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A total of 1172 patients were reviewed. 944 patients met exclusion criteria (586 patients
were excluded due to ICU or intermediate care unit transfer, 353 patients received
antibiotics for less than 48 h, and 5 patients were excluded due to hemodialysis receipt).Therefore,
a total of 228 patients were identified after review of 26 months of inpatient admissions:
101 patients on vanc monotherapy, 26 patients on piptazo monotherapy, and 101 patients
on combV/P. Baseline patient characteristics including age, gender, race, renal function
in creatinine clearance based on Cockcroft and Gault equation (CrCl), and body mass
index (BMI) are listed in Table 1. The majority of patients were male (64.9 %) and African-American (79.8 %). Co-morbidities
were common (39.9 % had hypertension, 21.9 % had HIV, and 21.5 % had diabetes). The
most common indications for antibiotic usage were skin/soft tissue infection followed
by pneumonia, bone or joint infection, and sepsis of unknown etiology. Piptazo doses
were appropriate according to renal function in 90 % of cases and vancomycin doses
were greater than 4 g daily in 5 % of cases. Median time of antibiotic exposure for
the patients with AKI was 68, 61 and 46 h for vanc, piptazo and combV/P groups respectively
(all p  0.05 between groups).

Table 1. Baseline patient characteristics

The overall incidence of AKI in the study was 11.8 % (27 of 228 patients). AKI occurred
in 4 of 101 patients in the vanc group (4.0 %), 4 of 26 patients in the piptazo group
(15.4 %), and 19 of 101 patients in the combV/P group (18.8 %). None of the patients
required renal replacement therapy due to AKI. However, there were significant differences
between the antibiotic treatment groups in demographic characteristics (Table 2). Patients receiving piptazo monotherapy were less likely to be African-American
(61.5 %) than those on vanc monotherapy (83.2 %, p = 0.02) or combV/P (81.2 %, P = 0.03).
Patients receiving piptazo monotherapy were more likely to be on concomitant NSAID
therapy (34.6 %) than those on vanc monotherapy (13.0 %, p = 0.01) or combV/P (8.9 %,
P = 0.001). Other nephrotoxic agents that were examined (intravenous contrast, tenofovir,
and aminoglycosides) were not used at significantly different rates between antibiotic
groups. None of the patients in the study received other agents known to be associated
with nephrotoxicity including amphotericin and calcineurin inhibitors.

Table 2. Baseline characteristics by antibiotic

Overall, patients on vanc or piptazo monotherapy had fewer cumulative comorbidities
than those on combV/P. Specifically, patients on vanc were less likely to have hypertension
(p = 0.01) and diabetes (p = 0.02) compared to patients on combV/P. Patients on piptazo
were less likely to have HIV than patients on vanc (p = 0.03) or combV/P (p = 0.01).
Not surprisingly, the indications for antibiotics were also significantly different
between groups. Compared to patients on vanc and combV/P, patients on piptazo were
significantly more likely to have urinary tract infection and intra-abdominal infection
but significantly less likely to have bone/joint infection. Patients on combV/P were
significantly more likely to have pneumonia than patients on vanc or piptazo monotherapy
(all P  0.05).

In the univariable analysis (Table 3), the odds of AKI were lower in the vanc group compared to both the comb V/P group
(OR 0.178, p = 0.003) and to the piptazo monotherapy group (OR 0.227, p = 0.047).
There was no significant difference in AKI between the piptazo and combV/P groups.
For the exploratory analysis using the most conservative measure of AKI (creatinine
increase of at least 0.3 mg/dl), the frequency was again higher in the combV/P group
(26 of 101 or 25.7 %) compared to the vanc monotherapy group (11 or 101 or 10.9 %,
p = 0.006). Also in this exploratory analysis, AKI occurred in 6 of 26 patients (23.1 %)
of the piptazo group, which was not statistically different compared to the vanc group
(p = 0.10) or compared to the combV/P group (p = 0.78).

Table 3. Univariable analysis for AKI [27 of 228 (11.8 %) patients with AKI]

Table 3 shows demographic variables that by univariable analysis (p ? 0.10 for inclusion
in multivariable model) were associated with increased or decreased odds of AKI: male
gender, OR 0.321 (95 % CI 0.141–0.731, p = 0.007), BMI ?30 kg/m
²
, OR = 2.667 (95 % CI 1.053–6.760, p = 0.04), and African-American race compared to
caucasian OR 5.5 (95 % CI 0.721–41.968 p = 0.10). Of the indications for antibiotics
(not listed in Table 3), pneumonia (OR 3.50, 95 % CI 1.491–8.219, p = 0.004) was associated with higher
odds of AKI while skin/soft tissue infection (OR 0.137, 95 % CI 0.032–0.596, p = 0.008)
was associated with a lower odds for AKI. Intra-abdominal infection (OR 2.819, 95 %
CI 0.934–8.504) tended to have higher odds of AKI (p = 0.07).

For the traditional multivariable analysis with logistic regression, there were 179
patients, 22 with AKI (see Table 4). By bootstrap bagging, the following factors occurred in over 50 % of models and
were thus kept in the model: antibiotic group (84.1 %), sex (67.4 %), baseline creatinine
clearance (per 10 ml/min increase) (65.4 %), African-American versus caucasian race
(57.3 %), and skin/soft tissue infection (52.1 %). The other factors from Tables 2 and 3 with p ? 0.10 occurred in 50 % of models and thus were not kept in the model. In
the final model, vanc monotherapy (OR 0.14, 95 % CI 0.04–0.52, p = 0.004) as well
as piptazo monotherapy (OR 0.15, 95 % CI 0.03–0.83, p = 0.03) were associated with
lower odds of AKI compared to comb V/P. Male sex was also associated with lower odds
of AKI (OR 0.28, 95 % CI 0.10–0.79, p = 0.02). There was also a trend for increasing
creatinine clearance to be associated with higher odds of AKI (p = 0.05) and for skin/soft
tissue infection to be associated with lower odds of AKI (p = 0.06).

Table 4. Multivariable logistic regression analysis for factors associated with AKI (179 patients
and 22 with AKI)

Given the very small number of patients in the piptazo group, we henceforth focused
the propensity score logistic regression analysis on only the vanc and combV/P groups.
The significant covariates from Tables 2 and 4 included race, baseline creatinine clearance, pneumonia, diabetes, hypertension and
skin/soft tissue infection. We did not include subjects who lacked creatinine clearance
data in the propensity score analysis, leaving 161 subjects to be analyzed by IPTW
(see Table 5). Vanc monotherapy again was associated with a decreased odds ratio for AKI compared
to combV/P (adjusted OR 0.17; 95 % CI 0.04–0.62, p = 0.008). Male sex was also again
associated with decreased odds ratio for AKI (adjusted OR 0.28, 95 % CI 0.09–0.89,
p = 0.03). There were no other statistically significant associations with AKI in
the propensity score analysis.

Table 5. Logistic regression with inverse probability of treatment weighting to address treatment
selection bias (n = 161)