ABSTRACT
The use of ceftriaxone, a highly protein-bound drug, in the setting of hypoalbuminemia may result in suboptimal drug exposure. Patients with obesity also exhibit higher absolute drug clearance. We aimed to evaluate the impact of hypoalbuminemia on clinical success among hospitalized adults with obesity who were treated with ceftriaxone. This retrospective review included adult inpatients with weight >100 kg or body mass index >40 kg/m2 who received ceftriaxone 2 g intravenously every 12 hours for at least 72 hours. The primary outcome was clinical success, a composite of clinical cure and microbiologic cure. Secondary outcomes included clinical cure, microbiologic cure, length of stay, ICU length of stay, mortality, 30-day readmission, and adverse events. In all, 137 patients were included, 34 of whom had a serum albumin of ≤2.5 g/dL. In a propensity-score-weighted analysis, clinical success was significantly more common among those without hypoalbuminemia (91.2%) as compared to those with hypoalbuminemia (77.8%) (P = 0.038). Death within 30 days (13.7% vs 0%, P < 0.001) and 30-day readmission (31.6% vs 12.0%, P = 0.008) were more common in the hypoalbuminemia group. In a univariate analysis, serum albumin and indication for ceftriaxone use were found to be predictors of clinical success. Hypoalbuminemia was associated with a lower rate of clinical success among patients with obesity who were treated with ceftriaxone 2 g every 12 hours.
KEYWORDS: ceftriaxone, hypoalbuminemia, pharmacokinetics, PK/PD, obesity
INTRODUCTION
Ceftriaxone is a highly protein-bound antibiotic that exhibits concentration-dependent binding site saturation at higher doses (1, 2). Low serum albumin impacts the pharmacokinetics of ceftriaxone by increasing the unbound fraction of the drug, thereby increasing the volume of distribution (3). Only the fraction of the drug not bound to plasma proteins can distribute outside of the plasma and eventually be cleared from the body. Hypoalbuminemia has therefore been hypothesized to lead to suboptimal drug exposure over the dosing interval due to increased volume of distribution and increased drug clearance (3, 4). Conversely, pharmacologists have endorsed that in the setting of hypoalbuminemia, the bound and hence total drug concentration decreases, while free/unbound concentration remains unchanged (5). Hypoalbuminemia has previously been shown to decrease the probability of target attainment with ceftriaxone intermittent dosing by as much as 20% (6).
Patients with obesity also exhibit higher absolute drug clearance compared to those without obesity (7). Ceftriaxone is routinely dosed at 2 g (g) intravenously (IV) every 12 hours for patients with obesity at our institution. It is unknown whether this ceftriaxone dosing strategy impacts treatment outcomes in the setting of hypoalbuminemia and obesity. In this retrospective cohort study, we aimed to evaluate the impact of hypoalbuminemia on clinical success among hospitalized adults with obesity who were treated with ceftriaxone for a bacterial infection.
RESULTS
A total of 137 patients were included, 34 of whom had a serum albumin of ≤2.5 g/dL. Patients were predominantly white (94.2%) and male (69.3%) with a median body mass index (BMI) of 48.6 (Table 1). The most common indications for ceftriaxone use were bacteremia (25.5%) followed by skin and soft tissue infection (20.4%) and pneumonia (18.2%). A total of 90 patients had positive sterile site cultures (Table 2). After propensity score (PS) weighting, the two groups were well balanced with respect to demographics, the Charlson Comorbidity Index, the need for ICU admission, and the indication for ceftriaxone use.
TABLE 1.
Baseline characteristicsa
| Unweighted cohort | Propensity-score-weighted cohort | ||||||
|---|---|---|---|---|---|---|---|
| Total (N = 137) | Albumin ≤ 2.5 g/dL (N = 34) |
Albumin >2.5 g/dL (N = 103) |
P value | Albumin ≤ 2.5 g/dL (N = 34) |
Albumin >2.5 g/dL (N = 103) |
P value | |
| Age (years), mean (SD) | 59.0 (12.5) | 57.1 (14.2) | 59.6 (11.9) | 0.32 | 60.7 (16.7) | 59.3 (11.6) | 0.64 |
| Sex | 0.30 | 0.16 | |||||
| Female | 42 (30.7%) | 8 (23.5%) | 34 (33.0%) | 17.6% | 29.8% | ||
| Male | 95 (69.3%) | 26 (76.5%) | 69 (67.0%) | 82.4% | 70.2% | ||
| Race | 0.023 | 0.57 | |||||
| White | 129 (94.2%) | 29 (85.3%) | 100 (97.1%) | 94.6% | 95.4% | ||
| African American | 2 (1.5%) | 1 (2.9%) | 1 (1.0%) | 1.0% | 1.5% | ||
| Other | 1 (0.7%) | 0 (0.0%) | 1 (1.0%) | 0.0% | 1.9% | ||
| Unknown | 5 (3.6%) | 4 (11.8%) | 1 (1.0%) | 4.4% | 1.2% | ||
| Ethnicity | 0.040 | 0.47 | |||||
| Hispanic or Latino | 2 (1.5%) | 0 (0.0%) | 2 (1.9%) | 0.0% | 2.8% | ||
| Non-Hispanic or Latino | 129 (94.2%) | 30 (88.2%) | 99 (96.1%) | 95.6% | 95.3% | ||
| Unknown | 6 (4.4%) | 4 (11.8%) | 2 (1.9%) | 4.4% | 2.0% | ||
| Height (cm), median (IQR) | 178 (168, 183) | 180 (170, 182) | 175 (168, 183) | 177 (168, 183) | 174 (168, 183) | ||
| Weight (kg), median (IQR) | 147.1 (131.3, 167.3) | 143.8 (131.3, 164.1) | 147.8 (131.2, 173.7) | 0.63 | 139.2 (127.5, 164.2) | 147.6 (131.2, 173.0) | 0.95 |
| BMI, median (IQR) | 48.6 (42.8, 56.6) | 46.5 (42.1, 52.5) | 49.5 (43.4, 57.2) | 47.5 (41.9, 52.7) | 49.2 (43.0, 56.7) | ||
| Charlson Comorbidity Index, median (IQR) | 3 (2, 6) | 3.5 (2, 6) | 3 (2, 6) | 0.74 | 3 (2, 5) | 3 (2, 6) | 0.76 |
| Albumin, median (IQR) | 3.0 (2.6, 3.6) | 2.3 (2.1, 2.4) | 3.3 (2.9, 3.7) | -- | 2.2 (2.1, 2.4) | 3.2 (2.8, 3.7) | -- |
| Range | (1.5–4.6) | (1.5–2.5) | (2.6–4.6) | (1.5–2.5) | (2.6–4.6) | ||
| Number of ceftriaxone doses, median (IQR) |
10 (8, 14) | 13 (10, 19) | 10 (8, 14) | 0.017 | 11 (9, 17) | 9 (7, 13) | 0.67 |
| Range | (6-102) | (6-54) | (6-102) | (6-54) | (6-102) | ||
| ICU admission | 82 (59.9%) | 21 (61.8%) | 61 (59.2%) | 0.79 | 56.5% | 58.6% | 0.83 |
| Ceftriaxone indication | 0.24 | 0.92 | |||||
| Bacteremia | 35 (25.5%) | 13 (38.2%) | 22 (21.4%) | 32.8% | 22.9% | ||
| Bone and joint infection | 23 (16.8%) | 6 (17.6%) | 17 (16.5%) | 13.6% | 18.0% | ||
| Endocarditis | 8 (5.8%) | 3 (8.8%) | 5 (4.9%) | 6.0% | 5.5% | ||
| Intra-abdominal infection | 10 (7.3%) | 1 (2.9%) | 9 (8.7%) | 10.7% | 7.4% | ||
| Skin and soft tissue infection | 28 (20.4%) | 5 (14.7%) | 23 (22.3%) | 16.0% | 21.8% | ||
| Urinary tract infection | 7 (5.1%) | 3 (8.8%) | 4 (3.9%) | 6.7% | 5.6% | ||
| Pneumonia | 25 (18.2%) | 3 (8.8%) | 22 (21.4%) | 14.1% | 18.2% | ||
| Lyme disease | 1 (0.7%) | 0 (0.0%) | 1 (1.0%) | 0.0% | 0.7% | ||
BMI, body mass index; cm, centimeters; g/dL, grams per deciliter; ICU, intensive care unit; IQR, interquartile range; kg, kilograms; SD, standard deviation.
TABLE 2.
Organisms cultureda
| Total (N = 137) | Albumin ≤ 2.5 g/dL (N = 34) |
Albumin > 2.5 g/dL (N = 103) |
|
|---|---|---|---|
| Aerococcus sanduinicola | 1 (0.7%) | 0 (0.0%) | 1 (1.0%) |
| Aggregatibacter aphrophilus | 1 (0.7%) | 0 (0.0%) | 1 (1.0%) |
| Corynebacterium spp. | 1 (0.7%) | 0 (0.0%) | 1 (1.0%) |
| Enterococcus faecalis | 1 (0.7%) | 0 (0.0%) | 1 (1.0%) |
| Escherichia coli | 9 (6.6%) | 2 (5.9%) | 7 (6.8%) |
| Finegoldia magna | 1 (0.7%) | 0 (0.0%) | 1 (1.0%) |
| Klebsiella pneumoniae | 1 (0.7%) | 1 (2.9%) | 0 (0.0%) |
| Morganella morganii | 1 (0.7%) | 1 (2.9%) | 0 (0.0%) |
| Neisseria gonorrhea | 1 (0.7%) | 1 (2.9%) | 0 (0.0%) |
| Proteus mirabilis | 1 (0.7%) | 1 (2.9%) | 0 (0.0%) |
| Staphylococcus aureus | 6 (4.4%) | 0 (0.0%) | 6 (5.8%) |
| Staphylococcus epidermidis | 1 (0.7%) | 1 (2.9%) | 0 (0.0%) |
| Staphylococcus lugdunensis | 1 (0.7%) | 0 (0.0%) | 1 (1.0%) |
| Streptococcus agalactiae | 9 (6.6%) | 3 (8.8%) | 6 (5.8%) |
| Streptococcus anginosus | 1 (0.7%) | 0 (0.0%) | 1 (1.0%) |
| Streptococcus bovis | 1 (0.7%) | 1 (2.9%) | 0 (0.0%) |
| Streptococcus dysgalactiae | 20 (14.6%) | 3 (8.8%) | 17 (16.5%) |
| Streptococcus intermedius | 1 (0.7%) | 0 (0.0%) | 1 (1.0%) |
| Streptococcus mitis | 6 (4.4%) | 3 (8.8%) | 3 (2.9%) |
| Streptococcus mutans | 1 (0.7%) | 0 (0.0%) | 1 (1.0%) |
| Streptococcus pneumoniae | 5 (3.6%) | 4 (11.8%) | 1 (1.0%) |
| Streptococcus pyogenes | 7 (5.1%) | 2 (5.9%) | 5 (4.9%) |
| Streptococcus sanguinous | 1 (0.7%) | 0 (0.0%) | 1 (1.0%) |
| Streptococcus zooepidemicus | 1 (0.7%) | 0 (0.0%) | 1 (1.0%) |
| Polymicrobial | 10 (7.3%) | 3 (8.8%) | 7 (6.8%) |
| None | 47 (34.3%) | 8 (23.5%) | 39 (37.9%) |
g/dL, grams per deciliter; spp, species.
In the propensity-score-weighted analysis, clinical success was achieved in 77.8% and 91.2% of those with and without hypoalbuminemia, respectively (P = 0.038) (Table 3). Clinical cure was significantly different with and without hypoalbuminemia (77.8% vs 92.0%, P = 0.024), while the microbiologic cure was not (81.9% vs 93.2%, P = 0.055). Five patients (13.5%) in the low albumin group died during hospitalization compared to those with normal albumin (P < 0.001). Death within 60 days occurred for 8 patients (22.6%) with hypoalbuminemia versus one patient (0.8%) without hypoalbuminemia (P < 0.001). Readmission within 30 days was also more common in the hypoalbuminemia group (31.6% vs 12.0%, P = 0.008). No significant differences were seen in hospital or ICU length of stay or incidence of adverse effects.
TABLE 3.
Patient outcomesa
| Unweighted cohort | Propensity-score-weighted cohort | |||||
|---|---|---|---|---|---|---|
| Albumin ≤ 2.5 g/dL (N = 34) |
Albumin >2.5 g/dL (N = 103) |
P value | Albumin ≤2.5 g/dL (N = 34) |
Albumin >2.5 g/dL (N = 103) |
P value | |
| Clinical success | 26 (76.5%) | 95 (92.2%) | 0.013 | 77.8% | 91.2% | 0.038 |
| Clinical cure | 26 (76.5%) | 96 (93.2%) | 0.007 | 77.8% | 92.0% | 0.024 |
| Microbiologic cure | 29 (85.3%) | 97 (94.2%) | 0.10 | 81.9% | 93.2% | 0.055 |
| Hospital length of stay (days), median (IQR) |
14 (8, 28) | 9 (6, 16) | 0.009 | 10 (7, 27) | 9 (6, 15) | 0.21 |
| ICU Length of stay (days), median (IQR) |
3.5 (2.1, 14.2) | 2.5 (1.5, 5.7) | 0.088 | 3.5 (2.0, 13.7) | 2.4 (1.3, 5.4) | 0.092 |
| Death during hospitalization | 5 (14.7%) | 0 (0.0%) | <0.001 | 13.5% | 0.0% | <0.001 |
| Death within 30 days | 5 (14.7%) | 0 (0.0%) | <0.001 | 13.7% | 0.0% | <0.001 |
| Death within 60 days | 8 (23.5%) | 1 (1.0%) | <0.001 | 22.6% | 0.8% | <0.001 |
| Readmission within 30 days | 8 (23.5%) | 12 (11.7%) | 0.089 | 31.6% | 12.0% | 0.008 |
| Adverse effects | 0.72 | 0.60 | ||||
| Neutropenia | 0 (0.0%) | 2 (1.9%) | 0.0% | 3.0% | ||
| Rash or other suspected IgE-mediated allergic reactionb | 1 (2.9%) | 3 (2.9%) | 2.7% | 2.6% | ||
| None identified | 33 (97.1%) | 98 (95.1%) | 97.3% | 94.4% | ||
ICU, intensive care unit; g/dL, grams per deciliter; IQR, interquartile range.
Suspected IgE-mediated reactions included hives, urticaria, angioedema, or anaphylaxis.
Results of a univariate analysis evaluating predictors of clinical success are shown in Table 4. Serum albumin and indication for ceftriaxone use were found to be predictors of clinical success.
TABLE 4.
Univariate associations between patient characteristics and clinical successa
| Clinical success (N = 121) | Clinical failure (N = 16) |
Odds ratio (95% CI) |
P value | |
|---|---|---|---|---|
| Age (years), mean (SD) | 59.1 (12.2) | 57.8 (14.7) | 1.01 (0.97–1.05) | 0.69 |
| Sex | ||||
| Female | 37 (30.6%) | 5 (31.3%) | 0.97 (0.31–2.99) | 0.96 |
| Male | 84 (69.4%) | 11 (68.8%) | Reference | |
| Height (cm), median (IQR) | 177 (168, 183) | 178 (170, 186) | 0.89 (0.53–1.52)b | 0.68 |
| Weight (kg), median (IQR) | 147.1 (131.6, 173.7) | 143.3 (129.6, 154.8) | 1.10 (0.91–1.32)b | 0.32 |
| BMI, median (IQR) | 49.3 (43.0, 57.1) | 44.9 (40.9, 55.1) | 1.04 (0.99–1.10) | 0.16 |
| Charlson comorbidity index, median (IQR) | 3 (2, 6) | 2 (2, 6) | 1.03 (0.87–1.22) | 0.74 |
| Albumin (g/dL), median (IQR) | ||||
| ≤2.5 | 26 (21.5%) | 8 (50.0%) | Reference | |
| >2.5 | 95 (78.5%) | 8 (50.0%) | 3.65 (1.25–10.67) | 0.018 |
| Ceftriaxone indication(s) | ||||
| Bacteremia | 42 (34.7%) | 4 (25.0%) | 1.60 (0.48–5.25) | 0.44 |
| Bone and joint infection | 22 (18.2%) | 4 (25.0%) | 0.67 (0.20–2.26) | 0.52 |
| Endocarditis | 5 (4.1%) | 3 (18.8%) | 0.19 (0.04–0.87) | 0.033 |
| Intra-abdominal infection | 11 (9.1%) | 0 (0.0%) | 3.43 (0.17–69.13) | 0.42 |
| Skin and soft tissue infection | 43 (35.5%) | 2 (12.5%) | 3.86 (0.84–17.78) | 0.083 |
| Urinary tract infection | 8 (6.6%) | 0 (0.0%) | 2.47 (0.12–53.22) | 0.56 |
| Pneumonia | 20 (16.5%) | 5 (31.3%) | 0.44 (0.14–1.39) | 0.16 |
| Number of ceftriaxone doses, median (IQR) | 10 (8, 14) | 10 (6, 15) | 1.04 (0.96–1.13) | 0.34 |
| Intensive care unit admission | 69 (57.0%) | 13 (81.3%) | 0.31 (0.08–1.13) | 0.076 |
BMI, body mass index; cm, centimeters; g/dL, grams per deciliter; IQR, interquartile range; kg, kilograms; SD, standard deviation.
Per 10 units.
DISCUSSION
In our study, hypoalbuminemia was associated with a lower rate of clinical success among patients with obesity who were treated with ceftriaxone 2 g IV every 12 hours. This result was primarily influenced by clinical cures rather than microbiologic cures. Patients with hypoalbuminemia were more likely to die in the hospital within 30 and 60 days.
Our results are consistent with a previous study by Baalbaki et al., who found that patients with hypoalbuminemia were four times more likely to experience clinical failure at 90 days in their study of ceftriaxone for the treatment of Enterobacterales bacteremia (8). Ackerman et al. also observed a higher rate of treatment failure among critically ill patients with hypoalbuminemia who received ceftriaxone in their unadjusted analysis, though hypoalbuminemia was not an independent predictor of treatment failure (9). Steere et al. compared clinical outcomes among patients with and without hypoalbuminemia receiving ceftriaxone for Enterobacterales bacteremia and found a numerically higher rate of treatment failure among patients with hypoalbuminemia, though the difference did not reach statistical significance (10). A similar result was seen in a subgroup of 96 patients with BMI ≥30 kg/m2, where the rate of treatment failure was 12.8% with hypoalbuminemia and 8.8% without (P = 0.52). Of note, in these studies, ceftriaxone was dosed at 1 or 2 g once daily. Increased mortality was associated with hypoalbuminemia in our study, and this finding has also been observed among patients treated with ertapenem, another highly protein-bound antibiotic (11).
Irrespective of serum albumin levels, a significantly higher rate of clinical failure has also been observed among patients with obesity treated with ceftriaxone compared to patients without obesity (12). However, patients who experienced clinical success had higher a BMI on average in our cohort, which is consistent with Alsiö et al., who observed a relative survival benefit of higher BMI in cases of severe bacterial infection (13). Obesity is not expected to impact the rate of protein binding but does increase absolute drug clearance and may increase the volume of distribution depending on the physiochemical properties of the drug (7).
A majority (60%) of patients in our study required ICU admission. Critically ill patients are at risk for hypoalbuminemia due to capillary leakage, down-regulation of hepatic synthesis, and malnutrition (3). Decreased protein binding of ceftriaxone may be further exacerbated by competitive binding of other highly protein-bound drugs and endogenous molecules such as bilirubin (14). Higher unbound fractions of ceftriaxone have been observed among critically ill patients compared to healthy volunteers (14, 15). Several pharmacokinetic simulations have found intermittent dosing of ceftriaxone at 2 g every 24 hours to be insufficient to achieve 100% time above the minimum inhibitory concentration in this patient population, especially for those with normal or augmented renal clearance (15–19). Ollivier et al. reported an adequate probability of target attainment with ceftriaxone 2 g every 12 hours, while Bos et al. and Leegwater et al. did not (17–19). Pharmacokinetic/pharmacodynamic studies of ceftriaxone in the setting of obesity are lacking.
Ceftriaxone dosed at 2 g every 12 hours was well-tolerated among our cohort, with only six patients having adverse effects noted in their medical records. Due to its tolerability and spectrum of activity, ceftriaxone is one of the most commonly used antibiotics for hospitalized patients in the United States (20). This highlights the need for pharmacokinetic studies measuring total and unbound ceftriaxone for patients with obesity and hypoalbuminemia. If the worse outcomes observed for patients with obesity and hypoalbuminemia receiving ceftriaxone are demonstrated to be a result of ceftriaxone under-exposure, alternate ceftriaxone dosing strategies may be needed. Every 8 hours, ceftriaxone dosing has been proposed for patients with hypoalbuminemia (3). Continuous infusion of ceftriaxone has been shown to improve the probability of target attainment among critically ill patients and may have a role for other populations at risk of suboptimal unbound ceftriaxone concentrations (19). Therapeutic drug monitoring and individualized dosing of ceftriaxone, particularly in the setting of extremes of body weight, may also warrant further study (21).
Our study has several limitations. The evaluation was retrospective, conducted at a single center, and limited by data available within the medical record. We conducted a propensity-score-weighted analysis to reduce the impact of between-group differences on our assessment. However, unmeasured confounding variables may have contributed to the different outcomes seen with and without hypoalbuminemia. Pharmacokinetic data were not collected; therefore, it is unknown if the worse outcomes observed for patients with obesity and hypoalbuminemia are the result of ceftriaxone under-exposure or a reflection of hypoalbuminemia as a surrogate marker of illness acuity. Hypoalbuminemia is a risk factor for mortality among hospitalized patients (22, 23). Patients with hypoalbuminemia may inherently be at higher risk for clinical failure due to higher severity of illness, and bacteremia and endocarditis were more common in the hypoalbuminemia group. However, the Charlson comorbidity index and the rate of ICU admission were similar between groups. Regardless, we observed that a relatively increased dose of ceftriaxone 2 g every 12 hours was not adequate to overcome negative clinical outcomes possibly caused by either disease severity and/or pharmacokinetic derangements in obese patients with hypoalbuminemia.
In conclusion, our results suggest that patients with obesity and hypoalbuminemia may experience worse outcomes when treated with ceftriaxone 2 g IV every 12 hours, and further research is needed to ascertain the cause. Alternative strategies such as the use of an alternative drug, ceftriaxone serum-level monitoring, or administration via continuous infusion may warrant consideration for patients with obesity and hypoalbuminemia.
MATERIALS AND METHODS
Study design and patient population
This retrospective cohort study included adult inpatients with weight >100 kg or with a BMI >40 kg/m2 who received ceftriaxone 2 g IV every 12 hours for at least 72 hours at a single center in Rochester, Minnesota from June 2010 to December 2020. Patients with at least one serum albumin concentration obtained within 7 days of ceftriaxone initiation were eligible for inclusion, and hypoalbuminemia was defined as a serum albumin of ≤2.5 g/dL (24). If multiple serum albumin concentrations were available, the lowest value within 24 hours of ceftriaxone administration was recorded. Minnesota residents who declined research authorization were excluded. Baseline characteristics and outcome data were collected via chart review. The Mayo Clinic Institutional Review Board deemed this study to be exempt (IRB #23-003505).
Clinical outcomes
The primary outcome was clinical success, which was defined as a composite of clinical cure and microbiologic cure. Clinical cure was defined as a resolution of signs and symptoms compatible with active infection without the need to change or extend antibiotic therapy due to the inadequate effect of ceftriaxone. Microbiologic cure was defined as negative repeat sterile site cultures, if applicable. Secondary outcomes included clinical cure, microbiologic cure, length of stay, ICU length of stay, mortality, 30-day readmission, and adverse events.
Statistical analysis
Categorical variables were compared between those with serum albumin ≤2.5 g/dL and those with serum albumin >2.5 g/dL using Pearson’s chi-squared test or Fisher’s exact test. Continuous variables were compared between groups using the Mann-Whitney U test. PS weighting was used to reduce the potential imbalance in baseline covariates between groups. The PS was estimated using a logistic regression model with variables: patient age, sex, race, weight, Charlson comorbidity index, and indication for ceftriaxone use. The PS weights were 1/PS for those with hypoalbuminemia and 1/(1 − PS) for those without hypoalbuminemia. The weights in each group were divided by the mean weight of that group so the sum of the weights was equal to the original sample size. Weighted versions of the analyses were used to compare variables between groups in the PS-weighted cohort. In the full cohort, univariate logistic regression analysis was also conducted to evaluate predictors of clinical success. All analyses were performed using SAS version 9.4 software (SAS Institute, Inc., Cary, NC). All tests were two-sided, and P values of ≤0.05 were considered statistically significant.
ACKNOWLEDGMENTS
Publication of this work was funded by a grant from the Mayo Midwest Pharmacy Research Committee.
Contributor Information
Kellie Arensman Hannan, Email: hannan.kellie@mayo.edu.
James E. Leggett, Providence Portland Med Ctr, Portland, USA
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