Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin Levels.

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 (AUC0-24), clearance (CL), and central volume of distribution (V1) 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 AUC0-24 (r = 0.03; P = 0.84), CL (r = -0.07; P = 0.68), or V1 (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 AUC0-24 (r = 0.45; P = 0.005) and was associated with higher clearance (r = -0.31; P = 0.062) and somewhat higher V1 (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 µg/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.

Betamethasone and dexamethasone in adult community-acquired bacterial meningitis: a quality registry study from 1995 to 2014.

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 non-corticosteroid-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.

Adult bacterial meningitis-a quality registry study: earlier treatment and favourable outcome if initial management by infectious diseases physicians.

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.

Candidaemia in Sweden: a nationwide prospective observational survey.

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 100 000 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 6-29% 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 amphotericin B, and one had reduced susceptibility to caspofungin.

Neurointensive care of patients with severe community-acquired meningitis.

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), ß-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.

Propensity to release endotoxin after two repeated doses of cefuroxime in an in vitro kinetic model: higher release after the second dose.

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.

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 voriconazole.

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.

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.

Treatments targeting complement receptors have been demonstrated to improve outcome in experimental sepsis. The regulation of the complement receptors in sepsis is not clear. Lipopolysaccharide (LPS) stimulation of granulocytes ex vivo has been shown to reduce C5a receptor (CD88) expression and to increase CD35 and CD11b/CD18 expressions in whole blood but not on isolated cells, indicating an indirect effect mediated via factors in the blood. With the aim to study whether these effects could be attributed to C5a, tumour necrosis factor (TNF)-alpha and interleukin (IL)-8, whole blood or isolated granulocytes and monocytes from healthy individuals were investigated. After incubation with C5a in a dose range of 1 x 10(-9)-1 x 10(-7) mol/l, and TNF-alpha and IL-8 at doses of 1-100 ng/ml, the expressions of the complement receptors CD88, CD35, CD11b/CD18 were analysed by flow cytometry. Incubation with C5a reduced granulocyte CD88 expression by 44+/-6.9% and 82+/-4.2%, whereas monocyte CD88 expression decreased by 21+/-4.0 and 30+/-17% (whole blood and isolated cells). IL-8 and TNF-alpha incubation of granulocytes induced similar results. Granulocyte CD35 expression was significantly increased by 367, 175 and 336% by C5a, TNF-alpha, IL-8, respectively; CD11b expression was similarly increased. Consistent with findings in septic patients and after LPS incubation, it is concluded that all stimuli reduced granulocyte CD88 expression, whereas CD35 and CD11b were increased.

Differential expression of the C5a receptor and complement receptors 1 and 3 after LPS stimulation of neutrophils and monocytes.

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.

Penetration of fusidic acid and rifampicin into cerebrospinal fluid in low-grade inflammatory meningitis caused by Staphylococcus epidermidis.

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.

Efficacy and safety of cefotaxime in combination with metronidazole for empirical treatment of brain abscess in clinical practice: a retrospective study of 66 consecutive cases.

Sixty-six consecutive patients with brain abscesses referred to a department of neurosurgery during a 10-year period and treated with cefotaxime were studied retrospectively by means of a prospectively designed protocol whose main areas of emphasis were duration of antibiotic treatment, sterilization rate, clinical outcome in relation to prognostic factors, and side effects. Sixty-two of these patients were treated additionally with metronidazole, and surgery was performed in 53 patients. Mental status was altered in 33 patients, 11 of whom were comatose. Rupture of the abscess into the ventricles occurred in eight patients. Death was attributable to brain abscess formation in three patients (4.5%). Forty-six percent of the surviving patients recovered without any neurological deficits. Reversible adverse reactions, which occurred in 38 patients, were the most common reason for withdrawal of cefotaxime. In 76% of these cases, there was a significant improvement before the onset of the adverse reaction. The median duration of parenteral antibiotic treatment was 36, 41, 22, and 46 days in patients treated with excision, aspiration, evacuation of subdural empyema, and antibiotics alone, respectively. Taking prognostic factors into consideration, mortality attributable to brain abscess was lower than previously reported. This finding, along with the abscess sterilization results, indicates that cefotaxime in combination with metronidazole is a highly effective treatment but is associated with a high frequency of reversible side effects. The results indicate that a shorter duration of treatment should be investigated.

Low utilisation of unactivated protein C in a patient with meningococcal septic shock and disseminated intravascular coagulation.

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.

Circulating soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in immunocompetent and renal transplant patients: correlation with cytomegalovirus disease and renal function.

The plasma levels of the soluble adhesion molecules, soluble vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1), were measured before and after transplantation in 26 renal transplant recipients, and in 173 longitudinally collected samples in 17 of the patients. The patients were carefully monitored for the presence of cytomegalovirus (CMV) infection and rejection. Forty healthy blood donors and 12 otherwise healthy subjects with symptomatic primary CMV infections served as controls. During CMV disease, plasma levels of sVCAM-1 and sICAM-1 were elevated in both renal transplant patients and otherwise healthy subjects with CMV disease. The sVCAM-1 levels were strongly elevated before transplantation in renal transplant recipients and correlated with creatinine levels. Increased sVCAM-1 levels were also registered during rejection episodes. CMV disease, per se, is associated with markedly increased levels of sVCAM-1 and sICAM-1. There is also a correlation of sVCAM-1 levels with serum creatinine levels. Thus, the presence of CMV infection and renal function are factors that must be considered in further studies of soluble adhesion molecules.

Coccidioidomycosis as imported atypical pneumonia in Sweden.

Coccidioidomycosis, an endemic fungal infection of the western hemisphere causes serious disease in immunocompromised individuals. In immunocompetent patients, a moderate flu-like disease may develop. We report here an imported Scandinavian case of a culture-proven coccidioidomycosis, initially presenting as an atypical pneumonia. Pleuritic symptoms, positive epidemiology and eosinophilia led to suspicion of the diagnosis, which was further supported by serology.

Granulocyte-macrophage colony-stimulating factor as immunomodulating factor together with influenza vaccination in stem cell transplant patients.

The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the serological response at influenza vaccination was studied in 117 patients who had undergone stem cell transplantation (SCT). The vaccine response was evaluated as significant increases in levels of influenza hemagglutination-inhibition (HAI) antibodies and of IgG antibodies measured by enzyme-linked immunosorbent assay (ELISA). There was no difference in antibody response to either influenza A or B in 64 patients who received GM-CSF at vaccination, compared with the 53 who did not. In the subgroup of allogeneic SCT patients, HAI showed that the response rate to the influenza B vaccine was significantly higher in the treatment group (P<.05). ELISA showed that autologous SCT patients with breast cancer who received GM-CSF had a better response to influenza A (P<.05) and B (P<.01). At early vaccination, 4-12 months after stem cell transplantation, these responses were more pronounced. GM-CSF appears to improve the response to influenza vaccination in some groups of SCT patients, but only to a limited extent.

Endotoxin release from Escherichia coli after exposure to tobramycin: dose-dependency and reduction in cefuroxime-induced endotoxin release.

OBJECTIVE: To study the release of free endotoxin from Escherichia coli exposed to varying concentrations of the penicillin-binding protein (PBP) 3-specific beta-lactam antibiotic cefuroxime, the aminoglycoside tobramycin, and a combination of the two, and to test the relationship between bacterial killing rate and endotoxin release. METHODS: A clinical isolate of Escherichia coli in logarithmic phase was exposed to 0.1, 2, 10, and 50 x minimum inhibitory concentration (MIC) of cefuroxime, tobramycin, and a combination of the two. Samples for viable counts and endotoxin analysis were drawn immediately before and after the addition of the antibiotics and at 1, 2, 4, 6, and 24 h. All experiments were performed in triplicate. For the analysis of endotoxin, a chromogenic limulus amoebocyte lysate assay was used. RESULTS: Endotoxin liberation was found to be proportional to the number of killed bacteria for each antibiotic regimen at each concentration level justifying the endotoxin-liberating potential to be expressed as release of endotoxin per killed bacterium, an expression that was independent of the inoculum size. At all concentration levels there was a statistically significant difference between the treatments, with the highest release of endotoxin per killed bacterium for cefuroxime, lower for tobramycin and the lowest for the combination of the two drugs (P < 0.001). With increasing doses, there was a significant reduction (P < 0.001) in the propensity to release endotoxin. When the bacterial killing rate was correlated to the propensity to release endotoxin in bacteria exposed to tobramycin or the combination of tobramycin and cefuroxime, a significant negative correlation was found (P < 0.01). This reduction in endotoxin release was not caused by an unspecific endotoxin binding of tobramycin. CONCLUSIONS: Addition of tobramycin reduced the cefuroxime-induced endotoxin release per killed bacterium to a level which was even lower than that of tobramycin alone in spite of an increased killing rate. Increasing concentrations of tobramycin led to reduction in endotoxin release, which may be of benefit when dosing aminoglycosides once daily.

Subsets of T-cells and in vitro cytokine production after measles and varicellae-zoster virus antigen stimulation in allogeneic BMT patients.

This study was performed to analyse differences in T-cell proliferation induced by a latent virus, varicellae-zoster virus (VZV) and a non-latent virus, measles virus, in patients after allogeneic bone marrow transplantation (BMT). The lymphoproliferative response to measles antigen, VZV-antigen (VZV-ag), and phytohemagglutinin (PHA) was measured by 3H-thymidine incorporation, and interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) analyses in supernatants after in vitro stimulation of peripheral blood mononuclear cells (PBMC) from 22 patients and 18 healthy controls. The cytokine levels were correlated with T-cell subsets by FACS analyses. At the antigen concentrations used, VZV-ag induced higher levels of IFN-gamma (p < 0.05) than did the measles antigen, whereas the levels of IL-10 were similar. Patients without a cell mediated immune (CMI) response to VZV-ag or measles antigen had lower CD4+ T-cell counts than did controls (p < 0.01 in both cases) and lower IFN-gamma production after non-specific PHA stimulation (p <0.01). The IFN-gamma and IL-10 levels after measles antigen stimulation correlated with the number of CD4+ T-cells (p < 0.01 and p < 0.05, respectively), and after VZV-ag mainly to the number of CD8+ T-cells (p < 0.01 and p < 0.05, respectively). These results suggest that there is a difference in the types of T-cells that respond to VZV-ag and measles antigen stimulation, respectively. The impaired CMI response to viral antigens seen in many patients may be explained both by a low number of CD4+ T-cells and by a cell dysfunction.

Th1 and Th2 cytokine responses after measles antigen stimulation in vitro in bone marrow transplant patients: response to measles vaccination.

In seronegative autologous bone marrow transplanted (ABMT) patients, a sustained cell-mediated immunity (CMI) has been shown to impair the antibody response after measles vaccination. To investigate if this might be caused by a preferential Th1 cytokine response, interferon (IFN)-gamma and interleukin (IL)-10 production of peripheral blood mononuclear cells (PBMC) was analyzed after measles antigen (M-ag) stimulation in vitro. The non-specific immune response was measured by IFN-alpha, and IL-12 analyses. Fifty non-vaccinated patients following ABMT or allogeneic bone marrow transplantation (BMT) were included. IFN-gamma production was significantly higher in patients with a retained CMI to measles than in patients without (2.3 vs 0.8 IU/ml; P = 0.01). Only a non-significant tendency was seen in IL-10 production (48.6 vs 26.7 pg/ml; NS), whereas no difference was found in IFN-alpha or IL-12 production. A positive correlation between IFN-gamma and IL-10 production was found (r(s) = 0.49; P < 0.001). After vaccination of 14 ABMT children, there was an increase in PBMC IFN-gamma production in vitro (2.5 vs <0.1 IU/ml; P < 0.05), whereas no changes were seen in the IL-10, IFN-alpha, or antibody levels. These results suggest that both Th1 and Th2 cytokine production are increased by M-ag stimulation in patients with a retained CMI to measles, but the Th1 response seems to be stronger. The preferential Th1 stimulation and increase in IFN-gamma production after vaccination may lead to a reduction in the humoral immune response which may explain the negative correlation between antibody production and T cell reactivity prior to vaccination.