Introduction to the Special Issue on Clostridioides difficile Infection, Second Edition.

Clostridioides difficile (CD) is a Gram-positive, anaerobic bacterium that is one of the most common causes of infective diarrhoea worldwide [...].

The Evolving Challenge of Appropriate Antibiotics Use in Hospitalized COVID-19 Patients: A Systematic Literature Review.

The issue of bacterial infections in COVID-19 patients has received increasing attention. Scant data are available on the impact of bacterial superinfection and antibiotic administration on the outcome of hospitalized COVID-19 patients. We conducted a literature review from 1 January 2022 to 31 March 2024 to assess the current burden of bacterial infection and the evidence for antibiotic use in hospitalized COVID-19 patients. Published articles providing data on antibiotic use in COVID-19 patients were identified through computerized literature searches with the search terms [(antibiotic) AND (COVID-19)] or [(antibiotic treatment) AND (COVID-19)]. PubMed and SCOPUS databases were searched from 1 January 2022 to 31 March 2024. No attempt was made to obtain information about unpublished studies. English language restriction was applied. The quality of the included studies was evaluated by the tool recommended by the Joanna Briggs Institute. Both quantitative and qualitative information were summarized by means of textual descriptions. Five hundred fifty-one studies were identified, and twenty-nine studies were included in this systematic review. Of the 29 included studies, 18 studies were on the prevalence of bacterial infection and antibiotic use in hospitalized COVID-19 patients; 4 studies reported on the efficacy of early antibiotic use in COVID-19; 4 studies were on the use of sepsis biomarkers to improve antibiotic use; 3 studies were on the efficacy of antimicrobial stewardship programs and predictive models among COVID-19-hospitalized patients. The quality of included studies was high in 35% and medium in 62%. High rates of hospital-acquired infections were reported among COVID-19 patients, ranging between 7.5 and 37.7%. A high antibiotic resistance rate was reported among COVID-19 patients developing hospital-acquired infections, with a high in-hospital mortality rate. The studies evaluating multi-faceted antimicrobial stewardship interventions reported efficacy in decreasing antibiotic consumption and lower in-hospital mortality.

The impact of armed conflict on the development and global spread of antibiotic resistance: a systematic review.

BACKGROUND: Scant data are available on the link between armed conflicts and the development and spread of antimicrobial resistance. OBJECTIVES: We performed a systematic review with the aim to summarize the available data on the prevalence and features of antibiotic resistance and the causes of antibiotic resistance development during armed conflicts in the 21st century. METHODS: Data sources: PubMed and SCOPUS databases were searched from 1 January 2000 to 30 November 2023. STUDY ELIGIBILITY CRITERIA: Original articles reporting data on armed conflicts and antimicrobial resistance were included in this systematic review. No attempt was made to obtain information from unpublished studies. No language restriction was applied. Methods of data synthesis: Both quantitative and qualitative information were summarized by means of textual descriptions. PARTICIPANTS: Patients or soldiers deployed in armed conflict zones. TESTS: culture-dependent antibiotic sensitivity testing or molecular detection of the genetic determinants of antibiotic resistance after a confirmed diagnosis of bacterial infection. Assessment of risk of bias: To evaluate the quality of the included studies, we adapted the tool recommended by the Joanna Briggs Institute. RESULTS: Thirty-four studies were identified, published between November 2004 and November 2023. The quality of included studies was high and medium in 47% and 53% of the studies, respectively. The included studies reported high infection and colonization rates of multidrug-resistant bacteria. Studies performed during the Eastern Ukraine conflict reported high rates of New Delhi metallo-ß-lactamase producers. DISCUSSION: Our findings confirm that wars lead to a large pool of multidrug-resistant infections that could potentially spread. Infection control in healthcare facilities in conflict zones and proper antimicrobial stewardship are crucial.

On the use of intravenous metronidazole for severe and complicated Clostridioides difficile infection: a review and meta-analysis.

The European Society of Clinical Microbiology and Infectious Disease (ESCMID) has advised against the use of metronidazole for fulminant Clostridioides difficile (C. difficile) infection (CDI) in their latest guidelines. They suggest using oral vancomycin alone instead. This recommendation is based on a few retrospective studies, which have multiple biases. We evaluated the three studies that led ESCMID to advise against intravenous metronidazole for fulminant CDI and performed a meta-analysis. The meta-analysis revealed a mild (2.7%), not statistically significant (p=0.8) difference in mortality between the two groups. The high heterogeneity (I2= 89%) should also be noted. The decision to add or remove metronidazole should be discussed in the near future. In the meantime, combination therapy could be a cautious treatment for fulminant CDI.

Intravenous Fosfomycin for Systemic Multidrug-Resistant Pseudomonas aeruginosa Infections.

Human Pseudomonas infections have high morbidity and mortality rates. Pseudomonas bacteria can cause sepsis or septic shock; they produce biofilm and commonly exhibit a multidrug-resistant phenotype. The choice of antimicrobial therapy in many cases is challenging, and deep knowledge of clinical, microbiological, and pharmacological issues is required. Intravenous fosfomycin is being repurposed in a combination given its favorable pharmacokinetic/pharmacodynamic properties (a small molecule with favorable kinetic both in bloodstream infection and in deep-seated infections), antibiofilm activity, and its interesting synergistic effects with other antimicrobials. Recent literature on epidemiological, microbiological, pharmacological, and clinical data on intravenous fosfomycin therapy against Pseudomonas is herein reviewed and discussed.

Tackling Acinetobacter baumannii.

Globally, multidrug-resistant (MDR) bacteria represent a menace to public health [...].

Streptococcus intermedius Brain Abscess with Lung Abscess and Aortic Valve Endocarditis: A Case Report and Literature Review.

Streptococcus intermedius is frequently associated with brain and liver abscesses, while pleuropulmonary infections are considered rarer. Even less frequent is the association of lung and brain abscesses due to this agent with infective endocarditis. We describe the case of a 40-year-old man complaining of cough, fever, and headache who was diagnosed with a brain abscess due to S. intermedius, a concomitant lung abscess, and aortic native valve endocarditis. He was treated with surgical drainage of the brain abscess and a 4-week course of intravenous ceftriaxone, followed by oral amoxicillin/clavulanate, obtaining healing of the lesions without relapse of the infection.

Clostridioides difficile and Enterococci's Interplay in the Human Gut: Bacterial Alliance or Competition? A Systematic Literature Review.

Clostridioides difficile and Enterococcus spp. are two common bacterial pathogens populating the human microbiota. We possess scant data on how Clostridioides difficile interacts with Enterococcus spp. in the gut microbiota in subjects colonized with Clostridioides difficile or during a Clostridioides difficile infection. We carried out a systematic review of studies on Enterococcus spp. and Clostridioides difficile's interaction in the gut microbiota and on the effect of Enterococcus spp. gut colonization on CDI development. Studies on Enterococcus spp. and Clostridioides difficile's interaction in the gut microbiota and on the effect of Enterococcus spp. gut colonization on CDI were searched using the search terms "clostridium", "clostridioides", "difficile" and "enterococcus" on the MEDLINE and SCOPUS databases. PubMed was searched until 1 May 2023. An English language restriction was applied. The risk of bias in the included studies was not assessed. Quantitative and qualitative information was summarized in textual descriptions. Fourteen studies, published from August 2012 to November 2022, on Clostridioides difficile and Enterococcus spp.'s interaction in the gut microbiota met the inclusion criteria. The studies included in our systematic review reported evidence that the Enterococcus spp. intestinal burden represents a risk factor for the occurrence of CDI. There is supporting evidence that Enterococcus spp. play a role in CDI development and clinical outcomes.

Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations.

Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only. Contrariwise, the selection pressure in the germinal center on CD27bright memory B cells is decreased in CVID patients with autoimmune manifestations. Finally, functionally, T cell-dependent activation showed that naive B cells in CVID patients are badly equipped for activation and induction of mismatch repair genes. We conclude that central tolerance is functional whereas peripheral selection is defective in CVID patients with autoimmune manifestations, which could underpin the development of autoimmunity.

Efficacy of bezlotoxumab in preventing the recurrence of Clostridioides difficile infection: an Italian multicenter cohort study.

OBJECTIVES: Bezlotoxumab (BEZ) is a promising tool for preventing the recurrence of Clostridioides difficile infection (rCDI). The aim of the study was to emulate, in a real-world setting, the MODIFY trials in a cohort of participants with multiple risk factors for rCDI treated with BEZ in addition to the standard of care (SoC) versus SoC alone. METHODS: A multicenter cohort study was conducted including 442 patients with Clostridioides difficile infection from 2018 to 2022, collected from 18 Italian centers. The main outcome was the 30-day occurrence of rCDI. The secondary outcomes were (i) all-cause mortality at 30 days (ii) and the composite outcome (30-day recurrence and/or all-cause death). RESULTS: rCDI at day 30 occurred in 54 (12%): 11 in the BEZ + SoC group and 43 treated with SoC alone (8% vs 14%, odds ratio [OR] = 0.58, 95% confidence interval [CI]: 0.31-1.09, P = 0.09). The difference between BEZ + SoC versus SoC was statistically significant after controlling for confounding factors (adjusted OR = 0.40, 95% CI: 018-0.88, P = 0.02) and even more using the composite outcome (adjusted OR = 0.35, 95% CI: 0.17-0.73, P = 0.005). CONCLUSION: Our study confirms the efficacy of BEZ + SoC for the prevention of rCDI and death in a real-world setting. BEZ should be routinely considered among participants at high risk of rCDI regardless of age, type of Clostridioides difficile infection therapy (vancomycin vs fidaxomicin), and number of risk factors.

Antibiotics Use in COVID-19 Patients: A Systematic Literature Review.

The issue of bacterial infections in COVID-19 patients has received increasing attention among scientists. Antibiotics were widely prescribed during the early phase of the pandemic. We performed a literature review to assess the reasons, evidence and practices on the use of antibiotics in COVID-19 in- and outpatients. Published articles providing data on antibiotics use in COVID-19 patients were identified through computerized literature searches on the MEDLINE and SCOPUS databases. Searching the MEDLINE database, the following search terms were adopted: ((antibiotic) AND (COVID-19)). Searching the SCOPUS database, the following search terms were used: ((antibiotic treatment) AND (COVID-19)). The risk of bias in the included studies was not assessed. Both quantitative and qualitative information were summarized by means of textual descriptions. Five-hundred-ninety-three studies were identified, published from January 2020 to 30 October 2022. Thirty-six studies were included in this systematic review. Of the 36 included studies, 32 studies were on the use of antibiotics in COVID-19 inpatients and 4 on antibiotic use in COVID-19 outpatients. Apart from the studies identified and included in the review, the main recommendations on antibiotic treatment from 5 guidelines for the clinical management of COVID-19 were also summarized in a separate paragraph. Antibiotics should not be prescribed during COVID-19 unless there is a strong clinical suspicion of bacterial coinfection or superinfection.

Bezlotoxumab in Patients with a Primary Clostridioides difficile Infection: A Literature Review.

BACKGROUND: Nowadays, one of the main issues in the management of Clostridioides difficile infection (CDI) is the high rate of recurrences (rCDI), causing increased mortality and higher health care costs. OBJECTIVES: To assess the available evidence on the use of bezlotoxumab for the prevention of rCDI during a first CDI episode. METHODS: Published articles on bezlotoxumab during a primary CDI episode were identified through computerized literature searches with the search terms [(bezlotoxumab) AND (CDI) OR (Clostridioides difficile infection)] using PubMed and by reviewing the references of retrieved articles. PubMed was searched until 31 August 2022. RESULTS: Eighty-eight studies were identified as published from December 2014 to June 2022. Five studies were included in this study, one was a phase III clinical trial and four were sub-analyses or extensions of the previous phase III clinical trial. In the phase III clinical trial, the subgroup analysis on the included primary CDI patients showed that 13.5% of patients receiving bezlotoxumab had an rCDI, whilst 20.9% of patients in the placebo group had an rCDI at the twelve weeks follow-up (absolute difference: -7.4). CONCLUSIONS: Bezlotoxumab administration during the standard of care antibiotic therapy is effective and safe in reducing the rate of rCDI. Despite its high cost, evidence suggests considering bezlotoxumab in patients with a primary CDI episode. Further studies are needed to assess the benefit in specific subgroups of primary CDI patients and to define the risk factors to guide bezlotoxumab use.

Gram Negatives and Antimicrobial Resistance: Two Faces of the Same Coin.

The evolution, emergence and spread of bacterial antimicrobial resistance (AMR) represent threatening healthcare concerns of worldwide proportions [...].

Alveolar-Arterial Gradient Is an Early Marker to Predict Severe Pneumonia in COVID-19 Patients.

Background: One of the main challenges in the management of COVID-19 patients is to early assess and stratify them according to their risk of developing severe pneumonia. The alveolar−arterial oxygen gradient (D(A-a)O2) is defined as the difference between the alveolar and arteriolar concentration of oxygen, an accurate index of the ventilatory function. The aim of this study is to evaluate D(A-a)O2 as a marker for predicting severe pneumonia in COVID-19 patients, in comparison to the PaO2/FiO2. Methods: This retrospective, multicentric cohort study included COVID-19 patients admitted to two Italian hospitals between April and July 2020. Clinical and laboratory data were retrospectively collected at the time of hospital admission and during hospitalization. The presence of severe COVID-19 pneumonia was evaluated, as defined by the Infectious Diseases Society of America (IDSA) criteria for community-acquired pneumonia (CAP). Patients were divided in severe and non-severe groups. Results: Overall, 53 COVID-19 patients were included in the study: male were 30/53 (57%), and 10/53 (19%) had severe pneumonia. Patients with severe pneumonia reported dyspnea more often than non-severe patients (90% vs. 39.5%; p = 0.031). A history of chronic obstructive pulmonary disease (COPD) was recalled by 5/10 (50%) patients with severe pneumonia, and only in 6/43 (1.4%) of non-severe cases (p = 0.023). A ROC curve, for D(A-a)O2 >60 mmHg in detecting severe pneumonia, showed an area under the curve (AUC) of 0.877 (95% CI: 0.675−1), while the AUC of PaO2/FiO2 < 263 mmHg resulted 0.802 (95% CI: 0.544−1). D(A-a)O2 in comparison to PaO2/FiO2 had a higher sensibility (77.8% vs. 66.7%), positive predictive value (75% vs. 71.4%), negative predictive value (94% vs. 91%), and similar specificity (94.4% vs. 95.5%). Conclusions: Our study suggests that the D(A-a)O2 is more appropriate than PaO2/FiO2 to identify COVID-19 patients at risk of developing severe pneumonia early.

Durlobactam in the Treatment of Multidrug-Resistant Acinetobacter baumannii Infections: A Systematic Review.

A. baumannii is a frequent cause of difficult-to-treat healthcare-associated infections. The use of a novel beta-lactamase inhibitor, durlobactam, has been proposed against multidrug-resistant A. baumannii. A systematic review of studies assessing the efficacy and safety of durlobactam in the treatment of multidrug-resistant A. baumannii infections was carried out. The study protocol was pre-registered on PROSPERO (CRD42022311723). Published articles on durlobactam were identified through computerized literature searches with the search terms "durlobactam" and "ETX2514" using PubMed. PubMed was searched until 15 February 2022. Articles providing data on the main characteristics of durlobactam and on the efficacy and safety of durlobactam in the treatment of A. baumannii infections were included in this systematic review. Attempt was made to obtain information about unpublished studies. English language restriction was applied. The risk of bias in the included studies was not assessed. Both quantitative and qualitative information were summarized by means of textual descriptions. Thirty studies on durlobactam were identified, published from June 2017 to November 2020. Sixteen studies met the inclusion criteria. Durlobactam is effective against A. baumannii when used in combination with sulbactam. Future clinical trials are needed to confirm the possibility to treat infections caused by multidrug-resistant A. baumannii with this combination.