Triple Combination Therapy With 2 Antivirals and Monoclonal Antibodies for Persistent or Relapsed Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Immunocompromised Patients.

BACKGROUND: Severely immunocompromised patients are at risk for prolonged or relapsed Coronavirus Disease 2019 (COVID-19), leading to increased morbidity and mortality. We aimed to evaluate efficacy and safety of combination treatment in immunocompromised COVID-19 patients. METHODS: We included all immunocompromised patients with prolonged/relapsed COVID-19 treated with combination therapy with 2 antivirals (remdesivir plus nirmatrelvir/ritonavir, or molnupiravir in case of renal failure) plus, if available, anti-spike monoclonal antibodies (mAbs), between February and October 2022. The main outcomes were virological response at day 14 (negative Severe Acute Respiratory Syndrome Coronavirus 2 [SARS-CoV-2] swab) and virological and clinical response (alive, asymptomatic, with negative SARS-CoV-2 swab) at day 30 and the last follow-up. RESULTS: Overall, 22 patients (Omicron variant in 17/18) were included: 18 received full combination of 2 antivirals and mAbs and 4 received 2 antivirals only; in 20 of 22 (91%) patients, 2 antivirals were nirmatrelvir/ritonavir plus remdesivir. Nineteen (86%) patients had hematological malignancy, and 15 (68%) had received anti-CD20 therapy. All were symptomatic; 8 (36%) required oxygen. Four patients received a second course of combination treatment. The response rate at day 14, day 30, and last follow-up was 75% (15/20 evaluable), 73% (16/22), and 82% (18/22), respectively. Day 14 and 30 response rates were significantly higher when combination therapy included mAbs. Higher number of vaccine doses was associated with better final outcome. Two patients (9%) developed severe side effects (bradycardia leading to remdesivir discontinuation and myocardial infarction). CONCLUSIONS: Combination therapy including 2 antivirals (mainly remdesivir and nirmatrelvir/ritonavir) and mAbs was associated with high rate of virological and clinical response in immunocompromised patients with prolonged/relapsed COVID-19.

Outcome of early treatment of SARS-CoV-2 infection in patients with haematological disorders.

Outcome of early treatment of COVID-19 with antivirals or anti-spike monoclonal antibodies (MABs) in patients with haematological malignancies (HM) is unknown. A retrospective study of HM patients treated for mild/moderate COVID-19 between March 2021 and July 2022 was performed. The main composite end-point was treatment failure (severe COVID-19 or COVID-19-related death). We included 328 consecutive patients who received MABs (n = 120, 37%; sotrovimab, n = 73) or antivirals (n = 208, 63%; nirmatrelvir/ritonavir, n = 116) over a median of two days after symptoms started; 111 (33.8%) had non-Hodgkin lymphoma (NHL); 89 (27%) were transplant/CAR-T (chimaeric antigen receptor T-cell therapy) recipients. Most infections (n = 309, 94%) occurred during the Omicron period. Failure developed in 31 patients (9.5%). Its independent predictors were older age, fewer vaccine doses, and treatment with MABs. Rate of failure was lower in the Omicron versus the pre-Omicron period (7.8% versus 36.8%, p < 0.001). During the Omicron period, predictors of failure were age, fewer vaccine doses and diagnosis of acute myeloid leukaemia/myelodysplastic syndrome (AML/MDS). Independent predictors of longer viral shedding were age, comorbidities, hospital admission at diagnosis, NHL/CLL, treatment with MABs. COVID-19-associated mortality was 3.4% (n = 11). The mortality in those who developed severe COVID-19 after early treatment was 26% in the Omicron period. Patients with HM had a significant risk of failure of early treatment, even during the Omicron period, with high mortality rate.

Changes in the relative prevalence of candidaemia due to non-albicans Candida species in adult in-patients: A systematic review, meta-analysis and meta-regression.

BACKGROUND: Candidaemia remains associated with high mortality and increased costs worldwide. OBJECTIVE: To assess the changes over time in the relative prevalence of non-albicans candidaemia (NAC). METHODS: A systematic review, meta-analysis and meta-regression were performed. Observational studies investigating the epidemiology of consecutive, non-selected, candidaemia episodes were included. Two separated analyses were conducted: (a) whole hospital analysis and (b) intensive care unit (ICU) analysis. RESULTS: Starting from an initial total of 7726 records, 220 studies fulfilled inclusion criteria. The pooled prevalence of NAC in whole hospital analysis was 49.5% (95% confidence intervals [CI] 48.0-51.1, I2 93.1%), while the pooled prevalence in ICU analysis was 50.6% (95% CI 46.6-54.6; I2 86.7%). In meta-regression, a progressive increase in NAC prevalence was observed in whole hospital analysis, although it explained only a small portion of between-study variance (estimated yearly prevalence change +0.3%, 95% CI from +0.1% to +0.5%, P = .003; adjusted R2 3.42%) and was observed only in some continents in subgroup analyses. No relevant changes over time were observed in NAC prevalence for ICU studies. CONCLUSIONS: We registered an increasing trend in the relative prevalence of NAC, which, nonetheless, seems to be limited to some continents and to contribute only minimally to explain the observed differences in NAC prevalence across studies.

COVID-19 throughout pandemic waves and virus variants: a real-life experience in an Italian hospital.

New therapies and vaccines changed the management of COVID-19. The aim of this retrospective study was to describe characteristics, in-hospital mortality and its predictors in patients with moderate/severe COVID-19, considering the 4 different pandemic waves and viral variants' prevalence from February 2020 to January 2022. Among 1135 patients included, 873 (77%) had at least one comorbidity, 177 (16%) were immunocompromised. From waves 1 to 4, patients with severe respiratory failure and ICU admission decreased over time (p < 0.001), like the length of in-hospital stay (p < 0.001). Despite a reduction of in-hospital mortality from 19% to 11%, increased risk of death was related to older age and immunocompromising conditions, especially during the 4th wave (HR = 5.07 and HR = 10.86, p < 0.001 respectively) while remdesivir treatment in the 3rd wave (HR = 0.41, p = 0.010) and positive serology (aHR = 0.66, p = 0.027) were protective for survival. These data support the need for tailoring vaccine campaign for future COVID-19 waves.

Neutralizing monoclonal antibodies for the prevention of severe COVID-19: a retrospective study during Omicron BA.1 variant surge.

Among treatment options for Coronavirus disease 2019 (COVID-19), monoclonal antibodies (mAbs) showed to be effective in preventing disease progression, but real-world data during the Omicron variant surge are still lacking. Multicentre retrospective study evaluating the effectiveness of sotrovimab and casirivimab-imdevimab in fragile patients with mild SARS-CoV-2 infection between November 2021 and March 2022. Unfavourable outcome was defined as increased need for oxygen supplementation and/or death. Of 268 study-participants, 12 (4.48%) previously needed supplemental oxygen, while 6 (2.24%) had active solid neoplasia (2.24%); 186 (69%) have previously received SARS-CoV-2 vaccination. Overall, 22 (8%) had unfavourable outcomes (42% versus 6% of patients with and without previous oxygen need and 50% versus 7% of patients with and without active solid neoplasia). Both supplemental oxygen therapy before SARS-CoV-2 infection and solid malignant tumour have shown to be risk factors for treatment failure. Log-rank test did not identify differences between sotrovimab and casirivimab-imdevimab treatment. Despite diffusion of Omicron variant, the rate of unfavourable outcome was higher than expected. The presence of underlying risk factors, including solid cancer and previous oxygen therapy are independently associated with risk of COVID-19 progression, suggesting the need for antiviral treatments not limited to mAbs and implementation of vaccine campaign.

New antibiotics for Gram-negative pneumonia.

Pneumonia is frequently encountered in clinical practice, and Gram-negative bacilli constitute a significant proportion of its aetiology, especially when it is acquired in a hospital setting. With the alarming global rise in multidrug resistance in Gram-negative bacilli, antibiotic therapy for treating patients with pneumonia is challenging and must be guided by in vitro susceptibility results. In this review, we provide an overview of antibiotics newly approved for the treatment of pneumonia caused by Gram-negative bacilli. Ceftazidime-avibactam, imipenem-relebactam and meropenem-vaborbactam have potent activity against some of the carbapenem-resistant Enterobacterales, especially Klebsiella pneumoniae carbapenemase producers. Several novel antibiotics have potent activity against multidrug-resistant Pseudomonas aeruginosa, such as ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relabactam and cefiderocol. Cefiderocol may also play an important role in the management of pneumonia caused by Acinetobacter baumannii, along with plazomicin and eravacycline.

Case report: Sotrovimab, remdesivir and nirmatrelvir/ritonavir combination as salvage treatment option in two immunocompromised patients hospitalized for COVID-19.

COVID-19 in immunocompromised patients is difficult to treat. SARS-CoV-2 interaction with the host immune system and the role of therapy still remains only partly understood. There are no data regarding the use of monoclonal antibodies and the combination of two antivirals in fighting viral replication and disease progression. We report the cases of two patients, both treated with rituximab for non-Hodgkin lymphoma and granulomatosis with polyangiitis, respectively, and both hospitalized for COVID-19 with positive SARS-CoV-2 RNAemia, who were successfully treated with a salvage combination therapy with sotrovimab, remdesivir and nirmatrelvir/ritonavir.

Early Clinical Experience with Molnupiravir for Mild to Moderate Breakthrough COVID-19 among Fully Vaccinated Patients at Risk for Disease Progression.

Information on the efficacy and safety of molnupiravir in daily clinical practice is very scarce. We aimed to describe the clinical characteristics and outcomes of fully vaccinated patients with mild to moderate breakthrough COVID-19 treated with molnupiravir between January 2022 and February 2022. Overall, 145 patients were enrolled. Their median age was 71.0 years, and 60.7% were males. The most common underlying condition was a severe cardiovascular disease (37.2%), followed by primary or acquired immunodeficiency (22.8%), and oncological/onco-hematological disease in the active phase (22.1%). At 30 days after breakthrough COVID-19 diagnosis, only 4 out of 145 patients (2.7%) required hospital admission. No patients developed severe COVID-19, were admitted to the ICU, or died during the follow-up period. Adverse events, mild in intensity, occurred in 2 patients (1.4%). Our results support the current evidence establishing positive clinical and safety outcomes of molnupiravir in fully vaccinated patients with mild or moderate breakthrough COVID-19.

Healthcare Worker Study Cohort to Determine the Level and Durability of Cellular and Humoral Immune Responses after Two Doses of SARS-CoV-2 Vaccination.

We prospectively studied immunological response against SARS-CoV-2 after vaccination among healthcare workers without (group A) and with previous infection (group B). The analyses were collected at T0 (before the BNT162b2), T1 (before the second dose), T2 and T6 (1 and 6 months after the second dose). For cellular immune response, the activation-induced cell marker assay was performed with CD4 and CD8 Spike peptide megapools expressed as Stimulation Index. For humoral immune response, we determined antibodies to Spike-1 and nucleocapsid protein. The linear mixed model compared specific times to T0. The CD4+ Spike response overall rate of change was significant at T1 (p = 0.038) and at T2 (p < 0.001), while decreasing at T6. For CD8+ Spike reactivity, the interaction between the time and group was significant (p = 0.0265), and the p value for group comparison was significant at the baseline (p = 0.0030) with higher SI in previously infected subjects. Overall, the anti-S Abs significantly increased from T1 to T6 compared to T0. The group B at T6 retained high anti-S titer (p < 0.001). At T6, in both groups we found a persistent humoral response and a high CD4+ T cell response able to cross recognize SARS-COV-2 variants including epsilon, even if not a circulating virus at that time.

Second outbreak of Trichinella pseudospiralis in Europe: clinical patterns, epidemiological investigation and identification of the etiological agent based on the western blot patterns of the patients' serum.

Trichinellosis is a zoonotic disease due to the ingestion of raw or undercooked meat from animals infected with the larvae of nematodes belonging to the genus Trichinella. In January-February 2015, an outbreak of trichinellosis occurred in Genoa, Northern Italy. The epidemiological link was traced back to a dinner served at an agritourism farm on 31 December 2014, where a majority of the 52 guests had consumed the 'beef' steak tartare. The source of infection was not traced; however, it was noted that the amount of beef purchased officially for providing at the dinner did not correspond with that served, suggesting that meat of a different origin had been added to the beef to prepare the steak tartare. Clinical and laboratory data of 30 individuals out of the 52 (57.7%), of which four were hospitalized, were consistent with that of the case definition of trichinellosis. Western blot patterns of the sera from patients with confirmed trichinellosis were similar to the diagnostic pattern identified for the reference sera of Trichinella pseudospiralis but different from those of the control sera tested for patients infected with Trichinella spiralis and Trichinella britovi. Identification of T. pseudospiralis as the aetiological agent responsible for the outbreak of trichinellosis using an indirect tool represents an advancement in the epidemiological investigation of this zoonotic disease.

Bedaquiline: A New Hope for Shorter and Better Anti-Tuberculosis Regimens.

BACKGROUND: In 2014, an estimated 1.8 million people died from Mycobacterium tuberculosis (MTB); moreover, 680,000 people developed multidrug-resistant TB (MDRTB). METHODS: Currently available anti-MDR and XDR regimens are long-lasting and expensive, need high adherence and are undermined by a high frequency of adverse drug events, thus leading to a low success rate; furthermore, in the last 50 years only two new molecules, bedaquiline (BDQ) and delamanid, have been approved and released for the treatment of MDR-TB. RESULTS: BDQ, patent number US 7,498,343B2, is a diarylquinoline anti-mycobacterial drug, active regardless of the state of MTB; in fact, its efficacy is conserved against replicating and non-replicating bacilli, despite extracellular or intracellular location. BDQ has been approved by the Food and Drug Administration (FDA) only for combination treatment of pulmonary multidrug-resistant tuberculosis (MDR-TB), in adult patients, when an effective treatment cannot be provided otherwise due to resistance or poor tolerability; however, due to high bactericidal activity, BDQ may be used in future to treat extrapulmonary tuberculosis and Mycobacterium other than tuberculosis (MOTT) infection. CONCLUSION: BDQ may play a major role to get closer to TB eradication and to ensure higher retention in care, even in fully susceptible MTB strains and against non-replicating mycobacteria in latent-TB, providing an alternative to standard regimen.

Hepatitis B Virus Vaccination in HIV: Immunogenicity and Persistence of Seroprotection up to 7 Years Following a Primary Immunization Course.

Vaccination against hepatitis B virus (HBV) is recommended in people living with HIV (PLHIV), although immune response rates are lower than in healthy individuals. We aimed at assessing response rates and predictors as well as persistence of seroprotection in a cohort of PLHIV with no serological evidence of current or previous HBV infection. PLHIV followed at our site were retrospectively included if they started a primary HBV vaccination course (20 mcg three-dose schedule, alone or combined with inactivated hepatitis A virus) between 2007 and 2012. Serological response was defined as hepatitis B surface antibodies (HBsAb) ≥10 IU/liter 4 to 24 weeks after the third vaccine dose. Among 134 patients included, 119 completed the primary HBV vaccination schedule. Of them, 68% developed serological response. HIV viral suppression was associated with HBsAb ≥10 IU/liter [adjustedOR (odds ratio) 0.52, 95% confidence interval (CI) 0.33-0.82, p = .005], whereas CD4-T cell count was not (adjustedOR 1.001, 95% CI 1.001-1.003, p = .1). HBsAb titer declined over time, since 69.3% and 26.9% of vaccinees had HBsAb ≥10 IU/liter 36 and 84 months after the third HBV vaccine dose. Time-updated CD4-T cell count was associated with persistence of seroprotection [adjustedHR (hazard ratio) 1.17, 95% CI 1.06-1.30, p = .003], independently from quantitative HBV surface antigen titer achieved at the end of the primary vaccination schedule (HR 1.02, 95% CI 0.96-1.08, p = .64). The longer the time interval from vaccination, the higher the risk of loss of seroprotection. Repeating HBsAb titer 5 years after a successful HBV vaccination may be used to guide booster vaccination, as the majority of subjects may no longer have seroprotective HbsAb titers.