Protocol for the pBDG2 Study: Prospective Evaluation of 1.3-β-D-Glucan in the Peritoneal Fluid for the Diagnosis of Intra-Abdominal Candidiasis in Critically Ill Patients

Background: The delayed diagnosis of the presence of Candida in severe intra-abdominal infections exposes patients to an increased risk of mortality. The prevalence of intra-abdominal candidiasis (IAC) varies with the type of intra-abdominal infection, the underlying conditions and the presence of risk factors for Candida infection. This study aims to evaluate the interest of the measure of 1.3-β-D-glucan (BDG) in the peritoneal fluid for the early diagnosis of IAC. Methods and analysis: This is a prospective multicenter (n = 5) non-interventional study, focusing on all critically ill patients with an intra-abdominal infection requiring intra-abdominal surgery. The primary objective is to assess the diagnostic performance of the BDG measured in the peritoneal fluid for the early detection of IAC using the Candida culture as the gold standard. The secondary objective is to report the prevalence of IAC in the selected population. This study aims to enroll 200 patients within 48 months. By estimating the prevalence of IAC in the selected population at 30%, 50 patients with IAC (cases) are expected. These 50 IAC cases will be matched with 50 non-IAC patients (as a control group). The peritoneal BDG will be measured a posteriori in all of these 100 selected patients. This article presents the protocol and the current status of the study. Only the prevalence of IAC is reported as preliminary result.

Therapeutic potential of Fosmanogepix (APX001) for intra-abdominal candidiasis: from lesion penetration to efficacy in a mouse model

Intra-abdominal candidiasis (IAC) is one of the most common yet underappreciated form of invasive candidiasis. IAC is difficult to treat, and therapeutic failure and drug resistant breakthrough infections are common in some institutions despite the use of echinocandins as first line agents. Fosmanogepix (FMGX, formerly APX001) is a first-in-class antifungal prodrug that can be administered both intravenously and orally. FMGX is currently in Phase 2 clinical development for the treatment of life-threatening invasive fungal infections. To explore the pharmacological property and therapeutic potential of FMGX for IAC, we evaluated both drug penetration and efficacy of the active moiety manogepix (MGX, formerly APX001A) in infected liver tissues in a clinically relevant IAC mouse model due to C. albicans. Matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed absolute drug quantitation were employed to evaluate drug penetration into liver abscess lesions both spatially and quantitatively. The partitioning of MGX into lesions occurred slowly after a single dose; however robust accumulation in the lesion was achieved after 3 days of repeated dosing. Associated with this drug penetration pattern, reduction in fungal burden and clearance in the liver were observed in mice receiving the multi-day FMGX regimen. In comparison, administration of micafungin resulted in marginal reduction in fungal burden at the end of 4 days of treatment. These results suggest that FMGX is a promising candidate for the treatment of IAC.

Performance of the T2Candida Panel for the Diagnosis of Intra-abdominal Candidiasis

Performance of T2Candida for detecting intra-abdominal candidiasis (IAC) was assessed in 48 high-risk patients. T2Candida sensitivity/specificity and positive/negative predictive values were 33%/93% and 71%/74%, respectively. IAC was present in 100% of cases with concordant positive T2Candida/1,3-beta-d-glucan and absent in 90% of concordant negative results. Combination T2Candida/1,3-beta-d-glucan may help guide treatment decisions.

Penetration of Ibrexafungerp (Formerly SCY-078) at the Site of Infection in an Intra-abdominal Candidiasis Mouse Model

ABSTRACT Ibrexafungerp (IBX), formerly SCY-078, is a novel, oral and intravenous, semisynthetic triterpenoid glucan synthase inhibitor in clinical development for treating multiple fungal infections, including invasive candidiasis. Intra-abdominal candidiasis (IAC) is one of the most common types of invasive candidiasis associated with high mortality largely due to poor drug exposure in infected lesions. To better understand the potential of IBX to treat such infections, we investigated its penetration at the site of infection. Using matrix-assisted laser desorption ionization–mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed high-pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), we investigated tissue distribution and lesion-specific drug exposure of IBX in a clinically relevant IAC mouse model. After a single-dose treatment, IBX quickly distributed into tissues and efficiently accumulated within lesions. Drug concentrations of IBX within the liver abscesses were almost 100-fold higher than the serum concentration. In addition, drug penetration after repeated treatment of IBX was compared with micafungin. IBX exhibited robust and long-lasting lesion penetration after repeated treatment. These data indicate that IBX penetrates into intra-abdominal abscesses highly efficiently and holds promise as a potential therapeutic option for IAC patients.

Roles of the multiplex real-time PCR assay and β-D-glucan in a high-risk population for intra-abdominal candidiasis (IAC)

Multiplex quantitative real-time PCR (MRT-PCR) using blood can improve the diagnosis of intra-abdominal candidiasis (IAC). We prospectively studied 39 patients with suspected IAC in the absence of previous antifungal therapy. Blood cultures, MRT-PCR, and β-D-glucan (BDG) in serum were performed in all patients. IAC was defined according to the 2013 European Consensus criteria. For MRT-PCR, the probes targeted the ITS1 or ITS2 regions of ribosomal DNA. Candidaemia was confirmed only in four patients (10%), and IAC criteria were present in 17 patients (43.6%). The sensitivity of MRT-PCR was 25% but increased to 63.6% (P = .06) in plasma obtained prior to volume overload and transfusion; specificity was above 85% in all cases. BDG performance was improved using a cutoff > 260 pg/ml, and improvement was not observed in samples obtained before transfusion. In this cohort of high risk of IAC and low rate of bloodstream infection, the performance of non-culture-based methods (MRT-PCR or BDG) was moderate but may be a complementary tool given the limitations of diagnostic methods available in clinical practice. Volume overload requirements, in combination with other factors, decrease the accuracy of MRT-PCR in patients with IAC.

Unusual case of intra-abdominal candidiasis following laparoscopic hysterectomy

A 41-year-old woman with menorrhagia secondary to adenomyosis underwent an elective uncomplicated total laparoscopic hysterectomy after failed medical therapy. She developed fever, epigastric pain, nausea and diarrhoea on postoperative day (POD) 2. CT of abdomen and pelvis performed on POD 3 revealed an 8×3×3 cm fluid collection superior to the bladder. She did not respond to conservative treatment with intravenous antibiotics and therefore underwent an ultrasound-guided drainage on POD 7. The green-debris-laden fluid that was drained grewCandida. Investigations to screen for an immunocompromised state were negative. Her symptoms resolved after commencement of fluconazole and she was discharged home on POD 12. Repeat scans in 4 weeks’ time showed a marked reduction in collection. In a well patient, the presence of green intra-abdominal fluid should raise a suspicion for intra-abdominal candidiasis after ruling out bowel injury.