الفهرس 
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Abstract
IAFIs is an invasive infection with increasing frequencies in the recent years, largely due to the increasing size of the population at risk, which includes organ transplant patients, immunosuppressed patients and patients undergoing peritoneal dialysis. Additionally, they are considered not uncommon and associated with considerable morbidity and mortality.
̵ A total of 143 patients diagnosed with IAIs hospitalized at Ain Shams University Specialized Hospital were included in this study.
̵ A total of 104 patients (72.7%) were males while 39 cases (27.3 %) were females. Patients ≥ 40 years old represented 81.1% (116 cases) while patients <40 represented only 18.9% (27 cases).
̵ Of the 143 cases of IAIs, fungi were found to be the causal agents of 39.2% (56 cases) of the cases, while bacteria accounted for 60.8% (87 cases) of the cases.
̵ Cultures of 170 specimens collected from 143 patients during the present study. 65 specimens were positive for fungi while 105 specimens were positive for bacteria, fungi were significantly more prevalent than bacteria in tissue biopsy samples only.
̵ Both IAFIs and IABIs had statistically similar incidence rates among liver transplant (41.5% and 58.5% respectively) and kidney transplant recipients (45.8% and 54.2%, respectively). while incidence of IABIs among peritoneal dialysis patients and appendectomy patients were statistically higher than that of IAFIs. The only IAIs recorded in HIV patient in this study was an IAFI.
̵ For IAFIs, gender did not affect the prevalence of fungal infection among all risk groups, while in case of IABIs, males had higher rates of infection in liver transplant recipients and peritoneal dialysis patients. Age showed no significant effect on the prevalence of IAIs except for liver transplant recipients and peritoneal dialysis patients with IABI, where infections were more likely to develop among patients ≥40 years old.
̵ Of the 56 cases of IAFIs, 26 cases represented infection by filamentous fungi (46.4%) while yeast fungi were the causal agent of 30 cases (53.6%).
̵ The highest number of positive cultures were from post-operative redivac drain samples (30.8%), followed by peritoneal fluid samples (23.1%) and tissue biopsies (21.5%) respectively. The difference in the number of positive cultures between filamentous fungi and yeasts was significant in case of blood samples only, where all the positive cultures yielded yeast only.
̵ Liver transplantation followed by peritoneal dialysis were the most common underlying conditions for IAFIs caused by both filamentous and yeast fungi, representing about 39.3 and 37.5% of the positive cases respectively. Kidney transplantation represented only 19.6% of the underlying conditions. One isolate of yeast fungi was isolated from appendectomy patients and another one from an HIV patient while none of filamentous fungi were isolated from these risk groups.
̵ Demographic characteristics of the studied population revealed that incidence rates of both yeast and filamentous IAFIs were not affected by the gender nor the age of the patient.
̵ Secondary peritonitis was the most common clinical presentation of IAFIs, representing 62.5 % of all the cases followed by liver abscess (25%). cholecystitis/cholangitis was the least encountered manifestation (12.5%).
̵ 30 yeast isolates belonging to the genus Candida were identified morphologically and the identification was confirmed by MALDI- TOF MS as: C. parapsilosis (12), C. guilliermondii (9), C. tropicalis (4) and C. glabrata (4), C. lipolytica (1).
̵ Secondary peritonitis was the most frequently encountered yeast IAFI (17/30, 56.7%), followed by liver abscess (8/30, 26.7%). Cholecystitis/cholangitis was the least encountered type of infection (5/30, 16.6%).
̵ Antifungal susceptibility of yeast strains via VITEK- 2 system against fluconazole, voriconazole, caspofungin, micafungin, amphotericin B and flucytosine showed that C. parapsilosis, C. tropicalis and C. lipolytica were susceptible to all tested antifungals. Voriconazole was the most effective drug against C. parapsilosis, C. guilliermondii and C. lipolytica, while micafungin was the most effective drug against C. tropicalis and C. glabrata. C. guilliermondii was markedly resistant to amphotericin B, while C. glabrata was resistant to fluconazole and voriconazole.
̵ The recovered filamentous etiologic agents were identified morphologically as 7 species belonging to 4 genera including: A. flavus (11), A. fumigatus (8), A. nidulans (2), M. circinelloides (2), A. niger (1), A. strictum (1) and S. koningii (1).
̵ Aspergillus spp. were the most prevalent etiologic agents where they were recovered from 84.6% (22/26) of the cases. The most frequently encountered clinical presentation caused by Aspergillus groups was secondary peritonitis (14/22 cases, 63.6%) followed by liver abscess (6/22, 27.3%). Only two cases cholangitis/cholecystitis was recorded due to A. flavus and A. fumigatus. Other filamentous pathogens reported in this study caused secondary peritonitis only.
̵ The antifungal susceptibility of the recovered filamentous isolates was tested against fluconazole, voriconazole, itraconazole, micafungin, amphotericin B using broth dilution method.
̵ All the tested isolates showed marked resistance to fluconazole. Isolates belonging to Aspergillus groups were sensitive voriconazole, itraconazole, micafungin and amphotericin B. only A. niger was resistant to itraconazole. The most effective drug against all Aspergillus species was micafungin. M. circinelloides isolates were only susceptible to amphotericin B, while A. strictum and S. koningii were only susceptible to voriconazole.
̵ The animal model of IAFIs due to Candida species revealed that C. glabrata and C. tropicalis recorded 100% mortality rate, where all infected mice died in both immunosuppressed and immunocompetent groups. C. parapsilosis and C. guilliermondii also had 100% mortality rates among immunosuppressed groups but lower rates among immunocompetent ones (60% and 40% respectively). C. lipolytica recorded the least mortality rate among Candida species, where only 40% of the immunosuppressed mice died after infection while no mortalities were recorded among immunocompetent ones. No difference in the mean survival time was recorded between immunosuppressed and immunocompetent groups of mice infected with all Candida species.
̵ Treatment was applied for both immunosuppressed and immunocompetent models, using voriconazole for groups infected with C. parapsilosis, C. lipolytica and C. guilliermondii and micafungin for C. tropicalis and C. glabrata groups. It was found that treatment prolonged the mean survival time in immunosuppressed and immunocompetent groups.
̵ Dissected mice from all groups showed hepatosplenomegaly, enlarged, mottled, markedly congested liver and spleen with multiple variably sized abscesses were observed especially in case of C. glabrata. Kidneys were slightly enlarged with white patches in some infected animals and changed color in others. Multiple Abscesses also appeared on the peritoneum and mesenteric membranes.
̵ Generally, immunosuppressed mice had significantly higher tissue burdens than immunocompetent ones. Treatment decreased fungal tissue burden of all organs significantly in both immunosuppressed and immunocompetent groups. However, treated immunosuppressed groups kept significantly higher burdens of all organs than treated immunocompetent groups.
̵ Liver and spleen represented the most affected intra-abdominal site of infection in most immunosuppressed and immunocompetent groups. Only C. tropicalis displayed pancreatic fungal burden. Fungal disease progressed to the kidneys in all tested Candida isolates, sharing similar or higher fungal burdens than intra-abdominal organs. A fungicidal effect (i.e., organ sterilization) of voriconazole and micafungin was never observed among immunosuppressed animals despite the significant reduction of fungal burden. In immunocompetent groups, organs’ homogenates showed no detectable growth after treatment except kidney, liver and spleen of C. glabrata. Generally, C. glabrata and C. lipolytica are considered the most and the least virulent Candida species respectively, in terms of mortality, survival time and tissue burdens.
̵ In the filamentous fungi model of infection, all the tested filamentous species were able to kill all the infected immunosuppressed mice (100% mortality rate) during the experiment. In immunocompetent groups, A. flavus, A. fumigatus, A nidulans and M. circinelloides had 100% mortality rates. A. strictum killed 60% of the immunocompetent mice while the least mortality rates among immunocompetent mice were recorded among A. niger and S. koningii infected groups, 40% both each.
̵ After treatment, A. fumigatus and M. circinelloides killed 60% of the immunosuppressed mice while A. flavus caused only 40% mortalities. All the treated immunocompetent mice survived the whole duration of the experiment with no recorded mortalities.
̵ Immunosuppressed group had lower mean survival time than immunocompetent group, except for A. flavus, A. fumigatus and M. circinelloides. Treatment also significantly prolonged the mean survival time in the immunosuppressed and immunocompetent groups.
̵ Kidney and spleen were also the most affected organs in most of the immunosuppressed and immunocompetent mice infected, while peritoneal wash had the least fungal burdens.
̵ Treatment failed to completely clear the infection form organs of immunosuppressed mice infected with A. flavus, A. fumigatus and M. circinelloides. However, the infection was completely cleared from organs of immunosuppressed mice infected with A. nidulans, A. niger, A. strictum, S. koningii and all the immunocompetent mice models of all filamentous pathogens
̵ When comparing organs of all pathogens in both the immunosuppressed and the immunocompetent model of infection, it was found that kidney, liver, spleen and peritoneal wash of A. flavus and M. circinelloides had the highest fungal burdens, while A. niger had the least fungal burdens in almost all groups.
̵ After treatment of immunosuppressed groups, M. circinelloides had significantly the highest kidney, liver and peritoneal wash burdens, while A. fumigatus had the highest spleen fungal burdens only. A. flavus had the least fungal burden of all organs.