A 67-Year-Old Man with Chronic Lymphocytic Leukemia (CLL) on Maintenance Therapy with Ibrutinib with Persistent SARS-CoV-2 Infection Unresponsive to Antiviral Treatments.

BACKGROUND SARS-CoV-2 infection can persist in immunocompromised patients with hematological malignancies, despite antiviral treatment. This report is of a 67-year-old man with chronic lymphocytic leukemia (CLL), secondary hypogammaglobulinemia, and thrombocytopenia on maintenance therapy with ibrutinib, with persistent SARS-CoV-2 infection unresponsive to antiviral treatment, including remdesivir, nirmatrelvir/ritonavir (Paxlovid), and tixagevimab/cilgavimab (Evusheld). CASE REPORT The patient was admitted to our hospital 3 times. During his first hospitalization, he was treated with 5-day course of remdesivir and intravenous steroids; however, antigen and molecular nasopharyngeal swabs were persistently positive, and he was discharged home. Due to respiratory worsening, he was rehospitalized, and despite being treated initially with tixagevimab/cilgavimab, and subsequently with a remdesivir course of 5 days, SARS-CoV-2 tests remained persistently positive. During his third hospital stay, our patient was subjected to combined therapy with remdesivir and nirmatrelvir/ritonavir for 5 days, obtaining a significant reduction of viral load at both antigen and molecular testing. As an ultimate attempt to achieve a negative status before discharge, a 10-day course of combined remdesivir and nirmatrelvir/ritonavir was administered, with a temporary reduction of viral load, followed by a sudden increase immediately after the discontinuation of Paxlovid. Due to worsening hematological disease and bacterial over-infections, the patient gradually worsened until death. CONCLUSIONS This is an emblematic case of correlation between persistent SARS-CoV-2 infection and immunosuppression status in hematological hosts. In these patients, the viral load remains high, favoring the evolution of the virus, and the immunodeficiency makes it difficult to identify the appropriate therapeutic approach.

Multiple Sclerosis Onset before and after COVID-19 Vaccination: Can HLA Haplotype Be Determinant?

A few cases of multiple sclerosis (MS) onset after COVID-19 vaccination have been reported, although the evidence is insufficient to establish causality. The aim of this study is to compare cases of newly diagnosed relapsing-remitting MS before and after the outbreak of the COVID-19 pandemic and the impact of COVID-19 vaccination. Potential environmental and genetic predisposing factors were also investigated, as well as clinical patterns. This is a single-centre retrospective cohort study including all patients who presented with relapsing-remitting MS onset between January 2018 and July 2022. Data on COVID-19 vaccination administration, dose, and type were collected. HLA-DRB1 genotyping was performed in three subgroups. A total of 266 patients received a new diagnosis of relapsing-remitting MS in our centre, 143 before the COVID-19 pandemic (until and including March 2020), and 123 during the COVID-19 era (from April 2020). The mean number of new MS onset cases per year was not different before and during the COVID-19 era and neither were baseline patients' characteristics, type of onset, clinical recovery, or radiological patterns. Fourteen (11.4%) patients who subsequently received a new diagnosis of MS had a history of COVID-19 vaccination within one month before symptoms onset. Patients' characteristics, type of onset, clinical recovery, and radiological patterns did not differ from those of patients with non-vaccine-related new diagnoses of MS. The allele frequencies of HLA-DRB1*15 were 17.6% and 22.2% in patients with non-vaccine-related disease onset before and during the COVID-19 era, respectively, while no case of HLA-DRB1*15 was identified among patients with a new diagnosis of MS post-COVID-19 vaccine. In contrast, HLA-DRB1*08+ or HLA-DRB1*10+ MS patients were present only in this subgroup. Although a causal link between COVID-19 vaccination and relapsing-remitting MS cannot be detected, it is interesting to note and speculate about the peculiarities and heterogeneities underlying disease mechanisms of MS, where the interactions of genetics and the environment could be crucial also for the follow-up and the evaluation of therapeutic options.

Cerebrospinal fluid drain infection caused by pandrug-resistant Staphylococcus epidermidis successfully treated with ceftaroline in combination with fosfomycin and vancomycin.

External ventricular drain-related cerebrospinal fluid infection represents a fearsome complication of neurosurgical interventions. Although vancomycin represents the standard of care for methicillin-resistant CoNS healthcare-associated ventriculitis, resistance phenomena have been described. We reported a case of a persistent external ventricular fluid drain infection after device removal by pandrug-resistant Staphylococcus epidermidis successfully treated with intravenous ceftaroline in combination with fosfomycin and vancomycin. No evidence regarding pandrug-resistant S. epidermidis therapy currently exists to our knowledge. In this case, the S. epidermidis phenotype emerged during the therapy course, possibly due to initial device retention, biofilm formation and the host immune impaired response. Despite being poorly studied in vivo, ceftaroline may be considered an option when other alternatives are unavailable, thanks to its described activity against CoNS in vitro. This case extends the experience with ceftaroline for central nervous system infections suggesting it could also be used in high antimicrobial resistance settings for immunocompromised people.

Stroke and endocarditis: Reversing the point of view. A retrospective, cohort study.

STUDY OBJECTIVES: The primary objective of our study is to assess the endocarditis prevalence in patients admitted to the emergency department (ED) for a primary diagnosis of acute stroke (AS). Secondary objectives are the identification of early markers of endocarditis in AS patients and the analysis of the short-term outcome of this population. METHODS: In this observational, retrospective, cohort study we enrolled consecutive adult patients with a primary diagnosis of AS admitted to the Stroke Unit or to the Neurological Intensive Care Unit of our hospital who were then discharged with a diagnosis of endocarditis. These patients were then compared with age and sex-matched controls with a diagnosis of AS and atrial fibrillation. RESULTS: Endocarditis prevalence in patients admitted to the Stroke Unit or Neurological Intensive Care Unit with a primary diagnosis of AS is 1.0% (95% confidence interval 0.61-1.55). Fever on ED admission, concomitant cancer, low hemoglobin, low lymphocyte levels, a high neutrophils count and erythrocyte sedimentation levels could early differentiate among AS patients, those with endocarditis from those with atrial fibrillation. A moderate-to-severe valvular regurgitation is strongly suggestive of endocarditis. The short term-outcome is markedly worse in endocarditis patients compared to patients with atrial fibrillation, in terms of in-hospital mortality and discharge disability. CONCLUSIONS: Endocarditis prevalence in patients admitted for a primary diagnosis of AS is low, but this etiology leads to a poor outcome. Some laboratory, clinical-epidemiological and echocardiographic parameters may help the physician to early recognize this condition and, consequently, to promptly start an antibiotic therapy.

New Drugs for the Treatment of Pseudomonas aeruginosa Infections with Limited Treatment Options: A Narrative Review.

P. aeruginosa is still one of the most threatening pathogens responsible for serious hospital-acquired infections. It is intrinsically resistant to many antimicrobial agents and additional acquired resistance further complicates the management of such infections. High rates of combined antimicrobial resistance persist in many countries, especially in the eastern and south-eastern parts of Europe. The aim of this narrative review is to provide a comprehensive assessment of the epidemiology, latest data, and clinical evidence on the current and new available drugs active against P. aeruginosa isolates with limited treatment options. The latest evidence and recommendations supporting the use of ceftolozane-tazobactam and ceftazidime-avibactam, characterized by targeted clinical activity against a significant proportion of P. aeruginosa strains with limited treatment options, are described based on a review of the latest microbiological and clinical studies. Cefiderocol, with excellent in vitro activity against P. aeruginosa isolates, good stability to all ß-lactamases and against porin and efflux pumps mutations, is also examined. New carbapenem combinations are explored, reviewing the latest experimental and initial clinical evidence. One section is devoted to a review of new anti-pseudomonal antibiotics in the pipeline, such as cefepime-taniborbactam and cefepime-zidebactam. Finally, other "old" antimicrobials, mainly fosfomycin, that can be used as combination strategies, are described.

The Expanding Role of the Infectious Disease Expert in the Context of the MS Centre.

INTRODUCTION: The complexity of the MS patient's management is constantly growing. Consequently, the MS care unit requires a multidisciplinary approach, including an infectious disease specialist to minimise the risk of infectious complications related both to the disease and DMTs. MATERIALS AND METHODS: We retrospectively evaluated the infectious disease consultations performed from 2015 to 2019 in our MS centre. RESULTS: We identified 107 patients with at least one infectious disease consultation out of 1088 patients. We found a progressive increase in the number of consultations from 2015 to 2019. Nearly half of the consultations were requested at the time of starting MS treatment. The most frequent requests were represented by chronic or acute infections. The most prevalent infectious agents were Herpesviridae and Mycobacterium tuberculosis. Antibiotic or antiviral treatment and prophylactic treatment or vaccination represented together the most frequent outcomes of the consultations. Finally, a treatment delay was significantly associated with the advice of a prophylactic treatment or of a vaccination. CONCLUSION: There is an increasing awareness of the potential infectious complications of MS and of exposure to DMTs. The interaction between the MS neurologist and infectious disease specialist is fundamental to minimise the infectious risk related to the disease and to the DMTs, with a progressive shift from complication management to a broader prevention workup at the time of MS diagnosis, including both vaccination and prophylactic treatments.

Compassionate use of meropenem/vaborbactam for infections caused by KPC-producing Klebsiella pneumoniae: a multicentre study.

Objectives: To explore the real-life performance of meropenem/vaborbactam for treating serious KPC-producing Klebsiella pneumoniae infections, including those resistant to ceftazidime/avibactam. Methods: A retrospective observational cohort study was conducted in 12 Italian hospitals. Enrolled patients had K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) infections (59.5% of which were ceftazidime/avibactam resistant). Patients who received ≥72 h of meropenem/vaborbactam therapy (with or without other antimicrobials) in a compassionate-use setting were included. Results: The 37 infections (all hospital-acquired) were mainly bacteraemic (BSIs, n = 23) or lower respiratory tract infections (LRTIs, n = 10). Clinical cure was achieved in 28 (75.6%) cases and microbiologically confirmed in all 25 with follow-up cultures. Three (10.7%) of the 28 clinical cures (all BSIs, 2/3 microbiologically confirmed) were followed by in-hospital recurrences after meropenem/vaborbactam was discontinued (median interval: 18 days). All three recurrences were susceptible to meropenem/vaborbactam and successfully managed with meropenem/vaborbactam combined with colistin or fosfomycin. Nine patients (24.3%) (all with BSIs or LRTIs) died in hospital with persistent signs of infection. Most were aged over 60 years, with high comorbidity burdens and INCREMENT scores ≥8. Only one had received meropenem/vaborbactam monotherapy. Six began meropenem/vaborbactam therapy >48 h after infection onset. Outcomes were unrelated to the isolate's ceftazidime/avibactam susceptibility status. The single adverse event observed consisted of severe leukopenia with thrombocytopenia. Conclusions: With the well-known limitations of real-life retrospective studies, our results support previous findings indicating that meropenem/vaborbactam therapy will be a safe, effective tool for managing serious KPC-Kp infections, including the increasing proportion displaying resistance to ceftazidime/avibactam.

XDR-Pseudomonas aeruginosa Outside the ICU: Is There Still Place for Colistin?

BACKGROUND: Pseudomonas aeruginosa represents, among the nosocomial pathogens, one of the most serious threats, both for the severity of its clinical manifestations and its ability to develop complex profiles of resistance; Methods: we retrospectively collected the data of 21 patients admitted to a tertiary-care University Hospital of Rome with infections due to XDR-P. aeruginosa isolates during the second half of 2020; Results: in our institution, the percentage of XDR-P. aeruginosa isolates is 3.1%. None of the patients was admitted to the intensive care unit at the moment of the infection's onset. Susceptibility to colistin was preserved in all the tested isolates. Rates of resistance to ceftolozane/tazobactam and ceftazidime/avibactam in these XDR strains were consistent; Conclusions: XDR-P. aeruginosa can be a threatening problem even outside the ICUs, especially in frail patients in wards with features of long-term acute care hospitals. In such a setting, ceftolozane/tazobactam and ceftazidime/avibactam should be administered with caution taking into account the microbiological susceptibility results. Colistin, even with its known safety and efficacy limits, could represent the only available therapeutic option due to its highly preserved susceptibility against XDR isolates of P. aeruginosa.

Lung Ultrasound for COVID-19 Patchy Pneumonia: Extended or Limited Evaluations?

OBJECTIVES: The 2019 novel coronavirus (severe acute respiratory syndrome coronavirus 2) is causing cases of severe pneumonia. Lung ultrasound (LUS) could be a useful tool for physicians detecting a bilateral heterogeneous patchy distribution of pathologic findings in a symptomatic suggestive context. The aim of this study was to focus on the implications of limiting LUS examinations to specific regions of the chest. METHODS: Patients were evaluated with a standard sequence of LUS scans in 14 anatomic areas. A scoring system of LUS findings was reported, ranging from 0 to 3 (worst score, 3). The scores reported on anterior, lateral, and posterior landmarks were analyzed separately and compared with each other and with the global findings. RESULTS: Thirty-eight patients were enrolled. A higher prevalence of score 0 was observed in the anterior region (44.08%). On the contrary, 21.05% of posterior regions and 13.62% of lateral regions were evaluated as score 3, whereas only 5.92% of anterior regions were classified as score 3. Findings from chest computed tomography performed in 16 patients with coronavirus disease 2019 correlated with and matched the distribution of findings from LUS. CONCLUSIONS: To assess the quantity and severity of lung disease, a comprehensive LUS examination is recommended. Omitting areas of the chest misses involved lung.

Molecular Mechanisms, Epidemiology, and Clinical Importance of ß-Lactam Resistance in Enterobacteriaceae.

Despite being members of gut microbiota, Enterobacteriaceae are associated with many severe infections such as bloodstream infections. The ß-lactam drugs have been the cornerstone of antibiotic therapy for such infections. However, the overuse of these antibiotics has contributed to select ß-lactam-resistant Enterobacteriaceae isolates, so that ß-lactam resistance is nowadays a major concern worldwide. The production of enzymes that inactivate ß-lactams, mainly extended-spectrum ß-lactamases and carbapenemases, can confer multidrug resistance patterns that seriously compromise therapeutic options. Further, ß-lactam resistance may result in increases in the drug toxicity, mortality, and healthcare costs associated with Enterobacteriaceae infections. Here, we summarize the updated evidence about the molecular mechanisms and epidemiology of ß-lactamase-mediated ß-lactam resistance in Enterobacteriaceae, and their potential impact on clinical outcomes of ß-lactam-resistant Enterobacteriaceae infections.

Is serological response to SARS-CoV-2 preserved in MS patients on ocrelizumab treatment? A case report.

The emergency represented by the COVID-19 pandemic represents a new challenge for clinicians who deal with autoimmune diseases because of patients undergoing immunosuppressive therapy. Few cases of Multiple Sclerosis (MS) patients receiving ocrelizumab who contracted COVID-19 with a benign course have recently been published. We present the case of a MS patient with mild COVID-19 who developed SARS-CoV-2 specific IgA without IgG ten weeks after infection. Patients on B-cell depleting drugs have a reduced antibody immune response to viral neoantigens. A relative sparing of mucosal-associated lymphoid tissues (MALT) could be responsible for IgA response in our patient.

The diagnosis of pneumonia in a pregnant woman with coronavirus disease 2019 using maternal lung ultrasound.

Lung ultrasound examination has been demonstrated to be an accurate imaging method to detect pulmonary and pleural conditions. During pregnancy, there is a need for rapid assessment of the maternal lung in patients with suspected coronavirus disease 2019. We report our experience on lung ultrasound examination in the diagnosis of coronavirus disease 2019 pneumonia in a pregnant woman. Typical ultrasound features of this pulmonary pathology, including diffuse hyperechoic vertical artifacts with thickened pleural line and "white lung" with patchy distribution, were observed. We suggest point-of-care lung ultrasound examination as a diagnostic imaging tool in pregnant women with suspected coronavirus disease 2019.

Meropenem/vaborbactam: a next generation ß-lactam ß-lactamase inhibitor combination.

INTRODUCTION: infections due to carbapenem-resistant Enterobacterales (CRE) constitute a worldwide threat and are associated with significant mortality, especially in fragile patients, and costs. Meropenem-vaborbactam (M/V) is a combination of a group 2 carbapenem with a novel cyclic boronic acid-based ß-lactamase inhibitor which has shown good efficacy against KPC carbapenemase-producing Klebsiella pneumoniae, which are amongst the most prevalent types of CRE. AREAS COVERED: This article reviews the microbiological and pharmacological profile and current clinical experience and safety of M/V in the treatment of infections caused by CRE. EXPERT OPINION: M/V is a promising drug for the treatment of infections due to KPC-producing CRE (KPC-CRE). It exhibited an almost complete coverage of KPC-CRE isolates from large surveillance studies and a low propensity for resistance selection, retaining activity also against strains producing KPC mutants resistant to ceftazidime-avibactam. Both meropenem and vaborbactam have a favorable pharmacokinetic profile, with similar kinetic properties, a good intrapulmonary penetration, and are efficiently cleared during continuous venovenous hemofiltration (CVVH). According to available data, M/V monotherapy is associated with higher clinical cure rates and lower rates of adverse events, especially in terms of nephrotoxicity, if compared to 'older' combination therapies.

The role of carbapenem-resistant pathogens in cSSTI and how to manage them.

PURPOSE OF REVIEW: Skin and soft tissue infections (SSTIs) with a wide spectrum of disease severity ranging from uncomplicated to potentially lethal are still a leading cause of morbidity and mortality. The burden of carbapenem-resistant gram-negative bacteria (CR-GNB) in SSTIs is increasing. Luckily, the armamentarium of drugs available is recently expanding as well. The present review looks at data on the role CR-GNB in SSTIs and on the old and new drugs available for the treatment of carbapenem-resistant Enterobacteriaceae (CRE), Pseudomonas, and Acinetobacter. RECENT FINDINGS: The most recent information concern the availability of new antibiotics that, even if no specific clinical trials on complicated SSTIs (cSSTIs) have been performed, may play a role in clinical practice also for the treatment of cSSTIs caused by CR-GNB. Ceftolozane-tazobactam has been found to be a good option for CR Pseudomonas infections including SSTIs. Ceftazidime-avibactam is approved for several indications, including aerobic GNB infections with limited treatment options. Meropenem-vaborbactam therapy has been associated with decreased mortality in infections caused by CRE. Eravacycline has the potential to become useful for the treatment of CR Acinetobacter for which the treatment options are limited. SUMMARY: In the carbapenem resistance era, the physicians goal should be to stratify patients according to risk factors for CR-GNB causing SSTIs in order to minimize inappropriate initial therapies. Some recently approved drugs seem destined to become the backbone of target therapy in patients with severe infections caused by susceptible CR-GNB strains. Prompt diagnosis of cSSTIs is crucial and, when feasible, surgical debridement as source control is essential as well.

Predictors of Mortality with Staphylococcus aureus Bacteremia in Elderly Adults.

OBJECTIVES: To analyze risk factors for early and late mortality in individuals aged 75 and older with Staphylococcus aureus bacteremia (SAB) in Italy. DESIGN: Four-year retrospective observational study (January 2011-December 2014). SETTING: Two tertiary care university hospitals in Italy (Santa Maria Misericordia Hospital in Udine, Policlinico Universitario Agostino Gemelli in Rome). PARTICIPANTS: All adults consecutively admitted with SAB. MEASUREMENTS: Clinical presentation, infection characteristics, and clinical outcomes of individuals aged 75 and older were compared with those of individuals younger than 75. RESULTS: Three hundred thirty-seven cases of SAB were diagnosed during the study period, 118 of which (35%) occurred in those aged 75 and older. Seven- (20.3% vs 9.2%) and 30-day (35.7% vs 20.7%) mortality were significantly higher in elderly than younger adults. Clinical presentation with septic shock, adequacy of empiric antibiotic treatment, and liver cirrhosis were found to be predictors of 7-day mortality in elderly adults with SAB. Risk factors independently associated with 30-day mortality included isolation of methicillin-resistant Staphylococcus aureus (MRSA) and not receiving an infectious disease consultation. CONCLUSION: Mortality is significantly higher in elderly than in younger adults with SAB, particularly in those presenting with septic shock, liver cirrhosis, or SAB due to MRSA. Additional risk factors for mortality included inappropriate empiric antibiotic treatment and not receiving an infectious disease consultation.

Characteristics of Staphylococcus aureus Bacteraemia and Predictors of Early and Late Mortality.

We aimed to describe the characteristics of patients with Staphylococcus aureus bacteremia and to evaluate the risk factors associated with early (7-day) and late (30-day) mortality. We performed an observational study including all consecutive episodes of Staphylococcus aureus bacteremia diagnosed at two Italian university hospitals during 2010-2014. A total of 337 patients were included. Mean age was 69 years (range, 57-78) and 65% were males. Methicillin-resistant S. aureus (MRSA) was identified in 132/337 (39%)cases. Overall 7- and 30-day mortality were 13% and 26%, respectively. Early mortality was associated with increased Charlson scores (OR 1.3, 95% CI 1.1-1.5), MRSA bacteremia (OR 3.2, 95% CI 1.4-8.1), presentation with septic shock (OR 13.5, 95% CI 5.4-36.4), and occurrence of endocarditis (OR 4.5, 95%CI 1.4-14.6). Similar risk factors were identified for late mortality, including increased Charlson scores (OR 1.2, 95% CI 1.1-1.4), MRSA bacteremia (OR 2.1, 95% CI 1.2-3.9), presentation with septic shock (OR 4, 95%CI 1.7-9.7), occurrence of endocarditis (OR 3.8, 95% CI 1.4-10.2) as well as Child C cirrhosis (OR 3.9, 95% CI 1.1-14.4) and primary bacteremia (OR 2.5, 95%CI 1.3-5). Infectious disease consultation resulted in better outcomes both at 7 (OR 0.1, 95% CI 0.05-0.4) and at 30 days (OR 0.4, 95% CI 0.2-0.7). In conclusion, our study highlighted high rates of MRSA infection in nosocomial Staphylococcus aureus bacteremia. Multiple comorbidities, disease severity and methicillin-resistance are key factors for early and late mortality in this group. In patients with Staphylococcus aureus bacteremia, infectious disease consultation remains a valuable tool to improve clinical outcome.