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Introduction
The incidence of serious fungal infections continues to increase in both the immunocompetent and immunocompromised patient populations [1–7]. Among the broad spectrum of invasive candidal diseases, Candida peritonitis is one of the most common manifestations of infection [8–10]. Peritonitis, an inflammation of the peritoneal lining of the abdomen usually secondary to infection, is a particular problem among surgical patients with hollow viscus perforation or those with intra-abdominal surgical drains [1, 11, 12]. The recovery of bacteria along with Candida in peritoneal fluid samples in these patients is an increasingly common occurrence that raises questions about the role of Candida as a pathogen, co-pathogen, or an innocent bystander in the disease process [12–15].
Overall, fungal peritonitis accounts for approximately 12% of all cases of peritonitis, but the rate can be much higher [16, 17]. The most common cause of fungal peritonitis is Candida, whereas intra-abdominal infections with other fungi, such as Aspergillus, Paecilomyces, Penicillium, and Zygomycetes, are relatively rare [17, 18]. The most common species of Candida that causes intra-abdominal infections is C. albicans, but a shift toward non-albicans Candida, such as C. parapsilosis, C. glabrata, C. tropicalis, C. krusei, and C. lusitaniae, with reduced susceptibility to commonly used antifungal agents was recently observed [7, 11, 17, 19–23].
Left untreated, Candida peritonitis can lead to systemic infection, multiorgan failure, and death. The mortality of Candida peritonitis is very high and has been estimated between 20 and 70% [1, 14, 19]. Despite this, there is still debate about the significance of positive peritoneal fungal cultures and whether antifungal therapy should be started [24]. Adding to the debate is the fact that patients with Candida peritonitis often die of complications of infection even with antifungal therapy [25–27]. Furthermore, there is very little published research on this topic. It is, therefore, important to address the role of Candida in patients with peritonitis secondary to polymicrobial infections. The purpose of this review was to present the latest research on secondary Candida peritonitis in the context of polymicrobial infections and the latest in diagnosis and treatment to guide clinicians in the management of such infections. Candida peritonitis associated with peritoneal dialysis is not within the scope of this article.
Epidemiology
Peritonitis is classified as primary, secondary, or tertiary [8]. Primary peritonitis is spontaneous peritonitis with no apparent breach in the gastrointestinal (GI) tract [28]. Secondary peritonitis, the most common form of Candida peritonitis, is a local infectious process within the abdominal cavity with a distinct cause. It generally occurs as a result of GI tract pathology, allowing translocation of micro-organisms across the bowel wall, perforation of a hollow viscus, an abscess within the abdominal cavity, instrumentation of the GI tract, or GI tract surgery [8]. Tertiary peritonitis usually refers to refractory peritonitis following generally adequate pharmacological and surgical treatment for secondary peritonitis [8, 10].
Candida is one of the leading pathogens isolated in secondary and tertiary peritonitis [8, 17, 29–31]. Candida spp. are involved in an estimated 40–45% of secondary nonappendicitis peritonitis [32]. The distinction between community-acquired versus nosocomial Candida peritonitis also is important and is discussed more below. Nosocomial infections are defined as Candida peritonitis that becomes evident ≥48 h after admission and are an independent risk factor of mortality [25].
Risk factors
The natural flora of the gastrointestinal tract is polymicrobial, and the main organisms are Gram-negative and anaerobic bacteria. Primary invasive organisms of the gastrointestinal tract include Escherichia coli and Bacteroides fragilis [33]. Candida spp. are well-established gut commensals [34]. Under certain conditions, Candida can heavily colonize the digestive tract, invade the mucosa, and spread locally or disseminate distantly [35]. Factors that influence this colonization and infection are outlined in Table 1. Clinical and surgical risk factors for Candida peritonitis are outlined in Tables 2 and 3, respectively.
Overall the two main risk factors that predispose patients to infections with Candida spp. include: (1) colonization of skin and mucous membranes; and (2) breaches in natural host defenses, such as through surgery, loss of integrity of skin, mucosal barriers and gut epithelium, and insertion of intravascular and urinary catheters and surgical drains [11, 36]. Surgery is a major risk factor for Candida peritonitis for several reasons: (1) there are direct breaches in natural barriers of defense; (2) in the case of GI surgery there is direct soiling of the intra-abdominal compartment; (3) patients often require intravascular and urinary catheters and surgical drains; (4) patients often require resting of the GI tract and total parenteral nutrition (TPN), which causes villous atrophy and translocation of bacteria and fungi; and (5) patients may develop hemorrhagic shock, which leads to gut ischemia and bacterial and fungal translocation across the gut wall [17, 24, 25, 27, 37, 38]. The latter is why thoracic surgery is a risk factor for Candida peritonitis; a decrease in blood pressure during surgery causes GI tract hypoperfusion resulting in gut ischemia, compromise, and translocation of fungi and bacteria. Studies have shown that secretory IgA, a principle immunologic defense at the gut mucosal surface, may be depleted by TPN, bowel rest, steroids, hemorrhagic shock, and microbial degradation facilitating microbial translocation across the gut wall [39–41].
In a study of 49 patients who had spontaneous hollow viscus perforation or surgical opening of the GI tract and positive Candida cultures of intra-abdominal specimens, Candida caused infections in 19 patients (39%) [27]. Of these patients, 7 had intra-abdominal abscesses and 12 peritonitis. Candida was more likely to cause infection in those patients who had surgery for acute pancreatitis than other surgical conditions. Importantly, the overall mortality was much higher in those with intra-abdominal candidal infections (7/19 patients, 37%) than in surgical patients without such infection. One notable result from this study was that Candida was more likely to be isolated in peritoneal fluids samples when the source of infection was the upper GI tract than when it was the lower GI tract. The outcome also was worse for the former. These results were similar in several other studies [17, 24, 37, 38]. An upper GI tract site of infection was found to be independent risk factor of mortality in nosocomial Candida peritonitis [25]. Interestingly, Spanakis et al. found that statin use correlated with decreased positive cultures (blood, sputum, urine, peritoneal fluid) among patients with type 2 diabetes mellitus who underwent lower GI surgery [42].
Surgical patients often are transferred to intensive care units (ICU) where despite constant improvements in standards of care, there is still a high mortality attributed to intra-abdominal sepsis [14]. Yeasts are isolated in 5–22% of peritoneal samples in this setting with an overall increase in mortality as high as 70% [11, 14, 15, 26, 30]. Studies have shown high rates of Candida colonization, up to 64%, and infection in surgical ICU patients with higher mortality in colonized patients [35, 43]. Independent risk factors of yeast isolation in peritoneal fluid samples in this patient group include: female gender; mechanical ventilation; ventilator-associated pneumonia; bacteremia; surgical complications; an upper GI tract source of infection; intraoperative cardiovascular failure; previous antimicrobial therapy ≥48 h before the onset of peritonitis; laparotomy; TPN; diabetes mellitus; immunosuppression; and body temperature >38.2°C [14, 21, 25, 44]. The key outcome of these studies is that they identify groups of critically ill patients in which antifungal prophylaxis may be beneficial [45].
Pathogenicity
Bacteria can influence fungal growth, physiology, and pathogenicity directly or indirectly, and fungi can do the same to bacteria [46–55]. Several studies have shown increased mortality with dual infections with C. albicans and E. coli [46, 54, 56]. Sawyer et al. examined the role of C. albicans in the pathogenesis of mixed fungal and bacterial peritonitis in murine models and whether these infectious elements were synergistic, competitive, or neutral [12]. The authors developed murine models of peritonitis with abscess formation and a high mortality with C. albicans, E. coli, and B. fragilis alone or in combination as part of a polymicrobial infection. Components of each system were eliminated with directed antimicrobial therapy. The results showed that both C. albicans and bacteria contributed to mortality in mixed infections and treatment with both bacterial and fungal antimicrobial agents increased survival from 50 to 90%. With regards to abscess formation, C. albicans, E. coli, and B. fragilis caused parallel infections that were not synergistic and had no effect on the growth of the other species. Similar studies in mice, however, have shown that there is some bacterial–fungal synergistic effect on mortality [55, 57]. This synergy is species-specific and did not occur in similar murine models using C. albicans and Staphylococcus aureus, Serratia marcescens, or Enterococcus faecalis [57–63].
Unfortunately, we still do not know the factors that transform Candida into a pathogen in this setting. There is an exciting area of research into the role of Candida spp. in polymicrobial infections and, in particular, the ability of Candida spp. to modulate the virulence of bacteria during coinfection [46, 47, 64, 65]. Work done so far indicates that during Candida coinfection with bacteria, especially Gram-negative pathogens, such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Salmonella enterica serovar Typhimurium, there is a pathogen–pathogen interaction that centers on quorum-sensing molecules of Candida and bacteria [66, 67]. This interaction may augment bacterial virulence during peritonitis, in a similar way that it has been theorized during Pseudomonas pneumonia [68].
Diagnosis
The clinical picture is usually indistinguishable from that of bacterial sepsis, especially when early blood cultures are negative for fungi or return positive late in the course of disease. For that reason, it is important to have a high index of suspicion of fungal superinfection in the presence of sepsis, especially when symptoms of sepsis persist despite antibiotic therapy [69]. Nonspecific elements of clinical picture suggestive of Candida peritonitis include high fever, rigors, diaphoresis, hypotension, and adynamic ileus (Table 4) [8].
Laboratory findings include leukocytosis with neutrophilia, high C-reactive protein (CRP), high procalcitonin, purulent exudates, and positive peritoneal fluid cultures with budding fungi on microscopy [8, 70–73]. Interestingly, procalcitonin seems to have a higher specificity and sensitivity as a marker of infection compared with CRP [70–72].
Histopathological diagnosis in tissue samples or growth of Candida in culture media is still considered the “gold standard” for diagnosis [74]. Blood, peritoneal fluid, and fluid from indwelling drains should be sent for microscopy and fungal culture [1]. Fungal cultures, however, take more than a week to yield results. Perioperative isolation of Candida in body fluid or tissue samples has higher clinical significance than isolation from postoperative drains [3]. Importantly, cases of disseminated candidiasis with negative blood cultures have been reported in patients on systemic antifungal agents or steroids, as well as cases of abdominal candidiasis with negative peritoneal fluid cultures [75].
Serological assays can be useful to screen for invasive candidal infections, but their sensitivity and specificity are variable [76]. They involved detection of antibodies against highly immunogenic fungal cell wall components, such as 1 → 3 β-d-Glucan (BDG), galactomannan, and mannan [74, 77–81]. BDG and galactomannan are nonspecific markers of fungal infection that are positive in other fungal infections [74, 77]. The Candida anti-mannan antibody assay may be more specific for the diagnosis of Candida infection [77].
Serological assays may be combined with deoxyribonucleic acid (DNA) detection methods to improve their sensitivity and specificity [77]. Highly sensitive and specific assays using DNA genomic amplification by polymerase chain reaction (PCR) have been developed to detect Candida infections with good results [33, 77, 82, 83]. The average time for detection and speciation is just more than 2 days. A specialized semi-nested PCR (snPCR) improves sensitivity by ten times with the detection limit <10 yeast cells compared with a genus-specific PCR [33]. DNA microarray chip technology, consisting of oligonucleotide probes fixed on a solid support using photolithographic methods, also can be used for C. albicans detection [84, 85].
A new diagnostic tool for Candida detection is mass spectrometry. Raman spectroscopy can identify Candida strains with 90% accuracy within 12–24 h [86]. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) is a very promising experimental mass spectrometry assay that can identify fungi in approximately 1 h, but currently has limitations (discussed in [87–89]).
Treatment
The treatment of Candida peritonitis includes conservative, medical, and surgical measures (Table 4). Conservative measures include removal of all foreign bodies, such as intravascular and urinary catheters, drains, and prosthetic materials, because fungi can colonize these materials and form biofilms [2, 9, 18, 19]. Removal of peritoneal catheters can be delayed for peritoneal lavage with antimycotics via these catheters [19, 90]. Surgical measures, such as identifying and draining visceral abscesses, are essential for the treatment of secondary peritonitis [1, 91].
In general, there are four classes of antifungal agents used in the medical management of Candida peritonitis: polyenes (deoxycholate and liposomal formulations of amphotericin B); azoles (fluconazole, itraconazole and the newer extended spectrum voriconazole and posaconazole); echinocandins (caspofungin, micafungin, and anidulafungin); and flucytosine [8, 92–101]. While selecting antifungal agents, clinicians should consider severity of the illness, the length of stay in the hospital, the type of peritonitis, recent exposure to antifungal agents, the resistance profile of the Candida species involved, relevant comorbid conditions (such as renal, liver, and bone marrow failure), and evidence of CNS, cardiac valve, and visceral organ involvement [94, 95, 102, 103].
The azoles are fungistatic against most Candida spp., whereas the polyenes and echinocandins are fungicidal [98]. Fluconazole is recommended for patients with community-acquired Candida peritonitis, no prior azole exposure, and those not at high risk of infection with fluconazole-resistant strains (such as C. krusei and C. glabrata) [104–106]. These high-risk patients include the elderly, diabetic, and cancer patients [8, 19, 94]. With good oral bioavailability and peritoneal penetration, fluconazole can be used orally or intravenously [19]. Fluconazole is popular because of its good side-effect profile and consequently resistance Candida strains are common [21, 94]. Empiric therapy with fluconazole is not recommended for most mild-to-moderate community-acquired cases of peritonitis, except in neonates where Candida infection is suspected [107]. A cumulative stay in hospital ≥29 days is a strong predictor for the isolation of nonfluconazole-susceptible Candida isolates among critically ill emergency surgery patients [103]. For high-risk patients with clinical suspicion of Candida peritonitis, culture confirmation is not necessary and treatment should commence promptly [1, 107]. If there is no detectable Candida in peritoneal fluid samples, the decision to treat should be based on clinical findings and risk factors combined with other variables. Overall, it is important to treat early to prevent dissemination of infection and to continue surveillance of blood cultures (and if they are positive, evaluate the patient for Candida endophthalmitis) [101, 108].
In a joint meeting between the American Surgical Infection Society (SIS) and the Infection Diseases Society of America (IDSA), echinocandins were recommended for patients infected with fluconazole-resistant species of Candida and those who were critically ill [107, 109]. Some centers recommend the use of echinocandins from the outset in patients with moderate-to-severe disease and those with prior azole exposure [94]. The echinocandins have a high clinical efficacy and good side-effect profile, making them another attractive option for treating Candida peritonitis [89, 94]. These antifungals have been used with success, especially for the treatment of non-albicans Candida, which can have a high resistance to triazoles [89].
With regards to the polyene antifungals, amphotericin B can be given intravenously, but it is highly protein bound resulting in poor penetration of the peritoneum [19, 110]. Peritoneal lavage with amphotericin B can be used, but it can cause peritoneal irritation leading to abdominal pain [19]. Amphotericin B also is associated with renal toxicity (liposomal formulations of amphotericin B have less renal toxicity) and electrolyte abnormalities [1, 2].
Flucytosine has good peritoneal penetration with oral administration [19]. It must be used in combination with other antifungal agents because the risk of resistance is high [19, 110]. Some centers use amphotericin B and flucytosine as first-line agents [19, 111]. Fluconazole and flucytosine can be used in combination for peritoneal lavage when intra-abdominal catheters cannot be removed [19]. Flucytosine is hepatotoxic and causes bone marrow toxicity; therefore, its use is contraindicated in patients with bone marrow depression or hematological disease and patients taking other drugs that suppress bone marrow [19]. Its use necessitates therapeutic drug monitoring and regular monitoring of full blood count and liver function tests.
Of the newer extended-spectrum triazoles, voriconazole and posaconazole are the only two currently available for use [92, 94–96]. The newer triazoles have improved safety profiles and a broad spectrum of activity, making them attractive choices for treatment [92–97, 99, 100]. Voriconazole has intravenous and oral preparations, whereas posaconazole is only effective when given orally [19]. Although well tolerated, voriconazole can cause hepatotoxicity, adverse visual events, and rashes [19]. Posaconazole can be used as salvage therapy for refractive infections and in rare cases can cause hepatotoxicity [19, 92, 96, 97]. For Candida strains with increased resistant to azoles, such as C. glabrata and C. krusei, echinocandins or preparations of amphotericin B can be used as alternatives [2]. C. parapsilosis and C. guilliermondii are less susceptible to echinocandins, and C. lusitaniae can be resistant to amphotericin B [95, 96]. The efficacy of the new extended spectrum triazoles has not been studied in detail against these Candida strains [95, 96].
Most experts agree that the duration of antifungal treatment should be continued for a minimum of 2 weeks after documented clearance in peritoneal fluid or blood samples [94]. Patients are likely to improve within a day or two of starting antifungal therapy. If there is a lack of improvement within 3–4 days of starting antifungal agents, therapeutic failure must be considered. Therapeutic failures can be defined as the lack of clinical resolution of symptoms and signs, persistent positive fungal cultures from peritoneal fluid samples or blood cultures, and persistently raised makers of inflammation, such as neutrophilia and raised C-reactive protein. Treatment must then be escalated by moving to second-line agents, combination therapy, or imaging and surgical exploration. Antifungal susceptibility should always guide the choice of antifungal agents.
Outcome
The outcome of Candida peritonitis is variable. The risk factors associated with increased mortality in Candida peritonitis include: extremes of age; Candida cultured in peritoneal fluid samples; candidemia; upper GI tract source of infection; patient comorbidities, such as cardiac insufficiency, cirrhosis, and diabetes mellitus; respiratory failure; renal failure before initiation of treatment; uncontrolled undrained infections; high APACHE II score; and multiorgan failure [8, 18, 25, 26, 31, 37, 86, 91]. The most important risk factor of mortality is isolation of Candida from peritoneal fluid samples and an upper GI source of infection [37]. In general, if Candida is detected on direct examination of peritoneal fluid, the outcome is worse. In one study, the attributable mortality of candidemia and Candida peritonitis was 37% with an overall mortality of 57% [1]. The attributable mortality of Candida peritonitis in surgical patients was 37% in this study. The mortality rate in patients with Candida peritonitis is high despite treatment with antifungal agents, but this is likely because treatment is started late [25]. There is evidence to suggest that patients with nosocomial Candida peritonitis have a higher mortality rate compared with patients with community-acquired Candida peritonitis [25].
Prophylaxis
Prevention against fungal infection starts with conservative measures, such as good hygiene, hand washing, and hospital infection control measures [2]. Pharmacological prophylaxis also is important in some patients. Fluconazole is currently the drug of choice for prophylaxis against Candida infection, especially for high-risk patients [2]. Caspofungin also has been used with some success [112, 113]. However, when to start prophylaxis and the duration of therapy needs to be determined and the results thus far are mixed [22, 45].
Published systematic reviews on the effects of fluconazole prophylaxis in non-neutropenic critically ill adult patients showed significantly reduced invasive fungal infections [113–115]. In some cases, a shift to triazole-resistant Candida strains was observed, such as C. krusei [116].
A policy of antifungal prophylaxis based on risk-factors alone can lead to an extensive use of prophylaxis and the selection of resistant strains of Candida [45]. Risk factors must be combined with other variables to determine in which patients to start antifungal prophylaxis. Special consideration is given to ICU patients who are heavily colonized with Candida spp. Using Candida colonization scores may help to determine patients who should receive antifungal prophylaxis [22, 45]. One such scoring system, the “Candida score,” was developed to determine when to initiate antifungal treatment in non-neutropenic critically ill patients with Candida colonization by using surveillance of urine, tracheal, and gastric samples [117]. A Candida score of >2.5 accurately predicted patients who would benefit from early antifungal treatment, including patients on TPN, those who had undergone recent abdominal surgery, and those with severe sepsis. Of note, central venous catheters were not a risk factor for invasive Candida infection.
Conclusions
Candida peritonitis is important because of its increasing incidence and high mortality rate. Although C. albicans is the most common yeast causing Candida peritonitis, a shift to non-albicans strains, which are increasingly drug-resistant has been observed. The most common species causing Candida peritonitis include C. albicans, C. parapsilosis, C. glabrata, C. tropicalis, and C. krusei. The interpretation of microbiological cultures is difficult, because cultured Candida spp. can represent a contaminant as part of mixed gut flora or a pathogen causing peritonitis. However, isolated Candida spp. must be treated as a pathogen contributing to peritonitis. We still need to study the Candida pathogenesis and the interaction of this pathogen with enteric bacteria. Prompt diagnosis, effective antifungal therapy, and skilled surgical management are an essential component of treatment.
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The authors thank Dr. Nicholas Tritos for review of the manuscript.
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EM has received research funding from Astellas Pharma, Inc. and T2 Biosystems, Inc.
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Carneiro, H.A., Mavrakis, A. & Mylonakis, E. Candida Peritonitis: An Update on the Latest Research and Treatments. World J Surg 35, 2650–2659 (2011). https://doi.org/10.1007/s00268-011-1305-2
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DOI: https://doi.org/10.1007/s00268-011-1305-2