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Author(s): Jordi Rello [sup.1] [sup.2] [sup.3], Adrien Bouglé [sup.4], Jean-Jacques Rouby [sup.5] Author Affiliations: (1) grid.430994.3, 0000 0004 1763 0287, Global Health eCore, Vall d'Hebron Institute of Research (VHIR), , [...]

Global emergence of multidrug-resistant and extensive drug-resistant gram-negative bacteria has increased the risk of treatment failure, especially for healthcare- or ventilator-associated pneumonia (HAP/VAP). Nebulization of antibiotics, by providing high intrapulmonary antibiotic concentrations, represents a promising approach to optimize the treatment of HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria, while limiting systemic antibiotic exposure. Aminoglycosides and colistin methanesulfonate are the most common nebulized antibiotics. Although optimal nebulized drug dosing regimen is not clearly established, high antibiotic doses should be administered using vibrating-mesh nebulizer with optimized ventilator settings to ensure safe and effective intrapulmonary concentrations. When used preventively, nebulized antibiotics reduced the incidence of VAP without any effect on mortality. This approach is not yet recommended and large randomized controlled trials should be conducted to confirm its benefit and explore the impact on antibiotic selection pressure. Compared with high-dose intravenous administration, high-dose nebulized colistin methanesulfonate seems to be more effective and safer in the treatment of ventilator-associated tracheobronchitis and VAP caused by multidrug resistant and extensive-drug resistant gram-negative bacteria. Adjunctive nebulized aminoglycosides could increase the clinical cure rate and bacteriological eradication in patients suffering from HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria. As nebulized aminoglycosides broadly diffuse in the systemic circulation of patients with extensive bronchopneumonia, monitoring of plasma trough concentrations is recommended during the period of nebulization. Large randomized controlled trials comparing high dose of nebulized colistin methanesulfonate to high dose of intravenous colistin methanesulfonate or to intravenous new β-lactams in HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria are urgently needed. [ABSTRACT FROM AUTHOR]

Background: Transmission of antimicrobial-resistant Gram-negative bacteria (AMR-GNB) amongst hospitalised patients can lead to new cases of carriage, infection and outbreaks, hence the need for early carrier identification. We aim to explore two key elements that may guide control policies for colonisation/infection in hospital settings: screening practices on admission to hospital wards and risk of developing infection from colonisation.Methods: We searched on PubMed, Scopus and Cochrane databases for studies published from 2010 up to 2021 reporting on adult patients hospitalised in high-income countries.Results: The search retrieved 11,853 articles. After screening, 100 studies were included. Combining target patient groups and setting type, we identified six screening approaches. The most reported approach was all admitted patients to high-risk (HR) wards (49.4%). The overall prevalence of AMR-GNB was 13.8% (95%CI 9.3-19.0) with significant differences across regions and time. Risk of progression to infection amongst colonised patients was 11.0% (95%CI 8.0-14.3) and varied according to setting and pathogens' group (p value<0.0001), with higher values reported for Klebsiella species (18.1%; 95%CI 8.9-29.3).Conclusions: While providing a comprehensive overview of the screening approaches, our study underlines the considerable burden of AMR-GNB colonisation and risk of progression to infection in hospitals by pathogen, setting and time. [ABSTRACT FROM AUTHOR]

Background: Antibiotics may be indicated in patients with COVID-19 due to suspected or confirmed bacterial superinfection.Objectives: To investigate antibiotic prescribing practices in patients with COVID-19.Methods: We performed an international web-based survey and investigated the pattern of antibiotic use as reported by physicians involved in treatment of COVID-19. SPSS Statistics version 25 was used for data analysis.Results: The survey was completed by 166 participants from 23 countries and 82 different hospitals. Local guidelines for antibiotic use in COVID-19 patients were reported by 61.8% (n = 102) of participants and for 82.9% (n = 136) they did not differ from local community-acquired pneumonia guidelines. Clinical presentation was recognized as the most important reason for the start of antibiotics (mean score = 4.07 and SD = 1.095 on grading scale from 1 to 5). When antibiotics were started, most respondents rated as the highest the need for coverage of atypical pathogens (mean score = 2.8 and SD = 0.99), followed by Staphylococcus aureus (mean score = 2.67 and SD = 1.05 on bi-modal scale, with values 1 and 2 for disagreement and values 3 and 4 for agreement). In the patients on the ward, 29.1% of respondents chose not to prescribe any antibiotic. Combination of β-lactams and macrolides or fluoroquinolones was reported by 52.4% (n = 87) of respondents. In patients in the ICU, piperacillin/tazobactam was the most commonly prescribed antibiotic. The mean reported duration of antibiotic treatment was 7.12 (SD = 2.44) days.Conclusions: The study revealed widespread broad-spectrum antibiotic use in patients with COVID-19. Implementation of antimicrobial stewardship principles is warranted to mitigate the negative consequences of antibiotic therapy. [ABSTRACT FROM AUTHOR]

Background: Patients with severe bacterial infections often experience delay in receiving appropriate treatment. Consolidated evidence of the impact of delayed appropriate treatment is needed to guide treatment and improve outcomes.Research Question: What is the impact of delayed appropriate antibacterial therapy on clinical outcomes in patients with severe bacterial infections?Study Design and Methods: Literature searches of MEDLINE and Embase, conducted on July 24, 2018, identified studies published after 2007 reporting the impact of delayed appropriate therapy on clinical outcomes for hospitalized adult patients with bacterial infections. Where appropriate, results were pooled and analyzed with delayed therapy modeled three ways: delay vs no delay in receiving appropriate therapy; duration of delay; and inappropriate vs appropriate initial therapy. This article reports meta-analyses on the effect of delay and duration of delay.Results: The eligibility criteria were met by 145 studies, of which 37 contributed data to analyses of effect of delay. Mortality was significantly lower in patients receiving appropriate therapy without delay compared with those experiencing delay (OR, 0.57; 95% CI, 0.45-0.72). Mortality was also lower in the no-delay group compared with the delay group in subgroups of studies reporting mortality at 20 to 30 days, during ICU stay, or in patients with bacteremia (OR, 0.57 [95% CI, 0.43-0.76]; OR, 0.47 [95% CI, 0.27-0.80]; and OR, 0.54 [95% CI, 0.40-0.75], respectively). No difference was found in time to appropriate therapy between those who died and those who survived (P = .09), but heterogeneity between studies was high.Interpretation: Avoiding delayed appropriate therapy is essential to reduce mortality in patients with severe bacterial infections.Clinical Trial Registration: PROSPERO; No.: CRD42018104669; URL: www.crd.york.ac.uk/prospero/. [ABSTRACT FROM AUTHOR]

Community-acquired pneumonia (CAP) is the leading cause of death among infectious diseases and an important health problem, having considerable implications for healthcare systems worldwide. Despite important advances in prevention through vaccines, new rapid diagnostic tests and antibiotics, CAP management still has significant drawbacks. Mortality remains very high in severely ill patients presenting with respiratory failure or shock but is also high in the elderly. Even after a CAP episode, higher risk of death remains during a long period, a risk mainly driven by inflammation and patient-related co-morbidities. CAP microbiology has been altered by new molecular diagnostic tests that have turned viruses into the most identified pathogens, notwithstanding uncertainties about the specific role of each virus in CAP pathogenesis. Pneumococcal vaccines also impacted CAP etiology and thus had changed Streptococcus pneumoniae circulating serotypes. Pathogens from specific regions should also be kept in mind when treating CAP. New antibiotics for CAP treatment were not tested in severely ill patients and focused on multidrug-resistant pathogens that are unrelated to CAP, limiting their general use and indications for intensive care unit (ICU) patients. Similarly, CAP management could be personalized through the use of adjunctive therapies that showed outcome improvements in particular patient groups. Although pneumococcal vaccination was only convincingly shown to reduce invasive pneumococcal disease, with a less significant effect in pneumococcal CAP, it remains the best therapeutic intervention to prevent bacterial CAP. Further research in CAP is needed to reduce its population impact and improve individual outcomes. [ABSTRACT FROM AUTHOR]

Introduction: The rise of antibiotic resistance, the limited efficacy and the adverse events associated with antibiotics have urged the development of alternative measures to treat bacterial infections. Novel therapies which are pathogen specific and are safer to the healthy microbiome are being developed. Areas covered: This manuscript provides a compact overview of the feasibility and clinical impact of the latest novel therapies, with a focus on monoclonal antibodies (mAbs), vaccines, stem cells, bacteriophages, and liposomes. This is a follow-up of a previous manuscript (doi: 10.1080/17512433.2016.1241141); a database search (PubMed, EMBASE, Cochrane) was used to identify recently published literature (from January 2016) which was not covered in the previous publication. Expert opinion: Among non-traditional agents, monoclonal antibodies have not been as successful as in other therapeutic areas. In particular many are developed to prevent hospital-acquired infections caused by S. aureus or P. aeruginosa and, so far, results have been overall disappointing. Stem cells and bacteriophages still have a long way to go. Vaccines are always desirable to prevent infections but again there is a lack of confirmatory results. Broad spectrum liposomes have shown promising results in treating severely infected patients and could be game changers in patient management. [ABSTRACT FROM AUTHOR]

The increasing emergence of multidrug-resistant organisms creates a therapeutic challenge for physicians treating ventilator-associated respiratory infections. As the production of new systemic antibiotics lags far behind the emergence of worsening antibiotic resistance, intensivists are turning to inhaled antibiotics to use as adjunctive therapy. When given properly, these drugs can provide high concentrations of drug in the lung that could not be achieved with intravenous antibiotics without significant systemic toxicity. This review summarizes current evidence describing the use of inhaled antibiotics for the treatment of bacterial ventilator-associated infections. Inhaled adjunctive therapy has been described in numerous small nonrandomized studies and in six recent randomized placebo-controlled trials. Inhaled therapy has also been used to treat ventilator-associated tracheobronchitis. These preliminary data suggest aerosolized delivery of antimicrobials may effectively treat resistant pathogens with high minimum inhibitory concentrations when used in time-limited protocols and delivered with devices known to deposit antibiotics in the area of infection. Large, multisite, clinical, randomized placebo-controlled studies are needed to confirm these data. [ABSTRACT FROM AUTHOR]

BACKGROUND: Intratracheal antibiotic administration is increasingly used for treating respiratory infections. Limited information is available on delivery devices, techniques, and safety. METHODS: An online survey on intratracheal administration of anti-infective agents in mechanically ventilated adults was answered by health-care workers from 192 ICUs to assess the most commonly used devices, current delivery practices, and safety issues. We investigated whether ICU usage experience (≥3 y) impacted its performance. RESULTS: Intratracheal antibiotic administration was a current practice in 87 ICUs (45.3%), with 40 (46%) having experience with the technique ≥S3 y). Sixty-six (78.6%) of 84 health-care workers reported avoiding intratracheal antibiotic administration due to an absence of evidence-based guidelines (78.6%). Jet nebulizers were the most commonly used devices for delivery, in 24 less experienced ICUs (27.6%) and in 18 (20.7%) experienced ICUs. Direct tracheal instillation (6; 6.9%) was still considered for drug prescription in 12 ICUs (6.9%). More experience resulted in neither greater adherence to measures improving the drug's delivery efficiency (93 measures in the experienced group; 27.9%) nor a greater adoption of measures to increase safety. Indeed, the expiratory filter was changed after each nebulization in only 2 experienced ICUs (6.9%), whereas 15 (51.7%) changed it daily instead. CONCLUSIONS: Intratracheal antibiotic administration is a common therapeutic modality in ICUs, but inadequate practices were widely encountered, independent of the level of experience with the technique. This suggests a need to develop standardization to reduce variability and improve safety and efficacy. [ABSTRACT FROM AUTHOR]

Background: Severe sepsis, may be present on hospital arrival in approximately one-third of patients with community-acquired pneumonia (CAP). Objective: To determine the host characteristics and micro-organisms associated with severe sepsis in patients hospitalized with CAP. Results: We performed a prospective multicenter cohort study in 13 Spanish hospital, on 4070 hospitalized CAP patients, 1529 of whom (37.6%) presented with severe sepsis. Severe sepsis CAP was independently associated with older age (>65 years), alcohol abuse (OR, 1.31; 95% CI, 1.07–1.61), chronic obstructive pulmonary disease (COPD) (OR, 1.75; 95% CI, 1.50–2.04) and renal disease (OR, 1.57; 95% CI, 1.21–2.03), whereas prior antibiotic treatment was a protective factor (OR, 0.62; 95% CI, 0.52–0.73). Bacteremia (OR, 1.37; 95% CI, 1.05–1.79), S pneumoniae (OR, 1.59; 95% CI, 1.31–1.95) and mixed microbial etiology (OR, 1.65; 95% CI, 1.10–2.49) were associated with severe sepsis CAP. Conclusions: CAP patients with COPD, renal disease and alcohol abuse, as well as those with CAP due to S pneumonia or mixed micro-organisms are more likely to present to the hospital with severe sepsis. [ABSTRACT FROM AUTHOR]

Objectives: We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic/pharmacodynamic and clinical outcomes between prolonged-infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies.Methods: This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries.Results: Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT>MIC (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic/pharmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving β-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30); P = 0.012]. Additionally, in patients with a SOFA score of ≥9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20); P = 0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20); P = 0.025].Conclusions: Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to compare intensive care unit mortality due to non-pneumococcal severe community-acquired pneumonia between the periods 2000-2002 and 2008-2014, and the impact of the improvement in antibiotic strategies on outcomes.Methods: This was a matched case-control study enrolling 144 patients with non-pneumococcal severe pneumonia: 72 patients from the 2000-2002 database (CAPUCI I group) were paired with 72 from the 2008-2014 period (CAPUCI II group), matched by the following variables: microorganism, shock at admission, invasive mechanical ventilation, immunocompromise, chronic obstructive pulmonary disease, and age over 65 years.Results: The most frequent microorganism was methicillin-susceptible Staphylococcus aureus (22.1%) followed by Legionella pneumophila and Haemophilus influenzae (each 20.7%); prevalence of shock was 59.7%, while 73.6% of patients needed invasive mechanical ventilation. Intensive care unit mortality was significantly lower in the CAPUCI II group (34.7% versus 16.7%; odds ratio (OR) 0.78, 95% confidence interval (CI) 0.64-0.95; p = 0.02). Appropriate therapy according to microorganism was 91.5% in CAPUCI I and 92.7% in CAPUCI II, while combined therapy and early antibiotic treatment were significantly higher in CAPUCI II (76.4 versus 90.3% and 37.5 versus 63.9%; p < 0.05). In the multivariate analysis, combined antibiotic therapy (OR 0.23, 95% CI 0.07-0.74) and early antibiotic treatment (OR 0.07, 95% CI 0.02-0.22) were independently associated with decreased intensive care unit mortality.Conclusions: In non-pneumococcal severe community-acquired pneumonia , early antibiotic administration and use of combined antibiotic therapy were both associated with increased intensive care unit survival during the study period. [ABSTRACT FROM AUTHOR]

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The article discusses the concept of salvage treatment used in anti-cancer chemotherapy. It examines a survey conducted on the patients to understand the change in the attitude and behaviour. It proposes that various drugs including colistin, fosfomycin, and meropenem are misused and the need for surveillance of medications.

Summary Lower respiratory tract infections in mechanically ventilated patients are a frequent cause of antibiotic treatment in intensive-care units. These infections present as severe sepsis or septic shock with respiratory dysfunction in intubated patients. Purulent respiratory secretions are needed for diagnosis, but distinguishing between pneumonia and tracheobronchitis is not easy. Both presentations are associated with longlasting mechanical ventilation and extended intensive-care unit stay, providing a rationale for antibiotic treatment initiation. Differentiation of colonisers from true pathogens is difficult, and microbiological data show Staphylococcus aureus and Pseudomonas aeruginosa to be of great concern because of clinical outcomes and therapeutic challenges. Key management issues include identification of the pathogen, choice of initial empirical antibiotic, and decisions with regard to the resolution pattern. [ABSTRACT FROM AUTHOR]

Background: Infectious complications are frequent in severe acute pancreatitis (SAP) but multinational epidemiologic data are lacking. The aim of the study was to analyze the characteristics of the infectious complications and antimicrobial use in this setting. Methods: One-day point prevalence study of infection in critically ill patients (Extended Prevalence of Infection in the ICU-II study), performed in 1,265 ICUs in 75 countries. Results: Of the 13,796 patients in the study, 159 were admitted with SAP. One-hundred sixteen (73%) had infections: 31% intra-abdominal, 16% extra-abdominal, and 26% both. Gram-negative bacteria were more prevalent than gram-positive organisms, anaerobes, or fungi. Therapeutically, penicillins and other beta-lactams were used most frequently. Prophylactic antibiotics were administered to 24% of the patients with SAP. Conclusions: Infections are frequent in patients admitted with SAP; most are intra-abdominal infections. Microbiology is diverse with gram-negative micro-organisms most frequently isolated. Most patients admitted to the ICU for SAP receive antibiotics at some point. [ABSTRACT FROM AUTHOR]

The article presents a study which compared the antibiotic prescribing practices and survival in the intensive care unit (ICU) for patients with pneumococcal severe community-acquired pneumonia (SCAP) in 2000-2013. In the study, 80 patients from the Community-Acquired Pneumonia en la Unidad de Cuidados Intensivos (CAPUCI) II study were matched from CAPUCI I. The data obtained include shock at admission, need of mechanical ventilation, and immunosuppression.

It remains unknown whether the type of aerosol generating device is affecting efficacy and safety among non-cystic fibrosis bronchiectasis (NCFB) adults. The proposal of this network meta-analysis (NMA) is to evaluate effectiveness and safety of inhaled antibiotics administered via dry powder inhaler (DPI) and via nebulizers (SVN) among adult patients with NCFB. Inclusion criteria were randomized-controlled trials, adults (≥18 years) with NCFB, and inhaled antibiotics administered via DPI as intervention. Search strategy was performed in PubMed, Web of Science, and Cochrane Library from 2000 to 2019. Sixteen trials (2870 patients) were included. Three trials (all ciprofloxacin) used DPIs and thirteen used SVN (three ciprofloxacin). Both DPI and SVN devices achieved similar safety outcomes (adverse events, antibiotic discontinuation, severe adverse events, and bronchospasm). Administration of ciprofloxacin via DPI significantly improved time to first exacerbation (87 days, 95% CI 34.3–139.7) and quality of life (MD −7.52; 95% CI −13.06 to −1.98) when compared with via SVN. No other significant differences were documented in clinical efficacy (at least one exacerbation, FEV1% predicted) and microbiologic response (bacterial eradication, emergence of new potential pathogens, and emergence of antimicrobial resistance) when comparing devices. Our NMA documented that time to first exacerbation and quality of life, were more favorable for DPIs. Decisions on the choice of devices should incorporate these findings plus other criteria, such as simplicity, costs or maintenance requirements. [ABSTRACT FROM AUTHOR]

Purpose: As per 2005 American Thoracic Society and Infectious Disease Society of America (ATS/IDSA) guidelines for managing hospital-acquired pneumonia, patients with early-onset pneumonia and without risk factors do not need to be treated for potentially resistant microorganisms (PRM). Methods: This was a secondary analysis of a prospective, observational, cohort, multicentre study conducted in 27 ICUs from nine European countries. Results: From a total of 689 patients with nosocomial pneumonia who required mechanical ventilation, 485 patients with confirmed etiology and antibiotic susceptibility were further analysed. Of these patients, 152 (31.3 %) were allocated to group 1 with early-onset pneumonia and no risk factors for PRM acquisition, and 333 (68.7 %) were classified into group 2 with early-onset pneumonia with risk factors for PRM or late-onset pneumonia. Group 2 patients were older and had more chronic renal failure and more severe illness (SAPS II score, 44.6 ± 16.5 vs. 47.4 ± 17.8, p = 0.04) than group 1 patients. Trauma patients were more frequent and surgical patients less frequent in group 1 than in group 2 ( p < 0.01). In group 1, 77 patients (50.7 %) had PRM in spite of the absence of classic risk factors recognised by the current guidelines. A logistic regression analysis identified that presence of severe sepsis/septic shock (OR = 3.7, 95 % CI 1.5-8.9) and pneumonia developed in centres with greater than 25 % prevalence of PRM (OR = 11.3, 95 % CI 2.1-59.3) were independently associated with PRM in group 1 patients. Conclusions: In patients admitted to ICUs with a prevalence of PRM greater than 25 % or with severe sepsis/septic shock, empiric therapy for group 1 nosocomial pneumonia requiring mechanical ventilation should also include agents likely to be effective for PRM pathogens. [ABSTRACT FROM AUTHOR]

Initial care has been associated with improved survival of community-acquired pneumonia (CAP). We aimed to investigate patient comorbidities and health status measured by the Charlson index and clinical signs at diagnosis associated with adherence to recommended processes of care in CAP. We studied 3844 patients hospitalized with CAP. The evaluated recommendations were antibiotic adherence to Spanish guidelines, first antibiotic dose <6 hours and oxygen assessment. Antibiotic adherence was 72.6%, first dose <6 h was 73.4% and oxygen assessment was 90.2%. Antibiotic adherence was negatively associated with a high Charlson score (Odds ratio [OR], 0.91), confusion (OR, 0.66) and tachycardia ≥100 bpm (OR, 0.77). Delayed first dose was significantly lower in those with tachycardia (OR, 0.75). Initial oxygen assessment was negatively associated with fever (OR, 0.61), whereas tachypnea ≥30 (OR, 1.58), tachycardia (OR, 1.39), age >65 (OR, 1.51) and COPD (OR, 1.80) were protective factors. The combination of antibiotic adherence and timing <6 hours was negatively associated with confusion (OR, 0.69) and a high Charlson score (OR, 0.92) adjusting for severity and hospital effect, whereas age was not an independent factor. Deficient health status and confusion, rather than age, are associated with lower compliance with antibiotic therapy recommendations and timing, thus identifying a subpopulation more prone to receiving lower quality care. [ABSTRACT FROM AUTHOR]

Background: The clinical effects of varying pharmacokinetic exposures of antibiotics (antibacterials and antifungals) on outcome in infected critically ill patients are poorly described. A large-scale multi-centre study (DALI Study) is currently underway describing the clinical outcomes of patients achieving pre-defined antibiotic exposures. This report describes the protocol. Methods: DALI will recruit over 500 patients administered a wide range of either beta-lactam or glycopeptide antibiotics or triazole or echinocandin antifungals in a pharmacokinetic point-prevalence study. It is anticipated that over 60 European intensive care units (ICUs) will participate. The primary aim will be to determine whether contemporary antibiotic dosing for critically ill patients achieves plasma concentrations associated with maximal activity. Secondary aims will compare antibiotic pharmacokinetic exposures with patient outcome and will describe the population pharmacokinetics of the antibiotics included. Various subgroup analyses will be conducted to determine patient groups that may be at risk of very low or very high concentrations of antibiotics. Discussion: The DALI study should inform clinicians of the potential clinical advantages of achieving certain antibiotic pharmacokinetic exposures in infected critically ill patients. [ABSTRACT FROM AUTHOR]

The article examines antibiotic dosing for patients with septic shock who are also suffering from multiple organ dysfunction syndrome (MODS). According to the authors, that two factors that produce significant variation in terms of pharmacokinetics and pharmacodynamics among MODS patients are drug volume of distribution and clearance. They add that disease and clinician-driven changes often lead to increased distribution volume and lower plasma drug concentrations during the first days of treatment.

The article discusses a study which investigated the extent and patterns of infection in intensive care units (ICU). The study collected data for several patients in 1265 participating ICUs from 75 countries during the study day, and analyses focused on patients 18 years or older. It was found that 7087 of 13,796 patients were infected, while 9084 were receiving antibiotics. The study also concluded that infections are common in patients in contemporary ICUs and there is high risk of infection with duration of stay in the ICUs.

It remains uncertain why immunocompetent patients with bacterial community-acquired pneumonia (CAP) die, in spite of adequate antibiotics. This is a secondary analysis of the CAPUCI database which was a prospective observational multicentre study. Two hundred and twelve immunocompetent patients admitted to 33 Spanish ICUs for CAP were analyzed. Comparisons were made for lifestyle risk factors, comorbidities and severity of illness. ICU mortality was the principal outcome variable. Bacteremic CAP (43.3 vs. 21.1%) and empyema (11.5 vs. 2.2%) were more frequent ( P < 0.05) in patients with Streptococcus pneumoniae CAP. Higher rates of adequate empiric therapy (95.8 vs. 75.5%, P < 0.05) were observed in patients with S. pneumoniae CAP. Patients with non-pneumococcal CAP experienced more shock (66.7 vs. 50.8%, P < 0.05), and need for mechanical ventilation (83.3 vs. 61.5%, P < 0.05). ICU mortality was 20.7 and 28% [OR 1.49(0.74–2.98)] among immunocompetent patients with S. pneumoniae ( n = 122) and non-pneumococci ( n = 90), in spite of initial adequate antibiotic. Multivariable regression analysis in these 184 immunocompetent patients with adequate empirical antibiotic treatment identified the following variables as independently associated with mortality: shock (HR 13.03); acute renal failure (HR 4.79), and APACHE II score higher than 24 (HR 2.22). Mortality remains unacceptably high in immunocompetent patients admitted to the ICU with bacterial pneumonia, despite adequate initial antibiotics and comorbidities management. Patients with shock, acute renal failure and APACHE II score higher than 24 should be considered for inclusion in trials of adjunctive therapy in order to improve CAP survival. [ABSTRACT FROM AUTHOR]

The article presents information on a study assessing the impact of guidelines aiding clinicians in choosing antibiotics to treat patients with severe community-acquired pneumonia (SCAP). The guidelines from the U.S. based Infectious Disease Society of America, on the duration of mechanical ventilation was particularly studied. It was found that failure to follow formal antibiotic-prescribing guidelines in SCAP adversely impacts morbidity and resource use.

Objective: To determine the efficacy of minocycline and rifampin-impregnated catheters compared to non-impregnated catheters in critically ill patients.Design: Prospective, randomized, double-blind, controlled, multicenter trial.Setting: Intensive care units of seven acute-care teaching hospitals in Spain. PATIENTS. Intensive care unit patients requiring triple-lumen central venous catheter for more than 3 days.Interventions: At catheter insertion, 228 patients were randomized to minocycline and rifampin-impregnated catheters and 237 to non-impregnated catheters. Skin, catheter tip, subcutaneous segment, hub cultures, peripheral blood and infusate cultures were performed at catheter withdrawal. The rate of colonization, catheter-related bloodstream infection (CRBSI) and catheter-related clinical infectious complications (purulence at the insertion site or CRBSI) were assessed.Measurements and Main Results: In the intention-to-treat analysis (primary analysis), the episodes per 1000 catheter days of clinical infectious complications decreased from 8.6 to 5.7 (RR =0.67, 95% CI 0.31-1.44), CRBSI from 5.9 to 3.1 (RR =0.53, 95% CI 0.2-1.44) and tip colonization from 24 to 10.4 (RR =0.43, 95% CI 0.26-0.73). Antimicrobial-impregnated catheters were associated with a significant decrease of coagulase-negative staphylococci colonization (RR =0.24, 95% CI 0.13-0.45) and a significant increase of Candida spp. colonization (RR =5.84, 95% CI 1.31-26.1).Conclusions: The use of antimicrobial-impregnated catheters was associated with a significantly lower rate of coagulase-negative staphylococci colonization and a significant increase in Candida spp. colonization, although a decrease in CRBSI, increase in 30-day survival or reduced length of stay was not observed. [ABSTRACT FROM AUTHOR]

We performed a prospective, international, observational study of 844 hospitalized patients with blood cultures positive for Streptococcus pneumoniae. Fifteen percent of isolates had in vitro intermediate susceptibility to penicillin (minimum inhibitory concentration [MIC], 0.12-1 mg/mL), and 9.6% of isolates were resistant (MIC, 32 mg/mL). Age, severity of illness, and underlying disease with immunosuppression were significantly associated with mortality; penicillin resistance was not a risk factor for mortality. The impact of concordant antibiotic therapy (i.e., receipt of a single antibiotic with in vitro activity against S. pneumoniae) versus discordant therapy (inactive in vitro) on mortality was assessed at 14 days. Discordant therapy with penicillins, cefotaxime, and ceftriaxone (but not cefuroxime) did not result in a higher mortality rate. Similarly, time required fordefervescence and frequency of suppurative complications were not associated with concordance of b-lactam antibiotic therapy. b-Lactam antibiotics should still be useful for treatment of pneumococcal infections that do not involve cere-brospinal fluid, regardless of in vitro susceptibility, as determined by current NCCLS breakpoints. [ABSTRACT FROM AUTHOR]

Therapy of ventilator-associated pneumonia should be a patient-based approach focusing on some key features are listed here: early initial therapy should be based on broad-spectrum antibiotics. Empirical treatment may be targeted after direct staining and should be modified according to good-quality quantitative microbiological findings, but should never be withdrawn in presence of negative direct staining or delayed until microbiological results are available. Courses of therapy should be given at high doses according to pharmacodynamic and tissue penetration properties. Prolonging antibiotic treatment does not prevent recurrences. Methicillin-sensitive Staphylococcus aureus should be expected in comatose patients. Methicillin-resistant Staphylococcus aureus should not be expected in patients without previous antibiotic coverage. Pseudomonas aeruginosa should be covered with combination therapy. Antifungal therapy, even when Candida spp is isolated in significant concentrations, is not recommended for intubated nonneutropenic patients. Vancomycin, given at the standard doses and route of administration for the treatment of VAP caused by Gram-positive pathogens, is associated with poor outcomes. The choice of initial antibiotic should be based on the patient's previous antibiotic exposure and comorbidities, and local antibiotic susceptibility patterns, which should be updated regularly. [ABSTRACT FROM AUTHOR]

Design: The objectives were to characterize the prognostic factors and evaluate the impact of inappropriate empiric antibiotic treatment and systemic response on the outcome of critically ill patients with community-acquired bloodstream infection (BSI). Patients: A prospective, multicenter, observational study was carried out in 339 patients admitted in 30 ICUs for BSI. Results: Crude mortality was 41.5%. Septic shock was present in 184 patients (55%). The pathogens most frequently associated with septic shock or death were Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae, which accounted for approximately half of the deaths. Antibiotic treatment was found to be inappropriate in 14.5% of episodes. Patients in septic shock with inappropriate treatment had a survival rate below 20%. Multivariate analysis identified a significant association between septic shock and four variables: age ≥ 60 years (odds ratio [OR], 1.96), previous corticosteroid therapy (OR, 2.58), leukopenia (OR, 2.32), and BSI secondary to intra-abdominal (OR, 2.38) and genitourinary tract (OR, 2.29) infections. The variables that independently predicted death at ICU admission were APACHE (acute physiology and chronic health evaluation) II score ≥ 15 (OR, 2.42), development of septic shock (OR, 3.22), and inappropriate empiric antibiotic treatment (OR, 4.11). This last variable was independently associated with an unknown source of sepsis (OR, 2.49). Mortality attributable to inappropriate antibiotic treatment increased with the severity of illness at ICU admission (10.7% for APACHE II score < 15 and 41.8% for APACHE II score ≥ 25, p < 0.01). Conclusions: Inappropriate antimicrobial treatment is the most important influence on outcome in patients admitted to the ICU for community-acquired BSI, particularly in presence of septic shock or high degrees of severity. Initial broad-spectrum therapy should be prescribed to septic patients in whom the source is unknown or in... [ABSTRACT FROM AUTHOR]

The article discusses several risk factors for Pseudomonas aeruginosa (PSA) pneumonia identified in the early 21st century. The risk factors include advanced age and length of mechanical ventilation, antibiotics at admission, and admission to a ward with a high incidence of patients with Pseudomonas infections. Also presented are studies on the implications of these risks factors for infection management and control.

The authors discuss a study regarding the antibiotic prescription for intubated patients in Europe which include causes of anti-methicillin-resistant staphylococcus aureus (MRSA) prescription. They cite the study by E. Bouza and colleagues which addresses the intensive care problem of ventilator-associated pneumonia (VAP). They add that the inflammatory response from an infective response is among the eternal problems in intensive care unit (ICU).

The article examines the use of antibiotics and the risk of ventilator-associated pneumonia. The majority of antibiotics used in the ICUs are active against the normal oropharyngeal flora. Antibiotic use was useful as preemptive therapy for early-onset pneumonia in patients who were admitted to the hospital with coma, but it was associated with an increase in pneumonia due to antibiotic-resistant microorganisms in patients admitted because of trauma. Although antibiotic exposure may reduce the rate of early-onset pneumonia, researchers need to look forward and to assess the effect of antibiotics on delayed nosocomial infection and length of stay, and mortality rate.

Lists the top ten studies published in various periodicals regarding antibiotic policy in the intensive care unit. Strategies for improving antimicrobial prescription; Strategies for preventing antimicrobial resistance; Antibiotic cycling and scheduled antibiotic changes; Strategies for antimicrobial decolonization; Strategies for restricting antibiotic use.

Abstract: Despite remarkable advances in its management, community-acquired pneumonia (CAP) remains an important cause of morbidity and mortality leading to significant consumption of health, social and economic resources. The assessment of CAP severity is a cornerstone in its management, facilitating selection of the most appropriate site of care and empirical antibiotic therapy. Several clinical scoring systems based on 30-day mortality have been developed to identify those patients with the highest risk of death. Although well validated in appropriate patient groups, each system has its own limitations and each exhibits different sensitivity and specificity values. These problems have increased interest in the use of biomarkers to predict CAP severity. Although so far no ideal solution has been identified, recent advances in bacterial genomic load quantification have made this tool very attractive. Early antibiotic therapy is essential to the reduction of CAP mortality and the selection of antibiotic treatment according to clinical guidelines is also associated with an improved outcome. In addition, the addition of a macrolide to standard empirical therapy seems to improve outcome in severe CAP although the mechanism of this is unclear. Finally, the role of adjuvant therapy has not yet been satisfactorily established. In this review we will present our opinion on current best practice in the assessment of severity and treatment of severe CAP. [Copyright &y& Elsevier]

• IA use in stable NCFB had microbiologic benefit with 10% reduction of exacerbations. • IA therapy in NCFB increased antimicrobial resistance, with NNT of 6. • Minimal benefit in terms of patient-centered outcomes was documented. • Further research is required in high inflammatory phenotypes and alternative strategies. Inhaled antibiotics (IA) in non-cystic fibrosis bronchiectasis (NCFB) are recommended by some clinical practice guidelines for prevention or treatment of NCFB exacerbations. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of IA use for treatment of adults with NCFB and Pseudomonas aeruginosa chronic bronchial infection. The search was performed in the Cochrane Library, PubMed, and Web of Science databases from 2000 to 2019. Studies of IA for treatment of stable or exacerbated NCFB adults (≥18 years) with P. aeruginosa infection were considered eligible. PROSPERO Registration number: CRD42019136154. Twelve trials (2476 participants) were included. IA therapy increased P. aeruginosa eradication from sputum in patients with exacerbations (OR: 3.19, 95%CI: 1.70–5.99) with similar effects on stable patients (OR: 7.22, 95%CI: 2.81–18.59), and a trend to reduced emergence of new respiratory pathogens (OR: 0.58, 95%CI: 0.28–1.18). IA achieved significant reduced exacerbation rates (RR: 0.90; 95%CI: 0.82–0.98) in stable patients, with a number needed to treat (NNT) of 59, but no significant changes in FEV 1 , mortality, hospitalizations or quality of life were identified. In stable patients, IA use increased antimicrobial resistance (RR: 2.10, 95%CI: 1.35–3.27) at the end of therapy, with a number needed to treat of 6. IA therapy achieved a statistically significant eradication of P. aeruginosa from sputum, with a 10% reduction of exacerbations in stable patients. This effect has to be balanced with significant increases in antimicrobial resistance. Our meta-analysis failed to show a significant benefit in terms of patient-centered outcomes. [ABSTRACT FROM AUTHOR]

The 2019 Nîmes International Symposium in Antibiotic Therapy Optimisation aimed at determining the best approaches of a number of the antibiotic management strategies for critically ill patients. Experts reviewed the latest literature relating to requirements for an optimal antibiotic stewardship program, risks of sub-therapeutic dosing of antibiotics in critically ill patients, persisting issues about efficiency of combination therapy and the value of de-escalation, new perspectives of pharmacokinetics, drug toxicities including collateral damages-associated with antibiotics, the place of nebulisation of antibiotics, management of patients receiving extracorporeal therapies and the place of new antibiotics. In this paper, each of these issues is discussed with key messages presented after a brief review of evidence. [ABSTRACT FROM AUTHOR]

The global public health threat of antibiotic-resistant infections as well as the lack of new treatments in clinical development is a critical issue. Reasons for this include diminished commercial incentives for pharmaceutical companies to develop new antibiotics, which part-reflects a shift in antibiotic marketing paradigm from broad deployment to targeted therapy in relatively small patient populations. Such changes are encouraged by antimicrobial stewardship (AMS). Other factors include a lack of recognition in the traditional assessment of new antibiotics by regulators, health technology assessors and payers of the broad range of benefits of new agents, particularly their value to health care, economies and society. Recognising the seriousness of the situation, there have been recent changes and proposals by regulators for modification of the assessment process to accommodate a broader range of acceptable data supporting new drug applications. There is also increasing recognition by some payers of the societal benefit of new antibiotics and the need for financial incentives for those developing high-priority antibiotics. However, progress is slow, with recent publications focusing on industry and strategic perspectives rather than clinical implications. In this opinion piece, we therefore focus on clinicians and the practical steps they can take to drive and contribute to increasing awareness and understanding of the value of antibiotics. This includes identifying and gathering appropriate alternative data sources, educating on AMS and prescribing habits, and contributing to international antibiotic susceptibility surveillance models. [ABSTRACT FROM AUTHOR]

The article determines whether postponed oxygenation assessment delays initiation of antibiotic therapy and adversely affects intensive care unit survival in patients with severe community-acquired pneumonia in the U.S. Early oxygenation assessment was associated with antibiotic delivery and better intensive care unit survival. Those data suggest the potential value of an early care bundle focusing on implementation of oxygenation assessment immediately after arrival to the emergency department.

Nosocomial respiratory tract infections are the leading type of nosocomial infections. Despite the development of new antibiotic therapies, they are associated with an increased morbidity and mortality. Patients with comorbidities are especially predisposed to acquire these infections, as are patients exposed to respiratory therapy. Aspiration of colonized secretions from the oropharynx is the main mechanism of infection development. Barrier techniques to reduce aspiration and antimicrobial agents to alter bacterial flora are important in preventing pneumonia episodes. The initial institution of an adequate antibiotic regimen is a determinant of outcome. Nosocomial pneumonias are often difficult to treat due to antibiotic-resistant bacteria. Antibiotic policies are crucial in avoiding a progression in antibiotic resistance. [Copyright &y& Elsevier]