not possible to establish a definitive diagnosis of mated to be at high risk for acquiring a fungal infection, antifun- fungal infection in all cases, it is often reasonable to express the gal prophylaxis has reduced infection rates by about 50%; howev- diagnosis in terms of the degree of certainty about the presence of er, it has not been shown to improve mortality significantly. infection. Fungal infections can thus be classified as definite or This chapter outlines an approach to the workup and manage- probable.10 In brief, a definite fungal infection is present when ment of the nonneutropenic surgical patient with a suspected can- deep tissue invasion is seen on a biopsy or culture from a sterile didal infection, taking into account epidemiology, risk factors, site in conjunction with clinical or radiologic abnormalities.10 diagnostic evaluation, and therapy. Noncandidal infections (asper- Unfortunately, there is currently no agreement as to what signs gillosis and zygomycosis) are considered as well. and symptoms constitute a probable or possible fungal infection in a nonneutropenic patient.16-18 Definition and Classification TYPES OF FUNGAL INFECTION FUNGAL COLONIZATION VERSUS FUNGAL INFECTION Candidemia A positive blood culture has traditionally been the gold standard Colonization for the diagnosis of candidemia and is now universally accepted as Fungal pathogens can be isolated under a number of clinical establishing the presence of a fungal infection.16,17 Because blood- conditions. 2-7 Isolation of a fungal pathogen in the absence of any borne Candida can originate from a variety of different sites— signs or symptoms of clinical infection is termed colonization. including deep-seated infections (via hematogenous spread), Fungal colonization, by itself, does not suffice to define fungal catheter-related infections, and the gastrointestinal tract (via infection, but it remains an important risk factor for future inva- translocation), to name but a few—it is imperative that clinicians sive fungal infection. It is believed that once colonization has evaluating candidemic patients search carefully for all potential occurred, Candida pathogens can gain access to the bloodstream sources of infection. The search should include assessment of via three major routes: through the GI tract mucosal barrier, from intravascular catheter sites, evaluation for peripheral septic throm- an intravascular catheter, and from a localized source of fungal bophlebitis, and examination of the abdomen as a possible site of infection. 2-7 A prolonged stay in an intensive care unit is associat- infection. Because metastatic infection may develop from can- ed with an increased risk of fungal infection. Depending on the didemia, new sources of fungal pathogens (e.g., endophthalmitis, patient population and the rigor and thoroughness with which infective endocardititis, hepatosplenic candidiasis, and arthritis) sites are cultured, as many as 50% to 80% of critically ill patients may arise over time.16,17
  • 2.
    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 2 Identify patient at risk for Candida infection Major risk factors include • Previous bacterial infection and therapy with multiple antibiotics. • Isolation of Candida from ≥ 2 sites. • Disruption of the intestinal mucosal barrier (total parenteral nutrition, severe diarrhea, colitis, major operation, trauma, or extensive burns). • Immunosuppression (neutropenia, cancer, organ transplantation, hemodialysis, or extensive burns). Other risk factors include • Central venous catheters • Urinary catheters • Prematurity • Neonates • Heroin addiction. Initiate measures to diagnose candidiasis Look for findings that may signal hematogenous candidiasis: • Endophthalmitis • Suppurative thrombophlebitis • High-grade candiduria without instrumentation of the bladder or the renal pelvis. Obtain cultures of sputum, oropharynx, stool, urine, drain sites, and blood. Obtain 2 sets of blood cultures daily for 2 days (or longer if the patient remains febrile). Consider serologic tests and histologic analyses (see text). Look for findings that may signal hematogenous candidiasis: • Endophthalmitis • Suppurative thrombophlebitis • High-grade candiduria without instrumentation of the bladder or the renal pelvis. Exclude other possible causes of persistent fever. Blood cultures are positive for Candida, or clinical or laboratory signal of potential hematogenous candidiasis is present Patient is hemodynamically stable, does not have high-grade candidemia, and does not appear to have organ infection Remove all venous catheters (preferred). or Leave venous catheter in place initially, and consider removal if clinical condition deteriorates or does not improve after 2 days of therapy. Patient is infected or colonized by C. albicans, Patient is infected or colonized by C. tropicalis, C. parapsilosis, or other germ C. krusei, C. glabrata, or C. lusitaniae tube–positive candidal organism Give an echinocandin (e.g., caspofungin, Give fluconazole, 6 mg/kg/day I.V. for 2–3 days, 70 mg I.V., loading dose, followed by 50 then, if possible, switch to 400 mg/day p.o. mg/day I.V.). Treat for 7–10 days (patient should be free of Treat for 5–7 days (patient should be signs and symptoms of infection for 5 days free of signs and symptoms of infection before treatment is ended). for 5 days before treatment is ended).
  • 3.
    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 3 Approach to the Surgical Patient at Risk for Candidiasis Blood cultures are negative for Candida, and no Blood cultures are negative for Candida, clinical or laboratory signal of potential hematogenous no clinical or laboratory signal of potential candidiasis is present, but Candida is isolated hematogenous candidiasis is found, and from ≥ 2 remote sites (≥ 1 site for C. tropicalis) Candida is isolated from ≤ 1 remote site (0 sites for C. tropicalis) Consider fluconazole, 400 mg/day I.V. for 2–3 days, then 400 mg/day p.o. If decolonization is required when a Continue surveillance cultures weekly. resistant species is present, consider an alternative agent, such as an echinocandin or amphotericin B, 0.5 mg/kg/day. (Consider adding flucytosine, 25 mg/kg/day p.o. in 2 divided doses, for C. glabrata and C. lusitaniae.) Continue treatment for as long as patient remains critically ill. Patient is hemodynamically unstable, has high-grade candidemia, or shows evidence of organ infection Remove all venous catheters. Treat any associated syndromes of hematogenous candidiasis (e.g., endophthalmitis, pericarditis, suppurative thrombophlebitis, endocarditis). Patient is infected or colonized by C. albicans, Patient is infected or colonized by C. tropicalis, C. parapsilosis, or other germ tube–positive C. krusei, C. glabrata, or C. lusitaniae candidal organism Give an echinocandin, or give amphotericin B, Give fluconazole, 800 mg/day I.V. (Consider adding 0.7–1.0 mg/kg/day I.V. (Consider adding flucytosine, 25 mg/kg/day p.o. in 2 divided doses.) flucytosine, 25 mg/kg/day p.o. in 2 divided Treat for 10–14 days after disappearance of all signs and doses. Also consider adding G-CSF, 300 g/day.) symptoms of infection. Treat for 10–14 days after disappearance of all signs and symptoms of infection.
  • 4.
    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 4 A positive blood culture is an indication for initiation of anti- 9.2% of all bloodstream infections diagnosed in the surgical ICUs, fungal therapy.16,17 However, systemic Candida infection may be and more than half of the isolates were non-albicans species. present even in the absence of a positive blood culture. Blood cul- The morbidity and mortality associated with fungal infections tures have a 50% false-negative rate and may take as long as 4 are considerable.27-30 Between 1980 and 1997, multiple-cause days to yield results. Accordingly, clinicians should not assume mortality from mycoses in the United States rose from 1,557 that the absence of a positive blood culture or tissue biopsy means deaths to 6,534 (most of which were associated with Candida, that a fungal infection is not present; nearly 44% of patients with Aspergillus, and Cryptococcus species).27 Two case-control studies a negative blood culture have evidence of disseminated fungal performed at a single institution 15 years apart revealed no infection at autopsy.19 Increasingly, candidal invasion is being improvement in the mortality attributable to candidemia: the observed on autopsy specimens in cases where the diagnosis had attributable mortality was 38% in the earlier study (1983–1986)31 not been clinically suspected.20 and 49% in the later one (1997–2001).32 Moreover, fungal infections place a substantial economic bur- Disseminated Candidiasis den on the health care system.28-31,33 In one study, costs were, on Patients in whom several noncontiguous organs are infected by average, $41,000 (in 1993 dollars) higher for high-risk ICU pa- Candida species are considered to have a disseminated infection tients than for low-risk ICU patients.30 In a large European study, acquired through hematogenous spread. To establish the diagno- patients with Candida infection stayed longer both in the ICU sis, the organism must be identified by means of histologic analy- (12.7 days) and in the hospital (15.5 days), and the direct costs sis, culture of tissue samples obtained from at least one internal associated with their care were higher by almost 16,000 euros.30 In organ, or both, and there should be radiographic, pathologic, or an earlier study from my institution (Johns Hopkins Hospital), the culture-derived evidence of infection in at least one other organ. attributable increase in the cost of ICU care for surgical patients The presence of candidemia in association with Candida skin with fungal infections was $21,590 (in 1996 dollars).29 lesions or of endophthalmitis in a setting consistent with a diag- IDENTIFICATION OF AT-RISK nosis of Candida infection is also diagnostic of disseminated can- SURGICAL PATIENTS didiasis.17 Hepatosplenic candidiasis is a more chronic form of disseminated Candida infection that typically develops in neu- The risk factors associated tropenic cancer patients.17 with the acquisition of fungal infections have been well defined [see Table 1].2,11-14,34,35 Epidemiology and Risk Factors General factors contributing to both the risk of incurring a fun- MAGNITUDE OF THE PROBLEM IN SURGICAL PATIENTS gal infection and the outcome to be expected after such an infec- Hospital-acquired, invasive Candida infections have become tion include disruption of cutaneous or mucosal barriers, defects increasingly common causes of morbidity and mortality in hospi- in the number and function of neutrophils or in cell-mediated talized patients. Between 1979 and 2000, the incidence of immunity, metabolic derangements (as seen in preoperative and Candida bloodstream infections increased by 207%.1,21,22 Data postoperative patients), and extreme youth or advanced age (see from the National Nosocomial Infections Surveillance System above). In an effort to create a rule for identifying a patient pop- (NNIS) indicated that in the period from 1989 to 1998, C. albi- ulation with at least a 10% risk of fungal infection, a database of cans was the seventh most common cause of nosocomial infection 2,890 patients who had stayed in an ICU for more than 4 days in the ICU setting, accounting for 4.9% of bloodstream infections was subjected to retrospective review and statistical modeling.14 and 4.8% of surgical site infections.23 Data from another nation- The best rule the authors were able to formulate included either al surveillance study, Surveillance and Control of Pathogens of the use of a systemic antibiotic or the presence of an intravenous Epidemiological Importance (SCOPE), indicated that in the peri- central line, along with any two of the following: total parenteral od from 1995 to 2002, Candida species, as a group, were the nutrition, any dialysis, surgery, pancreatitis, or immunosuppres- fourth most common cause of nosocomial bloodstream infection sive agents. This rule captured 34% of patients with fungal infec- (after coagulase-negative staphylococci, Staphylococcus aureus, and tions. More important, it had a high negative predictive value and enterococci).24 In ICU patients, Candida species were the third could be used to help exclude fungal infection as a likely possibil- most common cause of nosocomial bloodstream infection. ity. Several other authors have attempted to predict a high-risk Between 1995 and 2002, the percentage of bloodstream isolates patient population, but to date, these models have not been used accounted for by Candida species rose from 8% to 12%. successfully in published papers or clinical trials and thus have not Population-based studies have identified certain demographic entered clinical practice.8,15 groups that appear to be at special risk for invasive Candida infec- Of surgical patients, those in the ICU, those who have sus- tion.1,25 One such group consists of patients at the extremes of age, tained trauma or burns, and those who have received solid organ with neonates being one of the most rapidly growing at-risk transplants (liver, pancreas, and small bowel transplant recipients, groups. Race appears to play a role as well. In one study, the inci- in particular) appear to be at higher risk for invasive fungal infec- dence of fungal infections in neonates younger than 30 days was tion. The incidence of invasive Candida infection in liver trans- reported to be 466/100,000 (960/100,000 in black neonates and plant patients ranges from 1.3% to 15% for those receiving anti- 238/100,000 in white neonates).25 Surgical patients are also at par- fungal prophylaxis36-38 and may be as high as 23% for those not ticular risk for fungal infection: more than 50% of all fungal infec- receiving prophylaxis.39 In pancreas transplant recipients, the inci- tions occur in this patient population.24 In the National dence of invasive fungal infection is approximately 9%40; in small Epidemiology of Mycosis Survey (NEMIS), 42 Candida blood- bowel transplant recipients, it may be as high as 59%.41 Longer stream infections were identified in 4,276 patients admitted to six stays in the ICU, GI surgery, and the presence of invasive central surgical ICUs between 1993 and 1995, for an incidence of 9.8 venous lines appear to impart special risk to surgical patients.3,26,42 such infections per 1,000 admissions.26 Candida species caused One of the most important steps in treating fungal infection is rec-
  • 5.
    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 5 Table 1 Clinical Presentation and Diagnostic Methods for Common Fungal Infections 147 Host Fungus Major Clinical Presentations Diagnostic Methods Normal host Aspergillus Allergic bronchopulmonary Serum IgE, precipitins Blastomyces Acute pneumonitis: chronic lung or skin Culture, tissue Candida Vaginitis, thrush, candidemia, I.V. catheter Culture/smear Coccidioides Acute pneumonitis, chronic cavitary, pulmonary nodule Precipitins, complement fixation, culture Cryptococcus Pulmonary, meningitis Culture, latex agglutination Histoplasma Acute pulmonary, progressive dissemination in infants and elderly, Culture, antigen detection chronic cavitary in chronic airway obstruction Compromised host Diabetes mellitus Candida Disseminated, pyelonephritis, vaginitis Culture/smear C. glabrata Pyelonephritis Culture Zygomycetes (Mucor, Rhizopus) Rhinocerebral, paranasal, pulmonary, gastrointestinal, cutaneous Culture, tissue Malignancy or corticosteroids Aspergillus Invasive/lung, sinuses, disseminated Culture, tissue Candida Fungemia, acute and chronic disseminated candidiasis Culture, tissue Coccidioides Disseminated Culture, precipitins, complement fixation Cryptococcus Pulmonary, meningeal, disseminated Culture, latex agglutination, India ink preparation Dematiaceous fungi Lung, sinuses, brain, disseminated Culture, tissue Fusarium Lung, sinuses, cellulitis at site of onychomycosis, disseminated Culture, tissue Histoplasma Progressive disseminated Culture, antigen detection C. glabrata Disseminated Culture, tissue Trichosporon Disseminated Culture, tissue Zygomycetes (Mucor, Rhizopus) Rhinocerebral, paranasal, pulmonary, gastrointestinal, cutaneous, Culture, tissue disseminated Extensive surgery and previous antibiotic therapy Candida Vaginitis, thrush, esophagitis, disseminated Culture, tissue C. glabrata Disseminated Culture ognizing that a particular patient is at risk for this condition.16-18 As absence of bladder instrumentation may each provide special clues noted [see Definition and Classification, Fungal Colonization ver- suggesting an increased risk for fungal infection. A careful eye sus Fungal Infection, above], fungal colonization is certainly an examination to identify the presence of candidal infection should important risk factor for invasive fungal infection.2-7 be performed while the results of cultures of various sites are being Whereas most fungal infections probably originate from endoge- awaited [see Investigative Studies, Culture, below], and a repeat nous sources, some undoubtedly originate from interactions with examination should be performed after therapy for proven can- patients’ external environments—in particular, from interactions didemia. Candidal endophthalmitis may remain asymptomatic with health care workers.43-47 Cross-infection with Candida via until late in the course of infection.17,18,50,51 hand transmission has been described in several studies.43-47 In one The presence of peripheral suppurative phlebitis that fails to yield study, 6% of nurses’ hand cultures contained fungal pathogens, bacteria or does not respond to antibacterial agents may be an early with which 2 of 57 patients with candidemia could be linked by clue to the presence of hematogenous candidiasis. Gentle squeezing means of DNA fingerprinting.48 In another, nail contamination in of the venous catheter exit site may express pus that yields Candida the operating room was linked to an outbreak of C. tropi- species on a smear or culture. Surgical excision of the infected vein calis–infected sternal wounds.47 Parenteral nutrition has also been usually reveals Candida infection in its lumen.17,18,50,52 identified as a potential source of contamination with Candida.49 The presence of high-grade candiduria in surgical patients who have not undergone instrumentation of the renal pelvis or the bladder suggests hematogenous candidiasis and should prompt a Clinical Evaluation workup for this infection. In this setting, candiduria may result Patients with candidemia or from seeding or filtering through the kidney.17,18,50,53-58 disseminated candidiasis can Fever is sometimes the only sign of infection; however, it may present with a wide variety of be absent in infected patients who are receiving corticosteroids. clinical signs and symp- Because fungal pathogens interact with the Toll-like receptors toms.11,17,18,50 Identification of (TLRs), just as bacterial pathogens do, patients with fungal high-risk patients is probably the infections may present with the systemic inflammatory response single most important step in syndrome (SIRS) or septic shock. Accordingly, the diagnosis establishing the diagnosis of candidiasis.8,14,15,17,18,36,50 Although should be seriously considered in high-risk patients who are per- they are not very common presenting signs or symptoms, candidal sistently febrile. Because of the high mortality associated with endophthalmitis, suppurative phlebitis, and candiduria in the fungal infection, empirical antifungal therapy is recommended
  • 6.
    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 6 Table 2 Antimicrobial Agents of Choice for Candidal Infections* Infection Agent of Choice Alternative Agents Comments Hematogenous Candidemia and acute dis- Fluconazole, or echinocandin, Lipid formulations of ampho- Fluconazole should be given for C. albicans; if a fluconazole- seminated candidiasis or amphotericin B ± flucytosine tericin B resistant species is known to be present or azole use has been prolonged, one of the echinocandins should be select- ed; amphotericin B should be selected in unusual cases when Candida is not the infecting pathogen; a two-drug regi- men can be given to hemodynamically unstable patients with persistent high-grade fungemia Candida endophthalmitis Fluconazole Amphotericin B + flucytosine; Patients with vitral involvement require vitrectomy in addition to voriconazole; caspofungin antifungal therapy Suppurative phlebitis Fluconazole + flucytosine Amphotericin B + flucytosine The central venous catheter should be removed and the infect- ed vein excised Endocarditis Amphotericin B + flucytosine Fluconazole + caspofungin Surgical replacement or repair of valves is essential to prevent death from embolization or cardiac failure; oral fluconazole should be given after successful completion of a prolonged course of amphotericin B therapy; there is anecdotal evi- dence that fluconazole and caspofungin can be beneficial Pericarditis Amphotericin B Fluconazole — Prosthetic device–related Fluconazole or amphotericin B — Removal of device is required for successful therapy infection Arthritis Fluconazole — — Osteomyelitis Amphotericin B Fluconazole Surgical drainage of pus is required Meningitis Amphotericin B + flucytosine Fluconazole + flucytosine — Nonhematogenous Oropharyngeal Otherwise normal host Nystatin Ketoconazole, fluconazole, — clotrimazole troches Patients at risk for hema- Fluconazole Ketoconazole — togenous infection (e.g., cancer patients, surgical patients) Deep candidiasis Esophagitis and GI Fluconazole Echinocandin; amphotericin B Amphotericin B should be reserved for cases of failure of flu- candidiasis conazole therapy without endoscopic evidence of other causes of disease Peritonitis and intra- Fluconazole Echinocandin; amphotericin B — abdominal Wound Fluconazole Amphotericin B Antifungal therapy should be given to patients who do not respond to antibacterial therapy Urinary tract Cystitis Fluconazole Amphotericin B Fluconazole is preferable because of its high drug concentra- tion in urine and because it is better tolerated; echinocandins Pyelitis appear to yield low urinary tract concentrations Without papillitis Fluconazole — With papillitis Fluconazole + flucytosine Amphotericin B — Pyelonephritis Fluconazole + flucytosine Amphotericin B — *Therapy is individualized on the basis of the patient's clinical condition and the infecting species. for early treatment of a clinical occult infection or for prevention inexpensive test is the germ tube test, which can distinguish C. albi- of a new infection. cans (positive result) from other Candida species. More than 90% of C.albicans isolates produce germ tubes when incubated in serum for 2 to 3 hours at 37° C. Several commercial products are now Investigative Studies available to aid in the rapid identification of Candida species.59,60 Positive cultures from nonsterile sites (sputum, urine, and wound CULTURE drainage) must be interpreted with caution because of the frequent The workup of a surgical patient with suspected hematogenous occurrence of Candida as a normal commensal of humans. Such candidiasis begins with a complete set of cultures of sputum, cultures are useful mainly as an indication of colonization and, con- oropharynx, stool, urine, all drain sites, and blood [see Table 2]. sequently, of the risk of infection in the appropriate setting. Candidiasis rarely develops in patients whose cultures show no evi- ANTIBODY DETECTION, ANTIGEN DETECTION, POLYMERASE dence of Candida at any site.6,7,43 Obtaining more than six sets of CHAIN REACTION, AND METABOLITE ASSAY blood cultures has little value, and there is no evidence to support obtaining arterial cultures. Once a blood culture has turned posi- Many published papers and commercial products have touted tive for Candida, the species must be rapidly identified so that the the benefits of various auxiliary serologic tests in the identification correct antifungal agent can be selected for treatment. A rapid and of patients with fungal infection. At present, however, assays for
  • 7.
    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 7 fungal wall elements (mannan), D-arabinitol (a cell membrane Management of Candidemia metabolite), or enolase (cell cytoplasm) appear to be of limited and Acute Disseminated value, as do polymerase chain reaction (PCR)–based assays.50,59-67 Candidiasis These tests have mixed sensitivities and specificities that prohibit Patients who have Candida their widespread application. A 2005 study evaluated the assay for infections can now be treated (1→3)-β-D-glucan, an important constituent of fungal cell walls with any of a number of anti- that is absent from bacterial cell walls.59 At a cutoff value of 60 fungal agents, including pg/ml, the assay had a sensitivity of 69.9% and a specificity of amphotericin B, the azoles (flu- 87.1%, with a positive predictive value of 83.8% and a negative conazole, itraconazole, voriconazole, and posaconazole), flucyto- predictive value of 75.1%. At a cutoff value of 80 pg/ml, it had a sine, the lipid amphotericin products (see below), and the sensitivity of 64.4% and a specificity of 92.4%, with a positive pre- echinocandins (caspofungin, micafungin, and anidulafungin) [see dictive value of 89% and a negative predictive value of 73%. Of Table 3].68-79 Randomized, controlled trials designed to determine the 107 patients with proven candidiasis, 81.3% showed positive noninferiority have demonstrated that several agents—namely, flu- results at a cutoff value of 60 pg/ml, and 77.6% showed positive conazole, itraconazole, voriconazole, caspofungin, and micafun- results at a cutoff value of 80 pg/ml.This screening test may be of gin—can be considered not inferior to the previous standard ther- some use in following high-risk patients, especially when per- apy—namely, amphotericin B or lipid formulations thereof.68-78 formed serially. Because of the emergence of non-albicans species as significant pathogens, it is vital that surgeons be aware of the variety of HISTOLOGIC ANALYSIS Candida species that may be encountered and the relevant drug Analysis of fungal smears is a relatively insensitive method of sensitivities.80-83 Most C. albicans isolates are sensitive to all of the diagnosing candidiasis and other fungal infections in otherwise currently available agents, but some low-level resistance has been sterile sites (e.g., joint fluid, peritoneal fluid, vitreous humor, or reported, especially with previous long-term exposure to azoles at cerebrospinal fluid).67 Centrifugation of these fluids and examina- low dosages.80-83 C. glabrata may be resistant to fluconazole or tion of the sediment may improve the diagnostic yield.50 require some modification of the dosage; C. krusei is resistant to Conventional fungal stains, such as hematoxylin-eosin, periodic fluconazole; and C. lusitaniae may be resistant to amphotericin acid–Schiff (PAS), and Gomori methenamine-silver (GMS), are B.80-83 The selection of the initial antifungal agent to be used is useful. The most sensitive stain is calcofluor white, but unfortu- based on estimation of the likelihood of infection, assessment of nately, it requires fluorescent microscopy. Deep tissue biopsy pro- the probable sensitivity or resistance of the fungal species, consid- vides a definitive diagnosis of candidiasis. eration of specific patient risk factors (e.g., renal or hepatic insuf- Table 3 Antifungal Chemotherapy68-79 Route of Drug Indications Major Side Effects Administration Hematogenous and deep-seated candidiasis; aspergillosis; blastomy- Anemia, headache, chills, fever, nausea, renal dysfunc- Amphotericin B I.V., intrathecal cosis; coccidioidomycosis; histoplasmosis; cryptococcosis tion, hypotension, tachypnea, hypokalemia, phlebitis Clotrimazole Oropharyngeal candidiasis Oral — Candidiasis (bloodstream infection, endocarditis, urinary tract infec- Leukopenia, thrombocytopenia, liver dysfunction, Flucytosine Oral diarrhea tion); cryptococcosis Oropharyngeal and esophageal candidiasis; hematogenous candidal Fluconazole infection; other candidal infections (e.g., urinary tract infection, peri- Oral, I.V. Nausea and vomiting, skin rash, liver dysfunction tonitis); meningeal coccidioidomycosis; cryptococcosis Itraconazole Histoplasmosis; blastomycosis; aspergillosis Oral Nausea, vomiting, liver dysfunction Candidiasis (chronic mucocutaneous candidiasis or oropharyngeal Ketoconazole candidiasis); candiduria; blastomycosis; coccidioidomycosis; histo- Oral Hepatotoxicity, nausea or vomiting, occasional suppres- plasmosis; chromomycosis; paracoccidioidomycosis sion of adrenal function Aspergillosis (invasive); candidiasis (chronic mucocutaneous candidia- Photophobia, visual hallucinations, photosensitivity/rash, Voriconazole sis or oropharyngeal candidiasis) and hematogenous candidal infec- Oral, I.V. drug interactions, hepatotoxicity, nausea and vomiting, tion; candiduria; Fusarium or Scedosporium infection fever Abdominal pain, nausea or vomiting, diarrhea, drug inter- Posaconazole Disseminated candidiasis; prophylaxis of aspergillosis or oropharyn- Oral actions, prolonged QT interval, hyperbilirubinemia, he- geal canidiasis in immunocompromised patients. patotoxicity, occasional suppression of adrenal function Candidiasis (chronic mucocutaneous candidiasis or oropharyngeal Caspofungin candidiasis); hematogenous candidal infection; aspergillosis I.V. Rash, pruritus, nausea, vomiting, thrombophlebitis, (refractory) headache, fever, increased liver enzymes Micafungin Candidiasis (chronic mucocutaneous candidiasis or oropharyngeal I.V. Rash, pruritus, nausea, vomiting, diarrhea, throm- candidiasis); candidiasis prophylaxis; stem cell transplantation bophlebitis, headache, fever, increased liver enzymes Candidiasis (chronic mucocutaneous candidiasis or oropharyngeal Hypokalemia, diarrhea Anidulafungin I.V. candidiasis); hematogenous candidal infection
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    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 8 ficiency), and determination of whether the patient should receive ness analysis, both amphotericin B deoxycholate and its lipid the agent orally or intravenously.68-79 In addition, selection of the products provided fewer discounted lives saved than either flu- best antifungal agent for a specific at-risk or infected patient is conazole or caspofungin did (according to the data available at the facilitated and enhanced by familiarity with the typical pathogens time of publication).89 in the local community. At present, there are no evidence-based guidelines concerning Several oral and intravenous azoles are available for clinical the optimal duration of therapy.17,18 This decision should be based use.17,18,69,72,74-77 Clotrimazole and miconazole are not suitable for in part on the severity of the patient’s illness, as well as on his or systemic therapy. Ketaconazole has very poor and erratic GI her immune constitution. In general, therapy should be continued absorption and thus is not used for systemic therapy. Itraconazole for at least 14 days after the last positive cultures and the resolu- also has very erratic GI absorption and therefore should not be tion of all signs and symptoms of infection in the most seriously ill used for systemic therapy either.17,18 A single trial conducted in a patients. Shorter courses of therapy may be appropriate in careful- pediatric population found that itraconazole at a dosage of 10 ly selected patient populations without signs of hemodynamic mg/kg/day orally was clinically similar to fluconazole at a dosage of instability or evidence of distant metastatic infection. 200 mg/day orally for treatment of candidemia.84 The I.V. agent CATHETER MANAGEMENT fluconazole is a well-tolerated triazole that shows good activity in candidemic patients. Individual clinical trials involving nonneu- The fundamental controversy about whether central venous tropenic patients with candidemia, as well as a meta-analysis of access lines should be removed when identified in patients with these trials, indicate that amphotericin deoxycholate and flucona- candidemia stems from the multiple routes by which infection zole yield similar outcomes in terms of overall mortality, attribut- occurs in different patient populations.91-94 When the GI tract is able mortality, and clinical and microbiologic response but differ the source of candidemia (as in cancer patients with mucositis),95 in terms of toxicity, with fluconazole appearing to be less toxic.85- catheter removal is unlikely to yield any significant benefit. On the 88 Thus, it is reasonable to use fluconazole to treat patients with other hand, when an I.V. catheter is a source of ongoing can- candidemia. didemia, there is some evidence to suggest that removal of the The 2004 treatment guidelines published by the Infectious catheter may shorten the time to blood clearance and perhaps Disease Society of America suggest that physicians may choose even improve overall survival. In a study examining catheter among three alternatives for primary treatment of candidemia in exchange in patients without cancer, replacement of all vascular nonneutropenic adult patients: (1) amphotericin B deoxycholate catheters shortened the duration of candidemia from 5.6 days to (0.6 to 1.0 mg/kg/day, or one of the lipid formulations); (2) flu- 2.6 days.91 The current state of knowledge regarding the impor- conazole (400 to 800 mg orally or I.V.); and (3) caspofungin tance of biofilm, the penetration of antifungal agents, and the (loading dose of 70 mg I.V., followed by 50 mg/day I.V. or, if the attachment of new pathogens tends to favor removal of catheters patient has severe obstructive hepatic disease, 35 mg/day I.V.).17 If to the extent possible after candidemia. Given the available data, the species is known or believed to be C. albicans, fluconazole physicians should consider removing all intravascular catheters (loading dose of 12 mg/kg I.V., followed by I.V. infusion of 6 from inpatients who have candidemia with persistent fever, persis- mg/kg/day) is appropriate. Fluconazole has excellent oral bioavail- tent or high-grade fungemia, or C. parapsilosis infection (which is ability and frequently can be delivered orally after the first few more likely to be catheter related than infection with another days. Dose adjustments must be considered if renal insufficiency Candida species would be). is present. 17,18,69,72,74-77 If the patient has received long-term azole IMMUNOTHERAPY therapy, is known to be colonized with C. glabrata or C. krusei, or both, then one of the echinocandins—either caspofungin (loading Despite the availability of newer antifungal agents, treatment dose of 70 mg I.V., followed by 50 mg/day I.V.) or micafungin failures remain significant problems. Physicians’ familiarity with (100 mg/day I.V.)—should be administered.68,71,73,78,89 If the the roles of both innate and acquired immunity in the acquisition species then proves sensitive to fluconazole, this agent may then be and resolution of fungal infections has grown substantially over the given orally to continue therapy. Although clinical trials have past several years.96 The development of adjunctive immunother- shown voriconazole (6 mg/kg I.V. every 12 hours for the first 24 apies based on an understanding of the host immune response has hours, then 3 mg/kg I.V. every 12 hours, p.o. switch 200 mg every led to preliminary trials with cytokines such as interferon gamma 12 hours) to be an acceptable agent for treating candidemia,90 and granulocyte colony-stimulating factor (G-CSF),97 as well as there are many drug interactions and side effects of which the with granulocyte transfusion.98 Although these trials have demon- physician must be aware when using this drug. In particular, strated safety and (perhaps) proof of principle, they do not support patients who have undergone transplantation and those with HIV clinical use of these agents, especially in nonneutropenic patients. infections are very likely to be taking agents that interact with Active investigation into the TLR-mediated pathogen recognition voriconazole. and signal transduction pathway and the means by which Candida The current role of amphotericin B in the treatment of can- evades the TLR-mediated host immune response may lead to new didemia is limited by its toxicity [see Systemic Antifungal Agents, immunotherapies in the future. Because both persons at risk and Amphotericin B, below]. The lipid-associated formulations of host risk factors are identifiable, host vaccination remains a prime amphotericin B are less nephrotoxic than the parent compound.61 focus of investigation into prevention.96 Three such formulations are available: (1) amphotericin B lipid ANTIFUNGAL PROPHYLAXIS complex (Abelcet), (2) amphotericin B colloidal dispersion (Amphocil, Amphotec), and (3) liposomal amphotericin B The use of antifungal prophylaxis remains a controversial (AmBisome). A prospective, randomized trial found Abelcet to be topic,3,99-108 though four recent meta-analyses109-112 and a as efficacious as conventional amphotericin B for treating hema- Cochrane review111 have all concluded that prophylactic adminis- togenous candidiasis.62 If, however, the patient is known to have a tration of antifungal agents to high-risk critically ill or surgical Candida infection, the infection can and should be treated with patients reduces the incidence of invasive fungal infection but has one of the agents previously mentioned. In a 2005 cost-effective- no proven effect on mortality. These analyses illustrate the prob-
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    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 9 a b c Figure 1 Candida endophthalmitis is common in patients with persistent fungemia. On funduscopy, a charac- teristic white, cotton-wool–like exudate can be seen (a). Cut section of an eye shows Candida retinitis (b). A microscopic view of Candida chorioretinitis is also provided (c).146 lems inherent in attempting to combine data from small trials that The data do not yet support widespread or routine use of anti- employed different agents (ketoconazole and fluconazole) at dif- fungal prophylaxis. Accordingly, it is worthwhile to formulate ferent dosages in different at-risk patient populations. Perhaps the some general conclusions regarding which patients should receive most difficult issue in determining whether antifungal prophylax- antifungal prophylaxis and which agent should be used. It is rea- is should be employed involves the lack of a consensus on how sonable to consider antifungal prophylaxis in patients similar to fungal infection should be defined. Without a well-understood those in the aforementioned studies (see above), including organ end point, it is impossible to decide whether a therapy should be transplant patients3,17,109-112 and patients enrolled in referenced widely applied. clinical trials. In most of these patient populations, fluconazole is To date, there have been eight major studies of antifungal pro- the most appropriate agent for prevention of Candida infection: it phylaxis that are applicable to the critically ill surgical patient pop- has few side effects, it can be administered orally, and out of the ulation.3,102-108 The three largest of these are of particular rele- agents that have been well studied, it is the most reasonably vance. In one study, a large number of liver transplant recipients priced. In view of the increasing reports of resistance, however, the were randomly assigned to receive either placebo or fluconazole use of fluconazole should not be extended to additional patient for a period of 10 weeks (during which administration switched populations, especially those who are less ill and certainly those from I.V. to oral).105 Definitions of fungal infections included both who are at less risk. The key question in making the decision for deep and superficial infections.The authors documented a signif- or against antifungal prophylaxis should be whether the benefits icant decrease in fungal colonization and fungal infection (both achievable in the patient population being considered for prophy- superficial and deep) in the fluconazole group but reported no sig- laxis are significant enough to outweigh the cost and the risk of nificant difference in mortality between groups. Although hepato- eventual (and even expedited) resistance developing with exces- toxicity was absent in the fluconazole group, neurologic toxicity sive use. was higher than in the placebo group, presumably as a conse- ORGAN INFECTIONS quence of increases in cyclosporine levels, which must be adjust- ed in patients receiving prophylactic fluconazole. In a large study that enrolled 220 patients in the medical or sur- Candidal Endophthalmitis gical ICU on or after their third day in the unit, prophylaxis with The diagnosis of candidal endophthalmitis usually implies fluconazole, 100 mg I.V., was compared with placebo.108 The hematogenous spread to multiple organs and the need for sys- patients enrolled in this trial were critically ill, were receiving res- temic antifungal therapy. Identification of eye involvement early in piratory support from a mechanical ventilator, and were undergo- therapy is crucial for preserving visual acuity [see Figure 1].51 ing selective decontamination of the GI tract. Candidemia was Patients who have only chorioretinitis respond better to drug ther- virtually eliminated in the fluconazole group. In addition, the inci- apy alone than patients who show vitreal involvement. Treatment dence of invasive candidal infection was lower in this group (3.9% depends on achieving an adequate concentration of an agent versus 8.9%), and fungal colonization was both less frequent and effective against the fungal pathogen within the vitreous compart- less intense. ment.51 Because antifungal drugs do not penetrate the vitreous Finally, in a single-institution, randomized, double-blind, place- body as well as they do the other ocular compartments,113 patients bo-controlled trial that compared enteral fluconazole (800 mg with vitreal involvement require early vitrectomy in addition to loading dose, followed by 400 mg/day) with placebo for preven- antifungal therapy. tion of fungal infections in high-risk critically ill surgical patients, Fluconazole is currently the drug of choice because of its the authors reported that fluconazole prophylaxis yielded a two- proven efficacy and its higher concentration (20% to 70% of the to threefold reduction in fungal infection but had no effect on corresponding plasma level) in ocular tissue, including the vitre- mortality.3 Using a strict case definition that did not include fun- ous body.51,114 Accordingly, I recommend 800 mg/day of flucona- gal colonization, the intent-to-treat analysis demonstrated 20 zole until a major response is observed, at which time it may be patients with fungal infections (15.3%) in the placebo group and possible to reduce the dose to 400 mg/day. Many other Candida 11 such patients (8.5%), including four with infections that were and non-Candida fungal species may also cause endophthalmitis, unknown at enrollment, in the fluconazole group. The number and in such cases, fluconazole may not provide effective coverage. needed to treat (i.e., the number of patients who would have to If the infecting organism (especially C. krusei) is potentially resis- receive antifungal prophylaxis for a single fungal infection to be tant to fluconazole, the recommended therapy is amphotericin B prevented) was 14.5, a low number that suggests a highly signifi- (0.7 to 1.0 mg/kg/day I.V.), preferably in conjunction with flucy- cant effect. tosine.115 Intravitreal injection of amphotericin B is recommend-
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    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 10 ed for vitreal infections. Both voriconazole and caspofungin have Successful treatment of fungal arthritis with fluconazole has had limited success in patients with more resistant infections.51 been reported in several cases.122 I recommend giving fluconazole The optimal duration of therapy for endogenous endoph- at a dosage of 400 to 800 mg/day for 6 to 12 months; others sug- thalmitis is unknown. Ophthalmologic consultation is critical in gest giving amphotericin B first for 1 to 2 weeks, then switching to establishing the diagnosis, assessing the patient’s response to ther- fluconazole.17 Fluconazole can be used for short-term therapy, apy, detecting complications, and determining whether early vit- either alone or in combination with surgery, as well as for long- rectomy is indicated to prevent loss of sight.116 term suppressive therapy in patients who are at risk for recurrence or who cannot undergo surgical debridement. In general, surgical Suppurative Thrombophlebitis, Endocarditis, and Pericarditis resection of the involved joint is required. A rare but serious consequence of hematogenous candidemia is Except for sternal infections complicating median sternotomy, suppurative thrombophlebitis, which results from infection of a most cases of candidal osteomyelitis develop through hematoge- vessel traumatized by prolonged catheterization. Endothelial dis- nous spread. Vertebral body involvement is common. Back pain ruption exposes the basement membrane and leads to thrombus and fever may be followed by radiculopathy. Surgical drainage of formation and propagation. Suppurative thrombophlebitis is par- all purulent collections is essential for a good response; however, ticularly serious because intravascular infection results in a persis- surgical debridement of bony lesions may not be needed. tent high-density fungemia. Management of this disease consists Although amphotericin B has been the standard drug of choice for of high-dose antifungal therapy, removal of the central venous candidal osteomyelitis, fluconazole may be considered as an alter- catheter, and excision of the infected vein (when possible).52,117 native. Amphotericin B should not be used for mediastinal irriga- Typically, blood cultures remain positive for several days; some- tion after drainage and debridement of a mediastinal infection, times, they remain positive for as long as 3 to 4 weeks despite because there is a high probability of chemical mediastinitis. appropriate antifungal therapy, if the infected vein is not excised. Fungal infections account for between 1% and 10% of all Meningitis pathogens isolated from patients with infective endocarditis.17 In Candidal meningitis may follow hematogenous spread, or it patients with prosthetic valves, the rate at which fungi are isolated may be a complication of neurosurgery or the implantation of ven- may be as high as 10%. The overall outcome of candidal infective triculoperitoneal shunts. In neonates, Candida infection may be endocarditis is grim, carrying a reported mortality of up to 80%, present without previous surgery and without previously docu- especially when complicated by congestive heart failure and persis- mented fungemia, but often, an intravascular catheter is pre- tent fungemia.118 Embolic phenomena are more commonly associ- sent.123 The infection is insidious and sometimes goes undiag- ated with fungal endocarditis than with the nonfungal variety. nosed. Most patients with candidal meningitis have recently Candidal endocarditis is very difficult to treat. A 2005 review received antibacterial agents, and half have previously had bacter- found that patients with candidal endocarditis who underwent ial meningitis. The overall mortality is around 10%. adjunctive surgery had a lower reported mortality.118 Thus, surgi- The standard therapeutic regimen for candidal meningitis con- cal replacement or repair of valves is required to prevent death sists of amphotericin B with flucytosine. As an alternative, a com- from embolization or cardiac failure in patients with complicated bination of high-dose fluconazole (800 mg/day) and flucytosine (50 prosthetic valve endocarditis. Amphotericin B, with or without mg/kg/day) may be considered; this is a particularly attractive flucytosine, has been the therapy of choice; however, neither the approach because of the high CSF concentrations achieved with optimal dosage nor the optimal duration of therapy has been both agents. Removal of the infected shunts, as well as the intravas- determined. There is some anecdotal information suggesting that cular catheter, is recommended when possible.17,123 The duration fluconazole, with or without caspofungin, may be successfully of treatment should be based on the patient’s clinical response and employed in this setting, primarily as long-term suppressive ther- the culture results. In general, prolonged treatment (more than 4 apy after the initial administration of amphotericin B.119 Because weeks beyond the resolution of symptoms) is suggested. of the high risk of late relapse, long-term maintenance therapy with oral fluconazole should be considered in patients unwilling or Pneumonia unable to undergo surgical treatment. True candidal pneumonia is rare, but it can occur through Candidal pericarditis is a very rare complication of hematoge- hematogenous dissemination into the lung as one of many sites of nous candidiasis. The surgical patients at risk for purulent peri- infection.17,124,125 Oropharyngeal aspiration of oral and upper tra- carditis caused by Candida are those who have undergone a car- cheal organisms does not typically cause pneumonia.The value of diac operation, those who have a malignancy and whose host deep tracheal suction or even bronchoalveolar lavage in defining defenses are impaired, and those who have a debilitating chronic this disease should be questioned. Histopathologic confirmation is disease.120 Patients should be treated with surgical drainage or recommended.17 Laryngeal infection should be considered; some debridement and with high-dose amphotericin B or fluconazole. case reports suggest that it can be rapidly progressive. Arthritis and Osteomyelitis Candidal joint infections can develop via hematogenous spread Management of Nonhematogenous Candidiasis as a consequence of inadvertent direct inoculation during joint pro- SUPERFICIAL INFECTION cedures or intra-articular injection of corticosteroids. Such infec- tions typically involve a single joint (most frequently the knee or the Oral candidiasis (thrush) appears as a whitish, patchy hip) and tend to occur in patients with rheumatoid arthritis or pros- pseudomembrane covering an inflamed oropharynx; it common- thetic joint devices.121 Local symptoms (i.e., pain on weight bear- ly involves the tongue, the hard and soft palates, and the tonsillar ing or on full extension) may be present. Diagnosis is best achieved pillars. Controlled trials have shown nystatin suspension, oral by visualizing the organisms or growing them from the joint fluid. amphotericin B, clotrimazole troches, oral ketoconazole, flucona- Early diagnosis and systemic antifungal therapy are vital for pre- zole, and itraconazole to be efficacious for eradicating the clinical venting destruction of the cartilage or loosening of the prosthesis. symptoms of oral candidiasis.17
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    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 11 Nystatin should be given as a 10 to 30 ml suspension five times daily, and the patient should be instructed to swish it around the mouth before swallowing; alternatively, the patient may take one or two troches five times daily. Clotrimazole is given five times daily in the form of a 10 mg troche that should be held in the mouth until dissolved. In surgical patients at risk for hematoge- nous infection, systemic therapy with ketoconazole (200 to 400 mg once daily), itraconazole (200 mg/day), or fluconazole (100 mg once daily) is preferred.17 Antifungal therapy should be administered for 7 to 14 days. Ketoconazole and itraconazole are slightly less effective than fluconazole because of variable GI absorption. Repeated episodes of oral candidiasis are common. DEEP CANDIDIASIS Esophagitis and Gastrointestinal Candidiasis Superficial candidiasis involving only mucosal surfaces used to be a common finding at autopsy in surgical patients who had had Figure 2 Superficial candidiasis may be found at all levels of the a protracted hospital stay characterized by recurrent sepsis. Such GI tract. Here, the esophagus of a patient found at autopsy to have lesions may arise at any site in the GI tract but appear most com- disseminated candidiasis shows disrupted epithelium, submucosal monly in the esophagus and the small bowel; in some cases, they inflammation, and the presence of yeast in the submucosa. progress to hematogenous infection [see Figure 2]. In a minority of patients, the pathology of candidal infection of the lower GI tract may change from diarrhea without demonstra- Such infections are often located in the abdomen, the liver, the bil- ble tissue invasion to direct penetration into the submucosa, iary tree, the pancreas, or the peritoneal cavity. Percutaneous which eventually leads to pseudomembranous enterocolitis. drainage can play an important role in the management of these Direct vascular invasion through the bowel wall may occur in difficult problems; however, one retrospective review of percuta- immunosuppressed patients; these patients may exhibit extensive neous drainage of fungal collections in the abdomen or thorax involvement of the GI tract from mouth to anus. Nonneutropenic suggested that clinical failures occur more often when complex surgical patients may exhibit more localized GI involvement. fluid collections are visible radiographically, when patients have a The preferred therapy for esophageal candidiasis consists of flu- history of malignancy, and when patients are critically ill.127 conazole (100 mg/day orally) or itraconazole (200 mg/day) for 14 Patients with peritonitis and intra-abdominal abscesses should to 21 days.17 In patients who remain symptomatic after 7 days of receive systemic antifungal therapy, usually in combination with therapy, endoscopy is indicated to rule out other causes of antibacterial therapy (given that these infections are almost always esophagitis. If endoscopy proves that esophagitis is being caused polymicrobial in origin). The risk of dissemination is increased by candidal infection, low-dose amphotericin B (0.4 mg/kg/day) both by the recurrence of intra-abdominal infection and by the may be administered. Alternatively, caspofungin or voriconazole presence of extensive areas of communication between the may be given,17 though it should be kept in mind that voricona- abdominal cavity and the external environment via either fistulas zole causes more adverse events without being more efficacious. or drain tracts. Because fluconazole is very safe and is capable of Therapy for esophageal candidiasis should be continued for at reaching high concentrations in peritoneal fluid, it is useful in the least 4 days after symptoms resolve; immunosuppressed patients management of candidal peritonitis and should be considered the generally require more extended therapy to prevent relapse. agent of choice in cases where the pathogens are susceptible to Because stool cultures do not differentiate between coloniza- it.107 Fluconazole should be given at a dosage similar to that tion and infection, candidiasis in the lower GI tract is usually a employed in treating systemic disease (loading dose of 12 mg/kg postmortem diagnosis; hence, there are no reliable criteria govern- I.V., followed by 6 mg/kg/day I.V.), with a 50% dosage reduction ing when and how to treat this condition. It has been reported, in cases of renal impairment.When pathogens are resistant to flu- however, that patients who have diarrhea that can only have been conazole, caspofungin and voriconazole at systemic dosages are caused by heavy colonization with Candida species may respond acceptable alternatives.17 dramatically to 2 to 4 days of nystatin therapy. On rare occasions, candidal peritonitis occurs after long-term ambulatory peritoneal dialysis. This infection is not clinically dis- Peritonitis and Intra-abdominal Abscess tinguishable from bacterial peritonitis. In such cases, the infection Perhaps the most controversial issue in the management of tends to remain localized and to manifest with low-grade fever and Candida infectious syndromes in surgical patients is the question abdominal pain and tenderness.The peritoneal dialysate is usual- of whether specific systemic therapy is required to eradicate the ly cloudy and contains more than 100 neutrophils/mm3. Therapy infection within intra-abdominal abscesses, peritoneal fluid, or fis- consists of systemic antifungal therapy and removal of the peri- tula drainage.17 Candida is frequently cultured from intra-abdom- toneal catheter. The abdominal pain caused by the addition of inal infectious foci but should be considered a serious threat only amphotericin B to the dialysate has raised concern that chemical in high-risk patients.126 Four risk factors for intra-abdominal can- peritonitis might give rise to adhesions and thus impair the effica- didiasis have been identified: (1) gastrointestinal perforations, cy of dialysis. Accordingly, this agent should not be used for peri- especially in the upper GI tract, (2) anastomotic leakage, (3) toneal irrigation. Immediate removal of the peritoneal catheter has surgery for acute pancreatitis, and (4) splenectomy.107,126 In been recommended. Fluconazole should be considered as the patients with a localized fungal infection necessitating drainage, agent of choice and should be given for 1 to 14 days. A new there is no replacement for adequate drainage and debridement. catheter should not be placed for 4 to 6 weeks. In centers with a
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    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 12 high rate of fungal peritonitis secondary to peritoneal dialysis, nys- Hematogenous infections of the kidneys leading to multiple tatin prophylaxis may be considered. A prospective, randomized renal abscesses are treated as instances of hematogenous candidi- study of patients on continuous ambulatory dialysis found that asis. However, because both fluconazole and flucytosine are well Candida peritonitis was successfully prevented with oral nystatin tolerated, have good tissue diffusion, and are excreted in the urine (tablets containing 500,000 units given four times a day).128 in high concentrations, it is reasonable to assume that the combi- Occasionally, Candida species may cause cholangitis, biliary nation of these two agents represents the therapy of choice for tract disease, pancreatic abscess, or liver abscess. This problem is such infections. increasingly found in cancer patients with percutaneously placed GENITAL CANDIDIASIS drainage catheters. Such patients must be given systemic therapy if there is any clinical evidence of infection (e.g., candidemia), and Fungal vulvovaginitis is a common problem in women and is the drainage catheter must be changed. Diverticulitis complicated often associated with antibiotic therapy and poor glucose control. by candidal pylephlebitis has also been reported. It may be divided into simple and complex forms, with more than 90% of women having the simple form and the remaining 10% Wound Infections experiencing recurrent symptoms. The diagnosis is based on the Diagnosis and treatment of candidal wound infections are prob- clinical findings and on the presence of pseudohyphae on a fungal lematic. Recovery of Candida species from drains and wounds does smear. not necessarily mean that this organism is causing tissue infection; Antifungal agents, including oral azoles (fluconazole, 150 mg in however, isolation of Candida or demonstration of invasive forms a single dose; ketoconazole, 400 mg/day for 5 days; or itraconazole, on biopsies at reoperation would suggest that invasive infection is 200 mg in a single dose) and topical medications (suppositories, present. Antifungal therapy should be administered to patients creams, and vaginal tablets), are effective against more than 90% of with demonstrated invasive infection and possibly to those in uncomplicated infections. However, women who have experienced whom antibacterial therapy has failed and Candida has been iso- four or more episodes of vulvovaginal candidiasis during a 12- lated. If a deep sternal wound culture is obtained and is positive month period and those who have sustained acute severe attacks of for Candida after coronary bypass surgery, antifungal agents candidal vaginitis are less likely to respond to conventional therapy. should be given to prevent the establishment of candidal osteo- Preventive measures include control of host factors such as dia- myelitis of the sternum. betes mellitus, antifungal prophylaxis during the course of antibiot- ic therapy and under other high-risk conditions, and avoidance of CANDIDURIA systemic corticosteroids, oral contraceptives, and antibiotics if pos- Candida is either the most common or the second most com- sible. Therapy with oral fluconazole, itraconazole, or ketoconazole mon pathogen isolated from the urine in surgical ICU patients. should be provided for approximately 14 days to ensure clinical The term urinary candidiasis refers to an ill-defined group of syn- remission and negative fungal cultures, followed by a maintenance dromes, many of which probably represent colonization rather regimen of fluconazole (150 mg once weekly for 6 months). than infection. Thus, the actual importance and meaning of can- Recurrence of vulvovaginal candidiasis is common, arising in 30% diduria are controversial.53-58 Candiduria is very common in hos- to 40% of patients after cessation of the maintenance regimen.130 pitalized patients who have had urinary catheters in place for more than 14 days.58 In this setting, it is more likely to reflect coloniza- tion than infection. In ICU patients, however, the significance of Management of Other Fungal Infections candiduria is less clear-cut: it may represent either upper tract dis- ASPERGILLOSIS ease or hematogenous disease and filtration of the pathogens into the urine.129 Increasing concentrations of Candida in the urine, Aspergillosis, a rare infection in general surgical patients, is now, especially after a catheter exchange and particularly in a critically unfortunately, becoming increasingly common in certain subpop- ill surgical patient with known risk factors, should raise concerns ulations, such as patients who experience marked immunosup- about possible upper-tract or disseminated disease. pression after undergoing chemotherapy with cytotoxic agents, Besides simple colonization, the spectrum of candidal urinary those being given adrenal corticosteroids, and those who have tract infection includes cystitis, pyelitis (i.e., infection of the renal recently received antirejection therapy.82 Most cases of nosocomi- pelvis), fungus ball of the ureter, and renal abscesses.The diagno- al aspergillosis are acquired via airborne transmission. Colonization sis of cystitis is based on the presence of symptoms of cystitis, dif- of the respiratory tract is followed by invasive disease if the predis- fuse erythema or fungal plaques on cystoscopy, candiduria, and posing factors are present. Sources of airborne fungi in microepi- pyuria. Candida cystitis warrants therapy. If a triple-lumen catheter demics frequently are associated with construction within the hos- is in place, bladder irrigation with amphotericin B (50 mg/L/day pital or at adjacent sites. Other modes of transmission have also for 2 days) may be tried. Fluconazole (200 mg once daily) is a been reported for aspergillosis, including foreign bodies, catheters, more attractive approach because of the convenience, the lower and bandages. cost, and the very high drug concentrations achieved in the Acute invasive pulmonary aspergillosis is the most common urine.54 Flucytosine is excreted in the urine in high concentrations form of Aspergillus infection in immunocompromised surgical and may be particularly useful against C. glabrata infection. patients.82 The organisms tend to invade blood vessels and cause Management of pyelitis depends on whether the renal papillae thrombosis and infarction of the surrounding tissues. The infec- are invaded or the ureter is obstructed with a fungus ball. Patients tion may manifest itself in the form of acute vascular events such with no papillitis and an open ureter usually respond to irrigation as pulmonary embolisms or, more rarely, myocardial infarction, with amphotericin B through a ureteral or percutaneous catheter. cerebral hemorrhage, or Budd-Chiari syndrome. Pulmonary If papillitis is present, systemic antifungal therapy with fluconazole Aspergillus infections include necrotizing bronchopneumonia (400 mg/day) is recommended. If fungus balls are present, surgi- and hemorrhagic pulmonary infarction, each accounting for cal removal should be considered in addition to treatment with about one third of these infections. Pulmonary aspergillosis may antifungal agents.54 extend to contiguous organs or be disseminated. The rhinocere-
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    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 13 Table 4 Characteristics of Currently Available Azoles*68-79 Ketoconazole Fluconazole Itraconazole Voriconazole Posaconazole Spectrum Narrow Expanded Expanded Expanded Expanded Route(s) of administration Oral Oral, I.V. Oral Oral, I.V. Oral Erratic, requires gastric Erratic, requires gastric Bioavailability Excellent Excellent With meals acidity acidity Dose dependent, Plasma half-life (hr) 6–9 30 20–40 19–35 nonlinear Hepatotoxicity Occasional Occasional Occasional Occasional Occasional GI intolerance Frequent Occasional Occasional Occasional Occasional CSF penetration No Yes No Yes — Renal excretion No Yes No Yes No Interaction with other drugs Frequent Occasional Frequent Very frequent Very frequent *Intravenous miconazole is also available but offers no advantage over the currently available azoles. bral form of aspergillosis occurs less often than the pulmonary pulmonary, GI, cutaneous, or (very rarely) disseminated. Any form. It originates in the sinuses and progresses through soft tis- patient with a necrotic lesion on the skin, soft, hard palate or nose sues, cartilage, and bone, causing lesions in the palate and the should be considered to have an angioinvasive mold infection nose. Occasionally, the infection progresses through the base of until emergency biopsy proves otherwise. the skull and involves the brain. Appropriate management of zygomycosis consists of extensive Diagnosis of Aspergillus infection is difficult. Computed tomog- surgical debridement of infected areas, rapid correction of the raphy can be diagnostic131 and often allows early recognition of underlying disease, and administration of an appropriate antifun- aspergillosis. In one study that used CT scans as a means of inves- gal agent. One of the lipid amphotericin products should be the tigation, the mean time to diagnosis of invasive pulmonary first-line therapeutic agent, with high-dose amphotericin B deoxy- aspergillosis fell from 7 days to less than 2 days, and this reduction cholate a second choice. was associated with a decrease in mortality. CT may also be com- EMERGING PATHOGENS bined with detection of Aspergillus antigen (galactomannan), an approach that shows promise for early diagnosis of invasive pul- Fusarium and Scedosporium species are increasingly common monary aspergillosis.132 Often, however, diagnosis of Aspergillus causes of infections in surgical patients, especially in recipients of infection depends on identifying the organism in culture or histo- stem cell or organ transplants.82,134 Most cases of Scedosporium pathologic specimens.82 Recovery of Aspergillus species from the infection present as disseminated disease; skin lesions are com- respiratory tract culture of a surgical patient should be considered mon, and the lungs and the CNS are frequently involved. to represent contamination or colonization unless the patient is Surgeons may be tempted to use amphotericin B to treat these symptomatic and severely immunosuppressed. unusual molds, but voriconazole has been shown to yield better All of the antifungal agents currently used for primary treat- outcomes with both Fusarium and Scedosporium. ment of Aspergillus are associated with relatively high incidences Many other mold species are also emerging as significant of treatment failures and fairly poor outcomes. At present, pathogens. In an at-risk patient, recovery of any fungus from any voriconazole (at the dosage previously described [see site should prompt an evaluation by an infectious disease special- Management of Candidemia and Acute Disseminated ist to determine the clinical significance of the isolate. Candidiasis, above]) is the treatment of choice, with lipid amphotericin B formulations as secondary agents. In some insti- tutions, combination therapy with an echinocandin is occasion- Systemic Antifungal Agents ally employed as an alternative. AMPHOTERICIN B ZYGOMYCOSIS (MUCOR AND RHIZOPUS) Amphotericin B was the first systemic antifungal agent and has Some of the most rapidly advancing forms of angioinvasive fun- historically been considered the gold standard for antifungal ther- gal infection are caused by the Zygomycetes Mucor and apy. Today, however, its usefulness in daily practice is substantial- Rhizopus.133 The reservoir, the mode of transmission, the patho- ly less than it once was, primarily because of the proliferation of genesis, and the clinical presentations are similar to those of many alternative agents that are less toxic (but that also may pos- Aspergillus species. Zygomycosis is being seen with increasing fre- sess a more limited spectrum of activity) [see Table 4].17,135,136 quency in stem cell transplant recipients who have been receiving Amphotericin B is lipophilic and binds avidly to ergosterol, the voriconazole prophylaxis. In surgical patients, the major risk fac- principal sterol in the fungal cytoplasmic membrane.This binding tors include diabetic ketoacidosis, immunosuppression after cyto- disrupts the integrity of the membrane, resulting in leakage of toxic chemotherapy, adrenal corticosteroid therapy, organ trans- intracellular contents and cell death. The clinical effectiveness of plantation, skin damage (e.g., from adhesive tape, an arm board, amphotericin B against fungi is believed to be attributable to the or severe burns), iron overload, and a prolonged postoperative drug’s stronger affinity for ergosterol (found in fungal cell mem- stay.133 Zygomycotic infections may be rhinocerebral, paranasal, branes) than for cholesterol (the principal sterol found in mam-
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    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 14 malian cell membranes). Another proposed mechanism of action liposomal amphotericin B (AmBisome) is the one that is best tol- is oxidation-dependent amphotericin B–induced stimulation of erated. It should be noted that all of these formulations do still macrophages.99 Most of the fungal species that cause human have some negative effect on renal function. infections are susceptible to amphotericin B. FLUCYTOSINE Because amphotericin B is lipophilic, it must be complexed with a bile salt (deoxycholate) to be able to stay in solution. Flucytosine can be useful for the treatment of hematogenous Unfortunately, about 20% of patients receiving amphotericin B candidiasis. When used as a single agent, however, it is associated deoxycholate experience an acute infusion-related reaction con- with a high failure rate and secondary emergence of resistance. sisting of fever, hypotension, and tachycardia.135 Premedication Accordingly, flucytosine is usually employed in combination ther- with acetaminophen may blunt this response; if it does not, pre- apy, typically to treat Cryptococcus infections. Its major toxic effect medication with hydrocortisone (25 to 50 mg I.V.) or meperi- is marrow suppression, especially when it is given at the prescribed dine (25 to 50 mg I.V.) is recommended. Hypotension, hyper- dosage (i.e., 37.5 mg/kg every 6 hours). tension, hypothermia, and bradycardia have also been reported Administration of flucytosine at a dosage of 25 mg/kg/day every as infusion-related toxic effects of amphotericin B deoxycholate. 12 hours will often yield effective serum peak and trough levels. Ventricular arrhythmias have been associated with rapid infusion Peak serum concentrations should be monitored and the dosage of amphotericin B deoxycholate and with administration of this adjusted so as to maintain a peak level of about 25 μg/ml. agent to patients with severe hypokalemia or renal failure. Flucytosine penetrates well into the eye and the CNS and thus Through inhibition of erythropoietic production secondary to may be used as a component of combination therapy for candidal nephrotoxicity, amphotericin B suppresses the production of red endophthalmitis, meningitis, and endocarditis. It is removed by blood cells, causing a normocytic, normochromic anemia. As a hemodialysis and peritoneal dialysis. Patients undergoing result of renal tubular loss, acidosis, hypokalemia, and hypomag- hemodialysis should receive a 37.5 mg/kg dose of flucytosine after nesia are common. The need to replace lost electrolytes should each dialysis session unless their initial peak serum concentration be expected. Patients should be kept well hydrated. is higher than 25 μg/ml or their postdialysis concentration is high- Common practice is to give a 1 mg test dose and observe the er than 10 μg/ml. Patients undergoing peritoneal dialysis should patient for 1 hour in the hope of identifying patients at risk for receive a single 37.5 mg/kg dose daily. severe acute reactions.The full dose of the drug (0.6 to 1 mg/kg/ FLUCONAZOLE day) is then infused over a period of 4 to 6 hours, though there is evidence to suggest that much shorter infusion times (e.g., 1 The mechanism of action of fluconazole is preferential inhibi- hour in patients with adequate cardiopulmonary and renal func- tion of cytochrome P-450 enzymes in fungal organisms. Several tion) may be acceptable.The total dose depends on the extent of Candida species, including C. tropicalis, are susceptible to this the infection and the patient’s condition. Patients must be mon- agent; however, C. krusei is highly resistant. C. glabrata may be sus- itored carefully during the first day of therapy. The infusion ceptible, resistant, or susceptible–dose dependent (S-DD) (i.e., should be discontinued if the patient becomes hemodynamical- exhibiting dose-dependent sensitivity).81 Because fluconazole is ly unstable. relatively nontoxic at its recommended dosage, larger doses (up to If acute reactions limit the amount of drug that can be infused, 1,600 mg) may be given to achieve the higher minimum inhibito- patients are premedicated with hydrocortisone (25 to 50 mg I.V.), ry concentrations (MICs) required to treat S-DD C. glabrata (16 either alone or in combination with meperidine (25 to 50 mg I.V.), to 32 μg/ml, compared with less than 8 μg/ml for susceptible 30 minutes before amphotericin B infusion is begun. strains). Fluconazole is not clinically active against Aspergillus Renal toxicity and hypokalemia are the primary toxicities of species. amphotericin B [see Table 3]. Amphotericin B–induced nephrotox- Fluconazole is available in both oral forms (pill and suspension) icity may be glomerular (characterized by a decrease in glomeru- and an I.V. form. In any form, it is rapidly and almost completely lar filtration rate and renal blood flow) or tubular (with urinary absorbed from the GI tract: serum concentrations achieved after casts, hypokalemia, hypomagnesemia, renal tubular acidosis, and oral administration are almost identical to those achieved after I.V. nephrocalcinosis).100 All of these abnormalities occur to varying infusion. This high degree of GI absorption, which is not affected degrees in almost all patients receiving the drug. In most patients, by gastric acidity or the presence of food, is a major advantage that renal dysfunction gradually resolves after discontinuance of thera- fluconazole has over ketoconazole. An initial loading dose that is py. Amphotericin B nephrotoxicity may be minimized by refrain- twice the usual daily dose is recommended. Fluconazole is distrib- ing from using it with other agents that exert synergistic nephro- uted evenly in body tissues, penetrates into the vitreous humor toxic effects135 (e.g., aminoglycosides, vancomycin, cisplatin, and and the aqueous humor of the eye, and crosses the blood-brain cyclosporine) and by providing sodium suplementation. Sodium barrier. It is excreted largely unchanged in the urine and under- supplementation consists of I.V. infusion of 500 ml of 0.9% saline goes only minimal metabolism in the liver. Consequently, dosage solution 30 minutes before the administration of amphotericin B, schedules must be adjusted in patients with renal impairment. followed by a second infusion of the same amount of saline after Hemodialysis substantially reduces serum concentrations of flu- the amphotericin B infusion is completed. conazole, and peritoneal dialysis also appears to remove the drug. To minimize synergistic nephrotoxicity when amphotericin B is A standard dose should be given after each course of dialysis. used in conjunction with other nephrotoxic agents, use of one of The toxic effects of fluconazole are similar to those of other the less nephrotoxic lipid formulations of amphotericin B—such azoles, including nausea and vomiting (in about 2% of patients), as amphotericin B lipid complex (Abelcet), amphotericin B col- headache, fatigue, abdominal pain, and diarrhea68-78; exfoliative loidal dispersion (Amphocil, Amphotec), or liposomal ampho- dermatitis also occurs, but very rarely. Transient abnormalities of tericin B (AmBisome)—may be indicated.136 These preparations liver function are observed in approximately 3% of patients who differ from each other with respect to the amount of amphotericin receive fluconazole. Fatal hepatic necrosis was reported to have B present and the type of lipid used, as well as with respect to their developed in two patients who were receiving fluconazole, but it physical forms, pharmacokinetics, and toxicities. Of the three, was unclear whether the drug played a causal role. Fluconazole
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    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 15 does not induce adrenal suppression. On occasion, fluconazole cytopenia, and abdominal pain occasionally occur. As a conse- administration may lead to prolongation of the QT interval. quence of hepatic metabolism, posaconazole has been associated Because fluconazole interacts with warfarin, phenytoin, and with elevated liver enzyme levels, hyperbilirubinemia, and hepato- cyclosporine when given in a daily dose of 200 mg or higher, cellular damage. Liver function test results should be monitored serum concentrations of these agents should be monitored when at baseline and throughout the course of posaconazole therapy. they are used in conjunction with fluconazole. Prolongation of the QT interval and adrenal insufficiency may also be seen with administration of this agent. ITRACONAZOLE Because posaconazole is an inhibitor of cytochrome P-450 Itraconazole is a synthetic triazole that is similar to other imida- 34A, it may be expected to increase the plasma concentrations of zoles (e.g., ketaconazole). Its mechanism of action involves inhibi- drugs metabolized via this pathway.Various drug interactions may tion of cytochrome P-450 and prevention of ergosterol synthesis occur, and it frequently proves necessary to adjust the dosages of in fungal cell membranes. Itraconazole is active against Aspergillus other agents being given simultaneously with posaconazole. The species and several of the endemic fungi (Histoplasma, Crypto- adult dosage for posaconazole is 200 mg three times daily, taken coccus, and Coccidioides, to name a few). It is available in two oral with a full meal or a liquid nutritional supplement.138 The use of forms: a capsule (100 mg) and a suspension (10 mg/ml). The this agent in pregnant patients is not recommended. bioavailability of the capsule is approximately 55%. Absorption is KETOCONAZOLE enhanced by the presence of food in the stomach but is signifi- cantly reduced by the presence of antacids or H2-receptor block- Ketoconazole is effective against yeast infections of the skin and ers. The bioavailability of the suspension is higher; this formula- the mucous membranes; however, it should not be used to treat tion should be given on an empty stomach. In some patient pop- hematogenous candidiasis. Ketoconazole is not available in an I.V. ulations, however, GI absorption of itraconazole is erratic, and form, and the serum levels it is capable of reaching depend large- oral administration might be ineffective. In such cases, I.V. infu- ly on gastric acidity [see Table 4]. The same adverse events and sion should be considered. drug-drug interactions observed with itraconazole occur with Itraconazole is metabolized to a large degree in the liver, and ketoconazole. this process yields an active metabolite, hydroxyitraconazole. ECHINOCANDINS (CASPOFUNGIN, MICAFUNGIN, Accordingly, the dosage must be adjusted in patients with hepatic ANIDULAFUNGIN) failure; however, the pharmacokinetics of itraconazole are not affected by renal impairment or hemodialysis. Serum concentra- The echinocandins are lipopeptides that have been syntheti- tions of digoxin may increase when this agent is given with itra- cally modified from the fermentation broths of various fungi.68- conazole,104 and the metabolism of itraconazole may be accelerat- 70,73,78 They act by weakening the fungal cell wall. More specif- ed when drugs that induce hepatic enzymes are given simultane- ically, they bind to (1→3)-β-D-glucan synthase, thereby block- ously.84,104 Serum concentrations of itraconazole should therefore ing synthesis of (1→3)-β-D-glucan, a substance that, along with be measured in patients with invasive infections. Itraconazole is a chitin, provides shape and integrity to the fungal cell wall. The potent inhibitor of cytochrome P-450 34A and may increase the plasma concentrations of drugs metabolized via this pathway. Itraconazole is generally well tolerated in dosages as high as 400 a mg/day.The most common side effects are nausea, vomiting, diar- rhea, and abdominal discomfort. Headaches, rash, pruritus, and dizziness occasionally occur. At higher doses, a mineralocorticoid excess syndrome (characterized by hypokalemia, hypertension, and edema) has been described, and hypokalemia develops in as many as 6% of patients who take 400 mg/day for several months.104 The Federal Drug Administration (FDA) has issued a black box warning against the use of itraconazole in patients with congestive heart failure and those at risk for drug-drug interac- b c d tions. Because itraconazole may be teratogenic, it should be avoided in pregnant patients as well. Itraconazole is currently approved only for treating blastomycosis, histoplasmosis, and aspergillosis, but it is also effective for treating candidiasis and cryptococcosis. POSACONAZOLE Posaconazole, the newest of the triazoles, also prevents synthe- sis of ergosterol by inhibiting lanosterol 14-α-demethylase. It is Figure 3 Candida takes several forms as it grows. A blastospore highly selective for fungal cytochrome P-450 systems, but unlike is a unicellular form (a). Blastospores divide by budding, a other azoles, it is not extensively metabolized by cytochrome P- process in which new cellular material grows from a site on the 450 enzymes.137 Posaconazole is active against Candida and blastospore (b). Nuclear division then occurs, and a septum forms Aspergillus species, as well as against Cryptococcus, Fusarium, the between the two new cells. A hypha is a long tube of several cells Zygomycetes, and filamentous fungi. divided by septa (c). A mycelium is a cellular aggregate that Like the other azoles, posaconazole is well tolerated even with includes a hypha and its branches (d). A pseudohypha differs long-term administration.137 The most common side effects are from a true hypha in that it is composed of morphologically dis- fever, nausea, vomiting, diarrhea, and headaches. Rash, thrombo- tinct, elongated blastospores.
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    © 2007 WebMD,Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 19 FUNGAL INFECTION — 16 resulting loss of fungal cell wall integrity leads to osmotic lysis nonenzymatic peptide hydrolysis and N-acetylation to yield two of the cell. inactive metabolites. Micafungin is metabolized into three metabo- The echinocandins, as a class, are active against Candida lites71; cytochrome P-450 3A plays a minor role in this process. species, including C. krusei and C. glabrata.68-70,73,78 In addition, Anidulafungin undergoes spontaneous degradation into an inactive they are active against Aspergillus species, including A. fumigatus,A. open ring peptide; no hepatic metabolism has been observed. flavus, and A. terres; in this setting, they show some synergism with Both caspofungin and micafungin have been shown to be not itraconazole and voriconazole. None of the echinocandins are inferior to lipid formulations of amphotericin B for the treatment active against Cryptococcus, and none should be used for this indi- of invasive candidiasis. In addition, they have been found to have cation. The emerging fungi Fusarium, Rhizopus, Mucor, fewer adverse effects, especially those effects that would necessitate Scedosporium, and Pseudallescheria boydii are all resistant to each of discontinuance of therapy (e.g., renal toxicity). One study has the echinocandins. found anidulafungin to be superior to fluconazole.139 All of the echinocandins are available solely as I.V. formulations. Overall, the echinocandins are well tolerated. They are all asso- Caspofungin is given in a loading dose of 70 mg I.V., followed by ciated with essentially the same set of adverse effects, which on the infusion of 50 mg/day.70 Anidulafungin is given in a 200 mg loading whole are not serious. Phlebitis, fever, nausea and vomiting are dose on day 1, followed by infusion of 100 mg/day.79 Micafungin among the most commonly reported adverse effects. does not require a loading dose and is given at a dosage of 100 Thrombocytopenia, hypokalemia, and abnormal liver function mg/day.71 Caspofungin is slowly metabolized in the liver through test results are occasionally reported. Discussion Pathogenesis of Candida Infection eral pathways.The first such pathway is phagocytosis. Ingestion by For Candida to move from commensal to pathogen, it must phagocytes brings Candida into an intracellular position, and the invade either epithelial or endothelial cells. Even when this organ- leuckocytes then move across the endothelial cell lining and into ism causes superficial disease, it is capable of eluding detection by the bloodstream. Candida species have indeed been observed the immune system. One way in which Candida avoids recogni- within circulating leukocytes; however, the observation that fungal tion is to assume an intraepithelial position. A key virulence factor infections are common in neutropenic patients argues that a for C. albicans is its ability to change from a blastospore to a fila- mechanism other than phagocytosis must also play a major role. mentous hyphal form, and vice versa [see Figure 3]. Most of the The second pathway is passage of Candida pathogens between evidence suggests that invasive disease is caused by the hyphal endothelial cells and thence into the bloodstream.The fenestrated form, given that hyphae are found within cells140 and blastospores endothelium in the kidney is one site at which this process might on the epithelial surface or between cells (see below). Candida can occur. The final pathway is endocytosis by the endothelial cells gain entry to epithelial cells either through production of lytic themselves.The process of endocytosis requires intact endothelial enzymes141 or through endocytosis.142 The lytic enzymes pro- cell microfilaments and microtubules and is in part governed by duced include secreted aspartyl proteinases (SAPs), which are tyrosine phosphorylation of endothelial cell proteins. Both killed believed to digest the epithelial cell surface and thereby give and live Candida are ingested by this mechanism. In vitro studies Candida access to the interior of the cell. Mutated forms of SAPs have shpown that Candida hyphae induce their own endocytosis and substances that inhibit SAPs can reduce the ability of Candida by expressing the invasinlike protein Als3, which binds to N-cad- to enter epithelial cells. Hyphal forms of Candida have a greater herin on the cell surface.144 This binding then induces phosphory- capacity for inducing endocytosis than blastospores do, which lation,145 causing rearrangement of the microfilaments to produce suggests that the hyphae express invasinlike molecules on their cell pseudopods and initiate endocytosis. surfaces143; however, the exact identities of these molecules are not It should be kept in mind that this is a highly simplified expla- yet known. nation and does not detail the many unknown specifics of the cel- In susceptible patients, Candida species can enter the blood- lular processes involved. How Candida blastospores like those stream either through translocation across the GI mucosa or via seen with C. glabrata gain access to the bloodstream is currently an intravascular catheter.This invasion occurs through three gen- unknown.
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