Treatment of infections caused by multidrug-resistant Gram-negative bacilli: a practical approach by the Italian (SIMIT) and French (SPILF) Societies of Infectious Diseases.

INTRODUCTION: The emergence of multidrug-resistant Gram-negative bacilli, and the development of new antibiotics have complexified selection of optimal regimens. International guidelines are valuable tools, though limited by scarcity of high-quality randomized trials in many situations. METHODS: A panel of experts from the French and Italian Societies of Infectious Diseases aimed to address unresolved issues in clinical practice based on their experience, updated literature review, and open discussions. RESULTS: The panel reached a consensus for the following 'first-choices': i) cefepime for ventilator-acquired pneumonia due to AmpC ß-lactamase-producing Enterobacterales; ii) The ß-lactam/ß-lactamase inhibitors combination most active in vitro, or cefiderocol combined with fosfomycin, and aerosolized colistin or aminoglycosides, for severe pneumonia due to Pseudomonas aeruginosa resistant to ceftolozane-tazobactam; iii) high-dose piperacillin-tazobactam (including loading dose and continuous infusion), for complicated urinary tract infections (cUTIs) caused by ESBL-producing Enterobacterales with piperacillin-tazobactam MIC ≤8 mg/L; iv) high-dose cefepime for cUTIs due to AmpC ß-lactamase-producing Enterobacterales other than Enterobacter species if cefepime MIC ≤2 mg/L; v) ceftolozane-tazobactam or ceftazidime-avibactam plus metronidazole for intra-abdominal infections (IAIs) due to 3rd generation cephalosporin-resistant Enterobacterales; vi) ceftazidime-avibactam plus aztreonam plus metronidazole for IAIs due to metallo ß-lactamase-producing Enterobacterales; vii) ampicillin-sulbactam plus colistin for bloodstream infections (BSIs) caused by carbapenem-resistant Acinetobacter baumannii (CRAB); viii) meropenem-vaborbactam for BSI caused by KPC-producing Enterobacterales; ix) ceftazidime-avibactam plus fosfomycin for neurological infections caused by carbapenem-resistant P. aeruginosa. CONCLUSIONS: These expert choices were based on the necessary balance between antimicrobial stewardship principles, and the need to provide optimal treatment for individual patients in each situation.

Efficacy and safety of antibiotics targeting Gram-negative bacteria in nosocomial pneumonia: a systematic review and Bayesian network meta-analysis.

BACKGROUND: Multiple randomized controlled studies have compared numerous antibiotic regimens, including new, recently commercialized antibiotics in the treatment of nosocomial pneumonia (NP). The objective of this Bayesian network meta-analysis (NMA) was to compare the efficacy and the safety of different antibiotic treatments for NP. METHODS: We conducted a systematic search of PubMed, Medline, Web of Science, EMBASE and the Cochrane Library databases from 2000 through 2021. The study selection included studies comparing antibiotics targeting Gram-negative bacilli in the setting of NP. The primary endpoint was 28 day mortality. Secondary outcomes were clinical cure, microbiological cure and adverse events. RESULTS: Sixteen studies encompassing 4993 patients were included in this analysis comparing 13 antibiotic regimens. The level of evidence for mortality comparisons ranged from very low to moderate. No significant difference in 28 day mortality was found among all beta-lactam regimens. Only the combination of meropenem plus aerosolized colistin was associated with a significant decrease of mortality compared to using intravenous colistin alone (OR = 0.43; 95% credible interval [0.17-0.94]), based on the results of the smallest trial included. The clinical failure rate of ceftazidime was higher than meropenem with (OR = 1.97; 95% CrI [1.19-3.45]) or without aerosolized colistin (OR = 1.40; 95% CrI [1.00-2.01]), imipemen/cilastatin/relebactam (OR = 1.74; 95% CrI [1.03-2.90]) and ceftazidime/avibactam (OR = 1.48; 95% CrI [1.02-2.20]). For microbiological cure, no substantial difference between regimens was found, but ceftolozane/tazobactam had the highest probability of being superior to comparators. In safety analyses, there was no significant difference between treatments for the occurrence of adverse events, but acute kidney failure was more common in patients receiving intravenous colistin. CONCLUSIONS: This network meta-analysis suggests that most antibiotic regimens, including new combinations and cefiderocol, have similar efficacy and safety in treating susceptible Gram-negative bacilli in NP. Further studies are necessary for NP caused by multidrug-resistant bacteria. Registration PROSPERO CRD42021226603.

Pleural penetration of amoxicillin and metronidazole during pleural infection: An ambispective cohort study.

OBJECTIVES: The pharmacokinetics of antibiotics in pleural fluid during pleural infections has been poorly described. This study aimed to explore amoxicillin and metronidazole diffusion into the pleural space. METHODS: This was an ambispective, single-centre study that included patients with complicated parapneumonic effusion or pleural empyema managed with repeated therapeutic thoracentesis as first-line treatment between 2014 and 2022. Pleural steady-state or trough concentrations of amoxicillin and metronidazole were measured, with a lower limit of quantification of 5 mg/L. RESULTS: Seventy paired blood and pleural samples were analysed from 40 patients. The median (interquartile range) patient age was 55 years (45-67 years) and 88% were male. The median patient weight was 65.8 kg (57.3-82 kg) and median plasma albumin concentration was 29.7 g/L (23.7-33.9 g/L). Median creatinine clearance was 106 mL/min (95-117 mL/min). Median amoxicillin pleural concentrations in patients treated with oral, bolus and continuous intravenous administrations (6 g/day) were, respectively, 5.2 (<5-6.4), 9.4 (8-13.1) and 10.8 (7.1-13.1) mg/L. Pleural concentrations were <5 mg/L in 5/11 samples (45%) with oral treatment and 6/59 (10%) with intravenous treatment. Median metronidazole pleural concentrations were 18.4 (15.7-22.8) mg/L, with all patients being treated orally (1.5 g/day). CONCLUSIONS: Oral metronidazole (1.5 g/day) and intravenous amoxicillin (6 g/day) achieved therapeutic targets in pleural fluid in most cases, but oral amoxicillin did not.

Prognostic value of serum Krebs von den Lungen-6 (KL-6) levels in COVID-19 pneumonia.

BACKGROUND AND OBJECTIVES: Krebs von den Lungen-6 (KL-6), expressed by damaged type II pneumocytes, is useful in the diagnosis and severity assessment of many diffuse interstitial lung diseases. The objective of our study was to determine the prognostic value of the initial KL-6 plasma level in COVID-19 pneumonia. METHODS: All patients hospitalized for a suspected COVID-19 pneumonia between March and May 2020 in our Chest department of a French university hospital were included. KL-6 serum concentrations were measured within 72 h of diagnostic suspicion by chemiluminescence enzyme immunoassay Survival analysis was performed using a Cox regression and modeled by a Kaplan-Meier curve. RESULTS: Sixty-six COVID-19 patients (average age = 64 ± 14 years, 71.2 % males) with KL-6 serum measurement were included. Median KL-6 serum concentration was 409 ± 312 U/mL. KL-6 was significantly higher in men (p = 0.003), elders (p = 0.0001) and in patients with greater Charlson's score (p = 0.002). Higher KL-6 concentration was significantly associated with in-hospital mortality (HR: 8.66; 95 % CI:1.1-69.2, p = 0.014), radiological extension of lesions on chest CT scan (p = 0.004) and higher WHO severity score (p = 0.042), but not with admission in intensive care unit. In 9 (14 %) non-surviving COVID-19 patients, KL-6 serum concentration increased whereas it remained stable or decreased in survivors. At 3 months follow-up (n = 48), DLCO was negatively correlated with the initial KL-6 value (r = 0.47, p = 0.001), while FVC, FEV1 and MRC score were not. CONCLUSION: Initial KL-6 serum concentration is significantly associated with in-hospital mortality, unfavorable outcome, and persistent impairment of DLCO at 3 months. Initial KL-6 plasma determination appears as a prognostic biomarker in COVID-19 pneumonia.

Infections in autoimmune pulmonary alveolar proteinosis: a large retrospective cohort.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease, predisposing to an increased risk of infection. A complete picture of these infections is lacking. RESEARCH QUESTION: Describe the characteristics and clinical outcomes of patients diagnosed with aPAP, and to identify risk factors associated with opportunistic infections. METHODS: We conducted a retrospective cohort including all patients diagnosed with aPAP between 2008 and 2018 in France and Belgium. Data were collected using a standardised questionnaire including demographics, comorbidities, imaging features, outcomes and microbiological data. RESULTS: We included 104 patients, 2/3 were men and median age at diagnosis was 45 years. With a median follow-up of 3.4 years (IQR 1.7-6.6 years), 60 patients (58%), developed at least one infection, including 23 (22%) with opportunistic infections. Nocardia spp was the main pathogen identified (n=10). Thirty-five (34%) patients were hospitalised due to infection. In univariate analysis, male gender was associated with opportunistic infections (p=0.04, OR=3.88; 95% CI (1.02 to 22.06)). Anti-granulocyte macrophage colony-stimulating factor antibody titre at diagnosis was significantly higher among patients who developed nocardiosis (1058 (316-1591) vs 580 (200-1190), p=0.01). Nine patients had died (9%), but only one death was related to infection. INTERPRETATION: Patients with aPAP often presented with opportunistic infections, especially nocardiosis, which highlights the importance of systematic search for slow-growing bacteria in bronchoalveolar lavage or whole lung lavage.

Early detection of plasma d-lactate: Toward a new highly-specific biomarker of bacteraemia?

Background: Bloodstream infections are a leading cause of mortality. Their detection relies on blood cultures (BCs) but time to positivity is often between tens of hours and days. d-lactate is a metabolite widely produced by bacteria but very few in human. We aimed to evaluate d-lactate, d-lactate/l-lactate ratio and d-lactate/total lactate ratio in plasma as potential early biomarkers of bacteraemia on a strictly biological standpoint. Methods: A total of 228 plasma specimens were collected from patients who had confirmed bacteraemia (n = 131) and healthy outpatients (n = 97). Specific l-lactate and d-lactate analyses were performed using enzymatic assays and analytical performances of d-lactate, d-lactate/total lactate and d-lactate/l-lactate ratios for the diagnosis of bacteraemia were assessed. Results: A preliminary in vitro study confirmed that all strains of Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus were able to produce d-lactate at significant levels. In patients, plasma d-lactate level was the most specific biomarker predicting a bacteraemia profile with a specificity and predictive positive value of 100% using a cut-off of 131 µmol.L-1. However, sensitivity and negative predictive value were rather low, estimated at 31% and 52%, respectively. d-lactate displayed an Area Under Receiver Operating Characteristic (AUROC) curve of 0.696 with a P value < 0.0001. There was no difference of d-lactate levels between BCs bottles positive for Gram-positive or Gram-negative bacteria (p = 0.55). Conclusion: d-lactate shows promise as a specific early biomarker of bacterial metabolism. The development of rapid automated assays could raise clinical applications for infectious diseases diagnosis including early bacteraemia prediction.

B-cell malignancies and COVID-19: a narrative review.

BACKGROUND: COVID-19 has been extensively characterized in immunocompetent hosts and to a lesser extent in immunocompromised populations. Among the latter, patients treated for B-cell malignancies have immunosuppression generated by B-cell lymphodepletion/aplasia resulting in an increased susceptibility to respiratory virus infections and poor response to vaccination. The consequence is that these patients are likely to develop severe or critical COVID-19. OBJECTIVES: To examine the overall impact of COVID-19 in patients treated for a B-cell malignancy or receiving chimeric antigen receptor T (CAR-T) immunotherapy administered in case of relapsed or refractory disease. SOURCES: We searched in the MEDLINE database to identify relevant studies, trials, reviews, or meta-analyses focusing on SARS-CoV-2 vaccination or COVID-19 management in patients treated for a B-cell malignancy or recipients of CAR-T cell therapy up to 8 July 2022. CONTENT: The epidemiology and outcomes of COVID-19 in patients with B-cell malignancy and CAR-T cell recipients are summarized. Vaccine efficacy in these subgroups is compiled. Considering the successive surges of variants of concern, we propose a critical appraisal of treatment strategies by discussing the use of neutralizing monoclonal antibodies, convalescent plasma therapy, direct-acting antiviral drugs, corticosteroids, and immunomodulators. IMPLICATIONS: For patients with B-cell malignancy, preventive vaccination against SARS-CoV-2 remains essential and the management of COVID-19 includes control of viral replication because of protracted SARS-CoV-2 shedding. Passive immunotherapy (monoclonal neutralizing antibody therapy and convalescent plasma therapy) and direct-active antivirals, such as remdesivir and nirmatrelvir/ritonavir are the best currently available treatments. Real-world data and subgroup analyses in larger trials are warranted to assess COVID-19 therapeutics in B-cell depleted populations.

Incidence and characteristics of COVID-19 in French professional football players during the 2020-2021 season.

OBJECTIVES: To describe the epidemiology of COVID-19 in French professional football players, and to compare the infection incidence with the general population across the first three waves. METHODS: During the 2020-2021 season, all professional football players (n = 1217) in the two primary French leagues underwent weekly testing for SARS-CoV-2 infection by nasopharyngeal PCR, in combination with rigorous infection control measures. RESULTS: Among all players, 572 (47%) tested positive at least once, with no COVID-19-related death or hospital admission. Monthly incidence estimates in players ranged from 1486 to 6731 per 100,000 individuals, i.e. 2-17 times higher than incidence estimates in the general population in France during the study period. CONCLUSION: Almost 50% of professional football players developed SARS-CoV-2 infection during the 2020-2021 season in France, with no severe complication.

The burden of SARS-CoV-2 in patients receiving chimeric antigen receptor T cell immunotherapy: everything to lose.

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cell immunotherapy has revolutionized the prognosis of refractory or relapsed B-cell malignancies. CAR-T cell recipients have immunosuppression generated by B-cell aplasia, leading to a higher susceptibility to respiratory virus infections and poor response to vaccination. AREAS COVERED: This review focuses on the challenge posed by B-cell targeted immunotherapies: managing long-lasting B-cell impairment during the successive surges of a deadly viral pandemic. We restricted this report to data regarding vaccine efficacy in CAR-T cell recipients, outcomes after developing COVID-19 and specificities of treatment management. We searched in MEDLINE database to identify relevant studies until 31 March 2022. EXPERT OPINION: Among available observational studies, the pooled mortality rate reached 40% in CAR-T cell recipients infected by SARS-CoV-2. Additionally, vaccine responses seem to be widely impaired in recipients (seroconversion 20%, T-cell response 50%). In this setting of B-cell depletion, passive immunotherapy is the backbone of treatment. Convalescent plasma therapy has proven to be a highly effective curative treatment with rare adverse events. Neutralizing monoclonal antibodies could be used as pre-exposure prophylaxis or early treatment but their neutralizing activity is constantly challenged by new variants. In order to reduce viral replication, direct-acting antiviral drugs should be considered.

Microbiology and antibiotics after second-stage revision of periprosthetic joint infections: A two-year follow-up cohort.

BACKGROUND: Optimal duration of antimicrobial regimen after reimplantation of two-stage procedures for periprosthetic joint infection (PJI) is poorly standardized. The aim of this study was to assess the characteristics of reimplantation microbiology with 6 weeks (2nd stage positive culture) or 10 days (2nd stage negative culture) of antibiotics in patients with complex chronic PJI and factors associated with microbiology at reimplantation. PATIENTS AND METHODS: We performed a retrospective single-center study including all consecutive complex PJI recipients managed by two-stage surgery in a referral centre, from 2015 to 2018. Outcome was assessed at a minimum 2-year follow-up. Logistic regression analysis was performed to assess predictors of reimplantation microbiology. RESULTS: Fifty patients (median age 69 [62-77] years) were included. PJI predominantly involved the hip (48%). The most common microorganisms were Staphylococcus aureus (36%), and coagulase-negative staphylococci (24%). At the second stage, reimplantation microbiology was positive for 10 patients (20%). Documentation was obtained within 48hours. With median follow-up of 41 [30-50] months after reimplantation, treatment failure occurred in 4 patients (8%). Using log-rank to compare Kaplan-Meier survival curves, no difference in the probability of treatment failure was found according to reimplantation microbiology (P=0.34). After adjustment, relapse was not associated with positive reimplantation microbiology (P=0.53). CONCLUSIONS: In this work, positive microbiology at reimplantation did not predict treatment failure. Rapid growth at post-reimplantation suggests that antibiotic use should not exceed 10 days when cultures are negative. Additional studies are needed to determine the optimal duration of antibiotic therapy in case of negative microbiology.

Malnutrition and decreased food intake at diagnosis are associated with hospitalization and mortality of idiopathic pulmonary fibrosis patients.

INTRODUCTION AND AIMS: Malnutrition is frequent in patients with idiopathic pulmonary fibrosis (IPF). We examined the relationship between malnutrition at diagnosis and all-cause hospitalization, survival, and acute exacerbation in newly diagnosed IPF patients. METHODS: In this prospective cohort study, the nutritional status of 153 consecutive newly-diagnosed IPF outpatients was evaluated by measuring body mass index (BMI), fat-free mass index (FFMI) with bioelectrical impedance analysis, and food intake with the Self Evaluation of Food Intake (SEFI)®. Diagnosis was taken as the baseline date and malnutrition was defined as an FFMI below 17 (men) or 15 kg/m2 (women). To determine the factors associated with all-cause hospitalization and mortality, univariate Cox regression analyses were performed and variables with P < 0.2 were included in a stepwise multivariable analysis. RESULTS: A quarter (26%; 40/153) of the patients were suffering from malnutrition at baseline, which was more frequent (62%) in patients whose BMI was <25 kg/m2. Patients whose baseline FFMI was low were more likely to be hospitalized (Hazard Ratio (HR) = 1.98 [95% confidence interval, 1.15; 3.41], P = 0.0139) and/or die (HR = 1.79 [1.11; 2.89], P = 0.0165), but their acute exacerbation rate was similar to that of patients with normal FFMIs. Decreased food intake (SEFI®<7) at baseline was associated with all-cause hospitalization (P = 0.003) and mortality (P < 0.0001) during follow-up. Baseline higher gender-age-physiology (GAP) scores (HR = 1.24 [1.01; 1.52], P = 0.0434; HR = 1.71 [1.37; 2.14], P < 0.0001, respectively), lower BMI (HR = 0.89 [0.83; 0.96], P = 0.003; HR = 0.89 [0.82; 0.96], P = 0.003), and decreased food intake (SEFI® score) (HR = 0.81 [0.71; 0.93], P = 0.003; HR = 0.72 [0.64; 0.81], P < 0.0001), but not FFMI, were independently associated with all-cause hospitalization and mortality rates during follow-up. CONCLUSIONS: Malnutrition and decreased food intake at IPF diagnosis are associated with all-cause hospitalization and mortality. Future studies will determine whether dedicated interventions to improve food intake and nutritional status could improve outcomes for IPF patients.

Soluble CD163 is produced by monocyte-derived and alveolar macrophages, and is not associated with the severity of idiopathic pulmonary fibrosis.

The soluble form of the membrane hemoglobin scavenger receptor CD163 (sCD163), released by shedding, is a strong marker for macrophage activation. Serum sCD163 levels rise in several acute inflammatory states and some fibrosing diseases. Monocyte-derived macrophages (MoDM) differentiated by macrophage colony-stimulating factor (M-MoDM) contribute to the pathophysiology of idiopathic pulmonary fibrosis (IPF), an irreversible and rapidly fatal interstitial lung disease. Since M-MoDM express high membrane CD163 levels, we thus postulated that sCD163 could be a relevant biomarker for macrophage activation in IPF. We found that M-MoDM constitutively released higher amounts of sCD163 (49.5 ± 24.5 ng/ml) than monocytes (0.45 ± 0.32 ng/ml) or MoDM differentiated with granulocyte macrophage-stimulating factor (2.24 ± 0.98 ng/ml). The basal production of sCD163 by M-MoDM was increased following stimulation with lipopolysaccharide (123.4 ± 54.9 ng/ml) or ATP (168.9 ± 41.8 ng/ml). The sCD163 release was controlled by metalloproteases but not through ADAM17 activation. Moreover, CD163-positive macrophages and sCD163 were detected in pulmonary tissues and alveolar fluids of Caucasian patients with IPF, respectively. IPF alveolar macrophages constitutively secreted sCD163 amounts (67.6 ± 44.6 ng/µg RNA) which were significantly higher than those released by alveolar macrophages isolated from controls (19.2 ± 7.6 ng/µg RNA) or patients with other interstitial lung disease (31.5 ± 16.6 ng/µg RNA). However, the concentrations of sCD163 in blood serum collected from 155 patients with IPF did not correlate with the severity of their disease. In conclusion, our results show that M-MoDM constituted a pertinent model to study the regulation of sCD163 production. Yet, serum sCD163 values could not provide a prognostic biomarker for IPF in our cohort.

The Association Between Antibiotic Use and Outcome Among Metastatic Melanoma Patients Receiving Immunotherapy.

BACKGROUND: Several observational studies have reported a decreased response to immune checkpoint inhibitors (ICI) following antibiotic use. ICI activity has been hypothesized to be impaired by antibiotic-induced gut dysbiosis. METHODS: Patients with advanced melanoma receiving an anti-PD-1 antibody as a first-line therapy between 2015 and 2017 in France were selected using the French Health Insurance database. We compared overall survival and time-to-treatment discontinuation according to antibiotic exposure in the 3 months prior to the initiation of anti-PD-1 antibody. To disentangle a causal effect of antibiotics from a confounding bias, we balanced characteristics of patients exposed and nonexposed to antibiotics using an overlap weighting method based on a propensity score. We also evaluated a control cohort of patients with advanced melanoma receiving first-line targeted therapy, as there is no rationale for decreased efficacy of targeted therapy following antibiotic treatment. RESULTS: The anti-PD-1 antibody cohort comprised 2605 individuals. Antibiotic exposure in the 3 months prior to anti-PD-1 antibody initiation was not associated with shorter overall survival (weighted hazard ratio = 1.01, 95% confidence interval = 0.88 to 1.17) or time-to-treatment discontinuation (weighted hazard ratio = 1.00, 95% confidence interval = 0.89 to 1.11). Consistent results were observed when the time frame of antibiotics was narrowed to 1 month prior to anti-PD-1 initiation or when exposure was restricted to antibiotics leading to more profound gut dysbiosis. Similar results were observed in the targeted therapy cohort. CONCLUSIONS: In a large cohort of advanced melanoma patients, we showed that antibiotic use preceding anti-PD-1 antibody was not associated with worse outcome. Physicians should not delay immunotherapy for patients who have recently received antibiotics.

Chronic use of inhaled corticosteroids in patients admitted for respiratory virus infections: a 6-year prospective multicenter study.

Inhaled corticosteroids (ICS) have been associated with increased risk of pneumonia. Their impact on respiratory virus infections is unclear. We performed a post-hoc analysis of the FLUVAC cohort, a multicenter prospective cohort study of adults hospitalized with influenza-like illness (ILI) during six consecutive influenza seasons (2012-2018). All patients were tested for respiratory virus infection by multiplex PCR on nasopharyngeal swabs and/or bronchoalveolar lavage. Risk factors were identified by logistic regression analysis. Among the 2658 patients included, 537 (20.2%) were treated with ICS before admission, of whom 282 (52.5%, 282/537) tested positive for at least one respiratory virus. Patients on ICS were more likely to test positive for non-influenza respiratory viruses (25.1% vs. 19.5%, P = 0.004), especially for adenovirus (aOR 2.36, 95% CI 1.18-4.58), and respiratory syncytial virus (aOR 2.08, 95% CI 1.39-3.09). Complications were reported in 55.9% of patients on ICS (300/537), primarily pneumonia (171/535, 32%). Among patients on chronic ICS who tested positive for respiratory virus, 14.2% (40/282) were admitted to intensive care unit, and in-hospital mortality rate was 2.8% (8/282). Chronic use of ICS is associated with an increased risk of adenovirus or RSV infections in patients admitted for ILI.