A Practical Approach to Clinical Antibiotic Stewardship in the ICU Patient with Severe Infection.

Patients with severe infections are often treated with multiple courses of antibiotics in the intensive care unit (ICU), making the ICU a true antibiotic hotspot. The increasing incidence of multidrug resistance worldwide emphasizes the need for continued efforts in developing and implementing antibiotic stewardship programs. Using a pragmatic approach for the bedside clinical team, this review will highlight different key moments for antibiotic decision making throughout the course of the antibiotic treatment in patients with severe infections. We will focus especially on the importance of adequate empirical therapy, source control in infections, assessment of immune status, and two separate antibiotic time-out moments early in the course, as well as the moment of stopping antibiotics. Additionally, the importance of a team-based approach and clinical decision support systems will be highlighted.

Impact of de-escalation of beta-lactam antibiotics on the emergence of antibiotic resistance in ICU patients: a retrospective observational study.

PURPOSE: Antibiotic de-escalation is promoted to limit prolonged exposure to broad-spectrum antibiotics, but proof that it prevents the emergence of resistance is lacking. We evaluated determinants of antibiotic de-escalation in an attempt to assess whether the latter is associated with a lower emergence of antimicrobial resistance. METHODS: Antibiotic treatments, starting with empirical beta-lactam prescriptions, were prospectively documented during 2013 and 2014 in a tertiary intensive care unit (ICU) and categorized as continuation, de-escalation or escalation of the empirical antimicrobial treatment. Determinants of the de-escalation or escalation treatments were identified by multivariate logistic regression; the continuation category was used as the reference group. Using systematically collected diagnostic and surveillance cultures, we estimated the cumulative incidence of antimicrobial resistance following de-escalation or continuation of therapy, with adjustment for ICU discharge and death as competing risks. RESULTS: Of 478 anti-pseudomonal antibiotic prescriptions, 42 (9 %) were classified as escalation of the antimicrobial treatment and 121 (25 %) were classified as de-escalation, mainly through replacement of the originally prescribed antibiotics with those having a narrower spectrum. In multivariate analysis, de-escalation was associated with the identification of etiologic pathogens (p < 0.001). The duration of the antibiotic course in the ICU in de-escalated versus continued prescriptions was 8 (range 6-10) versus 5 (range 4-7) days, respectively (p < 0.001). Mortality did not differ between patients in the de-escalation and continuation categories. The cumulative incidence estimates of the emergence of resistance to the initial beta-lactam antibiotic on day 14 were 30.6 and 23.5 % for de-escalation and continuation, respectively (p = 0.22). For the selection of multi-drug resistant pathogens, these values were 23.5 (de-escalation) and 18.6 % (continuation) respectively (p = 0.35). CONCLUSION: The emergence of antibiotic-resistant bacteria after exposure to anti-pseudomonal beta-lactam antibiotics was not lower following de-escalation.

Development of antibiotic treatment algorithms based on local ecology and respiratory surveillance cultures to restrict the use of broad-spectrum antimicrobial drugs in the treatment of hospital-acquired pneumonia in the intensive care unit: a retrospective analysis.

INTRODUCTION: Timely administration of appropriate antibiotic therapy has been shown to improve outcome in hospital-acquired pneumonia (HAP). Empirical treatment guidelines tailored to local ecology have been advocated in antibiotic stewardship programs. We compared a local ecology based algorithm (LEBA) to a surveillance culture based algorithm (SCBA) in terms of appropriate coverage and spectrum of antimicrobial activity. METHODS: We retrospectively assessed 2 hypothetical empirical antibiotic treatment algorithms for HAP on an existing high-quality prospectively collected database in a mixed 36-bed tertiary intensive care unit (ICU). Data on consecutive episodes of microbiologically confirmed HAP were collected over a period of 40 months and divided in a derivation (1 July 2009 to 31 October 2010) and validation (1 November 2010 until 31 October 2012) cohort. On the derivation cohort we constructed a LEBA, based on overall observed bacterial resistance patterns, and a SCBA, which targeted therapy to surveillance culture (SC) in the individual patient. Therapy was directed against pathogens found in respiratory SC collected two to five days before HAP, and in the absence of these, presence or absence of multi-drug resistant (MDR) pathogens in other SC dictated broad-spectrum, respectively narrow spectrum antibiotic therapy. Subsequently, LEBA and SCBA were retrospectively reviewed and compared with actually prescribed antibiotics in the validation cohort. RESULTS: The first 100 HAP episodes made up the derivation cohort and the subsequent 113 HAP episodes the validation cohort. Appropriate antibiotic coverage rates by applying LEBA and SCBA were 88.5% and 87.6%, respectively, and did not differ significantly with respect to appropriateness of the actually prescribed initial therapy (84.1%). SCBA proposed more narrow spectrum therapy as compared to LEBA and the actually prescribed antimicrobials (P <0.001). SCBA recommended significantly less combination therapy and carbapenems compared to LEBA (P <0.001). SCBA targeted antibiotics to recent respiratory SC in 38.1% (43 out of 113 episodes) of HAP; in these cases adequacy was 93% (40 out of 43). CONCLUSION: Rates of appropriate antimicrobial coverage were identical in LEBA and SCBA. However, in this setting of moderate MDR prevalence, the use of SCBA would result in a significant reduction of the use of broad-spectrum drugs and may be a preferential strategy when implementing antibiotic stewardship programs.

Impact of organ dysfunction on mortality in ICU patients with hematologic malignancies.

PURPOSE: To compare evolution in organ dysfunction (OD) between hematologic malignancy patients with and without bacterial infection (BI) precipitating intensive care unit (ICU) admission, and to assess its impact on mortality. METHODS: Retrospective analysis of prospectively collected data was performed. Sequential Organ Failure Assessment (SOFA) scores from day 1 to 5 were calculated in all consecutive hematologic malignancy patients admitted to the ICU (2000-2006). Patients were categorized according to the presence or absence, the diagnostic certainty, and the site of BI. RESULTS: Of the 344 patients admitted, 258 were still in the ICU at day 3 and 164 at day 5. Patients admitted because of BI had more severe OD on day 1 (SOFA 9.7 ± 4.0 vs. 8.4 ± 4.0, p = 0.008) but a more rapidly reversible OD within the first 3 days (ΔSOFA -1.12 ± 3.10 vs. 0.03 ± 3.40, p = 0.013) and a lower in-hospital (43.2% vs. 62.9%, p < 0.001) and 6-month mortality (52.1% vs. 71.7%, p < 0.001) than patients with other complications. In a multivariate analysis, BI remained associated with a lower risk of death (OR 0.20, 95% CI 0.1-0.4, p < 0.001) even after adjustment for the SOFA on day 1 (OR 1.36, 95% CI 1.22-1.52, p < 0.001) and the ΔSOFA (OR 1.48, 95% CI 1.29-1.68, p < 0.001). These findings remained significant regardless of the site and the diagnostic certainty of BI. CONCLUSION: BI is associated with a more severe initial but a more rapidly reversible OD and a subsequent lower mortality compared to other complications in ICU patients with hematologic malignancies. These findings further support the recommendation that these patients should certainly benefit from advanced life support, and in the case of an uncertain long-term prognosis due to the underlying malignancy, at least from a 3-day ICU trial.

Mechanical ventilation in cancer patients: clinical characteristics and outcomes.

Acute respiratory failure with the need for mechanical ventilation is a severe and frequent complication, and a leading reason for admission to the intensive care unit (ICU) in patients with malignancies. Nevertheless, improvements in patient survival have been observed over the last decade. This article reviews the epidemiology of adult patients with malignancies requiring ventilatory support. Criteria used to assist decisions to admit a patient to the ICU and to select the initial ventilatory strategy are discussed.

The impact of the initial ventilatory strategy on survival in hematological patients with acute hypoxemic respiratory failure.

PURPOSE: The aim of this study was to assess the impact of the 3 types of initial respiratory support (noninvasive positive pressure ventilation vs invasive positive pressure ventilation vs supplemental oxygen only) in hematological patients with acute hypoxemic respiratory failure (ARF). MATERIALS AND METHODS: This study is a retrospective analysis of a cohort of hematological patients admitted to the intensive care unit (ICU) of a tertiary care hospital between January 1, 2002, and June 30, 2006. RESULTS: One hundred thirty-seven hematological patients were admitted at the ICU with ARF (defined as Pao(2)/Fio(2) <200): within the first 24 hours, 24 and 67 patients received noninvasive positive pressure ventilation and invasive positive pressure ventilation, respectively, and 46 received supplemental oxygen only. Intensive care unit mortality in the 3 patient categories was 71%, 63%, and 32%, respectively (P = .001), and in-hospital mortality was 75%, 80%, and 47%, respectively (P = .001). In multivariate regression analysis, increasing cancer-specific severity-of-illness score upon admission and more organ failure after 24 hours of ICU admission, but not the type of initial respiratory support, were significantly associated with ICU or in-hospital mortality. CONCLUSIONS: Intensive care unit and in-hospital mortality in our population of hematological patients with hypoxemic ARF was determined by severity of illness and not by the type of initial respiratory support.

Determinants and impact of multidrug antibiotic resistance in pathogens causing ventilator-associated-pneumonia.

INTRODUCTION: The idea that multidrug resistance (MDR) to antibiotics in pathogens causing ventilator-associated pneumonia (VAP) is an independent risk factor for adverse outcome is still debated. We aimed to identify the determinants of MDR versus non-MDR microbial aetiology in VAP and assessed whether MDR versus non-MDR VAP was independently associated with increased 30-day mortality. METHODS: We performed a retrospective analysis of a prospectively registered cohort of adult patients with microbiologically confirmed VAP, diagnosed at a university hospital intensive care unit during a three-year period. Determinants of MDR as compared with non-MDR microbial aetiology and impact of MDR versus non-MDR aetiology on mortality were investigated using multivariate logistic and competing risk regression analysis. RESULTS: MDR pathogens were involved in 52 of 192 episodes of VAP (27%): methicillin-resistant Staphylococcus aureus in 12 (6%), extended-spectrum beta-lactamase producing Enterobacteriaceae in 28 (15%), MDR Pseudomonas aeruginosa and other non-fermenting pathogens in 12 (6%). Multivariable logistic regression identified the Charlson index of comorbidity (odds ratio (OR) = 1.38, 95% confidence interval (CI) = 1.08 to 1.75, p = 0.01) and previous exposure to more than two different antibiotic classes (OR = 5.11, 95% CI = 1.38 to 18.89, p = 0.01) as predictors of MDR aetiology. Thirty-day mortality after VAP diagnosis caused by MDR versus non-MDR was 37% and 20% (p = 0.02), respectively. A multivariate competing risk regression analysis showed that renal replacement therapy before VAP (standardised hazard ratio (SHR) = 2.69, 95% CI = 1.47 to 4.94, p = 0.01), the Charlson index of comorbidity (SHR = 1.21, 95% CI = 1.03 to 1.41, p = 0.03) and septic shock on admission to the intensive care unit (SHR = 1.86, 95% CI = 1.03 to 3.35, p = 0.03), but not MDR aetiology of VAP, were independent predictors of mortality. CONCLUSIONS: The risk of MDR pathogens causing VAP was mainly determined by comorbidity and prior exposure to more than two antibiotics. The increased mortality of VAP caused by MDR as compared with non-MDR pathogens was explained by more severe comorbidity and organ failure before VAP.

Outcome in critically ill cancer patients: past and present: [review]

BACKGROUND AND OBJECTIVES: Until the end of the previous century it remained controversial to admit cancer patients to the ICU for advanced-life-supporting therapy. However, over the past few years several centres over the world have shown that it is possible to achieve a meaningful survival in these patients. The aim of this review is to focus on the improvement in outcome that has been achieved over the past two decades in critically ill cancer patients. CONTENTS: We performed a MEDLINE search (period of 1980 to November 2007) to identify full-text English language publications on critically ill patients with solid tumors or hematological malignancies with particular interest for the outcome and treatment. Major MESH search terms included; cancer, solid tumor, hematologic or hematological malignancies, immunosupression, ICU, ventilation, organ failure, sepsis and infection. Additional studies were identified through a manual search of citations from retrieved articles. CONCLUSIONS: In this review, we first focus on the grim prognosis in the past, subsequently we discuss the improvements in outcome over the past few years across subgroups of cancer patients with increasing degree of severity of illness, and finally, we focus on the value of non-invasive ventilation since it is considered the initial ventilatory strategy in these patients.

JUSTIFICATIVA E OBJETIVOS: Até o final do século passado, havia grande incerteza quanto a propriedade de internar pacientes com câncer em unidades de terapia intensiva (UTI) para medidas de suporte avançado. Contudo, ao longo dos últimos anos, vários centros ao redor do mundo têm reportado aumento significativo da sobrevida de tais pacientes. O objetivo deste estudo foi rever os principais artigos publicados nas duas últimas décadas, com foco na melhoria do prognóstico de pacientes com câncer criticamente enfermos. CONTEÚDO: Realizou-se uma busca bibliográfica no sistema MedLine - PubMed (www.pubmed.gov) para identificar artigos em linguagem inglesa sobre cuidados intensivos no pacientes com tumores sólidos ou neoplasias hematológicas, com ênfase no prognóstico e no tratamento. Utilizaram-se os seguintes unitermos: cancer, solid tumor, hematologic or hematological malignancies, immunosupression, ICU, ventilation, organ failure, sepsis and infection. Estudos referenciados nos artigos selecionados na busca também foram utilizados. CONCLUSÕES: O tema será abordado de forma sistematizada. Inicialmente, haverá uma discussão sobre o prognóstico sombrio experimentado por estes pacientes no passado. Subseqüentemente, serão discutidos os estudos publicados nos anos recentes sobre a melhoria do prognóstico para os diversos subgrupos de pacientes, a despeito de uma maior gravidade das complicações agudas. Para finalizar, será discutido o papel da ventilação não-invasiva como estratégia inicial de ventilação para estes pacientes.

Daily cost of antimicrobial therapy in patients with Intensive Care Unit-acquired, laboratory-confirmed bloodstream infection.

This study analysed daily antimicrobial costs of Intensive Care Unit (ICU)-acquired, laboratory-confirmed bloodstream infection (BSI) per patient admitted to the ICU of a university hospital, based on prospectively collected data over a 4-year period (2003-2006). Costs were calculated based on the price of the agent(s) initiated on the first day of appropriate treatment and according to: (i) focus of infection; (ii) pathogen; and (iii) antimicrobial agent. The study included 310 adult patients who developed 446 BSI episodes. Mean overall daily antimicrobial cost was euro114.25. Daily antimicrobial cost was most expensive for BSIs with unknown focus (euro137.70), followed by catheter-related (euro122.73), pulmonary (euro112.80), abdominal (euro98.00), wound (euro89.21), urinary (euro87.85) and other inciting focuses (euro81.59). Coagulase-negative staphylococci were the most prevalent pathogens isolated. Treatment of BSIs caused by Candida spp. was the most costly. The daily antimicrobial costs per infected patient with multidrug-resistant BSI was ca. 50% higher compared with those without (euro165.09 vs. euro82.67; P<0.001). Among the total of 852 prescriptions, beta-lactam antibiotics accounted for approximately one-third of the overall daily cost of antimicrobial agents. The antibiotic cost associated with ICU-acquired, laboratory-confirmed BSI is significant and should be reduced by implementing infection control measures and preventive strategies.

Impact of recent intravenous chemotherapy on outcome in severe sepsis and septic shock patients with hematological malignancies.

OBJECTIVE: To compare the characteristics and outcome of patients with hematological malignancies referred to the ICU with severe sepsis and septic shock who had or had not received recent intravenous chemotherapy, defined as within 3 weeks prior to ICU admission. DESIGN AND SETTING: Retrospective observational cohort study on prospectively collected data in a medical ICU of a university hospital. PATIENTS: 186 ICU patients with hematological malignancies with severe sepsis or septic shock (2000-2006). MEASUREMENTS AND RESULTS: There were 77 patients admitted with severe sepsis and 109 with septic shock; 91 (49%) had received recent intravenous chemotherapy. Patients with recent chemotherapy more often had a high-grade malignancy and were more often neutropenic, less often had pulmonary infiltrates, and less often required mechanical ventilation. ICU, 28-day, in-hospital, and 6-month mortality rates were 33% vs. 48.4%, 40.7% vs. 57.4%, 45.1% vs. 58.9%, and 50.5% vs. 63.2% in patients with and without recent chemotherapy, respectively. Logistic regression identified four variables independently associated with 28-day mortality: SOFA score at ICU admission, pulmonary site of infection, and fungal infection were associated with worse outcome whereas previous intravenous chemotherapy was protective at borderline significance. After adjustment with a propensity score for recent chemotherapy, chemotherapy was not associated with outcome. CONCLUSIONS: Patients referred to the ICU with severe sepsis and septic shock complicating active chemotherapeutic treatment have better prognosis than commonly perceived.

Outcome in critically ill cancer patients: past and present.

BACKGROUND AND OBJECTIVES: Until the end of the previous century it remained controversial to admit cancer patients to the ICU for advanced-life-supporting therapy. However, over the past few years several centres over the world have shown that it is possible to achieve a meaningful survival in these patients. The aim of this review is to focus on the improvement in outcome that has been achieved over the past two decades in critically ill cancer patients. CONTENTS: We performed a MEDLINE search (period of 1980 to November 2007) to identify full-text English language publications on critically ill patients with solid tumors or hematological malignancies with particular interest for the outcome and treatment. Major MESH search terms included; cancer, solid tumor, hematologic or hematological malignancies, immunosupression, ICU, ventilation, organ failure, sepsis and infection. Additional studies were identified through a manual search of citations from retrieved articles. CONCLUSIONS: In this review, we first focus on the grim prognosis in the past, subsequently we discuss the improvements in outcome over the past few years across subgroups of cancer patients with increasing degree of severity of illness, and finally, we focus on the value of non-invasive ventilation since it is considered the initial ventilatory strategy in these patients.

Dynamics of C-reactive protein and white blood cell count in critically ill patients with nosocomial Gram positive vs. Gram negative bacteremia: a historical cohort study.

BACKGROUND: Nosocomial bacteremia is associated with a poor prognosis. Early adequate therapy has been shown to improve outcome. Consequently, rapid detection of a beginning sepsis is therefore of the utmost importance. This historical cohort study was designed to evaluate if different patterns can be observed in either C-reactive protein (CRP) and white blood cell count (WCC) between Gram positive bacteremia (GPB) vs. Gram negative bacteremia (GNB), and to assess the potential benefit of serial measurements of both biomarkers in terms of early antimicrobial therapy initiation. METHODS: A historical study (2003-2004) was conducted, including all adult intensive care unit patients with a nosocomial bacteremia. CRP and WCC count measurements were recorded daily from two days prior (d(-2)) until one day after onset of bacteremia (d(+1)). Delta (Delta) CRP and Delta WCC levels from the level at d-2 onward were calculated. RESULTS: CRP levels and WCC counts were substantially higher in patients with GNB. Logistic regression analysis demonstrated that GNB and Acute Physiology and Chronic Health Evaluation (APACHE) II score were independently associated with a CRP increase of 5 mg/dL from d-2 to d+1, and both were also independently associated with an increase of WCC levels from d(-2) to d(+1) of 5,000 x 10(3) cells/mm3. CONCLUSION: Increased levels of CRP and WCC are suggestive for GNB, while almost unchanged CRP and WCC levels are observed in patients with GPB. However, despite the different patterns observed, antimicrobial treatment as such cannot be guided based on both biomarkers.

Bacteremia in patients with ventilator-associated pneumonia is associated with increased mortality: A study comparing bacteremic vs. nonbacteremic ventilator-associated pneumonia.

OBJECTIVE: To assess whether bacteremic ventilator-associated pneumonia (B-VAP) differs in terms of risk factors, organisms, and outcomes from nonbacteremic VAP (NB-VAP). DESIGN: A retrospective, single-center, observational, cohort study. SETTING: Multidisciplinary teaching intensive care unit. PATIENTS: Adult patients requiring mechanical ventilation, identified as having VAP in a 44-month prospective surveillance database. INTERVENTIONS: Each B-VAP patient was matched with two controls with VAP and negative blood cultures based on the microbial etiology responsible for VAP, Acute Physiology and Chronic Health Evaluation II score on admission (+/-3 points), diagnostic category, and length of stay before pneumonia onset. MEASUREMENTS AND MAIN RESULTS: B-VAP was documented in 35 (17.6%) of 199 microbiologically confirmed VAP episodes. B-VAP developed later (median 8 vs. 5 days, p = .03) and was more frequent in previously hospitalized patients (34.3% vs. 11.0%, p < .01) and in older patients (57.4 +/- 15.2 vs. 49.5 +/- 19.3 yrs, p = .02). B-VAP was more often caused by methicillin-resistant Staphylococcus aureus (12 [20.7%] vs. 13 [5.1%] episodes, p < .01), whereas Haemophilus influenzae was associated with NB-VAP (52 [20.4%] vs. 0, p < .01). Multivariate analysis confirmed an association between B-VAP and both methicillin-resistant S. aureus (odds ratio 3.18; 95% confidence interval 1.15-8.76, p < .01) and prior hospitalization (odds ratio 2.56; 95% confidence interval 1.01-6.54, p = .05). After adjustment for potential confounders, B-VAP (hazard ratio for death 2.55; 95% confidence interval 1.25-5.23, p = .01) and vasopressor use (hazard ratio 2.43; 95% confidence interval 1.23-4.82, p = .01) remained associated with mortality. The estimated relative risk of death for bacteremic cases was 2.86 (95% confidence interval 1.09-7.51), since mortality for cases and matched NB-VAP controls was 40.6% (13 of 32) and 19.3% (11 of 57), respectively. CONCLUSIONS: B-VAP occurs later during intensive care unit stay, is more frequent in previously hospitalized patients, is more often caused by methicillin-resistant S. aureus, and is independently associated with increased intensive care unit mortality.

Antimicrobial resistance in nosocomial bloodstream infection associated with pneumonia and the value of systematic surveillance cultures in an adult intensive care unit.

OBJECTIVE: To study the occurrence of multiple-drug-resistant pathogens in nosocomial bloodstream infection associated with pneumonia. To evaluate prediction of multiple drug resistance by systematic surveillance cultures. DESIGN: A retrospective study of a prospectively gathered cohort. SETTING: Fifty-four-bed adult medical-surgical intensive care unit of a tertiary hospital. PATIENTS: One hundred twelve intensive care unit patients with nosocomial bloodstream infection associated with pneumonia from 1992 through 2001. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Concordance of blood cultures with prior surveillance culture was assessed. Surveillance cultures were taken routinely as thrice weekly urinary cultures and oral swabs, once weekly anal swabs, and thrice weekly tracheal aspirates in intubated patients. Tracheal surveillance cultures from 48 to 96 hrs before bloodstream infection and surveillance cultures from any site during the same intensive care unit episode but >or=48 hrs before bloodstream infection were evaluated separately. Forty-four bloodstream infections (39%) were caused by a multiple-drug-resistant pathogen. Multiple-drug-resistant pathogens were predicted by tracheal surveillance culture in 70% (concordant); in 15%, tracheal surveillance culture grew a multiple-drug-resistant pathogen not found in blood cultures (discordant). Multiple-drug-resistant pathogens were predicted by any surveillance culture in 88%, but these surveillance cultures grew additional multiple-drug-resistant pathogens not causing bloodstream infection in up to 46% of patients. In 86% of bloodstream infections, early (i.e., within 48 hrs) antibiotic therapy was appropriate. Patients were divided into four risk categories for multiple-drug-resistant bloodstream infection based on length of prior intensive care unit stay and prior antibiotic exposure. In patients with two risk factors, knowledge of surveillance cultures increased appropriateness of early antibiotic therapy from 75-79% to 90% (p<.05) while limiting use of broad-spectrum antibiotics such as antipseudomonal betalactams, fluoroquinolones, and carbapenems. CONCLUSIONS: In our intensive care unit, tracheal surveillance culture predicted multiple-drug-resistant etiology of bloodstream infection associated with pneumonia in 70% of patients but yielded discordant resistant pathogens in 15%. In the subgroup of patients with two risk factors for multiple-drug-resistant infection, incorporating results of surveillance cultures moderately contributed to adequacy of early antibiotic therapy while limiting antibiotic consumption.