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ispartof: Eurosurveillance vol:25 issue:12 status: published

An aim of the ECDC point prevalence survey (PPS) in European Union/European Economic Area acute care hospitals was to acquire standardised healthcare-associated infections (HAI) data. We analysed one of the most common HAIs in the ECDC PPS, healthcare-associated pneumonia (HAP). Standardised HAI case definitions were provided and countries were advised to recruit nationally representative subsets of hospitals. We calculated 95% confidence intervals (CIs) around prevalence estimates and adjusted for clustering at hospital level. Of 231,459 patients in the survey, 2,902 (1.3%; 95% CI: 1.2–1.3) fulfilled the case definition for a HAP. HAPs were most frequent in intensive care units (8.1%; 95% CI: 7.4–8.9) and among patients intubated on the day of the survey (15%; 95% CI: 14–17; n = 737 with HAP). The most frequently reported microorganism was Pseudomonas aeruginosa (17% of 1,403 isolates), followed by Staphylococcus aureus (12%) and Klebsiella spp. (12%). Antimicrobial resistance was common among isolated microorganisms. The most frequently prescribed antimicrobial group was penicillins, including combinations with beta-lactamase inhibitors. HAPs occur regularly among intubated and non-intubated patients, with marked differences between medical specialities. HAPs remain a priority for preventive interventions, including surveillance. Our data provide a reference for future prevalence of HAPs at various settings.

Contains fulltext : 193452.pdf (Publisher’s version ) (Open Access) Background: This study was conducted as part of the Driving Reinvestment in Research and Development and Responsible Antibiotic Use (DRIVE-AB) project and aimed to develop generic quality indicators (QIs) for responsible antibiotic use in the inpatient setting. Methods: A RAND-modified Delphi method was applied. First, QIs were identified by a systematic review. A complementary search was performed on web sites of relevant organizations. Duplicates were removed and disease and patient-specific QIs were combined into generic indicators. The relevance of these QIs was appraised by a multidisciplinary international stakeholder panel through two questionnaires and an in-between consensus meeting. Results: The systematic review retrieved 70 potential generic QIs. The QIs were appraised by 25 international stakeholders with diverse backgrounds (medical community, public health, patients, antibiotic research and development, regulators, governments). Ultimately, 51 QIs were selected in consensus. QIs with the highest relevance score included: (i) an antibiotic plan should be documented in the medical record at the start of the antibiotic treatment; (ii) the results of bacteriological susceptibility testing should be documented in the medical record; (iii) the local guidelines should correspond to the national guidelines but should be adapted based on local resistance patterns; (iv) an antibiotic stewardship programme should be in place at the healthcare facility; and (v) allergy status should be taken into account when antibiotics are prescribed. Conclusions: This systematic and stepwise method combining evidence from literature and stakeholder opinion led to multidisciplinary international consensus on generic inpatient QIs that can be used globally to assess the quality of antibiotic use.

Antimicrobial agents used to treat infections are lifesaving. Overuse may result in more frequent adverse effects and emergence of multidrug-resistant microorganisms. In 2016–17, we performed the second pointprevalence survey (PPS) of healthcare-associated infections (HAIs) and antimicrobial use in European acute care hospitals. We included 1,209 hospitals and 310,755 patients in 28 of 31 European Union/European Economic Area (EU/EEA) countries. The weighted prevalence of antimicrobial use in the EU/EEA was 30.5% (95% CI: 29.2–31.9%). The most common indication for prescribing antimicrobials was treatment of a community-acquired infection, followed by treatment of HAI and surgical prophylaxis. Over half (54.2%) of antimicrobials for surgical prophylaxis were prescribed for more than 1 day. The most common infections treated by antimicrobials were respiratory tract infections and the most commonly prescribed antimicrobial agents were penicillins with beta-lactamase inhibitors. There was wide variation of patients on antimicrobials, in the selection of antimicrobial agents and in antimicrobial stewardship resources and activities across the participating countries. The results of the PPS provide detailed information on antimicrobial use in European acute care hospitals, enable comparisons between countries and hospitals, and highlight key areas for national and European action that will support efforts towards prudent use of antimicrobials., peer-reviewed

Contains fulltext : 193591.pdf (Publisher’s version ) (Open Access) Background: Quantifying antibiotic use is an essential element of antibiotic stewardship since it allows comparison between different settings and time windows, and measurement of the impact of interventions. However, quantity metrics (QMs) and methods have not been standardized. Objectives: To propose a set of QMs for antibiotic use in inpatients (IQMs) that are accepted globally by professionals in a range of disciplines. The study was conducted within the Driving Reinvestment in Research and Development and Responsible Antibiotic Use (DRIVE-AB) project. Methods: A systematic literature review using MEDLINE identified articles on measuring inpatient antibiotic use, published up to 29 January 2015. A consensually selected list of national and international web sites was screened for additional IQMs. IQMs were classified according to the type of numerator used and presented to a multidisciplinary panel of stakeholders. A RAND-modified Delphi consensus procedure, which consisted of two online questionnaires and a face-to-face meeting, was performed. Results: The systematic literature review and web site search identified 168 eligible articles from which an initial list of 20 IQMs, composed of 20 different numerators and associated denominators was developed. The consensus procedure resulted in a final set of 12 IQMs. Among this final set, DDDs per 100(0) patient-days and days of therapy per patient-days were most frequently found in the review. The panel recommended that antibiotic use should be expressed in at least two metrics simultaneously. Conclusions: Our consensus procedure identified a set of IQMs that we propose as an evidence-based global standard.

Primary polydipsia (PP) is etiologically associated with physical factors and psychiatric disorders ("psychogenic polydipsia"). We present the case of a 28-year-old man with severe symptoms of polydipsia and polyuria. After a comprehensive physical assessment, the only finding was a lesion suggestive of pituitary microadenoma in the magnetic resonance imaging (MRI) scan of the brain. A thorough clinical and diagnostic assessment and the administration of a wide range of psychometric tools revealed no major psychiatric disorder apart from chronic anxiety and mild depressive symptoms. Our patient's PP symptoms might be associated with a dysfunction of the thirst center, which is located closely to the neuroanatomical lesion found in the MRI scan. Given that the underlying pathophysiology of PP remains, to a large extent, unclear, we emphasize on the difficulties to distinguish between PP's subtypes. Copyright © 2013 Lippincott Williams and Wilkins.

Lateral medullary infarction (LMI) or Wallenberg syndrome is a type of brain stem stroke, more specifically, a type of crossed brain stem syndrome. LMI is a well-described entity with several documented typical characteristics including pain and temperature impairment in the ipsilateral to the lesion side of the face and the contralateral side of the trunk and limbs. We present a case of LMI which describes a patient who presented with atypical features of analgesia and thermanaesthesia on the contralateral side of the face and absence of sensory deficit on the ipsilateral side. We attributed this pattern of involvement to a lesion that affects the ventral trigeminothalamic tract and spares the dorsolateral part of the medulla where the spinal trigeminal tract and its nucleus lie. This case report highlights the presence of atypical presentations of LMI that may initially challenge the physician's diagnostic reasoning.

Self-mutilating behaviors could be minor and benign, but more severe cases are usually associated with psychiatric disorders or with acquired nervous system lesions and could be life-threatening. The patient was a 66-year-old man who had been mutilating his fingers for 6 years. This behavior started as serious nail biting and continued as severe finger mutilation (by biting), resulting in loss of the terminal phalanges of all fingers in both hands. On admission, he complained only about insomnia. The electromyography showed severe peripheral nerve damage in both hands and feet caused by severe diabetic neuropathy. Cognitive decline was not established (Mini Mental State Examination score, 28), although the computed tomographic scan revealed serious brain atrophy. He was given a diagnosis of impulse control disorder not otherwise specified. His impulsive biting improved markedly when low doses of haloperidol (1.5 mg/day) were added to fluoxetine (80 mg/day). In our patient's case, self-mutilating behavior was associated with severe diabetic neuropathy, impulsivity, and social isolation. The administration of a combination of an antipsychotic and an antidepressant proved to be beneficial. Copyright © 2012 by Lippincott Williams & Wilkins.

A previous pharmacokinetic study on dosing of colistin methanesulfonate (CMS) at 240 mg (3 million units [MU]) every 8 h indicated that colistin has a long half-life, resulting in insufficient concentrations for the first 12 to 48 h after initiation of treatment. A loading dose would therefore be beneficial. The aim of this study was to evaluate CMS and colistin pharmacokinetics following a 480-mg (6-MU) loading dose in critically ill patients and to explore the bacterial kill following the use of different dosing regimens obtained by predictions from a pharmacokinetic-pharmacodynamic model developed from an in vitro study on Pseudomonas aeruginosa. The unbound fractions of colistin A and colistin B were determined using equilibrium dialysis and considered in the predictions. Ten critically ill patients (6 males; mean age, 54 years; mean creatinine clearance, 82 ml/min) with infections caused by multidrug-resistant Gram-negative bacteria were enrolled in the study. The pharmacokinetic data collected after the first and eighth doses were analyzed simultaneously with the data from the previous study (total, 28 patients) in the NONMEM program. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.026 and 2.2 h, respectively. For colistin, a one-compartment model was sufficient and the estimated half-life was 18.5 h. The unbound fractions of colistin in the patients were 26 to 41% at clinical concentrations. Colistin A, but not colistin B, had a concentration-dependent binding. The predictions suggested that the time to 3-log-unit bacterial kill for a 480-mg loading dose was reduced to half of that for the dose of 240 mg. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Debatable findings exist among various studies regarding the impact of single nucleotide polymorphisms (SNPs) within the promoter region of the tumor necrosis factor (TNF) gene for susceptibility to infections. Their impact was investigated in a cohort of mechanically ventilated patients who developed ventilator-associated pneumonia (VAP). Two-hundred and thirteen mechanically ventilated patients who developed VAP were enrolled. Genomic DNA was extracted and SNPs at the -376, -308 and -238 position of the promoter region of the TNF gene were assessed by restriction fragment length polymorphisms. Monocytes were isolated from 47 patients when they developed sepsis and stimulated by bacterial endotoxin for the production of TNFα and of interleukin-6 (IL-6). Patients were divided into two groups; 166 patients bearing only wild-type alleles of all three studied polymorphisms; and 47 patients carrying at least one A allele of the three studied SNPs. Time between start of mechanical ventilation and advent of VAP was significantly shorter in the second group than in the first group (log-rank: 4.416, p: 0.041). When VAP supervened, disease severity did not differ between groups. Stimulation of TNFα and of IL-6 was much greater by monocytes for patients carrying A alleles. Carriage of at least one A allele of the three studied SNPs at the promoter region of the TNF-gene is associated with shorter time to development of VAP but it is not associated with disease severity. Findings may be related with a role of the studied SNPs in the production of pro-inflammatory cytokines. © 2012 Elsevier Ltd.

Adaptive resistance is an autoregulated phenomenon characterised by induction of resistance in the presence of drug and reversal to the sensitive phenotype in its absence. This type of resistance is well documented for polycationic antibiotics, including aminoglycosides and polymyxins, in Pseudomonas aeruginosa and other aerobic Gram-negative bacilli. It is not caused by selection of resistant mutants but rather by phenotypic alterations in order to survive the lethal drug effect. Adaptive resistance to aminoglycosides is mainly mediated by the MexXY-OprM efflux pump that is rapidly upregulated in bacteria surviving the first exposure to aminoglycosides and is downregulated when bacteria are no longer in contact with the drug. A two-component regulatory system designated ParR-ParS plays a major role in adaptive resistance induced by cationic peptides. In the presence of cationic peptides, ParR-ParS activates the lipopolysaccharide modification operon (arnBCADTEF) leading to increased resistance in polymyxins and aminoglycosides. The bactericidal kinetics related to adaptive resistance have important clinical implications and provide a rationale for administering cationic antibiotics in larger initial and longer interval bolus dosing. A better understanding of this phenomenon and the molecular mechanisms responsible will be essential not only for optimum use of cationic antibiotics but also for developing new agents with ability to counteract the detrimental effects of adaptive resistance and thus enhance the therapeutic efficacy of polycationic compounds. © 2010 Elsevier B.V. and the International Society of Chemotherapy.

In recent years there has been renewed interest in colistin for the treatment of infections by multidrug-resistant Gram-negative bacteria, causing concern that increasing use may be accompanied by the emergence of resistance. This is a retrospective cohort study of colonization and infection by colistin-resistant (CR) gram-negative bacteria in critically ill patients. Colonization data were based on surveillance culture results. Among 150 patients, 78 (52%) were colonized by CR Gram-negative bacteria. Among them, 30 (20%) were colonized by Klebsiella pneumoniae isolates and 51 (34%) were colonized by intrinsically resistant to colistin (CIR) enterobacteriaceae. Seven cases of infection were caused by CR K. pneumoniae and 12 cases by CIR strains. The main risk factor for colonization by CR pathogens was colistin treatment. © 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.

Background: Differential diagnosis of patients with lung infiltrates remains a challenge. Triggering receptor expressed on myeloid cells (TREM)-1 is a neutrophil and monocyte receptor up-regulated during infection. The aim of this study was to evaluate the diagnostic accuracy of TREM-1 and of C-reactive protein (CRP) from patients with lung infiltrates to discern community acquired lung infections.Methods: 68 patients admitted to a medical ward with acute respiratory illness were enrolled in the study. Neutrophil and monocyte TREM-1 expression were measured by flow cytometry, sTREM-1 by an enzyme immunoassay and C-reactive protein by nephelometry. Clinical pulmonary infection score was recorded.Results: 34 patients were diagnosed with bacterial community acquired pneumonia (group A) and 34 with non-bacterial pulmonary disease (group B). Median serum TREM-1 concentration was 102.09 pg/ml in group A and lower than 15.10 pg/ml (p < 0.0001) in group B. Mean±SE neutrophil TREM-1 expression was 4.67 ± 0.53 MFI in group A and 2.64 ± 0.25 MFI (p = 0.001) in group B. Monocyte TREM-1 expression was 4.2 ± 0.42 MFI in group A and 2.64 ± 0.35 MFI (p = 0.007) in group B and mean±SE CRP was 18.03 ± 2 mg/ml in group A and 7.1 ± 1.54 mg/ml (p < 0.001) in group B. A cut-off of 19.53 pg/ml of sTREM-1 with sensitivity 82.6% and specificity 63% to discriminate between infectious and non-infectious pulmonary infiltrates was found. sTREM-1 at admission greater than 180 pg/ml was accompanied with unfavourable outcome.Conclusion: TREM-1 myeloid expression and sTREM-1 are reliable markers of bacterial infection among patients with pulmonary infiltrates; sTREM-1 is a predictor of final outcome. © 2010 Porfyridis et al; licensee BioMed Central Ltd.

Using a liquid chromatography-tandem mass spectrometry method, the serum and cerebrospinal fluid (CSF) concentrations of colistin were determined in patients aged 11?2 months to 14 years receiving intravenous colistimethate sodium (60,000 to 225,000 IU/kg of body weight/day). Only in one of five courses studied (a 14-year-old receiving 225,000 IU/kg/day) did serum concentrations exceed the 2 μg/ml CLSI/EUCAST breakpoint defining susceptibility to colistin for Pseudomonas and Acinetobacter. CSF colistin concentrations were

An analytical method for quantitation of colistin A and colistin B in plasma and culture medium is described. After protein precipitation with acetonitrile (ACN) containing 0.1% trifluoroacetic acid (TFA), the supernatants were diluted with 0.03% TFA. The compounds were separated on an Ultrasphere C18 column, 4.6 mm × 250 mm, 5 μm particle size with a mobile phase consisting of 25% ACN in 0.03% TFA and detected with tandem mass spectrometry. The instrument was operating in ESI negative ion mode and the precursor-product ion pairs were m/z 1167.7 → 1079.6 for colistin A and m/z 1153.7 → 1065.6 for colistin B. The lower limit of quantification (LLOQ) for 100 μL plasma was 19.4 and 10.5 ng/mL for colistin A and B, respectively, with CV

Clinical experience of prolonged use of linezolid in patients with bone infections is accumulating. However more efficacy and safety data are required. This is a case-control study of patients who received linezolid for difficult-to-treat, intolerant or resistant-to-other-antibiotics bone infections. Linezolid was administered Lv. or orally in 34 patients. Results concerning efficacy and safety were compared to a group of well-matched controls. The clinical arrest rate was 74% in the linezolid group and 68% in the control group (p=NS). Treatment was discontinued in 14 (44%) patients of the linezolid group and in 2 (6%) patients of the control group due to adverse events. In the linezolid group 11 (33%) patients developed anemia and 3 (9%) developed thrombocytopenia that led to discontinuation of treatment. Linezolid is effective in a substantial proportion of patients, but the incidence of hematologic adverse events makes close follow-up and laboratory monitoring mandatory.

Background: Procalcitonin (PCT) has been proposed as a diagnostic and prognostic sepsis marker, but has never been validated in febrile patients with prolonged ICU stay.Methods: Patients were included in the study provided they were hospitalised in the ICU for > 10 days, were free of infection and presented a new episode of SIRS, with fever >38°C being obligatory. Fifty patients fulfilled the above criteria. PCT was measured daily during the ICU stay. The primary outcome was proven infection.Results: Twenty-seven out of 50 patients were diagnosed with infection. Median PCT on the day of fever was 1.18 and 0.17 ng/ml for patients with and without proven infections (p < 0.001). The area under the curve for PCT was 0.85 (95% CI; 0.71-0.93), for CRP 0.65 (0.46-0.78) and for WBC 0.68 (0.49-0.81). A PCT level of 1 ng/mL yielded a negative predictive value of 72% for the presence of infection, while a PCT of 1.16 had a specificity of 100%. A two-fold increase of PCT between fever onset and the previous day was associated with proven infection (p 0.001) (OR = 8.55; 2.4-31.1), whereas a four-fold increase of PCT of any of the 6 preceding days was associated with a positive predictive value exceeding 69.65%. A PCT value less than 0.5 ng/ml on the third day after the advent of fever was associated with favorable survival (p 0.01).Conclusion: The reported data support that serial serum PCT may be a valuable diagnostic and prognostic marker in febrile chronic critically ill patients. © 2009 Tsangaris et al; licensee BioMed Central Ltd.

Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients. Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Stimulan™ was evaluated in vitro as a biodegradable carrier for local delivery of moxifloxacin and fusidic acid. Moxifloxacin or fusidic acid was mixed with calcium sulphate at a ratio of 95:5 to prepare five replicas per antibiotic. In vitro elution was estimated daily using a high-performance liquid chromatography (HPLC) system. Elution of moxifloxacin lasted for 31 days. Eluted concentrations reached their peak on Day 13 (mean level 745 μg/mL); the lowest eluted concentration was detected on Day 30 (mean level 367 μg/mL). Elution of fusidic acid lasted for 14 days. Eluted concentrations reached their peak on Day 6 (mean value 249.5 μg/mL); the lowest eluted concentration was detected on Day 13 (mean value 10.9 μg/mL). The presented results revealed that Stimulan™ may allow adequate in vitro elution of moxifloxacin and fusidic acid. The latter results support the application of this system in experimental models of osteomyelitis. © 2008 Elsevier B.V. and the International Society of Chemotherapy.

To elucidate the role of innate immunity in the pathogenesis of meningitis, the effects of cerebrospinal fluid (CSF) and of sera from patients with bacterial and abacterial meningitis were studied on monocytes because of their resemblance in function with brain microglial cells. Monocytes were isolated from the mononuclear fraction of blood of healthy donors. They were incubated in growth medium single and in the presence of purified lipopolysaccharide or lipoteichoic acid of intact cells of Streptococcus pneumoniae and of samples of CSF and sera of patients. Samples were drawn from 10 patients with bacterial and 26 with abacterial meningitis. Concentrations of tumor necrosis factor α, interleukin (IL) 1β, IL-6, IL-10, IL-12, and interferon γ were estimated in cell supernatants by enzyme-linked immunosorbent assay and of procalcitonin by an immunochemiluminometric assay. It was found that the addition of CSF from patients with bacterial meningitis induced higher concentrations of IL-β, IL-6, IL-10, IL-12, and procalcitonin than controls and than the addition of CSF from patients with abacterial meningitis. Intact cells of S. pneumoniae failed to elicit similar responses to CSF of patients. The presence of CSF from patients with abacterial meningitis induced higher levels of interferon γ and IL-6 than controls. It is concluded that cells of the innate immunity play a considerable role in the pathogenesis of meningitis. CSF triggering elicits cytokine responses that are higher in bacterial than abacterial meningitis; IL-1β, IL-6, IL-10, and procalcitonin are important mediators in bacterial meningitis and IL-6 and interferon γ in abacterial meningitis. Copyright © 2006 by Lippincott Williams & Wilkins.

Aim: To unravel the differences between systematic inflammatory response syndrome (SIRS) of acute pancreatitis compared to the same syndrome in sepsis. Methods: Twenty-five patients were enrolled, 12 with sepsis and 13 acute pancreatitis. After diagnosis 20 mL blood was sampled. Half were assayed for isolation of monocytes and 10 mL was centrifuged for serum test of tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6). Half of monocytes were incubated in the presence of patients' serum and supernatants were collected. The other half was treated for estimation of optical photometry under caspase-3 inhibition. TNFα and IL-6 were estimated by an enzyme immunoassay. Results: Median ± SE of serum IL-6 in septic patients and acute pancreatitis patients was 192.30 ± 35.40 ng/L and 21.00 ± 16.05 ng/L, respectively (P < 0.01). Respective values of caspase-3 were 0.94 ± 0.17 pmol/min 104 cells and 0.34 ± 0.09 pmol/min 104 cells (P < 0.05). IL-6 of monocyte supernatants of patients with sepsis was significantly increased after addition of patients' serum, while that of patients with acute pancreatitis did not show significant difference. Conclusion: The data have shown that monocyte activity is different between acute pancreatitis and sepsis. This phenomenon might be explained as a different pathway to the pro-inflammatory cytokines release or could be a novel anti-inflammatory response in acute pancreatitis. © 2006 The WJG Press. All rights reserved.

The potency of clarithromycin as immunomodulator was assessed in an experimental model of sepsis based on acute pyelonephritis by susceptible Escherichia coli. 55 rabbits were utilized; 5 for preliminary pharmacokinetic study and 50 for treatment. The latter were divided into 5 groups of treatment, A: controls; B: clarithromycin pretreatment; C: amikacin pretreatment; D: clarithromycin treatment on presentation of pulmonary oedema; and E; amikacin treatment on presentation of pulmonary oedema. Survival was recorded; tumour necrosis factor-alpha (TNFalpha), and malondialdehyde (MDA) were estimated in serum; activities of caspase-3 in monocyte cytosolic extracts were studied; and bacterial counts made in various organs. Median survival of animals of groups A, B, C, D and E was 1.0, 21.0, 12.5, 2.0 and 5.0 d, respectively. TNFa and MDA and monocyte caspase-3 activity of group A increased over time; no increases were detected in groups B and C. Concentrations of MDA and activities of monocytic caspase-3 were decreased after administration of clarithromycin in group D, an effect not occurring in group E. Bacterial load was decreased in renal tissue of group D compared to group A. It is concluded that intravenous clarithromycin might constitute a promising immunomodulator in sepsis even in the advent of pulmonary oedema.

The application of antimicrobial combinations on multidrug-resistant Pseudomonas aeruginosa might be of clinical relevance if they possess a significant postantibiotic effect (PAE). Twenty-two nosocomial isolates were exposed over time to ceftazidime, imipenem, or ciprofloxacin, and to their interaction with amikacin; all were applied at concentrations equal to their average serum level. After 24 h of exposure, live cells were washed and resuspended into fresh broth, and bacterial growth was monitored. PAE was found only for isolates subjected to the synergistic effect of the applied interactions. For these isolates, the mean PAEs (+/- SE) were 3.10 +/- 0.71 h for ceftazidime and amikacin, 4.38 +/- 0.83 h for imipenem and amikacin, and 3.33 +/- 2.83 h for ciprofloxacin and amikacin. The prolonged PAE documented after exposure to the interactions of the studied drugs strengthens the application of their combination for the management of infections by multidrug-resistant P. aeruginosa. (c) 2005 Elsevier Inc. All rights reserved.

In attempt to investigate the stimulatory effect of Pseudomonas aeruginosa on innate immunity and to correlate it to its level of resistance to antimicrobials, 20 isolates were applied; 8 isolates were susceptible and 12 multidrug-resistant. Genetic diversity was defined by PFGE. Human monocytes of two healthy volunteers were in vitro stimulated by the isolates for the production of pro-inflammatory (TNF-α, IL-1β, IL-6, IL-8 and IL-12) and anti-inflammatory cytokines (IL-10), of malondialdehyde and of procalcitonin. Cytokines were estimated by EIA, malondialdehyde by the thiobarbiturate assay and procalcitonin by an immunochemiluminometric assay. Survival of 48 Wistar rats was recorded after induction of sepsis by the intraperitoneal injection of three susceptible and three multidrug-resistant isolates. To test whether comparative effect of the latter isolates on survival correlates with any difference of monocyte-mediated release of pro-inflammatory mediators, monocytes of two rats were in vitro stimulated for the production of TNF-α and of malondialdehyde. In vitro stimulation of human monocytes by the susceptible isolates elicited elevated production of malondiadeheyde, of IL-1β and of IL-6 compared to stimulation by multidrug-resistant isolates. Similar differences were found for TNF-α and IL-8, but they were not statistically significant. Production of IL-10 and IL-12 was not detected after stimulation with any isolate. Levels of procalcitonin were similar after induction with either susceptible or multidrug-resistant isolates. Mean survival of animals was 7.56, 21.80 and 55.20 h, respectively, after challenge by the susceptible isolates and 28.89, 61.8 and more than 120 h, respectively, after challenge by the multidrug-resistant isolates. Differences of survival were accompanied by greater rodent monocyte-release of TNF-α and malondialdehyde after stimulation by the susceptible isolates compared to multidrug-resistant ones. It is concluded that considerable differences are encountered on the stimulation of human monocytes by susceptible and resistant isolates of Pseudomonas aeruginosa.These results correlate with in vivo evidence and might influence decision on therapeutics.

In order to assess the diagnostic value of procalcitonin, 158 patients with febrile neutropenia from centres across Europe were studied. Patients with fever were diagnosed on the basis of either: (1) clinical, radiological and microbiological criteria; or (2) the procalcitonin value. In the latter case, concentrations of 0.5-1.0 ng/mL were considered diagnostic of localised infection, concentrations of 1.0-5.0 ng/mL of bacteraemia, and concentrations of > 5.0 ng/mL of severe sepsis. Procalcitonin and C-reactive protein were estimated daily in serum by immunochemiluminescence and nephelometry, respectively. Overall, the sensitivity (specificity) of procalcitonin for bacteraemia was 44.2% (64.3%) at concentrations of 1.0-5.0 ng/mL, and 83.3% (100%) for severe sepsis at concentrations of > 5.0 ng/mL. It was concluded that procalcitonin is a marker strongly suggestive of severe sepsis at concentrations of > 5.0 ng/mL. Estimated concentrations of < 0.5 ng/mL indicate that infection is unlikely, but it was observed that bacteraemia associated with coagulase-negative staphylococci may fail to elevate serum procalcitonin levels.

Three multidrug-resistant strains of Pseudomonas aeruginosa were incubated ex vivo with sera sampled after a 10 min intravenous infusion of 25 mg/kg of arachidonic acid (AA) in 10 rabbits in the presence of ceftazidime and amikacin. Lipid peroxidation was assessed during bacterial growth. A statistically significant decrease in bacterial cells was found by the interaction of antimicrobials and serum sampled in the middle of infusion and 15 and 30 min after infusion of AA and was accompanied by elevated levels of malonodialdehyde. This effect of AA is probably attributed to lipid peroxidation and raises the possibility of its application in experimental infections.