Candida albicans peritonitis in a dog

Introduction

Candida spp. are dimorphic fungi in the family Cryptococcaceae. They are acquired by neonates during passage through the birth canal and subsequently colonize the upper respiratory tract, gastrointestinal tract and genital mucosa.¹ Cutaneous candidiasis,² systemic candidiasis,³Candida spp. cystitis,⁴ and intestinal candidiasis⁵ associated with parvoviral enteritis have all been reported in the veterinary literature, however, peritonitis associated with Candida albicans has not been reported. This case report documents a case of peritonitis with isolation of C. albicans from peritoneal fluid.

Case Report

A 15-week-old male Papillon, weighing 2 kg, was presented to the referring veterinarian after a 24-hour history of vomiting. Clinical examination and abdominal radiographs identified an abdominal mass, and an exploratory laporatomy was performed. A 1.5-cm spherical mass was reported to be attached to the wall of the jejunum with associated omental adhesions. Caseous material was noted to exude from the mass when incised. Examination of the mass revealed communication with the lumen of the small intestine. No other abnormalities were reported on examination of the abdominal cavity. Resection and anastomosis of the affected region of jejunum was performed followed by routine closure of the abdomen. Histopathology was not performed on the resected mass, which was discarded. Postoperative management included the oral administration of amoxicillin-clavulanic acid^a and carprofen.^b Ongoing vomiting 3 days after surgery prompted referral.

Physical examination on admission to the emergency center revealed a heart rate of 204/min and a distended, painful abdomen with evidence of a fluid wave suggestive of abdominal fluid. The remainder of the examination was unremarkable.

Hematologic evaluation revealed mild anemia with a red cell count of 5.54 × 10¹²/L (5.54 × 10⁶ cells/μL) (reference interval, 5.7–8.8 × 10¹²/L [5.7–8.8 × 10⁶ cells/μL]). The white cell count was 13.4 × 10⁹/L (13.4 × 10³ cells/μL) (reference interval, 5.2–13.9 × 10⁹/L [5.2–13.9 × 10³ cells/μL]) and the neutrophil count was 6.3 × 10⁹/L (6.3 × 10³ cells/μL) (reference interval, 3.9–8.0 × 10⁹/L [3.9–8.0 × 10³ cells/μL]) with 0.13 × 10⁹/L band forms (0.13 × 10³ cells/μL) (reference interval, 0.0–0.3 × 10⁹/L [0.0–0.3 × 10³ cells/μL]). Toxic changes were noted on cytologic examination of a blood smear. Biochemical evaluation revealed hypoalbuminemia (19.2 g/L [1.92 g/dL]; reference interval, 24–38 g/L [2.4–3.8 g/dL]) and decreased total protein (36.4 g/L [3.64 g/dL]; reference interval, 56–80 g/L [5.6–8.0 g/dL]). Borderline low normoglycemia was noted with glucose recorded at 3.6 mmol/L [64.9 mg/dL] (reference interval, 3.6–6.8 mmol/L [64.9–122.5 mg/dL]). A colloid osmotic pressure (COP) of 12.6 mm Hg (reference interval, 15.3–26.3 mm Hg) was also recorded.

Emergency management consisted of an intravenous (IV) bolus of 20 mL/kg Hartmann's solution^c over 15 minutes and fentanyl^d (2 μg/kg, IV), which resulted in a decrease in heart rate to 140/min. Ongoing IV fluid therapy was provided with 4 mL/kg/h of Hartmann's solution supplemented with 2.5% glucose, due to concerns that clinically significant hypoglycemia would develop.

Abdominal ultrasonography was performed, which confirmed the presence of a moderate amount of echogenic fluid within the peritoneal cavity. Generalized ileus of the gastrointestinal tract was reported along with focal thickening of the jejunum and loss of the normal wall layering. Multiple small echogenic foci were present with reverberation consistent with peritoneal gas.

Ultrasound-guided abdominocentesis yielded seropurulent fluid that was suggestive of peritonitis. Cytological analysis of the fluid revealed the presence of degenerate neutrophils with small numbers of intracellular and extracellular yeast and pseudohyphae. Bacteria were not evident on a Gram stain preparation. Culture of the fluid on sheep blood agar produced a moderate growth of C. albicans in pure culture. Susceptibility testing was unfortunately not performed.

Based on the clinical and sonographic findings, a second laparotomy was performed under general anesthesia. Anesthesia was induced using diazepam^e (0.2 mg/kg, IV) followed by propofol^f (2 mg/kg, IV) to effect. Anesthesia was maintained with isoflurane^g in 100% oxygen. Intraoperative analgesia was provided with fentanyl infused at rates up to 18 μg/kg/h. Intermittent positive-pressure ventilation was utilized throughout anesthesia. IV fluids were provided with a combination of Hartmann's solution supplemented with 2.5% glucose and pentastarch^h to maintain a systolic blood pressure of >80 mm Hg.

Exploration of the abdominal cavity revealed numerous fibrinous adhesions and pockets of seropurulent fluid. Gross intestinal content leakage was observed from the mesenteric border of the mid-jejunal anastomosis site. Revision enterectomy and anastomosis was performed followed by serosal patching, abdominal lavage and placement of a Jackson-Pratt abdominal drainⁱ before routine abdominal closure.

Postoperative supportive care included fluid therapy, analgesia, antiemetics, and antimicrobial therapy. Fluid therapy included fresh frozen plasma, pentastarch, and Hartmann's solution. Fresh frozen plasma was administered at doses up to 4 mL/kg/h in an attempt to correct the hypoalbuminaemia, maintain oncotic pressure and replace losses from abdominal fluid collected via the Jackson-Pratt drain. A COP of 8.8 mm Hg postoperatively prompted concurrent pentastarch administration at 2 mL/kg/h for oncotic support. Colloids were discontinued after COP was recorded at 18.9 mm Hg on day 6. The rate of Hartmann's administration was adjusted to provide maintenance fluid requirements and match urine output.

Analgesia was initially provided using fentanyl (4 μg/kg/h, IV) with concurrent administration of methadone^j (0.2 mg/kg, IM, q 4 h). On day 4, fentanyl and methadone were discontinued and replaced with buprenorphine^k (0.01 mg/kg, SC, q 6 h).

Metoclopramide^l (2 mg/kg/d, IV) and dolasetron^m (0.6 mg/kg, IV, q 24 h) were administered as symptomatic treatment for ileus and nausea. Despite this, ongoing vomiting and regurgitation 24 hours after surgery was observed. The cause was subsequently identified as megaesophagus by thoracic radiography. The megaesophagus was presumed to be secondary to esophagitis. Gastric protectants were commenced with ranitidineⁿ (2 mg/kg, IV, q 12 h), pantoprazole^o (1 mg/kg, IV, q 24 h), and a sucralfate^p slurry (0.5 g, PO, q 8 h).

Nutrition was provided by total parenteral nutrition due to persistent vomiting and regurgitation. Unfortunately, this had to be discontinued on the third postoperative day due to extravasation of total parenteral nutrition solution from the jugular catheter site into the subcutaneous tissues. The catheter was removed and bacteriologic culture and susceptibility of the catheter tip was performed. A heavy growth of Proteus spp. was isolated with susceptibility to amoxicillin-clavulanic acid and resistance to cephalexin. Enteral nutrition was successfully reintroduced on day 4 using cranial elevation of the patient during and after feeding to minimize regurgitation.

Perioperative antimicrobial therapy consisted of metronidazole^q (10 mg/kg, IV, q 12 h) and cephazolin^r (22 mg/kg, IV, q 8 h). Fluconazole^s was commenced postoperatively (loading dose of 10 mg/kg, IV, followed by 5 mg/kg, IV, q 24 h). On day 3, cephazolin was discontinued and amoxicillin-clavulanic acid was initiated (12.5 mg/kg, SC, q 24 h) based on culture and susceptibility results of the jugular catheter.

Analysis of the abdominal fluid was performed daily to assess progress of the peritonitis. Initially abdominal fluid production averaged 52 mL/kg/d on the first day after surgery with a refractometric reading of total plasma protein reported at 30 g/L [3 g/dL]. Estimation of the protein content via refractometry was likely to be limited by the concurrent administration of pentastarch. Three days postoperatively, fluid production continued to average 50 mL/kg/d. Analysis of fluid from the abdominal drain at this time revealed a predominance of nondegenerate polymorphonuclear cells. The total nucleated cell count was 34.2 × 10⁹/L (34.2 × 10³ cells/μL). A few chains of cocci coupled with rare macrophages displaying bacteriophagia were also reported. The presence of bacteria may have been the result of abdominal drain colonization from the suction bulb given the absence of bacteria before surgery. On day 4 after surgery, analysis of fluid from the abdominal drain revealed an ongoing predominance of nondegenerate polymorphonuclear cells. A subjective decrease in the number of cocci was reported along with an increase in the number of macrophages. Six days after surgery, analysis of the fluid from the abdominal drain revealed an absence of bacteria. This coupled with a progressive decrease in abdominal fluid production to 36 mL/kg/d prompted removal of the drain. Bacteriologic culture of the drain after removal produced a pure light growth of C. albicans.

Seven days after surgery, abdominal palpation revealed the presence of a firm 2 cm midabdominal mass. Abdominal ultrasonographic examination confirmed the presence of a smooth, rounded, and enlarged 12 × 20 mm cavitatory mesenteric lymph node in the region of the ileocecal junction. The solitary lymphadenopathy was suspected to be secondary to either fungal or bacterial infiltration. Repeat thoracic radiographs revealed resolution of the previously detected megaesophagus.

On the eighth day after surgery, oral fluids were introduced. Frequency of regurgitation progressively decreased. All parenteral medications were discontinued and the patient was discharged on day 9 with oral medications including omeprazole^t (1 mg/kg, PO, q 24 h) until the regurgitation resolved, amoxicillin-clavulanic acid (12.5 mg/kg, PO, q 12 h) for 1 week, and fluconazole (5 mg/kg, PO, q 24 h) for 1 month.

An abdominal ultrasonographic examination was repeated on the 11th day after surgery. The previously noted cavitatory abdominal lymph node was no longer detectable. Physical examination after completion of the course of fluconazole was unremarkable.

Discussion

This report details a case of peritonitis associated with C. albicans. The presence of the commensal organism in peritoneal fluid obtained from this patient would indicate disruption of normal mucosal barriers associated with enterectomy site dehiscence. Concurrent antibacterial therapy after the initial surgery may have contributed to intestinal overgrowth of the organism, increasing the risk of developing Candida peritonitis with intestinal surgical site dehiscence.¹ Given the age of the patient, an immature immune system may also have contributed to the Candida infection.⁶

C. albicans was detected with abdominal fluid cytologic examination and routine bacteriologic culture on blood agar in this patient. The prevalence of yeast retrieved from an intraoperative abdominal sample in human patients with gastrointestinal perforation is reported to vary from 0% to 31%.^7,8 Higher rates of recovery are reported from gastrointestinal perforation as compared with colorectal perforation.⁸ Similar studies utilizing selective yeast medium for culture have not been reported in veterinary medicine; however, Candida spp. grow well on blood agar and may be isolated from specimens submitted for bacteriologic culture.¹ Lanz et al⁹ recorded the presence of a yeast organism in 1 of 19 dogs with septic peritonitis for which bacteriologic evaluation of abdominal fluid was performed. The overall incidence is suspected to be low given the infrequency of reports of fungal peritonitis.

Mortality associated with postsurgical candidiasis has been reported to be as high as 63% in human patients. An increase in mortality has also been associated with recovery of Candida spp. from intraoperative abdominal samples and when associated with postsurgical peritonitis.^8,10,11 Despite the high mortality, there may be no difference in mortality rates between patients treated or not treated with antifungals, which implies that either the pathogenicity of Candida spp. isolated from peritoneal fluid, or the efficacy of treatment of Candida spp. is debatable.¹¹ It has been suggested that the presence of Candida spp. may simply be a surrogate marker for increased mortality and morbidity without actually being the primary cause of mortality. A retrospective study by Rutledge et al¹² reported on 39 humans with Candida spp. cultured from peritoneal fluid who did not receive treatment with antifungal agents. Of the 39 patients, only 1 patient developed an intra-abdominal abscess that responded to surgical drainage alone. A major concern with assessing the significance of Candida spp. present in peritoneal fluid is that reported studies are retrospective in nature and as such, may be influenced by clinician bias and severity of disease. An international consensus on the management and prevention of candidal infections had 100% agreement on the provision of antifungal therapy in patients with intraoperative evidence of peritonitis and positive cultures for Candida spp.¹³

The ability to determine if the presence of Candida spp. in peritoneal fluid is pathogenic may help guide prognosis and requirement for antifungal therapy. In humans, a high initial or increasing Candida spp. count in semiquantitative cultures,¹⁰ an increased incidence of yeast colonization of other body sites,¹⁴ or detection of Candida spp. in direct examination of peritoneal fluid have been suggested as determinants of pathogenicity.¹⁵ Other risk factors include nosocomial peritonitis and an upper gastrointestinal tract origin.¹¹ To the authors' knowledge, no studies exist comparing the different risk factors. The lack of correlation between organism presence, pathogenicity, and mortality may also be due to an inability to differentiate between colonization and infection by Candida spp. Given the difficulty in establishing pathogenicity, treatment of Candida spp. infection is frequently based on clinical judgment as it was in this case. Guidelines provided by the Infectious Diseases Society of America state antifungal agents as unnecessary in acute perforations of the gastrointestinal tract unless the patient is immunosuppressed or has postoperative or a recurrent intra-abdominal infection.¹⁶ Antifungal treatment in this dog was administered given the cytologic evidence of Candida peritonitis, presence of Candida spp. as a nosocomial postoperative infection, suspicion of sepsis, risk of pathogenicity, potential for hematogenous dissemination, reported high mortality rate in some studies of human patients and the lack of contraindications to fluconazole in the patient. Additionally, the failure of identification of other microorganisms on cytologic examination, or bacteriologic culture of abdominal fluid was taken as further indication that peritoneal Candida spp. was pathologically significant in this patient.

Candida peritonitis in this patient was associated with marked abdominal protein loss, requiring unusually high levels of plasma and artificial colloids for oncotic support. Proteinaceous fluid loss via the abdominal drain ranged from 52 mL/kg/d on the first day after surgery to 36 mL/kg/d on the sixth day after surgery. Mueller et al¹⁷ reported fluid production ranging from 1.6–38.5 mL/kg/d in 29 dogs with generalized peritonitis. This range is lower than the volumes that were produced by this patient. Fresh frozen plasma was provided at doses up to 96 mL/kg/d and pentastarch at 48 mL/kg/d in an effort to match abdominal fluid production, and maintain COP and normovolemia. Despite the high doses, no evidence of hypervolemia, over-hydration, or hyperproteinemia were detected, and COP remained below reference interval until the sixth day after surgery. Additionally, this patient repeatedly developed clinical parameters consistent with hypovolemia, including tachycardia and low central venous pressures, which normalized in response to increased fluid rates.

Fluconazole is a triazole fungistatic agent that acts by inhibition of C-14 α-demethylase. C-14 α-demethylase is part of the fungal cytochrome P450 complex and is required for ergosterol synthesis in fungal cell membranes. Inhibition therefore results in disruption of membrane synthesis. The half-life of oral fluconazole in dogs is 15 hours compared with 22 hours in humans and 25 hours in cats.¹⁸ Steady state concentrations of therapeutic agents are usually reached after a minimum of 4 half-lives, as such, a loading dose of fluconazole equal to twice the normal maintenance dose is recommended.^18–20 Dosage recommendations vary from 2.5 to 10 mg/kg every 12–24 hours for treatment of candidiasis.^1,21

Fluconazole was dosed at 5 mg/kg/d, which resulted in an effective response. In retrospect, this dose may have been lower than ideal. According to the Clinical and Laboratory Standards Institute, Candida isolates are qualified as susceptible to fluconazole if minimum inhibitory concentration (MIC) values are ≤8 μg/mL.²²C. albicans, however, has an MIC≤2 μg/mL.²³ Plasma clearance of fluconazole in dogs has been reported at 0.62 mL/kg/min for oral administration and 0.65 mL/kg/min for IV administration.¹⁸ Calculation of the dosing rate to achieve an MIC of 8 μg/mL at a dosing interval of 24 hours gives a required dose of approximately 7.14 mg/kg/d as compared with a dose of 1.8 mg/kg/d to achieve an MIC of 2 μg/mL. Based on the above information, a higher daily dosage should have been utilized pending isolate identification or MIC results.

Fluconazole was commenced IV in the patient due to persistent vomiting. Bioavailability of fluconazole has been reported at 100% following an oral dose, as such, oral dosing was continued at 5 mg/kg/d after resolution of vomiting.¹⁸ Low plasma protein binding results in wide distribution with good penetration into cerebrospinal fluid, peritoneal fluid, pulmonary epithelial lining fluid, and aqueous humor.^19,24

Alternatives to fluconazole in the treatment of candidiasis include an alternative imidazole derivative (eg, ketoconazole, itraconazole), amphotericin B, flucytosine, caspofungin, or combination therapy.¹ Fluconazole or amphotericin B are commonly utilized in human peritonitis cases.²⁵ Fluconazole was selected in this patient due to the low frequency of adverse effects, low hepatic metabolization, and extensive renal clearance.¹⁸ Duration of treatment of Candida peritonitis has not been defined, as such, Infectious Disease Society of America guidelines recommend that duration be guided by patient's response.¹⁶ In retrospect, the course of fluconazole could have been significantly shorter given the patient's improvement and absence of abdominal lymphadenopathy on the eleventh day after surgery.

Conclusion

The management of Candida peritonitis should be approached similarly to any other form of peritonitis. Immediate resuscitation should be followed by source control and postoperative management. Culture and susceptibility testing allows determination of microbial pathogens. The possibility of fungal involvement should be considered especially if risk factors like prior antibiotic therapy, gastrointestinal leakage, or immunosuppression are present. A markedly exudative abdominal effusion may be a potential complication in the postoperative phase requiring aggressive oncotic and fluid support. Clear guidelines for determination of pathogenicity in cases of Candida peritonitis in dogs and humans do not exist. As such, the decision to administer antifungal therapy should be based on the clinical and laboratory findings. The availability of fluconazole in an IV form, coupled with its safety profile and efficacy against Candida spp., make it an ideal drug in the treatment of Candida peritonitis.

Footnotes

^aClavulox, Pfizer Australia Pty Ltd, NSW, Australia.

^bRimadyl, Pfizer Australia Pty Ltd.

^cHartmann's Solution, Baxter Healthcare Pty Ltd, NSW, Australia.

^dFentanyl, Mayne Pharma Ltd, VIC, Australia.

^ePamlin, Parnell Laboratories Pty Ltd, NSW, Australia.

^fPropofol, Hospira Pty Ltd, VIC, Australia.

^gISO, Veterinary Companies of Australia Pty Ltd, NSW, Australia.

^hStarquin 200, Biomed Limited, Auckland, New Zealand.

ⁱJackson-Pratt, Cardinal Health Australia 200 Pty Ltd, NSW, Australia.

^jMethone, Parnell Laboratories Pty Ltd.

^kTemgesic, Reckitt Benckiser, NSW, Australia.

^lMetomide, Delvet Pty Ltd, NSW, Australia.

^mAnzemet, Sanofi-Aventis Australia Pty Ltd, NSW, Australia.

ⁿZantac, GalxoSmithKline, Australia Pty Ltd, VIC, Australia.

^oSomac, Nycomed Pty Ltd, NSW, Australia.

^pCarafate, Aspen Pharmacare Australia Pty Ltd, NSW, Australia.

^qMetronidazole BP, Baxter Healthcare Pty Ltd.

^rCephazolin Sodium, Mayne Pharma Ltd.

^sDiflucan, Pfizer Australia Pty Ltd.

^tLosec, AstraZeneca Pty Ltd, NSW, Australia.