Candida infections of the abdomen and thorax

INTRODUCTION — The clinical manifestations of infection with Candida species range from local mucous membrane infections to widespread dissemination with multisystem organ failure. Although Candida are considered normal microbiota in the gastrointestinal and genitourinary tracts of humans, they have the propensity to invade and cause disease when an imbalance is created in the ecological niche in which these organisms usually exist.

The immune response of the host is an important determinant of the type of infection caused by Candida. The different Candida species generally can cause all of the clinical syndromes, although infection with Candida albicans is the most common. The major importance of identifying the infecting organism is that some species are more resistant to azole antifungal agents than others. (See "Management of candidemia and invasive candidiasis in adults".)

This topic will review the manifestations of Candida infection involving the abdomen and thorax. Candida peritonitis can complicate continuous peritoneal dialysis in patients with end-stage kidney disease, as discussed separately (see "Fungal peritonitis in peritoneal dialysis"). Other manifestations of Candida infections are discussed separately. (See "Overview of Candida infections" and "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults" and "Chronic disseminated candidiasis (hepatosplenic candidiasis)" and "Candida infections in children".)

PERITONITIS AND INTRA-ABDOMINAL INFECTIONS

Risk factors — Candida species frequently contribute to polymicrobial infections that occur following surgery on the gastrointestinal (GI) tract; upper GI tract surgery is more likely to lead to intra-abdominal candidiasis than lower GI tract surgery [1,2]. Gut perforation, anastomotic leaks, and acute necrotizing pancreatitis are associated with intra-abdominal candidiasis [3-10]. A multicenter study performed from January 2015 to December 2016 that included 26 European intensive care units (ICU) found that recurrent gastrointestinal perforation, anastomotic leakage, presence of an abdominal drain, and prior receipt of antifungal drugs or antibiotics were independently associated with the development of intra-abdominal candidiasis [11].

Clinical manifestations — Intra-abdominal manifestations of Candida infection include discrete abscesses from a GI tract, biliary, or pancreatic source, secondary peritonitis from a GI tract, biliary, or pancreatic source, infected necrotic pancreas, gangrenous cholecystitis, and obstruction to the common bile duct with a Candida fungus ball [7,12-14]. Patients with intra-abdominal candidiasis may have candidemia, but the majority do not have blood cultures yielding Candida and present a more difficult diagnostic problem [15]. C. albicans is the predominant species isolated in intra-abdominal candidal infections, but Candida glabrata has assumed an increasing role at some centers [16,17].

The symptoms of Candida peritonitis do not differ from those of bacterial peritonitis, and in as many as two-thirds of patients, both bacteria and Candida are found as the cause of peritonitis [14]. Fevers, chills, and abdominal pain are prominent symptoms. Septic shock is commonly noted and in various studies is reported between 18 percent and 55 percent [14,17,18].

A retrospective review of 163 patients with intra-abdominal candidiasis between 2012 and 2013 at a single center noted that 55 percent had abscesses and 33 percent had secondary peritonitis that originated with a gastrointestinal source [14]. The remaining patients had pancreatitis with necrosis, cholecystitis, cholangitis, and primary peritonitis. Only 6 percent had candidemia. Source control within five days and antifungal therapy within five days were each implemented in 72 percent of patients. Overall mortality was 28 percent, but mortality among those who had primary or secondary peritonitis was 88 and 40 percent, respectively. Abscesses, early source control, and young age were independent predictors of decreased mortality.

A similar study retrospectively assessed outcomes for 82 patients who had intra-abdominal candidiasis, of which 61 percent had peritonitis, 23 percent had abscesses, and 16 percent had biliary tract infections. More than half (55 percent) of the patients had septic shock at the time intra-abdominal candidiasis was diagnosed. Appropriate source control (HR=0.08 [0.02-0.3], p<.001), appropriate antifungal therapy (HR=0.14 [0.04-0.55], p<.005), and a combination of both factors (HR=0.02 [0.0-0.08], p<.001]) were associated with improved 30-day survival [18].

Diagnosis — The diagnosis is best made by aspiration of fluid under computed tomographic (CT) or ultrasound guidance or at the time of surgery. Growth of Candida species from an abscess or peritoneal fluid should lead to the diagnosis of invasive intra-abdominal candidiasis and to appropriate treatment with an antifungal agent. Culture of Candida species from an indwelling drain is not adequate for the diagnosis of infection because it often reflects only colonization of the drain.

Blood cultures frequently show no growth in patients with intra-abdominal candidiasis [19]. In several large studies of patients with intra-abdominal candidiasis, only 6 to 20 percent had positive blood cultures [14,17,18].

The serum beta-D-glucan (BDG) assay appears to be a useful test in patients with intra-abdominal candidiasis [15]. BDG is present in the cell wall of many fungi, including Candida spp and is also present in some medications and other products that are used in the hospital setting. Because of this, a positive BDG test result cannot be used for the diagnosis of a specific fungal infection but rather can be viewed as a marker for a possible fungal infection that should be sought by more specific testing. In a prospective cohort study that included 89 patients who had been in the intensive care unit for ≥72 hours and who were considered to be at high risk for intra-abdominal candidiasis because of recurrent gastrointestinal tract perforation or acute necrotizing pancreatitis, 29 (33 percent) developed intra-abdominal candidiasis; 27 of 29 patients (93 percent) had negative blood cultures [20]. The sensitivity and specificity of two consecutive positive BDG results for predicting intra-abdominal candidiasis were 65 and 78 percent, respectively. BDG results became positive in patients with intra-abdominal candidiasis a median of five days before the diagnosis was confirmed by culture of intra-abdominal specimens [20].

Conversely, and more importantly, a negative BDG test in a patient at risk for intra-abdominal candidiasis is highly predictive of the absence of invasive candidiasis and can be used as a means by which antifungal therapy, which is often given empirically in an ICU setting, can be safely stopped [19,21-23]. Thus, obtaining a BDG test on admission to the intensive care unit in patients with intra-abdominal events, such as bowel perforation or necrotizing pancreatitis, may provide a clue as to whether intra-abdominal candidiasis is a possibility or seems unlikely. This assay does not supplant cultures, which are needed to identify which specific fungal species might be causing infection. The BDG assay is discussed in greater detail separately. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults", section on 'Beta-D-glucan assay'.)

Treatment — Treatment of intra-abdominal candidiasis usually entails both surgical intervention and antifungal therapy [23,24]. Surgical management involves drainage of abscesses and relief of biliary tract obstruction. Adequate source control was independently associated with improved survival in a retrospective study of intra-abdominal candidiasis [14]. Depending on the location of the abscess, drainage can often be performed by an interventional radiologist, obviating the need for a laparotomy. Initial antifungal therapy is similar to that for candidemia [23].

The preferred initial treatment is an echinocandin (micafungin 100 mg intravenously [IV] daily; anidulafungin 200 mg loading dose, then 100 mg IV daily; or caspofungin 70 mg loading dose, then 50 mg IV daily) (table 1). Fluconazole (800 mg [12 mg/kg] loading dose, then 400 mg [6 mg/kg] orally daily) is an alternative that can be used in patients who are not critically ill, who have not been treated recently with fluconazole, and who are not considered likely to have a fluconazole-resistant isolate (eg, not colonized with a fluconazole-resistant species, such as C. glabrata) [23]. A lipid formulation of amphotericin B (3 to 5 mg/kg IV daily) is another alternative, but it is used infrequently because of the greater toxicity (particularly nephrotoxicity) of this agent.

Following identification of the infecting species, treatment can be modified as follows, provided that the patient is clinically stable:

●For fluconazole-susceptible species, such as C. albicans, Candida parapsilosis, and Candida tropicalis, fluconazole (800 mg [12 mg/kg] loading dose, then 400 mg [6 mg/kg] orally daily) can be used. The concentrations of fluconazole achieved in bile are as high or higher than the levels achieved in serum [13], and excellent concentrations are achieved in peritoneal fluid. (See "Pharmacology of azoles".)

●When C. glabrata is the cause of infection, the preferred initial agent is an echinocandin. Voriconazole has also been approved for the treatment of Candida intra-abdominal infections and can be used for oral step-down therapy after initial intravenous echinocandin therapy once the patient has shown improvement and the source of the infection is adequately controlled. However, susceptibilities should be obtained before using voriconazole for fluconazole-resistant C. glabrata isolates because of the high probability of cross-resistance with fluconazole. (See "Management of candidemia and invasive candidiasis in adults".)

Therapy should continue for at least two weeks and often longer, until the abscess and signs and symptoms of peritonitis are resolved.

PNEUMONIA — Primary pneumonia due to Candida species is extremely rare. The pathogenesis of lung involvement is that of hematogenous spread rather than aspiration of oropharyngeal secretions. Thus, multiple microabscesses are found scattered widely throughout the lung parenchyma, and lobar infiltrates are uncommon. Autopsy studies from cancer centers have documented that primary Candida pneumonia, in which infection is limited to the lungs, occurs in less than 1 percent of cases [25,26]. Much more commonly, the lungs are one of many organs involved in the course of disseminated infection with Candida in immunosuppressed patients [23,25]. In a review of a 20-year experience from the MD Anderson Cancer Center, there were only 31 cases of clearly documented primary Candida pneumonia in over 7000 autopsies in cancer patients [25].

In one study of 17 hematopoietic cell transplant recipients who had histologically proven pulmonary candidiasis, the computed tomographic (CT) findings included multiple nodules ranging from 3 to 30 mm in diameter in 15 patients, air-space consolidation in 11 patients, and nodules surrounded by discrete areas of ground-glass opacity (CT halo sign) in five patients [27].

Studies in both cancer patients and nonneutropenic patients in an intensive care unit (ICU) setting have confirmed the lack of specificity of sputum or bronchoalveolar lavage (BAL) specimens for the diagnosis of pulmonary invasion by Candida [26,28-30]. Among 36 cancer patients with autopsy evidence of Candida pneumonia in whom sputum and/or BAL were performed ≤4 weeks before death, the sensitivity and specificity was found to be 85 and 60 percent for sputum culture and 71 and 57 percent for BAL [26].

In a prospective study of 232 ICU patients who died with pneumonia and underwent autopsy, none of 77 patients with Candida spp isolated from a tracheal aspirate or BAL fluid had histopathologic evidence of Candida pneumonia [31]. Similarly, in a study of 1077 BAL specimens obtained from 555 mechanically ventilated patients in an intensive care unit, only 8 percent yielded Candida species [30]. Of these 85 samples, 92 percent were judged to reflect colonization only. Only two patients were treated for presumed Candida pneumonia.

Treatment — Treatment is not recommended for Candida isolated from sputum or BAL specimens [23]. Patients with disseminated candidiasis who develop secondary Candida pneumonia should be treated for disseminated disease. (See "Management of candidemia and invasive candidiasis in adults".)

EMPYEMA — In four series of patients with Candida empyema, the most common pathogen was C. albicans, followed by either C. glabrata or C. tropicalis [32-35]. In one series including 81 patients, bacterial pathogens were isolated along with Candida in half of the patients, and more than one bacterial species was isolated in nearly one-third of cases [32]. Most patients were severely ill in the intensive care unit and many had antecedent surgery or an invasive procedure on the thorax or abdomen prior to development of Candida empyema. Spontaneous rupture of the esophagus was noted in several reports and carried a poor prognosis [32,35].

Most patients were managed with an antifungal agent and closed drainage [32-35]; in one study, video-assisted thorascopic surgery or open thoracotomy were also performed [32]. The overall mortality rate for the two reports that focused on Candida empyema ranged from 27 to 62 percent [32,34]; it is uncertain whether a more aggressive drainage approach contributed to lower mortality.

Treatment — Empiric treatment of Candida empyema consists of either an echinocandin or an azole. Targeted treatment should be guided by microbiologic identification, species-based risk for azole resistance, and antifungal susceptibility test results.

Data on the concentration of antifungal agents in empyema fluid are limited [36]. Most data are from case reports that provide values for one antifungal agent in a single patient. One series that included 81 patients noted an association between increased mortality and use of an echinocandin rather than fluconazole (odds ratio 4.5, 95% CI 1.1-18.8), raising questions regarding echinocandin penetration and activity in the pleural space [32]. However, limitations of this study were the retrospective design and that only one agent (caspofungin) was evaluated; it is possible that illness severity may have led clinicians to select an echinocandin over fluconazole [32].

The duration of antifungal therapy should be guided by individual circumstances. A minimum of two weeks of antifungal therapy following decortication or chest tube removal may be sufficient; in some circumstances, a longer duration may be needed.

MEDIASTINITIS — Candida mediastinitis almost always occurs as a complication of thoracic surgical procedures [37-40]. In a report of nine cases of Candida mediastinitis, the primary clinical manifestations included chest wall erythema and/or drainage, fever, and sternal instability [37]. These findings are similar to those seen with bacterial causes of postoperative mediastinitis. (See "Postoperative mediastinitis after cardiac surgery".)

All patients had received prior antibiotic therapy, and the median time from surgery to disease onset was 11 days (range 6 to 100 days) [37]. The course was complicated in seven patients by contiguous or hematogenous spread. The diagnosis was delayed in three patients because intraoperative cultures were not obtained or cultures positive for Candida were considered contaminants.

In this study and an earlier review of 39 published cases of Candida mediastinitis, mortality was 55 percent [37,39]. In the latter report, no patient who had not undergone a mediastinal drainage procedure survived compared with survival in 11 of 13 patients (85 percent) who underwent mediastinal drainage [39].

Treatment — Mediastinal drainage with debridement of affected bone in combination with antifungal therapy is essential for cure. The choice of agent should be similar to that recommended for candidemia. Thus, an echinocandin (micafungin 100 mg intravenously [IV] daily; anidulafungin 200 mg loading dose, then 100 mg IV daily; or caspofungin 70 mg loading dose, then 50 mg IV daily) is recommended (table 1). Fluconazole (800 mg [12 mg/kg] loading dose, then 400 mg [6 mg/kg] daily) can be used for susceptible species. A lipid formulation of amphotericin B (3 to 5 mg/kg IV daily) is an alternative. Therapy is prolonged in most cases and only stopped when all clinical and laboratory signs of infection have resolved.

In many cases, sternal osteomyelitis accompanies mediastinal infection, which requires prolonged therapy with oral fluconazole for susceptible species. For patients who have C. glabrata mediastinitis and perhaps osteomyelitis, voriconazole is the most appropriate agent for long-term oral therapy provided that the isolate is susceptible. It is important to note that susceptibilities should be obtained before using voriconazole for fluconazole-resistant C. glabrata isolates because of the high probability of cross-resistance with fluconazole (see "Management of candidemia and invasive candidiasis in adults"). If sternal involvement is present, the duration of therapy may extend to six months or longer. Clinical response, improvement in inflammatory markers (erythrocyte sedimentation rate, C-reactive protein), and resolution of computed tomographic scan findings are the usual parameters that help determine length of oral therapy.

PERICARDITIS — Purulent pericarditis due to Candida species is rare but life threatening. It most often arises as a complication of previous thoracic surgery or contiguous spread from an adjacent focus, but hematogenous spread can occur [41-43]. C. albicans is the most common pathogen, but infection with C. tropicalis and C. glabrata have been described [42-44].

In a literature review of 25 cases, 21 had either undergone thoracic surgery or had disseminated candidiasis [42]. Immunocompromise and antibiotic therapy are risk factors, as they are for almost all Candida infections [41]. (See "Overview of Candida infections", section on 'Risk factors for invasive infection'.)

The clinical presentation may be subtle and nonspecific in some patients [41], but other patients will present with an enlarging cardiac shadow on chest radiography and/or signs of cardiac tamponade. The diagnosis is confirmed by a positive culture of pericardial fluid or finding yeast forms on pericardial biopsy.

Treatment — Untreated Candida pericarditis is almost uniformly fatal [41,42]. Tamponade must be treated emergently with decompression and subsequently with a pericardial window or pericardiectomy to prevent recurrent hemodynamic compromise [23,41-44]. Although not recommended, occasional patients have survived with only pericardiocentesis and antifungal therapy [42,45]. (See "Cardiac tamponade".)

Therapy with an echinocandin (micafungin 100 mg intravenously [IV] daily; anidulafungin 200 mg loading dose, then 100 mg IV daily; or caspofungin 70 mg loading dose, then 50 mg IV daily) is recommended (table 2) [23]. If the organism is fluconazole susceptible, fluconazole (800 mg [12 mg/kg] loading dose, then 400 [6 mg/kg] orally daily) can be used. A lipid formulation of amphotericin B (3 to 5 mg/kg IV daily) is an alternative. Patients receiving an echinocandin can be switched to oral fluconazole (400 to 800 mg [6 to 12 mg/kg] daily) if the organism is susceptible when they are clinically stable.

For pericarditis due to C. glabrata, echinocandin therapy followed by oral voriconazole (400 mg orally twice daily for two doses, then 200 mg twice daily) is an option. However, susceptibilities should be obtained before using voriconazole for fluconazole-resistant C. glabrata isolates because of the high probability of cross-resistance with fluconazole. (See "Management of candidemia and invasive candidiasis in adults".)

The optimal length of therapy is not known. The patient should be followed clinically and therapy stopped only when there are no signs of ongoing pericardial inflammation and all systemic signs of infection, such as an elevated erythrocyte sedimentation rate and anemia, have resolved.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Candidiasis".)

SUMMARY AND RECOMMENDATIONS

●Intra-abdominal infections

•Sources – Candida species frequently contribute to polymicrobial intra-abdominal infections. Sources include gut perforation, anastomotic leaks after bowel surgery, acute necrotizing pancreatitis, peritoneal dialysis infection, gangrenous cholecystitis, and common bile duct fungus balls. Discrete abscesses with or without peritonitis can occur. (See 'Clinical manifestations' above.)

•Microbiology – Candida albicans is the predominant species isolated in intra-abdominal candidal infections, but Candida glabrata has assumed an increasing role at some centers. (See 'Peritonitis and intra-abdominal infections' above.)

•Diagnosis – Growth of Candida species from an abscess or peritoneal fluid should lead to the diagnosis of invasive intra-abdominal candidiasis and to appropriate treatment with an antifungal agent. Culture of Candida species from an indwelling drain is not adequate for the diagnosis of infection. The serum beta-D-glucan (BDG) assay can be a useful adjunct to cultures of an abscess or peritoneal fluid and may become positive before the diagnosis is established by culture. (See 'Peritonitis and intra-abdominal infections' above.)

•Treatment – Treatment usually entails both surgical intervention and antifungal therapy. The choice of agent depends upon the Candida species. Surgical management involves drainage of abscesses and relief of biliary tract obstruction. An echinocandin is recommended, but fluconazole is an alternative for fluconazole-susceptible isolates (table 1). A lipid formulation of amphotericin B is another alternative, but it is used infrequently because of the greater toxicity of this agent. (See 'Treatment' above.)

●Infections of the thorax

•Pneumonia – Primary pneumonia due to Candida species is extremely rare. The pathogenesis of lung involvement is that of hematogenous spread rather than aspiration of oropharyngeal secretions. Thus, multiple microabscesses are found scattered widely throughout the lung parenchyma, and lobar infiltrates are uncommon. Treatment is not recommended for Candida isolated from sputum or bronchoalveolar lavage specimens. Patients with disseminated candidiasis who develop secondary Candida pneumonia should be treated for disseminated disease. (See 'Pneumonia' above.)

•Empyema – Empiric treatment of Candida empyema consists of either an echinocandin or an azole. Targeted treatment should be guided by microbiologic identification, species-based risk for azole resistance, and antifungal susceptibility test results. (See 'Empyema' above.)

•Mediastinitis – Candida mediastinitis almost always occurs as a complication of thoracic surgical procedures. Mediastinal drainage with debridement of affected bone in combination with antifungal therapy is essential for cure. The choice of agent should be similar to that recommended for candidemia. An echinocandin is the preferred initial agent. Fluconazole is an alternative if the isolate is susceptible. A lipid formulation of amphotericin B is a less frequently used alternative. Therapy is prolonged in most cases and only stopped when all clinical and laboratory signs of infection have resolved. (See 'Mediastinitis' above.)

•Pericarditis – Purulent pericarditis due to Candida species is rare but life threatening. It most often arises as a complication of previous thoracic surgery or contiguous spread from an adjacent focus, but hematogenous spread can occur. An echinocandin is the preferred initial agent. Fluconazole is an alternative for fluconazole-susceptible isolates. A lipid formulation of amphotericin B is another alternative. (See 'Pericarditis' above.)

●Antifungal regimens

•Echinocandins – Micafungin 100 mg intravenously (IV) daily; anidulafungin 200 mg loading dose, then 100 mg IV daily; or caspofungin 70 mg loading dose, then 50 mg IV daily

•A lipid formulation of amphotericin B – 3 to 5 mg/kg IV daily

•Fluconazole – 800 mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) orally daily\