Role of Cefiderocol in Multidrug-Resistant Gram-Negative Central Nervous System Infections: Real Life Experience and State-of-the-Art.

Cefiderocol is a new molecule effective against multidrug-resistant (MDR) Gram-negative pathogens. Currently, there is limited evidence regarding the use of cefiderocol in central nervous system (CNS) infections. Data on the cerebrospinal fluid penetration rate of cefiderocol are limited and heterogeneous, and there is no consensus on the dosing scheme of cefiderocol to penetrate the blood-brain barrier. We present a case series and a literature review of CNS infections caused by MDR pathogens that were treated with cefiderocol: some of these patients were treated with different dose schemes of cefiderocol and underwent therapeutic drug monitoring both on plasma and cerebrospinal fluid (CSF). The CSF penetration rates and the clinical outcomes were evaluated.

Use of nebulized liposomal amphotericin B and posaconazole as antifungal prophylaxis in patients with severe SARS-CoV2 infection in intensive care unit.

PURPOSE: COVID-19 associated pulmonary aspergillosis (CAPA) is common and linked with high fatality rates. To assess the impact on the incidence and outcome of CAPA of an antifungal prophylaxis (AFP) we compared two cohorts of COVID-19 patients admitted to intensive care units (ICU) in Brescia, Italy, from January to August 2021. METHODS: The study cohort included all mechanically ventilated patients observed between April 2021 and August 2021 with SARS-CoV-2-pneumonia, who received AFP with oral posaconazole (200 mg every 6 h) and nebulized liposomal amphotericin B (50 mg every 2 weeks) from ICU admission to 7 days after discharge or, if applicable, until tracheostomy removal. The control cohort included COVID-19 patients admitted to the same ICU between January and March 2021 who did not receive any AFP. Subjects with CAPA at ICU admission were excluded. RESULTS: We included 270 patients, of whom 64 (23.7%) received AFP. In patients in the study group, CAPA-related mortality was significantly reduced (29% vs. 48% p = 0.04), as well as the incidence of CAPA (3.1% vs 12.1%, p = 0.03). Patients who developed CAPA were older (mean of 70-y-old vs 63-y-old, p < 0.001). One subject discontinued posaconazole due to an adverse reaction. Among the 46 patients who received it, only one patient reached an effective plasma concentration of posaconazole. CONCLUSION: AFP was associated with reduced incidence and mortality from CAPA and was well tolerated in patients with severe COVID-19. Posaconazole concentrations below the efficacy threshold in almost all patients may be attributable to drug interactions and prompt further studies to define its clinical significance.

Actinomyces spp. Prosthetic Vascular Graft Infection (PVGI): A Multicenter Case-Series and Narrative Review of the Literature.

BACKGROUND: Actinomycosis represents a challenging and under-reported complication of vascular surgery. Optimal management of Actinomyces spp. prosthetic vascular graft infection (PVGI) is highly uncertain because of the paucity of reports on this disease. METHODS: We conducted a retrospective case-series of Actinomyces-PVGI that occurred in the last five years in two major university hospitals in northern Italy. We searched for previously published cases in the scientific literature. RESULTS: We report five original cases of Actinomyces spp. prosthetic vascular graft infection following aortic aneurysm repair. Our literature review retrieved eight similar cases. Most patients were immunocompetent males. Most infections were polymicrobial (11/13 cases), with a prevalence of A. odontolyticus involvement (3/13 cases were associated with. Salmonella spp. infection). All cases had a late presentation (≥4 months from graft placement), with 61% associated with an aorto-enteric fistula. All patients received antibiotic therapy, but the duration was highly heterogeneous (from two weeks to life-long antibiotics). The patients without surgical revision experienced septic recurrences (2/13), permanent dysfunction (1/13), or a fatal outcome (2/13), while of the remainder who underwent vascular graft explant, six recovered completely and one developed a periprosthetic abscess. In two cases follow-up was not available. CONCLUSIONS: This case-series aims to raise the diagnostic suspicion and to describe the current management of Actinomyces-PVGIs. We highlight a high heterogeneity in antibiotic duration, choice of the antibiotic regimen, and surgical management. Higher reporting rate is advisable to produce better evidence and optimize management of this rare complication of vascular surgery.

Trichosporon asahii Infective Endocarditis of Prosthetic Valve: A Case Report and Literature Review.

Trichosporon spp. endocarditis is a severe and hard-to-treat infection. Immunosuppressed subjects and carriers of prosthetic valves or intracardiac devices are at risk. This article presents the case of an immunocompetent 74-year-old man affected by endocarditis of the prosthetic aortic valve. After Bentall surgery, cultures of the removed valve demonstrated Trichosporon ashaii as the etiological agent. The patient was treated with amphotericin B at first and subsequently with fluconazole. Given the fragility of the patient and the aggressiveness of the pathogen, life-long prophylactic therapy with fluconazole was prescribed. After 5 years follow-up, no drug-related toxicities were reported and the patient never showed any signs of recurrence. The review of the literature illustrates that Trichosporon spp. endocarditis may present even many years after heart surgery, and it is often associated with massive valve vegetations, severe embolic complications, and unfavorable outcome. Due to the absence of international guidelines, there is no unanimous therapeutic approach, but amphotericin B and azoles are usually prescribed. Additionally, a prompt surgical intervention seems to be of paramount importance. When dealing with a life-threatening disease, such as mycotic endocarditis of prosthetic valves, it is essential to consider and treat even rare etiological agents such as Trichosporon spp.

Bacterial and fungal superinfections are detected at higher frequency in critically ill patients affected by SARS CoV-2 infection than negative patients and are associated to a worse outcome.

Patients with viral infections are at higher risk to acquire bacterial and fungal superinfections associated with a worse prognosis. We explored this critical point in the setting of patients with severe COVID-19 disease. The study included 1911 patients admitted to intensive care unit (ICU) during a 2-year study period (March 2020-March 2022). Of them, 713 (37.3%) were infected with SARS-CoV-2 and 1198 were negative (62.7%). Regression analysis was performed to determine risk factors associated with the presence of bacterial and/or fungal superinfections in SARS-CoV-2 patients and to evaluate predictors of ICU mortality. Of the 713 patients with SARS-CoV-2 infection, 473 (66.3%) had respiratory and/or bloodstream bacterial and/or fungal superinfections, while of the 1198 COVID-19-negative patients, only 369 (30%) showed respiratory and/or bloodstream bacterial and/or fungal superinfections (p < 0.0001). Baseline characteristics of COVID-19 patients included a median age of 66 (interquartile range [IQR], 58-73), a predominance of males (72.7%), and the presence of a BMI higher than 24 (median 26; IQR, 24.5-30.4). Seventy-four percent (527, 73.9%) had one or more comorbidities and 135 (18.9%) of them had received previous antibiotic therapy. Furthermore, most of them (473, 66.3%) exhibited severe radiological pictures and needed invasive mechanical ventilation. Multivariate logistic regression analysis showed that 1 unit increment in BMI rises the risk of bacterial and/or fungal superinfections acquisition by 3% and 1-day increment in ICU stays rises the risk of bacterial and/or fungal superinfections acquisition by 11%. Furthermore, 1-day increment in mechanical ventilation rises the risk of bacterial and/or fungal superinfection acquisition by 2.7 times. Furthermore, patients with both bacterial and fungal infections had a significantly higher mortality rate than patients without superinfections (45.8% vs. 26.2%, p < 0.0001). Therefore, bacterial and fungal superinfections are frequent in COVID-19 patients admitted to ICU and their presence is associated with a worse outcome. This is an important consideration for targeted therapies in critically ill SARS-CoV-2 infected patients to improve their clinical course.

Strongyloides stercoralis infection: an underlying cause of invasive bacterial infections of enteric origin. Results from a prospective cross-sectional study of a northern Italian tertiary hospital.

PURPOSE OF THE STUDY: We assessed the prevalence of S. stercoralis in a cohort of inpatients with invasive bacterial infections of enteric origin to investigate whether the parasite may facilitate these bacterial infections even in the absence of larval hyperproliferation. METHODS: We performed a prospective cross-sectional study in a hospital in northern Italy. Subjects admitted due to invasive bacterial infection of enteric origin and potential previous exposure to S. stercoralis were systematically enrolled over a period of 10 months. S. stercoralis infection was investigated with an in-house PCR on a single stool sample and with at least one serological method (in-house IFAT and/or ELISA Bordier). Univariate, bi-variate and logistic regression analyses were performed. RESULTS: Strongyloidiasis was diagnosed in 14/57 patients (24.6%; 95% confidence interval 14.1-37.8%) of which 10 were Italians (10/49, 20.4%) and 4 were migrants (4/8, 50.0%). Stool PCR was performed in 43/57 patients (75.4%) and no positive results were obtained. Strongyloidiasis was found to be significantly associated (p ≤ 0.05) with male gender, long international travels to areas at higher endemicity, deep extra-intestinal infectious localization and solid tumors. In the logistic regression model, increased risk remained for the variables deep extra-intestinal infectious localization and oncologic malignancy. CONCLUSIONS: Our findings suggest a new role of chronic strongyloidiasis in favoring invasive bacterial infections of enteric origin even in the absence of evident larval dissemination outside the intestinal lumen. Further well-designed studies should be conducted to confirm our results, and possibly establish the underlying mechanisms.

Does the rapid initiation of antiretroviral therapy at HIV diagnosis impact virological response in a real-life setting? A single-centre experience in Northern Italy.

Rapid initiation of antiretroviral therapy (ART) has been proven efficacious and safe, but more investigations are needed to define feasibility of rapid ART approach in real-life settings.We conducted a retrospective, observational study on newly HIVdiagnosed patients referred to our Infectious Diseases Department from September 1st, 2015, to July 31st, 2019. According to the timing of ART initiation, we distinguished 3 groups of patients (rapid, intermediate and late group) and represented the trend of virological response during a 400-days-period. The hazard ratios of each predictor on viral suppression were estimated through the Cox proportional hazard model.The median time from HIV diagnosis to the first medical referral was 15 days and the median time from the first care access to therapy start was 24 days. Among patients, 37.6% started ART within 7 days, 20.6% between 8 and 30 days, and 41.8% after 30 days. Longer time to ART start and higher baseline viral load were associated with a lower probability of viral suppression. After one year, all groups showed a high viral suppression rate (99%). In a high-income setting the rapid ART approach seems useful to accelerate viral suppression which is great over time regardless of ART initiation timing.

Results of an Innovative Program for Surveillance, Prophylaxis, and Treatment of Infectious Complications Following Allogeneic Stem Cell Transplantation in Hematological Malignancies (BATMO Protocol).

Background: Infectious complications are a significant cause of morbidity and mortality in patients undergoing allogeneic haematopoietic stem cell transplantation (Allo-SCT). The BATMO (Best-Antimicrobial-Therapy-TMO) is an innovative program for infection prevention and management and has been used in our centre since 2019. The specific features of the BATMO protocol regard both prophylaxis during neutropenia (abandonment of fluoroquinolone, posaconazole use in high-risk patients, aerosolized liposomal amphotericin B use until engraftment or a need for antifungal treatment, and letermovir use in CMV-positive recipients from day 0 to day +100) and therapy (empirical antibiotics based on patient clinical history and colonization, new antibiotics used in second-line according to antibiogram with the exception of carbapenemase-producing K pneumoniae for which the use in first-line therapy is chosen). Methods: Data on the infectious complications of 116 transplant patients before BATMO protocol (Cohort A; 2016 - 2018) were compared to those of 84 transplant patients following the introduction of the BATMO protocol (Cohort B; 2019 - 2021). The clinical and transplant characteristics of the 2 Cohorts were comparable, even though patients in Cohort B were at a higher risk of developing bacterial, fungal, and CMV infections, due to a significantly higher proportion of myeloablative regimens and haploidentical donors. Results: No change in the incidence of infections with organ localization was observed between the two Cohorts. A significant reduction in Clostridioides difficile infections by day +100 was observed in Cohort B (47% vs. 15%; p=0.04). At day +30, a higher incidence of Gram-negative bloodstream infections (BSIs) was observed in Cohort B (12% vs. 23%; p=0.05). By day +100 and between days +100 and +180, the incidence of BSIs and of the various etiological agents, the mortality from Gram-negative bacteria, and the incidence of invasive fungal infections were not different in the two Cohorts. The incidence of CMV reactivations by day +100 dropped drastically in patients of Cohort B, following letermovir registration (51% vs. 15%; p=0.00001). Discussion: The results of this study suggest that the BATMO program is safe. In particular, the choice to avoid prophylaxis with fluoroquinolone was associated with an increase in Gram-negative BSIs by day +30, but this did not translate into higher levels of mortality. Moreover, this strategy was associated with a significant reduction of Clostridiodes difficile infections. The efficacy of anti-CMV prophylaxis with letermovir was confirmed by a significant reduction in CMV reactivations. Even though patients in Cohort B were at higher risk of developing fungal infections (more haploidentical transplants with more myeloablative regimens), the extensive use of posaconazole for prophylaxis balanced this risk, and no increase in the incidence of fungal-associated complications was observed.

Immunological Evolution of a Cohort of HIV-2 Infected Patients: Peculiarities of an Underestimated Infection.

Background: Human Immunodeficiency Virus type 2 (HIV-2) affects a minority of patients in Italy; nevertheless, the increasing migratory flow from higher prevalence areas led to the spread of this virus into our Country. We evaluate clinical, viro-immunological, and therapeutic characteristics of patients with HIV-2 infection and HIV-1/HIV-2 dual-infection and the early treatment impact on overall survival and incidence of AIDS events. Methods: We retrospectively analyzed all HIV-2, and HIV-1/HIV-2 positive patients followed in a large Italian clinic from January 1987 to December 2020. We recorded demographic, viro-immunological, clinical, and therapeutic data. We performed a descriptive analysis followed by a longitudinal analysis to explore the factors associated with the CD4+ lymphocyte trend; lastly, we studied the possible predictors of death and AIDS in our cohort in a multivariable model. Results: 32 subjects were enrolled, 17 (53%) HIV-2 infected and 15 (46.8%) HIV-1/HIV-2 dual-infected; 12 patients were lost to follow up, while 3 died. We found a lack of HIV-2 viremia in 12/32 subjects (37.5%). Most of the patients at baseline had a good viro-immunological profile with HIV-2 RNA <200 copies/ml and CD4+ lymphocyte >200 cell/mcl. We found a CD4+ lymphocyte improvement over time, both in the absolute number (ß 472.61, 95%CI 383.05-562.18, p<0.001) and in percentage (ß 25.28, 95%CI 21.91 - 28.66, p<0.001). Nevertheless, subjects taking cART had CD4+ lymphocyte percentage increase over time, and this trend appeared significantly better than those who did not receive therapy. Lastly, in the multivariable model CD4+, T-cell count increase was negatively associated with AIDS (HR 0.34 95%CI 0.13-0.91, p=0.032). Conclusion: We found a higher prevalence of HIV-1/2 dual infection than in previous observations. Subjects with HIV-2 infection showed a favorable immunological condition at diagnosis, and the benefits of cART in those who received treatment are undiscussed. Moreover, our data suggest a different disease course based on age at diagnosis, as in HIV-1 infections. We encourage starting cART at diagnosis in HIV-2 patients, regardless of CD4+ lymphocyte, because even in the new cART era, CD4+ lymphocyte decrease remains the strongest predictor of death and AIDS also in this population.

An exploratory pilot study on the involvement of APOE, HFE, C9ORF72 variants and comorbidities in neurocognitive and physical performance in a group of HIV-infected people.

Cognitive decline of aging is modulated by chronic inflammation and comorbidities. In people with HIV-infection (PWH) it may also be affected by HIV-induced inflammation, lifestyle and long-term effects of antiretroviral therapies (ART). The role of genetics in the susceptibility to HIV-associated neurocognitive disorders (HAND) is not fully understood. Here we explored the possible relations among variants in 3 genes involved in inflammation and neurodegenerative disorders (APOE: ε2/ε3/ε4; HFE: H63D; C9ORF72: hexanucleotide expansions ≥ 9 repeats), cognitive/functional impairment (MiniMental State Examination MMSE, Clock Drawing Test CDT, Short Physical Performance Battery SPPB), comorbidities and HIV-related variables in a cohort of > 50 years old PWH (n = 60) with at least 10 years efficient ART. Patients with diabetes or hypertension showed significantly lower MMSE (p = .031) or SPPB (p = .010) scores, respectively, while no relations between HIV-related variables and cognitive/functional scores were observed. Patients with at least one APOEε3 allele had higher CDT scores (p = .019), APOEε2/ε4 patients showing the lowest scores in all tests. Patients with HFE-H63D variant showed more frequently hypertriglyceridemia (p = .023) and those harboring C9ORF72 expansions > 9 repeats had higher CD4+-cell counts (p = .032) and CD4% (p = .041). Multiple linear regression analysis computed to verify possible associations among cognitive/functional scores and all variables further suggested positive association between higher CDT scores and the presence of at least one APOEε3 allele (2,2; 95% CI [0,03 0,8]; p = .037), independent of other variables, although the model did not reach the statistical significance (p = .14). These data suggest that in PWH on efficient ART cognitive abilities and physical performances may be partly associated with comorbidities and genetic background. However, further analyses are needed to establish whether they could be also dependent and influenced by comorbidities and genetic background.

Real-life experience with compassionate use of cefiderocol for difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections.

OBJECTIVES: To describe our real-life experience with cefiderocol in XDR and difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections without any other available treatment options. METHODS: We included patients with a proven infection due to an XDR/DTR-P, who had failed on previous regimens, and were treated with cefiderocol, following them prospectively to day 90 or until hospital discharge or death. RESULTS: Seventeen patients treated for >72 h with cefiderocol were included: 14 receiving combination regimens (82.4%) and 3 receiving monotherapy (17.6%). Fourteen patients were males (82%) with a median age of 64 years (IQR 58-73). Fifteen patients (88.2%) were admitted to the ICU and five had septic shock (29%). Seven cases (41.2%) were ventilator-associated pneumonia, of which 71% (5/7) occurred in COVID-19 patients. Four were complicated intrabdominal infections, one ecthyma gangrenosum, one nosocomial pneumonia and one empyema, one osteomyelitis, one primary bacteraemia, and one nosocomial external ventricular drainage meningitis. Clinical cure and microbiological cure rates were 70.6% and 76.5%, respectively. There were six deaths (35.3%) after a median of 8 days (IQR 3-10) from the end of treatment, but only two of them (11.7%) were associated with P. aeruginosa infection progression. CONCLUSIONS: Our experience collecting this large case series of DTR-P treated with cefiderocol may help clinicians consider this new option in this hard-to-manage setting. Our results are even more relevant in the current scenario of ceftolozane/tazobactam shortage. Importantly, this is the first study providing real-life data indicating adequate cefiderocol concentrations in CSF.

Impact of COVID-19 pandemic on HIV viremia: a single-center cohort study in northern Italy.

BACKGROUND: Brescia Province, northern Italy, was one of the worst epicenters of the COVID-19 pandemic. The division of infectious diseases of ASST (Azienda Socio Sanitaria Territoriale) Spedali Civili Hospital of Brescia had to face a great number of inpatients with severe COVID-19 infection and to ensure the continuum of care for almost 4000 outpatients with HIV infection actively followed by us. In a recent manuscript we described the impact of the pandemic on continuum of care in our HIV cohort expressed as number of missed visits, number of new HIV diagnosis, drop in ART (antiretroviral therapy) dispensation and number of hospitalized HIV patients due to SARS-CoV-2 infection. In this short communication, we completed the previous article with data of HIV plasmatic viremia of the same cohort before and during pandemic. METHODS: We considered all HIV-patients in stable ART for at least 6 months and with at least 1 available HIV viremia in the time window March 01-November 30, 2019, and another group of HIV patients with the same two requisites but in different time windows of the COVID-19 period (March 01-May 31, 2020, and June 01-November 30, 2020). For patients with positive viremia (PV) during COVID-19 period, we reported also the values of viral load (VL) just before and after PV. RESULTS: the percentage of patients with PV during COVID-19 period was lower than the previous year (2.8% vs 7%). Only 1% of our outpatients surely suffered from pandemic in term of loss of previous viral suppression. CONCLUSIONS: Our efforts to limit the impact of pandemic on our HIV outpatients were effective to ensure HIV continuum of care.

Pneumocystis jirovecii pneumonia in breast cancer mimicking SARS-CoV-2 pneumonia during pandemic.

Pneumocystis jirovecii pneumonia (PJP) is one of the most common HIV-related opportunistic infection. Apart from HIV patients, subjects treated with an associated therapy of high doses glucocorticoids and immunosuppressive drugs should be considered at risk. SARS-CoV-2 has become worldly known as the responsible of the pandemic that hit the world in late 2019 and that is still ongoing. Italy, and especially Brescia, was one of the area most struck by the pandemic, with a significant number of cases being reported (more than 112,648 as of October 2021). The diagnosis of SARS-CoV-2 is mainly based on RT-PCR assays performed on nasopharyngeal swab, X-ray of the chest and clinical manifestations. We describe two cases of PJP in two immunocompromised patients with breast cancer who were admitted at Spedali Civili of Brescia hospital, Italy, with an initial diagnosis of SARS-CoV-2 pneumonia, despite testing negative to RT-PCR on nasopharyngeal swabs. We also retrospectively reassessed all cases of pneumonia deemed as SARS-CoV-2-related upon admission and then converted to PJP as the final diagnosis. We describe the two following cases to emphasize that clinicians should always be alert about PJP, even during the SARS-CoV-2 pandemic, and avoid focusing on COVID-19 exclusively. PJP should always be considered as a differential diagnosis in patients, particularly if immunosuppressed, with an X-ray or TC of the chest suggestive of interstitial pneumonia and a negative SARS-CoV-2 RT-PCR on nasopharyngeal swabs.