Supplementary Online Content 2 Kaye KS, Bhowmick T, Metallidis S, et al. Effect of meropenem-vaborbactam vs piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection. JAMA. doi:10.1001/jama.2018.0438 efigure 1. Study Schema etable 1. Distribution of Patients by Site etable 2. Baseline Characteristics etable 3. Drug Resistance by EUCAST Criteria in Baseline Urinary Gram-Negative Pathogens (m-mitt population) etable 4. Overview of Adverse Events (MITT Population) ereferences This supplementary material has been provided by the authors to give readers additional information about their work.
efigure 1. Study Schema
etable 1. Distribution of Patients by Site Country Site/ID No. Patients Belarus 112-007 9 Belarus 112-002 16 Belarus 112-001 24 Belarus 112-003 6 Belarus 112-004 9 Belarus 112-006 10 Brazil 076-001 2 Brazil 076-003 9 Brazil 076-002 2 Brazil 076-004 1 Bulgaria 100-001 3 Bulgaria 100-007 15 Bulgaria 100-008 3 Bulgaria 100-006 10 Bulgaria 100-004 5 Bulgaria 100-002 10 Czech Republic 203-002 10 Czech Republic 203-003 3 Czech Republic 203-005 3 Czech Republic 203-007 2 Czech Republic 203-008 8 Greece 300-002 3 Greece 300-001 32 Greece 300-004 5 Greece 300-500 1 Hungary 348-001 1 Italy 380-007 3 Peru 604-005 6 Peru 604-004 3 Peru 604-002 7 Peru 604-001 2 Poland 616-006 2 Poland 616-003 6 Poland 616-004 1 Romania 642-001 17
Country Site/ID No. Patients Romania 642-002 14 Romania 642-003 4 Slovakia 703-001 17 Slovakia 703-004 1 Slovakia 703-005 13 Slovenia 705-001 2 Slovenia 705-002 4 South Korea 820-002 1 Spain 724-001 1 Spain 724-009 6 Taiwan 158-001 7 Taiwan 158-004 1 Ukraine 804-001 32 Ukraine 804-002 36 Ukraine 804003 19 Ukraine 804-005 46 Ukraine 804-006 11 Ukraine 804-007 19 Ukraine 804-008 16 Ukraine 804-009 34 United States 840-005 9 United States 840-014 2 United States 840-017 2 United States 840-020 2 United States 840-018 2 TOTAL 550
etable 2. Baseline Characteristics Baseline characteristics m-mitt population M-V (N=192) P-T (N=182) M-V (N=178) ME population P-T (N=169) Acute pyelonephritis, n (%) 120 (62.5) 101 (55.5) 111 (62.4) 92 (54.4) Complicated UTI, n (%) With removable source of infection a With nonremovable source of infection 72 (37.5) 35 (18.2) 37 (19.3) 81 (44.5) 38 (20.9) 43 (23.6) 67 (37.6) 34 (19.1) 33 (18.5) 77 (45.6) 34 (20.1) 43 (25.4) Age (y): mean (SD) 65 y, n (%) 53.1 (19.3) 62 (32.3) 55.5 (20.5) 77 (42.3) 53.2 (19.3) 55 (30.9) 54.5 (20.3) 68 (40.2) Gender, female, n (%) 125 (65.1) 120 (65.9) 115 (64.6) 112 (66.3) Race, white, n (%) 178 (92.7) 169 (92.9) 166 (93.3) 158 (93.5) Creatinine clearance (ml/min): mean (SD) 50 ml/min, n (%) 95.0 (34.7) 21 (10.9) 87.0 (35.5) 23 (12.6) 176 (35.4) 20 (11.2) 166 (35.1) 20 (11.8) Diabetes mellitus, n (%) 32 (16.7) 34 (18.7) 29 (16.3) 30 (17.8) Systemic inflammatory response syndrome b, n (%) 55 (28.6) 61 (33.5) 52 (29.2) 57 (33.7) Charlson Comorbidity Index c Score 3, n (%) 103 (53.6) 105 (57.7) 95 (53.4) 94 (55.6) Abbreviations: ME, microbiologic evaluable; m-mitt, microbiologic modified intent-to-treat; M-V, meropenem-vaborbactam; P-T, piperacillin-tazobactam; SD, standard deviation. a Removable source of infection includes urinary catheter or removable kidney stones. b Systemic inflammatory response syndrome is defined as the occurrence of 2 or more of the following: Fever of >38 C (100.4 F) or <36 C (96.8 F); heart rate of >90 beats per minute; respiratory rate of >20 breaths per minute or arterial carbon dioxide tension of <32 mm Hg; abnormal white blood cell count (>12,000/µL or <4,000/µL or >10% immature [band] forms) c Charlson Comorbidity Index is used to categorize comorbidities of patients based on the International Classification of Diseases diagnosis codes. Each comorbidity category has an associated weight ranging from 1 to 6, based on the adjusted risk of mortality or resource use. The sum of all the weights results in a comorbidity score. A higher score indicates a higher likelihood that the predicted outcome will result in mortality or higher resource use.
etable 3. Drug Resistance by EUCAST Criteria in the Most Common Baseline Urinary Gram- Negative Pathogens (m-mitt Population) No. (%) Resistant: EUCAST Criteria a,1,2 Drug resistance Antimicrobial M-V n (%) b P-T n (%) b Escherichia coli N =124 N =115 Meropenem 0 (0) 0 (0) Piperacillin-tazobactam 18 (14.5) 14 (12.2) Klebsiella pneumoniae N =30 N =27 Meropenem 1 (3.3) 2 (7.4) Piperacillin-tazobactam 15 (50) 12 (44.4) Abbreviations: EUCAST, European Committee on Antimicrobial Susceptibility Testing; m-mitt, microbiologic modified intent-to-treat; M-V, meropenemvaborbactam; P-T, piperacillin-tazobactam. a For P-T, the EUCAST breakpoint for resistance is a minimum inhibitory concentration of >16 µg/ml and for meropenem the breakpoint for resistance is a minimum inhibitory concentration of >8 ug/ml. b Percentage is calculated using N as the denominator, where N is the number of isolates tested for the relevant antimicrobial. Only pathogens with a frequency of at least 10 patients total are included. Only data from urinary isolates are included. If the same pathogen was isolated from the same source (urine or blood), only the result for the isolate with the highest minimum inhibitory concentration was included.
etable 4. Overview of Adverse Events (MITT Population) AE M-V (N=272) n (%) P-T (N=273) n (%) All treatment-emergent AEs 106 (39.0) 97 (35.5) Study drug-related AEs 41 (15.1) 35 (12.8) Life-threatening AEs 3 (1.1) 0 (0.0) All serious AEs 11 (4.0) 12 (4.4) Deaths 2 (0.7) 2 (0.7) Discontinuation of study drug due to treatment-emergent AE 7 (2.6) 14 (5.1) Discontinuation from study due to treatment-emergent AE 3 (1.1) 3 (1.1) Any severe AE 7 (2.6) 13 (4.8) ALT increased 0 (0.0) 1 (0.4) Anemia 1 (0.4) 2 (0.7) Aspiration pneumonia 0 (0.0) 1 (0.4) AST increased 1 (0.4) 1 (0.4) Azotemia 1 (0.4) 0 (0.0) Bile duct stone 1 (0.4) 0 (0.0) Blood creatine phosphokinase increased 0 (0.0) 1 (0.4) Blood creatinine increased 0 (0.0) 1 (0.4) Cerebrovascular accident 0 (0.0) 1 (0.4) Colon cancer 1 (0.4) 1 (0.4) Convulsion 0 (0.0) 1 (0.4) Dyspnea 0 (0.0) 1 (0.4) Fibrin D dimer increased 0 (0.0) 1 (0.4) Hypoglycemia 1 (0.4) 0 (0.0) Infusion-related reaction 1 (0.4) 0 (0.0) Oliguria 1 (0.4) 0 (0.0) Ureteric obstruction 1 (0.4) 0 (0.0) UTI 0 (0.0) 1 (0.4) Frequency data are for numbers of participants experiencing an event, not for numbers of adverse events. Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; M-V, meropenem-vaborbactam; MITT, modified intent-to-treat; P-T, piperacillin-tazobactam.
ereferences 1. Meronem I.V. 500 mg. SmPC. Luton, UK; AstraZeneca UK Ltd. 2012. http://www.medicines.org.uk/emc/medicine/11215/spc. Accessed December 6, 2017. 2. Piperacillin/Tazobactam 4g/0.5g Powder for Solution for Infusion. SmPC. Wrexham, UK. Wockhardt UK Limited. 2017. http://www.medicines.org.uk/emc/medicine/21655/spc. Accessed December 6, 2017.