Candidemia in Internal Medicine: Facing the New Challenge.

Candidemia is an alarming problem in critically ill patients including those admitted in Internal Medicine Wards (IMWs). Here, we analyzed all cases of candidemia in adult patients hospitalized over nine years (2010-2018) in IMWs of a 980-bedded University Hospital of Ancona, Italy. During the study period, 218/505 (43%) episodes of candidemia occurred in IMWs patients. The cumulative incidence was 2.5/1000 hospital admission and increased significantly over time (p = 0.013). Patients were predominantly male, with a median age of 68 years. Cardiovascular diseases and solid tumors were the most frequent comorbidities. Candida albicans accounted for 51% of the cases, followed by C. parapsilosis (25%), C. tropicalis (9%) and C. glabrata (7%). Thirty-day mortality was 28% and did not increased significantly over time. By multivariate logistic regression analysis, the presence of neutropenia (OR 7.247 [CI95% 1,368-38,400; p = 0.020]), pneumonia (OR 2.323 [CI95% 1,105-4,884; p = 0.026]), and being infected with C. albicans (OR 2.642 [95% CI 1,223-5,708; p = 0.013) emerged as independent predictors of mortality. The type of antifungal therapy did not influence the outcome. Overall, these data indicate that patients admitted to IMWs are increasingly at higher risk of developing candidemia. Mortality rate remains high and significantly associated with both microbiologic- and host-related factors.

Central venous catheter unrelated candidemia influences the outcome of infection in patients with solid tumors.

Systemic infections due to Candida spp. is common among immunocompromised patients, including those with solid tumors (ST). Clinical characteristics of candidemia in 114 patients with ST were compared with those of 249 candidemic patients without ST (non-ST). Patients with ST were more likely to be hospitalized in medical departments, to have a significantly higher Charlson's score and to undergo a significantly later central venous catheter (CVC) removal (P < 0.001). Similarly, the use of total parenteral nutrition was more common in ST patients (P = 0.026). Although there was a trend toward a more appropriate use of antifungal therapy in ST (60%) than in non-ST patients (49%), the difference was not statistically significant (P = 0.059). Thirty-day mortality was significantly higher in ST (49%) than in non-ST patients (36%, P = 0.016). Multivariate analysis showed that either higher age or septic shock was an independent risk factor for mortality in both groups of patients. Conversely, a CVC-unrelated candidemia represented an independent risk factor for mortality in ST patients (HR 3.581 [CI 95% 1.412-9.087, P = 0.007]). Overall, these data show that candidemia in ST patients is characterized by an extremely high mortality rate.

Characterisation of candidemia in patients with recent surgery: A 7-year experience.

Candidemia can complicate major surgical procedures. However, literature data are scanty on this topic. In this study, we evaluated the epidemiology, clinical and microbiologic characteristics and outcome of candidemia in adult patients with recent surgery hospitalised in a single University Hospital in Central Italy from 2010 to 2016. Of the 304 episodes of candidemia, 160 (53%) occurred in surgical patients (SPs) while the remaining 144 (47%) in patients without history of recent surgery (non-SPs). Although either underlying chronic comorbidities (ie haematological malignancies, neurological and gastrointestinal diseases) or acute complications (ie pneumonia and septic shock) were less likely to occur in SPs than in non-SPs, 30-day mortality did not differ between groups being 38% and 42%, respectively. The specific risk factors significantly more common in SPs who died within 30 days were as follows: male gender, older age, being hospitalised in ICU rather than in other wards, having a higher Charlson's score, undergoing previous invasive procedures, haemodialysis, the presence of pneumonia, septic shock, acute kidney failure and the type of surgery. In particular, either gastrointestinal or cardiovascular surgeries were characterised by the highest mortality rates. Multivariate analysis showed that the occurrence of septic shock (HR 10.3131 [CI95% 1.176-90.466; P = .035] and ICU stay (HR 2.016 [CI95% 1.178-3.448; P = .011] was independently associated with higher mortality in SPs. Overall, these data show that candidemia in SPs is characterised by significant mortality and distinctive features.

Epidemiology, clinical characteristics, and outcome of candidemia in a tertiary referral center in Italy from 2010 to 2014.

PURPOSE: We evaluated the epidemiology, clinical characteristics and outcome of candidemia in a single institution from 2010 to 2014. METHODS: A retrospective observational study of all cases of candidemia was carried out at a University Hospital in Central Italy including five intensive care units (ICUs), 11 medical and 11 surgical wards. Data regarding demographic characteristics and clinical risk factors were collected from the patient's medical records. Antifungal susceptibility testing was performed and MIC results were interpreted according to species-specific clinical breakpoints. RESULTS: A total of 270 episodes of candidemia were identified. Overall incidence rate was 1.5 episodes/1000 hospital admissions. Although Candida albicans represented the most commonly isolated species, its percentage significantly decreased from 68 to 48 % (p = 0.040). The overall 30-day mortality was 35 %. The variables independently associated with a significant higher risk of mortality were: older age; being hospitalized in ICU or in medical wards vs surgical wards; being infected with C. albicans vs other species; the occurrence of septic shock, pneumonia and acute renal failure; the presence of a solid organ tumor or a chronic pulmonary disease. Conversely, an appropriate treatment was confirmed to be significantly associated with a lower risk of mortality. The overall resistance was low and it was noted only among triazoles. CONCLUSIONS: Our study shows that candidemia is a significant source of morbidity and mortality. The identification of risk factors associated with mortality along with the knowledge of local susceptibility may lead to a better management in terms of preventive and therapeutic measures.

Factors related to outcome of bloodstream infections due to Candida parapsilosis complex.

BACKGROUND: Although Candida albicans is the most common cause of fungal blood stream infections (BSIs), infections due to Candida species other than C. albicans are rising. Candida parapsilosis complex has emerged as an important fungal pathogen and became one of the main causes of fungemia in specific geographical areas. We analyzed the factors related to outcome of candidemia due to C. parapsilosis in a single tertiary referral hospital over a five-year period. METHODS: A retrospective observational study of all cases of candidemia was carried out at a 980-bedded University Hospital in Italy. Data regarding demographic characteristics and clinical risk factors were collected from the patient's medical records. Antifungal susceptibility testing was performed and MIC results were interpreted according to CLSI species-specific clinical breakpoints. RESULTS: Of 270 patients diagnosed with Candida BSIs during the study period, 63 (23 %) were infected with isolates of C. parapsilosis complex which represented the second most frequently isolated yeast after C. albicans. The overall incidence rate was 0.4 episodes/1000 hospital admissions. All the strains were in vitro susceptible to all antifungal agents. The overall crude mortality at 30 days was 27 % (17/63), which was significantly lower than that reported for C. albicans BSIs (42 % [61/146], p = 0.042). Being hospitalized in ICU resulted independently associated with a significant higher risk of mortality (HR 4.625 [CI95% 1.015-21.080], p = 0.048). Conversely, early CVC removal was confirmed to be significantly associated with a lower risk of mortality (HR 0.299 [CI95% 0.102-0.874], p = 0.027). Finally, the type of primary antifungal therapy did not influence the outcome of infection. CONCLUSIONS: Candidemia due to C. parapsilosis complex, the second most commonly causative agent of yeast BSIs in our center, is characterized by a non-negligible mortality at 30 days. An early CVC removal is associated with a significant reduced mortality.

Comparison of liver fibrosis progression in HIV/HCV co-infected and HCV mono-infected patients by transient elastometry.

Monitoring of liver fibrosis (LF) is an essential tool for preventing liver-related complications in HIV/HCV co-infected patients. In this study, we compared LF progression by transient elastometry (TE) in 50 HIV/HCV co-infected and 115 HCV mono-infected patients followed in our institution between June 2006 and December 2011. Patients naive to interferon therapy and with at least two measurements of liver stiffness by TE were included. In all, 76% of HIV/HCV co-infected and 75% of HCV mono-infected patients remained in the same stage of LF over time. Conversely, 19% and 15% of HIV/HCV co-infected and HCV mono-infected subjects, respectively, had progression to advanced LF (≥ F3). Our study found a similar proportion of HIV/HCV co-infected and HCV mono-infected patients that developed an advanced LF during the follow-up time considered. Alcohol abuse was the only factor significantly associated with the progression as evidenced by multiple quantile regression analysis.

In vitro activity of the protegrin IB-367 alone and in combination compared with conventional antifungal agents against dermatophytes.

The occurrence of resistance or side effects in patients receiving antifungal agents leads to failure in the treatment of mycosis. The aim of this experimental study was to investigate the in vitro effects of IB-367 alone and in combination with three standard antifungal drugs, fluconazole (FLU), itraconazole (ITRA) and terbinafine (TERB), against 20 clinical isolates of dermatophytes belonging to three species. Minimum inhibitory concentrations (MICs), minimal fungicidal concentrations (MFCs), synergy test, time-kill curves, fungal biomass (FB) and hyphal damage using 2,3-bis-(2-methoxy-4-nitro-5-sulfenylamino carbonil)-2H-tetrazolium hydroxide assay (XTT) were performed to study the efficacy of IB-367. In this study, we observed that TERB and ITRA had MICs lower values for all the strains compared to IB-367 and FLU. Synergy was found in 35%, 30% and 25% of IB-367/FLU, IB-367/ITRA and IB-367/TERB interactions respectively. IB-367 exerted a fungicidal activity against Trichophyton mentagrophytes, T. rubrum and Microsporum canis at concentrations starting from 1x MIC. At a concentration of 5x MIC, IB-367 showed the highest rates of hyphae damage for M. canis 53% and T. mentagrophytes 50%; against the same isolates it caused a reduction of 1 log of the total viable count cell hyphae damage. We propose IB-367 as a promising candidate for the future design of antifungal drugs.

Candidemia in intensive care units over nine years at a large Italian university hospital: Comparison with other wards.

PURPOSE: Candidemia is an alarming problem in critically ill patients including those admitted in intensive care units (ICUs). We aimed to describe the clinical and microbiological characteristics of bloodstream infections (BSIs) due to Candida spp. in patients admitted to ICUs of an italian tertiary referral university hospital over nine years. METHODS: A retrospective observational study of all cases of candidemia in adult patients was carried out from January 1, 2010 to December 31, 2018 at a 980-bedded University Hospital in Ancona, Italy, counting five ICUs. The incidence, demographics, clinical and microbiologic characteristics, therapeutic approaches and outcomes of ICU-patients with candidemia were collected. Non-ICU patients with candidemia hospitalized during the same time period were considered for comparison purposes. Early (7 days from the occurrence of the episode of Candida BSI) and late (30 days) mortality rates were calculated. RESULTS: During the study period, 188/505 (36%) episodes of candidemia occurred in ICU patients. Cumulative incidence was 9.9/1000 ICU admission and it showed to be stable over time. Candida albicans accounted for 52% of the cases, followed by C. parapsilosis (24%), and C. glabrata (14%). There was not a significant difference in species distribution between ICU and non-ICU patients. With the exception of isolates of C. tropicalis which showed to be fluconazole resistant in 25% of the cases, resistance to antifungals was not of concern in our patients. Early and late mortality rates, were 19% and 41% respectively, the latter being significantly higher than that observed in non-ICU patients. At multivariate analysis, factors associated with increased risk of death were septic shock, acute kidney failure, pulmonary embolism and lack of antifungal therapy. The type of antifungal therapy did not influence the outcome. Mortality did not increased significantly over time. CONCLUSION: Neither cumulative incidence nor crude mortality of candidemia in ICU patients increased over time at our institution. However, mortality rate remained high and significantly associated with specific host-related factors in the majority of cases.

Bloodstream infections in the COVID-19 era: results from an Italian multi-centre study.

BACKGROUND: Correlation between coronavirus disease 2019 (COVID-19) and superinfections has been investigated, but remains to be fully assessed. This multi-centre study reports the impact of the pandemic on bloodstream infections (BSIs). METHODS: This study included all patients with BSIs admitted to four Italian hospitals between 1 January and 30 June 2020. Clinical, demographic and microbiologic data were compared with data for patients hospitalized during the same period in 2019. RESULTS: Among 26,012 patients admitted between 1 January and 30 June 2020, 1182 had COVID-19. Among the patients with COVID-19, 107 BSIs were observed, with an incidence rate of 8.19 episodes per 1000 patient-days. The incidence of BSI was significantly higher in these patients compared with patients without COVID-19 (2.72/1000 patient-days) and patients admitted in 2019 (2.76/1000 patient-days). In comparison with patients without COVID-19, BSI onset in patients with COVID-19 was delayed during the course of hospitalization (16.0 vs 5 days, respectively). Thirty-day mortality among patients with COVID-19 was 40.2%, which was significantly higher compared with patients without COVID-19 (23.7%). BSIs in patients with COVID-19 were frequently caused by multi-drug-resistant pathogens, which were often centre-dependent. CONCLUSIONS: BSIs are a common secondary infection in patients with COVID-19, characterized by increased risk during hospitalization and potentially burdened with high mortality.

Species distribution and antifungal susceptibilities of bloodstream Candida isolates: a nine-years single center survey.

This study analyzed the epidemiology of bloodstream infections due to Candida spp. in a tertiary referral hospital of Ancona, Italy, and their susceptibility to antifungals. The retrospective observational study from January 2010 to December 2018 identified 504 episodes of candidemia in 461 patients. Although Candida albicans remained the species most frequently isolated, Candida spp. other than C. albicans caused 49% of the overall episodes of candidemia. According to CLSI interpretation, most of the isolates resulted susceptible to antifungals. Azoles vs Candida tropicalis represented an exception. Echinocandin non-susceptibility was rare across the species. In conclusion, with the exception of C. tropicalis, the isolation of a non-susceptible Candida strains against azoles, echinocandins and amphotericin B was a rare event.

Candidemia in the elderly: What does it change?

BACKGROUND: Candidemia is a life-threatening fungal infection and it can affect patients of all ages. Characterization of candidemia in the elderly is lacking. METHODS: We performed a retrospective study of adults (≥ 18 years) with candidemia diagnosed in our center in 2010-2015. Demographics, comorbidities, clinical and microbiologic characteristics, antifungal treatment and outcome were compared between older (≤65 years) and younger (>65 years) patients. RESULTS: Among 302 patients with candidemia identified during the study period, 188 (62%) belonged to the elderly group. Comorbidities were significantly more frequent in older patients and included chronic pulmonary diseases, cardiovascular diseases, diabetes mellitus, and chronic renal failure (p ranging from <0.0001 to 0.017). A significantly higher proportion of older patients had septic shock (p = 0.040) at the time of candidemia. Candida albicans accounted for 53% of isolates and there were no significant differences between patients' age and Candida species. Thirty-day mortality was significantly higher in older (45%) than in younger (28%) patients (p = 0.003). Factors associated with a significant higher proportion of death in the elderly included older age (i.e.: old-old), being hospitalized in ICU rather than in other wards, suffering from chronic pulmonary diseases, the presence of septic shock, multiple organ failure, dialysis and being infected with C. glabrata (p ranging from <0.0001 to 0.034). On multivariate analysis septic shock (HR 1.744 [CI95% 1.049-2.898], p = 0.032) and multiple organ failure (HR 2.242 [CI95% 1.070-4.698], p = 0.032) were independently associated with a higher risk of death. The probability of 30-days survival of older patients was significantly reduced when compared to that of younger patients (p = 0.005) who did not receive any treatment. In the elderly, there was a trend toward higher MICs for fluconazole/C. albicans, fluconazole/C. glabrata, amphotericin B/C. albicans, and caspofungin/C. glabrata. CONCLUSIONS: In our study, we found that elderly patients with Candida bloodstream infections are characterized by a high mortality rate. In particular, the lack of any antifungal therapy as well as the occurrence of septic shock increased significantly the overall mortality. Additionally, we found that there was a trend of higher MIC for specific drug/Candida combination.

Efficacy of the Quorum Sensing Inhibitor FS10 Alone and in Combination with Tigecycline in an Animal Model of Staphylococcal Infected Wound.

In staphylococci, quorum sensing regulates both biofilm formation and toxin production, moreover it has been demonstrated to be inhibited by RNAIII inhibiting peptide (RIP). Aim our study was to evaluate the in vitro activity and its in vivo efficacy of the combined administration of FS10, a novel RIP derivative, and tigecycline in an animal model of methicillin-resistant (MR) and methicillin-sensitive (MS) Staphylococcus aureus wound infection. Using a 1.x2 cm template, one full thickness wound was established through the panniculus carnosus on the back subcutaneous tissue of each animal. Infection was determined by inoculation of 5x107 CFU/ml of bacteria, that produced an abscess within 24 h, after this, treatment was initiated. The study included, for each strain, a control group without infection, a control infected group that did not receive any treatment and a control infected group with drug-free foam dressing, and three infected groups treated, respectively, with: FS10-soaked foam dressing (containing 20 µg FS10), daily intraperitoneal tigecycline (7 mg/Kg), FS10-soaked foam dressing (containing 20 µg FS10) and daily intraperitoneal injections of tigecycline (7 mg/Kg). The main outcome measures were quantitative culture and histological examination of tissue repair. The highest inhibition of infection was achieved in the group that received FS10-soaked and parenteral tigecycline reducing the bacterial load from 107 CFU/ml to about 103 CFU/g for MSSA and to about 104 CFU/g for MRSA. The group treated with FS10-soaked foam dressing associated with parenteral tigecycline showed, histologically, better overall healing with epithelialization and collagen scores significantly higher than those of the other groups in both strains. In conclusion, the combined use of topical FS10 with i.p. tigecycline induced positive interaction in vivo, resulting in an enhanced therapeutic benefit versus staphylococcal infections in murine wound models.

Antiretroviral therapy management and rationalisation of available resources.

The treatment of HIV disease has led to a new division of management costs by shifting most of the necessary resources from inpatient treatment to outpatient management. Among the initiatives aimed at rationalising the resources available, we compared efficacy, tolerability and pharmacoeconomic impact of different regimes of antiretroviral therapy (ART). The survey covered the first 50 patients, clinically stable and with good viro-immunological response, who switched in June 2012 from an ART based on the triple combination of tenofovir (TDF), emtricitabine (FTC) and a protease inhibitor boosted with ritonavir (PI/r) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), to a treatment based on abacavir (ABC), lamivudine (3TC) and a PI/r or NNRTI. Of the 50 patients who operated the switch, 39 replaced a PI with nevirapine (NVP), for which the largest group of patients was treated with ABC + 3TC + NVP. On 31 May 2015, all patients completed the observation period of 96 weeks, with a mean observation period of 132 weeks and clinical-laboratory checks every four months. Laboratory analysis revealed an optimal maintenance of viral suppression and absolute and relative number of CD4 + lymphocytes and improving trend of creatinine, proteinuria, serum phosphate and bone alkaline phosphatase. There was a variable effect on lipids, with a drop in triglycerides associated with a modest increase in total cholesterol. Much of the HIV-positive population reporting to our hospitals (>50%) comprises individuals who have for years been in stable viraemic suppression, making a satisfactory immune recovery while in good overall clinical condition. This type of patient was the target of the present survey. At the end of 96 weeks of observation the new regimes were well tolerated and did not lead to viro-immunological or clinical deterioration. Pharmacoeconomic analysis showed better containment of the overall costs. No patient needed to be hospitalised during the observation period.

Evaluating Liver Fibrosis by Transient Elastometry in Patients With HIV-HCV Coinfection and Monoinfection.

BACKGROUND: Due to the high efficacy of combination antiretroviral therapy (cART), the number of patients living with HIV is increasing. Chronic HCV infection has become a leading cause of non-AIDS related morbidity and mortality in patients with HIV infection. OBJECTIVES: The aim of this cross-sectional study was to identify factors associated with liver fibrosis (LF) in patients with HIV monoinfection and HIV-HCV coinfection. PATIENTS AND METHODS: We analyzed LF by transient elastometry ([TE], Fibroscan) in three groups of patients (HIV, HIV-HCV and HCV) followed at the Infectious Diseases Department of University of Ancona, Italy, between October 2009 and November 2012. RESULTS: In total, 354 adults including 98 HIV, 70 HIV-HCV and 186 HCV patients were studied. HIV-HCV patients had a longer duration of HIV (P < 0.006) and HCV (P < 0.001) infections. Additionally, they were receiving cART therapy for a longer period (P < 0.001); they had higher prevalence of lipodystrophy (P < 0.001) and higher HCV load (P = 0.004). LF was significantly more pronounced in HCV and HIV-HCV compared to HIV patients (P < 0.001). A total of 13.3%, 39.2% and 51.4% of HIV, HCV and HIV-HCV, respectively, showed a LF ≥ F2. Additionally, a severe LF (F = 4) was significantly more frequent among HIV-HCV compared to other groups. A longer exposure to didanosine, stavudine, lopinavir/ritonavir and fosamprenavir resulted in increased LF by univariate analysis (P ranging from < 0.001 to 0.007). By logistic regression analysis, the only variables significantly associated with increased LF were HCV coinfection, older age, and high AST values (P ranging from < 0.001 to 0.036). CONCLUSIONS: HCV coinfection, older age and AST were associated with LF in patients with HIV infection.

Quorum sensing inhibitor FS3-coated vascular graft enhances daptomycin efficacy in a rat model of staphylococcal infection.

The aim of the study was to investigate the efficacy of the quorum sensing inhibitor FS3 and daptomycin in preventing prosthesis biofilm in a rat model of staphylococcal vascular graft infection. Graft infections were established in the back subcutaneous tissue of adult male Wistar rats by implantation of Dacron prostheses followed by topical inoculation with 2×10(7) colony-forming units of Staphylococcus aureus, strain Smith diffuse. The study included a control group, a contaminated group that did not receive any antibiotic prophylaxis and three contaminated groups that received: (i) intraperitoneal daptomycin, (ii) FS3-soacked graft, and (iii) daptomycin plus FS3-soaked graft, respectively. Each group included 15 animals. The infection burden was evaluated by using sonication and quantitative agar culture. Moreover, an in vitro binding-study was performed to quantify the how much FS3 was coated to the surface of the prosthesis. The in vitro studies showed, that minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values for daptomycin were lower in presence of FS3. In in vivo studies, when tested alone, daptomycin and FS3 showed good efficacies. Their combination showed efficacies significantly higher than that of each single compound. Daptomycin is an important candidate for prevention of staphylococcal biofilm related infection and FS3 could serve as an interesting anti-staphylococcal antibiotic enhancer.