Risk factors and outcome associated with coinfection with carbapenem-resistant Klebsiella pneumoniae and carbapenem-resistant Pseudomonas aeruginosa or Acinetobacter baumanii: a descriptive analysis.

Background: Nearly 30% of patients infected with carbapenem-resistant Klebsiella pneumoniae (CRKP) were previously shown to be coinfected with carbapenem-resistant Pseudomonas aeruginosa (CRPA) or Acinetobacter baumannii (CRAB). Infections caused by multiple carbapenem-resistant pathogens present significant challenge to infection control and therapeutic management. The study objective was to identify risk factors for acquisition of multiple carbapenem-resistant pathogens and associated outcomes. Methods: A descriptive analysis of adults infected with either CRKP alone or coinfected with CRPA or CRAB was performed. Patient groups were compared on demographics, clinical characteristics, treatment, and outcome. Results: 86 patients with CRKP monoinfection and 60 patients with coinfections were evaluated. Respiratory tract was the predominant infection site for coinfected patients involving mostly CRPA whereas urinary tract was the primary site for CRKP-only group. More coinfected patients were severely debilitated, had prior carbapenem exposure (37% vs 13%, p<0.001) and history of pneumonia in the past year (67% vs 41%, p<0.01). More coinfected patients required direct ICU admission (45% vs 27%, p=0.02) and had prolonged length of stay (median 15 vs 10 days, p<0.01) than the CRKP-only group but mortality rates (18% vs 16%) were similar. Conclusions: CRKP coinfection with another carbapenem-resistant pathogen adds significant morbidity and healthcare burden overall. Empiric therapy with reliable activity against both CRKP and carbapenem-resistant Pseudomonas aeruginosa may be prudent for at risk patients with pneumonia.

Machine learning to identify risk factors associated with the development of ventilated hospital-acquired pneumonia and mortality: implications for antibiotic therapy selection.

Background: Among patients with nosocomial bacterial pneumonia, those who decompensated to requiring mechanical ventilation (vHABP) faced the highest mortality followed by ventilator-associated pneumonia (VABP) and non-ventilated hospital-acquired pneumonia (nvHABP). The objectives of this study were to identify risk factors associated with the development and mortality of vHABP and to evaluate antibiotic management. Methods: A multicenter retrospective cohort study of adult inpatients with nosocomial pneumonia during 2014-2019 was performed. Groups were stratified by vHABP, nvHABP, and VABP and compared on demographics, clinical characteristics, treatment, and outcomes. Multivariable models were generated via machine learning to identify risk factors for progression to vHABP as well as pneumonia-associated mortality for each cohort. Results: 457 patients (32% nvHABP, 37% vHABP, and 31% VABP) were evaluated. The vHABP and nvHABP groups were similar in age (median age 66.4 years) with 77% having multiple comorbidities but more vHABP patients had liver disease (18.2% vs. 7.7% p = 0.005), alcohol use disorder (27% vs. 7.1%, p < 0.0001), and were hospitalized within the past 30 days (30.4% vs. 19.5%, p = 0.02). An immediate need for ventilatory support occurred in 70% of vHABP patients on the day of diagnosis. Mortality was the highest in vHABP followed by VABP and nvHABP groups (44.6% vs. 36% vs. 14.3%, p < 0.0001). Nearly all (96%) vHABP patients had positive cultures, with Gram-negative pathogens accounting for 58.8% whereby 33.0% were resistant to extended-spectrum ß-lactams (ESBLs), ceftriaxone (17.5%), fluoroquinolones (20.6%), and carbapenems (12.4%). Up to half of the vHABP patients with ESBL-Enterobacterales or P. aeruginosa did not receive an effective empiric regimen; over 50% increase in mortality rate was observed among patients whom effective therapy was initiated past the day of pneumonia diagnosis. Risk factors associated with vHABP development were alcohol use disorder, APACHE II score, vasopressor therapy prior to infection, and culture positive for ESBL-Enterobacterales whereas history of hospitalization in the past 30 days, active malignancy, isolation of ceftriaxone-resistant pathogens or Pseudomonas aeruginosa, and vasopressor therapy were risk factors for vHABP-associated mortality. Conclusion: Patients with vHABP experienced an acute and severe decompensation upon diagnosis. The risk factors identified in this study could provide actionable data for clinicians to identify those at risk for vHABP at the onset of pneumonia and to target antimicrobial stewardship efforts to improve treatment success.

Unvaccinated Non-Elderly Adult Population Hospitalized for COVID-19: Risk for Severe Disease and Poor Outcomes.

INTRODUCTION: Vaccination offers significant protection against hospitalization and death due to severe COVID-19. However, a significant portion of the nonelderly U.S. adult population remains unvaccinated. METHODS: This retrospective analysis of adult patients aged under 65 years hospitalized with PCR-confirmed SARS-CoV-2 between March and November 2021 assessed the age-biased risk for severe disease and outcome in non-elderly unvaccinated adults hospitalized for COVID-19. Main measures included predisposing risk factors, disease severity and progression, and outcomes in non-elderly adults compared between (1) vaccinated and unvaccinated individuals and (2) unvaccinated individuals grouped by 10-year age increment. RESULTS: Two hundred nineteen non-elderly adults were included; of whom, 82.6% were unvaccinated. Overall, unvaccinated patients were more likely to be obese (60% vs 29%, P < .001) while vaccinated patients were more likely to have cardiovascular disease (50% vs 29%, P = .03). Unvaccinated individuals had prolonged ICU stay (11 vs 2 days, P = .002) and overall length of stay (6 vs 5 days, P < .0001), and higher proportion requiring oxygen at discharge (54% vs 29%, P < .0001). An age-stratified analysis of the unvaccinated cohort found that the time to discharge increased with age (P = .003). Compared to unvaccinated patients aged <46 years, unvaccinated patients aged ≥46 years demonstrated 1.47- and 3.49-times higher likelihood of oxygen dependency upon discharge (P = .002) and requiring higher level of care or worse at discharge (P = .004), respectively. CONCLUSION: Results from our non-elderly cohort affirm the benefit of vaccination despite a subset requiring hospitalization for breakthrough infection. In unvaccinated non-elderly adults, risk for worse outcomes and severe disease increased substantially from middle age onward and provides strong support for vaccination efforts in this population.

Temporal Dynamics of Host Immune Response Associated With Disease Severity and Time to Recovery in Patients Hospitalized for COVID-19.

OBJECTIVES: The objective of this study was to compare the temporal dynamics of two viral-induced inflammatory proteins interferon gamma inducible protein-10 (IP-10) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as well as C-reactive protein (CRP) among patients hospitalized for COVID-19 and examine their prognostic significance. DESIGN: Prospective observational cohort study. SETTING: Multicenter, inpatient. PATIENTS: Adult patients infected with severe acute respiratory syndrome coronavirus 2 between March 2021 and October 2021. INTERVENTIONS: Patient sera were collected on days 1, 3, 5, and 7 of hospitalization. Levels of IP-10, TRAIL, and CRP were measured using a point-of-need diagnostic immunoassay platform (MeMed BV, MeMed, Haifa, Israel) and compared between patients grouped by disease severity (severe vs nonsevere). MEASUREMENTS AND MAIN RESULTS: Baseline characteristics were similar regardless of severity except for a higher prevalence of diabetes and heart failure among severe patients. The immune profile at admission was similar between groups; IP-10 and CRP levels generally decreased while TRAIL levels increased over time in all patients. However, the severe group had higher IP-10 (median 713 vs 328 pg/mL; p = 0.045) and lower TRAIL levels (median 21 vs 30 pg/mL; p = 0.003) on day 3 compared with nonsevere patients. A breakpoint IP-10 level of greater than or equal to 570 pg/mL and TRAIL level of less than 25 pg/mL on day 3 were associated with COVID-19 severity. Patients with elevated day 3 IP-10 levels (≥ 570 pg/mL) were more likely to experience prolonged recovery time (median 12 vs 3 d; p < 0.001). The severe group had prolonged use of corticosteroids (12 vs 5 d; p < 0.001) and had a higher rate of secondary infections (20% vs 6%; p = 0.04) and in-hospital mortality (20% vs 0%; p < 0.001) as compared with nonsevere patients. CONCLUSIONS: The observed patterns in host immune response revealed a turning point in COVID-19 disease on hospital day 3 and the potential utility of IP-10 and TRAIL as sensitive markers associated with disease severity and time to recovery.

Factors associated with prompt recovery among hospitalised patients with coronavirus disease 2019.

BACKGROUND: Patients who survived hospitalisation for COVID-19 experienced varying durations of illness but the factors associated with prompt recovery are unknown. This study identifies factors differentiating hospitalised patients who recovered promptly versus survived a prolonged course of illness because of COVID-19. METHODS: This was a retrospective study from March-August 2020 of hospitalised adults with COVID-19 which were grouped based on time to recovery: short (≤3 days), intermediate (4-10 days) and prolonged (>10 days). Recovery was defined as resolution of fever, tachypnea, hypotension, extubation and return of mental status at baseline. Multivariate analysis was used to evaluate factors associated with prompt recovery. RESULTS: Among 508 patients hospitalised for COVID-19, 401 (79%) survived. Of those, prompt recovery (within 3 days) was achieved in 43% (174/401), whereas 23% (92/401) recovered after a prolonged period of >10 days. Overall, median age was 64 years with 73% admitted from home and 25% from a skilled nursing facility. Predictors for prompt recovery upon admission included female sex (OR, 1.8; 95% CI, 1.1-2.7; P = .01), no fever (OR, 1.6; 95% CI, 1.1-2.6; P = .03), longer time from symptom onset to hospitalisation (OR, 1.1; 95% CI, 1.0-1.1; P = .001), no supplemental oxygen (OR, 1.9; 95% CI, 1.2-3.0; P = .004), no direct ICU admission (OR, 41.7; 95% CI, 2.4-740.4; P = .01) and absence of bacterial co-infections (OR, 2.5; 95% CI, 1.5-4.0, P = .0003). CONCLUSIONS: Our study provides relevant data that could help clinicians triage competing resources in health systems that are challenged by the ebb and flow of COVID-19 cases by identifying clinical features of COVID-19 patients who may require less intensive management including avoidance of unnecessary antibacterial therapy.

Risk factors and outcome associated with infection or colonization due to carbapenem-heteroresistant Escherichia coli.

BACKGROUND: Up to 32% of ESBL-producing Enterobacterales strains display a carbapenem-heteroresistant (cHR) phenotype but its clinical relevance is unknown. OBJECTIVES: To determine risk factors and clinical outcome associated with infection due to cHR ESBL-producing Escherichia coli (ESBL-EC). METHODS: A retrospective, case-control study was conducted on patients from whom a pair of clonally related E. coli strains were isolated during separate healthcare encounters with (case) or without (control) development of cHR phenotype in the latter strain. Study groups were compared for host and microbial characteristics and carbapenem exposure. Outcome measures included ICU admission, length of hospitalization, and mortality. RESULTS: Study patients (15 cases, 10 controls) were elderly (median age: 74 years) with half admitted from home (52%), most (80%) having ≥3 comorbid conditions and severe functional impairment. Case patients were more likely to have 'index' ESBL-EC isolating from blood (27% versus 0%; P = 0.125) and have greater cumulative amount and duration of carbapenem exposure than controls. All control 'subsequent' isolates were from urine whereas five cHR case isolates were from blood or respiratory sources. More hospitalized case patients required ICU admission (23% versus 0%; P = 0.257) and prolonged hospital stay (>7 days) than controls (62% versus 38%%; P = 0.387). CONCLUSIONS: Our findings deserve confirmation with a larger study population and call attention to the potential for increased morbidity with cHR ESBL-EC infections, which underscores the need to screen for cHR phenotype in patients with repeated growth of ESBL-EC, particularly from systemic sites and patients that have had extensive carbapenem exposure.

Cytokine measurements add value to clinical variables in predicting outcomes for Staphylococcus aureus bacteremia.

BACKGROUND: We demonstrated that an early dysregulated cytokine response [high interleukin-10 to tissue necrosis factor (IL-10/TNF) ratio] predicted poor outcomes in patients with Staphylococcus aureus bacteremia (SAB). However, high interpatient variability in cytokine levels were observed. We grouped cytokine measurements in quartiles and assessed their additive value to clinical variables for predicting bacterial persistence and 30-day mortality in patients with SAB. METHODS: A multicenter observational study was conducted in hospitalized patients with SAB. Medical charts were reviewed for relevant information. Blood samples were obtained for cytokine measurements by ELISA: interferon-gamma (IFNγ), interleukin (IL-1ß, IL-6, IL-8, IL-10, IL-17) and tissue necrosis factor (TNF). Cytokine measurements were grouped into quartiles. Significant predictors for bacterial persistence and 30-day mortality were determined by multivariable logistic regression analysis. Area under the ROC curve (AUC) analysis was performed and predictive performance was compared between models with and without cytokine quartiles. RESULTS: Among 606 patients with SAB, a subset of patients (n = 239) had Day 1 cytokine measurements and clinical data collected; of those, 53 (22%) had persistent bacteremia. Accounting for septic shock, the addition of either IL-10 (AUC 0.708) or TNF (AUC 0.714) quartiles measured on Day 1 improved model performance for predicting bacterial persistence. All patients had Day 4 cytokine measurements; 52 patients (8.5%) died within 30-days of SAB onset. Inclusion of either IL-10 (AUC 0.873) or TNF (AUC 0.879) quartiles, but not both, measured on Day 4 to the significant clinical predictors (coronary artery disease, Pitt bacteremia score ≥ 4, and septic shock) improved model performance for mortality. CONCLUSIONS: IL-10 or TNF levels falling within the range in the upper quartiles, when combined with clinical variables, improved model performance for predicting outcomes, and may potentially be used to support aggressive management and biomarker-guided studies to evaluate the benefit of adjunctive immunotherapy for SAB in the future.

Prevalence of the carbapenem-heteroresistant phenotype among ESBL-producing Escherichia coli and Klebsiella pneumoniae clinical isolates.

OBJECTIVES: Carbapenem-heteroresistant (cHR) Enterobacteriaceae strains have been reported worldwide; however, the prevalence among clinical ESBL-producing Enterobacteriaceae isolates obtained from patients with repeated hospital admissions remains largely unknown. METHODS: Heteroresistance was screened by disc diffusion and confirmed by a modified population analysis profiling (PAP) method against ertapenem, imipenem, meropenem and ceftolozane/tazobactam. MIC testing was performed by broth microdilution against carbapenems and a panel of agents with potential activity against ESBL-producing strains. RESULTS: One hundred and seventy-three ESBL-producing meropenem-susceptible Escherichia coli and Klebsiella pneumoniae isolates were selected for testing. A total of 519 bacteria/carbapenem combinations were screened by disc diffusion; 84 combinations were identified as cHR. Modified PAP confirmed 70 bacteria/carbapenem combinations as heteroresistant; most (63%, 44/70) confirmed cHR colonies grew within the ertapenem zone of inhibition, followed by imipenem (30%, 21/70), then meropenem (7%, 5/70). In total, one-third of the unique patient isolates (32%, 55/173) were identified as being heteroresistant to at least one carbapenem; of those patients, 16% (9/55) had a carbapenem-non-susceptible isolate on subsequent visits. Only two cHR isolates screened positive for ceftolozane/tazobactam heteroresistance (1%, 2/173), of which one was confirmed heteroresistant by modified PAP. cHR isolates were more likely to be collected from a non-urinary source (e.g. respiratory) compared with non-cHR isolates (31% versus 19%, P = 0.02). MIC distributions of all tested antibiotic agents did not differ between non-cHR and cHR isolates. CONCLUSIONS: Our findings raise concerns for the continued use of carbapenems as first-line therapy for ESBL infections and for the potential selection for strains with full carbapenem resistance.

Defining the Breakpoint Duration of Staphylococcus aureus Bacteremia Predictive of Poor Outcomes.

BACKGROUND: Persistent Staphylococcus aureus bacteremia (SAB) is defined based on varying duration in literature. The primary objective was to determine the risk of poor outcomes in relation to bacteremia duration. METHODS: Multicenter, prospective, observational study of adult hospitalized patients with SAB. Medical records were reviewed for pertinent data. Patients were grouped by bacteremia duration: short (1-2 days), intermediate (3-6 days), and prolonged (≥7 days) and compared for risk factors and outcomes. RESULTS: Of 884 patients, 63% had short, 28% intermediate, and 9% prolonged bacteremia. Overall mean age was 57 years, and 70% were male. The prolonged group had the highest proportion of methicillin-resistant SAB (P < .0001). Choice of antibiotic therapy did not significantly affect bacteremia duration; however, time to source-control procedure was delayed in the prolonged and intermediate groups compared with the short group (3.5 vs 3 vs 1 day, P < .0001). Metastatic complications, length of stay, and 30-day mortality were progressively worse as bacteremia duration increased (P < .0001). Every continued day of bacteremia was associated with a relative risk of death of 1.16 (95% confidence interval, 1.10-1.22; P < .0001), with a significant increase in risk starting at 3 days as determined by receiver operating characteristic analysis. CONCLUSIONS: Optimal management of SAB should target bacterial clearance as soon as possible to minimize incremental risk of mortality with each day of positive blood culture. Delay in source control but not type of antistaphylococcal therapy was significantly associated with prolonged bacteremia and worse outcomes.

Utility of qSOFA score in identifying patients at risk for poor outcome in Staphylococcus aureus bacteremia.

BACKGROUND: The prognostic capability of the quick Sequential Organ Failure Assessment (qSOFA) bedside scoring tool is uncertain in non-ICU patients with sepsis due to bacteremia given the low number of patients previously evaluated. METHODS: We performed a retrospective cohort study of adult hospitalized patients with Staphylococcus aureus bacteremia (SAB). Medical charts were reviewed to determine qSOFA score, systemic inflammatory response syndrome (SIRS) criteria, and Pitt bacteremia score (PBS) at initial presentation; their predictive values were compared for ICU admission within 48 h, ICU stay duration > 72 h, and 30-day mortality. RESULTS: Four hundred twenty-two patients were included; 22% had qSOFA score ≥2. Overall, mean age was 56y and 75% were male. More patients with qSOFA ≥2 had altered mentation (23% vs 5%, p < 0.0001), were infected with MRSA (42% vs 30%, p = 0.03), had endocarditis or pneumonia (29% vs 15%, p = 0.0028), and bacterial persistence ≥4d (34% vs 20%, p = 0.0039) compared to qSOFA <2 patients. Predictive performance based on AUROC was better (p < 0.0001) with qSOFA than SIRS criteria for all three outcomes, but similar to PBS ≥2. qSOFA≥2 was the strongest predictor for poor outcome by multivariable analysis and showed improved specificity but lower sensitivity than SIRS ≥2. CONCLUSIONS: qSOFA is a simple 3-variable bedside tool for use at the time of sepsis presentation that is more specific than SIRS and simpler to calculate than PBS in identifying septic patients at high risk for poor outcomes later confirmed to have S. aureus bacteremia.

Leveraging Antimicrobial Stewardship in the Emergency Department to Improve the Quality of Urinary Tract Infection Management and Outcomes.

BACKGROUND: The complex and fast-paced emergency department (ED) practice setting presents unique challenges that demand a tailored approach to antimicrobial stewardship. In this article, we describe the strategies applied by 1 institution's antimicrobial stewardship program (ASP) that were successful in improving prescribing practices and outcomes for urinary tract infection (UTI) in the ED. METHODS: Core strategies included pre-implementation research characterizing the patient population, antimicrobial resistance patterns, prescribing behavior, and morbidity related to infection; collaboration across multiple disciplines; development and implementation of a UTI treatment algorithm; education to increase awareness of the algorithm and the background and rationale supporting it; audit and feedback; and early evaluation of post-implementation outcomes. RESULTS: We observed a rapid change in prescribing post-implementation with increased empiric nitrofurantoin use and reduced cephalosporin use (P < .05). Our elevation of nitrofurantoin to firstline status was supported by our post-implementation analysis showing that its use was independently associated with reduced 30-day return visits (adjusted odds ratio, 0.547; 95% confidence interval, 0.312-0.960). Furthermore, despite a shift to a higher risk population and a corresponding decrease in antimicrobial susceptibility rates post-implementation, the preferential use of nitrofurantoin did not result in higher bug-drug mismatches while 30-day return visits to the ED remained stable. CONCLUSIONS: We demonstrate that an outcomes-based ASP can impart meaningful change to knowledge and attitudes affecting prescribing practices in the ED. The success of our program may be used by other institutions as support for ASP expansion to the ED.

Risk factors for early return visits to the emergency department in patients with urinary tract infection.

BACKGROUND: Optimal management of urinary tract infections (UTIs) in the emergency department (ED) is challenging due to high patient turnover, decreased continuity of care, and treatment decisions made in the absence of microbiologic data. We sought to identify risk factors for return visits in ED patients treated for UTI. METHODS: A random sample of 350 adult ED patients with UTI by ICD 9/10 codes was selected for review. Relevant data was extracted from medical charts and compared between patients with and without ED return visits within 30days (ERVs). RESULTS: We identified 51 patients (15%) with 59 ERVs, of whom 6% returned within 72h. Nearly half of ERVs (47%) were UTI-related and 33% of ERV patients required hospitalization. ERVs were significantly more likely (P<0.05) in patients with the following: age≥65years; pregnancy; skilled nursing facility residence; dementia; psychiatric disorder; obstructive uropathy; healthcare exposure; temperature≥38 °C heart rate>100; and bacteremia. Escherichia coli was the most common uropathogen (70%) and susceptibility rates to most oral antibiotics were below 80% in both groups except nitrofurantoin (99% susceptible). Cephalexin was the most frequently prescribed antibiotic (51% vs. 44%; P=0.32). Cephalexin bug-drug mismatches were more common in ERV patients (41% vs. 15%; P=0.02). Culture follow-up occurred less frequently in ERV patients (75% vs. 100%; P<0.05). CONCLUSIONS: ERV in UTI patients may be minimized by using ED-source specific antibiogram data to guide empiric treatment decisions and by targeting at-risk patients for post-discharge follow-up.

Staphylococcus aureus Bacteremia in Patients not Meeting Sepsis Criteria: Clinical Features, Host Immune Response and Outcomes.

BACKGROUND: Limitations regarding the sensitivity and specificity of the systemic inflammatory response (SIRS) criteria prompted the recent revision in consensus definitions of sepsis and septic shock. We evaluated patients with Staphylococcus aureus bacteremia (SAB) who did not meet SIRS criteria for sepsis (SIRS-negative, SIRS-N) to compare host immune response and outcomes with SIRS-positive (P) patients. METHODS: A prospective observational study of patients hospitalized for SAB during 2012-2015 was conducted. Pro- (TNFα, IL6, IL8) and anti-inflammatory (IL10) cytokine levels (pg/mL) were compared between SIRS-N and SIRS-P patients. Outcome endpoints were day 4 persistence and 30-day mortality. RESULTS: Of the 353 study patients, 23% were SIRS-N. A similar proportion of SIRS-N and SIRS-P patients had an infection-related admitting diagnosis (70% vs. 66%, p=0.5946), and both groups received timely antibiotic administration. Less than 1/3 of SIRS-N group had abnormal WBC count, tachycardia, or tachypnea while <15% had fever/hypothermia or hypotension. Initial proand anti-inflammatory cytokine levels were significantly lower and in balance as indicated by IL10/TNF ratio in SIRS-N compared to SIRS-P patients. IL10/TNF ratio increased progressively in patients with increasing sepsis severity and mortality. CONCLUSIONS: Clinical management of patients with SAB seemed driven largely by clinician assessment rather than SIRS criteria alone, with one in 4 patients not meeting SIRS criteria. Importantly, the severity of presentation and outcomes of SAB correspond well to the magnitude of underlying imbalance in pro- and anti-inflammatory cytokine levels, supporting the updated sepsis definition as "life-threatening organ dysfunction caused by a dysregulated host response to infection". KEY POINTS: In a prospective observational study of 353 patients with Staphylococcus aureus bacteremia, 23% did not meet SIRS criteria for sepsis. Severity of sepsis and risk of death is supported by a dysregulated host cytokine response with progressively increasing IL10/TNF ratio.

A Dysregulated Balance of Proinflammatory and Anti-Inflammatory Host Cytokine Response Early During Therapy Predicts Persistence and Mortality in Staphylococcus aureus Bacteremia.

OBJECTIVES: The contribution of individual immune response to Staphylococcus aureus bacteremia on outcome has not been well studied. The objective was to relate the host cytokine response to outcome of Staphylococcus aureus bacteremia. DESIGN: Prospective observational study. SETTING: Three U.S. university-affiliated medical centers. PATIENTS: Adult patients infected with Staphylococcus aureus bacteremia hospitalized between July 2012 and August 2014. INTERVENTIONS: Blood specimens were obtained at Staphylococcus aureus bacteremia onset and 72 hours after therapy initiation. Levels of tissue necrosis factor, interleukin-6, interleukin-8, interleukin-17A, and interleukin-10 were measured by enzyme-linked immunosorbent assay at each time point and compared between those with persistent bacteremia (≥ 4 d) and resolving bacteremia. Primary outcome was persistent bacteremia after 4 days of effective therapy. Secondary outcomes were 30-day mortality and 30-day recurrence. MEASUREMENTS AND MAIN RESULTS: A total of 196 patients were included (mean age, 59 yr); of them, 33% had methicillin-resistant Staphylococcus aureus bacteremia. Forty-seven percent of the methicillin-resistant Staphylococcus aureus strains were staphylococcal cassette chromosome mec IV. Persistent bacteremia occurred in 24% of patients (47/196); they were more likely to die than resolving bacteremia group (28% vs 5%; p < 0.001). Compared with resolving bacteremia group, persistent bacteremia patients had higher initial median levels of tissue necrosis factor (44.73 vs 21.68 pg/mL; p < 0.001), interleukin-8 (124.76 vs 47.48 pg/mL; p = 0.028), and interleukin-10 (104.31 vs 29.72 pg/mL; p < 0.001). Despite 72 hours of treatment, levels remained higher for the persistent bacteremia group than for the resolving bacteremia group (tissue necrosis factor: 26.95 vs 18.38 pg/mL, p = 0.02; interleukin-8: 70.75 vs 27.86 pg/mL, p = 0.002; interleukin-6: 67.50 vs 21.81 pg/mL, p = 0.005; and interleukin-10: 30.98 vs 12.60 pg/mL, p < 0.001). Interleukin-17A levels were similar between groups at both time points. After controlling for confounding variables by multivariate analysis, interleukin-10/tissue necrosis factor ratio at 72 hours most significantly predicted persistence (odds ratio, 2.98; 95% CI, 1.39-6.39; p = 0.005) and mortality (odds ratio, 9.87; 95% CI, 2.64-36.91; p < 0.001) at values more than 1.00 and more than 2.56, respectively. CONCLUSIONS: Sustained elevation of interleukin-10/tissue necrosis factor ratio at 72 hours suggests a dysregulated immune response and may be used to guide management to improve outcomes.

Impact of carbapenem resistance on epidemiology and outcomes of nonbacteremic Klebsiella pneumoniae infections.

BACKGROUND: Although high mortality associated with carbapenem-resistant Klebsiella pneumoniae (CRKP) bacteremia has been well described, the epidemiology and outcomes of nonbacteremic infection are unknown. METHODS: Medical charts of adults hospitalized for CRKP pneumonia or urinary tract infection between January 2011 and December 2013 were reviewed retrospectively for relevant demographic and clinical details. Cases were matched to controls (non-carbapenem-resistant, non-extended-spectrum beta-lactamase [ESBL]-producing K pneumoniae [NRKP]) by the primary site of infection and year of isolation and compared in terms of risk of acquisition and outcomes. RESULTS: The CRKP and NRKP arms (n = 48 each) were elderly (median age, 74 years). Compared with controls, more patients in the CRKP arm resided in skilled nursing/long-term acute care facilities (77% vs 29%; P < .01), had a chronic tracheostomy (29% vs 0%; P < .001), decubitus ulcers (69% vs 17%; P < .01), higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores (median, 21.5 vs 14; P = .02), and required intensive care unit admission (54% vs 31%; P = .04). More patients in the CRKP arm had previous ESBL infection (23% vs 6%; P = .04), and this arm had at least a 10-fold greater risk of coinfection with other carbapenem-resistant pathogens (44% vs 4%; P < .01), as well as a 7-fold greater likelihood of previous carbapenem therapy (23% vs 4%; P = .01). Patients in the CRKP arm had prolonged hospitalization (median, 13 days) and a 32% rate of readmission within 30 days of discharge. CONCLUSIONS: CRKP nonbacteremic infections occur in debilitated patients and are associated with frequent previous carbapenem exposure and high resource utilization, underscoring the need to focus efforts on antimicrobial stewardship and infection control.

Patients presenting to the hospital with MRSA pneumonia: differentiating characteristics and outcomes with empiric treatment.

BACKGROUND: Concern for MRSA in patients presented to the hospital with pneumonia may be overestimated leading to excessive prescribing of empiric anti-MRSA therapy. This study aims to identify at-risk patients and treatment outcomes. METHODS: Adults hospitalized during 2005-2011 with pneumonia diagnosed within 48 h of admission were included. Medical charts were retrospectively reviewed for relevant data. Patients with MRSA were matched 1:1 to those with non-MRSA pathogen or negative culture. A published risk scoring system for MRSA pneumonia was applied. RESULTS: 268 elderly patients were included, 134 patients in each group. Compared to non-MRSA group, MRSA patients presented more acutely ill (p < 0.0001) (pneumonia severity index score, 150 vs 93; vasopressor therapy, 34% vs 6%; ICU admission, 47% vs 13%; and mechanical ventilation, 35% vs 10%) and had worse outcomes (p < 0.0001) (time to reach clinical stability, 6 vs 2.5d; length of stay, 10 vs 5d; clinical failure, 28% vs 4%; 28-day mortality, 22% vs 3%). When applied to our patients, a published risk scoring scheme had 93% sensitivity but lacked specificity at 55%; 40% of medium-risk patients did not have MRSA. A history of MRSA infection or pneumonia differentiated the latter group. Most MRSA patients (66%, 88/134) were treated empirically (primarily vancomycin) but outcome was not improved by receipt of empiric therapy. CONCLUSIONS: Use of a published risk scoring scheme with additional variables from this study can potentially reduce overprescribing of anti-MRSA empiric therapy in patients presented to the hospital with pneumonia. Prospective studies evaluating the treatment benefit of non-vancomycin alternatives as empiric therapy are needed.