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1 Supplementary Online Content Downes KJ, Cowden C, Laskin BL, et al. Association of acute kidney injury with concomitant vancomycin and piperacillin/tazobactam treatment among hospitalized children. JAMA Pediatr. Published online October 2, doi: /jamapediatrics eappendix. Methods efigure. Flow Diagram of Study Cohort Derivation etable 1. Diagnosis Codes Associated With Diseases of the Kidney Other Than Acute Kidney Injury and Procedures Associated With Chronic Kidney Disease etable 2. Nephrotoxic Medications etable 3. Vancomycin Trough Concentrations Among Recipients of Vancomycin Plus Piperacillin/Tazobactam or Vancomycin Plus Other Antipseudomonal Beta-Lactam Agents etable 4. Sensitivity Analysis of the Effect of an Unmeasured Confounder on the Association Between Combination Therapy Group and AA-AKI etable 5. Multiple Logistic Regression of Antibiotic-Associated AKI on In-Hospital Mortality Among Recipients of Vancomycin and an Antipseudomonal Beta-Lactam References. This supplementary material has been provided by the authors to give readers additional information about their work.

2 eappendix Methods. Quantitative Bias Analysis We conducted a quantitative sensitivity analysis to evaluate the potential influence of confounding by an unmeasured covariate on the observed measure of association between the combination therapy group and AA- AKI. 1,2 Patient-level values for a dichotomous confounder were simulated from a binomial distribution for a series of scenarios defined by varying the relevant bias parameters, namely the odds ratio for the association between the unmeasured confounder and the outcome among those who were not exposed (i.e., OR: 2-10), the prevalence of the confounder among the TZP group (i.e., 40%-95%), and the prevalence of the confounder among the unexposed (i.e., 1%-50%). The adjusted odds ratio was estimated by adding the simulated confounder information to the final discrete-time failure model. We simulated 6 scenarios varying the strength of association between the unmeasured confounder and AA-AKI and the prevalence of the confounder in exposed (TZP) and unexposed (other antipseudomonal beta-lactam agents) groups. We included three improbable scenarios (1-3, etable 5) where the unmeasured confounder might explain much of the observed association between exposure and outcome and three (4-6, etable 5), which represent more realistic scenarios.

3 efigure. Flow Diagram of Study Cohort Derivation Cohort derivation 30,082 admissions with IV antibiotics on hospital days 1 & 2 and adequate SCr measurements for AKI assessment a Exclusions 1,928 admissions in children with underlying kidney disease 28,157 admissions in children without kidney disease 19,419 admissions with no IV vancomycin administration on hospital days 1 & 2 8,738 admissions with IV vancomycin given on at least hospital days 1 & 2 2,421 multiple courses of vancomycin in individual subjects 6,317 first admissions with IV vancomycin given on at least hospital days 1 & 2 1,649 admissions with one or more SCr above upper limits of normal for age and gender or AKI on hospital days 0-2 4,668 admissions with normal SCr on hospital days patients with ECMO procedure or clinical resource utilization during first week of hospitalization 4,638 admissions with IV vancomycin given on at least hospital days 1 & 2 in patients with normal SCr days 0-2 Final cohort: 1,915 admissions with IV vancomycin and a single antipseudomonal beta-lactam agent given on at least hospital days 1 and 2 2,723 patients who did not receive an antipseudomonal beta-lactam agent concurrent with IV vancomycin on at least hospital days 1 and 2 a Adequate SCr measurement defined as at least one SCr on hospital days 0-2, at least one SCr on hospital days 3-7, and SCr measurements no less than every 4 days. b Underlying kidney disease defined based on ICD-9 codes (etable 1) or receipt of dialysis on hospital days 0-2.

4 etable 1. Diagnosis Codes Associated With Diseases of the Kidney Other Than Acute Kidney Injury and Procedures Associated With Chronic Kidney Disease ICD-9-CM Diagnosis , 587 Nephritis, Nephrotic syndrome, and Nephrosis Chronic pyelonephritis 591 Hydronephrosis 592, 592.0, 592.1, Calculus of kidney and ureter Hypertrophy of kidney Stricture or kinking of ureter Other ureteric obstruction Hydroureter 593.7, Vesicoureteral reflux 593.8, Other specified disorders of kidney and ureter ICD-9-CM Procedure Arteriovenostomy for renal dialysis Revision of arteriovenous shunt for renal dialysis Removal of arteriovenous shunt for renal dialysis Angioplasty or atherectomy non coronary vessel(s) Repair of arteriovenous fistula Insertion of vessel-to-vessel cannula Replacement of vessel-to-vessel cannula Nephrectomy of solitary kidney Removal of transplanted or rejected kidney Bilateral nephrectomy 55.6 Kidney transplant

5 etable 2. Nephrotoxic Medications IV antimicrobials Acyclovir Aminoglycosides Amphotericin Cidofovir Colistimethate sodium Foscarnet Ganciclovir Nonsteroidal anti-inflammatory drugs Ibuprofen Ketorolac Naproxen Other Furosemide All ACE Inhibitors & ACE inhibitor combinations Immune modulators Cyclosporine Mesalamine Methotrexate Sirolimus Sulfasalazine Tacrolimus Chemotherapeutics Carboplatin Cisplatin Ifosfamide

6 etable 3. Vancomycin Trough Concentrations Among Recipients of Vancomycin Plus Piperacillin/Tazobactam or Vancomycin Plus Other Antipseudomonal Beta-Lactam Agents a Covariate Vancomycin plus TZP, n = 1009 Vancomycin plus other antipseudomonal betalactam agent, n = 906 p- value No. of subjects with a vancomycin trough 558 (55.3) 619 (68.3) <.001 measured on days 1 or 2 (% of total in group) Day of first vancomycin trough measurement, N 0.70 (%) Day 1 Day (69.5) 170 (30.5) 424 (68.5) 195 (31.5) Vancomycin concentrations in mcg/ml, median (IQR) ( ) ( ) No. with vancomycin trough 15 mcg/ml (%) 58 (10.1) 47 (7.5) 0.11 No. with vancomycin trough 20 mcg/ml (%) 27 (4.7) 18 (2.9) 0.09 a The first vancomycin trough concentration measured on hospital day 1 or 2 for each subject was assessed. Data were available from five of six PHIS hospitals. Results without date/time stamps were not evaluated.

7 etable 4. Sensitivity Analysis of the Effect of an Unmeasured Confounder on the Association Between Combination Therapy Group and AA-AKI Scenario Strength of association (odds ratio) between the unknown confounder and AA-AKI Prevalence of the unknown confounder in the vancomycinpiperacillin/tazobactam group Prevalence of the unknown confounder in vancomycin-other antipseudomonal beta-lactam group Adjusted odds ratio with inclusion of the unknown confounder in final model a (95% CI) ( ) ( ) ( ) ( ) ( ) ( ) a Odds ratio between vancomycin-piperacillin/tazobactam receipt and AA-AKI in the full model without inclusion of the unmeasured confounder = 3.40 (95% CI: )

8 etable 5. Multiple Logistic Regression of Antibiotic-Associated AKI on In-Hospital Mortality Among Recipients of Vancomycin and an Antipseudomonal Beta-Lactam Covariate Adjusted Odds Ratio (95% CI) Antibiotic-associated AKI 2.91 ( ) Receipt of vancomycin plus: Cefepime, ceftazidime, meropenem, or imipenem/cilastin REF Piperacillin/tazobactam 0.60 ( ) ICU level of care at any time days ( ) 2 complex/chronic conditions 2.31 ( ) Caucasian race 0.35 ( ) Administration of 2 nephrotoxic medications on days ( ) PHIS hospital REF 0.40 ( ) 0.83 ( ) 0.68 ( ) 0.27 ( ) 0.42 ( )

9 ereferences. 1. Lash TL, Fox MP, Fink AK. Applying Quantitative Bias Analysis to Epidemiologic Data. New York, NY: Springer; Lash TL, Fox MP, MacLehose RF, Maldonado G, McCandless LC, Greenland S. Good practices for quantitative bias analysis. Int J Epidemiol. 2014;43(6):