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.

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.

Pediatric Obesity: Pharmacokinetic Alterations and Effects on Antimicrobial Dosing.

Limited data exist for appropriate drug dosing in obese children. This comprehensive review summarizes pharmacokinetic (PK) alterations that occur with age and obesity, and these effects on antimicrobial dosing. A thorough comparison of different measures of body weight and specific antimicrobial agents including cefazolin, cefepime, ceftazidime, daptomycin, doripenem, gentamicin, linezolid, meropenem, piperacillin-tazobactam, tobramycin, vancomycin, and voriconazole is presented. PubMed (1966-July 2015) and Cochrane Library searches were performed using these key terms: children, pharmacokinetic, obesity, overweight, body mass index, ideal body weight, lean body weight, body composition, and specific antimicrobial drugs. PK studies in obese children and, if necessary, data from adult studies were summarized. Knowledge of PK alterations stemming from physiologic changes that occur with age from the neonate to adolescent, as well as those that result from increased body fat, become an essential first step toward optimizing drug dosing in obese children. Excessive amounts of adipose tissue contribute significantly to body size, total body water content, and organ size and function that may modify drug distribution and clearance. PK studies that evaluated antimicrobial dosing primarily used total (or actual) body weight (TBW) for loading doses and TBW or adjusted body weight for maintenance doses, depending on the drugs' properties and dosing units. PK studies in obese children are imperative to elucidate drug distribution, clearance, and, consequently, the dose required for effective therapy in these children. Future studies should evaluate the effects of both age and obesity on drug dosing because the incidence of obesity is increasing in pediatric patients.

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.

Pharmacodynamic Characteristics of Nephrotoxicity Associated With Vancomycin Use in Children.

BACKGROUND: Limited studies incorporating population-based pharmacokinetic modeling have been conducted to determine pharmacodynamic indices associated with nephrotoxicity during vancomycin exposure in children. METHODS: A retrospective cohort analysis was conducted from September 2003 to December 2011 at 2 hospitals. Nephrotoxicity was defined as an increase in serum creatinine concentration (SCr) by ≥0.5 mg/dL, or ≥50% increase in baseline SCr, either persisting for ≥2 consecutive days. A 1-compartment model with first-order kinetics was used in NONMEM 7.2 to estimate trough concentrations (Cmin) and area under the curve over 24 hours (AUC). Univariate, classification and regression tree (CART), and multivariate analyses were conducted to identify factors contributing to nephrotoxicity. RESULTS: The analyses included 680 pediatric subjects with 1576 vancomycin serum concentrations. Based on univariate analysis, median Cmin (14.2 [interquartile range, IQR, 7.1-25.4] vs 8.4 [IQR, 5.5-12.4] mcg/mL; P = .001) and AUC (544 [IQR, 359-801] vs 378 [IQR, 304-494]; P < .001) were significantly higher in the nephrotoxic group compared with the non-nephrotoxic group. Using CART, we discovered that subjects with doses ≥60 mg/kg per day and AUC >1063 mg-h/L had a significantly higher occurrence of nephrotoxicity (P = .005). Adjusting for intensive care unit stay and concomitant nephrotoxic drugs, steady-state vancomycin Cmin ≥15 mcg/mL (adjusted odds ratio [aOR], 2.5; 95% confidence interval [CI], 1.1-5.8; P = .028) and AUC ≥800 mg-h/L (aOR, 3.7; 95% CI, 1.2-11.0; P = .018) were associated with increased risk of nephrotoxicity. CONCLUSIONS: Our study describes the pediatric exposure-nephrotoxicity relationships for vancomycin. Vancomycin Cmin ≥15 mcg/mL and AUC ≥800 mg-h/L in children are independently associated with a > 2.5-fold increased risk of nephrotoxicity and may provide justification for use of alternative antibiotics in selected situations.

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.