How do I manage refractory invasive pulmonary aspergillosis.

BACKGROUND: Invasive aspergillosis is associated with significant morbidity and mortality in patients with haematologic malignancies and haematopoietic cell transplant recipients. The prognosis is worse among patients who have failed primary antifungal treatment. OBJECTIVES: We aim to provide guidance on the diagnosis and management of refractory invasive pulmonary aspergillosis. SOURCES: Using PubMed, we performed a review of original articles, meta-analyses, and systematic reviews. CONTENT: We discuss the diagnostic criteria for invasive pulmonary aspergillosis and the evidence on the treatment of primary infection. We outline our diagnostic approach to refractory disease. We propose a treatment algorithm for refractory disease and discuss the role of experimental antifungal agents. IMPLICATIONS: For patients with worsening disease while on antifungal therapy, a thorough diagnostic evaluation is required to confirm the diagnosis of aspergillosis and exclude another concomitant infection. Treatment should be individualized. Current options include switching to another triazole, transitioning to a lipid formulation of amphotericin B, or using combination antifungal therapy.

Rifampin Based Therapy for Patients With Staphylococcus aureus Native Vertebral Osteomyelitis: A Systematic Review and Meta-analysis.

BACKGROUND: Native vertebral osteomyelitis (NVO) caused by Staphylococcus aureus is associated with high risk of treatment failure and increased morbidity. The role of rifampin-based therapy for the treatment of this condition is controversial. The goal of this systematic review and meta-analysis is to explore the efficacy and safety of rifampin-based therapy for the treatment of S. aureus NVO. METHODS: We searched Cochrane, Embase, Medline, Scopus, and Web of Science databases for studies published up to May 2023, focusing on adults with NVO treated with or without rifampin-containing regimens. A random-effects model meta-analysis estimated relative risks and risk difference with 95% confidence intervals (CI). RESULTS: Thirteen studies (2 randomized controlled trials and 11 comparative cohort studies), comprising 244 patients with S. aureus NVO who received rifampin and 435 who did not, were analyzed. Meta-analysis showed that rifampin-based regimens were associated with lower risk of clinical failure (risk difference, -14%; 95% CI, -19% to -8%; P < .001; I2 = 0%; relative risk, 0.58; 95% CI, .37-.92, P = .02, I2 = 21%). Only 1 study reported on adverse events. All studies had a high or uncertain risk of bias, and the certainty of evidence was rated as very low. CONCLUSIONS: Adjunctive rifampin therapy might be associated with lower risk of S. aureus NVO treatment failure; however, the low certainty of evidence precludes drawing definitive conclusions that would alter clinical practice. A randomized trial is necessary to corroborate these findings.

Dysregulated monocyte-derived macrophage response to Group B Streptococcus in newborns.

Introduction: Streptococcus agalactiae (Group B Streptococcus, GBS) is a leading pathogen of neonatal sepsis. The host-pathogen interactions underlying the progression to life-threatening infection in newborns are incompletely understood. Macrophages are first line in host defenses against GBS, contributing to the initiation, amplification, and termination of immune responses. The goal of this study was to compare the response of newborn and adult monocyte-derived macrophages (MDMs) to GBS. Methods: Monocytes from umbilical cord blood of healthy term newborns and from peripheral blood of healthy adult subjects were cultured with M-CSF to induce MDMs. M-CSF-MDMs, GM-CSF- and IFNγ-activated MDMs were exposed to GBS COH1, a reference strain for neonatal sepsis. Results: GBS induced a greater release of IL-1ß, IL-6, IL-10, IL-12p70 and IL-23 in newborn compared to adult MDMs, while IL-18, IL-21, IL-22, TNF, RANTES/CCL5, MCP-1/CCL2 and IL-8/CXCL8 were released at similar levels. MDM responses to GBS were strongly influenced by conditions of activation and were distinct from those to synthetic bacterial lipopeptides and lipopolysaccharides. Under similar conditions of opsonization, newborn MDMs phagocytosed and killed GBS as efficiently as adult MDMs. Discussion: Altogether, the production of excessive levels of Th1- (IL-12p70), Th17-related (IL-1ß, IL-6, IL-23) and anti-inflammatory (IL-10) cytokines is consistent with a dysregulated response to GBS in newborns. The high responsiveness of newborn MDMs may play a role in the progression of GBS infection in newborns, possibly contributing to the development of life-threatening organ dysfunction.

Recombinant C1 inhibitor in the prevention of severe COVID-19: a randomized, open-label, multi-center phase IIa trial.

Background: Conestat alfa (ConA), a recombinant human C1 inhibitor, may prevent thromboinflammation. Methods: We conducted a randomized, open-label, multi-national clinical trial in which hospitalized adults at risk for progression to severe COVID-19 were assigned in a 2:1 ratio to receive either 3 days of ConA plus standard of care (SOC) or SOC alone. Primary and secondary endpoints were day 7 disease severity on the WHO Ordinal Scale, time to clinical improvement within 14 days, and safety, respectively. Results: The trial was prematurely terminated because of futility after randomization of 84 patients, 56 in the ConA and 28 in the control arm. At baseline, higher WHO Ordinal Scale scores were more frequently observed in the ConA than in the control arm. On day 7, no relevant differences in the primary outcome were noted between the two arms (p = 0.11). The median time to defervescence was 3 days, and the median time to clinical improvement was 7 days in both arms (p = 0.22 and 0.56, respectively). Activation of plasma cascades and endothelial cells over time was similar in both groups. The incidence of adverse events (AEs) was higher in the intervention arm (any AE, 30% with ConA vs. 19% with SOC alone; serious AE, 27% vs. 15%; death, 11% vs. 0%). None of these were judged as being related to the study drug. Conclusion: The study results do not support the use of ConA to prevent COVID-19 progression. Clinical trial registration: https://clinicaltrials.gov, identifier NCT04414631.

Bloodstream Infection Due to Coagulase-Negative Staphylococci: Impact of Species on Prevalence of Infective Endocarditis.

(1) Background: Coagulase-negative staphylococci (CoNS) are an important group of organisms that can cause bloodstream infection (BSI) and infective endocarditis (IE). The prevalence of IE in patients with BSI due to different CoNS species, however, has received limited attention; (2) Methods: A retrospective study of adults with monomicrobial CoNS BSI who had undergone echocardiography and a risk factor analysis was done to determine the most common CoNS species that cause definite IE; (3) Results: 247 patients with CoNS BSI were included in the investigation; 49 (19.8%) had definite IE, 124 (50.2%) possible IE, and 74 (30.0%) BSI only. The latter two entities were grouped in one category for further analysis. The most common species in CoNS BSI was Staphylococcus epidermidis (79.4%) and most patients (83.2%) had possible IE/BSI only. 59.1% of patients with BSI due to S. lugdunensis had definite IE. The majority of CoNS were healthcare-associated/nosocomial bacteremia. Multivariable analysis demonstrated that valve disease (p = 0.002) and a foreign cardiovascular material (p < 0.001) were risk factors associated with definite IE. Patients with S. lugdunensis BSI had an 8-fold higher risk of definite IE than did those with S. epidermidis BSI and nearly a 13-fold higher risk than did patients with BSI due to other species of CoNS (p = 0.002); (4) Conclusions: The prevalence of definite IE in patients with BSI due to different CoNS species was significant. CoNS bacteremia, particularly with S. lugdunensis, confers a significant risk of IE, particularly in patients with a valve disease or intravascular foreign body material and should not be immediately dismissed as a contaminant.

Detection of blaCTX-M and blaDHA genes in stool samples of healthy people: comparison of culture- and shotgun metagenomic-based approaches.

We implemented culture- and shotgun metagenomic sequencing (SMS)-based methods to assess the gut colonization with extended-spectrum cephalosporin-resistant Enterobacterales (ESC-R-Ent) in 42 volunteers. Both methods were performed using native and pre-enriched (broth supplemented with cefuroxime) stools. Native culture screening on CHROMID® ESBL plates resulted in 17 positive samples, whereas the pre-enriched culture (gold-standard) identified 23 carriers. Overall, 26 ESC-R-Ent strains (24 Escherichia coli) were identified: 25 CTX-M and 3 DHA-1 producers (2 co-producing CTX-Ms). Using the SMS on native stool ("native SMS") with thresholds ≥60% for both identity and coverage, only 7 of the 23 pre-enriched culture-positive samples resulted positive for blaCTX-M/blaDHA genes (native SMS reads mapping to blaCTX-M/blaDHAs identified in gold-standard: sensitivity, 59.0%; specificity 100%). Moreover, an average of 31.5 and 24.6 antimicrobial resistance genes (ARGs) were detected in the 23 pre-enriched culture-positive and the 19 negative samples, respectively. When the pre-enriched SMS was implemented, more blaCTX-M/blaDHA genes were detected than in the native assay, including in stools that were pre-enriched culture-negative (pre-enriched SMS reads mapping to blaCTX-M/blaDHAs identified in gold-standard: sensitivity, 78.3%; specificity 75.0%). In addition, the pre-enriched SMS identified on average 38.6 ARGs/sample, whereas for the corresponding native SMS it was 29.4 ARGs/sample. Notably, stools resulting false-negative by using the native SMS had lower concentrations of ESC-R-Ent (average: ~105 vs. ~107 CFU/g) and E. coli classified reads (average: 193,959 vs. 1.45 million) than those of native SMS positive samples. Finally, the detection of blaCTX-M/blaDHA genes was compared with two well-established bioinformatic tools. In conclusion, only the pre-enriched SMS assured detection of most carriers of ESC-R-Ent. However, its performance was not comparable to the pre-enriched culture-based approach.

Escherichia ruysiae May Serve as a Reservoir of Antibiotic Resistance Genes across Multiple Settings and Regions.

Gut colonization with multidrug-resistant Enterobacterales (MDR-Ent) has reached worrisome levels worldwide. In this context, Escherichia ruysiae is a recently described species mostly found in animals. However, its spread and impact on humans is poorly understood. A stool sample from a healthy individual living in India was screened for the presence of MDR-Ent using culture-based methods. Colonies were routinely identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and phenotypically characterized by broth microdilution. Illumina and Nanopore whole-genome sequencing (WGS) platforms were implemented to generate a complete assembly. E. ruysiae genomes deposited in international databases were used for a core genome phylogenetic analysis. An extended-spectrum ß-lactamase (ESBL)-producing E. coli strain (S1-IND-07-A) was isolated from the stool. WGS confirmed that S1-IND-07-A was indeed E. ruysiae, belonged to sequence type 5792 (ST5792), core genome (cg) ST89059, serotype O13/O129-:H56-like, clade IV phylogroup, and possessed five virulence factors. A copy of blaCTX-M-15 and five other antimicrobial resistance genes (ARGs) were detected in a conjugative IncB/O/K/Z plasmid. A database search identified 70 further E. ruysiae strains from 16 countries (44, 15, and 11 strains isolated from animals, the environment, and humans, respectively). The core genome phylogeny revealed five major STs: ST6467, ST8084, ST2371, ST9287, and ST5792. Three out of the seventy strains possessed important ARGs: OTP1704 (blaCTX-M-14; ST6467), SN1013-18 (blaCTX-M-15; ST5792), and CE1758 (blaCMY-2; ST7531). These strains were of human, environmental, and wild animal origin, respectively. E. ruysiae may acquire clinically important ARGs and transmit them to other species. Due to its zoonotic potential, further efforts are needed to improve routine detection and surveillance across One Health settings. IMPORTANCE Escherichia ruysiae is a recently described species of the cryptic clades III and IV of the genus Escherichia and is commonly found in animals and the environment. This work highlights the zoonotic potential of E. ruysiae, as it has been shown to colonize the human intestinal tract. Importantly, E. ruysiae may be associated with conjugative plasmids carrying clinically relevant antibiotic resistance genes. Therefore, it is important to closely monitor this species. Overall, this study highlights the need for improved identification of Escherichia species and continued surveillance of zoonotic pathogens in One Health settings.

Do quantitative levels of antispike-IgG antibodies aid in predicting protection from SARS-CoV-2 infection? Results from a longitudinal study in a police cohort.

In a COVID-19 sero-surveillance cohort study with predominantly healthy and vaccinated individuals, the objectives were (i) to investigate longitudinally the factors associated with the quantitative dynamics of antispike (anti-S1) IgG antibody levels, (ii) to evaluate whether the levels were associated with protection from SARS-CoV-2 infection, and (iii) to assess whether the association was different in the pre-Omicron compared with the Omicron period. The QuantiVac Euroimmun ELISA test was used to quantify anti-S1 IgG levels. The entire study period (16 months), the 11-month pre-Omicron period and the cross-sectional analysis before the Omicron surge included 3219, 2310, and 895 reactive serum samples from 949, 919, and 895 individuals, respectively. Mixed-effect linear, mixed-effect time-to-event, and logistic regression models were used to achieve the objectives. Age and time since infection or vaccination were the only factors associated with a decline of anti-S1 IgG levels. Higher antibody levels were significantly associated with protection from SARS-CoV-2 infection (0.89, 95% confidence interval [CI] 0.82-0.97), and the association was higher during the time period when Omicron was predominantly circulating compared with the ones when Alpha and Delta variants were predominant (adjusted hazard ratio for interaction 0.66, 95% CI 0.53-0.84). In a prediction model, it was estimated that >8000 BAU/mL anti-S1 IgG was required to reduce the risk of infection with Omicron variants by approximately 20%-30% for 90 days. Though, such high levels were only found in 1.9% of the samples before the Omicron surge, and they were not durable for 3 months. Anti-S1 IgG antibody levels are statistically associated with protection from SARS-CoV-2 infection. However, the prediction impact of the antibody level findings on infection protection is limited.

Early switch from intravenous to oral antibiotic treatment in bone and joint infections.

OBJECTIVES: The timing of the switch from intravenous (i.v.) to oral antibiotic therapy for orthopaedic bone and joint infections (BJIs) is debated. In this narrative article, we discuss the evidence for and against an early switch in BJIs. DATA SOURCES: We performed a PubMed and internet search investigating the association between the duration of i.v. treatment for BJI and remission of infection among adult orthopaedic patients. CONTENT: Among eight randomized controlled trials and multiple retrospective studies, we failed to find any minimal duration of postsurgical i.v. therapy associated with clinical outcomes. We did not find scientific data to support the prolonged use of i.v. therapy or to inform a minimal duration of i.v. THERAPY: Growing evidence supports the safety of an early switch to oral medications once the patient is clinically stable. IMPLICATIONS: After surgery for BJI, a switch to oral antibiotics within a few days is reasonable in most cases. We recommend making the decision on the time point based on clinical criteria and in an interdisciplinary team at the bedside.

Dynamics of bacterial pathogens at the driveline exit site in patients with ventricular assist devices: A prospective, observational, single-center cohort study.

BACKGROUND: Driveline infections (DLIs) at the exit site are frequent in patients with left ventricular assist devices (LVADs). The dynamics from colonization to infection are yet to be investigated. We combined systematic swabbing at the driveline exit site and genomic analyses to study the dynamics of bacterial pathogens and get insights into DLIs pathogenesis. METHODS: A prospective, observational, single-center cohort study at the University Hospital of Bern, Switzerland was performed. Patients with LVAD were systematically swabbed at the driveline exit site between June 2019 and December 2021, irrespective of signs and symptoms of DLI. Bacterial isolates were identified and a subset was whole-genome sequenced. RESULTS: Fifty-three patients were screened, of which 45 (84.9%) were included in the final population. Bacterial colonization at the driveline exit site without manifestation of DLI was frequent and observed in 17 patients (37.8%). Twenty-two patients (48.9%) developed at least one DLI episode over the study period. Incidence of DLIs reached 2.3 cases per 1000 LVAD days. The majority of the organisms cultivated from exit sites were Staphylococcus species. Genome analysis revealed that bacteria persisted at the driveline exit site over time. In four patients, transition from colonization to clinical DLI was observed. CONCLUSIONS: Our study is the first to address bacterial colonization in the LVAD-DLI setting. We observed that bacterial colonization at the driveline exit site was a frequent phenomenon, and in a few cases, it preceded clinically relevant infections. We also provided acquisition of hospital-acquired multidrug-resistant bacteria and the transmission of pathogens between patients.

Penicillin-Susceptible Streptococcus pneumoniae Meningitis in Adults: Does the Ceftriaxone Dosing Matter?

The recommended empiric ceftriaxone dosing regimen for acute bacterial meningitis in adults is 2 g every 12 h. After penicillin-susceptible Streptococcus pneumoniae is isolated as a causative microorganism, the ceftriaxone dose may be continued or reduced to a single dose of 2 g every 24 h, per institutional preference. There is no clear guidance that indicates the superiority of one regimen over the other. The objective of this study was to evaluate the susceptibility of S. pneumoniae in the cerebral spinal fluid (CSF) of patients with meningitis and the relationship between ceftriaxone dose and clinical outcomes. We identified 52 patients with S. pneumoniae meningitis with positive CSF cultures who were treated at the University Hospital, Bern, Switzerland, over a 19-year period. We collected clinical and microbiological data for evaluation. Broth microdilution and Etest methods were performed to test penicillin and ceftriaxone susceptibility. All isolates were susceptible to ceftriaxone. Ceftriaxone was empirically used in 50 patients, with a starting dosing regimen of 2 g every 24 h in 15 patients and 2 g every 12 h in 35 patients. In 32 patients started on a twice-daily regimen (91%), doses were reduced to once daily after a median of 1.5 (95% CI 1-2) days. The overall in-hospital mortality was 15.4% (n = 8), and 45.7% of patients reported at least one sequela of meningitis at the last follow-up (median 375, 95% CI 189-1585 days). We found no statistical difference in outcome between the 2 g every 24 h and the 2 g every 12 h ceftriaxone dosing regimens. A ceftriaxone total daily dose of 2 g may be associated with similar outcomes to a 4 g total daily dose, provided that the causative organism is highly susceptible to ceftriaxone. The persistence of neurological and infection sequelae at the last follow-up underscores the need for optimal treatment of these complex infections.

Complete Genome Sequence of the First Colistin-Resistant Raoultella electrica Strain.

We present the full genome sequence of a colistin-resistant Raoultella electrica strain (MIC, >4 µg/mL) that was isolated from the stool of a healthy person living in India. The sequence consists of a chromosome and three plasmids (5,455,992-bp and 98,913-bp, 4,232-bp, and 3,961-bp, respectively). No previously described colistin resistance mechanisms were detected.

Guideline for management of septic arthritis in native joints (SANJO).

This clinical guideline is intended for use by orthopedic surgeons and physicians who care for patients with possible or documented septic arthritis of a native joint (SANJO). It includes evidence and opinion-based recommendations for the diagnosis and management of patients with SANJO.

Can the Future of ID Escape the Inertial Dogma of Its Past? The Exemplars of Shorter Is Better and Oral Is the New IV.

Like all fields of medicine, Infectious Diseases is rife with dogma that underpins much clinical practice. In this study, we discuss 2 specific examples of historical practice that have been overturned recently by numerous prospective studies: traditional durations of antimicrobial therapy and the necessity of intravenous (IV)-only therapy for specific infectious syndromes. These dogmas are based on uncontrolled case series from >50 years ago, amplified by the opinions of eminent experts. In contrast, more than 120 modern, randomized controlled trials have established that shorter durations of therapy are equally effective for many infections. Furthermore, 21 concordant randomized controlled trials have demonstrated that oral antibiotic therapy is at least as effective as IV-only therapy for osteomyelitis, bacteremia, and endocarditis. Nevertheless, practitioners in many clinical settings remain refractory to adopting these changes. It is time for Infectious Diseases to move beyond its history of eminent opinion-based medicine and truly into the era of evidenced-based medicine.

Targeting thromboinflammation in COVID-19 - A narrative review of the potential of C1 inhibitor to prevent disease progression.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is associated with a clinical spectrum ranging from asymptomatic carriers to critically ill patients with complications including thromboembolic events, myocardial injury, multisystemic inflammatory syndromes and death. Since the beginning of the pandemic several therapeutic options emerged, with a multitude of randomized trials, changing the medical landscape of COVID-19. The effect of various monoclonal antibodies, antiviral, anti-inflammatory and anticoagulation drugs have been studied, and to some extent, implemented into clinical practice. In addition, a multitude of trials improved the understanding of the disease and emerging evidence points towards a significant role of the complement system, kallikrein-kinin, and contact activation system as drivers of disease in severe COVID-19. Despite their involvement in COVID-19, treatments targeting these plasmatic cascades have neither been systematically studied nor introduced into clinical practice, and randomized studies with regards to these treatments are scarce. Given the multiple-action, multiple-target nature of C1 inhibitor (C1-INH), the natural inhibitor of these cascades, this drug may be an interesting candidate to prevent disease progression and combat thromboinflammation in COVID-19. This narrative review will discuss the current evidence with regards to the involvement of these plasmatic cascades as well as endothelial cells in COVID-19. Furthermore, we summarize the evidence of C1-INH in COVID-19 and potential benefits and pitfalls of C1-INH treatment in COVID-19.

Early Switch From Intravenous to Oral Antibiotics in Skin and Soft Tissue Infections: An Algorithm-Based Prospective Multicenter Pilot Trial.

Background: In hospitalized patients with skin and soft tissue infections (SSTIs), intravenous (IV) empiric antibiotic treatment is initiated. The best time point for switching from IV to oral treatment is unknown. We used an algorithm-based decision tree for the switch from IV to oral antibiotics within 48 hours and aimed to investigate the treatment outcome of this concept. Methods: In a nonrandomized trial, we prospectively enrolled 128 patients hospitalized with SSTI from July 2019 to May 2021 at 3 institutions. Clinical and biochemical response data during the first week and at follow-up after 30 days were analyzed. Patients fulfilling criteria for the switch from IV to oral antibiotics were assigned to the intervention group. The primary outcome was a composite definition consisting of the proportion of patients with clinical failure or death of any cause. Results: Ninety-seven (75.8%) patients were assigned to the intervention group. All of them showed signs of clinical improvement (ie, absence of fever or reduction of pain) within 48 hours of IV treatment, irrespective of erythema finding or biochemical response. The median total antibiotic treatment duration was 11 (interquartile range [IQR], 9-13) days in the invention group and 15 (IQR, 11-24) days in the nonintervention group (P < .001). The median duration of hospitalization was 5 (IQR, 4-6) days in the intervention group and 8 (IQR, 6-12) days in the nonintervention group (P < .001). There were 5 (5.2%) failures in the intervention group and 1 (3.2%) in the nonintervention group after a median follow-up of 37 days. Conclusions: In this pilot trial, the proposed decision algorithm for early switch from IV to oral antibiotics for SSTI treatment was successful in 95% of cases. Clinical Trials Registration. ISRCTN15245496.