Optimization of antimicrobial prescription in the hospital.

Internal Medicine wards are an appropriate focus of antibiotic stewardship, along with emergency departments and intensive care units, because a large proportion of patients are with parenteral broad-spectrum antibiotics. Given the unmet clinical need of antibiotic optimization in the hospital and the importance of front-line practitioners for antibiotic stewardship, the barriers and tactics to overcome them were discussed in a round table at the European Congress of Internal Medicine. Better rapid diagnostic tests should help to increase appropriate early antibiotic rates, favoring diversity in antibiotic choices adapted to the awareness of local resistance patterns. Providing such is a greater challenge in low-resource settings. Prescriptions should be personalized, adjusting dosage and source control to specific patients' conditions. Shorter antibiotic duration and de-escalation are major drivers to reduce adverse events, with mortality and recurrence rates being independent of antimicrobial duration. Appropriate diagnostic tests with quick turnaround times decrease excessive antibiotic use. Antimicrobial optimization requires a multidisciplinary approach and it should be a core competence of training specialists, improving opportunities to provide safer patient care.

Protecting adults at risk of pneumococcal infection and influenza from exposure to SARS-CoV-2.

There is a paucity of evidence linking pneumococcal infection and influenza with SARS-CoV-2 and COVID-19. There is circumstantial evidence of the possibility of an association between S. pneumoniae and SARS-CoV-2 such as the increased binding of S. pneumoniae to coronavirus-infected human airway epithelium, the frequent use of broad-spectrum antibiotics in the management of COVID-19 which could mask secondary bacterial infection, and the observation that pneumococcal vaccination is associated with decreased SARS-CoV-2 nasopharyngeal swab positivity. We performed a targeted literature review for the year 2020, using search terms S. pneumoniae, influenza, SARS-CoV-2, and found 25 relevant articles of a total of 291. Pneumococcal and influenza vaccinations have the potential to contribute toward efforts aimed at reducing the health burden of SARS-CoV-2, especially by reducing preventable admissions to hospital for pneumonia and the consequent risk of nosocomial SARS-CoV-2 transmission.

Secondary infections in mechanically ventilated patients with COVID-19: An overlooked matter?

OBJECTIVE: The susceptibility to infection probably increases in COVID-19 patients due to a combination of virusand drug-induced immunosuppression. The reported rate of secondary infections was quite low in previous studies. The objectives of our study were to investigate the rate of secondary infections, risk factors for secondary infections and risk factors for mortality in COVID-19 critically ill patients. METHODS: We performed a single-center retrospective study in mechanically ventilated critically ill COVID-19 patients admitted to our Critical Care Unit (CCU). We recorded the patients' demographic data; clinical data; microbiology data and incidence of secondary infection during CCU stay, including ventilator-associated pneumonia (VAP) and nosocomial bacteremia (primary and secondary). RESULTS: A total of 107 patients with a mean age 62.2 ± 10.6 years were included. Incidence of secondary infection during CCU stay was 43.0% (46 patients), including nosocomial bacteremia (34 patients) and VAP (35 patients). Age was related to development of secondary infection (65.2 ± 7.3 vs. 59.9 ± 12.2 years, p=0.007). Age ≥ 65 years and secondary infection were independent predictors of mortality (OR=2.692, 95% CI 1.068-6.782, p<0.036; and OR=3.658, 95% CI 1.385- 9.660, p=0.009, respectively). The hazard ratio for death within 90 days in the ≥ 65 years group and in patients infected by antimicrobial resistant pathogens was 1.901 (95% CI 1.198- 3.018; p= 0.005 by log-rank test) and 1.787 (95% CI 1.023-3.122; p= 0.036 by log-rank test), respectively. CONCLUSIONS: Our data suggest that the incidence of secondary infection and infection by antimicrobial resistant pathogens is very high in critically ill patients with COVID-19 with a significant impact on prognosis.

Correction to: Ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria: understanding nebulization of aminoglycosides and colistin.

The original version of this article unfortunately contained a mistake. There was a typographical error in Figure 1: "Nebulization time ≤ 30 min" (first light blue square) should be replaced by "Nebulization time ≤ 90 min". The authors apologize for the mistake.

Infection control bundles in intensive care: an international cross-sectional survey in low- and middle-income countries.

BACKGROUND: In low- and middle-income countries (LMICs), the burden of healthcare-associated infections (HCAIs) is not known due to a lack of national surveillance systems, standardized infection definitions, and paucity of infection prevention and control (IPC) organizations and legal infrastructure. AIM: To determine the status of IPC bundle practice and the most frequent interventional variables in LMICs. METHODS: A questionnaire was emailed to Infectious Diseases International Research Initiative (ID-IRI) Group Members and dedicated IPC doctors working in LMICs to examine self-reported practices/policies regarding IPC bundles. Responding country incomes were classified by World Bank definitions into low, middle, and high. Comparison of LMIC results was then made to a control group of high-income countries (HICs). FINDINGS: This survey reports practices from one low-income country (LIC), 16 middle-income countries (MICs) (13 European), compared to eight high-income countries (HICs). Eighteen (95%) MICs had an IPC committee in their hospital, 12 (63.2%) had an annual agreed programme and produced an HCAI report. Annual agreed programmes (87.5% vs 63.2%, respectively) and an annual HCAI report (75.0% vs 63.2%, respectively) were more common in HICs than MICs. All HICs had at least one invasive device-related surveillance programme. Seven (37%) MICs had no invasive device-related surveillance programme, six (32%) had no ventilator-associated pneumonia prevention bundles, seven (37%) had no catheter-associated urinary tract infection prevention bundles, and five (27%) had no central line-associated bloodstream infection prevention bundles. CONCLUSION: LMICs need to develop their own bundles with low-cost and high-level-of-evidence variables adapted to the limited resources, with further validation in reducing infection rates.

Current aspects in sepsis approach. Turning things around.

The incidence and prevalence of sepsis depend on the definitions and records that we use and we may be underestimating their impact. Up to 60% of the cases come from the community and in 30-60% we obtain microbiological information. Sometimes its presentation is ambiguous and there may be a delay in its detection, especially in the fragile population. Procalcitonin is the most validated biomarker for bacterial sepsis and the one that best discriminates the non-infectious cause. Presepsin and pro-adrenomedullin are useful for early diagnosis, risk stratification and prognosis in septic patients. The combination of biomarkers is even more useful to clarify an infectious cause than any isolated biomarker. Resuscitation with artificial colloids has worse results than crystalloids, especially in patients with renal insufficiency. The combination of saline solution and balanced crystalloids is associated with a better prognosis. Albumin is only recommended in patients who require a large volume of fluids. The modern molecular methods on the direct sample or the identification by MALDI-TOF on positive blood culture have helped to shorten the response times in diagnosis, to optimize the antibiotic treatment and to facilitate stewardship programs. The hemodynamic response in neonates and children is different from that in adults. In neonatal sepsis, persistent pulmonary hypertension leads to an increase in right ventricular afterload and heart failure with hepatomegaly. Hypotension, poor cardiac output with elevated systemic vascular resistance (cold shock) is often a terminal sign in septic shock. Developing ultra-fast Point-of-Care tests (less than 30 minutes), implementing technologies based on omics, big data or massive sequencing or restoring "healthy" microbiomes in critical patients after treatment are the main focuses of research in sepsis. The main benefits of establishing a sepsis code are to decrease the time to achieve diagnosis and treatment, improve organization, unify criteria, promote teamwork to achieve common goals, increase participation, motivation and satisfaction among team members, and reduce costs.

Towards precision medicine in sepsis: a position paper from the European Society of Clinical Microbiology and Infectious Diseases.

BACKGROUND: Our current understanding of the pathophysiology and management of sepsis is associated with a lack of progress in clinical trials, which partly reflects insufficient appreciation of the heterogeneity of this syndrome. Consequently, more patient-specific approaches to treatment should be explored. AIMS: To summarize the current evidence on precision medicine in sepsis, with an emphasis on translation from theory to clinical practice. A secondary objective is to develop a framework enclosing recommendations on management and priorities for further research. SOURCES: A global search strategy was performed in the MEDLINE database through the PubMed search engine (last search December 2017). No restrictions of study design, time, or language were imposed. CONTENT: The focus of this Position Paper is on the interplay between therapies, pathogens, and the host. Regarding the pathogen, microbiologic diagnostic approaches (such as blood cultures (BCs) and rapid diagnostic tests (RDTs)) are discussed, as well as targeted antibiotic treatment. Other topics include the disruption of host immune system and the use of biomarkers in sepsis management, patient stratification, and future clinical trial design. Lastly, personalized antibiotic treatment and stewardship are addressed (Fig. 1). IMPLICATIONS: A road map provides recommendations and future perspectives. RDTs and identifying drug-response phenotypes are clear challenges. The next step will be the implementation of precision medicine to sepsis management, based on theranostic methodology. This highly individualized approach will be essential for the design of novel clinical trials and improvement of care pathways.

Assessing prediction accuracy for outcomes of ventilator-associated events and infections in critically ill children: a prospective cohort study.

OBJECTIVES: To assess the prediction accuracy of the 2008 US Centers for Disease Control and Prevention (CDC) definitions for ventilator-associated pneumonia (VAP)/ventilator-associated tracheobronchitis (VAT), 2013 CDC definitions for ventilator-associated events (VAE) and a new VAE algorithm in the paediatric (Ped) population, the Ped-VAE. METHODS: We performed a prospective 13-month cohort study at a multidisciplinary paediatric intensive care unit (PICU). Primary endpoints were duration of ventilation episode, PICU or hospitalization length of stay from episode and episode mortality. Episodes without VAE (or VAP/VAT) served as comparison groups. RESULTS: One hundred eight episodes of ventilation (99 children) with 2554 ventilator-days were assessed. In episodes not meeting 2008 CDC definitions, a median of 6 ventilator-days (PICU stay 11 days) was documented (with eight deaths), not significantly different from episodes not meeting VAE or Ped-VAE definitions. Using 2008 CDC criteria, 11 (10.2%) respiratory infections (eight tracheobronchitis) were identified, seven VAEs using 2013 CDC criteria (6.4%) and 29 (26.8%) using Ped-VAE criteria (relative risk vs. 2008 CDC criteria 2.58; 95% confidence interval 1.36-4.91). In contrast with their comparison groups, episodes meeting 2008 CDC criteria did not significantly predict outcomes, whereas VAEs (only four possible VAPs) were associated with significantly more ventilation and PICU length of stay (12-day/8-day increase) and sevenfold increase in mortality. Ped-VAE did not increase mortality, but it was associated with 4-day increase in ventilation and PICU length of stay, with ten possible VAPs, and atelectasis (9/12) as the main paediatric ventilator-associated condition. CONCLUSIONS: The 2008 CDC criteria did not predict outcomes, whereas VAE only identified very severe events. The Ped-VAE algorithm had more accuracy predicting outcomes by characterizing lower oxygenation changes and identifying hypoxaemia severity, a major driver of management.

Drivers and impact of antifungal therapy in critically ill patients with Aspergillus-positive respiratory tract cultures.

Invasive pulmonary aspergillosis (IPA) is an increasingly recognised problem in critically ill patients. Little is known about how intensivists react to an Aspergillus-positive respiratory sample or the efficacy of antifungal therapy (AFT). This study aimed to identify drivers of AFT prescription and diagnostic workup in patients with Aspergillus isolation in respiratory specimens as well as the impact of AFT in these patients. ICU patients with an Aspergillus-positive respiratory sample from the database of a previous observational, multicentre study were analysed. Cases were classified as proven/putative IPA or Aspergillus colonisation. Demographic, microbiological, diagnostic and therapeutic data were collected. Outcome was recorded 12 weeks after Aspergillus isolation. Patients with putative/proven IPA were more likely to receive AFT than colonised patients (78.7% vs. 25.5%; P <0.001). Patients with host factors for invasive fungal disease were more likely to receive AFT (72.5% vs. 37.4%) as were those with multiorgan failure (SOFA score >7) (68.4% vs. 36.9%) (both P <0.001). Once adjusted for disease severity, initiation of AFT did not alter the odds of survival (HR = 1.40, 95% CI 0.89-2.21). Likewise, treatment within 48 h following diagnosis did not change the clinical outcome (75.7% vs. 61.4%; P = 0.63). Treatment decisions appear to be based on diagnostic criteria and underlying disease severity at the time of Aspergillus isolation. IPA in this population has a dire prognosis and AFT is not associated with reduced mortality. This may be explained by delayed diagnosis and an often inevitable death due to advanced multiorgan failure.

The clinical significance of pneumonia in patients with respiratory specimens harbouring multidrug-resistant Pseudomonas aeruginosa: a 5-year retrospective study following 5667 patients in four general ICUs.

Pseudomonas aeruginosa is the leading cause of pneumonia in intensive care units (ICUs), with multidrug-resistant (MDR) strains posing a serious threat. The aim of this study was to assess the clinical relevance of MDR Pseudomonas isolates in respiratory clinical specimens. A 5-year retrospective observational study in four medical-surgical ICUs from a referral hospital was carried out. Of 5667 adults admitted to the ICU, 69 had MDR-PA in respiratory samples: 31 were identified as having pneumonia (HAP/VAP): 21 ventilator-associated pneumonia (VAP) and ten hospital-acquired pneumonia (HAP). Twenty-one (67.7%) adults with MDR-PA HAP/VAP died after a median of 4 days (18 of the 21 deaths within 8 days), compared with one (2.6%) without pneumonia at day 8. In a Cox proportional regression model, MDR-PA pneumonia was an independent variable [adjusted hazard ratio (aHR) 5.92] associated with 30-day ICU mortality. Most strains (85.1%) were susceptible to amikacin and colistin. Resistance to beta-lactams (third-generation cephalosporins and piperacillin-tazobactam) ranged from 44.1% to 45.3%. Meropenem showed poor overall activity (MIC[50/90] 16/32 mg/dL), with 47.0% having a minimum inhibitory concentration (MIC) breakpoint >8 mg/L. Twenty-four (77.4%) HAP/VAP episodes received inappropriate empirical therapy. Although empirical combination therapy was associated with less inappropriate therapy than monotherapy (16.7% vs. 88.3%, p < 0.01), there was no difference in survival (30% vs. 33.3%, p = 0.8). Pneumonia was identified in one-third of adult ICU patients harbouring MDR-PA in respiratory clinical specimens. These patients have a 6-fold risk of (early) death compared to ventilator-associated tracheobronchitis (VAT) and respiratory colonisation. New antibiotics and adjuvant therapies are urgently needed to prevent and treat MDR-PA HAP/VAP.

Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the European Society of Clinical Microbiology and Infectious Diseases.

With an established role in cystic fibrosis and bronchiectasis, nebulized antibiotics are increasingly being used to treat respiratory infections in critically ill invasively mechanically ventilated adult patients. Although there is limited evidence describing their efficacy and safety, in an era when there is a need for new strategies to enhance antibiotic effectiveness because of a shortage of new agents and increases in antibiotic resistance, the potential of nebulization of antibiotics to optimize therapy is considered of high interest, particularly in patients infected with multidrug-resistant pathogens. This Position Paper of the European Society of Clinical Microbiology and Infectious Diseases provides recommendations based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology regarding the use of nebulized antibiotics in invasively mechanically ventilated adults, based on a systematic review and meta-analysis of the existing literature (last search July 2016). Overall, the panel recommends avoiding the use of nebulized antibiotics in clinical practice, due to a weak level of evidence of their efficacy and the high potential for underestimated risks of adverse events (particularly, respiratory complications). Higher-quality evidence is urgently needed to inform clinical practice. Priorities of future research are detailed in the second part of the Position Paper as guidance for researchers in this field. In particular, the panel identified an urgent need for randomized clinical trials of nebulized antibiotic therapy as part of a substitution approach to treatment of pneumonia due to multidrug-resistant pathogens.

Key considerations on nebulization of antimicrobial agents to mechanically ventilated patients.

Nebulized antibiotics have an established role in patients with cystic fibrosis or bronchiectasis. Their potential benefit to treat respiratory infections in mechanically ventilated patients is receiving increasing interest. In this consensus statement of the European Society of Clinical Microbiology and Infectious Diseases, the body of evidence of the therapeutic utility of aerosolized antibiotics in mechanically ventilated patients was reviewed and resulted in the following recommendations: Vibrating-mesh nebulizers should be preferred to jet or ultrasonic nebulizers. To decrease turbulence and limit circuit and tracheobronchial deposition, we recommend: (a) the use of specifically designed respiratory circuits avoiding sharp angles and characterized by smooth inner surfaces, (b) the use of specific ventilator settings during nebulization including use of a volume controlled mode using constant inspiratory flow, tidal volume 8 mL/kg, respiratory frequency 12 to 15 bpm, inspiratory:expiratory ratio 50%, inspiratory pause 20% and positive end-expiratory pressure 5 to 10 cm H2O and (c) the administration of a short-acting sedative agent if coordination between the patient and the ventilator is not obtained, to avoid patient's flow triggering and episodes of peak decelerating inspiratory flow. A filter should be inserted on the expiratory limb to protect the ventilator flow device and changed between each nebulization to avoid expiratory flow obstruction. A heat and moisture exchanger and/or conventional heated humidifier should be stopped during the nebulization period to avoid a massive loss of aerosolized particles through trapping and condensation. If these technical requirements are not followed, there is a high risk of treatment failure and adverse events in mechanically ventilated patients receiving nebulized antibiotics for pneumonia.

Infections in intensive care unit adult patients harboring multidrug-resistant Pseudomonas aeruginosa: implications for prevention and therapy.

The purpose of this paper was to report the burden and characteristics of infection by multidrug-resistant Pseudomonas aeruginosa (MDR-PA) in clinical samples from intensive care unit (ICU) adults, and to identify predictors. This was a retrospective observational study at four medical-surgical ICUs. The case cohort comprised adults with documented isolation of an MDR-PA strain from a clinical specimen during ICU stay. Multivariate analysis was performed to identify predictors for MDR-PA infection. During the study period, 5667 patients were admitted to the ICU and P. aeruginosa was isolated in 504 (8.8%). MDR-PA was identified in 142 clinical samples from 104 patients (20.6%); 62 (43.6%) of these samples appeared to be true infections. One hundred and eighteen (83.1%) isolates were susceptible only to amikacin and colistin, and 13 (9.2%) were susceptible only to colistin. Overall, the MIC50 to meropenem was 16 µg/mL and the MIC90 was >32 µg/mL, with 60.4% of respiratory samples being MIC >32 µg/mL to meropenem. Independent predictors for MDR-PA infection were fever/hypothermia [odds ratio (OR) 9.09], recent antipseudomonal cephalosporin therapy (OR 6.31), vasopressors at infection onset (OR 4.40), and PIRO (predisposition, infection, response, and organ dysfunction) score >2 (OR 2.06). This study provides novel information that may be of use for the clinical management of patients harboring MDR-PA and for the control of the spread of this organism.

Nosocomial pneumonia in 27 ICUs in Europe: perspectives from the EU-VAP/CAP study.

We report on intensive care nosocomial pneumonia (NP) in Europe through a review of EU-VAP/CAP manuscripts: a prospective observational study, enrolling patients from 27 ICUs in nine European countries. From 2,436 eligible ICU patients, 827 cases presented NP, with 18.3 episodes of VAP per 1000 ventilator-days. Most common findings were worsening oxygenation, purulent respiratory secretions and temperature increase. At least three criteria from Clinical Pulmonary Infection score (CPIS) were present in 77.9 % of episodes, but only 0.2 % met six CPIS criteria. Diagnosis was confirmed mainly noninvasively (74.8 %), with half qualitative and quantitative cultures. The dominant isolate was S. aureus in Spain, France, Belgium and Ireland, P. aeruginosa in Italy and Portugal, Acinetobacter in Greece and Turkey, but Escherichia coli in Germany. NP resulted in 6 % higher mortality, longer ICU stay and duration of mechanical ventilation (12 and 10 days). COPD and age ≥45 years were not associated with higher VAP incidence but did correlate with increased mortality. Trauma had higher VAP incidence but lower mortality. Bacteremia (led by MRSA and Acinetobacter baumannii) was documented in 14.6 %, being associated with extra ICU stay and mortality. Vasopressors and ICUs with above 25 % prevalence of Potential Resistant Organisms (PRM) were independently associated with PRM, being documented in 50.7 % of patients with early-onset VAP without known risk factors. Most patients initially received combination therapy. Delay in appropriate antimicrobial choice significantly increased mortality, and LOS in survivors was six days longer (p < 0.05). In conclusion, NP management in Europe presents local differences and major shifts when compared to reports from North America, outcomes of randomized trials and general guidelines.

Association between source control and mortality in 258 patients with intra-abdominal candidiasis: a retrospective multi-centric analysis comparing intensive care versus surgical wards in Spain.

Early empiric therapy and adequate resuscitation have been identified as main predictors of outcome in patients with candidemia or bacteremia. Moreover, source control is a major determinant in infectious sites when feasible, as a main technique to reduce microbiological burden. A retrospective, multicenter, cohort study was performed at surgical wards and intensive care units (ICU) of three University Hospitals in Spain between 2010 and 2014, with the aim of improving understanding of the interaction between source control, early antifungal therapy, and use of vasoactives in patients with intra-abdominal candidiasis (IAC). Source control was defined as all physical actions taken to control a focus of infection and reduce the favorable conditions that promote microorganism growth or that maintain the impairment of host defenses. Two hundred and fifty-eight patients with IAC were identified. Sixty-one patients were at ICU for diagnosis. Mortality was higher in the ICU group compared to what was documented for the non-ICU group (35 % vs 19.5 %, p = 0011). Adequate source control within 48 h of diagnosis was achieved in 60 % of the cohort. In multivariate analysis, inadequate source control was identified as the only common risk factor for 30-day mortality in both groups (ICU group OR: 13.78 (95% CI: 2.60-72.9, p = 0.002) and non-ICU group OR: 6.53 (95% CI: 2.56-16.61, p = <0.001). The population receiving both adequate source control and adequate antifungal treatment was the one associated with a higher survival rate, in both the ICU and surgical groups. Source control remains a key element in IAC, inside and outside the intensive care unit. Early antifungal treatment among ICU patients was associated with lower mortality.