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Clinical Therapeutics

Nephrotoxicity during Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime

W. Cliff Rutter, Jessica N. Cox, Craig A. Martin, Donna R. Burgess, David S. Burgess
W. Cliff Rutter
aUniversity of Kentucky College of Pharmacy, Lexington, Kentucky, USA
bUniversity of Kentucky HealthCare, Lexington, Kentucky, USA
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Jessica N. Cox
bUniversity of Kentucky HealthCare, Lexington, Kentucky, USA
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Craig A. Martin
aUniversity of Kentucky College of Pharmacy, Lexington, Kentucky, USA
bUniversity of Kentucky HealthCare, Lexington, Kentucky, USA
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Donna R. Burgess
aUniversity of Kentucky College of Pharmacy, Lexington, Kentucky, USA
bUniversity of Kentucky HealthCare, Lexington, Kentucky, USA
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David S. Burgess
aUniversity of Kentucky College of Pharmacy, Lexington, Kentucky, USA
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DOI: 10.1128/AAC.02089-16
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    FIG 1

    Patient selection diagram. CLCR, creatinine clearance; FEP, cefepime; OSH, outside hospital; TZP, piperacillin-tazobactam; VAN, vancomycin.

Tables

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  • TABLE 1

    Patient demographic and clinical characteristicsa

    CharacteristicUnmatched cohortMatched cohort
    TZP-VAN (n = 3,605)FEP-VAN (n = 588) P valueTZP-VAN (n = 1,633)FEP-VAN (n = 578) P value
    Mean ± SD age (yr)51.5 ± 16.049.4 ± 17.00.00649.7 ± 15.749.4 ± 170.7
    No. (%) of male patients2,177 (60.4)326 (55.4)0.03905 (55.4)323 (55.9)0.9
    Median (IQR) CCI3 (1–6)3 (1–5)0.23 (1–5)3 (1–5)1
    Median (IQR) baseline CLCR (ml/min)97 (74–125)101 (77–132)0.01100 (77–126)101 (77–132)0.4
    No. (%) of patients with:
        Hypotension946 (26.2)190 (32.3)0.002479 (29.3)186 (32.2)0.2
        Dehydration220 (6.1)36 (6.1)198 (6.0)34 (5.9)1
        Nephrotoxic drug exposure2,190 (60.7)349 (59.4)0.5939 (57.5)340 (58.8)0.6
        ACEI/ARB841 (23.3)139 (23.6)0.9370 (22.7)135 (23.4)0.8
    No. (%) of patients treated with or exposed to:
        Acyclovir70 (1.9)33 (5.6)<0.000128 (1.7)29 (5.0)<0.0001
        An aminoglycoside473 (13.1)101 (17.2)0.01209 (12.8)98 (17.0)0.02
        Amphotericin B63 (1.7)16 (2.7)0.127 (1.7)15 (2.6)0.2
        A calcineurin inhibitor114 (3.2)19 (3.2)135 (2.1)19 (3.3)0.2
        Contrast dye1,632 (45.3)343 (58.3)<0.0001921 (56.4)336 (58.1)0.5
        Foscarnet9 (0.2)1 (0.2)13 (0.2)1 (0.2)1
        A loop diuretic1,121 (31.1)166 (28.2)0.2496 (30.4)160 (27.7)0.2
        An NSAID547 (15.2)88 (15.0)0.9242 (14.8)83 (14.4)0.8
        Sulfonamide66 (1.8)9 (1.5)0.727 (1.7)9 (1.6)1
        Tenofovir21 (0.6)4 (0.7)0.88 (0.5)4 (0.7)0.5
    No. (%) of patients with the following no. of risk factors: 0.0003 0.3
        01,132 (31.4)177 (30.1) 531 (32.5)177 (30.6)
        11,163 (32.3)190 (32.3) 528 (32.3)187 (32.4)
        2795 (22.1)113 (19.2) 335 (20.5)113 (19.6)
        3379 (10.5)62 (10.5) 160 (10.4)60 (10.4)
        ≥4136 (3.8)46 (7.8) 79 (7.1)41 (7.1)
    Median (IQR) VAN dose (mg/day)2,000 (1,500–2,500)2,083 (1,600–2,737)<0.00012,000 (1,500–2,500)2,083 (1,600–2,700)0.002
    No. (%) of patients with a daily VAN dose of ≥4,000 mg39 (1.1)16 (2.7)0.00218 (1.1)16 (2.8)0.009
    No. (%) of patients with the following maximum VAN trough concn (μg/ml): 0.3 0.7
        <10438 (20.8)77 (21.1) 213 (21.8)76 (21.1)
        10–15507 (24.1)100 (27.4) 231 (23.7)98 (27.2)
        15–20521 (24.8)88 (24.1) 239 (24.9)87 (24.2)
        >20639 (30.4)100 (27.4) 293 (30.0)99 (27.5)
    No. of days of antibiotic therapyc
        Total5 (4–8)5 (4–8)0.055 (4–8)5 (4–8)0.4
        Combination therapy3 (3–5)4 (3–6)0.0014 (3–5)4 (3–6)0.008
        FEP or TZP therapy5 (3–7)5 (3–7)0.85 (3–7)5 (3–7)0.2
        VAN therapy4 (3–6)4 (3–7)<0.00014 (3–6)4 (3–7)<0.0001
    • ↵a ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCI, Charlson comorbidity index; CLCR, creatinine clearance; FEP, cefepime; IQR, interquartile range; NSAID, nonsteroidal anti-inflammatory drug; TZP, piperacillin-tazobactam; VAN, vancomycin.

  • TABLE 2

    Incidence of AKI in unmatched and matched cohortsa

    OutcomeUnmatched cohortMatched cohort
    No. (%) of patientsP valueNo. (%) of patientsP value
    VAN-TZP (n = 3,605)VAN-FEP (n = 588)VAN-TZP (n = 1,633)VAN-FEP (n = 578)
    Any AKI771 (21.4)74 (12.6)<0.0001349 (21.4)72 (12.5)<0.0001
    Risk422 (11.7)44 (7.5)0.003179 (11.0)42 (7.3)0.01
    Injury244 (6.8)21 (3.6)0.004113 (6.9)21 (3.6)0.006
    Failure105 (2.9)9 (1.5)0.0857 (3.5)9 (1.6)0.03
    • ↵a FEP, cefepime; TZP, piperacillin-tazobactam; VAN, vancomycin.

  • TABLE 3

    Multivariate regression results in matched cohorta

    Covariate and treatment groupAdjusted odds ratioCIP value
    TZP-VANReferenceReferenceReference
    FEP-VAN2.181.64–2.94<0.001
    VAN dose (mg/day)
        <1,0000.530.16–1.390.3
        1,000–1,4991.010.72–1.420.9
        1,500–1,999ReferenceReferenceReference
        2,000–2,4991.080.79–1.480.6
        2,500–2,9991.160.81–1.650.4
        3,000–3,9991.611.11–2.320.01
        ≥4,0001.30.5–3.050.6
    Duration of VAN therapy of ≥7 days1.471.14–1.890.003
    Acyclovir exposure2.221.17–4.070.01
    Amphotericin B exposure2.251.14–4.410.02
    Loop diuretic exposure2.782.22–3.50<0.001
    Calcineurin inhibitor exposure1.620.85–2.980.1
    Dehydration exposure1.811.18–2.720.005
    • ↵a FEP, cefepime; TZP, piperacillin-tazobactam; VAN, vancomycin.

  • TABLE 4

    Secondary endpointsa

    CharacteristicUnmatched cohortMatched cohort
    VAN-TZP (n = 3,605)VAN-FEP (n = 588)P valueVAN-TZP (n = 1,633)VAN-FEP (n = 578)P value
    Median (IQR) time (days) to AKI5 (3–9)8 (4–16.8)0.00065 (3–9)8 (4–17)0.0004
    Median (IQR) hospital length of stay (days)8 (4–15)8 (4–17)0.088 (4–15)8 (5–17)0.9
    No. (%) of patients with in-hospital mortality276 (7.7)53 (9.0)0.3113 (6.9)53 (9.2)0.09
    • ↵a FEP, cefepime; IQR, interquartile range; TZP, piperacillin-tazobactam; VAN, vancomycin.

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Nephrotoxicity during Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime
W. Cliff Rutter, Jessica N. Cox, Craig A. Martin, Donna R. Burgess, David S. Burgess
Antimicrobial Agents and Chemotherapy Jan 2017, 61 (2) e02089-16; DOI: 10.1128/AAC.02089-16

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Nephrotoxicity during Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime
W. Cliff Rutter, Jessica N. Cox, Craig A. Martin, Donna R. Burgess, David S. Burgess
Antimicrobial Agents and Chemotherapy Jan 2017, 61 (2) e02089-16; DOI: 10.1128/AAC.02089-16
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KEYWORDS

cephalosporins
Penicillanic Acid
vancomycin
nephrotoxicity
piperacillin-tazobactam
adverse drug effects
beta-lactams
cefepime
vancomycin

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