Supply Chain Delays in Antimicrobial Administration after the Initial Clinician Order and Mortality in Patients with Sepsis

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ALT DELAYS AND MORTALITY IN SEPSIS: ONLINE-ONLY SUPPLEMENT

Online Supplement

Supply Chain Delays in Antimicrobial Administration after the Initial Clinician Order and Mortality in Patients with Sepsis

Markos G. Kashiouris, MD, MPH

^{1, 2}

, Zachary Zemore, MD

³

, Zachary Kimball, MD

⁴

, Christos Stefanou, MD

⁴

, Alpha A. Fowler, MD

¹

, Bernard Fisher, BS

¹

, Marjolein de Wit, MD

¹

, Sammy Pedram, MD

^1,2

, Mathew Churpek, MD, Ph.D.

⁵

, Xian Qiao, MD

¹

, Curtis N. Sessler, MD FCCP, FCCM

^1,2

.

1) Division of Pulmonary Disease & Critical Care Medicine, Virginia Commonwealth University, Richmond, VA, USA

2) Center for Adult Critical Care (CACC), Virginia Commonwealth University, Richmond, VA, USA

3) Department of Emergency/Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA

4) Nepean Hospital, Sydney, NSW, Australia

5) Division of Pulmonary Disease & Critical Care Medicine, University of Chicago, IL, USA Corresponding author: Markos G. Kashiouris, MD, MPH, Division of Pulmonary Disease &

Critical Care Medicine, Virginia Commonwealth University, Box 980050, Richmond, VA 23298–0050. Reprints can be ordered only after written permission from the corresponding author.

E-mail: [email protected]

Telephone: 804-828-9893 Fax: 804-828-2578

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Online Supplement Contents

Supplement Table 1. Constants employed for data extraction, including the list of antimicrobials and ICD-9 codes...3

Supplement Table 2. The list of demographic, physiologic, laboratory, order and medication variables extracted from the electronic, along with their respective meta-data (date-times, units, etc.)...4

Supplement Table 3. Characteristics of the entire cohort...7

Supplement Table 4. Adjusted inpatient mortality. Adjusted for age, gender, race, initial MAP, FiO2, Initial serum lactate, and initial serum creatinine. ALT denotes antimicrobial lead time, which is the time to initiate the clinicians’ antimicrobial order... 9

Supplement Table 5-a. Multiple logistic regression of 28-day mortality, adjusting for the factors listed below...10

Supplement Table 5-b. Multiple logistic regressiona of 28-day mortality. This in based on 4,429 consecutive patients who were admitted to the Emergency Department (ED) with the diagnosis of sepsis, present on admission...12

Supplement Table 5-c. Multiple logistic regression^a of 28-day mortality, adjusting for the factors listed below. This in based on 4,429 consecutive patients who were admitted to the Emergency Department (ED) with the diagnosis of sepsis, present on admission...14

Supplement Table 5-d. Multiple logistic regressiona of 28-day mortality, adjusting for the factors listed below...17

Supplement Table 6. Analysis of ALT, in hours by the first antibiotic administered...19

Supplement Table 7. Sensitivity Analysis. Adjusted 28-Mortality and relationship with ICU status after Admission...21

Supplement Table 8. Inpatient Mortality. Sensitivity analysis examining the adjusted mortality, and actual observations in parentheses, among patients with differential ALT and time to the first sepsis recognition and intention-to-treat, as measured by the first antibiotic electronic order placement by the clinician, DTOT (Door-to-Order Time)... 24

Supplement Table 9. Missing Data Sensitivity Analysis. Multiple Logistic Regression a Examining the 28-Day Mortality Odds Ratio, only in the Subgroup of Patient’s who did not have a lactate measured (missing lactate)...25

Supplement Figure 1. Percentage Distribution of the antimicrobial Door-To-Order-Time (DTOT), expressed in hours. ... 27

Supplement Figure 2. Percentage Distribution of the antimicrobial Time from Triage-To-Antimicrobial Administration (TPAA), expressed in hours...28

Supplement Figure 3. Post-estimation model predicted hospital mortality...29

Supplement Figure 4. Robust locally weighted regression and smoothing scatterplot of ALT vs. DTOT, along with findings of a simple linear regression fit...30

Supplement Figure 5. Sensitivity Analysis of ED volumes and ALT...31

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Supplement Table 1. Constants employed for data extraction, including the list of antimicrobials and ICD-9 codes.

Constant - Antibiotic

Order Catalog Codes vancomycin,ceftriaxone,clindamycin,azithromycin,sulfamethoxazoletrimetho prim,daptomycin,metronidazole,doxycycline,linezolid,amoxicillinclavulanate, piperacillintazobactam,nafcillin,ciprofloxacin,levofloxacin,amikacin,gentamic in,tobramycin,fluconazole,posaconazole,voriconazole,micafungin,amphoteri cinb,oseltamivir,acyclovir,meropenem,ceftaroline,cefepime,cefoxitin,cefotax ime,allergenspecificigepenicilling,ampicillin,rifampin,aztreonam,cefazolin

Constant - Sepsis ICD

Codes 038.0,038.10,038.11,038.12,038.19,038.2,038.3,038.40,038.41,038.42,038 .43,038.44,038.49,038.8,038.9,040.82,785.52,785.59,998.02,995.91,995.9 2,A02.1,A22.7,A26.7,A32.7,A40.0,A40.1,A40.3,A40.8,A40.9,A41.01,A41.02 ,A41.1,A41.2,A41.3,A41.4,A41.5,A41.50,A41.51,A41.52,A41.53,A41.59,A4 1.81,A41.89,A41.9,A42.7,A48.3,A54.86,B37.7,R65.2,R65.2,R65.21,T81.12 XA

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Supplement Table 2. The list of demographic, physiologic, laboratory, order and medication variables extracted from the electronic, along with their respective meta-data (date-times, units, etc.)

1. Deidentified Study_ID 2. Arrive Date|Time 3. ADMIT_MODE

4. Source of Admission (Origin) 5. Referral for Admit Time 6. REG_DT_TM

7. Admit Order Time 8. USED_ED

9. ED Admit Order Time 10. ED Adult Triage Time 11. ED Mini Triage Time 12. Age

13. DECEASED_DT_TM 14. Gender

15. Race

16. Discharge Date|Time

17. Heart Rate: First >= 90 (Event Date / Heart Rate)

23. Temperature: First <= 36 (Event Date / Result)

25. Temperature: First >= 37.8 (Event Date / Result)

31. Respiratory Rate: First >= 25.0 (Event Date / Result)

33. Respiratory Rate: First >= 30.0 (Event Date / Result)

35. Systolic BP: First <= 90 (Event Date / BP Result)

37. Systolic BP: First <= 100 (Event Date / BP Result)

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39. Systolic BP: First 6 (Event Date / BP Result)

42. MAP: First <= 50.0 (Event Date / Result)

50. MAP: First 6 (Event Date / Result)

53. CVP: First (Event Date / Result)

55. SPO2 with Closest Previous Flow: First 6 (SPO2 Date / Result, Flow Type / Date / Result)

61. O2 Flow Information: First 6 (Event Date / Result)

64. O2 Flow Rate: First 6 (Event Date / Result)

67. PAC O2: First <= 31.99 (Event Date / Result)

69. White Blood Count: First >= 12.0 (Event Date / Result)

71. White Blood Count: First >= 14.0 (Event Date / Result)

73. White Blood Count: First <= 4.0 (Event Date / Result)

75. Bands: First >= 10.0% (Event Date / Result)

77. Lactate: First >= 2.0 (Event Date / Result)

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79. Lactate: First >= 4.0 (Event Date / Result)

81. Lactate: First 6 (Event Date / Result)

84. Creatinine: First 6 (Event Date / Result)

87. Blood Culture: First Drawn (Order Date / Drawn Date)

89. Urinalysis: First Ordered (Order Date / Collection Date / Result Date)

92. Antibiotic Orders: First 10 (Med Name, Order Date, Admin Date, Route)

97. Antibiotic Administration: First 10 (Med Name, Admin Date)

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Supplement Table 3. Characteristics of the entire cohort

Characteristic Sample Size (N) Mean (95% CI) Percent

Comorbidities

Congestive Heart Failure 1085 24.5%

Cardiac Arrhythmias 0 0.0%

Valvular Disease 245 5.5%

Pulmonary Circulation

Disorders 226 5.1%

Peripheral Vascular Disorders 86 1.9%

Hypertension, Uncomplicated 1535 34.7%

Paralysis 67 1.5%

Other Neurological Disorders 319 7.2%

Chronic Pulmonary Disease 984 22.2%

Diabetes, Uncomplicated 0 0.0%

Diabetes, Complicated 0 0.0%

Hypothyroidism 455 10.3%

Renal Failure 1237 27.9%

Liver Disease 627 14.2%

Peptic Ulcer Disease Excluding Bleeding

0 0.0%

AIDS/HIV 149 3.4%

Lymphoma 127 2.9%

Metastatic Cancer 273 6.2%

Solid Tumor Without

Metastasis 478 10.8%

Rheumatoid Arthritis/Collagen

Vascular 124 2.8%

Coagulopathy 347 7.8%

Obesity 0 0.0%

Weight Loss 458 10.3%

Fluid and Electrolyte

Disorders 2567 58.0%

Blood Loss Anemia 0 0.0%

Deficiency Anemia 55 1.2%

Alcohol Abuse 3 0.1%

Drug Abuse 138 3.1%

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Psychoses 118 2.7%

Depression 589 13.3%

Hypertension, Complicated 1050 23.7%

Race

White 1,872 ⎼⎼⎼ 42.3%

Black 2,385 ⎼⎼⎼ 53.9%

Asian 29 ⎼⎼⎼ 0.7%

Other 143 ⎼⎼⎼ 3.2%

Sex

Men 2,401 ⎼⎼⎼ 54.2%

Women 2,028 ⎼⎼⎼ 45.8%

Age 4,429 57.3 (56.8 - 57.8) ⎼⎼⎼

Initial MAP, mmHg 3,909 78.9 (78.4 - 79.5) ⎼⎼⎼

Initial FiO2 Delivered, % 1,342 64.63% (63.15 - 66.11) ⎼⎼⎼

Initial PaCO2, mmHg 883 26.72 (26.45 - 26.99) ⎼⎼⎼

Initial Creatinine, mg/dL 3,501 2.1 (2.0 - 2.2) ⎼⎼⎼

Initial Lactate, mmol/L 2,379 2.5 (2.4 - 2.6) ⎼⎼⎼

First Three Doses of Antimicrobials Received

Gram Positive Coverage 2,338 ⎼⎼⎼ 52.8%

Gram Negative Coverage 2,766 ⎼⎼⎼ 62.5%

Both Gram Positive and

Negative 1,452 32.8%

Sepsis Source

Cardiac 47 ⎼⎼⎼ 1.1%

CNS 29 ⎼⎼⎼ 0.7%

Device Related 77 ⎼⎼⎼ 1.7%

Intraabdominal 298 ⎼⎼⎼ 6.7%

Gynecological 20 ⎼⎼⎼ 0.5%

Bacteremia/ Septicemia 1,630 ⎼⎼⎼ 36.8%

HIV-Related 114 ⎼⎼⎼ 2.6%

Joint 20 ⎼⎼⎼ 0.5%

Lungs 1,279 ⎼⎼⎼ 28.9%

SSTI 235 ⎼⎼⎼ 5.3%

Urinary, or Kidney 637 ⎼⎼⎼ 14.4%

Unclear 43 ⎼⎼⎼ 1.0%

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Abbreviations: AIDS: Acquired Immune Deficiency Syndrome; CNS: Central Nervous System; FiO2: Inspired Oxygen Fraction; HIV: Human Immunodeficiency Virus; MAP: Mean Arterial Pressure; PaCO2: Arterial Carbon Dioxide Concentration; SSTI: Skin and Soft Tissue Infection

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Supplement Table 4. Adjusted inpatient mortality. Adjusted for age, gender, race, initial MAP, FiO2, Initial serum lactate, and initial serum creatinine.

ALT denotes antimicrobial lead time, which is the time to initiate the clinicians’ antimicrobial order.

ALT

Sample Size (N)

Adjusted Mortality (95% CI) SD Prior to

arrival

70 (1.6%) 31.3% (21.1% ‒ 41.5%) 5.2%

0 - 1

hours 1835 (41.4%) 25.5% (23.6% ‒ 27.4%) 1.0%

1 - 2

hours 1038 (23.4%) 30.0% (27.3% ‒ 32.7%) 1.4%

2 - 3

hours 516 (11.7%) 26.8% (23.2% ‒ 30.4%) 1.8%

3 - 6 hours

540 (12.2%) 33.9% (30.1% ‒ 37.6%) 1.9%

6 -12

hours 238 (5.4%) 31.1% (25.5% ‒ 36.7%) 2.9%

> 12

hours 166 (3.8%) 37.3% (30.2% ‒ 44.3%) 3.6%

Missing 26 (0.6%) 99.8% (99.7% ‒ 100.0%) 0.1%

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Supplement Table 5-a. Multiple logistic regression of 28-day mortality, adjusting for the factors listed below.

Characteristic Odds Ratio

for Death Standard

Error Z Score P-Value (95% CI) ALT (Order-to-Administration Time; compared

to antimicrobials given within one hour)

Prior to arrival 1.37 0.38 1.14 0.26 (0.80 - 2.36)

1 - 2 hours 1.28 0.12 2.69 0.007 (1.07 - 1.54)

2 - 3 hours 1.07 0.13 0.60 0.55 (0.85 - 1.36)

3 - 6 hours 1.57 0.18 4.02 <0.001 (1.26 - 1.95)

6 -12 hours 1.36 0.22 1.91 0.06 (0.99 - 1.86)

> 12 hours 1.85 0.34 3.35 0.001 (1.29 - 2.65)

Missing -^C -^C -^C -^C

Door-to-Order Time (ED arrival to first antimicrobial order request; compared to recognition within one hour)

Prior to arrival 1.29 0.21 1.56 0.12 (0.94 - 1.77)

1 - 2 hours 1.19 0.13 1.53 0.13 (0.95 - 1.48)

2 - 3 hours 0.96 0.12 -0.31 0.76 (0.76 - 1.22)

3 - 6 hours 0.97 0.11 -0.27 0.79 (0.77 - 1.22)

6 -12 hours 1.29 0.18 1.78 0.08 (0.97 - 1.70)

> 12 hours 1.47 0.23 2.45 0.01 (1.08 - 2.00)

Age (compared to age < 20 years)

20 - 30 years 1.07 0.43 0.17 0.862 (0.49 - 2.33)

30 - 40 years 0.89 0.35 -0.29 0.773 (0.42 - 1.92)

40 - 50 years 1.39 0.52 0.87 0.384 (0.66 - 2.89)

50 - 65 years 2.14 0.78 2.08 0.037 (1.05 - 4.39)

65 - 75 years 2.53 0.94 2.51 0.012 (1.23 - 5.23)

75 - 85 years 2.88 1.09 2.79 0.005 (1.37 - 6.04)

> 85 years 1.86 0.72 1.61 0.108 (0.87 - 3.97)

Male gender (compared to female) 0.79 0.06 -3.21 0.001 (0.69 - 0.91)

Race (compared to white)

Black 1.08 0.08 1.01 0.313 (0.93 - 1.25)

Asian 1.25 0.56 0.50 0.619 (0.52 - 3.01)

Other 1.01 0.21 0.04 0.972 (0.67 - 1.53)

Initial MAP (compared to MAP >65)

60 - 65 1.44 0.18 2.85 0.004 (1.12 - 1.84)

50 - 60 1.59 0.21 3.52 0.000 (1.23 - 2.05)

< 50 1.37 0.12 3.52 <0.001 (1.15 - 1.64)

Missing 1.23 0.15 1.63 0.103 (0.96 - 1.57)

FiO2 Requirement (compared to 21% room air)

21 - 40% 0.40 0.13 -2.91 0.004 (0.22 - 0.74)

40 - 60% 0.84 0.21 -0.72 0.472 (0.52 - 1.36)

60 - 80% 1.11 0.28 0.41 0.681 (0.68 - 1.82)

80 - 100% 1.37 0.32 1.34 0.179 (0.87 - 2.18)

Missing 0.47 0.10 -3.43 0.001 (0.30 - 0.72)

Initial Serum Lactate (compared to <2 mmol/L)

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2 - 4 mmol/L 1.34 0.15 2.60 0.009 (1.07 - 1.67)

> 4 mmol/L 1.85 0.26 4.32 0.000 (1.40 - 2.44)

Not Obtained 1.18 0.10 1.93 0.054 (1.00 - 1.40)

Initial Serum Creatinine (compared to <1.2 mg/dL)

1.2 - 2 mg/dL 1.33 0.14 2.71 0.007 (1.08 - 1.63)

2 - 3.5 mg/dL 1.89 0.23 5.34 <0.001 (1.50 - 2.39)

3.5 - 5 mg/dL 2.16 0.35 4.81 <0.001 (1.58 - 2.96)

> 5 mg/dL 1.73 0.24 3.89 <0.001 (1.31 - 2.27)

Missing 1.24 0.12 2.17 0.030 (1.02 - 1.51)

First Three Doses of Antimicrobials Received (Compared to Both Gram-Negative and Gram- Positive Coverage).

Limited Spectrum Coverage 0.90 0.10 -0.92 0.356 (0.72 - 1.13)

Gram-Positive Coverage Only 1.08 0.11 0.76 0.447 (0.88 - 1.32)

Gram-Negative Coverage Only 1.11 0.10 1.15 0.252 (0.93 - 1.33)

Abbreviations: ALT: antimicrobial lead time; DTOT: Door-To-Order-Time; ED: Emergency Department; FiO2: Fraction of the Inspired Oxygen; ICU: Intensive Care Unit; MAP: Mean Arterial Pressure; qSOFA: quick Sequential Organ Failure Assessment.

a : Adjusted for all the characteristics mentioned in the table. This in based on 4,429 consecutive patients who were admitted to the Emergency Department (ED) with the diagnosis of sepsis, present on admission. The Table below illustrates the adjusted odds ratios (OR) for each of the variables, in comparison with their reference within each group. The constant of the multiple logistic regression model was 0.16. Hosmer-Lemeshow goodness-of-fit P=0.21 and the AUC 0.7.

b : 28-Day Mortality

c : Sample too small to be calculated.

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Supplement Table 5-b. Multiple logistic regressiona of 28-day mortality.

This in based on 4,429 consecutive patients who were admitted to the Emergency Department (ED) with the diagnosis of sepsis, present on admission.

Characteristic Odds Ratio for

Death^b

Standar d Error

Z Score

P-Value ALT (Order-to-Administration Time; compared

to antimicrobials given within one hour)

Prior to arrival 1.71 (1.12 - 2.60) 0.37 2.49 0.013

1 - 2 hours 1.51

(0.95 - 2.40) 0.36 1.75 0.08

2 - 3 hours 1.98

(1.26 - 3.11) 0.46 2.96 0.003

3 - 6 hours 1.42

(0.81 - 2.51) 0.41 1.22 0.221

6 -12 hours 2.62

(1.41 - 4.86)

0.83 3.06 0.002

> 12 hours 1.71

(1.12 - 2.60) 0.37 2.49 0.013

Time interval between triage to antimicrobial administration (TPAA), each additional hour of delay

1.00

(1.00 - 1.00) 0.00 -0.61 0.54

Statistical Interactions of ALT-DTOT

Compared to Reference Category [ALT < 1hr] x [DTOT < 1hr]

[ALT < 1 hr] X [DTOT > 1hr] 1.34

(0.90 - 2.01) 0.28 1.43 0.152

[ALT >1 hr] X [DTOT < 1 hr] 0.77

(0.56 - 1.04) 0.12 -1.70 0.089

[ALT > 1hr] X [DTOT > 1hr] 1.00 (0.00 - 0.00)

(omitted) 0.00 <0.001 qSOFA, each additional Point 1.84 (1.60 - 2.12) 0.13 8.51 <0.001 Elixhauser comorbidity Index, each additional

point 1.24

(1.16 - 1.32) 0.04 6.75 <0.001

Age, each additional year 1.01

(1.01 - 1.02) 0.00 4.41 <0.001

Male gender (compared to female) 0.99

(0.81 - 1.21) 0.10 -0.09 0.932

Black 0.99

(0.81 - 1.21) 0.10 -0.09 0.927

Asian 0.80

(0.22 - 2.97)

0.54 -0.33 0.739

Other 1.80

(1.07 - 3.04) 0.48 2.20 0.028

60 - 65 1.33

(0.95 - 1.86) 0.23 1.67 0.094

50 - 60 1.29 0.22 1.52 0.127

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(0.93 - 1.80)

< 50 1.32

(1.04 - 1.68)

0.16 2.29 0.022

Missing 1.19

(0.75 - 1.89) 0.28 0.72 0.469

FiO2 Requirement (compared to 21% room air)

21 - 40% 0.83

(0.29 - 2.40) 0.45 -0.34 0.736

40 - 60% 2.03

(0.86 - 4.77) 0.89 1.62 0.105

60 - 80% 2.83

(1.20 - 6.71)

1.25 2.37 0.018

80 - 100% 3.72

(1.61 - 8.59) 1.59 3.08 0.002

Missing 1.25

(0.55 - 2.84) 0.52 0.53 0.598

Initial Serum Lactate (compared to <2 mmol/L)

2 - 4 mmol/L 1.89

(1.42 - 2.52)

0.28 4.35 <0.001

> 4 mmol/L 3.11

(2.24 - 4.32) 0.52 6.75 <0.001

Not Obtained 1.53

(1.19 - 1.96) 0.19 3.35 0.001

1.2 - 2 mg/dL 1.38

(1.03 - 1.85)

0.21 2.16 0.031

2 - 3.5 mg/dL 2.13

(1.55 - 2.91) 0.34 4.71 <0.001

3.5 - 5 mg/dL 1.76

(1.16 - 2.68) 0.38 2.64 0.008

> 5 mg/dL 1.24

(0.82 - 1.87) 0.26 1.03 0.304

Missing 1.22

(0.91 - 1.62)

0.18 1.35 0.178

Limited Spectrum Coverage 0.95

(0.68 - 1.32) 0.16 -0.31 0.76

Gram-Positive Coverage Only 1.06

(0.80 - 1.40)

0.15 0.41 0.685

Gram-Negative Coverage Only 1.23

(0.96 - 1.57) 0.15 1.64 0.101

Abbreviations: ALT: antimicrobial lead time; DTOT: Door-To-Order-Time; ED: Emergency Department; FiO2: Fraction of the Inspired Oxygen; ICU: Intensive Care Unit; MAP: Mean Arterial Pressure; qSOFA: quick Sequential Organ Failure Assessment.

a : Adjusted for all the characteristics mentioned in the table. The Table below illustrates the adjusted odds ratios (OR) of death for each of the variables, in comparison with their reference within each group. The constant OR of the multiple logistic regression model was 0.002. Hosmer-Lemeshow goodness-of-fit P=0.97 and the AUC 0.82.

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Supplement Table 5-c. Multiple logistic regression

^a

of 28-day mortality, adjusting for the factors listed below. This in based on 4,429 consecutive patients who were admitted to the Emergency Department (ED) with the diagnosis of sepsis, present on admission.

Death^b

Standard Error

Z Score P-Value ALT (Order-to-Administration Time;

compared to antimicrobials given within one hour)

Prior to arrival 1.54

(0.76 - 3.09) 0.55 1.21 0.228

1 - 2 hours 1.33

(1.04 - 1.70)

0.17 2.28 0.023

2 - 3 hours 1.14

(0.83 - 1.56) 0.18 0.82 0.415

3 - 6 hours 1.46

(1.08 - 1.96) 0.22 2.50 0.012

6 -12 hours 1.00

(0.65 - 1.56) 0.23 0.02 0.988

> 12 hours 1.69

(1.04 - 2.75)

0.42 2.13 0.033

Prior to arrival 1.08

(0.68 - 1.70) 0.25 0.33 0.745

1 - 2 hours 1.30

(0.97 - 1.75)

0.20 1.77 0.076

2 - 3 hours 1.19

(0.86 - 1.63) 0.19 1.04 0.297

3 - 6 hours 1.25

(0.92 - 1.70) 0.20 1.43 0.154

6 -12 hours 1.77

(1.22 - 2.59) 0.34 2.98 0.003

> 12 hours 1.44

(0.94 - 2.19)

0.31 1.68 0.093

Missing 0.00 0.00 -0.02 0.984

qSOFA, each additional Point 1.86

(1.62 - 2.13) 0.13 8.92 <0.001

Elixhauser comorbidity Index, each additional point

1.23 (1.16 - 1.31)

0.04 6.82 <0.001

(1.01 - 1.02) 0.00 4.92 <0.001

(0.80 - 1.17) 0.09 -0.32 0.752

Black 0.95

(0.78 - 1.16) 0.10 -0.49 0.625

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Asian 0.74 (0.20 - 2.73)

0.49 -0.46 0.648

Other 1.59

(0.95 - 2.64) 0.41 1.77 0.076

60 - 65 1.43

(1.04 - 1.97) 0.23 2.20 0.027

50 - 60 1.35

(0.99 - 1.85) 0.22 1.87 0.061

< 50 1.36

(1.08 - 1.71)

0.16 2.61 0.009

Missing 1.21

(0.78 - 1.88) 0.27 0.85 0.396

FiO2 Requirement (compared to 21% room air)

21 - 40% 0.66

(0.25 - 1.69) 0.32 -0.87 0.383

40 - 60% 1.66

(0.79 - 3.47)

0.63 1.34 0.181

60 - 80% 2.30

(1.09 - 4.87) 0.88 2.19 0.029

80 - 100% 3.25

(1.58 - 6.68) 1.19 3.21 0.001

Missing 1.02

(0.51 - 2.07) 0.37 0.07 0.946

Initial Serum Lactate (compared to <2 mmol/L)

2 - 4 mmol/L 1.89

(1.42 - 2.50) 0.27 4.43 <0.001

> 4 mmol/L 3.11

(2.26 - 4.28) 0.51 6.95 <0.001

Not Obtained 1.58

(1.25 - 2.01) 0.19 3.76 <0.001

1.2 - 2 mg/dL 1.42

(1.07 - 1.87) 0.20 2.44 0.015

2 - 3.5 mg/dL 2.08

(1.54 - 2.81) 0.32 4.76 <0.001

3.5 - 5 mg/dL 2.00

(1.33 - 2.99) 0.41 3.35 0.001

> 5 mg/dL 1.26

(0.85 - 1.86)

0.25 1.14 0.252

Missing 1.26

(0.95 - 1.66) 0.18 1.62 0.106

First Three Doses of Antimicrobials Received (Compared to Both Gram- Negative and Gram-Positive Coverage).

Limited Spectrum Coverage 0.97 (0.70 - 1.33)

0.16 -0.22 0.827

Broad Gram-Positive Coverage Only 1.04

(0.79 - 1.36) 0.14 0.27 0.79

Broad Gram-Negative Coverage Only 1.27 0.15 1.94 0.052

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Abbreviations: ALT: antimicrobial lead time; DTOT: Door-To-Order-Time; ED: Emergency Department; FiO2: Fraction of the Inspired Oxygen; ICU: Intensive Care Unit; MAP: Mean Arterial Pressure; qSOFA: quick Sequential Organ Failure Assessment. The Table below illustrates the adjusted odds ratios (OR) for each of the variables, in comparison with their reference within each group. The constant OR of the multiple logistic regression model was 0.002. Hosmer-Lemeshow goodness-of-fit P=0.97 and the AUC 0.82. In this version of the analysis, the patient age is adjusted as a continuous variable.

a : Adjusted for all the characteristics mentioned in the table.

(18)

Supplement Table 5-d. Multiple logistic regressiona of 28-day mortality, adjusting for the factors listed below.

Death^b Standard

Error Z

Score P-Value ALT (Order-to-Administration Time;

compared to antimicrobials given within one hour)

Prior to arrival 1.5 (0.7 - 3.1) 0.55 1.16 0.25

1 - 2 hours 1.3 (1.0 - 1.7) 0.16 2.07 0.04

2 - 3 hours 1.1 (0.8 - 1.6) 0.18 0.81 0.42

3 - 6 hours 1.4 (1.1 - 1.9) 0.22 2.34 0.02

6 -12 hours 1.0 (0.6 - 1.5) 0.22 -0.05 0.96

> 12 hours 1.6 (1.0 - 2.6) 0.40 1.93 0.05

Missing 4353460.0 (0.0

- ^c)

2010000000 0.03 0.97 Door-to-Order Time (ED arrival to first

antimicrobial order request; compared to recognition within one hour)

Prior to arrival 1.1 (0.7 - 1.7) 0.25 0.25 0.80

1 - 2 hours 1.3 (1.0 - 1.7) 0.19 1.63 0.10

2 - 3 hours 1.2 (0.8 - 1.6) 0.19 0.97 0.33

3 - 6 hours 1.3 (0.9 - 1.7) 0.20 1.50 0.13

6 -12 hours 1.8 (1.2 - 2.6) 0.34 2.93 0.00

> 12 hours 1.4 (0.9 - 2.2) 0.31 1.67 0.10

Missing 0.0 (0.0 - .^c) 0.00 -0.03 0.98

qSOFA, each additional Point 1.8 (1.6 - 2.1) 0.13 8.47 <0.001 Elixhauser comorbidity Index, each

additional point 1.2 (1.2 - 1.3) 0.04 6.58 <0.001

Age, each additional year 1.0 (1.0 - 1.0) 0.00 4.97 <0.001 Male gender (compared to female) 0.9 (0.8 - 1.1) 0.09 -0.65 0.52 Race (compared to white)

Black 1.0 (0.8 - 1.2) 0.10 -0.32 0.75

Asian 0.7 (0.2 - 2.7) 0.49 -0.49 0.63

Other 1.6 (0.9 - 2.7) 0.42 1.73 0.08

60 - 65 1.4 (1.0 - 1.9) 0.23 2.06 0.04

50 - 60 1.3 (0.9 - 1.8) 0.21 1.61 0.11

< 50 1.3 (1.0 - 1.6) 0.15 2.16 0.03

Missing 1.2 (0.8 - 1.9) 0.28 0.92 0.36

21 - 40% 0.6 (0.2 - 1.7) 0.31 -0.93 0.35

40 - 60% 1.5 (0.7 - 3.2) 0.58 1.09 0.28

60 - 80% 2.1 (1.0 - 4.5) 0.82 1.94 0.05

80 - 100% 3.0 (1.4 - 6.2) 1.11 2.91 0.00

(19)

Initial Serum Lactate (compared to <2 mmol/L)

2 - 4 mmol/L 1.9 (1.4 - 2.5) 0.27 4.29 <0.001

> 4 mmol/L 3.2 (2.3 - 4.4) 0.53 7.03 <0.001

Not Obtained 1.6 (1.3 - 2.0) 0.20 3.84 <0.001

1.2 - 2 mg/dL 1.5 (1.1 - 2.0) 0.22 2.81 0.01

2 - 3.5 mg/dL 2.2 (1.6 - 3.0) 0.34 5.00 <0.001

3.5 - 5 mg/dL 2.1 (1.4 - 3.2) 0.45 3.60 <0.001

> 5 mg/dL 1.4 (0.9 - 2.1) 0.29 1.66 0.10

Missing 1.3 (1.0 - 1.7) 0.18 1.76 0.08

First Three Doses of Antimicrobials Received (Compared to Both Gram- Negative and Gram-Positive Coverage)

Limited Spectrum Coverage 1.0 (0.7 - 1.3) 0.16 -0.27 0.78

Broad Gram-Positive Coverage Only 1.0 (0.8 - 1.3) 0.14 0.10 0.92 Broad Gram-Negative Coverage Only 1.2 (1.0 - 1.6) 0.15 1.68 0.09 Sepsis Source (compared to cardiac i.e.

endocarditis, pericarditis)

CNS 0.9 (0.2 - 3.2) 0.57 -0.24 0.81

Device Related 0.3 (0.1 - 1.0) 0.19 -1.92 0.06

Intraabdominal 1.3 (0.5 - 2.9) 0.54 0.55 0.58

Gynecological 1.0 (0.0 - 0.0) <0.001

Bacteremia 0.8 (0.3 - 1.7) 0.30 -0.71 0.48

HIV-Related 0.9 (0.3 - 2.3) 0.43 -0.32 0.75

Joint 1.0 (0.0 - 0.0)

Lungs 0.9 (0.4 - 2.1) 0.38 -0.16 0.88

SSTI 0.6 (0.3 - 1.6) 0.30 -0.95 0.34

Urinary, or Kidney 0.4 (0.2 - 0.9) 0.16 -2.32 0.02

Unclear 0.1 (0.0 - 0.8) 0.10 -2.11 0.04

Abbreviations: ALT: antimicrobial lead time; DTOT: Door-To-Order-Time; ED: Emergency Department; FiO2: Fraction of the Inspired Oxygen; ICU: Intensive Care Unit; MAP: Mean Arterial Pressure; qSOFA: quick Sequential Organ Failure Assessment; ; SSTI: Skin and Soft Tissue Infection

a : Adjusted for all the characteristics mentioned in the table. This in based on 4,429 consecutive patients who were admitted to the Emergency Department (ED) with the diagnosis of sepsis, present on admission. The Table below illustrates the adjusted odds ratios (OR) for each of the variables, in comparison with their reference within each group. This analysis accounts for sepsis source in addition to the breadth of antimicrobial coverage. The constant OR of the multiple logistic regression model was 0.003. Hosmer-Lemeshow goodness-of-fit P=0.99 and the AUC 0.83. In this version of the analysis, the patient age is adjusted as a continuous variable.

(20)

Supplement Table 6. Analysis of ALT, in hours by the first antibiotic administered

Antimicrobial Name N Mean Median 25th IQR 75th IQR

daptomycin 36 4.33 1.93 0.69 3.08

acyclovir 79 7.00 4.44 2.91 10.85

amoxicillin-

clavulanate 6 6.85 3.44 0.95 13.47

ampicillin 18 0.71 1.31 0.66 3.39

azithromycin 31 6.43 2.18 1.06 9.43

aztreonam 4 2.21 1.71 1.18 3.24

cefazolin 49 10.68 2.22 0.51 9.76

cefoxitin 18 1.52 1.06 0.51 2.44

ceftriaxone 532 1.75 0.73 0.36 1.49

cefepime 182 1.93 1.00 0.51 2.33

cefotaxime 5 1.02 0.87 0.69 1.13

ceftaroline 4 1.85 1.60 1.13 2.57

ciprofloxacin 63 3.79 1.89 0.76 5.61

clindamycin 34 1.55 0.80 0.33 1.57

doxycycline 16 3.01 0.91 0.33 3.71

fluconazole 43 9.24 5.39 1.53 13.98

gentamicin 15 1.89 1.46 0.87 2.29

levofloxacin 431 2.07 0.80 0.40 1.93

linezolid 14 6.74 1.35 0.69 9.87

meropenem 265 2.94 1.38 0.76 2.66

metronidazole 43 5.41 2.26 1.38 5.68

micafungin 13 5.30 2.69 0.98 11.00

nafcillin 10 4.06 3.70 1.42 4.70

(21)

oseltamivir 12 2.12 1.26 0.53 2.29

piperacillin-ta 1020 1.79 0.95 0.40 2.29

rifampin 5 18.26 4.95 1.57 17.40

trimethoprim/

sulfamethoxazole 20 9.24 4.02 1.71 9.25

tobramycin 4 2.69 2.79 0.60 4.77

vancomycin 1425 2.57 1.49 0.76 2.69

voriconazole 6 6.61 5.92 2.84 8.96

(22)

Supplement Table 7. Adjusted 28-Mortality and relationship with ICU status after Admission

ED  Ward ED  ICU ED Ward  ICU

Characteristic Odds Ratio

of Death^b P-Value Odds Ratio

of Death^b P-Value ALT

(Order-to-Administration Time; compared to antimicrobials given within one hour from order)

Prior to arrival -^C -^C -^C -^C -^C -^C

1 - 2 hours 2.06

(0.99 - 4.31) 0.054 1.67

(0.90 - 3.09) 0.106 1.39

(0.37 - 5.28) 0.627

2 - 3 hours 1.78

(0.79 - 4.00)

0.163 1.35

(0.69 - 2.65)

0.385 1.53

(0.36 - 6.57)

0.568

3 - 6 hours 1.86

(0.83 - 4.15) 0.129 1.85

(0.92 - 3.71) 0.082 3.39 (0.83 - 13.91)

0.09

6 -12 hours 3.13

(1.30 - 7.53) 0.011 0.60

(0.21 - 1.77) 0.357 0.96

(0.19 - 4.87) 0.957

> 12 hours 2.89

(1.06 - 7.88)

0.038 1.90

(0.49 - 7.32)

0.352 4.26

(0.77 - 23.7)

0.097

Missing -^C -^C -^C -^C -^C -^C

Time interval between triage to antimicrobial administration (TPAA), each additional hour of delay

1.00

(0.99 - 1.01) 0.711 0.99

(0.96 - 1.02) 0.485 1.00

(0.99 - 1.01) 0.949

Statistical Interactions of ALT-DTOT

Compared to Reference Category [ALT < 1hr] x [DTOT < 1hr]

[ALT < 1 hr] X [DTOT > 1hr] 1.27 (0.62 - 2.61)

0.522 1.52

(0.86 - 2.69)

0.15 1.40

(0.38 - 5.20)

0.618 [ALT >1 hr] X [DTOT < 1 hr] 0.60

(0.35 - 1.02) 0.06 0.84

(0.52 - 1.35) 0.463 1.42

(0.60 - 3.35) 0.425 [ALT > 1hr] X [DTOR > 1hr] 1.00 (-^C) -^C 1.00 (-^C) -^C

(23)

(1.64 - 2.53) (1.14 - 1.98) (0.90 - 1.84)

Elixhauser comorbidity Index, each additional

point 1.41

(1.27 - 1.55) <0.001 1.06

(0.95 - 1.17) 0.304 1.13

(0.96 - 1.32) 0.157

(1.01 - 1.03)

<0.001 1.02 (1.01 - 1.03)

<0.001 1.02 (1.00 - 1.04)

0.043

(0.64 - 1.23)

0.475 1.09

(0.79 - 1.49)

0.598 0.90

(0.54 - 1.50)

0.675 Race (compared to white)

Black 0.96

(0.69 - 1.33) 0.787 0.89

(0.64 - 1.23) 0.49 1.15

(0.66 - 2.00) 0.622

Asian 0.57

(0.06 - 5.13) 0.618 9.59

(0.48 - 191.7) 0.139 1.00

(-^C) <0.001

Other 1.23

(0.49 - 3.08) 0.659 1.40

(0.56 - 3.54) 0.472 7.72

(2.50 - 23.8) <0.001 Initial MAP (compared to MAP >65)

60 - 65 1.76

(1.02 - 3.02)

0.04 1.03

(0.62 - 1.70)

0.913 0.88

(0.33 - 2.33)

0.799

50 - 60 0.90

(0.48 - 1.68) 0.735 1.29

(0.79 - 2.12) 0.314 1.30 (0.57 -

2.95)

0.538

< 50 1.35

(0.91 - 1.99) 0.135 1.12

(0.77 - 1.63) 0.555 1.79

(0.95 - 3.40) 0.074

Missing 1.23

(0.67 - 2.26)

0.51 1.41

(0.05 - 40.12)

0.841 3.20

(1.13 - 9.04)

0.028 FiO2 Requirement (compared to 21% room air)

21 - 40% 2.13

(0.23 - 19.64) 0.504 1.35

(0.26 - 7.03) 0.722 0.15

(0.02 - 0.94) 0.043

40 - 60% 2.44

(0.30 - 19.81) 0.403 4.09

(1.14 - 14.68) 0.031 0.41

(0.06 - 2.63) 0.348

60 - 80% 4.25

(0.52 - 34.57) 0.176 4.46

(1.23 - 16.18) 0.023 0.65

(0.12 - 3.55) 0.617

80 - 100% 4.97

(0.62 - 40.11)

0.132 6.18

(1.76 - 21.68)

0.004 0.26

(0.05 - 1.30)

0.101

Missing 2.01

(0.27 - 15.28) 0.498 1.95

(0.55 - 6.90) 0.3 0.15

(0.02 - 0.94) 0.043 Initial Serum Lactate (compared to <2 mmol/L)

2 - 4 mmol/L 1.23

(0.76 - 2.00) 0.401 2.00

(1.29 - 3.11) 0.002 4.67

(2.21 - 9.87) <0.001

> 4 mmol/L 3.11

(1.73 - 5.57) <0.001 3.26

(2.06 - 5.16) <0.001 5.18

(1.79 - 15) 0.002

(24)

Not Obtained 0.93

(0.62 - 1.38) 0.714 2.62

(1.75 - 3.92) <0.001 3.23

(1.66 - 6.30) 0.001 Initial Serum Creatinine (compared to <1.2

mg/dL)

1.2 - 2 mg/dL 1.55

(0.99 - 2.42) 0.058 1.33

(0.82 - 2.16) 0.254 0.69

(0.31 - 1.54) 0.37

2 - 3.5 mg/dL 1.86

(1.10 - 3.13) 0.02 2.28

(1.41 - 3.72) 0.001 1.42 (0.6 -

3.44) 0.438

3.5 - 5 mg/dL 0.46

(0.15 - 1.43) 0.178 1.98

(1.08 - 3.63) 0.028 2.97

(1.14 - 7.74) 0.026

> 5 mg/dL 0.88

(0.40 - 1.91)

0.742 1.26

(0.68 - 2.34)

0.466 1.46

(0.55 - 3.92)

0.449

Missing 1.18

(0.76 - 1.83) 0.472 1.26

(0.78 - 2.03) 0.342 0.93

(0.45 - 1.9) 0.842 First Three Doses of Antimicrobials Received

(Compared to Both Gram-Negative and Gram- Positive Coverage).

Limited Spectrum Coverage 1.01

(0.61 - 1.67)

0.966 1.04

(0.55 - 1.94)

0.907 0.93

(0.40 - 2.15)

0.87

Gram-Positive Coverage Only 0.91

(0.56 - 1.49) 0.712 1.16

(0.75 - 1.79) 0.496 0.97

(0.46 - 2.02) 0.925

Gram-Negative Coverage Only 1.35

(0.89 - 2.03) 0.157 1.30

(0.90 - 1.90) 0.164 0.81

(0.42 - 1.59) 0.546

Abbreviations: ALT: antimicrobial lead time; DTOT: Door-To-Order-Time; ED: Emergency Department; FiO2: Fraction of the Inspired Oxygen; ICU: Intensive Care Unit; MAP: Mean Arterial Pressure; qSOFA: quick Sequential Organ Failure Assessment Score; TPAA: Time interval between triage to antimicrobial administration.

(25)

Supplement Table 8. Inpatient Mortality. Sensitivity analysis examining the adjusted mortality, and actual observations in parentheses, among patients with differential ALT and time to the first sepsis recognition and intention- to-treat, as measured by the first antibiotic electronic order placement by the clinician, DTOT (Door-to-Order Time).

Adjusted Mortality

Door-to-Order Time (DTOT) in Hours Order-to-

Administratio n Time (ALT)

in Hours

Prior 0-1 1-2 2-3 3-6 6-12 >12 Missin

g Prior 34.6%

(1) 29.7%

(8) 33.0%

(21) 29.0%

(6) 29.1%

(8) 34.6%

(10) 37.3%

(16) -

(-^C) 0 - 1 28.5%

(124)

24.1%

(314)

27.1%

(400)

23.5%

(350)

23.6%

(402)

28.5%

(148)

31.0%

(97)

- (-^C) 1 - 2 33.2%

(70) 28.4%

(227) 31.7%

(207) 27.8%

(188) 27.9%

(202) 33.3%

(78) 35.9%

(66) -

(-^C) 2 - 3 29.8%

(33) 25.3%

(105) 28.3%

(105) 24.7%

(84) 24.8%

(109) 29.9%

(44) 32.4%

(36) -

(-^C) 3 - 6 37.3%

(20) 32.2%

(104) 35.7%

(101) 31.5%

(80) 31.6%

(120) 37.4%

(67) 40.2%

(48) -

(-^C) 6 -12 34.4%

(13)

29.5%

(49)

32.8%

(47)

28.8%

(34)

28.9%

(56)

34.4%

(24)

37.1%

(15)

- (-^C)

> 12 40.9%

(20) 35.6%

(31) 39.2%

(29) 34.8%

(25) 34.9%

(24) 40.9%

(25) 43.8%

(12) Missing 100.0%

(2) 100.0%

(1) 100.0%

(2) 100.0%

(1) 100.0%

(1) -^C 61.6%

(18)

Abbreviations: ALT: antimicrobial lead time; DTOT: Door-To-Order-Time.

b : Inpatient Mortality

(26)

Supplement Table 9. Missing Data Sensitivity Analysis. Multiple Logistic Regression a Examining the 28-Day Mortality Odds Ratio, only in the Subgroup of Patient’s who did not have a lactate measured (missing lactate).

Characteristic Among Patients with Missing Lactate

Odds Ratio 95% CI^b

Stand.

Error

Z Score P-Value (95% CI) ALT (Order-to-Administration Time;

compared to antimicrobials given within one hour)

Prior to arrival 0.55 (3.11 - 0.00) 1.34 0.18 0.81

1 - 2 hours 1.36 (1.07 - 1.73) 0.17 2.53 0.011

2 - 3 hours 1.20 (0.88 - 1.62) 0.19 1.15 0.251

3 - 6 hours 1.43 (1.07 - 1.91) 0.21 2.42 0.016

6 -12 hours 1.10 (0.71 - 1.69) 0.24 0.43 0.667

> 12 hours 1.78 (1.10 - 2.87) 0.43 2.35 0.019

Prior to arrival 1.06 (0.67 - 1.66) 0.24 0.25 0.804

1 - 2 hours 1.35 (1.01 - 1.80) 0.20 2.03 0.042

2 - 3 hours 1.19 (0.87 - 1.63) 0.19 1.09 0.276

3 - 6 hours 1.33 (0.98 - 1.79) 0.20 1.84 0.065

6 -12 hours 1.83 (1.26 - 2.65) 0.35 3.19 0.001

> 12 hours 1.59 (1.05 - 2.40) 0.33 2.21 0.027

Age, y (each additional year) 1.02 (1.01 - 1.02) 0.00 5.77 <0.001 Male gender (compared to female) 0.92 (0.76 - 1.11) 0.09 -0.87 0.385 Race (compared to white)

Black 0.98 (0.81 - 1.19) 0.10 -0.18 0.858

Asian 0.61 (0.17 - 2.25) 0.41 -0.74 0.459

Other 1.39 (0.84 - 2.30) 0.36 1.29 0.198

60 - 65 1.34 (0.98 - 1.83) 0.21 1.82 0.069

50 - 60 1.42 (1.04 - 1.94) 0.22 2.22 0.026

< 50 1.19 (0.77 - 1.85) 0.27 0.78 0.434

Missing 1.34 (0.98 - 1.83) 0.21 1.82 0.069

21 - 40% 0.81 (0.32 - 2.05) 0.38 -0.45 0.654

40 - 60% 2.03 (0.98 - 4.20) 0.75 1.90 0.058

60 - 80% 2.82 (1.35 - 5.90) 1.06 2.76 0.006

80 - 100% 4.18 (2.05 - 8.50) 1.51 3.95 <0.001

(27)

1 2.17 (1.32 - 3.57) 0.55 3.06 0.002

2 4.17 (2.56 - 6.80) 1.04 5.73 <0.001

3 7.58 (4.55 - 12.63) 1.97 7.77 <0.001

1.2 - 2 mg/dL 1.75 (1.34 - 2.30) 0.24 4.06 <0.001

2 - 3.5 mg/dL 2.65 (1.98 - 3.54) 0.39 6.56 <0.001

3.5 - 5 mg/dL 2.62 (1.78 - 3.86) 0.52 4.86 <0.001

> 5 mg/dL 1.53 (1.04 - 2.23) 0.30 2.18 0.029

Missing 1.45 (1.11 - 1.90) 0.20 2.69 0.007

Gram-Negative Coverage Only 0.88 (0.72 - 1.08) 0.09 -1.25 0.21

Gram-Positive Coverage Only 1.09 (0.90 - 1.31) 0.11 0.84 0.399

Abbreviations: ALT: antimicrobial lead time; DTOT: Door-To-Order-Time; ED: Emergency Department; FiO2: Fraction of the Inspired Oxygen; ICU: Intensive Care Unit; MAP: Mean Arterial Pressure; qSOFA: quick Sequential Organ Failure Assessment Score; TPAA:

Time interval between triage to antimicrobial administration.

(28)

Supplement Figure 1. Percentage Distribution of the antimicrobial Door-To-

Order-Time (DTOT), expressed in hours.

(29)

Supplement Figure 2. Percentage Distribution of the antimicrobial Time

from Triage-To-Antimicrobial Administration (TPAA), expressed in hours.

(30)

Supplement Figure 3. Post-estimation model predicted hospital mortality

(31)

Supplement Figure 4. Robust locally weighted regression and smoothing scatterplot of ALT vs. DTOT, along with findings of a simple linear

regression fit.

(32)