[The morbidity after sepsis motivates person-centred clinical follow-up]. / Morbiditet efter sepsis motiv för personlig uppföljning.

The documented morbidity problems after sepsis motivated inclusion of routine clinical follow-up at 2-6 weeks after sepsis care in the national patient-centred clinical pathway for sepsis in Sweden. This routine has been evaluated in a pilot study, in which a nurse at a department of infectious diseases performed a structured telephone follow-up after sepsis care. The pilot study showed that the routine was resource demanding and illustrated that it is not optimal to use a uniform follow-up routine in a broad sepsis population. Thus, the clinical follow-up recommendations within the patient-centred clinical pathway for sepsis should be updated, adapted for broadly available health-care structures, and more person-centred.

EARLY DECREASED RESPIRATORY CHAIN CAPACITY IN RESUSCITATED EXPERIMENTAL SEPSIS IS A MAJOR CONTRIBUTOR TO LACTATE PRODUCTION.

ABSTRACT: Background : Increased plasma lactate levels in patients with sepsis may be due to insufficient oxygen delivery, but mitochondrial dysfunction or accelerated glycolysis may also contribute. We studied the effect of the latter on muscle metabolism by using microdialysis in a sepsis model with sustained oxygen delivery and decreased energy consumption or mitochondrial blockade. Methods : Pigs were subjected to continuous Escherichia coli infusion (sepsis group, n = 12) or saline infusion (sham group, n = 4) for 3 h. Protocolized interventions were applied to normalize the oxygen delivery and blood pressure. Microdialysis catheters were used to monitor muscle metabolism (naïve). The same catheters were used to block the electron transport chain with cyanide or the Na + /K + -ATPase inhibitor, ouabain locally. Results: All pigs in the sepsis group had positive blood cultures and a Sequential Organ Failure Assessment score increase by at least 2, fulfilling the sepsis criteria. Plasma lactate was higher in the sepsis group than in the sham group ( P < 0.001), whereas muscle glucose was lower in the sepsis group ( P < 0.01). There were no changes in muscle lactate levels over time but lactate to pyruvate ratio (LPR) was elevated in the sepsis versus the sham group ( P < 0.05). Muscle lactate, LPR, and glutamate levels were higher in the sepsis group than in the sham group in the cyanide catheters ( P < 0.001, all comparisons) and did not normalize in the former group. Conclusions: In this experimental study on resuscitated sepsis, we observed increased aerobic metabolism and preserved mitochondrial function. Sepsis and electron transport chain inhibition led to increased LPR, suggesting a decreased mitochondrial reserve capacity in early sepsis.

Qdenga® - A promising dengue fever vaccine; can it be recommended to non-immune travelers?

Qdenga® has been approved by the European Medicines Agency (EMA) for individuals > 4 years of age and for use according to national recommendations. The vaccine shows high efficacy against virologically confirmed dengue and severe dengue in clinical studies on 4-16-year old's living in endemic areas. For individuals 16-60 years old only serological data exists and there is no data for individuals > 60 years. Its use as a travel vaccine is still unclear. We present the studies behind the approval and the recommendations for travelers as issued by the Swedish Society for Infectious Diseases Physicians.

An experimental porcine model of invasive candidiasis.

BACKGROUND: Invasive candidiasis (IC) is a severe and often fatal fungal infection that affects critically ill patients. The development of animal models that mimic human disease is essential for advancing our understanding of IC pathophysiology and testing experimental or novel treatments. We aimed to develop a large animal model of IC that could provide a much-needed addition to the widely used murine models. RESULTS: A total of 25 pigs (including one control), aged between 9 and 12 weeks, with a median weight of 25.1 kg (IQR 24.1-26.2), were used to develop the porcine IC model. We present the setup, the results of the experiments, and the justification for the changes made to the model. The experiments were conducted in an intensive care setting, using clinically relevant anaesthesia, monitoring and interventions. The final model used corticosteroids, repeated Candida inoculation, and continuous endotoxin. The model consistently demonstrated quantifiable growth of Candida in blood and organs. The registered physiological data supported the development of the sepsis-induced circulatory distress observed in IC patients in the ICU. CONCLUSIONS: Our proposed porcine model of IC offers a potential new tool in the research of IC.

Enhanced bacterial clearance in early secondary sepsis in a porcine intensive care model.

Early secondary sepsis (ESS), occurring after recent inflammatory activation is associated with a reduced inflammatory response. If this attenuation also is associated with decreased bacterial killing, the need for antibiotic efficacy might be greater than in primary sepsis (PS). This prospective, randomised interventional study compares bacterial killing in ESS and PS in a large animal intensive care sepsis model. 38 pigs were intravenously administered live Escherichia coli for 3 h. Before baseline ESS was pre-exposed to endotoxin 24 h, whereas PS was not. Bacterial growth was measured in organs immediately post-mortem, repeatedly during 6 h in blood in vivo and for blood intrinsic bactericidal capacity ex vivo. Splenic growth was lower in ESS animals, than in PS animals (3.31 ± 0.12, vs. 3.84 ± 0.14 log10 CFU/mL, mean ± SEM) (p < 0.01) with a similar trend in hepatic growth (p = NS). Blood bacterial count at 2 h correlated with splenic bacterial count in ESS (ESS: r = 0.71, p < 0.001) and to blood killing capacity in PS (PS: r = 0.69, p < 0.001). Attenuated inflammation in ESS is associated with enhanced antibacterial capacities in the spleen. In ESS blood bacterial count is related to splenic killing and in PS to blood bactericidal capacity. The results suggest no increased need for synergistic antibiotic combinations in ESS.

Association between variables measured in the ambulance and in-hospital mortality among adult patients with and without infection: a prospective cohort study.

BACKGROUND: Patients presenting with infection to the ambulance are common, but risk factors for poor outcome are not known. The primary aim of the current study was to study the association between variables measured in the ambulance and mortality among adult patients with and without infection. The secondary aim was to study the association between these variables and mortality in a subgroup of patients who developed sepsis within 36 h. METHODS: Prospective cohort study of 553 ambulance patients with, and 318 patients without infection, performed in Stockholm during 2017-2018. The association between 21 variables (8 keywords related to medical history, 6 vital signs, 4 blood tests, and age, gender, comorbidity) and in-hospital mortality was analysed using logistic regression. RESULTS: Among patients with infection, inability of the patient to answer questions relating to certain symptoms such as pain and gastrointestinal symptoms was significantly associated with mortality in univariable analysis, in addition to oxygen saturation < 94%, heart rate > 110 /min, Glasgow Coma Scale (GCS) < 15, soluble urokinase Plasminogen Activator Receptor (suPAR) 4.0-7.9 ng/mL, suPAR ≥ 8.0 ng/mL and a Charlson comorbidity score ≥ 5. suPAR ≥ 8.0 ng/mL remained significant in multivariable analysis (OR 25.4; 95% CI, 3.2-199.8). Among patients without infection, suPAR ≥ 8.0 ng/mL and a Charlson comorbidity score ≥ 5 were significantly associated with mortality in univariable analysis, while suPAR ≥ 8.0 ng/mL remained significant in multivariable analysis (OR 56.1; 95% CI, 4.5-700.0). Among patients who developed sepsis, inability to answer questions relating to pain remained significant in multivariable analysis (OR 13.2; 95% CI, 2.2-78.9), in addition to suPAR ≥ 8.0 ng/mL (OR 16.1; 95% CI, 2.0-128.6). CONCLUSIONS: suPAR ≥ 8.0 ng/mL was associated with mortality in patients presenting to the ambulance both with and without infection and in those who developed sepsis. Furthermore, the inability of the ambulance patient with an infection to answer questions relating to specific symptoms was associated with a surprisingly high mortality. These results suggest that suPAR and medical history are valuable tools with which to identify patients at risk of poor outcome in the ambulance and could potentially signal the need of enhanced attention. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03249597. Registered 15 August 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03249597 .

Relationship between T-cell-dependent and T-cell-independent vaccines after neurotrauma; is the B-cell response preserved?

BACKGROUND: After trauma and central nervous system (CNS) injury, trauma-induced immune deficiency syndrome (TIDS) and CNS injury-induced immune deficiency syndrome (CIDS) may negatively affect responses to T-cell-dependent vaccines, such as pneumococcal conjugate vaccine (PCV) recommended after basilar fracture. This study (NCT02806284) aimed to investigate whether there after neurotrauma is a correlation between T-cell-dependent and independent vaccine responses and, thus, if B-cell activity is similarly depressed and whether the T-cell-dependent response is possible to predict. METHODS: Adult patients with basilar fracture (n = 33) and those undergoing pituitary gland surgery (n = 23) were within 10 days vaccinated with a T-cell-dependent vaccine against Haemophilus influenzae type b (Hib) and a T-cell-independent pneumococcal polysaccharide vaccine (PPSV). Samples reflecting the systemic inflammatory response and pre- and post-vaccination antibody levels after 3-6 weeks against Hib and PPSV were collected and determined by enzyme immunoassays. RESULTS: High and significant correlations were detected in the responses to different pneumococcal serotypes, but none between the Hib and PPSV responses. No differences in trauma scores, C-reactive protein, IL-6, IL-10, pentraxin 3, fractalkine or calprotectin plasma concentrations or in ex vivo TNF-α, IL-6 or IL-10 responses to endotoxin were found between Hib vaccination responders and non-responders. CONCLUSIONS: There was no correlation between the pneumococcal responses and that to Hib, indicating that B-cell function is not similarly depressed as T-cell function. Grading of the trauma or parameters reflecting the innate immune response could not predict the T-cell-dependent vaccine response. There is a need of further studies evaluating the vaccine response after neurotrauma.

Urine Hydrogen Peroxide Levels and Their Relation to Outcome in Patients with Sepsis, Septic Shock, and Major Burn Injury.

Hydrogen peroxide (H2O2) and oxidative stress have been suggested as possible instigators of both the systemic inflammatory response and the increased vascular permeability associated with sepsis and septic shock. We measured H2O2 concentrations in the urine of 82 patients with severe infections, such as sepsis, septic shock, and infections not fulfilling sepsis-3 criteria, in patients with major burn injury with associated systemic inflammation, and healthy subjects. The mean concentrations of H2O2 were found to be lower in patients with severe infections compared to burn injury patients and healthy subjects. Patients with acute kidney injury (AKI), vs. those without AKI, in all diagnostic groups displayed higher concentrations of urine H2O2 (p < 0.001). Likewise, urine concentrations of H2O2 were higher in non-survivors as compared to survivors (p < 0.001) at day 28 in all diagnostic groups, as well as in patients with severe infections and burn injury (p < 0.001 for both). In this cohort, increased H2O2 in urine is thus associated with mortality in patients with sepsis and septic shock as well as in patients with burn injury.

T2Candida Assay in the Diagnosis of Intraabdominal Candidiasis: A Prospective Multicenter Study.

The T2Candida magnetic resonance assay is a direct-from-blood pathogen detection assay that delivers a result within 3-5 h, targeting the most clinically relevant Candida species. Between February 2019 and March 2021, the study included consecutive patients aged >18 years admitted to an intensive care unit or surgical high-dependency unit due to gastrointestinal surgery or necrotizing pancreatitis and from whom diagnostic blood cultures were obtained. Blood samples were tested in parallel with T2Candida and 1,3-ß-D-glucan. Of 134 evaluable patients, 13 (10%) were classified as having proven intraabdominal candidiasis (IAC) according to the EORTC/MSG criteria. Two of the thirteen patients (15%) had concurrent candidemia. The sensitivity, specificity, positive predictive value, and negative predictive value, respectively, were 46%, 97%, 61%, and 94% for T2Candida and 85%, 83%, 36%, and 98% for 1,3-ß-D-glucan. All positive T2Candida results were consistent with the culture results at the species level, except for one case of dual infection. The performance of T2Candida was comparable with that of 1,3-ß-D-glucan for candidemic IAC but had a lower sensitivity for non-candidemic IAC (36% vs. 82%). In conclusion, T2Candida may be a valuable complement to 1,3-ß-D-glucan in the clinical management of high-risk surgical patients because of its rapid results and ease of use.

Human plasma protein levels alter the in vitro antifungal activity of caspofungin: An explanation to the effect in critically ill?

BACKGROUND: Recent studies have shown low caspofungin concentrations in critically ill patients. In some patients, the therapeutic target, area under the total plasma concentration curve in relation to the minimal inhibition concentration (AUCtot /MIC), seems not to be achieved and therapeutic drug monitoring (TDM) has been proposed. Caspofungin is highly protein-bound and the effect of reduced plasma protein levels on pharmacodynamics has not been investigated. OBJECTIVES: Fungal killing activity of caspofungin in vitro was investigated under varying levels of human plasma protein. METHODS: Time-kill studies were performed with clinically relevant caspofungin concentrations of 1-9 mg/L on four blood isolates of C. glabrata, three susceptible and one strain with reduced susceptibility, in human plasma and plasma diluted to 50% and 25% using Ringer's acetate. RESULTS: Enhanced fungal killing of the three susceptible strains was observed in plasma with lower protein content (p < .001). AUCtot /MIC required for a 1 log10 CFU/ml kill at 24 h in 50% and 25% plasma was reduced with 36 + 12 and 80 + 9%, respectively. The maximum effect was seen at total caspofungin concentrations of 4-9 × MIC. For the strain with reduced susceptibility, growth was significantly decreased at lower protein levels. CONCLUSIONS: Reduced human plasma protein levels increase the antifungal activity of caspofungin in vitro, most likely by increasing the free concentration. Low plasma protein levels in critically ill patients with candidemia might explain a better response to caspofungin than expected from generally accepted target attainment and should be taken into consideration when assessing TDM based on total plasma concentrations.

Performance of NEWS2, RETTS, clinical judgment and the Predict Sepsis screening tools with respect to identification of sepsis among ambulance patients with suspected infection: a prospective cohort study.

BACKGROUND: There is little evidence of which sepsis screening tool to use in the ambulance setting. The primary aim of the current study was to compare the performance of NEWS2 (National Early Warning score 2) and RETTS (Rapid Emergency Triage and Treatment System) with respect to identification of sepsis among ambulance patients with clinically suspected infection. The secondary aim was to compare the performance of the novel Predict Sepsis screening tools with that of NEWS2, RETTS and clinical judgment. METHODS: Prospective cohort study of 323 adult ambulance patients with clinically suspected infection, transported to hospitals in Stockholm, during 2017/2018. The sensitivity, specificity, and AUC (Area Under the receiver operating Curve) were calculated and compared by using McNemar´s test and DeLong's test. RESULTS: The prevalence of sepsis in the current study population was 44.6% (144 of 323 patients). No significant difference in AUC was demonstrated between NEWS2 ≥ 5 and RETTS ≥ orange. NEWS2 ≥ 7 demonstrated a significantly greater AUC than RETTS red. The Predict Sepsis screening tools ≥ 2 demonstrated the highest sensitivity (range 0.87-0.91), along with RETTS ≥ orange (0.83), but the lowest specificity (range 0.39-0.49). The AUC of NEWS2 (0.73) and the Predict Sepsis screening tools (range 0.75-0.77) was similar. CONCLUSIONS: The results indicate that NEWS2 could be the better alternative for sepsis identification in the ambulance, as compared to RETTS. The Predict Sepsis screening tools demonstrated a high sensitivity and AUCs similar to that of NEWS2. However, these results need to be interpreted with caution as the Predict Sepsis screening tools require external validation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03249597. Registered 15 August 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03249597 .

Mode of bacterial killing affects the inflammatory response and associated organ dysfunctions in a porcine E. coli intensive care sepsis model.

BACKGROUND: Sepsis is often treated with penicillin-binding protein 3 (PBP-3) acting ß-lactam antibiotics, such as piperacillin-tazobactam, cefotaxime, and meropenem. They cause considerable bacterial structural changes and have in vitro been associated with an increased inflammatory response. In a clinically relevant large animal sepsis model, our primary aim was to investigate whether bacteria killed by a PBP-3-active antibiotic has a greater effect on the early inflammatory response and organ dysfunction compared with corresponding amounts of live or heat-killed bacteria. A secondary aim was to determine whether the addition of an aminoglycoside could mitigate the cefuroxime-induced response. METHOD: Killed or live Escherichia coli were administrated as a 3-h infusion to 16 healthy pigs in a prospective, randomized controlled interventional experimental study. Cefuroxime was chosen as the PBP-3-active antibiotic and tobramycin represented the aminoglycosides. The animals were randomized to receive (I) bacteria killed by cefuroxime, (II) live bacteria, (III) bacteria killed by heat, or (IV) bacteria killed by the combination of cefuroxime and tobramycin. Plasma endotoxin, tumor necrosis factor alpha, interleukin-6, interleukin-10, leukocytes, and organ function were recorded at the start of the experiment and then hourly for 6 h. RESULTS: Differences in dynamics of concentration over time between the four treatment groups were found for the three cytokines (p < 0.001). Animals receiving cefuroxime-killed bacteria demonstrated higher responses than those receiving live (p < 0.05) or heat-killed bacteria (p < 0.01). The addition of tobramycin reduced the cefuroxime-induced responses (p < 0.001). The cytokine responses were associated with leucocyte activation that was further associated with pulmonary dysfunction and increases in lactate (p < 0.01). CONCLUSIONS: In comparison with live or heat-killed bacteria, bacteria killed by a PBP-3-active antibiotic induced an increased inflammatory response that appears to be associated with deteriorated organ and cellular function. The addition of an aminoglycoside to the PBP-3-active antibiotic reduced that response.

Reactive oxygen species as an initiator of toxic innate immune responses in retort to SARS-CoV-2 in an ageing population, consider N-acetylcysteine as early therapeutic intervention.

During the current COVID-19 pandemic, a need for evaluation of already available drugs for treatment of the disease is crucial. Hereby, based on literature review from the current pandemic and previous outbreaks with corona viruses we analyze the impact of the virus infection on cell stress responses and redox balance. High levels of mortality are noticed in elderly individuals infected with SARS-CoV2 and during the previous SARS-CoV1 outbreak. Elderly individuals maintain a chronic low level of inflammation which is associated with oxidative stress and inflammatory cytokine production, a condition that increases the severity of viral infections in this population. Coronavirus infections can lead to alterations of redox balance in infected cells through modulation of NAD + biosynthesis, PARP function along with altering proteasome and mitochondrial function in the cell thereby leading to enhanced cell stress responses which further exacerbate inflammation. ROS production can increase IL-6 production and lipid peroxidation resulting in cell damage. Therefore, early treatment with anti-oxidants such as NAC during COVID-19 can be a way to bypass the excessive inflammation and cell damage that lead to severe infection, thus early NAC as intervention should be evaluated in a clinical trial setting.

The predictive value of variables measurable in the ambulance and the development of the Predict Sepsis screening tools: a prospective cohort study.

BACKGROUND: Despite sepsis being a time critical condition with a high mortality, it is often not identified in a timely fashion. The aim of the current study was to create a screening tool based on bedside measurable variables predictive of sepsis among ambulance patients with infection according to clinical judgment by ambulance personnel. METHODS: Prospective cohort study of 551 adult patients presenting with suspected infection, performed in the ambulance setting of Stockholm during 2017-2018. 18 variables were measured in the ambulance (8 keywords related to medical history, 6 vital signs, 4 point-of-care blood tests, in addition to age, gender, and comorbidity. Logistic regression, area under the curve (AUC) and classification trees were used to study the association with sepsis. The AUC, sensitivity, specificity, predictive values and likelihood ratios were used to evaluate the predictive ability of sepsis screening models. RESULTS: The six variables with the strongest association with sepsis were: systolic blood pressure ≤ 100 mmHg, temperature > 38.5 °C, GCS < 15, lactate > 4 mmol/L, gastrointestinal symptoms, and a history of acute altered mental status. These were combined into the Predict Sepsis screening tool 1, with a sensitivity of 0.90, specificity 0.41, AUC 0.77; 95% confidence interval [CI] 0.73-0.81, PPV 0.52, and NPV 0.86. Combining a history of acute altered mental status with GCS < 15 and excluding lactate in the Predict Sepsis screening tool 2 did not noticeably affect the AUC. In addition, the AUCs of these models did not differ noticeably when compared to a model including vital signs alone, with novel calculated cut-offs; the Predict Sepsis screening tool 3. CONCLUSIONS: Systolic blood pressure ≤ 100 mmHg, temperature > 38.5 °C, GCS < 15, lactate > 4 mmol/L, gastrointestinal symptoms, and a history of acute altered mental status demonstrated the strongest association with sepsis. We present three screening tools to predict sepsis with similar sensitivity. The results indicated no noticeable increase of predictive ability by including symptom-variables and blood tests to a sepsis screening tool in the current study population. TRIAL REGISTRATION: NCT03249597.

Extension of Pharmacokinetic/Pharmacodynamic Time-Kill Studies To Include Lipopolysaccharide/Endotoxin Release from Escherichia coli Exposed to Cefuroxime.

The release of inflammatory bacterial products, such as lipopolysaccharide (LPS)/endotoxin, may be increased upon the administration of antibiotics. An improved quantitative understanding of endotoxin release and its relation to antibiotic exposure and bacterial growth/killing may be gained by an integrated analysis of these processes. The aim of this work was to establish a mathematical model that relates Escherichia coli growth/killing dynamics at various cefuroxime concentrations to endotoxin release in vitro Fifty-two time-kill experiments informed bacterial and endotoxin time courses and included both static (0×, 0.5×, 1×, 2×, 10×, and 50× MIC) and dynamic (0×, 15×, and 30× MIC) cefuroxime concentrations. A model for the antibiotic-bacterium interaction was established, and antibiotic-induced bacterial killing followed a sigmoidal Emax relation to the cefuroxime concentration (MIC-specific 50% effective concentration [EC50], maximum antibiotic-induced killing rate [Emax] = 3.26 h-1 and γ = 3.37). Endotoxin release was assessed in relation to the bacterial processes of growth, antibiotic-induced bacterial killing, and natural bacterial death and found to be quantitatively related to bacterial growth (0.000292 endotoxin units [EU]/CFU) and antibiotic-induced bacterial killing (0.00636 EU/CFU). Increased release following the administration of a second cefuroxime dose was described by the formation and subsequent antibiotic-induced killing of filaments (0.295 EU/CFU). Release due to growth was instantaneous, while release due to antibiotic-induced killing was delayed (mean transit time of 7.63 h). To conclude, the in vitro release of endotoxin is related to bacterial growth and antibiotic-induced killing, with higher rates of release upon the killing of formed filaments. Endotoxin release over 24 h is lowest when antibiotic exposure rapidly eradicates bacteria, while increased release is predicted to occur when growth and antibiotic-induced killing occur simultaneously.

Etiology, clinical presentation, outcome and the effect of initial management in immunocompromised patients with community acquired bacterial meningitis.

OBJECTIVES: The aim was to analyze differences in clinical presentation, etiology, management, and outcome between immunocompromised and immunocompetent patients with acute bacterial meningitis (ABM). METHODS: Data were extracted from 1056 adult ABM patients prospectively registered in the national Swedish quality register for ABM during 2008-2017. Primary endpoint was 30-day mortality and secondary endpoints 90-day mortality and unfavorable outcome. RESULTS: An immunocompromised state was observed in 352 (33%) of the 1056 patients. Streptococcus pneumoniae dominated in both immunocompromised and immunocompetent patients (53% in both groups), whereas L monocytogenes occurred in 11% and 2%, respectively. The unadjusted odds ratio (OR) for 30-day mortality in immunocompromised compared to immunocompetent patients was 1.68 (95% confidence interval (CI): 1.07-2.63). Adjusted for age, sex, and mental status on admission the OR was 1.34 (CI: 0.82-2.21). Adjusted also for time to antibiotic treatment and corticosteroids the OR was 1.10 (CI: 0.59-2.05), and in patients without Listeria meningitis 0.98 (CI: 0.50-1.90). Although, the ORs were higher for 90-day mortality and unfavorable outcome the effects of adjustments were similar. CONCLUSION: Mortality in immunocompromised patients with ABM is only moderately increased unless caused by Listeria. This difference is further reduced in patients given early antibiotic treatment and adjunctive corticosteroids. FUNDING: This work was supported by Stockholm County Council.

Endotoxin Removal in Septic Shock with the Alteco LPS Adsorber Was Safe But Showed no Benefit Compared to Placebo in the Double-Blind Randomized Controlled Trial-the Asset Study.

PURPOSE: Lipopolysaccharides (LPS) are presumed to contribute to the inflammatory response in sepsis. We investigated if extracorporeal Alteco LPS Adsorber for LPS removal in early gram-negative septic shock was feasible and safe. Also, effects on endotoxin level, inflammatory response, and organ function were assessed. METHODS: A pilot, double-blinded, randomized, Phase IIa, feasibility clinical investigation was undertaken in six Scandinavian intensive care units aiming to allocate 32 septic shock patients with abdominal or urogenital focus on LPS Adsorber therapy or a Sham Adsorber, therapy without active LPS binding. The study treatment was initiated within 12 h of inclusion and given for 6 h daily on first 2 days. LPS was measured in all patients. RESULTS: The investigation was terminated after 527 days with eight patients included in the LPS Adsorber group and seven in the Sham group. Twenty-one adverse effects, judged not to be related to the device, were reported in three patients in the LPS Adsorber group and two in the Sham group. Two patients in the Sham group and no patients in the LPS Adsorber group died within 28 days. Plasma LPS levels were low without groups differences during or after adsorber therapy. The changes in inflammatory markers and organ function were similar in the groups. CONCLUSIONS: In a small cohort of patients with presumed gram-negative septic shock, levels of circulating endotoxin were low and no adverse effects within 28 days after LPS adsorber-treatment were observed. No benefit compared with a sham device was seen when using a LPS adsorber in addition to standard care. TRIAL REGISTRATION: Clinicaltrials.gov NCT02335723. Registered: November 28, 2014.

Meropenem versus Cefotaxime and Ampicillin as Empirical Antibiotic Treatment in Adult Bacterial Meningitis: a Quality Registry Study, 2008 to 2016.

Cefotaxime, alone or with ampicillin, is frequently used in empirical treatment of acute bacterial meningitis (ABM). Meropenem is a less extensively investigated alternative. The aim of the study was to investigate the effects of empirical treatment with meropenem compared to cefotaxime plus ampicillin on outcome in ABM. The study was based on data from the Swedish quality register for ABM collected between January 2008 and December 2016. Propensity score matching was performed to adjust for baseline differences between the groups. Mortality within 30 days was the primary outcome. The treatment regimens of interest were administered to 623 patients; 328 were given cefotaxime plus ampicillin whereas 295 received meropenem. Using propensity score matching, the 30-day mortality rates were 3.2% in the cefotaxime plus ampicillin group and 3.6% in the meropenem group. For matched cases, the odds ratio (OR) for 30-day mortality for meropenem versus cefotaxime plus ampicillin was 1.15 (confidence interval [CI], 0.41 to 3.22; P = 0.79). The OR for 90-day mortality was 1.47 (CI, 0.62 to 3.52; P = 0.38) and for unfavorable outcome was 1.10 (CI, 0.75 to 1.63; P = 0.62). The findings of our study indicate that meropenem is an effective empirical treatment option for adults with community-acquired ABM. However, to spare carbapenems, guidelines should continue to recommend third-generation cephalosporins as an empirical treatment for the majority of patients with ABM.

The impact of the systemic inflammatory response on hepatic bacterial elimination in experimental abdominal sepsis.

BACKGROUND: Bacterial translocation from the gut has been suggested to induce a systemic inflammatory response syndrome (SIRS) and organ dysfunction. The liver has a pivotal role in eliminating circulating bacteria entering from the gut. We investigated whether pre-existing inflammation affects hepatic bacterial elimination. METHODS: Fifteen anaesthetised piglets were infused with E. coli in the portal vein for 3 h. The naive group (n = 6) received the bacterial infusion without endotoxin exposure. SIRS (SIRS group, n = 6) was induced by endotoxin infusion 24 h before the bacterial infusion. For effects of anaesthesia, controls (n = 3) received saline instead of endotoxin for 24 h. Bacterial counts and endotoxin levels in the portal and hepatic veins were analysed during bacterial infusion. RESULTS: The bacterial killing rate was higher in the naive group compared with the SIRS group (p = 0.001). The ratio of hepatic to portal venous bacterial counts, i.e. the median bacterial influx from the splanchnic circulation, was 0.06 (IQR 0.01-0.11) in the naive group and 0.71 (0.03-1.77) in the SIRS group at 3 h, and a magnitude lower in the naive group during bacteraemia (p = 0.03). Similar results were seen for hepatic endotoxin elimination. Peak log tumour necrosis factor alpha was higher in the naive 4.84 (4.77-4.89) vs. the SIRS group 3.27 (3.26-3.32) mg/L (p < 0.001). CONCLUSIONS: Our results suggest that hepatic bacterial and endotoxin elimination is impaired in pigs with pre-existing SIRS while the inflammatory response to bacterial infusion is diminished. If similar mechanisms operate in human critical illness, the hepatic elimination of bacteria from the gut could be impaired by SIRS.

Cost-effectiveness analysis of isavuconazole versus voriconazole for the treatment of patients with possible invasive aspergillosis in Sweden.

BACKGROUND: Voriconazole is well established as standard treatment for invasive aspergillosis (IA). In 2017, isavuconazole, a new antifungal from the azole class, with a broader pathogen spectrum, was introduced in Sweden. A model has therefore been developed to compare the cost-effectiveness of isavuconazole and voriconazole in the treatment of possible IA in adults in Sweden. METHODS: The cost-effectiveness of isavuconazole versus voriconazole was evaluated using a decision-tree model. Patients with possible IA entered the model, with 6% assumed to actually have mucormycosis. It was also assumed that pathogen information would become available during the course of treatment for only 50% of patients, with differential diagnosis unavailable for the remainder. Patients who were considered unresponsive to first-line treatment were switched to second-line treatment with liposomal amphotericin-B. Data and clinical definitions included in the model were taken from the published randomised clinical trial comparing isavuconazole with voriconazole for the treatment of IA and other filamentous fungi (SECURE) and the single-arm, open-label trial and case-control analysis of isavuconazole for the treatment of mucormycosis (VITAL). A probabilistic sensitivity analysis was used to estimate the combined parameter uncertainty, and a deterministic sensitivity analysis and a scenario analysis were performed to test the robustness of the model assumptions. The model followed a Swedish healthcare payer perspective, therefore only considering direct medical costs. RESULTS: The base case analysis showed that isavuconazole resulted in an incremental cost-effectiveness ratio (ICER) of 174,890 Swedish krona (SEK) per additional quality adjusted life-year (QALY) gained. This was mainly due to the efficacy of isavuconazole against IA and mucormycosis, as opposed to voriconazole, which is only effective against IA. Sensitivity and scenario analyses of the data showed that the average ICER consistently fell below the willingness to pay (WTP) threshold of 1,000,000 SEK. The probability of isavuconazole being cost-effective at a WTP of 170,000 SEK per QALY gained was 50% and at a WTP of 500,000 SEK per QALY gained was 100%. CONCLUSIONS: This model suggests that the treatment of possible IA with isavuconazole is cost-effective compared with treatment with voriconazole from a Swedish healthcare payer perspective.