C5a Receptor Expression in Severe Sepsis and Septic Shock

In patients with sepsis, the activation of the cascade systems, for example the complement system with the generation of C5a, is followed by a state of immunosuppression with impaired bactericidal capacity caused by suppression of the neutrophil granulocytes. To inhibit the C5a-induced systemic inflammatory and the following anti-inflammatory responses, different anti-C5a strategies have been successful in experimental models of sepsis. In animals and in healthy volunteers after injection of lipopolysaccharide (LPS), an up-regulation of the C5a receptor (C5aR) has been reported. Before designing clinical studies, it was of importance to increase the knowledge of C5a and C5aR regulation in humans. At the time when the diagnosis of severe sepsis or septic shock can be established clinically, granulocyte C5aR expression, analysed by flow cytometer, was shown to be reduced, whereas monocyte C5aR expression was unchanged. There was a correlation between granulocyte C5aR expression and the severity of disease, as measured by the APACHE II score. Ex vivo incubation of whole blood with LPS resulted in a reduction in granulocyte C5aR expression. Such a reduction was not found in isolated cells, indicating that the effect was mediated via plasma factors, such as C5a, IL-8 and TNF-α which all were shown to reduce C5aR expression ex vivo. Although there was a trend between chemotaxis, as measured by migration in a modified Boyden chamber, and C5aR expression on granulocytes from patients with severe sepsis or septic shock or from healthy individuals, the correlation failed to reach statistical significance. It is concluded that granulocyte C5aR expression is affected by several plasma factors and that a reduction is clinically evident at the time of the sepsis diagnosis. Reduced granulocyte C5aR expression is associated with an impaired chemotaxis but does not alone limit the chemotactic response

Invasive fungal infection by Peziza ostracoderma in an immunocompromised patient

We report for the first time a case of disseminated infection caused by Peziza ostracoderma, a mold not previously associated with invasive infections in humans. P. ostracoderma occurs in natural and sterilized soil and may cause hypersensitivity pneumonitis in greenhouse workers. The immunocompromised patient presented with neutropenic fever that did not respond to broad-spectrum antibiotics and developed multiple skin and lung lesions. A skin biopsy demonstrated an angioinvasive mold, identified as Peziza ostracoderma by culture and DNA sequencing. Minimum inhibitory concentration (MIC) for amphotericin B was 0.125 mg/L, for isavuconazole 0.125 mg/L, for voriconazole 0.06 mg/L, and for posaconazole 0.03 mg/L. The skin lesions have resolved completely, and the lung lesions have decreased significantly in size after 14 months of mold-active antifungal therapy, mostly isavuconazole. In conclusion, Peziza species can be opportunistic pathogens causing considerable morbidity in immunocompromised hosts. The infection may be successfully treated with mold-active antifungal drugs

Korsallergi mellan penicilliner och övriga betalaktam-antibiotika - Risken är betydligt mindre än man tidigare trott.

Severe IgE-mediated allergic reactions to penicillins are rare but might be fatal. Because some studies demonstrated a high risk of cross-sensitivity to cephalosporins and carbapenems it has been recommended to avoid these antibiotics in patients with suspected hypersensitivity to penicillins. However, recent studies and analyses conclude that the risk of cross-reactivity was overestimated in the earlier studies and that it is in fact very low for parenteral cephalosporins and perhaps even negligible for carbapenems. The new knowledge has implications for the choice of therapy for bacterial infections in patients with a history of penicillin hypersensitivity, because alternative antibiotic regimens are often inferior to beta-lactam antibiotics. The aim of the present review is to present existing knowledge on cross-sensitivity between beta-lactams, as well as to discuss the management of patients with suspected allergic reactions to these antibiotics

Low attainment to PK/PD-targets for β-lactams in a multi-center study on the first 72 h of treatment in ICU patients

Severe infections are life-threatening conditions commonly seen in the intensive care units (ICUs). Antibiotic treatment with adequate concentrations is of great importance during the first days when the bacterial load is the highest. Therapeutic drug monitoring (TDM) of β-lactam antibiotics has been suggested to monitor target attainment and to improve the outcome. This prospective multi-center study in seven ICUs in Sweden investigated pharmacokinetic/pharmacodynamic-target (PK/PD-target) attainment for cefotaxime, piperacillin-tazobactam and meropenem, commonly used β-lactams in Sweden. A mid-dose and trough antibiotic concentration blood sample were taken from patients with severe infection daily during the first 72 h of treatment. Antibiotic plasma concentrations were analysed by liquid chromatography-mass spectrometry (LC–MS). Antibiotic concentrations 100% time above MIC (minimal inhibitory concentration), (100% T &gt; MIC) and four times above MIC 50% of the time (50% T &gt; 4xMIC) were used as PK/PD-targets. We included 138 patients with the median age of 67 years and the median Simplified Acute Physiology Score 3 (SAPS3) of 59. Forty-five percent of the study-population failed to reach 100% T &gt; MIC during the first day of treatment. The results were similar the following two days. There was a three-fold risk of not meeting the PK/PD target if the patient was treated with cefotaxime. For the cefotaxime treated patients 8 out of 55 (15%) had at least one end-dose concentrations below the level of detection during the study. Low age, low illness severity, low plasma creatinine, lower respiratory tract infection and cefotaxime treatment were risk factors for not reaching 100% T &gt; MIC. In Swedish ICU-patients treated with β-lactam antibiotics, a high proportion of patients did not reach the PK/PD target. TDM could identify patients that need individual higher dosing regimens already on the first day of treatment. Further studies on optimal empirical start dosing of β-lactams, especially for cefotaxime, in the ICU are needed.Title in Web of Science: Low attainment to PK/PD-targets for beta-lactams in a multi-center study on the first 72 h of treatment in ICU patients</p

Population pharmacokinetics of cefotaxime in intensive care patients

PURPOSE: To characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates. METHODS: This work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000-3000 mg given 2-6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis. RESULTS: A two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p &lt; 0.001), reducing IIV from 68 to 49%. CONCLUSION: A population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support

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

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

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

Background Recent studies have shown low caspofungin concentrations in critically ill patients. In some patients, the therapeutic target, area under the total plasma concentration curve in relation to the minimal inhibition concentration (AUCtot/MIC), seems not to be achieved and therapeutic drug monitoring (TDM) has been proposed. Caspofungin is highly protein-bound and the effect of reduced plasma protein levels on pharmacodynamics has not been investigated. Objectives Fungal killing activity of caspofungin in vitro was investigated under varying levels of human plasma protein. Methods Time-kill studies were performed with clinically relevant caspofungin concentrations of 1-9 mg/L on four blood isolates of C. glabrata, three susceptible and one strain with reduced susceptibility, in human plasma and plasma diluted to 50% and 25% using Ringer's acetate. Results Enhanced fungal killing of the three susceptible strains was observed in plasma with lower protein content (p &lt; .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