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PipEracillin Tazobactam versus mERoPENem for treatment of bloodstream infections caused by cephalosporin-resistant Enterobacteriaceae - a non-inferiority randomized controlled trial (PeterPen)
ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2020-040210
Article Type: Protocol
Date Submitted by the 02-Jul-2020 Author:
Complete List of Authors: Bitterman, Roni; Rambam Health Care Campus, Division of Infectious Diseases; Technion Israel Institute of Technology Ruth and Bruce Rappaport Faculty of Medicine Koppel, Fidi; Rambam Health Care Campus, Division of Infectious Diseases Mussini, Cristina; University Hospital Modena Geffen, Yuval; Rambam Health Care Campus, Microbiology Laboratory Chowers, Michal; Meir Medical Center, Infectious Diseases Unit; Tel Aviv University Sackler Faculty of Medicine Rahav, Galia; sheba medical center, Infectious Diseases Unit; Tel Aviv university, Sackler school of medicine Nesher, Lior; Soroka Medical Center, Infectious Diseases Unit; Ben- http://bmjopen.bmj.com/ Gurion University of the Negev Faculty of Health Sciences Ben-Ami, Ronen; Tel Aviv Sourasky Medical Center, Infectious Diseases Unit; Tel Aviv University Sackler Faculty of Medicine Turjeman, Adi; Rabin Medical Center, Internal Medicine E; Tel Aviv University Sackler Faculty of Medicine Huberman Samuel, Maayan ; Rabin Medical Center, Internal Medicine E Cheng, Matthew; McGill Interdisciplinary Initiative in Infection and Immunity Clinical Trials Platform
Lee, Todd; McGill Interdisciplinary Initiative in Infection and Immunity on September 26, 2021 by guest. Protected copyright. Clinical Trials Platform Leibovici, Leonard; Rabin Medical Center, Internal Medicine E; Tel Aviv University Sackler Faculty of Medicine Yahav, Dafna; Rabin Medical Center, Infectious Diseases Unit; Tel Aviv University Sackler Faculty of Medicine Paul, Mical; Rambam Health Care Campus, Division of Infectious Diseases; Technion Israel Institute of Technology Ruth and Bruce Rappaport Faculty of Medicine
Epidemiology < INFECTIOUS DISEASES, Infection control < INFECTIOUS Keywords: DISEASES, MICROBIOLOGY
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45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Page 1 1 2 3 PipEracillin Tazobactam versus mERoPENem for treatment of BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 bloodstream infections caused by cephalosporin-resistant 7 8 9 Enterobacteriaceae - a non-inferiority randomized controlled trial 10 11 12 (PeterPen) 13 14 15 Roni Bitterman1,2, Fidi Koppel1, Cristina Mussini3, Yuval Geffen4, Michal 16 17 Chowers5,6, Galia Rahav6,7, Lior Nesher8,9, Ronen Ben-Ami6,10Adi Turjeman6,11, 18 For peer review only 19 Maayan Huberman Samuel11, Matthew P. Cheng12, Todd C. Lee12, Leonard 20 21 22 Leibovici6,11, Dafna Yahav6,13, Mical Paul1,2 for the PeterPen study group 23 24 25 26 27 28 1. Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel 29 30 31 2. The Ruth and Bruce Rappaport Faculty of Medicine, Technion- Israel Institute 32 33 of Technology, Haifa, Israel 34 35 3. Modena University Hospital, Modena, Italy 36
37 http://bmjopen.bmj.com/ 38 4. Microbiology Laboratory, Rambam Health Care Campus, Haifa, Israel 39 40 5. Infectious Diseases Unit, Meir Medical Center, Kefar Sava, Israel 41 42 6. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 43 44
45 7. Infectious Diseases Unit, The Chaim Sheba Medical Center at Tel Hashomer, on September 26, 2021 by guest. Protected copyright. 46 47 Ramat Gan, Israel 48 49 8. Infectious Diseases Unit, Soroka Medical Center, Be'er Sheva, Israel 50 51 9. Faculty of Health Sciences, Ben-Gurion University, Be'er Sheva, Israel 52 53 54 10. Infectious Diseases Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel 55 56 11. Internal Medicine E, Rabin medical Center (Beilinson), Petah Tikva, Israel 57 58 59 60
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Page 2 1 2 3 12. McGill Interdisciplinary Initiative in Infection and Immunity Clinical Trials BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Platform, Montreal, Canada 7 8 13. Infectious Diseases Unit, Rabin medical Center (Beilinson), Petah Tikva, 9 10 Israel 11 12 13 14 15 16 17 Corresponding author: 18 For peer review only 19 20 Roni Bitterman, MD 21 22 23 Division of Infectious Diseases, 24 25 Rambam Health Care Campus, 26 27 Haifa 31096, Israel 28 29 30 Tel. +972-4-7772291 31 32 Fax: +972-4-7773284 33 34 Email: [email protected] 35 36
37 http://bmjopen.bmj.com/ 38 39 40 Word count: 3382 41 42 43 44
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Page 3 1 2 3 Key words: extended spectrum beta-lactamase, carbapenem, beta-lactam beta- BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 lactamase inhibitor, randomized controlled trial 7 8 9 10 Strengths and limitations of the study 11 12 13 The question of whether combination beta-lactam beta-lactamase inhibitors 14 15 are non-inferior to carbapenems for the treatment of ESBL infections remains 16 17 unanswered. 18 For peer review only 19 20 We propose an open-label, randomized controlled trial comparing piperacillin- 21 22 tazobactam with meropenem for treatment of bloodstream infections with 23 24 cephalosporin-resistant Escherichia coli and Klebsiella. 25 26 27 Mortality at 30-days and treatment failure at day seven are the co-primary 28 29 endpoints. 30 31 A sample size of 542 patients per arm was calculated. 32 33 34 35 36
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45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Page 4 1 2 3 Background BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Extended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae, once limited 7 8 to hospital-acquired infections, have now become prevalent in the community (1) and 9 10 11 pose a serious public health threat (2). Mortality rates following ESBL bloodstream 12 13 infections (BSIs) are high, with 30-day mortality ranging from 17% in Escherichia 14 15 coli to 34% in Klebsiella pneumoniae ESBL BSI in a contemporary large cohort (3), 16 17 reinforcing the need for optimal treatment of these infections (4). Carbapenems have 18 For peer review only 19 20 traditionally been considered the treatment of choice for Enterobacteriaceae 21 22 producing ESBL or AmpC due to concerns over imprecision of phenotypic 23 24 susceptibility testing and the potential of an inoculum effect (5). However extensive 25 26 27 use of carbapenems is associated with the emergence of both carbapenemase 28 29 producing and non-carbapenemase producing carbapenem-resistant Gram negative 30 31 bacteria (2). 32 33 34 Several retrospective observational studies compared treatment with carbapenems and 35 36
37 beta-lactam beta-lactamase inhibitors (BLBLI) for BSIs caused by ESBL-producing http://bmjopen.bmj.com/ 38 39 Enterobacteriaceae. These studies differed in the pathogens evaluated (Klebsiella spp. 40 41 vs. E. coli vs. all Enterobacteriaceae), the type and dose of BLBLI or carbapenem 42 43 44 used, the site of infection primarily assessed, whether empirical or definitive
45 on September 26, 2021 by guest. Protected copyright. 46 treatment was evaluated, and the outcome defined. Paterson et al were the first to 47 48 demonstrate significantly lower 14-day mortality with carbapenems, establishing a 49 50 51 dogma of carbapenem's advantage in ESBL K. pneumoniae BSIs more than 15 years 52 53 ago (6). Studies published later were inconsistent regarding the apparent efficacy of 54 55 BLBLI; however, the bulk of the published observational data show no difference 56 57 between empiric or definitive treatment with BLBLIs vs. carbapenems (6–10). The 58 59 60 MERINO trial by Harris et al was the first randomized controlled trial (RCT) to
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Page 5 1 2 3 compare piperacillin-tazobactam (PTZ) with meropenem for ESBL-producing BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Enterobacteriaceae BSI (11). This multicenter non-inferiority trial enrolled adults with 7 8 ceftriaxone-resistant (presumed ESBL-producing) E. coli or Klebsiella spp. The trial 9 10 originally targeted a sample size of 454 patients was terminated prematurely on the 11 12 third interim analysis since demonstration of non-inferiority by end of enrolment was 13 14 15 deemed unlikely. At termination, the overall 30-day mortality among 379 patients 16 17 included in the analysis was 7.9% (30 events), with 23/187 (12.3%) deaths in those 18 For peer review only 19 treated with PTZ vs. 7/191 (3.7%) in those treated with meropenem (risk difference 20 21 22 8.6%, 97.5% one sided confidence interval -∞ to 14.5). Thus, PTZ could not be 23 24 demonstrated to be non-inferior to meropenem. Re-calculation of the risk difference 25 26 as 2-sided 95% CI shows a significant difference between groups (risk difference 8.6 27 28 29 (3.3% to 14.5%)). Phenotypic ESBL production was confirmed in 86% of isolates 30 31 (85% of E. coli and 92.5% of Klebsiella spp.). Most patients had a urinary tract 32 33 infection (UTI, 60.9%) and most BSIs were caused by E. coli (86.5%). The risk 34 35 difference (2-sided 95% CIs) among patients with UTI (RD 3.7, 95% CI -2 to 10.7, 36
37 http://bmjopen.bmj.com/ 38 N=230) was lower than the risk difference among patients with a non-UTI source (RD 39 40 14.1, 95% CI 3.6-24.5, N=148). The risk difference for Klebsiella spp. (RD 23.1, 95% 41 42 CI 8.1-42.3, N=51) was larger than that for E. coli (RD 6.3, 95% CI 0.7-12.6, N=328). 43 44
45 on September 26, 2021 by guest. Protected copyright. 46 Rationale for replication 47 48 49 While the MERINO trial was the first RCT comparing PTZ to meropenem for ESBL 50 51 bacteremia, allowing estimation of effects without selection bias, there are several 52 53 reasons justifying further RCTs. The 3-fold difference in mortality between arms is 54 55 56 striking, and was never observed previously in a randomized comparison between 57 58 antibiotics. Such results warrant confirmation given the profound practice 59 60 implications. Several factors in the trial design favored non-inferiority, including the
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Page 6 1 2 3 recruitment of patients with mild sepsis (median Pitt score one at randomization, with BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 40.7% of patients having resolved signs of infection at randomization), relatively 7 8 short duration of the intervention (median six days out of the median 13 days of 9 10 treatment for the bacteremia) and “contamination” of drug exposure between the two 11 12 groups, due to use of the comparator for empirical treatment and stepdown therapy 13 14 15 after the minimal duration of the intervention of four days. Considering these, the 16 17 large difference in mortality observed between groups is even more striking. 18 For peer review only 19 20 Several factors in the MERINO trial design are worth discussion. Primarily, the 21 22 23 underlying assumptions which informed the non-inferiority sample size calculation. 24 25 In MERINO, the sample size calculation assumed 14% mortality for meropenem and 26 27 10% mortality for PTZ with a 5% non-inferiority margin. This was not included in 28 29 the initial manuscript but later appeared as an erratum (12). The a priori assumption 30 31 32 that mortality would be 4% lower for PTZ allows for a smaller total sample size, but 33 34 does so reliant on an assumption which is not supported by the observational 35 36 evidence. Removing that assumption and assuming that PTZ mortality would also be 37 http://bmjopen.bmj.com/ 38 39 14% (with the same one-sided alpha 2.5%, 80% power, and 10% loss to follow-up) 40 41 yields a sample size of 1683. Therefore, the MERINO trial as conducted was 42 43 terminated after recruiting 22.5% of the sample size required under a more realistic 44
45 on September 26, 2021 by guest. Protected copyright. 46 estimate of PTZ mortality. An underpowered non-inferiority trial is at high risk of 47 48 concluding “could not demonstrate non-inferiority”. 49 50 51 Moreover, the interim analysis at that point (379 patients with 30 deaths), might have 52 53 occurred at a time-point allowing random overestimation of the difference (13). A 54 55 56 systematic review comparing trials stopped early for benefit vs. trials that tested the 57 58 same interventions but completing recruitment showed that trials stopped early for 59 60 benefit exaggerate effects, especially when the number of events is small (14,15).
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Page 7 1 2 3 Approximately half of RCTs performed subsequent to a trial being stopped for BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 benefit, assessing the same intervention, confirmed the terminated trial’s benefit while 7 8 the other half found no difference or significance in the opposite direction (16). 9 10 11 Authors of the MERINO trial are currently investigating the reliability of VITEK and 12 13 gradient strips for determination of PTZ resistance (17) as well as the association 14 15 16 between genetic resistance mechanisms and PTZ minimal inhibitory concentrations 17 18 (MICs) (18,19).For The MERINO peer investigators review assessed PTZonly MICs of 321/379 isolates 19 20 by broth microdilution (BMD) in a central laboratory and found that 17.8% and 6.4% 21 22 23 were resistant to PTZ by EUCAST and CLSI criteria, respectively (18). Also 24 25 blaOXA-1 genes were highly prevalent (67%) in the MERINO trial (11). This may 26 27 explain the high failure rate seen with PTZ, as co-carriage of OXA-1 and CTX-M-15 28 29 (the most common ESBL gene in the MERINO trial) is associated with PTZ MICs as 30 31 32 high as 8-16 mcg/mL (20). These MICs, although still susceptible, have a much 33 34 higher chance (up to 20%) for inadequate PTZ pharmacokinetics when using the 35 36 dosing strategies employed in MERINO (21). 37 http://bmjopen.bmj.com/ 38 39 Other reasons for replication have been raised following the trial's publication (22). 40 41 42 These include: imbalances between treatment groups; differences between sites with 43 44 respect to the effect shown; the large number of deaths due to terminal cancer; and the 45 on September 26, 2021 by guest. Protected copyright. 46 pharmacokinetically non-optimized administration schedule of PTZ, particularly with 47 48 49 respect to organisms with PTZ MICs above 2mcg/L. 50 51 We are therefore left with clinical equipoise regarding the treatment of ESBL 52 53 infections with carbapenems as compared to BLBLIs. Microbiological and clinical 54 55 56 data suggest a possible benefit to carbapenems. However, many centers do not treat 57 58 patients with ESBL infections routinely with a carbapenem, due to the ecological 59 60 impact on these and other patients. This is especially true for centers with high
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Page 8 1 2 3 endemicity of carbapenem-resistant Gram-negative bacteria and high rates of ESBL BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 infections. Accepting without reservation the superiority of carbapenems as shown in 7 8 the MERINO trial will increase their use dramatically for the treatment of all ESBL- 9 10 positive bacteremias, spilling by default also to empirical treatment and treatment of 11 12 non-bacteremic ESBL infections. The implication of switching to a primary 13 14 15 carbapenem strategy for ESBLs is concerning in settings where ESBLs and 16 17 carbapenem-resistant Gram-negative bacteria are frequent. At a time of increasing 18 For peer review only 19 drug-resistance on one hand and on the other a serious lack of new antibiotics under 20 21 22 development (23), it seems imprudent to embrace the MERINO findings without 23 24 further corroboration. 25 26 For these reasons, we plan a second RCT comparing PTZ to meropenem for 27 28 29 bacteremia caused by third-generation cephalosporin non-susceptible E. coli and 30 31 Klebsiella spp. We aim to show the non-inferiority of PTZ to meropenem. This is a 32 33 replication trial attempting to address the findings and potential shortcomings of the 34 35 MERINO trial. Learning from the MERINO experience, we hope to also improve the 36
37 http://bmjopen.bmj.com/ 38 standardization of microbiological methods, baseline variable data collection, and 39 40 sample size issues. 41 42 43 44
45 on September 26, 2021 by guest. Protected copyright. 46 Methods 47 48 Design 49 50 51 The study is a multicenter randomized controlled non-inferiority open-label trial. 52 53 54 Study hypothesis and aims 55 56 We aim to evaluate the effect of definitive treatment with meropenem vs. PTZ, both 57 58 given as extended-infusions, on the outcome of patients with bacteremia due to PTZ 59 60
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Page 9 1 2 3 susceptible, third-generation cephalosporin-non-susceptible E. coli and Klebsiella spp. BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 (assumed ESBL-producing Enterobacteriaceae). We aim to demonstrate that PTZ is 7 8 non-inferior to meropenem. 9 10 11 Setting 12 13 The study will be conducted in three countries: in Israel at the Rambam Health Care 14 15 16 Campus (RHCC), Rabin Medical Center (Beilinson Hospital), Tel-Aviv Sourasky 17 18 Medical Center,For Soroka Medicalpeer Center, review Meir Medical only Center, and Sheba Medical 19 20 Center; in Italy at Modena University Hospital, and in Canada at the McGill 21 22 23 University Health Centre and Jewish General Hospital of Montreal. We are currently 24 25 recruiting other centers in all study countries. 26 27 28 Inclusion and exclusion criteria 29 30 We will include adults with community or hospital-acquired monomicrobial BSI with 31 32 33 E. coli or Klebsiella spp. non-susceptible to third generation cephalosporins and 34 35 susceptible to both PTZ and meropenem. Detailed inclusion and exclusion criteria are 36 37 listed in Table 1. http://bmjopen.bmj.com/ 38 39 40 Inclusion will be based on antibiotic susceptibility testing performed locally (Table 2). 41 42 43 We will ask all participating laboratories to document local MICs for PTZ and 44
45 meropenem for the study patients. The index culture will be kept frozen at -70ºC for on September 26, 2021 by guest. Protected copyright. 46 47 subsequent antimicrobial susceptibility confirmation and genotypic ESBL testing in a 48 49 reference laboratory using optimized uniform methodology. The primary analysis will 50 51 52 be performed as randomized (based on local susceptibility testing). A secondary 53 54 analysis will be performed based on the reference laboratory susceptibility test using 55 56 the EUCAST and CLSI standards that will apply at the time of analysis (24,25). 57 58 59 60
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Page 10 1 2 3 Patients in whom an exclusion criterion arises after randomization will be included in BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 the intention to treat population. 7 8 9 Patient randomization 10 11 12 Patients will be randomized to PTZ or meropenem in a 1:1 ratio. Randomization will 13 14 be done by a computer-generated list of random numbers allocated centrally through a 15 16 web site, stratified by country; infecting organism (E. coli vs. Klebsiella spp.); source 17 18 For peer review only 19 of infection (UTI vs other); and empirical antibiotics (covering antibiotics in the first 20 21 24 hours from culture taking or non-covering). The random sequence will be 22 23 generated using random permuted blocks of 4 to 8. 24 25 26 Intervention 27 28 The intervention group will receive PTZ 4.5 grams q6h and the control group will 29 30 receive meropenem 1 gram q8h. Dose adjustments for patients with renal 31 32 33 insufficiency are listed in Table 3. For both treatment arms the first dose will be 34 35 administered as a 30-minute bolus and the following doses will be administered as 36 37 three hours prolonged infusion. If patients receive PTZ or meropenem empirically http://bmjopen.bmj.com/ 38 39 using other dosing regimens they will switch to the trial dosing regimen, without a 40 41 42 bolus infusion if the same antibiotic is continued. 43 44 The study drug will be administered for a minimum of four to five days to complete at 45 on September 26, 2021 by guest. Protected copyright. 46 least seven days of antibiotic treatment. The use of other antibiotics will not be 47 48 49 allowed in the first week of treatment. 50 51 52 In order to maximize the ability of additional centers to join, minimize the study 53 54 infrastructure required in each center, and contain study costs for this, as yet unfunded 55 56 international trial, we have chosen to perform this trial open label. For the primary 57 58 59 endpoint of mortality, which is objective, we do not anticipate any risk of bias. For the 60
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Page 11 1 2 3 second primary endpoint, and any subjective secondary endpoints, these will be BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 adjudicated and analyzed by blinded members of the study team. 7 8 9 Pharmacokinetic / pharmacodynamic considerations 10 11 Dosing strategies of β-lactams for patients with sepsis is a matter of debate and 12 13 ongoing study. Nonetheless, studies on population pharmacokinetics for PTZ show 14 15 16 that up to 20% of patients with an isolate with an MIC of 2mcg/L treated with 4.5g 17 18 q8h by intermittentFor infusion peer will not achievereview the conservative only pharmacokinetic target 19 20 of at least 50% of the dosing interval (50% fT>MIC) (21,26). Increasing the 21 22 23 frequency to q6h improves this to about 10% at 2mcg/L but this again reaches 20% at 24 25 an MIC of 8mcg/L which is still considered susceptible by both EUCAST and the 26 27 CLSI (24,25). Another study evaluating therapeutic drug monitoring for β-lactams 28 29 showed that bolus administration of PTZ 4.5g q6h was insufficient in up to 49% of 30 31 32 patients to achieve the study's pharmacokinetic/pharmacodynamic target (27). Taking 33 34 into consideration that patients may be obese (28), have augmented renal clearance 35 36 (29) and/or have febrile neutropenia (30) only reinforces the need for high-dose 37 http://bmjopen.bmj.com/ 38 39 extended-infusion of PTZ. A recently-published systematic review and meta-analysis 40 41 on continuous/prolonged vs. intermittent infusion of β-lactams has shown reduced 42 43 mortality with continuous/prolonged infusion (31), lending further support for an 44
45 on September 26, 2021 by guest. Protected copyright. 46 optimized PTZ dosing schedule in future trials. 47 48 Prior to starting this trial, we conducted a survey among interested sites regarding 49 50 current and recommended dosing practices. Seven of 16 centers in Israel, Italy and 51 52 Canada stated they currently use either four-daily dosing of PTZ and/or extended 53 54 55 infusion. Two thirds recommended either 4.5g PTZ q6h extended infusion or 56 57 individualized dosing (using high dose extended infusion for obese, febrile 58 59 neutropenia, high MIC and severe sepsis). 60
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Page 12 1 2 3 As we believe that one of the MERINO shortcomings is the sub-optimal PTZ dosing BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 strategy; taking into consideration the previously mentioned pharmacokinetic studies 7 8 favoring a q6h extended infusion; and realizing that some PTZ susceptibility tests are 9 10 imprecise (17,32) and we could inadvertently include patients with higher MICs; we 11 12 chose a PTZ dosing of 4.5g q6h extended infusion. While we were intrigued by 13 14 15 individualized dosing, we believed that since this is more complicated and might not 16 17 be applied similarly across sites, the external validity of our trial might be 18 For peer review only 19 compromised. 20 21 22 23 We considered a meropenem dose of 1 gram TID sufficient, since this was the dose 24 25 studied in the MERINO trial for the same indications and this was the common dose 26 27 used in the study centers. Pharmacokinetic/pharmacodynamics studies support this 28 29 dosing regimen, especially when using extended infusions (33) and for the organisms 30 31 32 in this study which will all be carbapenem susceptible with low MICs. We chose to 33 34 give the meropenem as extended infusion so that non-inferiority would be 35 36 demonstrated against the best case administration of meropenem. 37 http://bmjopen.bmj.com/ 38 39 Outcome measures 40 41 42 We defined two co-primary endpoints, the first being all-cause mortality at day 30 43 44 from randomization and the second being treatment failure at day seven from 45 on September 26, 2021 by guest. Protected copyright. 46 randomization. Treatment failure was defined as death, fever above 38°C in the 48 47 48 49 hours before the time point, symptoms attributed to the focus of infection still present, 50 51 Sequential Failure Organ Assessment (SOFA) score (34) increasing, or blood cultures 52 53 positive with the index pathogen by the time point assessed (Table 4). These 54 55 56 outcomes were selected according to consensus recommendations developed for 57 58 clinical trials regarding BSIs (35). 59 60
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Page 13 1 2 3 Secondary outcomes include all-cause mortality at 14 and 90 days; treatment failure at BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 14 and 30 days; microbiological failure defined as positive blood cultures with index 7 8 pathogen at seven and 14 days; relapsed BSI at 30 and 90 days defined as recurrent 9 10 positive blood cultures with index pathogen after prior sterilization; metastatic 11 12 infections with index pathogen; secondary infections; Clostridioides difficile 13 14 15 associated diarrhea; hospital re-admissions; development of resistance to study drugs 16 17 in clinical isolates; carriage of carbapenem-resistant Enterobacteriaceae 18 For peer review only 19 (carbapenemase-producing and non-producing); total in-hospital days; total antibiotic 20 21 22 days; liver function test abnormalities; allergic reactions; renal failure and other 23 24 adverse events. 25 26 27 Subgroup analyses will be performed for the primary outcome of 30-day mortality by 28 29 30 infecting organism (E. coli vs. Klebsiella spp.); INCREMENT score (< 11 vs. ≥11) 31 32 (36); bacteremia source (UTI vs. non-UTI); covering empirical therapy given in the 33 34 first 24 hours; patients not receiving the comparator drug empirically; and excluding 35 36
37 patients with an uncontrolled focus of infection. http://bmjopen.bmj.com/ 38 39 40 Microbiological methods 41 42 43 All laboratories from centers participating in the study are ISO 9001 accredited 44 45 laboratories. Following growth in blood culture, isolates will be identified using on September 26, 2021 by guest. Protected copyright. 46 47 automated methods (Vitek 2, BD Phoenix, Vitek MS, MALDI biotyper). Antibiotic 48 49 50 susceptibilities will be determined according to local practices, using either automated 51 52 methods, disk diffusion or gradient diffusion methods, and interpreted using either 53 54 CLSI or EUCAST breakpoints as per local protocols. All isolates will be made 55 56 57 available for future testing by a central laboratory where antibiotic susceptibility will 58 59 60
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Page 14 1 2 3 be determined using BMD and interpreted according to EUCAST standards. We will BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 also determine and characterize the presence of ESBL and ampC genes. 7 8 9 Assessment and follow up 10 11 All patients will be followed up till day 90 post randomization. During hospitalization 12 13 patients will be visited by infectious diseases specialists as needed. Management 14 15 16 decisions, such as diagnostic evaluation, other medical/surgical procedures and 17 18 discharge from Forhospital willpeer be left to review the discretion of onlythe treating physicians. We 19 20 will not mandate diagnostic testing further than those defined for outcome collection 21 22 23 and these will be done as clinically indicated. 24 25 26 Data will be collected from the study visits, laboratory reports and the electronic 27 28 health record. Following discharge, we will document re-admission and survival 29 30 status through the national electronic patient files in Israel, through regional databases 31 32 33 in Italy, and through local data and direct patient contact (text/email/phone/mail) in 34 35 Canada. Anonymous data will be entered into a central case report form (CRF) 36 37 designed in REDCap, a secure web application. http://bmjopen.bmj.com/ 38 39 40 Sample size 41 42 43 For the mortality endpoint we calculated a sample size of 542 patients per arm 44
45 assuming a 12.5% mortality rate in the control group with a 5% non-inferiority on September 26, 2021 by guest. Protected copyright. 46 47 margin and a 1-sided hypothesis with 5% α-risk and 80% power (37). The assumed 48 49 mortality rate of 12.5% was based on rates reported in contemporary observational 50 51 52 studies (17.3%) (7–9) and the MERINO RCT (7.9%) (11). 53 54 55 The sample size calculation for the treatment failure outcome assumes a 25% failure 56 57 rate at seven days in the control group. To test for non-inferiority of PTZ compared to 58 59 60
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Page 15 1 2 3 meropenem with a 1-sided 5% α-risk, 80% power and a non-inferiority margin of BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 10% we will need 232 patients per study group. 7 8 9 Monitoring and trial management 10 11 The trial will be monitored centrally by the coordinating center at RHCC. Data entry 12 13 will be monitored continuously on RedCap, checking for timely data entry, missing 14 15 16 data or suspected faulty data. Inconsistencies and logical rules have been pre-defined 17 18 to allow detectionFor of such peer events. We review will employ a risk-based only strategy, with sparse 19 20 on-site monitoring based on central inspection of the data. A steering committee has 21 22 23 been nominated and the trial will be followed by an independent safety monitoring 24 25 board. 26 27 28 Statistical analysis 29 30 31 We plan an interim analysis after recruitment of 250, 500 and 750 patients. The trial 32 33 will be stopped if an extreme difference between groups of p<0.001 will be observed 34 35 36 for the primary outcome of 30-day mortality. The difference was chosen based on the
37 http://bmjopen.bmj.com/ 38 MERINO trial stopping rule (11) and following the Haybittle-Peto rule (38,39) that 39 40 preserves the overall type I error rate at 0.05. The sample size of the first interim 41 42 43 analysis was selected based on the minimal sample size required to reach a difference 44
45 with p<0.001 presuming that the maximal difference between groups that we will on September 26, 2021 by guest. Protected copyright. 46 47 reach is the one observed in the MERINO trial (11). 48 49 50 The primary analysis will include all randomized patients following local 51 52 53 susceptibility testing. A secondary analysis will exclude patients in whom major 54 55 errors in susceptibility compared to BMD will be detected. A per protocol analysis 56 57 will include patients fulfilling inclusion based on central lab adjudication of 58 59 60
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Page 16 1 2 3 susceptibilities, without exclusion criteria and receiving the allocated intervention for BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 at least four calendar days. 7 8 9 Patients' baseline characteristics will be displayed descriptively. Outcome variables 10 11 will be compared using the chi-square test, Student's t-test or the Mann–Whitney U 12 13 test, as appropriate. Risk differences for dichotomous outcomes will be computed 14 15 16 with 95% confidence intervals. Non-inferiority will be fulfilled if the upper value of 17 18 the 1-sided 95%For CI for the peer risk difference review of meropenem only compared to PTZ will be 19 20 equal or lower to the defined non-inferiority margin. 21 22 23 Ethics 24 25 26 The ethics of recruiting patients into this study, after the MERINO trial, are embedded 27 28 29 in the considerations we previously raised. These concern the possibility that their 30 31 chance finding will not be observed in a larger repetition trial and some improvement 32 33 in the study design through obtaining a larger sample size and improving PTZ 34 35 36 pharmacokinetics. With these considerations, the study was approved by the ethics
37 http://bmjopen.bmj.com/ 38 committees of the above Israeli hospitals and is awaiting approval in other hospitals. 39 40 In Canada, institutional ethics approval has been provisionally granted and the study 41 42 43 will commence after Health Canada approval has been granted for a study involving 44
45 off-label use of approved pharmaceuticals. on September 26, 2021 by guest. Protected copyright. 46 47 Patient and public involvement 48 49 We have not involved patients or the public in the trial's design and planning. 50 51 52 Funding 53 54 We have not succeeded in obtaining funding for the study from the Israeli Ministry of 55 56 Health. The study received the support of ESCMID through the society's Research 57 58 59 Grant programme 2020 (30,000 Euro) which will be used for the ethics and insurance 60
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Page 17 1 2 3 requirements of the Italian sites and for onsite study visits. The Canadian sites are BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 seeking funding through the Canadian Institutes of Health Research. Should the study 7 8 receive substantial funding we plan to recruit additional hospitals who do not have the 9 10 infrastructure to recruit into clinical trials without specific funding and to revise the 11 12 protocol, mainly with respect to the microbiological methods so as to enable local 13 14 15 laboratories to perform BMD and test for resistance genes in real time. 16 17 Competing interests 18 For peer review only 19 None declared. 20 21 22 Authors' contributions 23 24 All authors contributed to conception, design, trial management and planned data 25 26 analysis. 27 28 29 RB, FK, DY and MP contributed to trial database and randomization site design. 30 31 RB and MP wrote the first draft of the manuscript. 32 33 All authors revised the protocol critically for important intellectual content and 34 35 approved the final manuscript. 36
37 http://bmjopen.bmj.com/ 38 Acknowledgements 39 40 Members of the PeterPen Trial Group: Roni Bitterman, Mical Paul, Fidi Koppel, 41 42 Yuval Geffen (Rambam Health Care Campus, Israel). Dafna Yahav, Leonard 43 44
45 Leibovici, Adi Turjeman, Maayan Huberman Samuel (Rabin Medical Center, on September 26, 2021 by guest. Protected copyright. 46 47 Beilinson Hospital, Israel). Hiba Abu-Zayyad (The Baruch Padeh (Poriya) Medical 48 49 Center, Israel). Bibiana Chazan (Emek Medical Center, Israel), Ronen Ben Ami 50 51 52 (Ichilov Medical Center, Israel). Lior Nesher (Soroka Medical Center, Israel). Michal 53 54 Chowers (Meir Medical Center, Israel). Regev Cohen (Laniado Hospital, Irael). Galia 55 56 Rahav (The Chaim Sheba Medical Center at Tel HaShomer, Israel). Jacob Srahilevitz 57 58 (Hadassah Ein Kerem Medical Center, Israel). Erica Franceschini, Cristina Mussini 59 60
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Page 18 1 2 3 (Modena University Hospital, Italy). Marco Falcone (Università di Pisa Cisanello BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Hospital, Italy). Elena Carrara, Evelina Tacconelli (University of Verona Hospital, 7 8 Italy). Maddalena Giannella (S. Orsola-Malpighi Hospital University of Bologna, 9 10 Italy). Antonella d’Arminio Monforte (University of Milan, ASST Santi Paolo e 11 12 Carlo, Italy). Alessia Zoncada, Angelo Pan (Hospital of Cremona ASST di Cremona, 13 14 15 Italy). Todd C. Lee, Matthew P. Cheng (McGill University Health Centre, Canada). 16 17 Leighanne Parkes (Jewish general hospital of Montreal, Canada). 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44
45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Page 19 1 2 3 Table 1: Inclusion and exclusion criteria BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Inclusion criteria Exclusion criteria 7 8 9 Adults (age ≥ 18 years) More than 72 hours elapsed since 10 11 New onset BSI due to E. coli or initial blood culture taken, regardless 12 13 of the time covering antibiotics were 14 Klebsiella spp. in one or more blood 15 16 cultures associated with evidence of started 17 18 infection For peer review Polymicrobial only bacteremia defined as 19 20 either growth of two or more 21 The microorganism will have to be 22 23 non-susceptible to third generation different species of microorganisms 24 25 cephalosporins (ceftriaxone and/or in the same blood culture, or growth 26 27 ceftazidime) and susceptible to both of different species in two or more 28 29 30 PTZ and meropenem separate blood cultures within the 31 32 We will permit the inclusion of same episode of infection 33 34 bacteremias due to E. coli or Patients with prior bacteremia or 35 36
37 Klebsiella spp. with concomitant infection that have not completed http://bmjopen.bmj.com/ 38 39 growth in blood of skin commensals antimicrobial therapy for the 40 41 considered as contaminants. previous infectious episode. 42 43 44 Patients with septic shock at the time
45 on September 26, 2021 by guest. Protected copyright. 46 of enrollment and randomization, 47 48 defined as at least 2 measurements 49 50 of systolic blood pressure < 90 51 52 53 mmHg and/or use of vasopressors 54 55 (dopamine>15μg/kg/min, 56 57 adrenalin>0.1μg/kg/min, 58 59 60
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Page 20 1 2 3 noradrenalin>0.1μg/kg/min, BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 vasopressin any dose) in the 12 7 8 hours prior to randomization. In the 9 10 absence of the use of vasopressors, a 11 12 13 systolic blood pressure <90 would 14 15 need to represent a deviation for the 16 17 patient’s known normal blood 18 For peer review only 19 pressure. 20 21 22 BSI due to specific infections known 23 24 at the time of randomization: 25 26 endocarditis / endovascular 27 28 29 infections, osteomyelitis (not 30 31 resected), central nervous system 32 33 infections 34 35 36 Allergy to any of the study drugs
37 http://bmjopen.bmj.com/ 38 confirmed by history taken by the 39 40 investigator 41 42 43 Previous enrollment in this trial 44
45 Concurrent participation in another on September 26, 2021 by guest. Protected copyright. 46 47 interventional clinical trial 48 49 50 Imminent death (researcher’s 51 52 assessment of expected death within 53 54 48 hours of recruitment after 55 56 57 discussion with treating team) 58 59 60
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Page 21 1 2 3 Table 2: CLSI and EUCAST breakpoint definitions for susceptibility BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 CLSI M100-ED28: 2018. 28th EUCAST v 9 (January, 2019) 6 7 8 Edition (25) (24) 9 10 MIC Disk diffusion MIC Disk diffusion 11 12 (mg/L) (mm) (mg/L) (mm) 13 14 15 Ceftriaxone ≤1 ≥23 ≤1 ≥25 16 17 Ceftazidime ≤4 ≥21 ≤1 ≥22 18 For peer review only 19 PTZ ≤16 ≥21 ≤8 ≥20 20 21 22 Meropenem ≤1 ≥23 ≤2 ≥22 23 24 Imipenem ≤1 ≥23 ≤2 ≥22 25 26 CLSI- clinical and laboratory standards institute; EUCAST- European committee on 27 28 29 antimicrobial susceptibility testing; MIC- minimal inhibitory concentration 30 31 32 33 34 35 36
37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44
45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Page 22 1 2 3 Table 3: Dose adjustment for study antibiotics BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Meropenem Piperacillin tazobactam 7 8 9 10 CrCl>50ml/min* 1g q8h 4.5g q6h 11 12 CrCl 26-50ml/min* 1g q12h 3.375g q6h (only if CCT<40) 13 14 15 CrCl 10-25ml/min* 0.5g q12h 2.25g q6h 16 17 CrCl<10ml/min* 0.5g q24h 2.25g q6h 18 For peer review only 19 Hemodialysis 0.5g q24h (+0.5g AD) 2.25g q8h (+0.75g AD) 20 21 22 Peritoneal dialysis 0.5g q24h 2.25g q8h 23 24 Continuous renal 1g q12h 4.5g q8h 25 26 replacement therapy 27 28 29 *CrCl should be expressed in mL/min/1.73m2, using the modification of diet in renal 30 31 disease (MDRD) formula, Cockroft and Gault equation or other means. 32 33 34 AD- after dialysis 35 36 37 In Canada, to conform with the existing product monograph and accounting for the http://bmjopen.bmj.com/ 38 39 40 unavailability of the 3.375g dosage form in most hospitals the following piperacillin- 41 42 tazobactam dosing strategy will be used (as extended infusion of 3 hours). 43 44 45 Piperacillin-tazobactam on September 26, 2021 by guest. Protected copyright. 46 47 CCT>40ml/min 4.5g QID 48 49 CCT 20-40ml/min 4.5g TID 50 51 CCT 10-20ml/min 2.25g QID 52 53 CCT<10ml/min 2.25g QID 54 Hemodialysis 2.25g TID (+0.75g AD) 55 56 Peritoneal dialysis 2.25g TID 57 58 Continuous renal replacement therapy 4.5g TID 59 60
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Page 23 1 2 3 Table 4: Outcomes BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 Outcome Definition 6 7 8 30-day all-cause 9 10 mortality (co- 11 12 primary outcome) 13 14 15 Composite of the following by day 7: 16 17 Death 18 For peer review only 19 20 Treatment failure Fever above 38°C in the last 48 hours 21 22 at day 7 (co- Symptoms attributed to the focus of infection still 23 24 primary outcome) present 25 26 27 SOFA score increasing 28 29 Blood cultures positive with the index pathogen 30 31 14- and 90-day 32 33 34 all-cause 35 36 mortality
37 http://bmjopen.bmj.com/ 38 Treatment failure 39 As defined above 40 41 at 14 & 30 days 42 43 Microbiological 44 Positive blood cultures with index pathogen at days 4-7 and 45 failure at 7 & 14 on September 26, 2021 by guest. Protected copyright. 46 11-14 47 days 48 49 50 Relapsed BSI at Positive blood cultures with index pathogen following prior 51 52 30 & 90 days sterilization at days 30 and 90 53 54 Metastatic focus Isolation of index pathogen from non-blood specimen related 55 56 57 of infection to metastatic spread of infection by day 90 58 59 60
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Page 24 1 2 3 Development of either clinically or microbiologically BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 documented infection within 90 days according to CDC 7 Superinfection 8 surveillance definitions of health-care associated infections for 9 10 bacterial infections 11 12 13 Resistant Clinical isolates resistant to PTZ and meropenem and any 14 15 infection carbapenem-resistant bacteria 16 17 Carriage of CPE and non-CPE CRE in-hospital till day 90, 18 Resistant For peer review only 19 20 detected by weekly rectal surveillance of carriage while in- 21 colonization 22 hospital 23 24 Number of hospital re-admissions until day 90 25 Re-admissions 26 27 28 CDI Clostridioides difficile associated diarrhea till 90 days 29 30 31 Abnormal liver enzymes and bilirubin 32 33 Renal failure using the RIFLE (40) criteria by day 30 34 35 but we will not rely on urine output because it is not 36
37 http://bmjopen.bmj.com/ 38 properly or accurately documented in many non-ICU 39 40 Adverse events inpatient units 41 42 Leukopenia, neutropenia, thrombocytopenia 43 44
45 Drug hypersensitivity on September 26, 2021 by guest. Protected copyright. 46 47 Diarrhea 48 49 Seizures 50 51 52 SOFA, Sequential Organ Failure Assessment; BSI, bloodstream infection; CDC, 53 54 Centers for Disease Control and Prevention; PTZ, piperacillin tazobactam; CPE, 55 56 cabapenemase-producing Enterobacteriaceae; CRE, Carbapenem-resistant 57 58 59 Enterobacteriaceae; CDI, Clostridioides difficile infection 60
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Page 25 1 2 3 References BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 1. Elnasasra A, Alnsasra H, Smolyakov R, Riesenberg K, Nesher L. Ethnic 7 8 9 diversity and increasing resistance patterns of hospitalized community-acquired 10 11 urinary tract infections in Southern Israel: A prospective study. Isr Med Assoc 12 13 J. 2017;19(9). 14 15 16 2. CDC. Antibiotic resistance threats in the United States, 2013. Current 17 18 For peer review only 19 [Internet]. 2013 [cited 2018 Mar 4];114. Available from: 20 21 https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf 22 23 24 3. Scheuerman O, Schechner V, Carmeli Y, Gutiérrez-Gutiérrez B, Calbo E, 25 26 Almirante B, et al. Comparison of Predictors and Mortality Between 27 28 29 Bloodstream Infections Caused by ESBL-Producing Escherichia coli and 30 31 ESBL-Producing Klebsiella pneumoniae. Infect Control Hosp Epidemiol 32 33 [Internet]. 2018 Apr 5 [cited 2018 May 5];1–8. Available from: 34 35 36 https://www.cambridge.org/core/product/identifier/S0899823X18000636/type/j
37 http://bmjopen.bmj.com/ 38 ournal_article 39 40 41 4. Paul M, Shani V, Muchtar E, Kariv G, Robenshtok E, Leibovici L. Systematic 42 43 review and meta-analysis of the efficacy of appropriate empiric antibiotic 44
45 on September 26, 2021 by guest. Protected copyright. 46 therapy for sepsis. Vol. 54, Antimicrobial Agents and Chemotherapy. 2010. p. 47 48 4851–63. 49 50 51 5. Tam VH, Ledesma KR, Chang K-T, Wang T-Y, Quinn JP. Killing of 52 53 Escherichia coli by β-lactams at different inocula. Diagn Microbiol Infect Dis 54 55 56 [Internet]. 2009 Jun [cited 2018 Aug 12];64(2):166–71. Available from: 57 58 http://www.ncbi.nlm.nih.gov/pubmed/19304437 59 60
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Page 26 1 2 3 6. Paterson DL, Ko W-C, Von Gottberg A, Mohapatra S, Casellas JM, Goossens BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 H, et al. Antibiotic Therapy for Klebsiella pneumoniae Bacteremia: 7 8 Implications of Production of Extended-Spectrum -Lactamases. Clin Infect Dis 9 10 [Internet]. 2004;39(1):31–7. Available from: 11 12 https://academic.oup.com/cid/article-lookup/doi/10.1086/420816 13 14 15 16 7. Rodríguez-Baño J, Navarro MD, Retamar P, Picón E, Pascual Á, Extended- 17 18 SpectrumFor Beta-Lactamases–Red peer review Española de Investigación only en Patología 19 20 Infecciosa/Grupo de Estudio de Infección Hospitalaria Group. β-Lactam/β- 21 22 23 lactam inhibitor combinations for the treatment of bacteremia due to extended- 24 25 spectrum β-lactamase-producing Escherichia coli: a post hoc analysis of 26 27 prospective cohorts. Clin Infect Dis [Internet]. 2012 Jan 15 [cited 2018 Mar 28 29 4];54(2):167–74. Available from: https://academic.oup.com/cid/article- 30 31 32 lookup/doi/10.1093/cid/cir790 33 34 35 8. Gutiérrez-Gutiérrez B, Pérez-Galera S, Salamanca E, de Cueto M, Calbo E, 36 37 Almirante B, et al. A Multinational, Preregistered Cohort Study of β-Lactam/β- http://bmjopen.bmj.com/ 38 39 Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections 40 41 42 Due to Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae. 43 44 Antimicrob Agents Chemother [Internet]. 2016 Jul [cited 2018 Mar 45 on September 26, 2021 by guest. Protected copyright. 46 4];60(7):4159–69. Available from: 47 48 49 http://aac.asm.org/lookup/doi/10.1128/AAC.00365-16 50 51 52 9. Tamma PD, Han JH, Rock C, Harris AD, Lautenbach E, Hsu AJ, et al. 53 54 Carbapenem therapy is associated with improved survival compared with 55 56 piperacillin-tazobactam for patients with extended-spectrum β-lactamase 57 58 59 bacteremia. Clin Infect Dis [Internet]. 2015 May 1 [cited 2018 Mar 60
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Page 27 1 2 3 4];60(9):1319–25. Available from: https://academic.oup.com/cid/article- BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 lookup/doi/10.1093/cid/civ003 7 8 9 10. Muhammed M, Flokas ME, Detsis M, Alevizakos M, Mylonakis E. 10 11 Comparison Between Carbapenems and β-Lactam/β-Lactamase Inhibitors in 12 13 the Treatment for Bloodstream Infections Caused by Extended-Spectrum β- 14 15 16 Lactamase-Producing Enterobacteriaceae: A Systematic Review and Meta- 17 18 Analysis.For Open forum peer Infect Dis review [Internet]. 2017 only [cited 2018 May 19 20 5];4(2):ofx099. Available from: https://academic.oup.com/ofid/article- 21 22 23 lookup/doi/10.1093/ofid/ofx099 24 25 26 11. Harris PNA, Tambyah PA, Lye DC, Mo Y, Lee TH, Yilmaz M, et al. Effect of 27 28 Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With 29 30 E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone 31 32 33 Resistance A Randomized Clinical Trial. JAMA. 2018;320(10):984–94. 34 35 36 12. Erratum. Missing Information on Sample Size. JAMA [Internet]. 2019 Jun 18
37 http://bmjopen.bmj.com/ 38 [cited 2020 Feb 27];321(23):2370. Available from: 39 40 http://www.ncbi.nlm.nih.gov/pubmed/31211326 41 42 43 13. Button KS, Ioannidis JPA, Mokrysz C, Nosek BA, Flint J, Robinson ESJ, et al. 44
45 on September 26, 2021 by guest. Protected copyright. 46 Power failure: Why small sample size undermines the reliability of 47 48 neuroscience. Nat Rev Neurosci. 2013; 49 50 51 14. Bassler D, Briel M, Montori VM, Lane M, Glasziou P, Zhou Q, et al. Stopping 52 53 randomized trials early for benefit and estimation of treatment effects: 54 55 56 systematic review and meta-regression analysis. JAMA [Internet]. 2010 Mar 24 57 58 [cited 2018 May 5];303(12):1180–7. Available from: 59 60
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Page 28 1 2 3 http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2010.310 BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 15. Montori VM, Devereaux PJ, Adhikari NKJ, Burns KEA, Eggert CH, Briel M, 7 8 9 et al. Randomized trials stopped early for benefit: a systematic review. JAMA 10 11 [Internet]. 2005 Nov 2 [cited 2018 May 5];294(17):2203–9. Available from: 12 13 http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.294.17.2203 14 15 16 16. Murad MH, Guyatt GH, Domecq JP, Vernooij RWM, Erwin PJ, Meerpohl JJ, 17 18 For peer review only 19 et al. Randomized trials addressing a similar question are commonly published 20 21 after a trial stopped early for benefit. J Clin Epidemiol [Internet]. 2017 Feb 22 23 [cited 2018 May 5];82:12–9. Available from: 24 25 26 http://linkinghub.elsevier.com/retrieve/pii/S0895435616305856 27 28 29 17. Problems with piperacillin-tazobactam gradient tests from two manufacturers. 30 31 EUCAST warnings concerning antimicrobial susceptibility testing products or 32 33 procedures. Available from: http://www.eucast.org/ast_of_bacteria/warnings/ 34 35 36
37 18. Andrew Henderson, Paul Tambyah, David Lye, Mesut Yilmaz, Thamer http://bmjopen.bmj.com/ 38 39 Alenazi, Matteo Bassetti, Elda Righi, Benjamin Rogers, Souha S. Kanj, Hasan 40 41 Bhally, Jon Iredell, Marc Mendelson, David Looke, Spiros Miyakis, Genevieve 42 43 Walls, Amy Crowe, Paul Ingram, Nick Dan PG, Eugene Athan, Leah Roberts, 44
45 on September 26, 2021 by guest. Protected copyright. 46 Scott Beatson, Michelle Bauer, Kyra Cottrell, Ernest Tan, Anton Peleg, Tiffany 47 48 Harris-Brown DLPPH. Association with 30-day mortality and MIC in patients 49 50 treated with piperacillin/tazobactam for Escherichia coli and Klebsiella 51 52 53 pneumoniae bloodstream infections that are non-susceptible to ceftriaxone 54 55 from patients enrolled in the MERINO trial. In: 29th ECCMID. 2019. 56 57 58 19. Harris PNA, Tambyah P, Paterson DL. Antibiotics for Ceftriaxone Resistant 59 60
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Page 29 1 2 3 Gram-Negative Bacterial Bloodstream Infections - Reply [Internet]. Vol. 321, BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 JAMA - Journal of the American Medical Association. American Medical 7 8 Association; 2019 [cited 2020 Feb 16]. p. 613–4. Available from: 9 10 http://www.ncbi.nlm.nih.gov/pubmed/30747963 11 12 13 20. Livermore DM, Day M, Cleary P, Hopkins KL, Toleman MA, Wareham DW, 14 15 16 et al. OXA-1 beta-lactamase and non-susceptibility to penicillin/beta-lactamase 17 18 inhibitor Forcombinations peer among reviewESBL-producing onlyEscherichia coli. J Antimicrob 19 20 Chemother. 2018 Nov;74(2):326–33. 21 22 23 21. Felton TW, Hope WW, Lomaestro BM, Butterfield JM, Kwa AL, Drusano GL, 24 25 26 et al. Population pharmacokinetics of extended-infusion piperacillin- 27 28 tazobactam in hospitalized patients with nosocomial infections. Antimicrob 29 30 Agents Chemother. 2012 Aug;56(8):4087–94. 31 32 33 22. Rodríguez-Baño J, Gutiérrez-Gutiérrez B, Kahlmeter G. Antibiotics for 34 35 36 Ceftriaxone-Resistant Gram-Negative Bacterial Bloodstream Infections
37 http://bmjopen.bmj.com/ 38 [Internet]. Vol. 321, JAMA - Journal of the American Medical Association. 39 40 American Medical Association; 2019 [cited 2020 Feb 16]. p. 612–3. Available 41 42 43 from: http://www.ncbi.nlm.nih.gov/pubmed/30747960 44
45 on September 26, 2021 by guest. Protected copyright. 46 23. WHO. ANTIBACTERIAL AGENTS IN CLINICAL DEVELOPMENT. 2017. 47 48 49 24. The European Committee on Antimicrobial Susceptibility Testing. Breakpoint 50 51 tables for interpretation of MICs and zone diameters. Version 9.0 [Internet]. 52 53 2019 [cited 2019 Feb 19]. Available from: http://www.eucast.org. 54 55 56 57 25. CLSI 2018. Clinical and Laboratory Standards Institute. Performance standards 58 59 for antimicrobial susceptibility testing [Internet]. 2018 [cited 2018 Mar 8]. 60
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Page 30 1 2 3 Available from: BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 https://clsi.org/standards/products/microbiology/documents/m100/ 7 8 9 26. Andersen MG, Thorsted A, Storgaard M, Kristoffersson AN, Friberg LE, 10 11 Öbrink-Hansen K. Population Pharmacokinetics of Piperacillin in Sepsis 12 13 Patients: Should Alternative Dosing Strategies Be Considered? Antimicrob 14 15 16 Agents Chemother [Internet]. 2018 May 5 [cited 2019 Mar 2];62(5). Available 17 18 from: http://aac.asm.org/lookup/doi/10.1128/AAC.02306-17For peer review only 19 20 21 27. Roberts JA, Ulldemolins M, Roberts MS, McWhinney B, Ungerer J, Paterson 22 23 DL, et al. Therapeutic drug monitoring of β-lactams in critically ill patients: 24 25 26 proof of concept. Int J Antimicrob Agents [Internet]. 2010 Oct [cited 2019 Mar 27 28 2];36(4):332–9. Available from: 29 30 http://www.ncbi.nlm.nih.gov/pubmed/20685085 31 32 33 28. Chung EK, Cheatham SC, Fleming MR, Healy DP, Shea KM, Kays MB. 34 35 36 Population pharmacokinetics and pharmacodynamics of piperacillin and
37 http://bmjopen.bmj.com/ 38 tazobactam administered by prolonged infusion in obese and nonobese patients. 39 40 J Clin Pharmacol [Internet]. 2015 Aug [cited 2019 Mar 2];55(8):899–908. 41 42 43 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25823963 44
45 on September 26, 2021 by guest. Protected copyright. 46 29. Udy AA, Lipman J, Jarrett P, Klein K, Wallis SC, Patel K, et al. Are standard 47 48 doses of piperacillin sufficient for critically ill patients with augmented 49 50 creatinine clearance? Crit Care [Internet]. 2015 Jan 30 [cited 2019 Mar 51 52 53 2];19(1):28. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25632974 54 55 56 30. Sime FB, Hahn U, Warner MS, Tiong IS, Roberts MS, Lipman J, et al. Using 57 58 Population Pharmacokinetic Modeling and Monte Carlo Simulations To 59 60
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Page 31 1 2 3 Determine whether Standard Doses of Piperacillin in Piperacillin-Tazobactam BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Regimens Are Adequate for the Management of Febrile Neutropenia. 7 8 Antimicrob Agents Chemother [Internet]. 2017 Nov [cited 2019 Mar 2];61(11). 9 10 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28807922 11 12 13 31. Vardakas KZ, Voulgaris GL, Maliaros A, Samonis G, Falagas ME. Prolonged 14 15 16 versus short-term intravenous infusion of antipseudomonal β-lactams for 17 18 patients withFor sepsis: peer a systematic review review and meta-analysis only of randomised 19 20 trials. Lancet Infect Dis [Internet]. 2018 Jan [cited 2019 Mar 2];18(1):108–20. 21 22 23 Available from: 24 25 https://linkinghub.elsevier.com/retrieve/pii/S1473309917306151 26 27 28 32. Mouton JW, Muller AE, Canton R, Giske CG, Kahlmeter G, Turnidge J. MIC- 29 30 based dose adjustment: facts and fables. J Antimicrob Chemother [Internet]. 31 32 33 2018 Mar 1 [cited 2019 Mar 2];73(3):564–8. Available from: 34 35 http://www.ncbi.nlm.nih.gov/pubmed/29216348 36
37 http://bmjopen.bmj.com/ 38 33. Isla A, Canut A, Arribas J, Asín-Prieto E, Rodríguez-Gascón A. Meropenem 39 40 dosing requirements against Enterobacteriaceae in critically ill patients: 41 42 43 influence of renal function, geographical area and presence of extended- 44
45 spectrum β-lactamases. Eur J Clin Microbiol Infect Dis. 2016 Mar on September 26, 2021 by guest. Protected copyright. 46 47 1;35(3):511–9. 48 49 50 34. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. 51 52 53 The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ 54 55 dysfunction/failure. On behalf of the Working Group on Sepsis-Related 56 57 Problems of the European Society of Intensive Care Medicine. Intensive Care 58 59 60 Med [Internet]. 1996 Jul [cited 2018 Mar 24];22(7):707–10. Available from:
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Page 32 1 2 3 http://www.ncbi.nlm.nih.gov/pubmed/8844239 BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 35. Harris PNA, McNamara JF, Lye DC, Davis JS, Bernard L, Cheng AC, et al. 7 8 9 Proposed primary endpoints for use in clinical trials that compare treatment 10 11 options for bloodstream infection in adults: a consensus definition. Clin 12 13 Microbiol Infect [Internet]. 2017 Aug [cited 2018 Mar 24];23(8):533–41. 14 15 16 Available from: 17 18 http://linkinghub.elsevier.com/retrieve/pii/S1198743X16305122For peer review only 19 20 21 36. Palacios-Baena ZR, Gutiérrez-Gutiérrez B, De Cueto M, Viale P, Venditti M, 22 23 Hernández-Torres A, et al. Development and validation of the INCREMENT- 24 25 26 ESBL predictive score for mortality in patients with bloodstream infections due 27 28 to extended-spectrum- β -lactamase-producing Enterobacteriaceae. J 29 30 Antimicrob Chemother [Internet]. 2017 Jan 6 [cited 2018 Mar 31 32 33 15];72(3):dkw513. Available from: 34 35 http://www.ncbi.nlm.nih.gov/pubmed/28062685 36
37 http://bmjopen.bmj.com/ 38 37. Sealed Envelope Ltd 2012. Power calculator for binary outcome non-inferiority 39 40 trial. 41 42 43 38. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard S V, et al. 44
45 on September 26, 2021 by guest. Protected copyright. 46 Design and analysis of randomized clinical trials requiring prolonged 47 48 observation of each patient. II. analysis and examples. Br J Cancer. 1977 49 50 Jan;35(1):1–39. 51 52 53 39. Haybittle JL. Repeated assessment of results in clinical trials of cancer 54 55 56 treatment. Br J Radiol. 1971 Oct;44(526):793–7. 57 58 59 40. Bellomo R, Kellum JA, Ronco C. Defining and classifying acute renal failure: 60
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Page 33 1 2 3 from advocacy to consensus and validation of the RIFLE criteria. Intensive BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Care Med [Internet]. 2007 Mar 26 [cited 2018 Mar 4];33(3):409–13. Available 7 8 from: http://link.springer.com/10.1007/s00134-006-0478-x 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44
45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 7 8 SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and 9 related documents* 10 11 Section/item Item Description 12 No 13 14 Administrative information 15 16 Done Title 1 Descriptive title identifying the study design, population, interventions, 17 and, if applicable, trial acronym 18 For peer review only 19 Done Trial 2a Trial identifier and registry name. If not yet registered, name of 20 registration intended registry 21 22 2b All items from the World Health Organization Trial Registration Data 23 24 Set 25 26 N/R Protocol 3 Date and version identifier 27 version 28 29 Done Funding 4 Sources and types of financial, material, and other support 30 31 Done Roles and 5a Names, affiliations, and roles of protocol contributors 32 responsibilities 33 5b Name and contact information for the trial sponsor 34 35 5c Role of study sponsor and funders, if any, in study design; collection, 36 management, analysis, and interpretation of data; writing of the report; 37 and the decision to submit the report for publication, including whether http://bmjopen.bmj.com/ 38 they will have ultimate authority over any of these activities 39 40 5d Composition, roles, and responsibilities of the coordinating centre, 41 42 steering committee, endpoint adjudication committee, data 43 management team, and other individuals or groups overseeing the 44 trial, if applicable (see Item 21a for data monitoring committee) 45 on September 26, 2021 by guest. Protected copyright. 46 Introduction 47 48 Done Background 6a Description of research question and justification for undertaking the 49 50 and rationale trial, including summary of relevant studies (published and 51 unpublished) examining benefits and harms for each intervention 52 53 6b Explanation for choice of comparators 54 55 Done Objectives 7 Specific objectives or hypotheses 56 57 58 59 60
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1 2 Done Trial design 8 Description of trial design including type of trial (eg, parallel group, 3 crossover, factorial, single group), allocation ratio, and framework (eg, BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 superiority, equivalence, noninferiority, exploratory) 5 6 7 8 Methods: Participants, interventions, and outcomes 9 10 Done Study 9 Description of study settings (eg, community clinic, academic hospital) 11 setting and list of countries where data will be collected. Reference to where 12 list of study sites can be obtained 13 14 Done Eligibility 10 Inclusion and exclusion criteria for participants. If applicable, eligibility 15 16 criteria criteria for study centres and individuals who will perform the 17 interventions (eg, surgeons, psychotherapists) 18 For peer review only 19 Done 11a Interventions for each group with sufficient detail to allow replication, 20 Interventions including how and when they will be administered 21 22 11b Criteria for discontinuing or modifying allocated interventions for a 23 given trial participant (eg, drug dose change in response to harms, 24 25 participant request, or improving/worsening disease) 26 27 11c Strategies to improve adherence to intervention protocols, and any 28 procedures for monitoring adherence (eg, drug tablet return, 29 laboratory tests) 30 31 11d Relevant concomitant care and interventions that are permitted or 32 prohibited during the trial 33 34 Done Outcomes 12 Primary, secondary, and other outcomes, including the specific 35 measurement variable (eg, systolic blood pressure), analysis metric 36
37 (eg, change from baseline, final value, time to event), method of http://bmjopen.bmj.com/ 38 aggregation (eg, median, proportion), and time point for each 39 outcome. Explanation of the clinical relevance of chosen efficacy and 40 harm outcomes is strongly recommended 41 42 Done Participant 13 Time schedule of enrolment, interventions (including any run-ins and 43 44 timeline washouts), assessments, and visits for participants. A schematic
45 diagram is highly recommended (see Figure) on September 26, 2021 by guest. Protected copyright. 46 47 Done Sample size 14 Estimated number of participants needed to achieve study objectives 48 and how it was determined, including clinical and statistical 49 assumptions supporting any sample size calculations 50 51 Done Recruitment 15 Strategies for achieving adequate participant enrolment to reach 52 53 target sample size 54 55 Methods: Assignment of interventions (for controlled trials) 56 Allocation: 57 58 59 60
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1 2 Done 16a Method of generating the allocation sequence (eg, computer- 3 Sequence generated random numbers), and list of any factors for stratification. BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 generation To reduce predictability of a random sequence, details of any planned 5 6 restriction (eg, blocking) should be provided in a separate document 7 that is unavailable to those who enrol participants or assign 8 interventions 9 10 Done 16b Mechanism of implementing the allocation sequence (eg, central 11 Allocation telephone; sequentially numbered, opaque, sealed envelopes), 12 13 concealment describing any steps to conceal the sequence until interventions are 14 mechanism assigned 15 16 Done 16c Who will generate the allocation sequence, who will enrol participants, 17 Implementation and who will assign participants to interventions 18 For peer review only 19 N/R Blinding 17a Who will be blinded after assignment to interventions (eg, trial 20 (masking) participants, care providers, outcome assessors, data analysts), and 21 how 22 23 17b If blinded, circumstances under which unblinding is permissible, and 24 25 procedure for revealing a participant’s allocated intervention during 26 the trial 27 28 Methods: Data collection, management, and analysis 29 30 Done Data 18a Plans for assessment and collection of outcome, baseline, and other 31 collection trial data, including any related processes to promote data quality (eg, 32 methods duplicate measurements, training of assessors) and a description of 33 34 study instruments (eg, questionnaires, laboratory tests) along with 35 their reliability and validity, if known. Reference to where data 36 collection forms can be found, if not in the protocol 37 http://bmjopen.bmj.com/ 38 18b Plans to promote participant retention and complete follow-up, 39 including list of any outcome data to be collected for participants who 40 41 discontinue or deviate from intervention protocols 42 Done Data 19 Plans for data entry, coding, security, and storage, including any 43 44 management related processes to promote data quality (eg, double data entry;
45 range checks for data values). Reference to where details of data on September 26, 2021 by guest. Protected copyright. 46 management procedures can be found, if not in the protocol 47 48 Done Statistical 20a Statistical methods for analysing primary and secondary outcomes. 49 methods Reference to where other details of the statistical analysis plan can be 50 51 found, if not in the protocol 52 53 20b Methods for any additional analyses (eg, subgroup and adjusted 54 analyses) 55 56 20c Definition of analysis population relating to protocol non-adherence 57 (eg, as randomised analysis), and any statistical methods to handle 58 missing data (eg, multiple imputation) 59 60
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1 2 Methods: Monitoring 3 BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 Done Data 21a Composition of data monitoring committee (DMC); summary of its role 5 monitoring and reporting structure; statement of whether it is independent from 6 the sponsor and competing interests; and reference to where further 7 8 details about its charter can be found, if not in the protocol. 9 Alternatively, an explanation of why a DMC is not needed 10 11 21b Description of any interim analyses and stopping guidelines, including 12 who will have access to these interim results and make the final 13 decision to terminate the trial 14 15 Done Harms 22 Plans for collecting, assessing, reporting, and managing solicited and 16 spontaneously reported adverse events and other unintended effects 17 18 Forof peer trial interventions review or trial conduct only 19 20 Done Auditing 23 Frequency and procedures for auditing trial conduct, if any, and 21 whether the process will be independent from investigators and the 22 sponsor 23 24 Ethics and dissemination 25 26 Done Research 24 Plans for seeking research ethics committee/institutional review board 27 28 ethics approval (REC/IRB) approval 29 30 N/R Protocol 25 Plans for communicating important protocol modifications (eg, 31 amendments changes to eligibility criteria, outcomes, analyses) to relevant parties 32 (eg, investigators, REC/IRBs, trial participants, trial registries, journals, 33 regulators) 34 35 Done Consent or 26a Who will obtain informed consent or assent from potential trial 36
37 assent participants or authorised surrogates, and how (see Item 32) http://bmjopen.bmj.com/ 38 26b Additional consent provisions for collection and use of participant data 39 40 and biological specimens in ancillary studies, if applicable 41 42 Done 27 How personal information about potential and enrolled participants will 43 Confidentiality be collected, shared, and maintained in order to protect confidentiality 44 before, during, and after the trial 45 on September 26, 2021 by guest. Protected copyright. 46 Done Declaration 28 Financial and other competing interests for principal investigators for 47 of interests the overall trial and each study site 48 49 Done Access to 29 Statement of who will have access to the final trial dataset, and 50 51 data disclosure of contractual agreements that limit such access for 52 investigators 53 54 N/R Ancillary and 30 Provisions, if any, for ancillary and post-trial care, and for 55 post-trial care compensation to those who suffer harm from trial participation 56 57 58 59 60
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1 2 Done 31a Plans for investigators and sponsor to communicate trial results to 3 Dissemination participants, healthcare professionals, the public, and other relevant BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 policy groups (eg, via publication, reporting in results databases, or other 5 6 data sharing arrangements), including any publication restrictions 7 8 31b Authorship eligibility guidelines and any intended use of professional 9 writers 10 11 31c Plans, if any, for granting public access to the full protocol, participant- 12 level dataset, and statistical code 13 14 Appendices 15 16 N/R Informed 32 Model consent form and other related documentation given to 17 consent materials participants and authorised surrogates 18 For peer review only 19 Done Biological 33 Plans for collection, laboratory evaluation, and storage of biological 20 21 specimens specimens for genetic or molecular analysis in the current trial and for 22 future use in ancillary studies, if applicable 23 24 *It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 25 Explanation & Elaboration for important clarification on the items. Amendments to the 26 protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT 27 Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” 28 29 license. 30 31 32 33 34 35 36
37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44
45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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PipEracillin Tazobactam versus mERoPENem for treatment of bloodstream infections caused by third generation cephalosporin-resistant Enterobacteriaceae – a study protocol for a non-inferiority open label randomized For peercontrolled review trial (PeterPen) only Journal: BMJ Open
Manuscript ID bmjopen-2020-040210.R1
Article Type: Protocol
Date Submitted by the 26-Oct-2020 Author:
Complete List of Authors: Bitterman, Roni; Rambam Health Care Campus, Division of Infectious Diseases; Technion Israel Institute of Technology Ruth and Bruce Rappaport Faculty of Medicine Koppel, Fidi; Rambam Health Care Campus, Division of Infectious Diseases Mussini, Cristina; University Hospital Modena Geffen, Yuval; Rambam Health Care Campus, Microbiology Laboratory Chowers, Michal; Meir Medical Center, Infectious Diseases Unit; Tel Aviv University Sackler Faculty of Medicine
Rahav, Galia; sheba medical center, Infectious Diseases Unit; Tel Aviv http://bmjopen.bmj.com/ university, Sackler school of medicine Nesher, Lior; Soroka Medical Center, Infectious Diseases Unit; Ben- Gurion University of the Negev Faculty of Health Sciences Ben-Ami, Ronen; Tel Aviv Sourasky Medical Center, Infectious Diseases Unit; Tel Aviv University Sackler Faculty of Medicine Turjeman, Adi; Rabin Medical Center, Internal Medicine E; Tel Aviv University Sackler Faculty of Medicine Huberman Samuel, Maayan ; Rabin Medical Center, Internal Medicine E Cheng, Matthew; McGill University, Division of Infectious Diseases, Department of Medicine on September 26, 2021 by guest. Protected copyright. Lee, Todd; McGill University, Division of Infectious Diseases, Department of Medicine Leibovici, Leonard; Rabin Medical Center, Internal Medicine E; Tel Aviv University Sackler Faculty of Medicine Yahav, Dafna; Rabin Medical Center, Infectious Diseases Unit; Tel Aviv University Sackler Faculty of Medicine Paul, Mical; Rambam Health Care Campus, Division of Infectious Diseases; Technion Israel Institute of Technology Ruth and Bruce Rappaport Faculty of Medicine
Primary Subject Infectious diseases Heading:
Secondary Subject Heading: Infectious diseases, Pharmacology and therapeutics, Research methods
Epidemiology < INFECTIOUS DISEASES, Infection control < INFECTIOUS Keywords: DISEASES, MICROBIOLOGY
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 38
1 2 3 BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 7 8 9 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined 10 in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors 11 who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance 12 with the terms applicable for US Federal Government officers or employees acting as part of their official 13 duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its 14 licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the 15 Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. 16 17 The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to 18 the Submitting Author Forunless you peer are acting as review an employee on behalf only of your employer or a postgraduate 19 student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open 20 Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and 21 intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative 22 Commons licence – details of these licences and which Creative Commons licence will apply to this Work are set 23 out in our licence referred to above. 24 25 Other than as permitted in any relevant BMJ Author’s Self Archiving Policies, I confirm this Work has not been 26 accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate 27 material already published. I confirm all authors consent to publication of this Work and authorise the granting 28 of this licence. 29 30 31 32 33 34 35 36
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45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Page 1 1 2 3 PipEracillin Tazobactam versus mERoPENem for treatment of BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 bloodstream infections caused by third generation cephalosporin- 7 8 9 resistant Enterobacteriaceae – a study protocol for a non-inferiority 10 11 12 open label randomized controlled trial (PeterPen) 13 14 15 Roni Bitterman1,2, Fidi Koppel1, Cristina Mussini3, Yuval Geffen4, Michal 16 17 Chowers5,6, Galia Rahav6,7, Lior Nesher8,9, Ronen Ben-Ami6,10Adi Turjeman6,11, 18 For peer review only 19 Maayan Huberman Samuel11, Matthew P. Cheng12, Todd C. Lee12, Leonard 20 21 22 Leibovici6,11, Dafna Yahav6,13, Mical Paul1,2 for the PeterPen study group 23 24 25 26 27 28 1. Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel 29 30 31 2. The Ruth and Bruce Rappaport Faculty of Medicine, Technion- Israel Institute 32 33 of Technology, Haifa, Israel 34 35 3. Modena University Hospital, Modena, Italy 36
37 http://bmjopen.bmj.com/ 38 4. Microbiology Laboratory, Rambam Health Care Campus, Haifa, Israel 39 40 5. Infectious Diseases Unit, Meir Medical Center, Kefar Sava, Israel 41 42 6. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 43 44
45 7. Infectious Diseases Unit, The Chaim Sheba Medical Center at Tel Hashomer, on September 26, 2021 by guest. Protected copyright. 46 47 Ramat Gan, Israel 48 49 8. Infectious Diseases Unit, Soroka Medical Center, Be'er Sheva, Israel 50 51 9. Faculty of Health Sciences, Ben-Gurion University, Be'er Sheva, Israel 52 53 54 10. Infectious Diseases Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel 55 56 11. Internal Medicine E, Rabin medical Center (Beilinson), Petah Tikva, Israel 57 58 59 60
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Page 2 1 2 3 12. Division of Infectious Diseases, Department of Medicine, McGill University, BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Montreal, Canada 7 8 13. Infectious Diseases Unit, Rabin medical Center (Beilinson), Petah Tikva, 9 10 Israel 11 12 13 14 15 16 17 18 For peer review only 19 20 21 Corresponding author: 22 23 24 Mical Paul, MD 25 26 Division of Infectious Diseases, 27 28 Rambam Health Care Campus, 29 30 31 Haifa 31096, Israel 32 33 Tel. +972-4-7772291 34 35 Fax: +972-4-7773284 36
37 http://bmjopen.bmj.com/ 38 Email: [email protected] 39 40 41 42 43 44 Word count: 3850
45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Page 3 1 2 3 Abstract BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Introduction: The optimal treatment for ESBL-producing Enterobacteriaceae 7 8 bloodstream infections has yet to be defined. Retrospective studies have shown 9 10 11 conflicting results, with most data suggesting the non-inferiority of beta-lactam beta- 12 13 lactamase inhibitor combinations compared to carbapenems. However, the recently 14 15 published MERINO trial failed to demonstrate the non-inferiority of piperacillin- 16 17 tazobactam to meropen. The potential implications of the MERINO trial are profound, 18 For peer review only 19 20 as widespread adoption of carbapenem treatment will have detrimental effects on 21 22 antimicrobial stewardship in areas endemic for ESBL and carbapenem-resistant 23 24 bacteria. Therefore, we believe that it is justified to re-examine the comparison in a 25 26 27 second randomized controlled trial prior to changing clinical practice. 28 29 Methods and analysis: PeterPen is a multicenter, investigator-initiated, open-label, 30 31 randomized controlled non-inferiority trial, comparing piperacillin-tazobactam with 32 33 34 meropenem for third generation cephalosporin-resistant Escherichia coli and 35 36 Klebsiella bloodstream infections. The study is currently being conducted in 6 centers
37 http://bmjopen.bmj.com/ 38 in Israel and 1 in Canada with other centers from Israel, Italy and Canada expected to 39 40 join. The two primary outcomes are all-cause mortality at day 30 from enrollment and 41 42 43 treatment failure at day seven (death, fever above 38°C in the last 48 hours, 44 45 continuous symptoms, increasing Sequential Organ Failure Assessment (SOFA) on September 26, 2021 by guest. Protected copyright. 46 47 score, or persistent blood cultures with the index pathogen). A sample size of 1084 48 49 50 patients was calculated for the mortality end point assuming a 12.5% mortality rate in 51 52 the control group with a 5% non-inferiority margin and assuming 100% follow-up for 53 54 this outcome. 55 56 57 58 59 60
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Page 4 1 2 3 Ethics and dissemination: The study is approved by local and national ethics BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 committees as required. Results will be published and trial data will be made 7 8 available. 9 10 11 Trial registration: ClinicalTrials.gov NCT 03671967 registered 13 September 2018; 12 13 Israeli Ministry of Health trials register MOH_2018-12-25_004857 registered 25 14 15 16 December 2018. 17 18 For peer review only 19 20 Key words: extended spectrum beta-lactamase, carbapenem, beta-lactam beta- 21 22 23 lactamase inhibitor, randomized controlled trial 24 25 26 27 Strengths and limitations of the study 28 29 The study addresses a question of critical importance to antibiotic stewardship. 30 31 32 Assuming the sample size estimates are correct, this pragmatic randomized 33 34 controlled trial will provide a more definitive answer. 35 36
37 Susceptibilities determined by automated methods may underestimate http://bmjopen.bmj.com/ 38 39 piperacillin-tazobactam resistance and resistance genes will not be available in 40 41 real-time. Hence there will be a small risk of misclassified patients. 42 43 44 Antibiotic levels will not be tested to direct dosing; however extended infusion
45 on September 26, 2021 by guest. Protected copyright. 46 regimens have been chosen to match high expected predicted target attainment 47 48 for most patients. 49 50 The study will reflect current standard of care provided to patients 51 52 53 54 55 56 57 58 59 60
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Page 5 1 2 3 Background BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Extended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae, once limited 7 8 to hospital-acquired infections, have now become prevalent in the community [1] and 9 10 11 pose a serious public health threat [2]. Mortality rates following ESBL bloodstream 12 13 infections (BSIs) are high, with 30-day mortality ranging from 17% in Escherichia 14 15 coli to 34% in Klebsiella pneumoniae ESBL BSI in a contemporary large cohort [3], 16 17 reinforcing the need for optimal treatment of these infections [4]. Carbapenems have 18 For peer review only 19 20 traditionally been considered the treatment of choice for Enterobacteriaceae 21 22 producing ESBL or AmpC due to concerns over imprecision of phenotypic 23 24 susceptibility testing and the potential of an inoculum effect [5]. However extensive 25 26 27 use of carbapenems is associated with the emergence of both carbapenemase 28 29 producing and non-carbapenemase producing carbapenem-resistant Gram negative 30 31 bacteria [2]. 32 33 34 Several retrospective observational studies compared treatment with carbapenems and 35 36
37 beta-lactam beta-lactamase inhibitors (BLBLI) for BSIs caused by ESBL-producing http://bmjopen.bmj.com/ 38 39 Enterobacteriaceae. These studies differed in the pathogens evaluated (Klebsiella spp. 40 41 vs. E. coli vs. all Enterobacteriaceae), the type and dose of BLBLI or carbapenem 42 43 44 used, the site of infection primarily assessed, whether empirical or definitive
45 on September 26, 2021 by guest. Protected copyright. 46 treatment was evaluated, and the outcome defined. Paterson et al were the first to 47 48 demonstrate significantly lower 14-day mortality with carbapenems, establishing the 49 50 51 dogma of a carbapenem advantage in ESBL K. pneumoniae BSIs more than 15 years 52 53 ago [6]. Studies published later were inconsistent regarding the apparent efficacy of 54 55 BLBLI; however, the bulk of the published observational data show no difference 56 57 between empiric or definitive treatment with BLBLIs vs. carbapenems [6–10]. The 58 59 60 MERINO trial by Harris et al was the first randomized controlled trial (RCT) to
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Page 6 1 2 3 compare piperacillin-tazobactam (PTZ) with meropenem for ESBL-producing BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Enterobacteriaceae BSI [11]. This multicenter non-inferiority trial enrolled adults with 7 8 ceftriaxone-resistant (presumed ESBL-producing) E. coli or Klebsiella spp. The trial 9 10 originally targeted a sample size of 454 patients and was terminated prematurely on 11 12 the third interim analysis since demonstration of non-inferiority by end of enrolment 13 14 15 was deemed unlikely. At termination, the overall 30-day mortality among 379 patients 16 17 included in the analysis was 7.9% (30 events), with 23/187 (12.3%) deaths in those 18 For peer review only 19 treated with PTZ vs. 7/191 (3.7%) in those treated with meropenem (risk difference 20 21 22 8.6%, 97.5% one sided confidence interval -∞ to 14.5). Thus, PTZ could not be 23 24 demonstrated to be non-inferior to meropenem. Re-calculation of the risk difference 25 26 as 2-sided 95% CI shows a significant difference between groups (risk difference 8.6 27 28 29 (3.3% to 14.5%)). Most deaths were related to underlying cancer. Phenotypic ESBL 30 31 production was confirmed in 86% of isolates (85% of E. coli and 92.5% of Klebsiella 32 33 spp.). Most patients had a urinary tract infection (UTI, 60.9%) and most BSIs were 34 35 caused by E. coli (86.5%). The risk difference (2-sided 95% CIs) among patients with 36
37 http://bmjopen.bmj.com/ 38 UTI (RD 3.7, 95% CI -2 to 10.7, N=230) was lower than the risk difference among 39 40 patients with a non-UTI source (RD 14.1, 95% CI 3.6-24.5, N=148). The risk 41 42 difference for Klebsiella spp. (RD 23.1, 95% CI 8.1-42.3, N=51) was larger than that 43 44
45 for E. coli (RD 6.3, 95% CI 0.7-12.6, N=328). on September 26, 2021 by guest. Protected copyright. 46 47 48 Rationale for replication 49 50 51 While the MERINO trial was the first RCT comparing PTZ to meropenem for ESBL 52 53 bacteremia, allowing estimation of effects without selection bias, there are several 54 55 56 reasons justifying further RCTs. The 3-fold difference in mortality between arms is 57 58 striking and such a mortality difference was never observed previously in a 59 60 randomized comparison between antibiotics. Such results warrant confirmation given
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Page 7 1 2 3 the profound practice implications. Several factors in the trial design favored non- BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 inferiority, including the recruitment of patients with mild sepsis (median Pitt score 7 8 one at randomization, with 40.7% of patients having resolved signs of infection at 9 10 randomization), relatively short duration of the intervention (median six days out of 11 12 the median 13 days of treatment for the bacteremia) and “contamination” of drug 13 14 15 exposure between the two groups, due to use of the comparator for empirical 16 17 treatment and stepdown therapy after the minimal duration of the intervention of four 18 For peer review only 19 days. Considering these, the large difference in mortality observed between groups is 20 21 22 even more surprising. 23 24 25 Several factors in the MERINO trial design are worth discussion. Primarily, the 26 27 underlying assumptions which informed the non-inferiority sample size calculation. 28 29 In MERINO, the sample size calculation assumed 14% mortality for meropenem and 30 31 32 10% mortality for PTZ with a 5% non-inferiority margin. This was not included in 33 34 the initial manuscript but later appeared as an erratum [12]. The a priori assumption 35 36 that mortality would be 4% lower for PTZ allows for a smaller total sample size but 37 http://bmjopen.bmj.com/ 38 39 does so reliant on an assumption which is not supported by the observational 40 41 evidence. Removing that assumption and assuming that PTZ mortality would also be 42 43 14% (with the same one-sided alpha 2.5%, 80% power, and 10% loss to follow-up) 44
45 on September 26, 2021 by guest. Protected copyright. 46 yields a sample size of 1683. Therefore, the MERINO trial as conducted was 47 48 terminated after recruiting 22.5% of the sample size required under a more realistic 49 50 estimate of PTZ mortality. An underpowered non-inferiority trial is at high risk of 51 52 concluding “could not demonstrate non-inferiority”. 53 54 55 56 Moreover, the interim analysis at that point (379 patients with 30 deaths), might have 57 58 occurred at a time-point allowing random overestimation of the difference [13]. A 59 60 systematic review comparing trials stopped early for benefit vs. trials that tested the
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Page 8 1 2 3 same interventions but completing recruitment showed that trials stopped early for BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 benefit exaggerate effects, especially when the number of events is small [14,15]. 7 8 Approximately half of RCTs performed subsequent to a trial being stopped for 9 10 benefit, assessing the same intervention, confirmed the terminated trial’s benefit while 11 12 the other half found no difference or significance in the opposite direction [16]. 13 14 15 16 Authors of the MERINO trial are currently investigating the reliability of VITEK and 17 18 gradient strips forFor determination peer of PTZreview resistance [17] only as well as the association 19 20 between genetic resistance mechanisms and PTZ minimal inhibitory concentrations 21 22 23 (MICs) [18,19]. The MERINO investigators assessed PTZ MICs of 321/379 isolates 24 25 by broth microdilution (BMD) in a central laboratory and found that 17.8% and 6.4% 26 27 were resistant to PTZ by EUCAST and CLSI criteria, respectively [18]. Also 28 29 blaOXA-1 genes were highly prevalent (67%) in the MERINO trial [11]. This may 30 31 32 explain the high failure rate seen with PTZ, as co-carriage of OXA-1 and CTX-M-15 33 34 (the most common ESBL gene in the MERINO trial) is associated with PTZ MICs as 35 36 high as 8-16 mcg/mL [20]. These MICs, although still susceptible, have a much 37 http://bmjopen.bmj.com/ 38 39 higher chance (up to 20%) for inadequate PTZ pharmacokinetics when using the 40 41 dosing strategies employed in MERINO [21]. 42 43 44 Other reasons for replication have been raised following the trial's publication [22]. 45 on September 26, 2021 by guest. Protected copyright. 46 These include: imbalances between treatment groups; differences between sites with 47 48 49 respect to the effect shown; the large number of deaths due to terminal cancer; and the 50 51 pharmacokinetically non-optimized administration schedule of PTZ, particularly with 52 53 respect to organisms with PTZ MICs above 2mcg/L. 54 55 56 We are therefore left with clinical equipoise regarding the treatment of ESBL 57 58 infections with carbapenems as compared to BLBLIs. Microbiological and clinical 59 60 trial data suggest a possible benefit to carbapenems. However, many centers do not
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Page 9 1 2 3 treat patients with ESBL infections routinely with a carbapenem, due to the ecological BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 impact on these and other patients. This is especially true for centers with high 7 8 endemicity of carbapenem-resistant Gram-negative bacteria and high rates of ESBL 9 10 infections. Accepting without reservation the superiority of carbapenems based on the 11 12 MERINO trial will increase their use dramatically for the treatment of all ESBL- 13 14 15 positive bacteremias, spilling by default also to empirical treatment and treatment of 16 17 non-bacteremic ESBL infections. The implication of switching to a primary 18 For peer review only 19 carbapenem strategy for ESBLs is concerning in settings where ESBLs and 20 21 22 carbapenem-resistant Gram-negative bacteria are frequent. At a time of increasing 23 24 drug-resistance on one hand and on the other a serious lack of new antibiotics under 25 26 development [23], it seems imprudent to embrace the MERINO findings without 27 28 29 further corroboration. 30 31 For these reasons, we plan a second RCT comparing PTZ to meropenem for 32 33 bacteremia caused by third-generation cephalosporin non-susceptible E. coli and 34 35 Klebsiella spp. We aim to show non-inferiority of PTZ to meropenem. This is a 36
37 http://bmjopen.bmj.com/ 38 replication trial attempting to address the findings and potential shortcomings of the 39 40 MERINO trial. Learning from the MERINO experience, we hope to also improve the 41 42 standardization of microbiological methods, baseline variable data collection, and 43 44
45 sample size issues. on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 Methods 51 52 53 Design 54 55 The study is a multicenter randomized controlled non-inferiority open-label trial. 56 57 58 Study hypothesis and aims 59 60
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Page 10 1 2 3 We aim to evaluate the effect of definitive treatment with meropenem vs. PTZ, both BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 given as extended-infusions, on the outcome of patients with bacteremia due to PTZ 7 8 susceptible, third-generation cephalosporin-non-susceptible E. coli and Klebsiella spp. 9 10 (assumed ESBL-producing Enterobacteriaceae). We aim to demonstrate that PTZ is 11 12 non-inferior to meropenem. 13 14 15 16 Setting 17 18 The study will beFor conducted peer in three countries:review in Israel only at the Rambam Health Care 19 20 Campus (RHCC), Rabin Medical Center (Beilinson Hospital), Tel-Aviv Sourasky 21 22 23 Medical Center, Soroka Medical Center, Meir Medical Center, and Sheba Medical 24 25 Center; in Italy at Modena University Hospital, and in Canada at the McGill 26 27 University Health Centre and the Jewish General Hospital. We are currently recruiting 28 29 other centers in all study countries. RHCC is the sponsor and assumes responsibility 30 31 32 for the trial. 33 34 35 Inclusion and exclusion criteria 36 37 We will include adults with community or hospital-acquired monomicrobial BSI with http://bmjopen.bmj.com/ 38 39 E. coli or Klebsiella spp. non-susceptible to third generation cephalosporins and 40 41 42 susceptible to both PTZ and meropenem. Detailed inclusion and exclusion criteria are 43 44 listed in Table 1. Patients in whom exclusion criteria arise after randomization will be 45 on September 26, 2021 by guest. Protected copyright. 46 included in the intention to treat population. 47 48 49 Inclusion will be based on antibiotic susceptibility testing performed locally (Table 2). 50 51 52 We will ask all participating laboratories to document local MICs for PTZ and 53 54 meropenem for the study patients. The index culture will be kept frozen at -70ºC for 55 56 subsequent antimicrobial susceptibility confirmation and genotypic ESBL testing in a 57 58 59 reference laboratory using optimized uniform methodology including BMD. The 60
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Page 11 1 2 3 primary analysis will be performed as randomized (based on local susceptibility BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 testing). A secondary analysis will be performed based on the reference laboratory 7 8 susceptibility test using the EUCAST and CLSI standards that will apply at the time 9 10 of analysis [24,25]. 11 12 13 Table 2: CLSI and EUCAST breakpoint definitions for susceptibility 14 15 th 16 CLSI M100-ED28: 2018. 28 EUCAST v 9 (January, 2019) 17 18 ForEdition peer [25] review [24]only 19 20 MIC Disk diffusion MIC Disk diffusion 21 22 (mg/L) (mm) (mg/L) (mm) 23 24 25 Ceftriaxone ≤1 ≥23 ≤1 ≥25 26 27 Ceftazidime ≤4 ≥21 ≤1 ≥22 28 29 PTZ ≤16 ≥21 ≤8 ≥20 30 31 32 Meropenem ≤1 ≥23 ≤2 ≥22 33 34 Imipenem ≤1 ≥23 ≤2 ≥22 35 36
37 CLSI- clinical and laboratory standards institute; EUCAST- European committee on http://bmjopen.bmj.com/ 38 39 antimicrobial susceptibility testing; MIC- minimal inhibitory concentration 40 41 42 Patient randomization 43 44 45 Patients will be randomized to PTZ or meropenem in a 1:1 ratio. Randomization will on September 26, 2021 by guest. Protected copyright. 46 47 be done by a computer-generated list of random numbers allocated centrally in 48 49 50 REDCap [26], stratified by country; infecting organism (E. coli vs. Klebsiella spp.); 51 52 source of infection (UTI vs other); and empirical antibiotics (covering antibiotics in 53 54 the first 24 hours from culture taken or non-covering). The random sequence will be 55 56 57 generated using random permuted blocks of 4 to 8. 58 59 Intervention 60
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Page 12 1 2 3 The intervention group will receive PTZ 4.5 grams q6h and the control group will BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 receive meropenem 1 gram q8h. Dose adjustments for patients with renal 7 8 insufficiency are listed in Table 3. For each treatment arm, the first dose will be 9 10 administered as a 30-minute bolus and the following doses will be administered as 11 12 three hours prolonged infusion. If patients receive PTZ or meropenem empirically 13 14 15 using other dosing regimens they will switch to the trial dosing regimen, without a 16 17 bolus infusion if the same antibiotic is continued. 18 For peer review only 19 The study drug will be administered for a minimum of four to five days to complete at 20 21 22 least seven days of antibiotic treatment. We will make a great effort to ensure that 23 24 patients will complete treatment with the assigned treatment arm. Switch to the 25 26 alternate arm antibiotic class or other antibiotics will not be permitted in the first week 27 28 29 of treatment, unless treatment fails or for secondary infections. Crossovers, if they 30 31 occur will be analyzed using appropriate statistical methods [27]. 32 33 34 In order to maximize the ability of additional centers to join, minimize the study 35 36 infrastructure required in each center, and contain study costs for this, as yet unfunded 37 http://bmjopen.bmj.com/ 38 39 international trial, we have chosen to perform this trial open label. This is also 40 41 essential as blinding a q8h drug vs. a q6h drug mathematically challenging. For the 42 43 primary endpoint of mortality, which is objective, we do not anticipate risk of 44
45 on September 26, 2021 by guest. Protected copyright. 46 detection bias. The second primary endpoint, and any subjective secondary endpoints, 47 48 will be adjudicated and analyzed by blinded members of the study team based on 49 50 discrete variables collected. 51 52 53 Pharmacokinetic / pharmacodynamic considerations 54 55 56 Dosing strategies of β-lactams for patients with sepsis is a matter of debate and 57 58 ongoing study. Nonetheless, studies on population pharmacokinetics for PTZ show 59 60 that up to 20% of patients with an isolate with an MIC of 2mcg/L treated with 4.5g
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Page 13 1 2 3 q8h by intermittent infusion will not achieve the conservative pharmacokinetic target BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 of at least 50% of the dosing interval (50% fT>MIC) [21,28]. Increasing the 7 8 frequency to q6h improves this to about 10% at 2mcg/L but this again reaches 20% at 9 10 an MIC of 8mcg/L which is still considered susceptible by both EUCAST and the 11 12 CLSI [24,25]. Another study evaluating therapeutic drug monitoring for β-lactams 13 14 15 showed that bolus administration of PTZ 4.5g q6h was insufficient in up to 49% of 16 17 patients to achieve the study's pharmacokinetic/pharmacodynamic target [29]. Taking 18 For peer review only 19 into consideration that patients may be obese [30], have augmented renal clearance 20 21 22 [31] and/or have febrile neutropenia [32] only reinforces the need for high-dose 23 24 extended-infusion of PTZ. A recently-published systematic review and meta-analysis 25 26 on continuous/prolonged vs. intermittent infusion of β-lactams has shown reduced 27 28 29 mortality with continuous/prolonged infusion [33], lending further support for an 30 31 optimized PTZ dosing schedule in future trials. Dosing for patients with continuous 32 33 renal replacement therapy by type of dialysis and flow rate; we based dosing on a 34 35 contemporary literature review [34]. 36
37 http://bmjopen.bmj.com/ 38 Prior to starting this trial, we conducted a survey among interested sites regarding 39 40 current and recommended dosing practices. Seven of 16 centers in Israel, Italy and 41 42 Canada stated they currently use either four-daily dosing of PTZ and/or extended 43 44
45 infusion. Two thirds recommended either 4.5g PTZ q6h extended infusion or on September 26, 2021 by guest. Protected copyright. 46 47 individualized dosing (using high dose extended infusion for obese, febrile 48 49 neutropenia, high MIC and severe sepsis). 50 51 52 As we believe that one of the MERINO shortcomings is the sub-optimal PTZ dosing 53 54 strategy; taking into consideration the previously mentioned pharmacokinetic studies 55 56 favoring a q6h extended infusion; and realizing that some PTZ susceptibility tests are 57 58 imprecise [17,35] and we could inadvertently include patients with higher MICs; we 59 60
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Page 14 1 2 3 chose a PTZ dosing of 4.5g q6h extended infusion. While we were intrigued by BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 individualized dosing, we believed that since this is more complicated and might not 7 8 be applied similarly across sites, the external validity of our trial might be 9 10 compromised. 11 12 13 We considered a meropenem dose of 1 gram TID sufficient, since this was the dose 14 15 16 studied in the MERINO trial for the same indications and this was the common dose 17 18 used in the studyFor centers. peer Pharmacokinetic/pharmacodynamics review only studies support this 19 20 dosing regimen, especially when using extended infusions [36] and for the organisms 21 22 23 in this study which will all be carbapenem susceptible with low MICs. We chose to 24 25 give the meropenem as extended infusion so that non-inferiority would be 26 27 demonstrated against the best-case administration of meropenem. 28 29 30 Outcome measures 31 32 33 We defined two co-primary endpoints, the first being all-cause mortality at day 30 34 35 from randomization and the second being treatment failure at day seven from 36 37 randomization. Treatment failure was defined as death, fever above 38°C in the 48 http://bmjopen.bmj.com/ 38 39 hours before the time point, symptoms attributed to the focus of infection still present, 40 41 42 Sequential Failure Organ Assessment (SOFA) score [37] increasing, or blood cultures 43 44 positive with the index pathogen by the time point assessed (Table 4). These 45 on September 26, 2021 by guest. Protected copyright. 46 outcomes were selected according to consensus recommendations for endpoints in 47 48 49 clinical trials regarding BSIs [38]. 50 51 Secondary outcomes include all-cause mortality at 14 and 90 days; treatment failure at 52 53 14 and 30 days; microbiological failure defined as positive blood cultures with index 54 55 56 pathogen at seven and 14 days; relapsed BSI at 30 and 90 days defined as recurrent 57 58 positive blood cultures with index pathogen after prior sterilization; metastatic 59 60 infections with index pathogen; secondary infections; Clostridioides difficile
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Page 15 1 2 3 associated diarrhea; hospital re-admissions; development of resistance to study drugs BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 in clinical isolates; carriage of carbapenem-resistant Enterobacteriaceae 7 8 (carbapenemase-producing and non-producing); total in-hospital days; total antibiotic 9 10 days; liver function test abnormalities; allergic reactions; renal failure and other pre- 11 12 defined adverse events. 13 14 15 16 Subgroup analyses will be performed for the primary outcome of 30-day mortality by 17 18 infecting organismFor (E. coli peer vs. Klebsiella review spp.); INCREMENT only score (< 11 vs. ≥11) 19 20 21 [39]; bacteremia source (UTI vs. non-UTI); covering empirical therapy given in the 22 23 first 24 hours; patients not receiving the comparator drug empirically; and excluding 24 25 patients with an uncontrolled focus of infection. 26 27 28 Table 4: Outcomes 29 30 Outcome Definition 31 32 33 30-day all-cause 34 35 mortality (co- 36 37 primary outcome) http://bmjopen.bmj.com/ 38 39 40 Composite of the following by day 7: 41 42 Death 43 44
Fever above 38°C in the last 48 hours on September 26, 2021 by guest. Protected copyright. 45 Treatment failure 46 47 at day 7 (co- Symptoms attributed to the focus of infection still 48 49 primary outcome) present 50 51 52 SOFA score increasing 53 54 Blood cultures positive with the index pathogen 55 56 57 58 59 60
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Page 16 1 2 3 14- and 90-day BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 all-cause 7 8 mortality 9 10 Treatment failure 11 As defined above 12 13 at 14 & 30 days 14 15 Microbiological 16 Positive blood cultures with index pathogen at days 4-7 and 17 failure at 7 & 14 18 For11-14 peer review only 19 20 days 21 22 Relapsed BSI at Positive blood cultures with index pathogen following prior 23 24 30 & 90 days sterilization at days 30 and 90 25 26 27 Metastatic focus Isolation of index pathogen from non-blood specimen related 28 29 of infection to metastatic spread of infection by day 90 30 31 Development of either clinically or microbiologically 32 33 documented infection within 90 days according to CDC 34 35 Superinfection 36 surveillance definitions of health-care associated infections for
37 http://bmjopen.bmj.com/ 38 bacterial infections 39 40 Resistant Clinical isolates resistant to PTZ and meropenem and any 41 42 43 infection carbapenem-resistant bacteria 44
45 Carriage of CPE and non-CPE CRE in-hospital till day 90, on September 26, 2021 by guest. Protected copyright. 46 Resistant 47 detected by weekly rectal surveillance of carriage while in- 48 colonization 49 50 hospital 51 52 Number of hospital re-admissions until day 90 53 Re-admissions 54 55 56 CDI Clostridioides difficile associated diarrhea till 90 days 57 58 Adverse events Abnormal liver enzymes and bilirubin 59 60
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Page 17 1 2 3 Renal failure using the RIFLE [40] criteria by day 30 BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 but we will not rely on urine output because it is not 7 8 properly or accurately documented in many non-ICU 9 10 inpatient units 11 12 13 Leukopenia, neutropenia, thrombocytopenia 14 15 Drug hypersensitivity 16 17 Diarrhea 18 For peer review only 19 20 Seizures 21 22 SOFA, Sequential Organ Failure Assessment; BSI, bloodstream infection; CDC, 23 24 Centers for Disease Control and Prevention; PTZ, piperacillin tazobactam; CPE, 25 26 27 cabapenemase-producing Enterobacteriaceae; CRE, Carbapenem-resistant 28 29 Enterobacteriaceae; CDI, Clostridioides difficile infection 30 31 32 Microbiological methods 33 34 35 All laboratories from centers participating in the study are ISO 9001 accredited 36
37 http://bmjopen.bmj.com/ 38 laboratories. Following growth in blood culture, isolates will be identified using 39 40 automated methods (Vitek 2, BD Phoenix, Vitek MS, MALDI biotyper). Antibiotic 41 42 susceptibilities will be determined according to local practices, using either automated 43 44
45 methods, disk diffusion, gradient diffusion, or a combination of these methods, and on September 26, 2021 by guest. Protected copyright. 46 47 interpreted using either CLSI or EUCAST breakpoints as per local protocols. All 48 49 isolates will be made available for future testing by a central laboratory where 50 51 antibiotic susceptibility will be determined using BMD and interpreted according to 52 53 54 EUCAST standards. Central laboratory personnel will be blinded to trial outcomes 55 56 and to local antibiotic susceptibility test results. We will also determine and 57 58 characterize the presence of ESBL and ampC genes using PCR. 59 60
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Page 18 1 2 3 Assessment and follow up BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Patients will be identified based on laboratory reports of Gram-negative bacteremia. 7 8 All patients will be followed up till day 90 post randomization in-hospital and on re- 9 10 admissions. During hospitalization patients will be visited by infectious diseases 11 12 specialists as needed. Management decisions, such as diagnostic evaluation, other 13 14 15 medical/surgical procedures and discharge from hospital will be left to the discretion 16 17 of the treating physicians. Defined adverse events will be collected from the patients' 18 For peer review only 19 charts and continuation of therapy will be similarly left of the discretion of treating 20 21 22 physicians. We will not mandate diagnostic testing further than those defined for 23 24 outcome collection and these will be done as clinically indicated. Patients will not be 25 26 asked to return for study visits after discharge. 27 28 29 Data will be collected from the study visits, laboratory reports and the electronic 30 31 32 health record. Following discharge, we will document re-admissions with outcome 33 34 events during readmissions; and survival status through the national electronic patient 35 36 files in Israel, through regional databases in Italy, and through local data and direct 37 http://bmjopen.bmj.com/ 38 39 patient contact (text/email/phone/mail) in Canada. Anonymous data will be entered 40 41 into a central case report form (CRF) designed in REDCap, a secure web application. 42 43 44 Sample size 45 on September 26, 2021 by guest. Protected copyright. 46 For the mortality endpoint we calculated a sample size of 542 patients per arm 47 48 49 assuming a 12.5% mortality rate in the control group with a 5% non-inferiority 50 51 margin and a 1-sided hypothesis with 5% α-risk and 80% power [41]. The assumed 52 53 mortality rate of 12.5% was based on rates reported in contemporary observational 54 55 56 studies (17.3%) [7–9] and the MERINO RCT (7.9%) [11]. We do not assume loss to 57 58 follow-up given complete 90 day follow-up in 719 patients with bloodstream 59 60 infections in two previous RCTs performed by our group [42,43].
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Page 19 1 2 3 The sample size calculation for the treatment failure outcome assumes a 25% failure BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 rate at seven days in the control group. To test for non-inferiority of PTZ compared to 7 8 meropenem with a 1-sided 5% α-risk, 80% power and a non-inferiority margin of 9 10 10% we will need 232 patients per study group. 11 12 13 Monitoring and trial management 14 15 16 The trial will be monitored centrally by the coordinating center at RHCC. Data entry 17 18 will be monitoredFor continuously peer on REDCap, review checking onlyfor timely data entry, missing 19 20 data or suspected faulty data. Inconsistencies and logical rules have been pre-defined 21 22 23 to allow detection of such events. We will employ a risk-based strategy, with sparse 24 25 on-site monitoring based on central inspection of the data. A steering committee has 26 27 been nominated (the PIs and selected investigators representing all countries) and the 28 29 trial will be followed by an independent safety monitoring board (two infectious 30 31 32 diseases specialists and one pharmacologist, all expert in clinical trials and external to 33 34 the study centers). 35 36 37 Statistical analysis http://bmjopen.bmj.com/ 38 39 40 We plan an interim analysis after recruitment of 250, 500 and 750 patients. The trial 41 42 43 will be stopped if an extreme difference between groups of p<0.001 will be observed 44
45 for the primary outcome of 30-day mortality. The difference was chosen based on the on September 26, 2021 by guest. Protected copyright. 46 47 MERINO trial stopping rule [11] and following the Haybittle-Peto rule [44,45] that 48 49 preserves the overall type I error rate at 0.05. The sample size of the first interim 50 51 52 analysis was selected based on the minimal sample size required to reach a difference 53 54 with p<0.001 presuming that the maximal difference between groups that we will 55 56 reach is the one observed in the MERINO trial [11]. 57 58 59 60
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Page 20 1 2 3 The primary analysis will include all randomized patients following local BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 susceptibility testing. A secondary analysis will exclude patients in whom major 7 8 errors in susceptibility compared to BMD will be detected. A per protocol analysis 9 10 will include patients fulfilling inclusion based on central lab adjudication of 11 12 susceptibilities, without exclusion criteria and receiving the allocated intervention for 13 14 15 at least four calendar days. 16 17 18 Patients' baselineFor characteristics peer will bereview displayed descriptively. only Outcome variables 19 20 will be compared using the chi-square test, Student's t-test or the Mann–Whitney U 21 22 23 test, as appropriate. Risk differences for dichotomous outcomes will be computed 24 25 with 95% confidence intervals. Non-inferiority will be fulfilled if the upper value of 26 27 the 1-sided 95% CI for the risk difference of meropenem compared to PTZ will be 28 29 equal or lower to the defined non-inferiority margin. 30 31 32 33 Ethics and dissemination 34 35 36 The ethics of recruiting patients into this study, after the MERINO trial, are embedded
37 http://bmjopen.bmj.com/ 38 in the considerations we previously raised. These concern the possibility that their 39 40 chance finding will not be observed in a larger repetition trial and some improvement 41 42 43 in the study design through obtaining a larger sample size and improving PTZ 44
45 pharmacokinetics. With these considerations, the study was approved by the ethics on September 26, 2021 by guest. Protected copyright. 46 47 committees of the above Israeli hospitals and is awaiting approval in other hospitals. 48 49 In Canada, institutional ethics approval has been granted for the Province of Quebec 50 51 52 and the study has received approval from Health Canada as required for studies 53 54 involving off-label use of approved pharmaceuticals. 55 56 Results of the study, whether completed or not, will be analyzed and made available 57 58 59 through publication. De-identified individual patient data collected during the trial 60
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Page 21 1 2 3 will be made available for an unlimited time period following publication of trial BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 results. Data will be available for researchers who provide a methodologically sound 7 8 proposal and contingent on both the researchers' and our ethics committee approval 9 10 and the signing of a data sharing agreement. 11 12 Patient and public involvement 13 14 15 We have not involved patients or the public in the trial's design and planning. We plan 16 17 to conduct a survey for bacteremia survivors and the public on the acceptability the 18 For peer review only 19 consensus endpoints defined for BSIs [38]. 20 21 22 Funding 23 24 We have not succeeded in obtaining funding for the study from the Israeli Ministry of 25 26 Health. The study received the support of ESCMID through the society's Research 27 28 29 Grant programme 2020 (30,000 Euro) which will be used for the ethics and insurance 30 31 requirements of the Italian sites and for onsite study visits. The Canadian sites are 32 33 seeking funding through the Canadian Institutes of Health Research. Should the study 34 35 receive substantial funding we plan to recruit additional hospitals who currently do 36
37 http://bmjopen.bmj.com/ 38 not have the infrastructure to recruit into clinical trials and to revise the protocol, 39 40 mainly with respect to the microbiological methods so as to enable local laboratories 41 42 to perform BMD and test for resistance genes in real time. 43 44
45 Competing interests on September 26, 2021 by guest. Protected copyright. 46 47 None declared. 48 49 Authors' contributions 50 51 52 RB, FK, CM, YG, MC, GR, LN, RBA, AT, MHS, MPC, TCL, LL, DY, MP 53 54 contributed to conception, design, trial management and planned data analysis. 55 56 RB, FK, DY and MP contributed to trial database and randomization site design. 57 58 RB and MP wrote the first draft of the manuscript. 59 60
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Page 22 1 2 3 All authors revised the protocol critically for important intellectual content and BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 approved the final manuscript. 7 8 Acknowledgements 9 10 Members of the PeterPen Trial Group: Roni Bitterman, Mical Paul, Fidi Koppel, 11 12 Yuval Geffen (Rambam Health Care Campus, Israel). Dafna Yahav, Leonard 13 14 15 Leibovici, Adi Turjeman, Maayan Huberman Samuel (Rabin Medical Center, 16 17 Beilinson Hospital, Israel). Hiba Abu-Zayyad (The Baruch Padeh (Poriya) Medical 18 For peer review only 19 Center, Israel). Bibiana Chazan (Emek Medical Center, Israel), Ronen Ben Ami 20 21 22 (Ichilov Medical Center, Israel). Lior Nesher (Soroka Medical Center, Israel). Michal 23 24 Chowers (Meir Medical Center, Israel). Regev Cohen (Laniado Hospital, Irael). Galia 25 26 Rahav (The Chaim Sheba Medical Center at Tel HaShomer, Israel). Jacob Srahilevitz 27 28 29 (Hadassah Ein Kerem Medical Center, Israel). Erica Franceschini, Cristina Mussini 30 31 (Modena University Hospital, Italy). Marco Falcone (Università di Pisa Cisanello 32 33 Hospital, Italy). Elena Carrara, Evelina Tacconelli (University of Verona Hospital, 34 35 Italy). Maddalena Giannella (S. Orsola-Malpighi Hospital University of Bologna, 36
37 http://bmjopen.bmj.com/ 38 Italy). Antonella d’Arminio Monforte (University of Milan, ASST Santi Paolo e 39 40 Carlo, Italy). Alessia Zoncada, Angelo Pan (Hospital of Cremona ASST di Cremona, 41 42 Italy). Todd C. Lee, Matthew P. Cheng (McGill University Health Centre, Canada). 43 44
45 Leighanne Parkes (Jewish general hospital of Montreal, Canada). on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Page 23 1 2 3 Table 1: Inclusion and exclusion criteria BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Inclusion criteria Exclusion criteria 7 8 9 Adults (age ≥ 18 years) More than 72 hours elapsed since 10 11 New onset BSI due to E. coli or initial blood culture taken, regardless 12 13 of the time covering antibiotics were 14 Klebsiella spp. in one or more blood 15 16 cultures associated with evidence of started 17 18 infection For peer review Polymicrobial only bacteremia defined as 19 20 either growth of two or more 21 The microorganism will have to be 22 23 non-susceptible to third generation different species of microorganisms 24 25 cephalosporins (ceftriaxone and/or in the same blood culture, or growth 26 27 ceftazidime) and susceptible to both of different species in two or more 28 29 30 PTZ and meropenem separate blood cultures within the 31 32 We will permit the inclusion of same episode of infection 33 34 bacteremias due to E. coli or Patients with prior bacteremia or 35 36
37 Klebsiella spp. with concomitant infection that have not completed http://bmjopen.bmj.com/ 38 39 growth in blood of skin commensals antimicrobial therapy for the 40 41 considered as contaminants. previous infectious episode. 42 43 44 Patients with septic shock at the time
45 on September 26, 2021 by guest. Protected copyright. 46 of enrollment and randomization, 47 48 defined as at least 2 measurements 49 50 of systolic blood pressure < 90 51 52 53 mmHg and/or use of vasopressors 54 55 (dopamine>15μg/kg/min, 56 57 adrenalin>0.1μg/kg/min, 58 59 60
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Page 24 1 2 3 noradrenalin>0.1μg/kg/min, BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 vasopressin any dose) in the 12 7 8 hours prior to randomization. In the 9 10 absence of the use of vasopressors, a 11 12 13 systolic blood pressure <90 would 14 15 need to represent a deviation for the 16 17 patient’s known normal blood 18 For peer review only 19 pressure. 20 21 22 BSI due to specific infections known 23 24 at the time of randomization: 25 26 endocarditis / endovascular 27 28 29 infections, osteomyelitis (not 30 31 resected), central nervous system 32 33 infections 34 35 36 Allergy to any of the study drugs
37 http://bmjopen.bmj.com/ 38 confirmed by history taken by the 39 40 investigator 41 42 43 Previous enrollment in this trial 44
45 Concurrent participation in another on September 26, 2021 by guest. Protected copyright. 46 47 interventional clinical trial 48 49 50 Imminent death (researcher’s 51 52 assessment of expected death within 53 54 48 hours of recruitment after 55 56 57 discussion with treating team) 58 59 60
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Page 25 1 2 3 Table 3: Dose adjustment for study antibiotics BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 A. All sites 7 8 Meropenem Piperacillin tazobactam 9 10 11 CrCl>50ml/min* 1g q8h 4.5g q6h 12 13 14 CrCl 26-50ml/min* 1g q12h 3.375g q6h (only if CCT<40) 15 16 CrCl 10-25ml/min* 0.5g q12h 2.25g q6h 17 18 For peer review only 19 CrCl<10ml/min* 0.5g q24h 2.25g q6h 20 21 Hemodialysis 0.5g q24h (+0.5g AD) 2.25g q8h (+0.75g AD) 22 23 Peritoneal dialysis 0.5g q24h 2.25g q8h 24 25 26 Continuous renal By flow rate based on recommendations in: 27 28 replacement therapy https://doi.org/10.3389/fphar.2020.00786 29 30 *CrCl should be expressed in mL/min/1.73m2, using the modification of diet in renal 31 32 disease (MDRD) formula, Cockroft and Gault equation or other means. 33 34 35 AD- after dialysis 36 37 B. In Canadian sites ** http://bmjopen.bmj.com/ 38 39 Piperacillin-tazobactam 40 41 42 CCT>40ml/min 4.5g QID 43 44 CCT 20-40ml/min 4.5g TID 45 on September 26, 2021 by guest. Protected copyright. 46 CCT 10-20ml/min 2.25g QID 47 48 49 CCT<10ml/min 2.25g QID 50 51 Hemodialysis 2.25g TID (+0.75g AD) 52 53 Peritoneal dialysis 2.25g TID 54 55 56 Continuous renal replacement therapy As above, by flow rate 57 58 59 60
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Page 26 1 2 3 ** In Canada, to conform with the existing product monograph and accounting for the BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 unavailability of the 3.375g dosage form in most hospitals the following piperacillin- 7 8 tazobactam dosing strategy will be used (as extended infusion of 3 hours). 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44
45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Page 27 1 2 3 References BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 1 Elnasasra A, Alnsasra H, Smolyakov R, et al. Ethnic diversity and increasing 7 8 9 resistance patterns of hospitalized community-acquired urinary tract infections 10 11 in Southern Israel: A prospective study. Isr Med Assoc J 2017;19. 12 13 14 2 CDC. Antibiotic resistance threats in the United States, 2013. Current 15 16 2013;:114. doi:CS239559-B 17 18 For peer review only 19 20 3 Scheuerman O, Schechner V, Carmeli Y, et al. Comparison of Predictors and 21 22 Mortality Between Bloodstream Infections Caused by ESBL-Producing 23 24 Escherichia coli and ESBL-Producing Klebsiella pneumoniae. Infect Control 25 26 Hosp Epidemiol 2018;:1–8. doi:10.1017/ice.2018.63 27 28 29 30 4 Paul M, Shani V, Muchtar E, et al. Systematic review and meta-analysis of the 31 32 efficacy of appropriate empiric antibiotic therapy for sepsis. Antimicrob. 33 34 Agents Chemother. 2010;54:4851–63. doi:10.1128/AAC.00627-10 35 36 37 5 Tam VH, Ledesma KR, Chang K-T, et al. Killing of Escherichia coli by β- http://bmjopen.bmj.com/ 38 39 40 lactams at different inocula. Diagn Microbiol Infect Dis 2009;64:166–71. 41 42 doi:10.1016/j.diagmicrobio.2009.01.018 43 44 45 6 Paterson DL, Ko W-C, Von Gottberg A, et al. Antibiotic Therapy for on September 26, 2021 by guest. Protected copyright. 46 47 Klebsiella pneumoniae Bacteremia: Implications of Production of Extended- 48 49 50 Spectrum -Lactamases. Clin Infect Dis 2004;39:31–7. doi:10.1086/420816 51 52 53 7 Rodríguez-Baño J, Navarro MD, Retamar P, et al. β-Lactam/β-lactam inhibitor 54 55 combinations for the treatment of bacteremia due to extended-spectrum β- 56 57 lactamase-producing Escherichia coli: a post hoc analysis of prospective 58 59 60 cohorts. Clin Infect Dis 2012;54:167–74. doi:10.1093/cid/cir790
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Page 28 1 2 3 8 Gutiérrez-Gutiérrez B, Pérez-Galera S, Salamanca E, et al. A Multinational, BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Preregistered Cohort Study of β-Lactam/β-Lactamase Inhibitor Combinations 7 8 for Treatment of Bloodstream Infections Due to Extended-Spectrum-β- 9 10 Lactamase-Producing Enterobacteriaceae. Antimicrob Agents Chemother 11 12 2016;60:4159–69. doi:10.1128/AAC.00365-16 13 14 15 16 9 Tamma PD, Han JH, Rock C, et al. Carbapenem therapy is associated with 17 18 improvedFor survival peer compared withreview piperacillin-tazobactam only for patients with 19 20 extended-spectrum β-lactamase bacteremia. Clin Infect Dis 2015;60:1319–25. 21 22 23 doi:10.1093/cid/civ003 24 25 26 10 Muhammed M, Flokas ME, Detsis M, et al. Comparison Between 27 28 Carbapenems and β-Lactam/β-Lactamase Inhibitors in the Treatment for 29 30 Bloodstream Infections Caused by Extended-Spectrum β-Lactamase-Producing 31 32 33 Enterobacteriaceae: A Systematic Review and Meta-Analysis. Open forum 34 35 Infect Dis 2017;4:ofx099. doi:10.1093/ofid/ofx099 36
37 http://bmjopen.bmj.com/ 38 11 Harris PNA, Tambyah PA, Lye DC, et al. Effect of Piperacillin-Tazobactam vs 39 40 Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella 41 42 43 pneumoniae Bloodstream Infection and Ceftriaxone Resistance A Randomized 44
45 Clinical Trial. JAMA 2018;320:984–94. doi:10.1001/jama.2018.12163 on September 26, 2021 by guest. Protected copyright. 46 47 48 12 Erratum. Missing Information on Sample Size. JAMA 2019;321:2370. 49 50 doi:10.1001/jama.2019.6706 51 52 53 13 Button KS, Ioannidis JPA, Mokrysz C, et al. Power failure: Why small sample 54 55 56 size undermines the reliability of neuroscience. Nat Rev Neurosci Published 57 58 Online First: 2013. doi:10.1038/nrn3475 59 60
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Page 29 1 2 3 14 Bassler D, Briel M, Montori VM, et al. Stopping randomized trials early for BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 benefit and estimation of treatment effects: systematic review and meta- 7 8 regression analysis. JAMA 2010;303:1180–7. doi:10.1001/jama.2010.310 9 10 11 15 Montori VM, Devereaux PJ, Adhikari NKJ, et al. Randomized trials stopped 12 13 early for benefit: a systematic review. JAMA 2005;294:2203–9. 14 15 16 doi:10.1001/jama.294.17.2203 17 18 For peer review only 19 16 Murad MH, Guyatt GH, Domecq JP, et al. Randomized trials addressing a 20 21 similar question are commonly published after a trial stopped early for benefit. 22 23 J Clin Epidemiol 2017;82:12–9. doi:10.1016/j.jclinepi.2016.10.006 24 25 26 17 Problems with piperacillin-tazobactam gradient tests from two manufacturers. 27 28 29 EUCAST warnings concerning antimicrobial susceptibility testing products or 30 31 procedures. http://www.eucast.org/ast_of_bacteria/warnings/ 32 33 34 18 Andrew Henderson, Paul Tambyah, David Lye, Mesut Yilmaz, Thamer 35 36
37 Alenazi, Matteo Bassetti, Elda Righi, Benjamin Rogers, Souha S. Kanj, Hasan http://bmjopen.bmj.com/ 38 39 Bhally, Jon Iredell, Marc Mendelson, David Looke, Spiros Miyakis, Genevieve 40 41 Walls, Amy Crowe, Paul Ingram, Nick Dan PG, Eugene Athan, Leah Roberts, 42 43 Scott Beatson, Michelle Bauer, Kyra Cottrell, Ernest Tan, Anton Peleg, Tiffany 44
45 on September 26, 2021 by guest. Protected copyright. 46 Harris-Brown DLPPH. Association with 30-day mortality and MIC in patients 47 48 treated with piperacillin/tazobactam for Escherichia coli and Klebsiella 49 50 pneumoniae bloodstream infections that are non-susceptible to ceftriaxone 51 52 53 from patients enrolled in the MERINO trial. In: 29th ECCMID. 2019. 54 55 56 19 Harris PNA, Tambyah P, Paterson DL. Antibiotics for Ceftriaxone Resistant 57 58 Gram-Negative Bacterial Bloodstream Infections - Reply. JAMA - J. Am. Med. 59 60
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Page 30 1 2 3 Assoc. 2019;321:613–4. doi:10.1001/jama.2018.19353 BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 20 Livermore DM, Day M, Cleary P, et al. OXA-1 beta-lactamase and non- 7 8 9 susceptibility to penicillin/beta-lactamase inhibitor combinations among ESBL- 10 11 producing Escherichia coli. J Antimicrob Chemother 2018;74:326–33. 12 13 doi:10.1093/jac/dky453 14 15 16 21 Felton TW, Hope WW, Lomaestro BM, et al. Population pharmacokinetics of 17 18 For peer review only 19 extended-infusion piperacillin-tazobactam in hospitalized patients with 20 21 nosocomial infections. Antimicrob Agents Chemother 2012;56:4087–94. 22 23 doi:10.1128/AAC.00521-12 24 25 26 22 Rodríguez-Baño J, Gutiérrez-Gutiérrez B, Kahlmeter G. Antibiotics for 27 28 29 Ceftriaxone-Resistant Gram-Negative Bacterial Bloodstream Infections. JAMA 30 31 - J. Am. Med. Assoc. 2019;321:612–3. doi:10.1001/jama.2018.19345 32 33 34 23 ANTIBACTERIAL AGENTS IN CLINICAL DEVELOPMENT. 35 36 37 24 The European Committee on Antimicrobial Susceptibility Testing. Breakpoint http://bmjopen.bmj.com/ 38 39 40 tables for interpretation of MICs and zone diameters. Version 9.0. 2019. 41 42 http://www.eucast.org. (accessed 19 Feb 2019). 43 44 45 25 CLSI 2018. Clinical and Laboratory Standards Institute. Performance standards on September 26, 2021 by guest. Protected copyright. 46 47 for antimicrobial susceptibility testing. 2018. 48 49 50 https://clsi.org/standards/products/microbiology/documents/m100/ (accessed 8 51 52 Mar 2018). 53 54 55 26 Harris PA, Taylor R, Minor BL, et al. The REDCap consortium: Building an 56 57 international community of software platform partners. J. Biomed. Inform. 58 59 60 2019;95. doi:10.1016/j.jbi.2019.103208
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Page 31 1 2 3 27 Mo Y, Lim C, Watson JA, et al. Non-adherence in non-inferiority trials: BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 Pitfalls and recommendations. BMJ 2020;370. doi:10.1136/bmj.m2215 7 8 9 28 Andersen MG, Thorsted A, Storgaard M, et al. Population Pharmacokinetics of 10 11 Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be 12 13 Considered? Antimicrob Agents Chemother 2018;62. doi:10.1128/AAC.02306- 14 15 16 17 17 18 For peer review only 19 29 Roberts JA, Ulldemolins M, Roberts MS, et al. Therapeutic drug monitoring of 20 21 β-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents 22 23 2010;36:332–9. doi:10.1016/j.ijantimicag.2010.06.008 24 25 26 30 Chung EK, Cheatham SC, Fleming MR, et al. Population pharmacokinetics 27 28 29 and pharmacodynamics of piperacillin and tazobactam administered by 30 31 prolonged infusion in obese and nonobese patients. J Clin Pharmacol 32 33 2015;55:899–908. doi:10.1002/jcph.505 34 35 36
37 31 Udy AA, Lipman J, Jarrett P, et al. Are standard doses of piperacillin sufficient http://bmjopen.bmj.com/ 38 39 for critically ill patients with augmented creatinine clearance? Crit Care 40 41 2015;19:28. doi:10.1186/s13054-015-0750-y 42 43 44 32 Sime FB, Hahn U, Warner MS, et al. Using Population Pharmacokinetic 45 on September 26, 2021 by guest. Protected copyright. 46 47 Modeling and Monte Carlo Simulations To Determine whether Standard Doses 48 49 of Piperacillin in Piperacillin-Tazobactam Regimens Are Adequate for the 50 51 Management of Febrile Neutropenia. Antimicrob Agents Chemother 2017;61. 52 53 doi:10.1128/AAC.00311-17 54 55 56 57 33 Vardakas KZ, Voulgaris GL, Maliaros A, et al. Prolonged versus short-term 58 59 intravenous infusion of antipseudomonal β-lactams for patients with sepsis: a 60
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Page 32 1 2 3 systematic review and meta-analysis of randomised trials. Lancet Infect Dis BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 2018;18:108–20. doi:10.1016/S1473-3099(17)30615-1 7 8 9 34 Li L, Li X, Xia Y, et al. Recommendation of Antimicrobial Dosing 10 11 Optimization During Continuous Renal Replacement Therapy. Front 12 13 Pharmacol 2020;11. doi:10.3389/fphar.2020.00786 14 15 16 35 Mouton JW, Muller AE, Canton R, et al. MIC-based dose adjustment: facts and 17 18 For peer review only 19 fables. J Antimicrob Chemother 2018;73:564–8. doi:10.1093/jac/dkx427 20 21 22 36 Isla A, Canut A, Arribas J, et al. Meropenem dosing requirements against 23 24 Enterobacteriaceae in critically ill patients: influence of renal function, 25 26 geographical area and presence of extended-spectrum β-lactamases. Eur J Clin 27 28 29 Microbiol Infect Dis 2016;35:511–9. doi:10.1007/s10096-015-2568-6 30 31 32 37 Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ 33 34 Failure Assessment) score to describe organ dysfunction/failure. On behalf of 35 36
37 the Working Group on Sepsis-Related Problems of the European Society of http://bmjopen.bmj.com/ 38 39 Intensive Care Medicine. Intensive Care Med 1996;22:707– 40 41 10.http://www.ncbi.nlm.nih.gov/pubmed/8844239 (accessed 24 Mar 2018). 42 43 44 38 Harris PNA, McNamara JF, Lye DC, et al. Proposed primary endpoints for use 45 on September 26, 2021 by guest. Protected copyright. 46 47 in clinical trials that compare treatment options for bloodstream infection in 48 49 adults: a consensus definition. Clin Microbiol Infect 2017;23:533–41. 50 51 doi:10.1016/j.cmi.2016.10.023 52 53 54 39 Palacios-Baena ZR, Gutiérrez-Gutiérrez B, De Cueto M, et al. Development 55 56 57 and validation of the INCREMENT-ESBL predictive score for mortality in 58 59 patients with bloodstream infections due to extended-spectrum- β -lactamase- 60
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Page 33 1 2 3 producing Enterobacteriaceae. J Antimicrob Chemother 2017;72:dkw513. BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 doi:10.1093/jac/dkw513 7 8 9 40 Bellomo R, Kellum JA, Ronco C. Defining and classifying acute renal failure: 10 11 from advocacy to consensus and validation of the RIFLE criteria. Intensive 12 13 Care Med 2007;33:409–13. doi:10.1007/s00134-006-0478-x 14 15 16 41 Sealed Envelope Ltd 2012. Power calculator for binary outcome non-inferiority 17 18 For peer review only 19 trial. 20 21 22 42 Yahav D, Franceschini E, Koppel F, et al. Seven Versus 14 Days of Antibiotic 23 24 Therapy for Uncomplicated Gram-negative Bacteremia: A Noninferiority 25 26 Randomized Controlled Trial. Clin Infect Dis 2019;69:1091–8. 27 28 29 doi:10.1093/cid/ciy1054 30 31 32 43 Cheng M, Lawandi A, Butler-Laporte G, et al. Adjunctive Daptomycin in the 33 34 Treatment of Methicillin-Susceptible Staphylococcus aureus Bacteremia: A 35 36
37 Randomized Controlled Trial. Clin Infect Dis Published Online First: 2020. http://bmjopen.bmj.com/ 38 39 doi:10.1093/cid/ciaa1000 40 41 42 44 Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical 43 44 trials requiring prolonged observation of each patient. II. analysis and 45 on September 26, 2021 by guest. Protected copyright. 46 47 examples. Br J Cancer 1977;35:1–39. 48 49 50 45 Haybittle JL. Repeated assessment of results in clinical trials of cancer 51 52 treatment. Br J Radiol 1971;44:793–7. doi:10.1259/0007-1285-44-526-793 53 54 55 56 57 58 59 60
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1 2 3 BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 5 6 7 SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and 8 9 related documents* 10 Section/item Pag Description 11 12 e 13 Administrative information 14 Title 1 PipEracillin Tazobactam versus mERoPENem for treatment of 15 bloodstream infections caused by third generation cephalosporin- 16 resistant Enterobacteriaceae – a study protocol for an open-label non- 17 18 Forinferiority peer randomized review controlled only trial (PeterPen) 19 Trial registration 4 NCT 03671967 20 21 Protocol version September 10 V1 22 23 Funding 18 The study received the support of ESCMID through the society's 24 Research Grant programme 2020 (30,000 Euro). 25 Roles and 17 Rambam Health Care Campus (RHCC) is the sponsor of the study. 26 responsibilities The principal investigators are Bitterman Roni and Paul Mical both 27 28 from RHCC. The trial is not funded. The sponsor takes responsibilities 29 for coordinating the protocol writing, design of the trial's database, 30 randomization scheme and data collection and randomization tools, 31 recruiting investigators and introducing the protocol to new sites. The 32 sponsor will perform the monitoring as specified in the protocol and 33 34 will ensure all ethics regulations are followed in the trial sites. The 35 sponsor is responsible for the trial database that will be shared with all 36 investigators and will perform the primary analyses. All investigators 37 will review the analysis and provide input. The roles and http://bmjopen.bmj.com/ 38 39 responsibilities of the data monitoring committee have been described 40 separately. 41 42 43 Introduction 44 Background and 5-9 Optimal treatment for ESBL-producing Enterobacteriaceae 45 rationale bloodstream infections has yet to be defined. Retrospective studies on September 26, 2021 by guest. Protected copyright. 46 have shown conflicting results, with the majority of data suggesting 47 48 the non-inferiority of beta-lactam beta-lactamase inhibitor 49 combinations compared to carbapenems. The recently published 50 MERINO trial reported the contrary with an apparent survival 51 advantage to meropenem over piperacillin-tazobactam. The potential 52 implications of the MERINO trial are profound, as widespread 53 54 adoption of carbapenem treatment will have detrimental effects on 55 antimicrobial stewardship in areas endemic for ESBL and 56 carbapenem-resistant bacteria. Therefore, we believe that it is 57 justified to re-examine the comparison in a second randomized 58 59 controlled trial prior to changing clinical practice forever. 60
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1 Objectives 9 Piperacillin tazobactam is non-inferior to meropenem for treatment of 2 3 third generation cephalosporin-resistant E. coli and Klebsiella BSI BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 Trial design 9 Open label non-inferiority randomized controlled trial 5 6 7 8 9 10 Methods: Participants, interventions, and outcomes 11 Study setting 10 Study is conducted at 6 hospitals in Israel, 1 hospital in Italy and 2 12 hospitals in Canada. More hospitals are joining. 13 Eligibility criteria 10- Inclusion 14 11 15 Adults (age ≥ 18 years) 16 New onset BSI due to E. coli or Klebsiella spp. in one or more 17 blood cultures associated with evidence of infection 18 For peerThe microorganism review will have only to be non-susceptible to third 19 generation cephalosporins (ceftriaxone and/or ceftazidime) and 20 21 susceptible to both PTZ and meropenem 22 Exclusion 23 More than 72 hours elapsed since initial blood culture taken, 24 regardless of the time covering antibiotics were started 25 26 Polymicrobial bacteremia 27 Patients with prior bacteremia or infection that have not completed 28 antimicrobial therapy for the previous infectious episode. 29 Patients with septic shock at the time of enrollment 30 31 BSI due to specific infections known at the time of randomization: 32 endocarditis / endovascular infections, osteomyelitis (not 33 resected), central nervous system infections 34 Allergy to any of the study drugs 35 36 Previous enrollment in this trial
37 Concurrent participation in another interventional clinical trial http://bmjopen.bmj.com/ 38 Imminent death 39 Interventions 11 The intervention group will receive PTZ 4.5 grams q6h and the control 40 41 group will receive meropenem 1 gram q8h. Dose adjustments for 42 patients with renal insufficiency are specified. The study drug will be 43 administered for a minimum of four to five days to complete at least 44 seven days of antibiotic treatment 45 on September 26, 2021 by guest. Protected copyright. 46 47 11 Research coordinators and investigators will monitor adherence to 48 study protocol 49 11 Concomitant antibiotics are prohibited during the first week of the trial, 50 51 unless secondary infections arise post-randomization an mandate 52 change. 53 Outcomes 13- We defined two co-primary endpoints, the first being all-cause 54 14 mortality at day 30 from randomization and the second being 55 treatment failure at day seven from randomization. 56 57 Secondary outcomes include all-cause mortality at 14 and 90 days; 58 treatment failure at 14 and 30 days; microbiological failure defined as 59 positive blood cultures with index pathogen at seven and 14 days; 60
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1 relapsed BSI at 30 and 90 days defined as recurrent positive blood 2 3 cultures with index pathogen after prior sterilization; metastatic BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 infections with index pathogen; secondary infections; Clostridioides 5 difficile associated diarrhea; hospital re-admissions; development of 6 resistance to study drugs in clinical isolates; carriage of carbapenem- 7 resistant Enterobacteriaceae (carbapenemase-producing and non- 8 9 producing); total in-hospital days; total antibiotic days; liver function 10 test abnormalities; allergic reactions; renal failure and other adverse 11 events. 12 The mortality outcome was chosen as this is the most relevant 13 patient-related outcome and since it is not subject to bias. Both 14 15 primary outcomes were selected based on a consensus statement of 16 endpoints for such a trial. 17 Participant Randomization has to occur within 72 hours from the time index blood 18 timeline Forculture peer was taken. review We minimized only need for mandatory tests and have 19 20 limited it to blood chemistry, CBC and blood gases obtained on 21 randomization and select time points (only as long as patient is 22 hospitalized). 23 Sample size 15- For the mortality endpoint we calculated a sample size of 542 patients 24 16 per arm assuming a 12.5% mortality rate in the control group with a 25 26 5% non-inferiority margin and a 1-sided hypothesis with 5% α-risk and 27 80% power. The assumed mortality rate of 12.5% was based on rates 28 reported in contemporary observational studies (17.3%) and the 29 MERINO RCT (7.9%). 30 31 The sample size calculation for the treatment failure outcome 32 assumes a 25% failure rate at seven days in the control group. To test 33 for non-inferiority of PTZ compared to meropenem with a 1-sided 5% 34 α-risk, 80% power and a non-inferiority margin of 10% we will need 35 232 patients per study group. 36
37 http://bmjopen.bmj.com/ 38 Recruitment Recruitment will be initiated by researchers and based on laboratory- 39 derived reports. Each center has flexibility can modify according to the 40 common practice in place. 41 42 Methods: Assignment of interventions (for controlled trials) 43 Allocation: 44 Sequence 11 Computer-generated list of random numbers 45 generation on September 26, 2021 by guest. Protected copyright. 46 47 Allocation 11 Allocated centrally through a web site 48 concealment 49 mechanism 50 Implementatio 11 Done by researches in each center 51 n 52 53 Blinding 14- There will be no blinding (except for staff at central laboratory for post- 54 (masking) 15 hoc analysis) 55 56 Methods: Data collection, management, and analysis 57 58 Data collection 15 Data will be collected from the study visits, laboratory reports and the 59 methods electronic health record. Following discharge, we will document re- 60 admission and survival status through the national electronic patient
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1 files in Israel, through regional databases in Italy, and through local 2 3 data and direct patient contact (text/email/phone/mail) in Canada. BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 All data will be collected for patients deviating from trial protocol 5 Data 15 Anonymous data will be entered into a central case report form (CRF) 6 management designed in REDCap, a secure web application. 7 8 Statistical 16- The primary analysis will include all randomized patients following 9 methods 17 local susceptibility testing. A secondary analysis will exclude patients 10 in whom major errors in susceptibility compared to BMD will be 11 detected. A per protocol analysis will include patients fulfilling 12 inclusion based on central lab adjudication of susceptibilities, without 13 14 exclusion criteria and receiving the allocated intervention for at least 15 four calendar days. 16 Patients' baseline characteristics will be displayed descriptively. 17 Outcome variables will be compared using the chi-square test, 18 ForStudent's peer t-test review or the Mann–Whitney only U test, as appropriate. Risk 19 20 differences for dichotomous outcomes will be computed with 95% 21 confidence intervals. Non-inferiority will be fulfilled if the upper value 22 of the 1-sided 95% CI for the risk difference of meropenem compared 23 to PTZ will be equal or lower to the defined non-inferiority margin. 24 25 14 Subgroup analyses will be performed for the primary outcome of 30- 26 day mortality by infecting organism (E. coli vs. Klebsiella spp.); 27 INCREMENT score (< 11 vs. ≥11); bacteremia source (UTI vs. non- 28 UTI); covering empirical therapy given in the first 24 hours; patients 29 not receiving the comparator drug empirically; and excluding patients 30 31 with an uncontrolled focus of infection. 32 33 34 Methods: Monitoring 35 36 Data monitoring 16 The trial will be monitored centrally by the coordinating center at
37 RHCC. Data entry will be monitored continuously on RedCap, http://bmjopen.bmj.com/ 38 checking for timely data entry, missing data or suspected faulty data. 39 Inconsistencies and logical rules have been pre-defined to allow 40 detection of such events. We will employ a risk-based strategy, with 41 42 sparse on-site monitoring based on central inspection of the data. 43 16 We plan an interim analysis after recruitment of 250, 500 and 750 44 patients. The trial will be stopped if an extreme difference between 45 groups of p<0.001 will be observed for the primary outcome of 30-day on September 26, 2021 by guest. Protected copyright. 46 47 mortality. The difference was chosen based on the MERINO trial 48 stopping rule and following the Haybittle-Peto rule that preserves the 49 overall type I error rate at 0.05. The sample size of the first interim 50 analysis was selected based on the minimal sample size required to 51 reach a difference with p<0.001 presuming that the maximal 52 53 difference between groups that we will reach is the one observed in 54 the MERINO trial. 55 56 Harms 16 All adverse events data will be collected into RedCap. Serious 57 58 adverse events will also be reported to local IRB. 59 Auditing 16 Monitoring will be mainly remote with minimal on-site monitoring 60
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1 2 Ethics and dissemination 3 Research ethics 17 IRB approval has been obtained in the specified centers and other BMJ Open: first published as 10.1136/bmjopen-2020-040210 on 8 February 2021. Downloaded from 4 approval centers are still seeking. 5 6 Protocol Protocol amendments will be distributed to participating sites by 7 amendments coordinating center. 8 Consent or Each center will obtain informed consent according to local 9 assent regulations 10 11 12 Confidentiality 15 All data will be shared anonymously 13 Declaration of 18 Principal investigators have no conflicts of interest 14 interests 15 Access to data The coordinating center (RHCC) will have access to the final 16 17 combined data set. 18 Ancillary and ForInsurance peer for reviewtrial participants isonly obtained according to local 19 post-trial care regulations 20 Dissemination 18 De-identified individual patient data collected during the trial will be 21 22 policy made available for an unlimited time period following publication of 23 trial results. Data will be available for researchers who provide a 24 methodologically sound proposal and contingent on both the 25 researchers' and our ethics committee approval and the signing of a 26 data sharing agreement 27 28 We do not intend to use professional writers. 29 30 31 Appendices 32 Informed consent 17 Local consent forms have been generated by each participating 33 materials center. 34 Biological 10 Blood sample for drug monitoring will be collected and stored for 35 36 specimens future analysis. The index bacteria isolate will be stored by each
37 center for further analysis. http://bmjopen.bmj.com/ 38 39 40 41 42 43 44
45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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