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.

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.

The impact of early therapies for COVID-19 on death, hospitalization and persisting symptoms: a retrospective study.

PURPOSE: Oral antivirals (nirmatrelvir/ritonavir and molnupiravir), intravenous short treatment of remdesivir and anti-SARS-CoV-2 monoclonal antibodies (mAbs) have been used for early COVID-19 treatments in high risk of disease progression patients. The term long COVID has been used to refer to a range of new, returning, or ongoing symptoms after SARS-CoV-2 infection. Little is known about the impact of such therapies on long COVID. METHODS: This is a retrospective observational study, including all outpatients evaluated from April 2021 to March 2022 in Brescia, Lombardy, northern Italy. Patients were stratified in three groups: (a) treated with mAbs, (b) treated with antivirals drugs and (c) controls (patients eligible for a or b who refused treatment). Data were collected at baseline and at month 1 and 3 (data on self-reported symptoms were collected using a telephone-administered questionnaire). We assessed early COVID-19 therapies effectiveness in preventing hospitalization, death at 1 or 3 months and persisting symptoms at 3 months after the onset of SARS-CoV-2 infection. RESULTS: A total of 649 patients were included in the study, of which 242 (37.3%) were treated with mAbs, 197 (30.3%) with antiviral drugs and 210 (32.4%) were not treated. Patients most frequently reported cerebro-cardiovascular diseases (36.7%) followed by obesity (22%). Overall, 29 patients (4.5%) died or were hospitalized at 1 or 3-month follow-up. Death or hospitalization was positively associated with older ages, with a significant linear trend (OR 3.05; 95% CI 1.16-8.06, for patients aged 80 or more years compared to those aged less than 65). Data on long COVID at 3 months were available for 323 (49.8%) patients. A positive association emerged for females compared to men, with an OR of 2.14 (95% CI 1.30-3.53) for any symptoms. Conversely, inverse associations were found for treatment groups as compared to the control one, with significant estimates among patients treated with antiviral drugs for any symptoms (OR 0.43, 95% CI 0.21-0.87) and patients treated with mAbs for any neuro-behavioral symptoms (OR 0.48, 95% CI 0.25-0.92). CONCLUSIONS: We report beneficial effect of early use of anti-SARS-CoV-2 antivirals and mAbs on long COVID.

Monoclonal Antibodies against SARS-CoV-2: Current Scenario and Future Perspectives.

Monoclonal antibodies (mAbs) have been known since the 1970s. However, their therapeutic potential in the medical field has recently emerged, with the advancement of manufacturing techniques. Initially exploited mainly in the oncology field, mAbs have become increasingly relevant in Infectious Diseases. Numerous mAbs have been developed against SARS-CoV 2 and have proven their effectiveness, especially in the management of the mild-to-moderate disease. In this review, we describe the monoclonal antibodies currently authorized for the treatment of the coronavirus disease 19 (COVID-19) and offer an insight into the clinical trials that led to their approval. We discuss the mechanisms of action and methods of administration as well as the prophylactic and therapeutic labelled indications (both in outpatient and hospital settings). Furthermore, we address the critical issues regarding mAbs, focusing on their effectiveness against the variants of concern (VoC) and their role now that a large part of the population has been vaccinated. The purpose is to offer the clinician an up-to-date overview of a therapeutic tool that could prove decisive in treating patients at high risk of progression to severe disease.

Lung Ultrasound May Support Diagnosis and Monitoring of COVID-19 Pneumonia.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) is characterized by severe pneumonia and/or acute respiratory distress syndrome in about 20% of infected patients. Computed tomography (CT) is the routine imaging technique for diagnosis and monitoring of COVID-19 pneumonia. Chest CT has high sensitivity for diagnosis of COVID-19, but is not universally available, requires an infected or unstable patient to be moved to the radiology unit with potential exposure of several people, necessitates proper sanification of the CT room after use and is underutilized in children and pregnant women because of concerns over radiation exposure. The increasing frequency of confirmed COVID-19 cases is striking, and new sensitive diagnostic tools are needed to guide clinical practice. Lung ultrasound (LUS) is an emerging non-invasive bedside technique that is used to diagnose interstitial lung syndrome through evaluation and quantitation of the number of B-lines, pleural irregularities and nodules or consolidations. In patients with COVID-19 pneumonia, LUS reveals a typical pattern of diffuse interstitial lung syndrome, characterized by multiple or confluent bilateral B-lines with spared areas, thickening of the pleural line with pleural line irregularity and peripheral consolidations. LUS has been found to be a promising tool for the diagnosis of COVID-19 pneumonia, and LUS findings correlate fairly with those of chest CT scan. Compared with CT, LUS has several other advantages, such as lack of exposure to radiation, bedside repeatability during follow-up, low cost and easier application in low-resource settings. Consequently, LUS may decrease utilization of conventional diagnostic imaging resources (CT scan and chest X-ray). LUS may help in early diagnosis, therapeutic decisions and follow-up monitoring of COVID-19 pneumonia, particularly in the critical care setting and in pregnant women, children and patients in areas with high rates of community transmission.

Prognostic role of inflammatory biomarkers in HIV-infected patients with a first diagnosis of hepatocellular carcinoma: A single-center study.

OBJECTIVES: To assess hepatocellular carcinoma (HCC) survival and to investigate the prognostic role of immunonutritional biomarkers, as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and prognostic nutritional index (PNI), in a cohort of human immunodeficiency virus (HIV)-infected patients. METHODS: All HIV-positive patients diagnosed with HCC at our Department from January 2000 to December 2013 were included. The outcomes were overall survival (OS), recurrence-free survival (RFS), and liver-related death (LRD). To examine the role of inflammatory biomarkers on the outcomes, univariate and multivariable Cox regression models were used. Receiver operating characteristic (ROC) curves were implemented to evaluate the prediction role of NLR, PLR, and PNI. RESULTS: A total of 40 patients (90% males) with a mean age of 48.3 years (SD = 5.6) were recruited. NLR ≥ 2.9 was associated with all causes mortality, as well as, PLR ≥ 126. NLR and PLR were predictors of OS, RFS, and LRD, while PNI did not emerge as a prognostic marker. According to the multivariate analysis, no HCC treatment was the only risk factor associated with risk of death. The areas under the ROC curves were 68.3 (95% confidence interval [CI], 54.5-82.1) for PLR and 66.3 (95% CI, 54.3-78.2) for NLR at 3 years; similar results were found at 5 years of follow-up. CONCLUSIONS: Although, if examined singularly, NLR and PLR are prognostic factors for HCC recurrence and survival in HIV-infected patients, at the multivariate analysis, "no HCC treatment" remains the only independent risk factor associated with fatal outcome.

Antiretroviral Therapy in HIV-Infected Children With Tuberculosis: A Systematic Review.

BACKGROUND: Tuberculosis (TB) is the major cause of mortality in HIV-infected children globally. Current guidelines about the management of antiretroviral therapy in children with TB are based on a limited number of nonrandomized studies involving small numbers of participants. The aim of the study was to systematically retrieve and critically appraise available evidence on the efficacy and safety of different antiretroviral regimens in children with HIV infection who are receiving treatment for active TB. METHODS: We conducted a systematic review of the literature according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Records were retrieved through March 2016 from Medline, Embase and manual screening of key conference proceedings. Four specific research questions assessing available treatment options were defined. RESULTS: Although 4 independent searches were conducted (1 for each Population, Intervention, Comparator, Outcomes question), results were elaborated and interpreted together because of significant overlap among the retrieved records. Six observational studies were selected for qualitative synthesis while meta-analysis could not be performed. CONCLUSION: Evidence for optimal treatment options for HIV/TB coinfected children is limited. As the global community strives to reach the fast-track HIV treatment targets and eliminate childhood TB deaths, it must ensure that coinfected children are included in key treatment studies and expand this neglected but crucial area of research.

[Contact lens-related Fusarium keratitis: a case report].

We aim to highlight the key factors for a good outcome of fungal keratitis. We describe a case of contact lens-related Fusarium keratitis in a young girl. After identification of Fusarium spp under direct microscopic examination and in culture, a prolonged treatment with topic natamycin 5% was started and administered for five months with restitutio ad integrum of the eye. Prompt microbiological diagnosis and a specific and prolonged treatment are essential for correct management of Fusarium keratitis.

A case of melioidosis probably acquired by inhalation of dusts during a helicopter flight in a healthy traveler returning from Singapore.

We present a case of melioidosis in an Italian male returning from Singapore after a short travel. He probably acquired the disease by inhalation, which is not the typical mode of transmission, in the absence of evident risk factors. The diagnosis was confirmed by real-time polymerase chain reaction of the culture while serology was useful to assess professional exposure among laboratory workers. Treatment consisted of an initial intensive phase with meropenem and trimethoprim-sulfamethaxazole (TMP-SMX), followed by 6 months of eradication therapy with TMP-SMX.

The impact of antiretroviral therapy on mortality in HIV positive people during tuberculosis treatment: a systematic review and meta-analysis.

OBJECTIVE: To quantify the impact of antiretroviral therapy (ART) on mortality in HIV-positive people during tuberculosis (TB) treatment. DESIGN: We conducted a systematic literature review and meta-analysis. Studies published from 1996 through February 15, 2013, were identified by searching electronic resources (Pubmed and Embase) and conference books, manual searches of references, and expert consultation. Pooled estimates for the outcome of interest were acquired using random effects meta-analysis. SUBJECTS: The study population included individuals receiving ART before or during TB treatment. MAIN OUTCOME MEASURES: Main outcome measures were: (i) TB-case fatality ratio (CFR), defined as the proportion of individuals dying during TB treatment and, if mortality in HIV-positive people not on ART was also reported, (ii) the relative risk of death during TB treatment by ART status. RESULTS: Twenty-one studies were included in the systematic review. Random effects pooled meta-analysis estimated the CFR between 8% and 14% (pooled estimate 11%). Among HIV-positive TB cases, those receiving ART had a reduction in mortality during TB treatment of between 44% and 71% (RR = 0.42, 95%CI: 0.29-0.56). CONCLUSION: Starting ART before or during TB therapy reduces the risk of death during TB treatment by around three-fifths in clinical settings. National programmes should continue to expand coverage of ART for HIV positive in order to control the dual epidemic.

Sustained virological response to peginterferon therapy in patients infected with HCV (genotypes 2 and 3), with or without HIV.

BACKGROUND: HIV infection leads to a faster progression of liver disease in subjects infected with HCV, as compared with HCV mono-infected patients. Previous reports suggest that sustained virological response (SVR) rates are lower in HIV/HCV coinfection than in HCV monoinfection. We aimed to compare SVR rates of these two populations. METHODS: We retrospectively analyzed clinical, biochemical and virological data of HCV and HIV/HCV infected patients with HCV genotypes 2 and 3 who started anti-HCV treatment between March 2004 and November 2012, at a single large center. Intention-to-treat (ITT) and per-protocol (PP) analysis were performed. Univariate and multivariate logistic regression analyses were performed to assess predictors of SVR. RESULTS: 461 patients were analyzed: 307 (66.6%) males, 76 (16.5%) infected with HIV. Several differences at baseline between HCV monoinfected and HIV/HCV coinfected patients were observed. HCV monoinfected group was characterized by higher prevalence of genotype 2 (53% vs 5.3%), higher baseline HCV viral load (50% vs 35%), shorter mean duration of treatment (19 vs 41 weeks), more frequent use of peginterferon alfa-2a (84.5% vs 69.7%), lower prevalence of cirrhosis (6% vs 31.6%). Globally, SVR was achieved by 353 (76.6%) patients and 321 (83.8%) in the PP analysis. No statistically relevant differences were found in SVR rates between the two groups, either in ITT [78.2% (n = 301/385) vs 68.4% (n = 52/76), p =0.066, respectively] than in PP analysis [83.6% (n = 276/330) vs 84.9% (n = 45/53), p = 0.8]. CONCLUSIONS: Higher baseline viral loads and interruption of peginterferon and/or ribavirin were associated with a poor outcome of anti-HCV treatment while HIV infection was not related to major or minor probability to achieve SVR.

Evaluation of boosted and unboosted atazanavir plasma concentration in HIV infected patients.

OBJECTIVES: The aim of the study was to identify variables that can influence atazanavir plasma concentration. METHODS: We retrospectively analysed atazanavir trough concentration of HIV infected patients who performed therapeutic drug monitoring between October 2007 and July 2011. Qualitative variables were compared with X(2) test while continuous ones with Mann-Whitney and Student's t-test. A linear regression model was used to investigate factors influencing atazanavir plasma concentration. Therefore, we analysed the impact of cirrhosis on atazanavir pharmacokinetic variability. RESULTS: 255 plasma samples from 179 patients were analysed. At the univariate analysis female gender (+144.4 ng/mL; p=0.05) and tenofovir (+196.8 ng/mL; p=0.002) were associated with higher atazanavir concentrations. The multivariate model confirmed these two variables (+164.6 ng/mL; p=0.02 and +150.4 ng/mL; p=0.01) as independently associated with higher atazanavir trough concentration. The analysis of cirrhotic population showed an influence of tenofovir (-255.9 ng/mL; p=0.01), increased AST (+95.3 ng/mL; p=0.09), ALT (+67.9 ng/mL; p=0.07) and creatinine (+517.2 ng/mL; p=0.04). The multivariate model confirm that tenofovir was associated with lower atazanavir trough concentration (-284.1 ng/mL; p=0.005) while AST values significantly increased atazanavir concentrations (+114.5 ng/mL; p=0.03). DISCUSSION: Atazanavir is a safe and manageable drug. Our results suggest that female patients tend to have higher atazanavir plasma concentration, while the effect of tenofovir needs to be better clarified.