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Purpose: Outpatient parenteral antimicrobial therapy (OPAT) is a standard for antimicrobial therapy internationally. With this prospective cohort study, we aimed to assess the impact of an OPAT service as part of antimicrobial stewardship (AMS) and evaluate the safety and efficiency of the program while illuminating the financial benefit for the hospital. Methods: Socio-demographic data, treatment regimen and outcomes were prospectively recorded for all patients assigned to the program of the OPAT unit of the University Hospital of Zurich between November 2018 and September 2022. Results: In total, we recorded 303 OPAT assignments of which 260 resulted in effective OPAT episodes. The 260 OPAT episodes were further optimized toward the choice of antimicrobial agent (n = 18) and length of therapy (n = 6). Moreover, OPAT resulted in alteration of patient assessment and care led by AMS strategies in 247 of 260 episodes (95%). While the bed days saved per year increased consistently with time, a total of 3934 in-hospital treatment days were saved amounting to a cost saving of 9,835,000 CHF over 47 months. Adverse events were recorded in 46 cases whilst only two of these have been the reason for readmission during OPAT treatment. Clinical cure was noted in 77% (199/260) and was negatively associated with Charlson Comorbidity Index (CCI; OR per 1 unit higher 0.85 (95% CI 0.78–0.93)). Conclusion: This study demonstrates the impact of an OPAT service in the framework of AMS as well as its benefits for the hospital whilst preserving safety and efficacy for the patient's parenteral antimicrobial treatment. [ABSTRACT FROM AUTHOR]

Placing sepsis as a core part of infection management strategies will provide opportunities to increase sepsis awareness on a variety of contexts thus reducing its burden on healthcare and rehabilitation systems. ECDC should also use its influence to include sepsis among the research priorities for EU-funded programs, and to include sepsis management in guidelines for the case management of communicable diseases. Costs of sepsis and benefits of quality improvement initiatives Sepsis is a huge burden for European health systems and society. In fact, sepsis quality improvement programs are expected to be cost saving for the health care systems [[23]] and can leverage from the experience on successful ECDC programs on preventing nosocomial infections. [Extracted from the article]

Purpose: Infective endocarditis (IE) is a severe bacterial infection. As a measure of prevention, the administration of antibiotic prophylaxis (AP) prior to dental procedures was recommended in the past. However, between 2007 and 2009, guidelines for IE prophylaxis changed all around the word, limiting or supporting the complete cessation of AP. It remains unclear whether AP is effective or not against IE. Methods: We conducted a systematic review whether the administration of AP in adults before any dental procedure, compared to the non-administration of such drugs, has an effect on the risk of developing IE. We searched for studies in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via OVID, and EMBASE. Two different authors filtered articles independently and data extraction was performed based on a pre-defined protocol. Results: The only cohort study meeting our criteria included patients at high-risk of IE. Analysis of the extracted data showed a non-significant decrease in the risk of IE when high-risk patients take AP prior to invasive dental procedures (RR 0.39, p-value 0.11). We did not find other studies including patients at low or moderate risk of IE. Qualitative evaluation of the excluded articles reveals diversity of results and suggests that most of the state-of-the-art articles are underpowered. Conclusions: Evidence to support or discourage the use of AP prior to dental procedures as a prevention for IE is very low. New high-quality studies are needed, even though such studies would require big settings and might not be immediately feasible. [ABSTRACT FROM AUTHOR]

Fungal osteomyelitis is an uncommon complication after cardiac surgery and associated with high mortality. A case of Candida albicans and Staphylococcus epidermidis osteomyelitis with device infection after implantation of a left ventricular assist device in a 60-year-old male patient is presented here. After clinical identification and confirmation with microbiological examinations and fluorodeoxyglucose positron emission tomography (FDG-PET) scan, debridement was performed. Surgical specimens grew C. albicans and S. epidermidis. Fluconazole, daptomycin, and negative pressure wound therapy were initiated, but failed to achieve healing. Total sternectomy and pectoralis flap reconstruction were performed. There was no recurrent infection for C. albicans on a prolonged antifungal regime. The combination of antifungal therapy and aggressive surgical debridement may be useful to control fungal osteomyelitis. [ABSTRACT FROM AUTHOR]

Purpose: To report and analyse factors affecting the outcome of streptococcal periprosthetic joint infections (PJIs). Methods: A retrospective analysis of consecutive streptococcal PJIs was performed. Musculoskeletal Infection Society 2013 criteria were used. Outcome was compared with a prospective PJI cohort from the same institution. Results: The most common isolated streptococcal species was Streptococcus dysgalactiae (9/22, 41%) among 22 patients included. Surgical treatment consisted of DAIR (debridement, antibiotics, irrigation and retention) in 12 (55%), one-stage revision arthroplasty in one (4%), two-stage revision arthroplasty in eight (37%) and implant removal in one (4%) patient. An infection free-outcome was achieved in 15 cases (68%), whilst seven (32%) patients failed initial revision and relapsed with the same pathogen, from which six were treated with DAIR and one with one-stage revision arthroplasty. No failures were observed in patients who received a two-stage revision. Failure rates did not differ in the cases treated with rifampin (1/5) from those without 6/17 (p = 0.55). There was no correlation between the length of antibiotic treatment and relapse (p = 0.723). In all failures, a persistent distant infection focus was identified at the time of relapse. Compared with our prospective PJI cohort, relapse rates were significantly higher 32% vs 12% (p < 0.05). Conclusion: No correlation with the use of rifampin or length of antibiotic treatment was found. No failures were observed in patients who received a two-stage revision, which may be the surgical treatment of choice. A distant persisting infection focus could be the reason for PJI relapse with recurrent hematogenous seeding in the joint. [ABSTRACT FROM AUTHOR]

B Correction: Intensive Care Med b https://doi.org/10.1007/s00134-023-07127-3 In this article starting in line 64 the sentence has been rephrased from: The York Health Economics group estimated the physical burden of sepsis to be as high as £15 0.6 billion across the United Kingdom with direct cost of the National Health Service over 2 billion [13]. to The York Health Economics group estimated the grand total of sepsis to be as high as £7.4 billion across the United Kingdom with a direct cost of the National Health Service over £0.6 billion [13]. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. [Extracted from the article]

Staphylococcus aureus endovascular infections retain a high morbidity and mortality despite antibiotics and supportive care. The destruction of endothelial cells (ECs) is a critical step in the pathogenesis of S. aureus endovascular infections. In order to better understand S. aureus-induced EC damage, we systematically screened a collection of two-component regulatory system mutants of methicillin-resistant S. aureus (MRSA) USA300 strain JE2 for damage induction in human umbilical vein ECs (HUVECs). This screen revealed that the two-component regulatory system ArlRS is required for maximum damage: arlRS inactivation leads to a > 70% reduction in damage. In a different genetic S. aureus background (RN6390, MSSA strain) arlRS inactivation had a smaller but also significant effect on EC damage. In both strains, the reduction in EC damage was accompanied by a significant reduction in internalization. In conclusion, we determined a novel role of ArlRS in S. aureus-induced EC damage, which will help to better understand the pathogenesis of S. aureus endovascular infection. [ABSTRACT FROM AUTHOR]

M1 protein, a major virulence factor of the leading invasive strain of group A Streptococcus, is sufficient to induce toxic-shock-like vascular leakage and tissue injury. These events are triggered by the formation of a complex between M1 and fibrinogen that, unlike M1 or fibrinogen alone, leads to neutrophil activation. Here we provide a structural explanation for the pathological properties of the complex formed between streptococcal M1 and human fibrinogen. A conformationally dynamic coiled-coil dimer of M1 was found to organize four fibrinogen molecules into a specific cross-like pattern. This pattern supported the construction of a supramolecular network that was required for neutrophil activation but was distinct from a fibrin clot. Disruption of this network into other supramolecular assemblies was not tolerated. These results have bearing on the pathophysiology of streptococcal toxic shock. [ABSTRACT FROM AUTHOR]

The hypoxic response is an ancient stress response triggered by low ambient oxygen (O2) (ref. 1) and controlled by hypoxia-inducible transcription factor-1 (HIF-1), whose α subunit is rapidly degraded under normoxia but stabilized when O2-dependent prolyl hydroxylases (PHDs) that target its O2-dependent degradation domain are inhibited. Thus, the amount of HIF-1α, which controls genes involved in energy metabolism and angiogenesis, is regulated post-translationally. Another ancient stress response is the innate immune response, regulated by several transcription factors, among which NF-κB plays a central role. NF-κB activation is controlled by IκB kinases (IKK), mainly IKK-β, needed for phosphorylation-induced degradation of IκB inhibitors in response to infection and inflammation. IKK-β is modestly activated in hypoxic cell cultures when PHDs that attenuate its activation are inhibited. However, defining the relationship between NF-κB and HIF-1α has proven elusive. Using in vitro systems, it was reported that HIF-1α activates NF-κB, that NF-κB controls HIF-1α transcription and that HIF-1α activation may be concurrent with inhibition of NF-κB. Here we show, with the use of mice lacking IKK-β in different cell types, that NF-κB is a critical transcriptional activator of HIF-1α and that basal NF-κB activity is required for HIF-1α protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals. IKK-β deficiency results in defective induction of HIF-1α target genes including vascular endothelial growth factor. IKK-β is also essential for HIF-1α accumulation in macrophages experiencing a bacterial infection. Hence, IKK-β is an important physiological contributor to the hypoxic response, linking it to innate immunity and inflammation. [ABSTRACT FROM AUTHOR]

The hypoxia-inducible transcription factor (HIF-1α) is a major regulator of energy homeostasis and cellular adaptation to low oxygen stress. Recently, HIF-1α has been discovered to function as a global regulator of macrophage and neutrophil inflammatory and innate immune functions, as befits these specialized phagocytic cells who must operate effectively in the hypoxic microenvironments of infected tissues. This review summarizes current knowledge of the role of HIF-1α in mammalian innate immunity, emphasizing insight gained from conditional gene targeting of the transcription factor in the myeloid cell lineage. Dynamic changes in HIF-1α expression in the course of bacterial, viral, or parasitic infections are outlined and inferences drawn regarding the consequences for pathogen and host. A better understanding of HIF-1α function may provide novel and rational approaches for boosting innate immune function in the therapy of certain complicated infectious disease conditions. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Treatment failure in biofilm-associated bacterial infections is an important healthcare issue. In vitro studies and mouse models suggest that bacteria enter a slow-growing/non-growing state that results in transient tolerance to antibiotics in the absence of a specific resistance mechanism. However, little clinical confirmation of antibiotic tolerant bacteria in patients exists. In this study we investigate a Staphylococcus epidermidis pacemaker-associated endocarditis, in a patient who developed a break-through bacteremia despite taking antibiotics to which the S. epidermidis isolate is fully susceptible in vitro. Characterization of the clinical S. epidermidis isolates reveals in-host evolution over the 16-week infection period, resulting in increased antibiotic tolerance of the entire population due to a prolonged lag time until growth resumption and a reduced growth rate. Furthermore, we observe adaptation towards an increased biofilm formation capacity and genetic diversification of the S. epidermidis isolates within the patient. Staphylococcus epidermidis is a frequent cause of medical implant-associated biofilm infections. Here, studying a patient with pacemaker-associated endocarditis, the authors report in-host evolution of S. epidermidis leading to phenotypes exhibiting increased biofilm formation and antibiotic tolerance. [ABSTRACT FROM AUTHOR]

Persisters are a subpopulation of bacteria that are not killed by antibiotics even though they lack genetic resistance. Here we provide evidence that persisters can manifest as small colony variants (SCVs) in clinical infections. We analyze growth kinetics of Staphylococcus aureus sampled from in vivo conditions and in vitro stress conditions that mimic growth in host compartments. We report that SCVs arise as a result of a long lag time, and that this phenotype emerges de novo during the growth phase in various stress conditions including abscesses and acidic media. We further observe that long lag time correlates with antibiotic usage. These observations suggest that treatment strategies should be carefully tailored to address bacterial persisters in clinics. Persisters are bacterial subpopulations that are not killed by antibiotics even though they lack genetic resistance. Here, the authors show that persisters can manifest as small colony variants in clinical infections, and arise as a result of a long lag time in stress conditions including antibiotic exposure. [ABSTRACT FROM AUTHOR]