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  • 1.
    Angelin, Martin
    et al.
    Umeå Univ, Dept Clin Microbiol, Infect Dis, Umeå, Sweden..
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Kahn, Fredrik
    Lund Univ, Dept Clin Sci, Div Infect Med, Lund, Sweden..
    Ljunghill Hedberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Rosdahl, Anja
    Örebro Univ, Sch Med Sci, Örebro, Sweden.;Örebro Univ Hosp, Dept Infect Dis, Örebro, Sweden..
    Skorup, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Werner, Simon
    Reg Skane, Skane Univ Hosp, Dept Infect Dis, Malmö, Sweden..
    Woxenius, Susanne
    Sahlgrens Univ Hosp, Dept Infect Dis, Gothenburg, Sweden..
    Askling, Helena H.
    Karolinska Inst, Dept Med, Div Infect Dis, Solna, Sweden.;Reg Stockholm, Stockholm Cty Hlth Care Serv, Acad Specialist Ctr, Stockholm, Sweden..
    Qdenga®- A promising dengue fever vaccine; can it be recommended to non-immune travelers?2023In: Travel Medicine and Infectious Disease, ISSN 1477-8939, E-ISSN 1873-0442, Vol. 54, article id 102598Article in journal (Refereed)
    Abstract [en]

    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.

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  • 2.
    Arnell, Kai
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Cesarini, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lagerqvist-Widh, Angela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Wester, Tomas
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cerebrospinal fluid shunt infections in children over a 13-year period: anaerobic cultures and comparison of clinical signs of infection with Propionibacterium acnes and with other bacteria2008In: Journal of neurosurgery. Pediatrics, ISSN 1933-0707, Vol. 1, no 5, p. 366-72Article in journal (Refereed)
    Abstract [en]

    OBJECT: Shunt infections represent a major problem with risk for sequelae and even death. The aim in this retrospective study was to analyze the incidence, origin, and clinical presentation of shunt infections, with special reference to the results of cultures for anaerobic organisms performed in addition to the usual tests, to prolonged incubation times, and to infections caused by Propionibacterium acnes. METHODS: The medical records of 237 hydrocephalic children (age range 0-15 years) in whom operations were performed by a pediatric surgeon at Uppsala University Hospital during a 13-year period were reviewed. RESULTS: Thirty-four verified or suspected intraventricular shunt infections and 5 distal catheter infections occurred after 474 operations. Skin bacteria, such as coagulase-negative staphylococci ([CoNS], 19 patients), Staphylococcus aureus (7 patients), and P. acnes (6 patients) predominated. The addition of anaerobic cultures and prolonged incubation times increased the verification of shunt infection by more than one third. Children with P. acnes infection were significantly older, had a lower body temperature, fewer cerebrospinal fluid (CSF) leukocytes, a higher CSF/blood glucose ratio, more distal catheter infections, and other sources of infection. Four had an abdominal pseudocyst. Children < 1 year of age and infected with CoNS were more affected than older children with systemic and local symptoms. In children with distal catheter infection and growth of propionibacteria at the time of the distal catheter and valve replacement, no follow-up antibiotic treatment was necessary. CONCLUSIONS: Addition of anaerobic cultures and prolonged incubation times led to an increase in the detection of shunt infections. Infections caused by propionibacteria often result in mild symptoms that may be overlooked if adequate anaerobic cultures are not obtained.

  • 3.
    Arnell, Kai
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Wester, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Treatment of cerebrospinal fluid shunt infections in children using systemic and intraventricular antibiotic therapy in combination with externalization of the ventricular catheter: efficacy in 34 consecutively treated infections2007In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 107, no 3, p. 213-219Article in journal (Refereed)
    Abstract [en]

    OBJECT: There are no randomized studies comparing the efficacy of different antibiotic regimens for the treatment of cerebrospinal fluid (CSF) shunt infections, and in the studies that have been reported, efficacy data are limited. The aim of this study was therefore to report the authors' experience using a specific protocol for the management of shunt infections in children. Standard treatment included a two-stage procedure involving externalization of the ventricular catheter in combination with intraventricular and systemic administration of antibiotic medication followed by shunt replacement. Intraventricular treatment consisted of daily instillations of vancomycin or gentamicin with trough concentrations held at high levels of 7 to 17 mg/L for both antibiotic agents. METHODS: During a 13-year study period, the authors treated 34 consecutive intraventricular shunt infections in 30 children. Infections with coagulase-negative staphylococci predominated, and Gram-negative bacterial infection occurred in five children. Ten of the children were initially treated with intravenous antibiotic therapy for at least 3 days, but this treatment did not sterilize the CSF. After externalization of the ventricular catheter, high-dose intraventricular treatment was given for a median of 8 days (range 3-17 days) before shunt replacement. RESULTS: The CSF was found to be sterile (cultures were negative for bacteria) in one of three, seven of eight, 20 of 20, and six of six cases after 1, 2, 3, and more than 3 days' treatment, respectively. In no case was any subsequent culture positive after a negative result had been obtained. Clinical symptoms resolved in parallel with the sterilization of the CSF. There were no relapses or deaths during the 6-month follow-up period, and there have been none as of April 2007. CONCLUSIONS: Despite the ventricular catheter being left in place and the short duration of therapy, the treatment regimen described by the authors resulted in quick sterilization of the CSF, a low relapse rate, and survival of all patients in this series.

  • 4.
    Brink, Magnus
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Infect Dis, Gothenburg, Sweden;Sahlgrens Univ Hosp, Dept Infect Dis, Gothenburg, Region Vastra G, Sweden.
    Glimåker, Martin
    Karolinska Inst, Dept Med, Div Infect Dis, Solna, Sweden;Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Naucler, Pontus
    Karolinska Inst, Dept Med, Div Infect Dis, Solna, Sweden;Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden.
    Meropenem versus Cefotaxime and Ampicillin as Empirical Antibiotic Treatment in Adult Bacterial Meningitis: a Quality Registry Study, 2008 to 20162019In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 63, no 11, article id e00883-19Article in journal (Refereed)
    Abstract [en]

    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.

  • 5.
    Carlsson, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Tano, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Eriksson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Inflammatory and circulatory effects of the reduction of endotoxin concentration in established porcine endotoxemic shock: a model of endotoxin elimination2009In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 37, no 3, p. 1031-e4Article in journal (Refereed)
    Abstract [en]

    Objective:

    To study whether a reduction of the endotoxin load, once a generalized inflammatory state has been established, reduces the inflammatory response and endotoxin-induced effects on circulation, hypoperfusion, and organ dysfunction.

    Design:

    Prospective parallel-grouped placebo-controlled randomized interventional experimental study.

    Setting:

    University research unit.

    Subjects:

    Healthy pigs.

    Interventions:

    The animals were subjected to a continuous endotoxin infusion rate of either 4.0 or 0.063 µg endotoxin × kg-1 × h-1 for 1, 2, or 6 hours. The 1- and 2-hour infusion groups represented the applied therapy by a reduction of the endotoxin load of 5/6 and 2/3, respectively.

    Measurements and Main Results:

    During a 6-hour experiment, laboratory and physiologic parameters were recorded hourly in 26 anesthetized and mechanically ventilated pigs. Primary end point was to detect differences in tumor necrosis factor-[alpha] (TNF-[alpha]) concentration during the last 3 hours of the experiment. Despite the early reduction of the endotoxin load, no effect on TNF-[alpha] concentration was observed. Similarly, in circulatory parameters, such as mean arterial pressure and oxygen delivery, and in platelet count and renal function, no effects were noted. However, there was some improvement in pulmonary compliance and function as determined by Pao2, Paco2, and pH. These changes were associated with slight improvements in leukocyte response and capillary leakage.

    Conclusions:

    Termination of the endotoxin infusion represents an incontestable model of endotoxin concentration reduction. Endotoxin elimination strategies applied at the TNF-[alpha] peak or later will have very little or no effect on TNF-[alpha]–mediated toxicity. Nevertheless, there was an effect on the leukocyte response that was associated with an improvement in respiratory function and microcirculation, making it impossible to rule out fully the beneficial effect of this strategy. However, the effects were limited in relation to the magnitude of the endotoxin concentration reduction and the very early application of the antiendotoxin measure.

  • 6.
    Castegren, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Jonasson, Mikaela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research Sörmland.
    Castegren, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research Sörmland.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Initial levels of organ failure, microbial findings and mortality in intensive care-treated primary, secondary and tertiary sepsis2015In: Critical Care and Resuscitation, ISSN 1441-2772, Vol. 17, no 3, p. 174-181Article in journal (Refereed)
    Abstract [en]

    Objective: Analysis of whether patients with primary, secondary and tertiary sepsis, defined by the presence or absence of recent systemic inflammation-inducing events before the onset of sepsis, differ in clinical presentation, microbiological test results, treatment received and outcome. Design, setting and participants: A retrospective observational study in a single, general intensive care unit, of all patients treated for severe sepsis or septic shock from 2006 to 2011. Patients with haematological malignancies, with immunosuppressive diseases or being treated with immunosuppressive drugs were excluded. Interventions: None. Main outcome measures: Sequential Organ Failure Assessment score, incidence of organ failure, microbiological results of blood cultures and mortality. Results: We included 213 patients, who were classified as having primary (n = 121), secondary (n = 65) or tertiary sepsis (n = 27). The groups differed significantly in SOFA score, the incidence of kidney failure and coagulation failure at onset of sepsis in the ICU, as well as in blood culture findings. No differences in 7-day or 28-day mortality were seen, but the time of death occurred earlier among non-survivors in the primary sepsis group. Conclusions: Inflammatory insults before the onset of sepsis affect the clinical picture, blood microbial findings, and in non-survivors, the time of death. These results could, if validated in a prospective study, form a basis for a novel and simple strategy for stratifying patients in clinical studies for immunomodulation therapies in sepsis.

  • 7.
    Castegren, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i D län (CKFD).
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Söderberg, Ewa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Skorup, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Eriksson, Mats
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Differences in Organ Dysfunction in Endotoxin Tolerant Pigs Under Intensive Care Exposed to a Second Hit of Endotoxin2012In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 37, no 5, p. 501-510Article in journal (Refereed)
    Abstract [en]

    Endotoxin tolerance is a well-studied phenomenon associated with a reduced inflammatory response. In the switch from an inflammatory to an anti-inflammatory response in clinical sepsis the concept of endotoxin tolerance is of obvious interest. However, only limited data exist regarding the effect of endotoxin tolerance on organ dysfunction and, therefore, this was investigated in a porcine intensive care sepsis model. Twenty-seven healthy pigs, including nine control animals, were included in the study. Twelve pigs pre-exposed to 24 h of intravenous endotoxin infusion and intensive care and six unexposed pigs were given either a high- or low-dose endotoxin challenge for 6 h. Inflammatory, circulatory, hypoperfusion and organ dysfunction parameters were followed. The inflammatory responses as well as parameters representing circulation, hypoperfusion, cardiac and renal function were all markedly attenuated in animals pre-exposed to endotoxin and intensive care as compared with animals not pre-exposed. In animals pre-exposed to endotoxin and given the high-dose of endotoxin challenge, deterioration in pulmonary function was equal to or even worse than in animals not pre-exposed.In contrast to the overall protective effect of endotoxin tolerance observed in other organ systems, the lungs of endotoxin tolerant animals demonstrated an increased responsiveness to high-dose endotoxin challenge.

  • 8.
    Castegren, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i D län (CKFD).
    Skorup, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Endotoxin tolerance variation over 24 h during porcine endotoxemia: association to changes in circulation and organ dysfunction2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 1, p. e53221-Article in journal (Refereed)
    Abstract [en]

    Endotoxin tolerance (ET), defined as reduced inflammatory responsiveness to endotoxin challenge following a first encounter with endotoxin, is an extensively studied phenomenon. Although reduced mortality and morbidity in the presence of ET has been demonstrated in animal studies, little is known about the temporal development of ET. Further, in acute respiratory distress syndrome ET correlates to the severity of the disease, suggesting a complicated relation between ET and organ dysfunction. Eighteen pigs were subjected to intensive care and a continuous endotoxin infusion for 24 h with the aim to study the time course of early ET and to relate ET to outcome in organ dysfunction. Three animals served as non-endotoxemic controls. Blood samples for cytokine analyses were taken and physiological variables registered every third hour. Production of TNF-α, IL-6, and IL-10 before and after endotoxin stimulation ex vivo was measured. The difference between cytokine values after and before ex vivo LPS stimulation (Δ-values) was calculated for all time points. ΔTNF-α was employed as the principal marker of ET and lower ΔTNF-α values were interpreted as higher levels of ET. During endotoxin infusion, there was suppression of ex vivo productions of TNF-α and IL-6 but not of IL-10 in comparison with that at 0 h. The ex vivo TNF-α values followed another time concentration curve than those in vivo. ΔTNF-α was at the lowest already at 6 h, followed by an increase during the ensuing hours. ΔTNF-α at 6 h correlated positively to blood pressure and systemic vascular resistance and negatively to cardiac index at 24 h. In this study a temporal variation of ET was demonstrated that did not follow changes in plasma TNF-α concentrations. Maximal ET occurred early in the course and the higher the ET, the more hyperdynamic the circulation 18 h later.

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  • 9. Chryssanthou, Erja
    et al.
    Loebig, Alissha
    Sjölin, Jan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Post-antifungal effect of amphotericin B and voriconazole against germinated Aspergillus fumigatus conidia2008In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 61, no 6, p. 1309-11Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The post-antifungal effect (PAFE) of amphotericin B and voriconazole on germinated Aspergillus fumigatus conidia was studied using the BacT/Alert detection system based on fungal CO(2) production. METHODS: Germinated conidia of A. fumigatus were exposed to 1-10x MIC of amphotericin B for 1 and 4 h and to 2.5-40x MIC of voriconazole for 4 and 24 h. After removal of the drug by washing, similar numbers of exposed and control germlings were inoculated into Pedi-BacT culture bottles. CO(2) production was automatically monitored until the bottles signalled positive. The difference in time for positive signals in drug-exposed and control bottles was used to calculate the PAFE. RESULTS: The killing rate of amphotericin B against germlings was both concentration- and time-dependent, as has been previously found for actively growing hyphae. Similarly, voriconazole showed fungicidal effect after 24 h of exposure, but not after 4 h. Amphotericin B induced a long concentration- and time-dependent PAFE, whereas voriconazole resulted in a short and dose-independent PAFE that was significantly longer after 24 h than after 4 h of exposure. CONCLUSIONS: An automated method is presented for the determination of PAFE on filamentous fungi using quantifiable numbers of germinated conidia. In contrast to previous results obtained from conidia, this method could demonstrate a PAFE of amphotericin B on Aspergillus that shared characteristics similar to that on Candida spp.

  • 10.
    Edberg, M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Furebring, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Neurointensive care of patients with severe community-acquired meningitis2011In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 55, no 6, p. 732-739Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Reports about neurointensive care of severe community-acquired meningitis are few. The aims of this retrospective study were to review the acute clinical course, management and outcome in a series of bacterial meningitis patients receiving neurointensive care.

    METHODS:

    Thirty patients (median age 51, range 1-81) admitted from a population of 2 million people during 7 years were studied. The neurointensive care protocol included escalated stepwise treatment with mild hyperventilation, cerebrospinal fluid (CSF) drainage, continuous thiopentotal infusion and decompressive craniectomy. Clinical outcome was assessed using the Glasgow outcome scale.

    RESULTS:

    Twenty-eight patients did not respond to commands on arrival, five were non-reacting and five had dilated pupils. Twenty-two patients had positive CSF cultures: Streptococcus pneumoniae (n=18), Neisseria meningitidis (n=2), β-streptococcus group A (n=1) and Staphylococcus aureus (n=1). Thirty-five patients were mechanically ventilated. Intracranial pressure (ICP) was monitored in 28 patients (intraventricular catheter=26, intracerebral transducers=2). CSF was drained in 15 patients. Three patients received thiopentothal. Increased ICP (>20 mmHg) was observed in 7/26 patients with available ICP data. Six patients died during neurointensive care: total brain infarction (n=4), cardiac arrest (n=1) and treatment withdrawal (n=1). Seven patients died after discharge, three due to meningitis complications. At follow-up, 14 patients showed good recovery, six moderate disability, two severe disability and 13 were dead.

    CONCLUSION:

    Patients judged to have severe meningitis should be admitted to neurointensive care units without delay for ICP monitoring and management according to modern neurointensive care principles.

  • 11. Ericsson, J.
    et al.
    Chryssanthou, E.
    Klingspor, L.
    Johansson, A. G.
    Ljungman, P.
    Svensson, E.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Candidaemia in Sweden: a nationwide prospective observational survey2013In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 19, no 4, p. E218-E221Article in journal (Refereed)
    Abstract [en]

    A prospective observational nationwide investigation was performed from September 2005 to August 2006 to study the epidemiology of candidaemia in Sweden. From 385 patients, 403 isolates were recovered, yielding an incidence of 4.2 cases per 100000 inhabitants. Candida albicans was the most common species (61%), followed by Candida glabrata (20%) and Candida parapsilosis (9%). The rates of resistance to fluconazole were 1% in C.albicans and 629% in non-albicans species other than C.glabrata and Candida krusei. Resistance to voriconazole was rare, except for C.glabrata and C.krusei. Only three isolates had reduced susceptibility to amphotericinB, and one had reduced susceptibility to caspofungin.

  • 12.
    Eriksson, Britt-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Nya rekommendationer för akut faryngotonsillit kan leda felRisk att patienter inte får nödvändig antibiotikabehandling: [New recommendations for acute pharyngotonsillitis can cause errors. There is a risk that patients will not receive proper antibiotic treatment].2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 3-4, p. 86-88Article in journal (Refereed)
    Abstract [sv]

    Akut faryngotonsillit är en av de vanligaste anledningarna till besök i öppen vård. 

    Cirka en tredjedel av fallen orsakas av bakterier, vanligen betahemolytiska streptokocker grupp A, men även grupp C och G förekommer. På senare år har Fusobacterium necrophorum uppmärksammats som en vanlig orsak, framför allt i åldersgruppen 16–30 år. 

    Akut faryngotonsillit kan ibland leda till allvarliga lokala eller generella komplikationer.

    Nuvarande svenska rekommendationer riskerar medföra att vissa patienter inte får erforderlig antibiotikabehandling.

  • 13.
    Floros, Lefteris
    et al.
    Covance Market Access, London, England.
    Kuessner, Daniel
    Basilea Pharmaceut Int Ltd, Basel, Switzerland.
    Posthumus, Jan
    Basilea Pharmaceut Int Ltd, Basel, Switzerland.
    Bagshaw, Emma
    Covance Market Access, London, England.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cost-effectiveness analysis of isavuconazole versus voriconazole for the treatment of patients with possible invasive aspergillosis in Sweden2019In: BMC Infectious Diseases, E-ISSN 1471-2334, Vol. 19, article id 134Article in journal (Refereed)
    Abstract [en]

    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.

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  • 14.
    Furebring, M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Håkansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Venge, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Klinisk kemi.
    Sjölin, J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    C5a, interleukin-8 and tumour necrosis factor-alpha-induced changes in granulocyte and monocyte expression of complement receptors in whole blood and on isolated leukocytes.2006In: Scand J Immunol, ISSN 0300-9475, Vol. 63, no 3, p. 208-16Article in journal (Refereed)
  • 15.
    Furebring, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Håkansson, Lena Douhan
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Expression of the C5a receptor (CD88) on granulocytes and monocytes in patients with severe sepsis2002In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 6, no 4, p. 363-370Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Treatment of patients with severe sepsis with agents antagonising the effects of C5a has been proposed based on beneficial effects in animal experiments and in vitro studies demonstrating upregulation of the C5a receptor (CD88) on granulocytes by endotoxin.

    MATERIALS AND METHODS: CD88 expression on leukocytes from 12 patients with severe sepsis or septic shock was analysed by flow cytometer, and serum complement factors C3a and C5b-9 were measured by enzyme immunoassay techniques.

    RESULTS: The granulocyte CD88 expression on day 1 was lowered (36; range, 2-59) in comparison with controls (63; range, 25-88) (P < 0.001), despite complement activation, while the monocyte CD88 expression was unchanged. The receptor reduction correlated significantly to the APACHE II score (r2 = 0.35, P < 0.05). The recovery of CD88 expression was slow.

    DISCUSSION: In contrast to the findings in animals, it is concluded that granulocyte CD88 expression is reduced at the time when the diagnosis of severe sepsis or septic shock can clinically be made. The reason for this needs further investigation but it may be due to a previous complement activation or to cytokine effects.

  • 16.
    Furebring, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Håkansson, Lena
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Differential expression of the C5a receptor and complement receptors 1 and 3 after LPS stimulation of neutrophils and monocytes2004In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 60, no 5, p. 494-499Article in journal (Refereed)
    Abstract [en]

    Animal experiments recently suggested that administration of anti-C5a, anti-C5a receptor or soluble complement receptor type-1 may be of value in the treatment of septic shock. Because results regarding C5a receptor expression (C5a-R, CD-88) have been found to differ between septic animals and patients, the aim of this study was to investigate the neutrophil and monocyte receptor expression of CD-88 and complement receptor-1 (CR-1, CD-35) after stimulation with lipopolysaccharide (LPS) ex vivo. Whole blood or isolated neutrophils and monocytes from healthy people were incubated with LPS in a dose range of 0.1-1000 ng/ml. The expressions of CD-88 and CD-35 were analysed by means of flow cytometry. For comparison, the expressions of complement receptor-3 (CR-3, CD-11b/CD-18), Fc-gamma receptor type-I (CD-64) and CEACAM-8 (CD-66b) were also investigated. In whole blood, CD-88 expression on neutrophils was reduced (P < 0.05). The expressions of CD-35 and CD-11b were increased both on neutrophils (P < 0.001; P < 0.05) and on monocytes (P < 0.001; P < 0.001). No effect was observed on isolated cells. In agreement with the findings in septic patients, LPS reduced the neutrophil C5a-R expression, whereas the expressions of CR-1 and CR-3 were increased. The effects of LPS were indirect and were mediated via factors in the blood. The clinical significance of this is not known, but may be associated with decreased chemotaxis.

  • 17. Glimaker, Martin
    et al.
    Johansson, Bibi
    Bell, Max
    Ericsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Blackberg, Jonas
    Brink, Magnus
    Lindquist, Lars
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Early lumbar puncture in adult bacterial meningitis-rationale for revised guidelines2013In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 9, p. 657-663Article, review/survey (Refereed)
    Abstract [en]

    Current international guidelines recommend cerebral computerized tomography (CT) before lumbar puncture (LP) in many adults with suspected acute bacterial meningitis (ABM), due to concern about LP-induced cerebral herniation. Despite guideline emphasis on early treatment based on symptoms, performing CT prior to LP implies a risk of delayed ABM treatment, which may be associated with a fatal outcome. Firm evidence for LP-induced herniation in adult ABM is absent and brain CT cannot discard herniation. Thus, the recommendation to perform CT before LP may contribute to an avoidable delay of LP and ABM treatment. The inappropriate use of the diagnostic treatment sequence of brain CT scan, followed by LP, followed by antibiotics and corticosteroids should be avoided in adults with suspected ABM by omitting needless contraindications for LP, thus eliminating an unnecessary fear of immediate LP. Revised Swedish guidelines regarding early LP are presented, and the background documentation and reasons for omitting impaired consciousness, new onset seizures, and immunocompromised state as contraindications to LP are discussed.

  • 18. Glimaker, Martin
    et al.
    Johansson, Bibi
    Grindborg, Orjan
    Bottai, Matteo
    Lindquist, Lars
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Adult Bacterial Meningitis: Earlier Treatment and Improved Outcome Following Guideline Revision Promoting Prompt Lumbar Puncture2015In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 60, no 8, p. 1162-1169Article in journal (Refereed)
    Abstract [en]

    Background. In suspected acute bacterial meningitis (ABM), cerebral computerized tomography (CT) is recommended before lumbar puncture (LP) if mental impairment. Despite guideline emphasis on early treatment, performing CT prior to LP implies a risk of delayed treatment and unfavorable outcome. Therefore, Swedish guidelines were revised in 2009, deleting impaired mental status as a contraindication for LP without prior CT scan. The aim of the present study was to evaluate the guideline revision. Methods. The Swedish quality registry for community-acquired ABM was analyzed retrospectively. Door-to-antibiotic time and outcome were compared among patients treated 2005-2009 (n = 394) and 2010-2012 (n = 318). The effect of different LP-CT sequences was analyzed during 2008-2012. Results. Adequate treatment was started 1.2 hours earlier, and significantly more patients were treated <2 hours from admission 2010-2012 than 2005-2009. Compared with CT before LP, immediate LP resulted in 1.6 hours earlier treatment, significant increase in door-to-antibiotic times of <1 and <2 hours, and a favorable outcome. In 2010-2012, mortality was lower (6.9% vs 11.7%) and the risk of sequelae at follow-up decreased (38% vs 49%) in comparison with 2005-2009. Treatment delay resulted in a significantly increased risk for fatal outcome, with a relative increase in mortality of 12.6% per hour of delay. Conclusions. The deletion of impaired mental status as contraindication for prompt LP and LP without prior CT scan are associated with significantly earlier treatment and a favorable outcome. A revision of current international guidelines should be considered.

  • 19. Glimaker, Martin
    et al.
    Johansson, Bibi
    Grindborg, Orjan
    Bottai, Matteo
    Lindquist, Lars
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Reply to Brouwer and van de Beek: Earlier Treatment and Improved Outcome in Adult Bacterial Meningitis Following Guideline Revision Promoting Prompt Lumbar Puncture Reply2015In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 61, no 4, p. 665-666Article in journal (Refereed)
  • 20.
    Glimaker, Martin
    et al.
    Karolinska Inst, Dept Med, Unit Infect Dis, S-17176 Stockholm, Sweden;Karolinska Univ Hosp, Dept Infect Dis, S-17176 Stockholm, Sweden.
    Naucler, Pontus
    Karolinska Inst, Dept Med, Unit Infect Dis, S-17176 Stockholm, Sweden;Karolinska Univ Hosp, Dept Infect Dis, S-17176 Stockholm, Sweden.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Etiology, clinical presentation, outcome and the effect of initial management in immunocompromised patients with community acquired bacterial meningitis2020In: Journal of Infection, ISSN 0163-4453, E-ISSN 1532-2742, Vol. 80, no 3, p. 291-297Article in journal (Refereed)
    Abstract [en]

    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.

  • 21.
    Glimåker, M.
    et al.
    Karolinska Inst, Infect Dis Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Infect Dis, S-17176 Stockholm, Sweden..
    Brink, M.
    Sahlgrens Univ Hosp, Inst Biomed, Dept Infect Dis, Gothenburg, Sweden..
    Naucler, P.
    Karolinska Inst, Infect Dis Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Infect Dis, S-17176 Stockholm, Sweden..
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Betamethasone and dexamethasone in adult community-acquired bacterial meningitis: a quality registry study from 1995 to 20142016In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 22, no 9, p. 814.e1-814.e7Article in journal (Refereed)
    Abstract [en]

    Acute bacterial meningitis (ABM) is a highly lethal disease. Available data support the use of corticosteroids in high-income countries, but the effect on mortality is still controversial. The effects of corticosteroids on mortality and sequelae were evaluated in the national Swedish quality registry. In total, during 1995-2014 1746 adults with ABM were included, of whom 989 were treated with corticosteroids (betamethasone, n = 766; dexamethasone, n = 248; methylprednisolone, n = 2), 498 were not given corticosteroids and in 259 patients data for corticosteroids were missing. Fatal outcome was observed in 8.9% of the patients in the corticosteroid-treated group vs. 17.9% in the non-corticosteroid-treated group (p < 0.001), resulting in an odds ratio (OR) of 0.57 with a 95% confidence interval (CI) of 0.40-0.81 adjusted for age, sex, mental status, and door-to-antibiotic time. In patients with meningitis caused by S. pneumoniae, mortality was 10.2% in the corticosteroid-treated group and 21.3% in the noncorticosteroid-treated group (p < 0.001) with an adjusted OR of 0.50 (95% CI 0.31-0.80). In ABM patients with non-pneumococcal aetiology the adjusted OR was 0.71 (95% CI 0.40-1.26). Lower mortality was observed in the corticosteroid-treated group with impaired mental status, whereas no significant difference was found in patients with unaffected mental status. The adjusted ORs for betamethasone and dexamethasone were 0.49 (95% CI 0.28-0.84) and 0.61 (95% CI 0.37-1.01), respectively. Corticosteroid treatment decreases mortality in ABM and should be administered initially with antibiotics in adult ABM patients with impaired mental status regardless of presumed aetiology. Betamethasone seems to be at least as effective as dexamethasone.

  • 22. Glimåker, Martin
    et al.
    Lindquist, Lars
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lumbar puncture in adult bacterial meningitis: time to reconsider guidelines?2013In: The BMJ, E-ISSN 1756-1833, Vol. 346, article id f361Article in journal (Refereed)
  • 23.
    Glimåker, Martin
    et al.
    Karolinska Inst, Dept Med, Infect Dis Unit, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lumbar Puncture Is Safe in Bacterial Meningitis: Impaired Mental Status Alone Does Not Motivate Cranial Computed Tomography Before Lumbar Puncture2019In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 68, no 1, p. 168-168Article in journal (Other academic)
  • 24. Glimåker, Martin
    et al.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Åkesson, Styrbjörn
    Naucler, Pontus
    Lumbar Puncture Performed Promptly or After Neuroimaging in Acute Bacterial Meningitis in Adults: A Prospective National Cohort Study Evaluating Different Guidelines.2018In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 66, no 3, p. 321-328Article in journal (Refereed)
    Abstract [en]

    Background: Early treatment is pivotal for favorable outcome in acute bacterial meningitis (ABM). Lumbar puncture (LP) is the diagnostic key. The aim was to evaluate the effect on outcome of adherence to European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), and Swedish guidelines regarding neuroimaging before LP.

    Methods: The cohort comprised 815 adult ABM patients in Sweden registered prospectively between 2008 and 2015. Primary endpoint was in-hospital mortality and secondary endpoint was favorable outcome at 2-6 months of follow-up.

    Results: Indications for neuroimaging before LP existed in 7%, 32%, and 65% according to Swedish, ESCMID, and IDSA guidelines, respectively. The adjusted odds ratio (aOR) was 0.48 (95% confidence interval [CI], .26-.89) for mortality and 1.52 (95% CI, 1.08-2.12) for favorable outcome if Swedish guidelines were followed. ESCMID guideline adherence resulted in aOR of 0.68 (95% CI, .38-1.23) for mortality and 1.05 (95% CI, .75-1.47) for favorable outcome. Following IDSA recommendations resulted in aOR of 1.09 (95% CI, .61-1.95) for mortality and 0.59 (95% CI, .42-.82) for favorable outcome. Performing prompt vs neuroimaging-preceded LP was associated with aOR of 0.38 (95% CI, .18-.77) for mortality and 2.11 (95% CI, 1.47-3.00) for favorable outcome. The beneficial effect of prompt LP was observed regardless of mental status and immunosuppression.

    Conclusions: Adherence to Swedish guidelines in ABM is associated with decreased mortality and increased favorable outcome in contrast to adherence to ESCMID or IDSA recommendations. Our findings support that impaired mental status and immunocompromised state should not be considered indications for neuroimaging before LP in patients with suspected ABM.

  • 25.
    Goscinski, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Eriksson, Mats B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tano, Eva
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Anti-inflammatory effects of the antibiotics ceftazidime and tobramycin in porcine endotoxin shock: are they really anti-inflammatory? Authors' response.2004In: Crit Care, ISSN 1466-609X, Vol. 8, no 2, p. 141-Article in journal (Other academic)
  • 26.
    Goscinski, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Eriksson, Mats B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tano, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Endotoxin neutralisation and anti-inflammatory effects by tobramycin and ceftazidime in porcine endotoxic shock2003In: Cricical Care, Vol. Suppl2, p. 125-Article in journal (Refereed)
  • 27. Goscinski, Gunilla
    et al.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Eriksson, Mats B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Tano, Eva
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Endotoxin neutralization and anti-inflammatory effects of tobramycin and ceftazidime in porcine endotoxin shock2004In: Critical care, ISSN 1364-8535, Vol. 8, no 1, p. 35-41Article in journal (Refereed)
  • 28.
    Goscinski, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tano, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Propensity to release endotoxin after two repeated doses of cefuroxime in an in vitro kinetic model: Higher release after the second dose2007In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 60, no 2, p. 328-333Article in journal (Refereed)
    Abstract [en]

    Objectives: To study endotoxin release from two strains of Escherichia coli after exposure to two repeated doses of cefuroxime in an in vitro kinetic model.

    Methods: Cefuroxime in concentrations simulating human pharmacokinetics was added to the bacterial solution with a repeated dose after 12 h. In another experiment, tobramycin was given concomitantly with the second dose of cefuroxime. Samples for viable counts and endotoxin analyses were drawn before the addition of antibiotics and at 2 and 4 h after each dose.

    Results: The propensity to release endotoxin, expressed as log10 endotoxin release (EU)/log10 killed bacteria, was higher after the second than after the first dose, 0.80 ± 0.04 and 0.65 ± 0.01, respectively, in the ATCC strain and 0.80 ± 0.04 and 0.65 ± 0.02, respectively, in the clinical strain (P < 0.001). Endotoxin was released earlier after the second dose (P < 0.001). Addition of tobramycin at the second dose reduced the endotoxin release in comparison with that of cefuroxime alone (P < 0.001).

    Conclusions: The propensity to liberate endotoxin is higher after the second dose of cefuroxime than after the first, resulting in a higher release of endotoxin than expected from bacterial count. The release after the second dose can be reduced by the addition of tobramycin.

  • 29.
    Goscinski, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tano, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Thulin, Pontus
    Norrby-Teglund, Anna
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Release of SpeA from Streptococcus pyogenes after exposure to penicillin: dependency on dose and inhibition by clindamycin2006In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 38, no 11-12, p. 983-987Article in journal (Refereed)
    Abstract [en]

    The amount and time course of SpeA release from group A streptococci (GAS) was studied at different starting inoculae after exposure to different doses of penicillin, clindamycin or a combination of the 2. The release was related to the bacterial concentration and killing rate. A clinical GAS strain was exposed to benzylpenicillin, 2 and 1000 × MIC, clindamycin, 2 and 32 × MIC, or combinations of the 2. Samples for viable counts and SpeA analyses were drawn before and after the addition of antibiotics and at 3, 6 and 24 h. The SpeA release was higher at low than at high concentrations of penicillin and the combination (both, p < 0.05). The addition of clindamycin to penicillin reduced SpeA production at both concentrations (p < 0.01). Most SpeA was released before 3 h, and for penicillin and the combination, the amount correlated to the number of killed bacteria during this period (r = 0.50; p < 0.05). A positive correlation was found between the inoculum size and the SpeA concentration at time zero (r = 0.54; p < 0.05). The SpeA concentration was dependent on the initial number of bacteria, the class of antibiotic, the dose of penicillin and the killing rate.

  • 30. Grindborg, O.
    et al.
    Naucler, P.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Glimaker, M.
    Adult bacterial meningitis-a quality registry study: earlier treatment and favourable outcome if initial management by infectious diseases physicians2015In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 21, no 6, p. 560-566Article in journal (Refereed)
    Abstract [en]

    Acute bacterial meningitis (ABM) is challenging for the admitting physician because it is a rare but fulminant disease, usually presenting without typical symptoms, and rapid treatment is pivotal. The purpose of this study was to evaluate the effect of initial management by infectious diseases (ID) physicians vs. non-ID physicians. A total of 520 consecutive adults (>17 years old), 110 with initial ID management and 410 with non-ID management, registered in the Swedish quality registry for community-acquired ABM January 2008 to December 2013, were analysed retrospectively. Primary outcome was appropriate treatment with antibiotics and corticosteroids <1 hour from admission. Secondary analyses were mortality during hospital stay and persisting neurological and hearing deficits at follow-up after 2 to 6 months. Differences in diagnostic treatment sequences also were analysed. Appropriate treatment <1 hour from admission was achieved, significantly more often (41%) by ID physicians vs. non-ID physicians (24%) with an odds ratio (OR) of 2.4 (95% confidence interval [CI]: 1.40 to 4.14; p < 0.01) adjusted for confounders. The door-to-antibiotic time was significantly shorter, and significantly more patients were administered corticosteroids together with the first doses of antibiotics in the ID group. A trend of decreased mortality (4.5% vs. 8.0%) and sequelae at follow-up (24% vs. 44%; adjusted OR 0.55: 95% CI 0.31 to 1.00; p 0.05) were observed in the ID group vs. the non-ID group. Antibiotics were started without prior neuroimaging more often in the ID group (86% vs. 57%; p < 0.001). Initial management at the emergency department by ID physicians is associated with earlier appropriate treatment, more appropriate diagnostic treatment sequences and favourable outcome.

  • 31. Gårdlund, Bengt
    et al.
    Cronqvist, Jonas
    Follin, Per
    Furebring, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Gille-Johnson, Patrik
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Svår sepsis och septisk chock kräver omedelbart omhändertagande: [Severe sepsis and septic shock require immediate care]2011In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 108, no 6, p. 271-275Article in journal (Refereed)
    Abstract [en]

    Severe sepsis and septic shock are life threatening conditions that require immediate medical attention. Such patients must be given highest priority in the health care system in a similar way that multitrauma and myocardial infarction are given today. During the first 24 h, the condition may deteriorate and after the initial resuscitation, the patient must be observed and monitored for vital functions and matched against the treatment goals. Severe sepsis and septic shock may occur within all medical and surgical specialities. Increased awareness of how elusive this condition may appear and of the necessity for prompt care is needed among all healthcare professionals.

  • 32. Hanberger, Håkan
    et al.
    Edlund, Charlotta
    Furebring, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    G Giske, Christian
    Melhus, Asa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Nilsson, Lennart E
    Petersson, Johan
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ternhag, Anders
    Werner, Maria
    Eliasson, Erik
    Rational use of aminoglycosides-Review and recommendations by the Swedish Reference Group for Antibiotics (SRGA)2013In: Scandinavian journal of infectious diseases, ISSN 1651-1980, Vol. 45, no 3, p. 161-175Article, review/survey (Refereed)
    Abstract [en]

    The Swedish Reference Group for Antibiotics (SRGA) has carried out a risk-benefit analysis of aminoglycoside treatment based on clinical efficacy, antibacterial spectrum, and synergistic effect with beta-lactam antibiotics, endotoxin release, toxicity, and side effects. In addition, SRGA has considered optimal dosage schedules and advice on serum concentration monitoring, with respect to variability in volume of drug distribution and renal clearance. SRGA recommends that aminoglycoside therapy should be considered in the following situations: (1) progressive severe sepsis and septic shock, in combination with broad-spectrum beta-lactam antibiotics, (2) sepsis without shock, in combination with broad-spectrum beta-lactam antibiotics if the infection is suspected to be caused by multi-resistant Gram-negative pathogens, (3) pyelonephritis, in combination with a beta-lactam or quinolone until culture and susceptibility results are obtained, or as monotherapy if a serious allergy to beta-lactam or quinolone antibiotics exists, (4) serious infections caused by multi-resistant Gram-negative bacteria when other alternatives are lacking, and (5) endocarditis caused by difficult-to-treat pathogens when monotherapy with beta-lactam antibiotics is not sufficient. Amikacin is generally more active against extended-spectrum beta-lactamase (ESBL)-producing and quinolone-resistant Escherichia coli than other aminoglycosides, making it a better option in cases of suspected infection caused by multidrug-resistant Enterobacteriaceae. Based on their resistance data, local drug committees should decide on the choice of first-line aminoglycoside. Unfortunately, aminoglycoside use is rarely followed up with audiometry, and in Sweden we currently have no systematic surveillance of adverse events after aminoglycoside treatment. We recommend routine assessment of adverse effects, including hearing loss and impairment of renal function, if possible at the start and after treatment with aminoglycosides, and that these data should be included in hospital patient safety surveillance and national quality registries.

  • 33.
    Hanslin, Katja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Skorup, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Wilske, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Frithiof, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Castegren, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lipcsey, Miklos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Pre-existing systemic inflammation attenuates bacterial clearance by the liver in porcine abdominal sepsis2016In: Intensive Care Medicine Experimental, E-ISSN 2197-425X, Vol. 3, no suppl. 1, p. A620-Article in journal (Refereed)
  • 34.
    Hanslin, Katja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Skorup, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Wilske, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Frithiof, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Castegren, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Perioperative Medicine and Intensive Care, Karolinska University Hospital and CLINTEC, Karolinska Institute, Stockholm, Sweden.
    Tano, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    The impact of the systemic inflammatory response on hepatic bacterial elimination in experimental abdominal sepsis2019In: Intensive Care Medicine Experimental, E-ISSN 2197-425X, Vol. 7, no 1, article id 52Article in journal (Refereed)
    Abstract [en]

    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.

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  • 35.
    Hedberg, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hårdemark, Hans-Göran
    Olsson-Liljequist, B.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Penetration of fusidic acid and rifampicin into cerebrospinal fluid in low-grade inflammatory meningitis caused by Staphylococcus epidermidis2004In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 10, no 8, p. 765-768Article in journal (Other academic)
    Abstract [en]

    Cerebrospinal fluid (CSF) concentration-time curves of rifampicin and fusidic acid were studied in a patient with post-operative meningitis caused by Staphylococcus epidermidis. The patient was treated with this combination of antimicrobial agents because of a severe hypersensitivity reaction to vancomycin. Peak CSF concentrations of rifampicin exceeded the MIC by > 60-fold, while those of fusidic acid just reached the MIC. CSF concentrations of fusidic acid were relatively stable within the range reported for patients with uninflamed meninges, but serum levels were surprisingly low. An increase in the metabolism of fusidic acid induced by rifampicin cannot be excluded.

  • 36.
    Jansson, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Efficacy and safety of cefotaxime in combination with metronidazole for empirical treatment of brain abscess in clinical practice: a retrospective study of 66 consecutive cases2004In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 23, no 1, p. 7-14Article in journal (Refereed)
  • 37.
    Jansson-Nettelbladt, Evelyn
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Meurling, Staffan
    Petrini, Björn
    Sjölin, Jan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Endogenous ethanol fermentation in a child with short bowel syndrome.2006In: Acta Paediatr, ISSN 0803-5253, Vol. 95, no 4, p. 502-4Article in journal (Other scientific)
  • 38.
    Krifors, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Lignell, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Swedish Med Prod Agcy, S-75103 Uppsala, Sweden.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care, Hedenstierna laboratory.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Castegren, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research Sörmland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    An experimental porcine model of invasive candidiasis2023In: Intensive Care Medicine Experimental, E-ISSN 2197-425X, Vol. 11, no 1, article id 27Article in journal (Refereed)
    Abstract [en]

    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.

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  • 39.
    Krifors, Anders
    et al.
    Karolinska Inst, Dept Physiol & Pharmacol, S-17165 Stockholm, Sweden.;Uppsala Univ, Hosp Vastmanland, Ctr Clin Res Vastmanland, S-72189 Västerås, Sweden..
    Ullberg, Mans
    Karolinska Univ Hosp, Dept Clin Microbiol, S-17176 Stockholm, Sweden..
    Castegren, Markus
    Karolinska Inst, Dept Physiol & Pharmacol, S-17165 Stockholm, Sweden.;Karolinska Univ Hosp, Perioperat Med & Intens Care PMI, S-17176 Stockholm, Sweden..
    Petersson, Johan
    Karolinska Inst, Dept Physiol & Pharmacol, S-17165 Stockholm, Sweden.;Karolinska Univ Hosp, Perioperat Med & Intens Care PMI, S-17176 Stockholm, Sweden..
    Sparrelid, Ernesto
    Karolinska Univ Hosp, Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, S-14152 Stockholm, Sweden..
    Hammarstroem, Helena
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Infect Dis, S-40234 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Infect Dis, Reg Vastra Gotaland, S-40234 Gothenburg, Sweden..
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    oezenci, Volkan
    Karolinska Univ Hosp, Dept Clin Microbiol, S-17176 Stockholm, Sweden.;Karolinska Inst, Div Clin Microbiol, Dept Lab Med, S-14152 Stockholm, Sweden..
    Blennow, Ola
    Karolinska Univ Hosp, Dept Infect Dis, S-17176 Stockholm, Sweden..
    T2Candida Assay in the Diagnosis of Intraabdominal Candidiasis: A Prospective Multicenter Study2022In: JOURNAL OF FUNGI, ISSN 2309-608X, Vol. 8, no 1, article id 86Article in journal (Refereed)
    Abstract [en]

    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-beta-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-beta-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-beta-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-beta-D-glucan in the clinical management of high-risk surgical patients because of its rapid results and ease of use.

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  • 40.
    Kurland, Siri
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Furebring, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Eliasson, E.
    Karolinska Inst, Karolinska Univ Hosp, Dept Lab Med, Clin Pharmacol, Stockholm, Sweden.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin Levels2019In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 63, no 6, article id e02466-18Article in journal (Refereed)
    Abstract [en]

    Caspofungin has a liver-dependent metabolism. Reduction of the dose is recommended based on Child-Pugh (C-P) score. In critically ill patients, drug pharmacokinetics (PK) may be altered. The aim of this study was to investigate the prevalence of abnormal liver function tests, increased C-P scores, their effects on caspofungin PK, and whether pharmacokinetic-pharmacodynamic (PK/PD) targets were attained in patients with suspected candidiasis. Intensive care unit patients receiving caspofungin were prospectively included. PK parameters were determined on days 2, 5, and 10, and their correlations to the individual liver function tests and the C-P score were analyzed. Forty-six patients were included with C-P class A (n = 5), B (n = 40), and C (n = 1). On day 5 (steady state), the median and interquartile range for area under the curve from 0 to 24 h (AUC(0-24)), clearance (CL), and central volume of distribution (V-1) were 57.8 (51.6 to 69.8) mg.h/liter, 0.88 (0.78 to 1.04) liters/h, and 11.9 (9.6 to 13.1) liters, respectively. The C-P score did not correlate with AUC(0-24) (r = 0.03; P = 0.84), CL (r = -0.07; P = 0.68), or V-1 (r = 0.19; P = 0.26), but there was a bilirubin-driven negative correlation with the elimination rate constant (r = -0.46; P = 0.004). Hypoalbuminemia correlated with low AUC(0-24) (r = 0.45; P = 0.005) and was associated with higher clearance (r = -0.31; P = 0.062) and somewhat higher V-1 (r = -0.15; P = 0.37), resulting in a negative correlation with the elimination rate constant (r = -0.34; P = 0.042). For Candida strains with minimal inhibitory concentrations of >= 0.064 mu g/ml, PK/PD targets were not attained in all patients. The caspofungin dose should not be reduced in critically ill patients in the absence of cirrhosis, and we advise against the use of the C-P score in patients with trauma- or sepsis-induced liver injury.

  • 41.
    Kurland, Siri
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Furebring, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Elimination ability of caspofungin in critically ill patients in relation to liver dysfunction in an ICU setting2017In: Mycoses, ISSN 0933-7407, E-ISSN 1439-0507, Vol. 60, p. 225-225Article in journal (Other academic)
  • 42.
    Kurland, Siri
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Furebring, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Shams, Ayda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Chryssanthou, Erja
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden..
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Breuer, Olof
    Karolinska Univ Hosp, Karolinska Inst, Dept Lab Med, Clin Pharmacol, Stockholm, Sweden..
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Human plasma protein levels alter the in vitro antifungal activity of caspofungin: An explanation to the effect in critically ill?2022In: Mycoses, ISSN 0933-7407, E-ISSN 1439-0507, Vol. 65, no 1, p. 79-87Article in journal (Refereed)
    Abstract [en]

    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 Cglabrata, 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.

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  • 43.
    Larsson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Klinisk kemi.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Hansson, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Klinisk kemi.
    Eriksson, Mats B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Slight Increase of Serum S-100B During Porcine Endotoxemic Shock May Indicate Blood-Brain Barrier Damage.2005In: Anesth Analg, ISSN 0003-2999, Vol. 101, no 5, p. 1465-9Article in journal (Refereed)
    Abstract [en]

    Septic shock is a condition that affects many organs, but little is known about the effects on the central nervous system. S-100B, an acidic low molecular weight protein, has attracted considerable interest as a marker for brain damage and disintegration of the blood-brain barrier. It is released into the cerebrospinal fluid and blood from brain tissue after brain damage. We studied S-100B in a porcine model of endotoxemic shock that resembles human Gram-negative septic shock. Ten piglets received IV endotoxin, and plasma samples were collected before the endotoxin infusion and each hour (1-6 h) during the endotoxin infusion. S-100B was measured by sandwich enzyme-linked immunosorbent assay. Low levels of plasma S-100B were detected, but there was a significant increase in S-100B during Hours 1-5 in comparison with the 0 values. We determined that endotoxemia causes a very small but significant increase in the levels of the widely used brain damage marker serum S-100B. However, it cannot be excluded that the increase in S-100B could be caused by release from organs other than the brain.

  • 44.
    Lignell, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Johansson, A.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    A new in-vitro kinetic model to study the pharmacodynamics of antifungal agents: inhibition of the fungicidal activity of amphotericin B against Candida albicans by voriconazole2007In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 13, no 6, p. 613-619Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to develop and validate a new in-vitro kinetic model for the combination of two drugs with different half-lives, and to use this model for the study of the pharmacodynamic effects of amphotericin B and voriconazole, alone or in combination, against a strain of Candida albicans. Bolus doses of voriconazole and amphotericin B were administered to a starting inoculum of C. albicans. Antifungal-containing medium was eliminated and replaced by fresh medium using a peristaltic pump, with the flow-rate adjusted to obtain the desired half-life of the drug with the shorter half-life. A computer-controlled dosing pump compensated for the agent with the longer half-life. Voriconazole and amphotericin B half-lives were set to 6 and 24 h, respectively. Pharmacokinetic parameters were close to target values when both single doses and sequential doses were simulated. Voriconazole and amphotericin B administered alone demonstrated fungistatic and fungicidal activity, respectively. Simultaneous administration resulted in fungicidal activity, whereas pre-exposure of C. albicans to voriconazole, followed by amphotericin at 8 and 32 h, resulted in fungistatic activity similar to that observed with voriconazole alone. Using this model, which allowed a combination of antifungal agents with different half-lives, it was possible to demonstrate an antagonistic effect of voriconazole on the fungicidal activity of amphotericin B. The characteristics and clinical relevance of this interaction require further investigation.

  • 45.
    Lignell, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Chryssanthou, Erja
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Posaconazole in human serum: A greater pharmacodynamic effect than predicted by the non-protein-bound serum concentration2011In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 55, no 7, p. 3099-3104Article in journal (Refereed)
    Abstract [en]

    It is generally accepted that only the unbound fraction of a drug is pharmacologically active. Posaconazole is an antifungal agent with a protein binding of 98 to 99%. Taking into account the degree of protein binding, plasma levels in patients, and MIC levels of susceptible strains, it can be assumed that the free concentration of posaconazole sometimes will be too low to exert the expected antifungal effect. The aim was therefore to test the activity of posaconazole in serum in comparison with that of the calculated unbound concentrations in protein-free media. Significant differences (P < 0.05) from the serum control were found at serum concentrations of posaconazole of 1.0 and 0.10 mg/liter, with calculated free concentrations corresponding to 1× MIC and 0.1× MIC, respectively, against one Candida lusitaniae strain selected for proof of principle. In RPMI 1640, the corresponding calculated unbound concentration of 0.015 mg/liter resulted in a significant effect, whereas that of 0.0015 mg/liter did not. Also, against seven additional Candida strains tested, there was an effect of the low posaconazole concentration in serum, in contrast to the results in RPMI 1640. Fluconazole, a low-grade-protein-bound antifungal, was used for comparison at corresponding concentrations in serum and RPMI 1640. No effect was observed at the serum concentration, resulting in a calculated unbound concentration of 0.1× MIC. In summary, there was a substantially greater pharmacodynamic effect of posaconazole in human serum than could be predicted by the non-protein-bound serum concentration. A flux from serum protein-bound to fungal lanosterol 14α-demethylase-bound posaconazole is suggested.

  • 46.
    Lignell, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sanglard, Dominique
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Voriconazole-induced inhibition of the fungicidal activity of amphotericin B in Candida strains with reduced susceptibility to voriconazole: an Effect Not Predicted by the MIC Value Alone2011In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 55, no 4, p. 1629-1637Article in journal (Refereed)
    Abstract [en]

    An antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B has previously been demonstrated in Candida albicans strains susceptible to voriconazole. Because treatment failure and the need to switch to other antifungals are expected to occur more often in infections that are caused by resistant strains, it was of interest to study whether the antagonistic effect was still seen in Candida strains with reduced susceptibility to voriconazole. With the hypothesis that antagonism will not occur in voriconazole resistant strains, C. albicans strains with characterized mechanisms of resistance against voriconazole, as well as C. glabrata and C. krusei strains with differences in degree of susceptibility to voriconazole were exposed to voriconazole and amphotericin B alone, simultaneously or sequentially in an in vitro kinetic model. Amphotericin B administered alone or simultaneously with voriconazole resulted in fungicidal activity. When amphotericin B was administered after voriconazole, its activity was reduced in median 61% (range 9-94%). Voriconazole-dependent inhibition of amphotericin B activity differed significantly among the strains but was not correlated with the MIC values (correlation coefficient -0.19; P=0.65). Inhibition was found in C. albicans strains with increases in CDR1 and CDR2 expression but not in the strain with an increase in MDR1 expression. In summary, decreased susceptibility to voriconazole does not abolish voriconazole-dependent inhibition of the fungicidal activity of amphotericin B in voriconazole resistant Candida strains. The degree of interaction could not be predicted by the MIC value alone.

  • 47.
    Lignell, Anders
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Löwdin, Elisabeth
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cars, Otto
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sjölin, Jan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Characterization of the inhibitory effect of voriconazole on the fungicidal activity of amphotericin B against Candida albicans in an in vitro kinetic model2008In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 62, no 1, p. 142-8Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The aim of the present investigation was to study and characterize the effect of voriconazole on the fungicidal activity of amphotericin B. METHODS: Four strains of Candida albicans susceptible to voriconazole were exposed to voriconazole and amphotericin B, either alone, simultaneously or sequentially in an in vitro kinetic model. Bolus doses resulting in voriconazole and amphotericin B concentrations of 0.005-5 and 2.5 mg/L, respectively, were administered. Antifungal-containing RPMI 1640 was eliminated and replaced by a fresh medium using a peristaltic pump, with a flow rate adjusted to obtain the desired half-lives. With two drugs tested, a computer-controlled dosing pump compensated for differences in the elimination rates. Using static time-kill methodology, one C. albicans strain was exposed to 5 mg/L voriconazole for varying durations followed by 2.5 mg/L amphotericin B after three repeated washes of voriconazole. RESULTS: Voriconazole and amphotericin B treatment alone resulted in fungistatic and fungicidal activities, respectively. Simultaneous administration of voriconazole and amphotericin B resulted in fungicidal activity, whereas only fungistatic activity was observed when repeated doses of amphotericin B were administered sequentially after voriconazole at 24-96 h. The inhibition of the fungicidal activity of amphotericin B was voriconazole dose-dependent, but seemed to be recovered once the voriconazole concentration fell below the MIC. The fungicidal activity was quickly regained after the removal of voriconazole, irrespective of the duration of voriconazole pre-exposure. CONCLUSIONS: Voriconazole inhibited the fungicidal effect of sequentially administered amphotericin B in a concentration- and time-dependent manner; the clinical significance of this needs further investigation.

  • 48.
    Lignell, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pauksen, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gedeborg, Rolf
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Low utilisation of unactivated protein C in a patient with meningococcal septic shock and disseminated intravascular coagulation2003In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 47, no 7, p. 897-900Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Activated protein C has recently been shown in a multicentre trial to significantly reduce mortality in patients with septic shock. There are also some case reports and minor studies demonstrating promising results with the unactivated form of protein C. However, in children with severe meningococcal infection, skin biopsies have demonstrated low expression of endothelial thrombomodulin and protein C receptors, suggesting low protein C activation capacity in severe meningococcal sepsis.

    METHODS: A patient with meningococcal septic shock was treated with two doses of the unactivated form of protein C, the first during intense activation of the coagulation system and the second during a phase of low grade or no activation. Repeated plasma samples were analysed for protein C concentration, which made it possible to compare pharmacokinetics and half-lives of the two administrations. A shorter half-life during intense coagulation was expected if there was an activation and consumption of the protein C administered.

    RESULTS: The calculated half-lives of protein C during intense and low grade activation were 32 h and 19 h, respectively, a magnitude similar to that reported in protein C-deficient patients without infection.

    CONCLUSION: The result indicates that whole body utilisation of the unactivated protein C was low. Endothelial impairment of protein C activation does not seem to be restricted to the skin vessels only.

  • 49. Linner, Anna
    et al.
    Darenberg, Jessica
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Henriques-Normark, Birgitta
    Norrby-Teglund, Anna
    Clinical Efficacy of Polyspecific Intravenous Immunoglobulin Therapy in Patients With Streptococcal Toxic Shock Syndrome: A Comparative Observational Study2014In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 59, no 6, p. 851-857Article in journal (Refereed)
    Abstract [en]

    Background. Streptococcal toxic shock syndrome (STSS) and necrotizing fasciitis are the 2 most severe invasive manifestations caused by group A Streptococcus (GAS). Intravenous immunoglobulin (IVIG) therapy has been suggested as adjunctive treatment with a beneficial effect on mortality. However the clinical evidence is limited. Here we aim to further document the clinical efficacy of administered IVIG therapy in a comparative observational study of well-defined patients with STSS. Methods. The effect of IVIG was evaluated in patients with STSS prospectively identified in a nationwide Swedish surveillance study conducted between April 2002 and December 2004. Detailed data on symptoms, severity of disease, treatment, and outcome were obtained from 67 patients. Crude and adjusted analyses with logistic regression were performed. Results. Twenty-three patients received IVIG therapy compared with 44 who did not. No significant difference in comorbidities, severity of disease, organ failures, or sex was seen, but the IVIG group was slightly younger and had a higher degree of necrotizing fasciitis (56% vs 14%). The primary endpoint was 28-day survival. Adjusted analysis revealed that factors influencing survival in STSS were Simplified Acute Physiology Score II (odds ratio [OR], 1.1; P = .007), clindamycin (OR, 8.6; P = .007), and IVIG (OR, 5.6; P = .030). Conclusions. This comparative observational study of prospectively identified STSS patients demonstrates that both IVIG and clindamycin therapy contribute to a significantly improved survival in STSS.

  • 50. Linner, Anna
    et al.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Darenberg, Jessica
    Henriques-Normark, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Norrby-Teglund, Anna
    Efficacy of Polyspecific Intravenous Immunoglobulin Therapy in Streptococcal Toxic Shock Syndrome Reply2015In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 60, no 2Article in journal (Refereed)
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