Beta-lactam antibiotics in continuous infusion in critically ill patients

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Bronchoalveolar lavage cytological alveolar damage in patients with severe pneumonia

INTRODUCTION: Histological examination of lung specimens from patients with pneumonia shows the presence of desquamated pneumocytes and erythrophages. We hypothesized that these modifications should also be present in bronchoalveolar lavage fluid (BAL) from patients with hospital-acquired pneumonia. METHODS: We conducted a prospective study in mechanically ventilated patients with clinical suspicion of pneumonia. Patients were classified as having hospital-acquired pneumonia or not, in accordance with the quantitative microbiological cultures of respiratory tract specimens. A group of severe community-acquired pneumonias requiring mechanical ventilation during the same period was used for comparison. A specimen of BAL (20 ml) was taken for cytological analysis. A semiquantitative analysis of the dominant leukocyte population, the presence of erythrophages/siderophages and desquamated type II pneumocytes was performed. RESULTS: In patients with confirmed hospital-acquired pneumonia, we found that 13 out of 39 patients (33.3%) had erythrophages/siderophages in BAL, 18 (46.2%) had desquamated pneumocytes and 8 (20.5%) fulfilled both criteria. Among the patients with community-acquired pneumonia, 7 out of 15 (46.7%) had erythrophages/siderophages and 6 (40%) had desquamated pneumocytes on BAL cytology. Only four (26.7%) fulfilled both criteria. No patient without hospital-acquired pneumonia had erythrophages/siderophages and only 3 out of 18 (16.7%) had desquamated pneumocytes on BAL cytology. CONCLUSION: Cytological analysis of BAL from patients with pneumonia (either community-acquired or hospital-acquired) shows elements of cytological alveolar damage as hemorrhage and desquamated type II pneumocytes much more frequently than in BAL from patients without pneumonia. These elements had a high specificity for an infectious cause of pulmonary infiltrates but low specificity. These lesions could serve as an adjunct to diagnosis in patients suspected of having ventilator-associated pneumonia

Recommended β-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy

Introduction: Sepsis is responsible for important alterations in the pharmacokinetics of antibiotics. Continuous renal replacement therapy (CRRT), which is commonly used in septic patients, may further contribute to pharmacokinetic changes. Current recommendations for antibiotic doses during CRRT combine data obtained from heterogeneous patient populations in which different CRRT devices and techniques have been used. We studied whether these recommendations met optimal pharmacokinetic criteria for broad-spectrum antibiotic levels in septic shock patients undergoing CRRT.Methods: This open, prospective study enrolled consecutive patients treated with CRRT and receiving either meropenem (MEM), piperacillin-tazobactam (TZP), cefepime (FEP) or ceftazidime (CAZ). Serum concentrations of these antibiotics were determined by high-performance liquid chromatography from samples taken before (t = 0) and 1, 2, 5, and 6 or 12 hours (depending on the β-lactam regimen) after the administration of each antibiotic. Series of measurements were separated into those taken during the early phase ( 48 hours).Results: A total of 69 series of serum samples were obtained in 53 patients (MEM, n = 17; TZP, n = 16; FEP, n = 8; CAZ, n = 12). Serum concentrations remained above four times the minimal inhibitory concentration for Pseudomonas spp. for the recommended time in 81% of patients treated with MEM, in 71% with TZP, in 53% with CAZ and in 0% with FEP. Accumulation after 48 hours of treatment was significant only for MEM.Conclusions: In septic patients receiving CRRT, recommended doses of β-lactams for Pseudomonas aeruginosa are adequate for MEM but not for TZP, FEP and CAZ; for these latter drugs, higher doses and/or extended infusions should be used to optimise serum concentrations. © 2011 Seyler et al. licensee BioMed Central Ltd.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

A Randomized Clinical Trial to Compare Fleroxacin-Rifampicin with Flucloxacillin or Vancomycin for the Treatment of Staphylococcal Infection

Background. Oral combination therapy with fluoroquinolones plus rifampicin is a promising alternative to standard parenteral therapy for staphylococcal infections. Methods. In a multicenter, randomized trial, we compared the efficacy, safety, and length of hospital stay for patients with staphylococcal infections treated either with an oral combination of a fluoroquinolone (fleroxacin) plus rifampicin or with standard parenteral treatment (flucloxacillin or vancomycin). Patients were included if cultures showed the presence of bacteremia or deep-seated infections with Staphylococcus aureus (104 patients) or catheter-related bacteremia due to drug-susceptible, coagulase-negative staphylococci (23 patients). Results. The cure rate in the intention-to-treat analysis was 78% for the fleroxacin-rifampicin group (68 patients) and 75% for the standard therapy group (59 patients; 47 received flucloxacillin, and 12 received vancomycin); in the population of clinically evaluable patients (n = 119), the cure rate was 82% and 80%, respectively; and in the population of microbiologically evaluable patients (n = 103), the cure rate was 86% and 84%, respectively. Clinical and bacteriological failures after S. aureus infections were documented in similar proportions of patients. The median length of hospital stay after study entry was 12 days in the fleroxacin-rifampicin group, compared with 23 days in the standard treatment group (P = .006). More adverse events probably related to the study drug were reported in the fleroxacin-rifampicin group than in the standard therapy group (15 of 68 vs. 5 of 59 patients; P = .05). Conclusions. This study suggests that an oral regimen containing a fluoroquinolone plus rifampicin may be effective for treating staphylococcal infections, allowing earlier discharge from the hospita

Evaluation of total body weight and body mass index cut-offs for increased cefazolin dose for surgical prophylaxis

AbstractFrench and American guidelines recommend increased dosage regimens of cefazolin (CFZ) for surgical prophylaxis in patients with a body mass index (BMI) ≥ 35 kg/m2 or with a total body weight (TBW) ≥ 120 kg. The objective of this study was to evaluate the accuracy of these cut-offs in identifying patients who require CFZ dose adjustment. A pharmacokinetic study was conducted in patients of varying TBW and BMI who received 2 g of CFZ intravenously for prophylaxis prior to digestive surgery. Adequacy of therapy, defined as a serum concentration of unbound CFZ (fCFZ) ≥ 4 mg/L, was evaluated 180 min (T180) and 240 min (T240) after the start of CFZ infusion. Possible factors associated with insufficient fCFZ levels were also assessed. A P-value of <0.05 was considered statistically significant. A total of 63 patients were included in the study, categorised according to BMI (<35 kg/m2, 20 patients; and ≥35 kg/m2, 43 patients) and TBW (<120 kg, 41 patients; and ≥120 kg, 22 patients). All patients had adequate drug levels at T180 but only 40/63 patients (63%) had adequate levels at T240. At T240, therapy was adequate in 15/20 patients (75%) and 25/43 patients (58%) with BMI <35 kg/m2 and ≥35 kg/m2, respectively (P = 0.20), and in 28/41 patients (68%) and 12/22 patients (55%) with TBW <120 kg and ≥120 kg, respectively (P = 0.28). No factor associated with insufficient fCFZ was identified. In conclusion, current BMI and TBW cut-offs are poor indicators of which patients could benefit from increased CFZ dosage regimens

Revisiting the loading dose of amikacin for patients with severe sepsis and septic shock

It has been proposed that doses of amikacin of >15 mg/kg should be used in conditions associated with an increased volume of distribution (Vd), such as severe sepsis and septic shock. The primary aim of this study was to determine whether 25 mg/kg (total body weight) of amikacin is an adequate loading dose for these patients.Clinical TrialJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

A Randomized, Blinded, Multicenter Trial of Lipid-Associated Amphotericin B Alone versus in Combination with an Antibody-Based Inhibitor of Heat Shock Protein 90 in Patients with Invasive Candidiasis

Background. Mycograb (NeuTec Pharma) is a human recombinant monoclonal antibody against heat shock protein 90 that, in laboratory studies, was revealed to have synergy with amphotericin B against a broad spectrum of Candida species. Methods. A double-blind, randomized study was conducted to determine whether lipid-associated amphotericin B plus Mycograb was superior to amphotericin B plus placebo in patients with culture-confirmed invasive candidiasis. Patients received a lipid-associated formulation of amphotericin B plus a 5-day course of Mycograb or placebo, having been stratified on the basis of Candida species (Candida albicans vs. non-albicans species of Candida). Inclusion criteria included clinical evidence of active infection at trial entry plus growth of Candida species on culture of a specimen from a clinically significant site within 3 days after initiation of study treatment. The primary efficacy variable was overall response to treatment (clinical and mycological resolution) by day 10. Results. Of the 139 patients enrolled from Europe and the United States, 117 were included in the modified intention-to-treat population. A complete overall response by day 10 was obtained for 29 (48%) of 61 patients in the amphotericin B group, compared with 47 (84%) of 56 patients in the Mycograb combination therapy group (odds ratio [OR], 5.8; 95% confidence interval [CI], 2.41-13.79; P < .001). The following efficacy criteria were also met: clinical response (52% vs. 86%; OR, 5.4; 95% CI, 2.21-13.39; P < .001), mycological response (54% vs. 89%; OR, 7.1; 95% CI, 2.64-18.94; P < .001), Candida-attributable mortality (18% vs. 4%; OR, 0.2; 95% CI, 0.04-0.80; P = .025), and rate of culture-confirmed clearance of the infection (hazard ratio, 2.3; 95% CI, 1.4-3.8; P = .001). Mycograb was well tolerated. Conclusions. Mycograb plus lipid-associated amphotericin B produced significant clinical and culture-confirmed improvement in outcome for patients with invasive candidiasi

Cultural corridors: An analysis of persistence in impacts on local development — A neo-Weberian perspective on South-East Europe

Culture matters for economic development. This postulate has been a main conceptual concern for “old” institutional economics (OIE) and has lately also been tested through neoclassically inspired econometric techniques. This conceptual foundation has been confirmed in several quantitative studies on developed countries, in particular cases from the USA, Germany, and Italy. In less developed regions with a wealth of cultural heritage, particularly in South-East Europe, this postulate is still an underexplored issue from the perspective of advanced econometric approaches. Our goal is to examine the impact of the so-called South-East European cultural corridors on welfare — and especially on total employment — at the local or regional level. Accounting for gross value added and sectoral specialization, we examine the effect of such corridors by considering the distance to a cultural corridor: namely, the East Trans-Balkan Road (crossing Romania, Bulgaria, and Greece) as an explanatory factor for regional development, particularly employment. Using the European University Institute (EUI) European Regional Dataset (ERD), as well as the geo-data from the Cultural Corridors of the South-East Europe website, we estimate a regression model using a 2SLS instrumental variable (IV) approach, with a pooled dataset at the NUTS 3 level (Eurostat) from 1980 to 2011. We then triangulate the results by using the distance to the cultural corridor concerned as a treatment effect in a propensity-score-matching and difference-in-differences exploratory analysis. The findings confirm the importance of distance to the cultural corridor under investigation as a strong predictor for local socio-economic development. The results further suggest that the slow evolution of culture over time is likely to lead to the gradual emergence of new geographical cultural centers and a new cultural path-dependence build-up of persistence chains

Towards a better detection of patients at-risk of linezolid toxicity in clinical practice: a prospective study in three Belgian hospital centers

Introduction: Linezolid is a last-resort antibiotic for infections caused by multidrug-resistant microorganisms. It is widely used for off-label indications and for longer than recommended treatment durations, exposing patients at higher risk of adverse drug reactions (ADRs), notably thrombocytopenia. This study aimed to investigate ADR incidence and risk factors, identify thrombocytopenia-related trough levels based on treatment duration, and evaluate the performance of predictive scores for ADR development.Methods: Adult in- and outpatients undergoing linezolid therapy were enrolled in three hospitals and ADRs and linezolid trough levels prospectively monitored over time. A population pharmacokinetic (pop-PK model) was used to estimate trough levels for blood samples collected at varying times.Results: A multivariate analysis based on 63 treatments identified treatment duration ≥10 days and trough levels &gt;8 mg/L as independent risk factors of developing thrombocytopenia, with high trough values correlated with impaired renal function. Five patients treated for &gt;28 days did not develop thrombocytopenia but maintained trough values in the target range (&lt;8 mg/L). The Buzelé predictive score, which combines an age-adjusted Charlson comorbidity index with treatment duration, demonstrated 77% specificity and 67% sensitivity to predict the risk of ADR.Conclusion: Our work supports the necessity of establishing guidelines for dose adjustment in patients with renal insufficiency and the systematic use of TDM in patients at-risk in order to keep trough values ≤8 mg/L. The Buzelé predictive score (if ≥7) may help to detect these at-risk patients, and pop-PK models can estimate trough levels based on plasma samples collected at varying times, reducing the logistical burden of TDM in clinical practice

Modulations de la synthèse de cytokines et de monoxyde d'azote au cours de l'infection expérimentale à "Trypanosoma cruzi"

Doctorat en sciences médicalesinfo:eu-repo/semantics/nonPublishe