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Background: Extrapulmonary Tubercolosis (EPTB) is an infectious disease that affects tissue outside the lungs. EPTB patients cannot be source of infection, therefore the findings in the community indicate that there are still active pul- monary TB patients acting as a source of infection. Understanding distributions of EPTB can be used as indicator to individu- ate the unmonitored source of TB transmission in the community. Objectives: The aim of this study is to analyze EPTB using spatial modeling based on patients’ location. Methods: This study is an observational research with spatial analysis approach using SatScanv.9.4.4 and ArcGis v.10.4. Involving 46 samples of EPTB patients in Anatomy Pathology Laboratory of RSUD Abdul Wahab Sjahranie in 2017 and 7 pul- monary TB patients who were contacts of EPTB patients. The distribution of EPTB patients is mostly located in areas with high population density. Results: The results showed that the dis- tribution pattern of EPTB patients was mostly in areas with high population densi- ties. Space-time permutation model shows there are 3 clusters of EPTB with a 2.91, 0.97, 1.13 km radius centered on -0.504177 S/117.092132 E, -0.476895 S /117.141700 E, -0.517031 S/117.092132 E. Conclusion: The distribution of patients with EPTB and pulmonary TB indicates there is an interaction between EPTB and pulmonary TB in the cluster area. Bernoulli model shows that there is 1 cluster of EPTB and pulmonary TB with relative risk 5.29, radius of 3.19 km, and centered on - 0.458159 S / 117.149945 E.

The role of intestinal Candida albicans in bacterial sepsis, in the absence of candidemia, was investigated in murine models. Live C albicans or normal saline solution (NSS) was administered orally once, followed by 5 days of daily oral antibiotic-mixtures (ATB). Cecal ligation and puncture (CLP) was then performed to induce sepsis.Fecal Candida was detected by culture only in models with Candida administration. Oral Candida administration with/without ATB enhanced gut-pathogenic bacteria as determined by microbiome analysis. Despite negative candidemia, serum (1→3)-β-D-glucan (BG) was higher in CLP with Candida preconditioning models than in CLP-controls (NSS-preconditioning) at 6 and/or 18 h post-CLP. Blood bacterial burdens were not increased with Candida administration.Additionally, CLP with high-dose Candida (10 colony forming units) induced higher levels of fecal Candida, serum BG, serum IL-6, and mortality than the lowest dose (100 colony forming units). Interestingly, fluconazole attenuated fecal Candida and improved survival in mice with live-Candida administration, but not in the CLP-controls. Heat-killed Candida preparations or their supernatants reduced bone marrow-derived macrophage killing activity in vitro but enhanced cytokine production.In conclusion, intestinal abundance of fungi and/or fungal-molecules was associated with increased bacterial sepsis severity, perhaps through cytokine storm induction and/or decreased macrophage killing activity. These observations suggest that further investigation of the potential role of intestinal fungal burdens in sepsis is warranted.

Candida albicans is the most common fungus in the human intestinal microbiota but not in mice. To make a murine sepsis model more closely resemble human sepsis and to explore the role of intestinal C. albicans, in the absence of candidemia, in bacterial sepsis, live- or heat-killed C. albicans was orally administered to mice at 3h prior to cecal ligation and puncture (CLP). A higher mortality rate of CLP was demonstrated with Candida-administration (live- or heat-killed) prior to CLP. Fecal Candida presented only in experiments with live-Candida administration. Despite the absence of candidemia, serum (1→3)-β-D-glucan (BG) was higher in CLP with Candida-administration than CLP-controls (normal saline administration) at 6h and/or 18h post-CLP. Interestingly, fluconazole attenuated the fecal Candida burden and improved survival in mice with live-Candida administration, but not CLP-control. Microbiota analysis revealed increased Bacteroides spp. and reduced Lactobacillus spp. in feces after Candida administration. Additionally, synergy in the elicitation of cytokine production from bone marrow-derived macrophages, in vitro, was demonstrated by co-exposure to heat-killed E. coli and BG. In conclusion, intestinal abundance of fungi and/or fungal-molecules was associated with increased bacterial sepsis-severity, perhaps through enhanced cytokine elicitation induced by synergistic responses to molecules from gut-derived bacteria and fungi. Conversely, reducing intestinal fungal burdens decreased serum BG and attenuated sepsis in our model.