Comparison of Empiric Antibiotic Treatment Regimens for Hospitalized, Non-severe Community-acquired Pneumonia: A Retrospective, Multicenter Cohort Study.

PURPOSE: Consensus guidelines for hospitalized, non-severe community-acquired pneumonia (CAP) recommend empiric macrolide + ß-lactam or respiratory fluoroquinolone monotherapy in patients with no risk factors for resistant organisms. In patients with allergies or contraindications, doxycycline + ß-lactam is a recommended alternative. The purpose of this study was to compare differences in outcomes among guideline-recommended regimens in this population. METHODS: This retrospective, multicenter cohort study included patients ≥18 years of age with CAP who received respiratory fluoroquinolone monotherapy, empiric macrolide + ß-lactam, or doxycycline + ß-lactam. Major exclusion criteria included patients with immunocompromising conditions, requiring vasopressors or invasive mechanical ventilation within 48 hours of admission, and receiving less than 2 days of total antibiotic therapy. The primary outcome was in-hospital mortality. Secondary outcomes included clinical failure, 14- and 30-day hospital readmission, and hospital length of stay. Safety outcomes included incidence of new Clostridioides difficile infection and aortic aneurysm ruptures. FINDINGS: Of 4685 included patients, 1722 patients received empiric respiratory fluoroquinolone monotherapy, 159 received empiric doxycycline + ß-lactam, and 2804 received empiric macrolide + ß-lactam. Incidence of in-hospital mortality was not observed to be significantly different among empiric regimens (doxycycline + ß-lactam group: 1.9% vs macrolide + ß-lactam: 1.9% vs respiratory fluoroquinolone monotherapy: 1.5%, P = 0.588). No secondary outcomes were observed to differ significantly among groups. IMPLICATIONS: We observed no differences in clinical or safety outcomes among three guideline-recommended empiric CAP regimens. Empiric doxycycline + ß-lactam may be a safe empiric regimen for hospitalized CAP patients with non-severe CAP, although additional research is needed to corroborate these observations with larger samples.

Evaluation of an individual examination remediation policy in a professional pharmacy course.

INTRODUCTION: Maintaining institutional remediation policies is required for pharmacy education accreditation, but specific policies and students' perceptions of remediation are not well described in the literature. The purpose of this research was to determine whether the individual examination remediation policy utilized in a biomedical literature evaluation course was a viable approach to ensuring positive student experiences and success. METHODS: This study utilized a pre-/post-quantitative survey design. An 11-item pre-remediation questionnaire was offered to all students enrolled in the course in 2022. A matched post-survey was administered to students eligible to remediate individual examinations. Survey items were assessed using a five-point Likert rating. Remediation examination grades were analyzed in aggregate. Descriptive statistics were utilized as appropriate. RESULTS: One hundred of the 108 (92.5%) enrolled students completed the pre-remediation survey. Students strongly agreed they would prefer to remediate individual examinations instead of taking one cumulative course remediation examination (median 5) and that remediating would improve their understanding of course material (median 5). Nineteen (44%) of 43 students eligible for individual examination remediation chose to remediate, and 16 (37%) responded to the post-remediation survey. Among those eligible, the most common reason for remediating was desire to receive a better score. Significantly more students improved their examination scores through remediation. CONCLUSIONS: Students in the course preferred to remediate individual examinations, but only 44% of students eligible to remediate chose to do so. Future studies with larger sample sizes and course outcome data are warranted to further explore examination remediation in professional pharmacy courses.

Impact of Stress Ulcer Prophylaxis Discontinuation Guidance in Mechanically Ventilated, Critically Ill Patients: A Pre-Post Cohort Study.

Purpose: Recent data highlight unclear efficacy and potential negative sequelae of stress ulcer prophylaxis (SUP) in the intensive care unit (ICU). Minimizing SUP exposure has pertinent clinical and other implications. This study assessed medication use and clinical outcomes before and after implementation of a practice guideline promoting early discontinuation of SUP in mechanically ventilated ICU patients. Methods: Retrospective, single-center, pre-post cohort study within a medical ICU at a large, academic medical center. Adult patients requiring mechanical ventilation and receiving SUP via a histamine-2 receptor antagonist (H2RA) or proton pump inhibitor (PPI) were eligible for inclusion. The clinical practice guideline was implemented on January 1, 2020. The impact of implementation was assessed via percent of patient-days with inappropriate SUP. Incidence of clinically important GI bleed was the primary safety outcome. Results: A total of 137 pre-guideline and 112 post-guideline patients were included. Comorbidity burden was similar between groups. A higher prevalence of baseline vasopressor receipt (39% vs 67%, P < .01) and acute kidney injury (56% vs 69%, P = .04) was observed in post-guideline patients. Post-guideline patients experienced a significantly lower percentage of patient-days of inappropriate SUP (25% vs 50%, P < .01) as well as higher rates of SUP discontinuation before extubation (71% vs 12%, P < .01) and during ICU stay (93% vs 50%, P < .01). Post-guideline patients observed a significantly lower incidence of SUP at hospital discharge (4% vs 35%, P < .01). No differences in bleeding outcomes were observed, though post-guideline patients experienced longer durations of mechanical ventilation, ICU stay, and hospital stay. Conclusions: Implementation of an early SUP discontinuation guideline was associated with significant improvements in SUP prescribing practices. Baseline differences between groups likely explain observed differences in clinical outcomes.

Machine learning to predict vasopressin responsiveness in patients with septic shock.

STUDY OBJECTIVES: The objective of this study was to develop and externally validate a model to predict adjunctive vasopressin response in patients with septic shock being treated with norepinephrine for bedside use in the intensive care unit. DESIGN: This was a retrospective analysis of two adult tertiary intensive care unit septic shock populations. SETTING: Barnes-Jewish Hospital (BJH) from 2010 to 2017 and Beth Israel Deaconess Medical Center (BIDMC) from 2001 to 2012. PATIENTS: Two septic shock populations (548 BJH patients and 464 BIDMC patients) that received vasopressin as second-line vasopressor. INTERVENTION: Patients who were vasopressin responsive were compared with those who were nonresponsive. Vasopressin response was defined as survival with at least a 20% decrease in maximum daily norepinephrine requirements by one calendar day after vasopressin initiation, without a third-line vasopressor. MEASUREMENTS: Two supervised machine learning models (gradient-boosting machine [XGBoost] and elastic net penalized logistic regression [EN]) were trained in 1000 bootstrap replications of the BJH data and externally validated in the BIDMC data to predict vasopressin responsiveness. MAIN RESULTS: Vasopressin responsiveness was similar among each cohort (BJH 45% and BIDMC 39%). Mortality was lower for vasopressin responders compared with nonresponders in the BJH (51% vs. 73%) and BIDMC (45% vs. 83%) cohorts, respectively. Both models demonstrated modest discrimination in the training (XGBoost area under receiver operator curve [AUROC] 0.61 [95% confidence interval (CI) 0.61-0.61], EN 0.59 [95% CI 0.58-0.59]) and external validation (XGBoost 0.68 [95% CI 0.63-0.73], EN 0.64 [95% CI 0.59-0.69]) datasets. CONCLUSION: Vasopressin nonresponsiveness is common and associated with increased mortality. The models' modest performances highlight the complexity of septic shock and indicate that more research will be required before clinical decision support tools can aid in anticipating patient-specific responsiveness to vasopressin.

Short- Versus Standard-Course Nonmacrolide Antibiotic Treatment in Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Retrospective, Observational Cohort Study.

PURPOSE: In critically ill patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and without positive microbiological data, the efficacy and tolerability of short-course nonmacrolide antibiotics are ill-described and have pertinent implications in antimicrobial stewardship. This study compared the efficacy and tolerability of nonmacrolide antibiotic strategies in critically ill patients with AECOPD and without pertinent positive microbiological testing. METHODS: This single-center, retrospective cohort study was conducted in culture-negative critically ill adults admitted to an intensive care unit (ICU) between July 1, 2014, and July 1, 2019, for the treatment of AECOPD. Included patients received treatment with an empiric corticosteroid, azithromycin, and/or a nonmacrolide antibiotic. Patients treated with a nonmacrolide antibiotic for ≤3 and >3 days made up the short- and standard-course groups, respectively. The prevalence of in-hospital mortality, progression to the need for ventilation, and/or readmission for AECOPD within 30 days (primary composite end point) was compared between the two groups. Additional end points included hospital and ICU lengths of stay (LOS), all-cause 30-day readmission, and prevalence of antibiotic-related adverse events. FINDINGS: A total of 135 patients were included (short course, 66; standard course, 69). The differences in the primary composite end point (short vs standard, 24.2% vs 39.1%; P = 0.06) and its individual components were not significant. The median ICU LOS (2 vs 3 days) and hospital LOS (4 vs 6 days) were shorter in the short-course group (both, P < 0.01). Multivariate logistic regression confirmed no association between group assignment and the primary end point. IMPLICATIONS: Short-course nonmacrolide therapy in patients with AECOPD and no positive microbiological testing was not associated with differences in mortality, progression to ventilation, readmission rate, or prevalence of adverse drug events. Larger-scale prospective studies are needed to validate these findings.

Racial Disparities in Readmissions Following Initial Hospitalization for Sepsis.

OBJECTIVES: To assess whether Black race is associated with a higher rate of all-cause readmission compared with White race following community-onset sepsis. DESIGN: Retrospective cohort study. SETTING: One-thousand three-hundred bed urban academic medical centers. PATIENTS: Three-thousand three-hundred ninety patients hospitalized with community-onset sepsis between January 1, 2010, and December 31, 2017. INTERVENTIONS: Community-onset sepsis was defined as patients admitted through the emergency department with an International Classification of Disease, ninth revision, Clinical Modification code for either severe sepsis (995.92) or septic shock (785.52). Beginning in 2015, we used International Classification of Disease, Tenth Revision, Clinical Modification codes R65.20 (severe sepsis) and R65.21 (septic shock). We excluded those individuals hospitalized at another acute care facility that were transferred to our facility. Race was abstracted electronically, and patients who expired or self-identified as a race other than Black or White race were excluded. Patients who experienced a subsequent hospitalization at our facility were considered to be readmitted. MEASUREMENTS AND MAIN RESULTS: Compared with White race, Black race demonstrated a significantly higher rate of all-cause readmission (60.8% vs 71.1%; p < 0.001), including a higher rate of readmission for sepsis (14.0% vs 19.8%; p < 0.001). Black patients also resided in zip codes with a lower median household income and were more likely to use public insurance compared with White race. Similar rates of comorbid diseases and disease burden were observed between the two groups, but vasopressors were less likely to be administered to Black patients. Multivariable analysis showed that Black race was associated with a 50% increased odds (odds ratio, 1.52, 99% CI, 1.25-1.84) in all-cause readmission risk compared with White race. CONCLUSIONS: Black race was associated with a higher rate of all-cause and sepsis readmission, possibly as a result of unaddressed health disparities, compared with White race. Programs addressing healthcare disparities should use readmission as another marker of equity.

Vancomycin Dosing Practices among Critical Care Pharmacists: A Survey of Society of Critical Care Medicine Pharmacists.

INTRODUCTION: Critically ill patients and their pharmacokinetics present complexities often not considered by consensus guidelines from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Prior surveys have suggested discordance between certain guideline recommendations and reported infectious disease pharmacist practice. Vancomycin dosing practices, including institutional considerations, have not previously been well described in the critically ill patient population. OBJECTIVES: To evaluate critical care pharmacists' self-reported vancomycin practices in comparison to the 2009 guideline recommendations and other best practices identified by the study investigators. METHODS: An online survey developed by the Research and Scholarship Committee of the Clinical Pharmacy and Pharmacology (CPP) Section of the Society of Critical Care Medicine (SCCM) was sent to pharmacist members of the SCCM CPP Section practicing in adult intensive care units in the spring of 2017. This survey queried pharmacists' self-reported practices regarding vancomycin dosing and monitoring in critically ill adults. RESULTS: Three-hundred and sixty-four responses were received for an estimated response rate of 26%. Critical care pharmacists self-reported largely following the 2009 vancomycin dosing and monitoring guidelines. The largest deviations in guideline recommendation compliance involve consistent use of a loading dose, dosing weight in obese patients, and quality improvement efforts related to systematically monitoring vancomycin-associated nephrotoxicity. Variation exists regarding pharmacist protocols and other practices of vancomycin use in critically ill patients. CONCLUSION: Among critical care pharmacists, reported vancomycin practices are largely consistent with the 2009 guideline recommendations. Variations in vancomycin dosing and monitoring protocols are identified, and rationale for guideline non-adherence with loading doses elucidated.

Outcomes of Macrolide Deescalation in Severe Community-acquired Pneumonia.

PURPOSE: Current data suggest potential benefits with ß-lactam plus macrolide combination therapy for empiric treatment of intensive care unit (ICU) patients with severe community-acquired pneumonia (CAP). However, it is unclear whether deescalation to ß-lactam monotherapy in the absence of positive results on diagnostic tests, such as the BioFire FilmArray Respiratory Panel 2 (BioFire polymerase chain reaction [PCR]), affects clinical outcomes. The purpose of this study was to compare outcomes between patients with negative BioFire PCR results deescalated to ß-lactam monotherapy with those not deescalated. METHODS: This single-center, retrospective cohort study assessed the in-hospital mortality rates of critically ill adults with CAP treated for ≥48 h with combination ß-lactam and azithromycin therapy. Additional end points included hospital length of stay (LOS), ICU LOS, duration of mechanical ventilatory support, 30-day readmission, and incidence of azithromycin-related adverse effects. FINDINGS: A total of 94 patients were included: 53 in the deescalation group and 41 in the nondeescalation group. No difference was observed with respect to in-hospital mortality (2.4% vs 11.3%, P = 0.312), although patients in the deescalated group experienced shorter ICU (1.9 vs 3.4 days, P = 0.029) and hospital LOS (6 vs 7 days, P = 0.025). No differences were found between groups with respect to additional secondary end points. Simple logistic regression confirmed that deescalation was not associated with hospital mortality (odds ratio = 0.17, 95% CI, 0.02-1.70). IMPLICATIONS: In this study of ICU patients with severe CAP and a negative BioFire PCR result, deescalation from combination ß-lactam and macrolide therapy to ß-lactam monotherapy was not associated with increased in-hospital mortality but was associated with decreased hospital and ICU LOS. Larger prospective studies are warranted to verify these findings.

2019 update of the WSES guidelines for management of Clostridioides (Clostridium) difficile infection in surgical patients.

In the last three decades, Clostridium difficile infection (CDI) has increased in incidence and severity in many countries worldwide. The increase in CDI incidence has been particularly apparent among surgical patients. Therefore, prevention of CDI and optimization of management in the surgical patient are paramount. An international multidisciplinary panel of experts from the World Society of Emergency Surgery (WSES) updated its guidelines for management of CDI in surgical patients according to the most recent available literature. The update includes recent changes introduced in the management of this infection.

Incidence of Acute Kidney Injury in Critically Ill Patients Receiving Vancomycin with Concomitant Piperacillin-Tazobactam, Cefepime, or Meropenem.

Critically ill patients are frequently treated with empirical antibiotic therapy, including vancomycin and ß-lactams. Recent evidence suggests an increased risk of acute kidney injury (AKI) in patients who received a combination of vancomycin and piperacillin-tazobactam (VPT) compared with patients who received vancomycin alone or vancomycin in combination with cefepime (VC) or meropenem (VM), but most studies were conducted predominately in the non-critically ill population. A retrospective cohort study that included 2,492 patients was conducted in the intensive care units of a large university hospital with the primary outcome being the development of any AKI. The rates of any AKI, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, were 39.3% for VPT patients, 24.2% for VC patients, and 23.5% for VM patients (P < 0.0001 for both comparisons). Similarly, the incidences of stage 2 and stage 3 AKI were also significantly higher for VPT patients than for the patients in the other groups. The rates of stage 2 and stage 3 AKI, respectively, were 15% and 6.6% for VPT patients, 5.8% and 1.8% for VC patients, and 6.6% and 1.3% for VM patients (P < 0.0001 for both comparisons). In multivariate analysis, the use of vancomycin in combination with piperacillin-tazobactam was found to be an independent predictor of AKI (odds ratio [OR], 2.161; 95% confidence interval [CI], 1.620 to 2.883). In conclusion, critically ill patients receiving the combination of VPT had the highest incidence of AKI compared to critically ill patients receiving either VC or VM.

Design and Validation of Patient-Centered Communication Tools (PaCT) to Measure Students' Communication Skills.

Objective. To develop a comprehensive instrument specific to student pharmacist-patient communication skills, and to determine face, content, construct, concurrent, and predictive validity and reliability of the instrument. Methods. A multi-step approach was used to create and validate an instrument, including the use of external experts for face and content validity, students for construct validity, comparisons to other rubrics for concurrent validity, comparisons to other coursework for predictive validity, and extensive reliability and inter-rater reliability testing with trained faculty assessors. Results. Patient-centered Communication Tools (PaCT) achieved face and content validity and performed well with multiple correlation tests with significant findings for reliability testing and when compared to an alternate rubric. Conclusion. PaCT is a useful instrument for assessing student pharmacist communication skills with patients.

A Prospective One-Year Microbiologic Survey of Combined Pneumonia and Respiratory Failure.

BACKGROUND: Pneumonia and respiratory failure are common problems in the intensive care unit (ICU) setting, often occurring together. The relative prevalence of pneumonia types (community acquired, hospital acquired, ventilator associated) and causative pathogens is not well described in patients with respiratory failure. METHODS: This was a prospective observational cohort study conducted in the medical ICU (34 beds) of Barnes-Jewish Hospital, an academic referral center of 1,300 beds from January 2016-December 2016. All patients who were prospectively adjudicated to have respiratory failure and pneumonia (RFP) regardless of pneumonia type were classified into one of four microbiologic categories: pathogen negative, antibiotic-susceptible pathogen (according to ceftriaxone susceptibility), antibiotic-resistant pathogen, and viruses. The primary outcomes assessed were the hospital mortality rate and inappropriate initial antibiotic therapy (IIAT) for non-viral pathogens. RESULTS: Among 364 consecutive patients with RFP, 63 (17.3%) had organisms that were antibiotic susceptible, 104 (28.6%) had antibiotic-resistant organisms, 118 (32.4%) were pathogen negative, and 79 (21.7%) had viral infections. For these categories, IIAT occurred in 3.2%, 21.2%, 0.8%, and 0, respectively (p < 0.001). Vasopressor-requiring shock was present in 61.9%, 72.1%, 68.6%, and 67.1%, respectively (p = 0.585), and the hospital mortality rates were 27.0%, 48.1%, 31.4%, and 36.7%, respectively (p = 0.020). Multivariable logistic regression analysis identified IIAT as an independent predictor of in-hospital death (adjusted odds ratio 5.28; 95% confidence interval 2.72-10.22; p = 0.012). Male gender, increasing Acute Physiology and Chronic Health Evaluation (APACHE) II scores, greater age, and the presence of shock also predicted death. CONCLUSIONS: Microbiologic categorization of patients with RFP suggests that antibiotic-resistant pathogens and viruses are associated with the highest mortality rates. Vasopressor-requiring shock was common regardless of the microbiologic categorization of RFP. Future development and use of rapid diagnostics and novel therapeutics targeting specific RFP pathogens may allow more timely administration of appropriate antimicrobial therapy and enhance antibiotic stewardship practices.

Controversies and advances in the management of ventilator associated pneumonia.

INTRODUCTION: Although national surveillance data suggests that the incidence of ventilator associated pneumonia (VAP) is down-trending, it remains one of the most commonly encountered hospital acquired infections in the United States and worldwide. Its association with increased healthcare costs and worsened patient outcomes warrants continued effort to improve the care of patients with VAP. Areas covered: The increasing prevalence of multi-drug resistant bacteria further drives the need to explore advances in diagnostic and treatment options. In this review, controversies pertaining to the definition and diagnosis of VAP as well as empiric treatment strategies will be discussed along with several developments related to rapid microbiologic testing methods and the use of non-traditional antimicrobial agents. Expert commentary: The application of rapid diagnostic techniques to identify microbial pathogens is perhaps one of the most impactful advancements in the treatment of serious nosocomial infections. This technology has the potential to reduce inappropriate initial antimicrobial therapy, unnecessary antimicrobial exposure, and mortality in patients with VAP. In addition, the anticipated approval of new antimicrobial agents within the next several years will provide a much-needed expansion of available treatment options in an era of growing antimicrobial resistance.

Enhanced antimicrobial de-escalation for pneumonia in mechanically ventilated patients: a cross-over study.

BACKGROUND: Antibiotics are commonly administered to hospitalized patients with infiltrates for possible bacterial pneumonia, often leading to unnecessary treatment and increasing the risk for resistance emergence. Therefore, we performed a study to determine if an enhanced antibiotic de-escalation practice could improve antibiotic utilization in mechanically ventilated patients with suspected pneumonia cared for in an academic closed intensive care unit (ICU). METHODS: This was a prospective cross-over trial comparing routine antibiotic management (RAM) and enhanced antimicrobial de-escalation (EAD) performed within two medical ICUs (total 34 beds) at Barnes-Jewish Hospital, an academic referral center. Patients in the EAD group had their antibiotic orders and microbiology results reviewed daily by a dedicated team comprised of a second-year critical care fellow, an ICU attending physician and an ICU pharmacist. Antibiotic de-escalation recommendations were made when appropriate based on microbiologic test results and clinical response to therapy. RESULTS: There were 283 patients evaluable, with suspected pneumonia requiring mechanical ventilation: 139 (49.1%) patients in the RAM group and 144 (50.9%) in the EAD group. Early treatment failure based on clinical deterioration occurred in 33 (23.7%) and 40 (27.8%) patients, respectively (P = 0.438). In the remaining patients, antimicrobial de-escalation occurred in 70 (66.0%) and 70 (67.3%), respectively (P = 0.845). There was no difference between groups in total antibiotic days ((median (interquartile range)) 7.0 days (4.0, 9.0) versus 7.0 days (4.0, 8.8) (P = 0.616)); hospital mortality (25.2% versus 35.4% (P = 0.061)); or hospital duration (12.0 days (6.0, 20.0) versus 11.0 days (6.0, 22.0) (P = 0.918). CONCLUSIONS: The addition of an EAD program to a high-intensity daytime staffing model already practicing a high-level of antibiotic stewardship in an academic ICU was not associated with greater antibiotic de-escalation or a reduction in the overall duration of antibiotic therapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02685930 . Registered on 26 January 2016.

Perceived Motivating Factors and Barriers for the Completion of Postgraduate Training Among American Pharmacy Students Prior to Beginning Advanced Pharmacy Practice Experiences.

Objective. To examine perceived motivating factors and barriers (MFB) to postgraduate training (PGT) pursuit among pharmacy students. Methods. Third-year pharmacy students at 13 schools of pharmacy provided demographics and their plan and perceived MFBs for pursuing PGT. Responses were characterized using descriptive statistics. Kruskal-Wallis equality-of-proportions rank tests determined if differences in perceived MFBs existed between students based on plan to pursue PGT. Results. Among 1218 (69.5%) respondents, 37.1% planned to pursue PGT (32.9% did not, 30% were undecided). Students introduced to PGT prior to beginning pharmacy school more frequently planned to pursue PGT. More students who planned to pursue PGT had hospital work experience. The primary PGT rationale was, "I desire to gain more knowledge and experience." Student debt was the most commonly cited barrier. Conclusion. Introducing pharmacy students early to PGT options and establishing work experiences in the hospital setting may increase students' desire to pursue PGT.

Effects of empiric antifungal therapy for septic shock on time to appropriate therapy for Candida infection: a pilot study.

PURPOSE: Inappropriate initial therapy for Candida-related septic shock is common and associated with a high mortality rate. This before-after pilot study was conducted to determine the feasibility of using empiric therapy for reducing the time to appropriate antifungal therapy in patients with Candida-related septic shock. METHODS: Patients aged 18-99 years with septic shock presenting to Barnes-Jewish Hospital, St. Louis, Missouri, in 2012-2013 were assigned to 1 of 2 groups. Patients presenting between January 1, 2012, and December 31, 2012, were managed according to local standard of care for patients with septic shock, to include antifungal therapy at the discretion of the treating physician (standard therapy group). Patients presenting between January 1, 2013, and December 31, 2013, received empiric antifungal therapy (primarily micafungin 100 mg/d or fluconazole 800 mg on day 1, followed by 400 mg/d), facilitated by a clinical pharmacist in the medical intensive care unit, until microbiologic cultures were available to determine the cause of septic shock (empiric therapy group). The primary outcome was time to appropriate therapy after shock onset. FINDINGS: A total of 28 patients were enrolled (mean age, 56.3 [15.1] years [range, 30-92 years]; 16 [57.1%] men). The time to appropriate therapy after shock onset was statistically shorter with empiric therapy (n = 13) compared with standard therapy (n = 15) (10.6 [15.8] vs 40.5 [26.0] hours; P = 0.001). Patients receiving empiric therapy were more likely to have received appropriate therapy within 12 hours (69.2% vs 6.7%; P = 0.001) and within 24 hours (76.9% vs 40.0%; P = NS) of shock onset. In an analysis to determine the number of septic shock patients needed to be treated with empiric antifungal therapy for 1 patient with Candida-related septic shock to receive appropriate treatment, 256 patients without Candida infection received a total of 687 doses of empiric antifungal therapy (mean, 2.7 doses per patient) compared with 136 patients who received 382 doses of standard antifungal therapy (mean, 2.8 doses per patient); the number needed to treat was 19.6. IMPLICATIONS: The present pilot study demonstrated that the use of empiric antifungal therapy for Candida-related septic shock was associated with a statistically shorter time to administration of appropriate treatment. ClinicalTrials.gov identifier.

Role of fidaxomicin for the treatment of Clostridium difficile infection.

Clostridium difficile is a gram-negative, anaerobic, spore-forming emerging pathogen within health care systems and community-based populations that has a high associated morbidity and mortality as well as cost for the health care system. Recent studies reported high rates of recurrence thus a need for new pharmacological agents to treat C difficile infections (CDIs). Fidaxomicin is a novel macrocyclic antibiotic, originally isolated from fermentation broth of Dactylosporangium aurantiacum spp Hamdenensis, with selective spectrum, unique pharmacokinetic and pharmacodynamics profile, adverse effect profile, efficacy, and role in the treatment of and time to recurrent CDI. Fidaxomicin data have similar clinical cure, when compared to vancomycin, with lower recurrence rates and higher global cure rates in non-BI/NAP1/027 strains. Fidaxomicin also lacks activity against gram-negative bacteria; hence, its potential effect on resistance development among enteric bacteria appears to be low. It appears to have minimal need for renal or hepatic adjustments and minimal concerns for drug-drug interactions. Overall, fidaxomicin has been generally well tolerated with the most common adverse effects reported as mild gastrointestinal complaints. Fidaxomicin appears to have a role in the treatment of CDI with potential lower rates of recurrence, especially in patients with severe disease or risk factors for recurrent CDI.

Prolonged infusion antibiotics for suspected gram-negative infections in the ICU: a before-after study.

BACKGROUND: ß-Lactam antibiotics demonstrate time-dependent killing. Prolonged infusion of these agents is commonly performed to optimize the time the unbound concentration of an antibiotic remains greater than the minimum inhibitory concentration and decrease costs, despite limited evidence suggesting improved clinical results. OBJECTIVE: To determine whether prolonged infusion of ß-lactam antibiotics improves outcomes in critically ill patients with suspected gram-negative infection. METHODS: We conducted a single-center, before-after, comparative effectiveness trial between January 2010 and January 2011 in the intensive care units at Barnes-Jewish Hospital, an urban teaching hospital affiliated with the Washington University School of Medicine in St. Louis, MO. Outcomes were compared between patients who received standardized dosing of meropenem, piperacillin-tazobactam, or cefepime as an intermittent infusion over 30 minutes (January 1, 2010, to June 30, 2010) and patients who received prolonged infusion over 3 hours (August 1, 2010, to January 31, 2011). RESULTS: A total of 503 patients (intermittent infusion, n = 242; prolonged infusion, n = 261) treated for gram-negative infection were included in the clinically evaluable population. Approximately 50% of patients in each group received cefepime and 20% received piperacillin-tazobactam. More patients in the intermittent infusion group received meropenem (35.5% vs 24.5%; p = 0.007). Baseline characteristics were similar between groups, with the exception of a greater occurrence of chronic obstructive pulmonary disease (COPD) in the intermittent infusion group. Treatment success rates in the clinically evaluable group were 56.6% for intermittent infusion and 51.0% for prolonged infusion (p = 0.204), and in the microbiologically evaluable population, 55.2% for intermittent infusion and 49.5% for prolonged infusion (p = 0.486). Fourteen-day, 30-day, and inhospital mortality rates in the clinically evaluable population for the intermittent and prolonged infusion groups were 13.2% versus 18.0% (p = 0.141), 23.6% versus 25.7% (p = 0.582), and 19.4% versus 23.0% (p = 0.329). CONCLUSIONS: Routine use of prolonged infusion of time-dependent antibiotics for the empiric treatment of gram-negative bacterial infections offers no advantage over intermittent infusion antibiotic therapy with regard to treatment success, mortality, or hospital length of stay. These results were confirmed after controlling for potential confounders in a multivariate analysis.

The determinants of hospital mortality among patients with septic shock receiving appropriate initial antibiotic treatment*.

OBJECTIVE: To identify the determinants of hospital mortality among patients with septic shock receiving appropriate initial antibiotic treatment. DESIGN: A retrospective cohort study of hospitalized patients with blood culture positive septic shock (January 2002-December 2007). SETTING: Barnes-Jewish Hospital, a 1,250-bed urban teaching hospital. PATIENTS: Four hundred thirty-six consecutive patients with septic shock and a positive blood culture. INTERVENTIONS: Data abstraction from computerized medical records. MEASUREMENTS AND MAIN RESULTS: Septic shock was associated with bloodstream infection due to Gram-negative bacteria (59.2%) and Gram-positive bacteria (40.8%). Two hundred twenty-four patients (51.4%) died during their hospitalization. The presence of infection attributed to antibiotic-resistant bacteria was similar for patients who survived and expired (22.6% vs. 20.1%; p = .516). Multivariate logistic regression analysis demonstrated that infection acquired in the intensive care unit (adjusted odds ratio 1.99; 95% confidence interval 1.52-2.60; p = .011) and increasing Acute Physiology and Chronic Health Evaluation II scores (one-point increments) (adjusted odds ratio 1.11; 95% confidence interval 1.09-1.14; p < .001) were independently associated with a greater risk of hospital mortality, whereas infection with methicillin-susceptible Staphylococcus aureus (adjusted odds ratio 0.32; 95% confidence interval 0.20-0.52; p = .017) was independently associated with a lower risk of hospital mortality. Patients infected with methicillin-susceptible Staphylococcus aureus infections were statistically younger and had lower Charlson comorbidity and Acute Physiology and Chronic Health Evaluation II scores compared to patients with non-methicillin-susceptible Staphylococcus aureus infections. CONCLUSIONS: Among patients with septic shock who receive appropriate initial antibiotic treatment, acquisition of infection in the intensive care unit and severity of illness appear to be the most important determinants of clinical outcome.