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Background Biofilm formation on endotracheal tubes (ETTs) is an early and frequent event in mechanically ventilated patients. The biofilm is believed to act as a reservoir for infecting microorganisms and thereby contribute to development and relapses of ventilator-associated pneumonia (VAP). Once a biofilm has formed on an ETT surface, it is difficult to eradicate. This clinical study aimed to compare biofilm formation on three widely used ETTs with different surface properties and to explore factors potentially predictive of biofilm formation. Methods We compared the grade of biofilm formation on ETTs made of uncoated polyvinyl chloride (PVC), silicone-coated PVC, and PVC coated with noble metals after > 24 h of mechanical ventilation in critically ill patients. The comparison was based on scanning electron microscopy of ETT surfaces, biofilm grading, surveillance and biofilm cultures, and occurrence of VAP. Results High-grade (score ≥ 7) biofilm formation on the ETTs was associated with development of VAP (OR 4.17 [95% CI 1.14–15.3], p = 0.031). Compared to uncoated PVC ETTs, the silicone-coated and noble-metal-coated PVC ETTs were independently associated with reduced high-grade biofilm formation (OR 0.18 [95% CI 0.06–0.59], p = 0.005, and OR 0.34 [95% CI 0.13–0.93], p = 0.036, respectively). No significant difference was observed between silicon-coated ETTs and noble-metal-coated ETTs (OR 0.54 [95% CI 0.17–1.65], p = 0.278). In 60% of the oropharyngeal cultures and 58% of the endotracheal cultures collected at intubation, the same microorganism was found in the ETT biofilm at extubation. In patients who developed VAP, the causative microbe remained in the biofilm in 56% of cases, despite appropriate antibiotic therapy. High-grade biofilm formation on ETTs was not predicted by either colonization with common VAP pathogens in surveillance cultures or duration of invasive ventilation. Conclusion High-grade biofilm formation on ETTs was associated with development of VAP. Compared to the uncoated PVC ETTs, the silicone-coated and noble-metal-coated PVC ETTs were independently associated with reduced high-grade biofilm formation. Further research on methods to prevent, monitor, and manage biofilm occurrence is needed. Trial registration ClinicalTrials.gov NCT02284438. Retrospectively registered on 21 October 2014.

Backgrounds The large, international, randomized controlled NeoPInS trial showed that procalcitonin (PCT)-guided decision making was superior to standard care in reducing the duration of antibiotic therapy and hospitalization in neonates suspected of early-onset sepsis (EOS), without increased adverse events. This study aimed to perform a cost-minimization study of the NeoPInS trial, comparing health care costs of standard care and PCT-guided decision making based on the NeoPInS algorithm, and to analyze subgroups based on country, risk category and gestational age. Methods Data from the NeoPInS trial in neonates born after 34 weeks of gestational age with suspected EOS in the first 72 h of life requiring antibiotic therapy were used. We performed a cost-minimization study of health care costs, comparing standard care to PCT-guided decision making. Results In total, 1489 neonates were included in the study, of which 754 were treated according to PCT-guided decision making and 735 received standard care. Mean health care costs of PCT-guided decision making were not significantly different from costs of standard care (€3649 vs. €3616). Considering subgroups, we found a significant reduction in health care costs of PCT-guided decision making for risk category ‘infection unlikely’ and for gestational age ≥ 37 weeks in the Netherlands, Switzerland and the Czech Republic, and for gestational age Conclusions Health care costs of PCT-guided decision making of term and late-preterm neonates with suspected EOS are not significantly different from costs of standard care. Significant cost reduction was found for risk category ‘infection unlikely,’ and is affected by both the price of PCT-testing and (prolonged) hospitalization due to SAEs.

Sepsis is a common consequence of infection, associated with a mortality rate > 25%. Although community-acquired sepsis is more common, hospital-acquired infection is more lethal. The most common site of infection is the lung, followed by abdominal infection, catheter-associated blood steam infection and urinary tract infection. Gram-negative sepsis is more common than gram-positive infection, but sepsis can also be due to fungal and viral pathogens. To reduce mortality, it is necessary to give immediate, empiric, broad-spectrum therapy to those with severe sepsis and/or shock, but this approach can drive antimicrobial overuse and resistance and should be accompanied by a commitment to de-escalation and antimicrobial stewardship. Biomarkers such a procalcitonin can provide decision support for antibiotic use, and may identify patients with a low likelihood of infection, and in some settings, can guide duration of antibiotic therapy. Sepsis can involve drug-resistant pathogens, and this often necessitates consideration of newer antimicrobial agents.

Sepsis is a common consequence of infection, associated with a mortality rate 25%. Although community-acquired sepsis is more common, hospital-acquired infection is more lethal. The most common site of infection is the lung, followed by abdominal infection, catheter-associated blood steam infection and urinary tract infection. Gram-negative sepsis is more common than gram-positive infection, but sepsis can also be due to fungal and viral pathogens. To reduce mortality, it is necessary to give immediate, empiric, broad-spectrum therapy to those with severe sepsis and/or shock, but this approach can drive antimicrobial overuse and resistance and should be accompanied by a commitment to de-escalation and antimicrobial stewardship. Biomarkers such a procalcitonin can provide decision support for antibiotic use, and may identify patients with a low likelihood of infection, and in some settings, can guide duration of antibiotic therapy. Sepsis can involve drug-resistant pathogens, and this often necessitates consideration of newer antimicrobial agents.

Using biomarkers as a guide to tailor the duration of antibiotic treatment in respiratory infections is an attractive hypothesis assessed in several studies. Recent work aiming to summarize the evidence assessed the effect of a procalcitonin (PCT)-guided antibiotic treatment on outcomes in acute lower respiratory tract infections (LRTI), suggesting that significant reductions in antibiotic duration occur when using a PCT-guided algorithm. However, controversial evidence also suggested PCT-guided algorithms were associated with increased antibiotic duration and increased incidence of Clostridium difficile, without any impact on mortality, in real-world settings. So, although using PCT-guided antibiotic stewardship is promising, after more than a decade of randomized controlled trials on this topic the evidence in its favor is still less than compelling due to limitations in trial design, not taking into consideration fundamental aspects of PCT biology, and the absence of evidence-based antimicrobial duration in intervention and control groups. In this commentary we highlight some questions and limitations of primary PCT study data that might impact interpretation and clinical use of PCT at the bedside.

Background De-escalation is strongly recommended for antibiotic stewardship. No studies have addressed this issue in the context of health care-associated intra-abdominal infections (HCIAI). We analyzed the factors that could interfere with this process and their clinical consequences in intensive care unit (ICU) patients with HCIAI. Methods All consecutive patients admitted for the management of HCIAI who survived more than 3 days following their diagnosis, who remained in the ICU for more than 3 days, and who did not undergo early reoperation during the first 3 days were analyzed prospectively in an observational, single-center study in a tertiary care university hospital. Results Overall, 311 patients with HCIAI were admitted to the ICU. De-escalation was applied in 110 patients (53 %), and no de-escalation was reported in 96 patients (47 %) (escalation in 65 [32 %] and unchanged regimen in 31 [15 %]). Lower proportions of Enterococcus faecium, nonfermenting Gram-negative bacilli (NFGNB), and multidrug-resistant (MDR) strains were cultured in the de-escalation group. No clinical difference was observed at day 7 between patients who were de-escalated and those who were not. Determinants of de-escalation in multivariate analysis were adequate empiric therapy (OR 9.60, 95 % CI 4.02–22.97) and empiric use of vancomycin (OR 3.39, 95 % CI 1.46–7.87), carbapenems (OR 2.64, 95 % CI 1.01–6.91), and aminoglycosides (OR 2.31 95 % CI 1.08–4.94). The presence of NFGNB (OR 0.28, 95 % CI 0.09–0.89) and the presence of MDR bacteria (OR 0.21, 95 % CI 0.09–0.52) were risk factors for non-de-escalation. De-escalation did not change the overall duration of therapy. The risk factors for death at day 28 were presence of fungi (HR 2.64, 95 % CI 1.34–5.17), Sequential Organ Failure Assessment score on admission (HR 1.29, 95 % CI 1.16–1.42), and age (HR 1.03, 95 % CI 1.01–1.05). The survival rate expressed by a Kaplan-Meier curve was similar between groups (log-rank test p value 0.176). Conclusions De-escalation is a feasible option in patients with polymicrobial infections such as HCIAI, but MDR organisms and NFGNB limit its implementation.

Sepsis is one of the oldest and most elusive syndromes in medicine. Every effort should be made to treat these patients with the best available evidence. As a milestone, empiric antimicrobial therapy is essential in order to reduce morbidity and mortality of septic patients. As a sticking point, the use of broad-spectrum antimicrobial agents may be associated with induction of resistance among common pathogens.

Introduction Two small randomized controlled trials have suggested beneficial effects of antibiotic treatment in patients with ventilator-associated tracheobronchitis (VAT). The primary aim of this study is to determine the impact of appropriate antibiotic treatment on transition from VAT to ventilator-associated pneumonia (VAP) in critically ill patients. The secondary objective was to determine the incidence of VAP in patients with VAT. Methods This was a prospective observational multicenter study. All patients with a first episode of VAT were eligible. Patients with tracheostomy at intensive care unit (ICU) admission, and those with VAP prior to VAT were excluded. VAT was defined using all the following criteria: fever > 38°C with no other cause, purulent tracheal secretions, positive tracheal aspirate (≥105 cfu/mL), and absence of new infiltrate on chest X ray. Only VAP episodes diagnosed during the 96 h following VAT, and caused by the same bacteria, were taken into account. Antibiotic treatment was at the discretion of attending physicians. Risk factors for transition from VAT to VAP were determined using univariate and multivariate analysis. All variables from univariate analysis with P values

The impact of appropriate antibiotic therapy on prognosis of patients with septic shock is well established. However, the prognostic influence of time to initiation of antibiotics remains debated. We evaluated the effect on 7-day mortality of time to initiation of appropriate antibiotic therapy in patients hospitalised in critical care for septic shock.

Traditionally infections are divided into community acquired (CAI) or hospital acquired (HAI). The authors study the association between healthcare-associated infections (HCAI) and inappropriate antibiotic therapy and hospital mortality.

The aim was to assess the impact of empiric antibiotic adequacy on ICU outcome of patients with ventilator-associated pneumonia (VAP), the reasons for inadequacy and risk factors for potential multidrug-resistant organisms.

Percutaneous bedside tracheostomy (PBT) is a frequently done procedure in the ICU. PBT is a clean-contaminated procedure, and the duration of the procedure is 15 to 20 minutes depending on the physician's procedural skills. The rate of infectious complications and efficacy of perioperative therapy in reducing infections after PBT is currently unknown. Currently there have been no definitive recommendations for prophylactic antibiotic therapy before PBT in the ICU.

Ventilator-associated pneumonia (VAP) is a common and serious problem in ICUs. Several studies have been conducted to determine the effectiveness of Gram stain of tracheal aspirates for diagnosing VAP. However, the effectiveness for predicting causative microorganisms and guiding appropriate initial antibiotic therapy has not been evaluated. The purpose of this study is to determine whether Gram stain of tracheal aspirates can guide appropriate initial antibiotic therapy for VAP.

Amikacin Inhale is an integrated drug-device combination in development by Bayer HealthCare through a collaboration with Nektar Therapeutics, to improve clinical outcome in intubated and mechanically ventilated patients with Gram-negative pneumonia. It is available in two configurations: on-vent for intubated patients and hand-held for extubated patients to complete aerosolized antibiotic therapy. Amikacin Inhale is a smart system that consists of the pulmonary drug delivery system with a vibrating mesh nebulizer and the specially formulated Amikacin Inhalation Solution (400 mg every 12 hours for 10 days). The objectives of this study were to evaluate the performance of the Amikacin Inhale hand-held configuration with supplemental O2 concentration supplied at different flow rates and in different orientations. We hypothesize that the delivered dose of amikacin will not significantly change with increased O2 flow rate or varying orientation.

The importance of imaging in establishing the focus of infection is recognised in current guidelines for the management of severe sepsis [1], with decisions regarding timing and modality of imaging left to the physicians' clinical judgement. In the emergency department (ED), clinical assessment combined with bedside investigations of chest X-ray (CXR) and urine dip can be used to confirm the two most common sources [2]. However, they may fail to identify occult sources of infection, such as intraabdominal collections and abscesses, the treatment of which may require alteration of empirical treatment or be refractory to antibiotic therapy alone. Further imaging is necessary to confirm the focus so that optimal treatment can be achieved.

In 2002 the international Surviving Sepsis Campaign was initiated. Following this, Dutch authorities introduced a nationwide safety campaign, encouraging screening for sepsis and advocating early treatment. In 2010, the Albert Schweitzer hospital, a large community hospital, introduced a screening program for sepsis in the emergency department (ED) [1]. The goal of this study was to evaluate the bacterial outcome in patients targeted with this campaign.

The administration of timely and appropriate antibiotic therapy is a well-known prognostic factor among severe sepsis patients [1-4]. The purpose of this study is to describe the magnitude of the impact of early and appropriate empirical antibiotic therapy on hospital mortality.

Introduction The optimal duration of antibiotic therapy for bloodstream infections is unknown. Shorter durations of therapy have been demonstrated to be as effective as longer durations for many common infections; similar findings in bacteremia could enable hospitals to reduce antibiotic utilization, adverse events, resistance and costs. Methods A search of the MEDLINE, EMBASE and COCHRANE databases was conducted for the years 1947-2010. Controlled trials were identified that randomized patients to shorter versus longer durations of treatment for bacteremia, or the infectious foci most commonly causing bacteremia in critically ill patients (catheter-related bloodstream infections (CRBSI), intra-abdominal infections, pneumonia, pyelonephritis and skin and soft-tissue infections (SSTI)). Results Twenty-four eligible trials were identified, including one trial focusing exclusively on bacteremia, zero in catheter related bloodstream infection, three in intra-abdominal infection, six in pyelonephritis, thirteen in pneumonia and one in skin and soft tissue infection. Thirteen studies reported on 227 patients with bacteremia allocated to 'shorter' or 'longer' durations of treatment. Outcome data were available for 155 bacteremic patients: neonatal bacteremia (n = 66); intra-abdominal infection (40); pyelonephritis (9); and pneumonia (40). Among bacteremic patients receiving shorter (5-7 days) versus longer (7-21 days) antibiotic therapy, no significant difference was detected with respect to rates of clinical cure (45/52 versus 47/49, risk ratio 0.88, 95% confidence interval [CI] 0.77-1.01), microbiologic cure (28/28 versus 30/32, risk ratio 1.05, 95% CI 0.91-1.21), and survival (15/17 versus 26/29, risk ratio 0.97, 95% CI 0.76-1.23). Conclusions No significant differences in clinical cure, microbiologic cure and survival were detected among bacteremic patients receiving shorter versus longer duration antibiotic therapy. An adequately powered randomized trial of bacteremic patients is needed to confirm these findings.

Pneumonia remains one of the commonest infectious causes of intensive care unit (ITU) admissions. Despite recent advances, mortality in the ITU from this diagnosis remains around 50% [1]. Early targeted antibiotic therapy to minimise the development of ventilator-associated pneumonia is recommended [2]. This requires an updated knowledge of aetiology of this common diagnosis in ITU settings.

Clara cell protein 10 (CC-10) has been associated with inflammatory and infectious pulmonary diseases. This study evaluates CC-10 concentrations in bronchoalveolar lavage (BAL) fluid as a potential marker of ventilator-associated pneumonia (VAP).Between January 2003 and December 2007, BAL fluid samples obtained from critically ill patients at the intensive care unit of the Maastricht University Medical Centre clinically suspected of having VAP were included. Patients were divided into two groups: (1) microbiologically confirmed VAP (the VAP group) and (2) microbiologically unconfirmed VAP (the non-VAP group). The concentration of CC-10 was measured by means of a commercially available enzyme-linked immunosorbent assay kit, and retrospective analysis was performed. Areas under the curve of receiver operating characteristic curves were calculated for CC-10 concentrations.A total of 196 patients (122 men, 74 women) were included. A total of 79 (40%) of 196 cases of suspected VAP were microbiologically confirmed. The median CC-10 concentration in the VAP group was 3,019 ng/mL (range, 282 to 65,546 ng/mL) versus 2,504 ng/mL (range, 62 to 30,240 ng/mL) in the non-VAP group (P = 0.03). There was no significant difference in CC-10 concentrations between patients treated with or without corticosteroids (P = 0.26) or antibiotic therapy (P = 0.9). The CC-10 concentration did not differ significantly between patients with Gram-positive versus Gram-negative bacteria that caused the VAP (P = 0.06). However, CC-10 concentrations did differ significantly between the late-onset VAP group and the non-VAP group.The CC-10 concentration in BAL fluid yielded low diagnostic accuracy in confirming the presence of VAP.

In inflammatory states, particularly in response to infectious stimuli, local procalcitonin (PCT) production rises, and because these tissues cannot further process PCT into calcitonin, serum levels increase. In the critical care setting, PCT should be considered a useful tool to help physicians in some specific, although frequent, situations. Serial measurements of PCT levels may indicate the effectiveness of medical decisions such as the appropriateness of antibiotic therapy, the detection of new infections, and the exclusion of a diagnosis of sepsis. PCT-guided algorithms may also help to decrease the duration of antimicrobial therapy. However, the role of PCT as a prognostic marker in critically ill patients is controversial. In a study by Karlsson and colleagues, PCT concentrations did not differ between hospital survivors and nonsurvivors, but the outcome was better in patients whose PCT concentrations decreased more than 50%. The study of PCT kinetics thus could offer an individual risk assessment in patients with severe sepsis.

In the setting of antimicrobial policy, the French authorities recommend assessing the quality of antibiotic therapy [1]. The aim of this study is to assess the adequacy of antibiotic therapy in the ICU, to good practice guidelines and unit protocols. The three steps of prescription are analysed: choice of treatment, modalities of prescription and treatment follow-up.

Procalcitonin (PCT) offers the possibility of differentiating bacterial infection from viral or non-infectious reactions. PCT can be used to support decision-making on initiation or discontinuation or change of antibiotic therapy. Our aim was to determine the usefulness of PCT in our ICU.

Prompt initiation of appropriate antibiotic therapy improves outcome in critically ill patients [1]. In a tertiary-level ICU, we evaluated the appropriateness of, and adherence to an antibiotic guideline (based on local bacterial epidemiology) in CDC-defined hospital-associated infections.

Introduction Procalcitonin (PCT) and C-reactive protein (CRP) are established markers of infection in the general population. In contrast, several studies reported falsely increased PCT levels in patients receiving T-cell antibodies. We evaluated the validity of these markers in patients scheduled for hemopoietic stem cell transplantation receiving anti-thymocyte globulin (ATG) during conditioning. We also assessed renal and liver functions and their relationship to PCT and CRP changes. Methods Twenty-six patients without clinical signs of infection were prospectively studied. ATG was administered in up to three doses over the course of 5 days. PCT, CRP, white blood cell (WBC) count, urea, creatinine, glomerular filtration rate, bilirubin, alanin amino-transferase (ALT), and gamma-glutamyl transferase (GGT) were assessed daily during ATG administration. Pharyngeal, nose, and rectal swabs and urine samples were cultured twice weekly. Blood cultures were obtained if clinical symptoms of infection were present. Results Baseline (BL) levels of both PCT and CRP before ATG administration were normal. WBC count decreased after ATG administration (P = 0.005). One day after ATG administration, both PCT and CRP levels increased significantly, returning to BL levels on day 4. Microbiological results were clinically unremarkable. There was no interrelationship between PCT levels and BL markers of renal or liver functions (P > 0.05 for all comparisons). Bilirubin and GGT were increased on days 2 to 5 and ALT was increased on day 3 (P < 0.05 versus BL). No difference in renal functions was observed. Three patients developed bacterial infection on days 7 to 11 with different dynamics of PCT and CRP. There was no association between the number of ATG doses and PCT levels or between the risk of developing infection and previous PCT levels. Conclusions ATG triggered a marked early surge in PCT and CRP followed by a steady decrease over the course of 3 days. The dynamics of both PCT and CRP were similar and were not associated with infection. PCT levels were independent of renal and liver functions and were not predictive of further infectious complications. A direct effect of ATG on T lymphocytes could be the underlying mechanism. Hepatotoxic effect could be a contributing factor. Neither PCT nor CRP is a useful marker that can identify infection in patients receiving ATG.

The Surviving Sepsis Campaign Guideline 2008 [1] recommends starting appropriate antibiotic therapy within 1 hour after making the diagnosis of septic shock. In the ICU of our emergency center, we perform empiric antibiotic therapy for septic shock patients within 6 hours after admission.

Procalcitonin (PCT) is routinely used as a specific marker of severe bacterial infections and sepsis. The highly sensitive method of PCT measurement allows using PCT as a marker of local bacterial infections. By this method, the normal value of PCT is defined as < 0.25 ng/ml – but according to some publications PCT < 0.1 ng/ml is a more reliable cutoff point to reject diagnosis of local bacterial infection. Some patients after major surgery have nonspecific signs of infection (for example, fever, leukocytosis) that is usually discussed as true infection and antibiotic therapy (ABT) is provided. We tried to optimize ABT in patients undergoing cardiac surgery with cardiopulmonary bypass using PCT.

A procalcitonin (PCT) algorithm was demonstrated to reduce antibiotic exposure in patients with lower respiratory tract infections (LRTI) in several randomised controlled trials. Data on the efficacy of PCT-guided antibiotic stewardship in real life and outside study conditions are lacking.

Appropriate antibiotic therapy in patients with severe sepsis and septic shock should mean prompt achievement and maintenance of optimal exposure at the infection site with broad-spectrum antimicrobial agents administered in a timely manner. Once the causative pathogens have been identified and tested for in vitro susceptibility, subsequent de-escalation of antimicrobial therapy should be applied whenever feasible. The goal of appropriate antibiotic therapy must be pursued resolutely and with continuity, in view of the ongoing explosion of antibiotic-resistant infections that plague the intensive care unit setting and of the continued decrease in new antibiotics emerging. This article provides some principles for the correct handling of antimicrobial dosing regimens in patients with severe sepsis and septic shock, in whom various pathophysiological conditions may significantly alter the pharmacokinetic behaviour of drugs.

Intervention: Using a 2-by-2 factorial design, subjects were randomly assigned to a) undergo bronchoalveolar lavage with quantitative culture of the bronchoalveolar-lavage fluid or endotracheal aspiration with nonquantitative culture of the aspirate, and to b) receive empirical combination antibiotic therapy or monotherapy. Empirical antibiotic therapy was initiated in all patients until culture results were available, at which point a protocol of targeted therapy was used for discontinuing or reducing the dose or number of antibiotics, or for resuming antibiotic therapy to treat a preenrollment condition if the culture was negative.

The article by Hochreiter and colleagues on the use of procalcitonin to guide duration of antibiotic therapy in intensive care patients is timely and significant, but it raises a number of unresolved issues [1]. First, it was entirely appropriate that the physician in charge of the surgical intensive care ward had the option to proceed with or to adjust the antibiotic treatment if there were clinical reasons to do so. Whether such adjustments were made either in the control group or in the procalcitonin-guided antibiotic therapy group, however, is not clear. Second, Table 1 in their article indicates a longer number of days in intensive care for those patients in the control group than for those undergoing procalcitonin-guided antibiotic therapy [1]. Since 36% of the patients in each group did not survive, however, the length of stay in intensive care for both groups may be confounded by death. Finally, again in Table 1 [1], were there differences in outcome for those patients diagnosed with pneumonia and those diagnosed with peritonitis in either the control group or the procalcitonin-guided antibiotic therapy group? Despite more than 10 years of research into the usefulness of procalcitonin therapy, Hausfater is right to point out that 'its exact place in the diagnostic process remains to be defined' [2]. Both the articles of McLean and of Christ-Crain and Muller have proposed further study of alternative novel biomarkers [3,4]. Early diagnosis of sepsis linked to timely but limited use of antibiotics remains paramount, whichever biomarkers make it possible to save more patients' lives in intensive care.