Introduction
Materials and methods
Study setting
Study population
Sampling and sample analysis
Data collection and definitions
Defining target intervals and categorization of antibiotic concentration results
Data analysis
Regression modeling
Ethical considerations
Results
Descriptive data
Variable | Full cohort 102 patients | Cefotaxime 72 patients | Meropenem 12 patients | Piperacillin 18 patients | Significant difference between any of the three groups |
---|---|---|---|---|---|
Gender % women (n) | 39.2% (40) | 44.4% (32) | 41.7% (5) | 16.7% (3) | p = 0.10 |
Age median (IQR) | 80 (74–86) | 82.5 (75–87.5) | 75 (72.5–80) | 80 (74–84) | p = 0.09 |
eGFR median (IQR) [MV] | 50 (36–71) [3] | 49.5 (37.3–68.8) [2] | 60.5 (34.9–86.3) [0] | 47 (31–71) [1] | p = 0.57 |
BMI median (IQR) [MV] | 23.9 (21.5–27.3) [15] | 23.5 (21.4–27.4) [13] | 22.9 (20.9–27.3) [1] | 24.5 (21.5–27.3) [1] | p = 0.98 |
Charlson/Deyo score Median (IQR) | 3 (1–4) | 3 (1–4) | 3 (0.8–4) | 3 (1.3–6) | p = 0.53 |
Each part of Charlson/Deyo comorbidity index % (n) | |||||
Myocardial infarction | 19.6% (20) | 16.7% (12) | 16.7% (2) | 33.3% (6) | p = 0.27 |
Congestive heart failure | 22.5% (23) | 23.6% (17) | 33.3% (4) | 11.1% (2) | p = 0.33 |
Peripheral vascular disease | 12.7% (13) | 12.5% (9) | 0 | 22.2% (4) | p = 0.20 |
Cerebrovascular disease | 19.6% (20) | 18.1% (13) | 33.3% (4) | 16.7% (3) | p = 0.44 |
Dementia | 2% (2) | 1.4% (1) | 0 | 5.6% (1) | p = 0.46 |
Chronic lung disease | 28.4% (29) | 31.9% (23) | 25% (3) | 16.7% (3) | p = 0.42 |
Rheumatologic disease | 19.6% (20) | 20.8% (15) | 16.7% (2) | 16.7% (3) | p = 0.89 |
Peptic ulcer disease | 2% (2) | 1.4% (1) | 0 | 5.6% (1) | p = 0.46 |
Mild liver disease | 2% (2) | 1.4% (1) | 0 | 5.6% (1) | p = 0.46 |
Diabetes without organ damage | 20.6% (21) | 20.8% (15) | 25% (3) | 16.7% (3) | p = 0.85 |
Diabetes with organ damage | 5.9%(6) | 4.2% (3) | 0 | 16.7% (3) | p = 0.09 |
Hemiplegia/paraplegia | 5% (5) | 5.6% (4) | 0 | 5.6% (1) | p = 0.70 |
Moderate or severe kidney disease | 12.7% (13) | 13.9% (10) | 25% (3) | 0 | p = 0.35 |
Tumor within the past 5 years | 30.4% (31) | 26.4% (19) | 58.3% (7) | 27.8% (5) | p = 0.39 |
Moderate/severe liver disease | 1% (1) | 0 | 0 | 5.6% (1) | p = 0.10 |
AIDS | 0 | 0 | 0 | 0 |
–
|
Malignant tumor with metastasis | 5.9% (6) | 4.2% (3) | 8.3% (1) | 11.1% (2) | p = 0.50 |
Trough antibiotic concentrations
Variable | Full cohort 102 patients | Cefotaxime 72 patient | Meropenem 12 patients | Piperacillin 18 patients | Significant difference between any of the three groups |
---|---|---|---|---|---|
Antibiotic concentration (mg/L) Mean (range) and median (IQR) [MV] 1. Concentration measurement 1 2. Concentration measurement 2 | – | 1. 6.1 (0–44) and 3.6 (1.3–7.9) [0] | 1. 3.1 (0.53–11) and 1.95 (1–3.6) [0] | 1. 34.5 (5.7–131) and 16.5 (9.9–43.8) [0] | – |
2. 7.0 (0–43) and 3.7 (2–11) [10] | 2. 3.8 (0–10) and 2.8 (1–6.3) [0] | 2. 25.8 (1.2–94) and 19 (11–36.5) [3] | |||
Proportion of patients not receiving recommended dose % (n) | 19.6% (20) | 23.6% (17) | 16.7% (2) | 5.6% (1) | p = 0.22 |
Proportion of patients with two trough values % (n) | 86.3% (88) | 84.7% (61) | 100% (12) | 83.3% (15) | – |
Proportion of patients with all concentrations within the interval % (n) | 36.3% (37) | 36.1% (26) | 33.3% (4) | 38.9% (7) | p = 0.78 |
Proportion of patients with at least one low value % (n) | 23.5% (24) | 22.2% (16) | 58.3% (7) | 5.6% (1) |
p = 0.003
|
Proportion of patients with two low values % (n) | 9.8% (10) | 8.3% (6) | 33.3% (4) | 0 |
p = 0.008
|
Proportion of patients with at least one high value % (n) | 40.2% (41) | 41.7% (30) | 8.3% (1) | 55.6% (10) |
p = 0.032
|
Proportion of patients with two high values % (n) | 23.5% (24) | 26.4% (19) | 0 | 27.8% (5) | p = 0.122 |
Proportion of patients with at least one very high value % (n) | 24.5% (25) | 25% (18) | 0 | 38.9% (7) | p = 0.052 |
Proportion of patients with two very high values % (n) | 12.7% (13) | 15.3% (11) | 0 | 11.1% (2) | p = 0.33 |
Univariate regressions of trough concentrations as outcomes of baseline predictors
Variable | Univariate regression Cefotaxime | Multivariate regression Cefotaxime | Univariate regression Meropenem1 | Univariate regression Piperacillin1 |
---|---|---|---|---|
Age | β = 0.42
p = < 0.001
| β = 0.31
p = 0.002
(95% CI 0.12–0.51) | β = − 0.18 p = 0.29 | β = − 0.27 p = 0.83 |
Gender | β = − 1.24 p = 0.48 | β = − 0.26 p = 0.90 | β = − 18 p = 0.43 | |
eGFR | β = − 0.11
p = 0.002
| β = − 0.05 p = 0.10 | β = − 0.31 p = 0.21 | |
BMI | β = − 0.14 p = 0.38 | β = − 0.33 p = 0.24 | β = − 0.69 p = 0.61 | |
Charlson/Deyo comorbidity index | β = 0.95
p = 0.032
| β = − 0.54 p = 0.22 | β = 0.96 p = 0.73 | |
Each part of Charlson/Deyo comorbidity index | Diabetes with organ damage β = 10.5
p = 0.014
Moderate/severe kidney failure β = 8.15
p = 0.001
| Diabetes with organ damage β = 9.94
p = 0.005
(95% CI 3.13–16.8) Moderate/severe kidney disease β = 6.92
p = 0.001
(95% CI 3.03–10.8) | Myocardial infarction β = 5.02
p = 0.039
| Peptic ulcer disease β = 84.7
p = 0.012
Moderate/severe liver disease β = 84.7
p = 0.012
|
Sepsis severity | β = 3.48
p = 0.007
| β = 3.43
p = 0.002
(95% CI 1.35–5.50) | β = − 1.06 p = 0.50 | β = − 4.67 p = 0.68 |
Day of treatment | β = 0.27 p = 0.52 | β = − 1.03 p = 0.14 | β = − 1.79 p = 0.74 | |
Dose interval | β = − 0.02 p = 0.94 | β = 1.40 p = 0.07 | β = 3.96 p = 0.38 | |
Dose given according to guidelines | β = β = − 0–4.34
p = 0.031
| β = − 4.27 p = 0.09 | β = 5.30 p = 0.89 |
Variable | Full cohort—univariate analyses (compared to conc. in the correct interval) A Low conc. B High conc. C Very high conc. | Full cohort—multivariate model (compared to conc. in the correct interval) A Low conc. B High conc. C Very high conc. | Those who have received dose of antibiotics according to guidelines- multivariate model (compared to conc. in the correct interval) A Low conc. B High conc. C Very high conc. |
---|---|---|---|
Age | A. β = − 0.01 (p = 0.727) B. β = 0.08 (p = 0.063) C. β = 0.14 (p = 0.002) | ||
Gender | A. β = 0.55 (p = 0.320) B. β = − 0.59 (p = 0.329) C. β = − 0.01 (p = 0.986) | ||
eGFR | A. β = 0.01 (p = 0.348) B. β = − 0.23 (p = 0.072) C. β = − 0.07 (p = 0.001) | A. β = 0.01 (p = 0.449) (95% CI − 0.01–0.03) B. β = − 0.06 (p = 0.004) (95% CI − 0.1–(−)0.02) C. β = − 0.07 (p = 0.002) (95% CI − 0.12–(−) 0.03) | A. β = 0.01 (p = 0.558) (95% CI − 0.01–0.03) B. β = − 0.02 (p = 0.269) (95% CI − 0.04–0.01) C. β = − 0.06 (p = 0.005) (95% CI − 0.10–(−) 0.02) |
BMI | A. β = 0.08 (p = 0.158) B. β = 0.06 (p = 0.265) C. β = − 0.05 (p = 0.297) | A. β = 0.08 (p = 0.254) (95% CI − 0.06–0.22) B. β = 0.15 (p = 0.041) (95% CI 0.01–0.29) C. β = 0.06 (p = 0.424) (95% CI − 0.09–0.21) | |
Charlson/Deyo comorbidity index | A. β = − 0.24 (p = 0.093) B. β = − 0.01 (p = 0.952) C. β = − 0.05 (p = 0.694) | ||
Sepsis severity | A. β = 0.88 (p = 0.039) B. β = 0.76 (p = 0.072) C. β = 1.24 (p = 0.005) | A. β = 1.06 (p = 0.034) (95% CI 0.08–2.03) B. β = 0.68 (p = 0.203) (95% CI − 0.36–1.72) C. β = 0.88 (p = 0.109) (95% CI − 0.2–1.95) | A. β = 1.06 (p = 0.025) (95% CI 0.13–1.99) B. β = 0.73 (p = 0.155) (95% CI − 0.28–1.74) C. β = 0.49 (p = 0.380) (95% CI − 0.61–1.59) |
Day of treatment | A. β = 0.25 (p = 0.208) B. β = − 0.31 (p = 0.278) C. β = 0.32 (p = 0.097) | ||
Dose interval | A. β = 1.17 (p = 0.289) B. β = − 0.94 (p = 0.141) C. β = − 1.02 (p = 0.113) |
Multivariate regressions of trough concentrations as outcomes of baseline predictors
Hospital stay, readmissions, and mortality
Variable | Full cohort 102 patients | Cefotaxime 72 patients | Meropenem 12 patients | Piperacillin 18 patients | Significant difference between any of the three groups |
---|---|---|---|---|---|
Days of hospitalization Median (IQR) | 9 (6–17) | 8 (6–14) | 10 (7.5–20.5) | 14 (8–19) | p = 0.12 |
2Mortality within 28 days % | 12.7% (13) | 9.7% (7) | 8.3% (1) | 27.8% (5) | p = 0.09 |
3Readmission within 28 days % | 22.5% (23) | 23.6% (17) | 16.7% (2) | 22.2% (4) | p = 0.87 |
3Readmission within 28 days due to treatment failure | 12.7% (13) | 11.1% (8) | 16.7% (2) | 22.2% (4) | p = 0.45 |
Change of antibiotic within 48 h due to lack of effect | 4.9% (5) | 5.6% (4) | 0% (0) | 5.6% (1) | p = 0.70 |
Variable | Duration of hospitalization | Readmission to hospital within 28 days | 28-day mortality |
---|---|---|---|
Low concentration | β = 1.12 p = 0.81 (95% CI – 7.87–10.1) | OR = 0.60 p = 0.47 (95% CI 0.15–2.44) | – |
High concentration | β = 12.01
p = 0.01
(95% CI 3.00–21.0) | OR = 1.13 p = 0.84 (95% CI 0.33–3.87) | OR = 1.18 p = 0.85 (95% CI 0.19–7.25) |
Very high concentration | β = 9.65
p = 0.048
(95% CI 0.10–19.2) | OR = 0.91 p = 0.87 (95% CI 0.25–3.34) | OR = 5.68
p = 0.027
(95% CI 1.22–26.46) |
Charlson/Deyo comorbidity index | β1 = − 0.24 p = 0.75 (95% CI2 − 1.69–1.21) | OR = 1.47
p = 0.005
(95% CI 1.12–1.94) | |
Age | β = − 0.43 p = 0.089 (95% CI2 − 0.92–0.066) |