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MADRID – A study designed to test the benefit of piperacillin-tazobactam in cephalosporin-resistant bloodstream infections has showed just the opposite: The combination can be fatal for these patients, conferring a threefold increased risk of death compared with meropenem.
The piperacillin-tazobactam combination (PTZ) was associated with a significantly higher 30-day mortality than that of meropenem (12.3% vs. 3.7%; RR 3.4), Patrick Harris, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
The number needed to harm with PTZ treatment was 12, said Dr. Harris of the University of Queensland, Australia.
“This was really not the result we wanted. We were expecting to show noninferiority, but the answer we did get was quite compelling. We have to say that in patients with these kinds of bloodstream infections, the use of piperacillin-tazobactam is definitely not supported.”
The signal came on strongly and quickly in the 32-country MERINO trial, he said. An independent data safety monitoring board stopped the study at 75% recruitment after reviewing the alarming interim results last summer.
The trial was designed to test a seemingly sound hypothesis. PTZ is an effective weapon against increasingly extended spectrum beta-lactamase–producing (ESBL) Escherichia coli and Klebsiella infections. These have long been treated with carbapenems, including meropenem, but the widespread global use of that class is putting heavy environmental pressure on these bacteria and creating carbapenem resistance, Dr. Harris said.
“Carbapenems have for many years been the top therapy for these infections, but it may well be a strong selection driver for carbapenem resistance in Gram negative bacilli. We should be thinking about carbapenem-sparing therapy, and it seemed that piperacillin-tazobactam could be useful here.”
Some observational studies do suggest a use for it in this setting but the combination had never been formally investigated. MERINO was designed to do so; investigators hoped to show that PTZ would be noninferior to meropenem in patients with septicemias caused by ESBL E. coli and K. pneumoniae.
The enrollment target for MERINO was 454 patients. Between 2014 and 2017, the study enrolled 391, of whom 379 were included in the final analysis. Patients had to start treatment with the study drugs within 72 hours of confirmatory blood culture. Both arms underwent 4 days of treatment with either PTZ 4.5 g every 6 hours or meropenem 1 g every 8 hours.
The study’s primary outcome was 30-day all-cause mortality. Secondary outcomes were days to clinical and microbiological resolution, clinical and microbiological success at day 4, relapsing septicemia or secondary infection with a PTZ- or meropenem-resistant organism, or Clostridium difficile infection.
The mean age of the patients was 66 years. Most (86%) were infected with resistant strains of E. coli; the rest had K. pneumoniae. About 60% of the infections were acquired in a health care or hospital setting, and about 50% originated in the urinary tract. APACHE II scores were different between the meropenem and PTZ groups (21 vs. 17.9). More patients in PTZ arm had immune compromise (27% vs. 21%).
By 30 days, 23 of those randomized to the combination therapy (12.3%) and seven (3.7%) of those randomized to meropenem had died – a significant 8.6% difference. This translated to more than a threefold increase in the risk of death for those taking the combination (RR 3.4; P = .002). The number needed to harm was just 12.
All of the secondary endpoints also favored meropenem, although the differences were not statistically significant. Patients taking meropenem experienced clinical and microbiological improvement a mean of 1 day sooner (2 vs. 3 days). Microbiological relapse occurred in 2% of those taking meropenem compared with 4.8% of those taking PTZ. The meropenem group was also less likely to develop a multidrug resistant organism or C. difficile infection (4.2% vs. 8%).
The investigators performed several subgroup analyses looking for other trends in 30-day mortality. The difference remained significant no matter how the groups were analyzed.
“Patients with urinary tract infections had a slightly lower risk of mortality, but even after adjusting for risk in several multivariate regression models, the increased risk of 30-day mortality remained,” Dr. Harris said.
The Australasian Society for Antimicrobials and the International Society for Chemotherapy funded the work. Dr. Harris reported having no financial declarations.
MADRID – A study designed to test the benefit of piperacillin-tazobactam in cephalosporin-resistant bloodstream infections has showed just the opposite: The combination can be fatal for these patients, conferring a threefold increased risk of death compared with meropenem.
The piperacillin-tazobactam combination (PTZ) was associated with a significantly higher 30-day mortality than that of meropenem (12.3% vs. 3.7%; RR 3.4), Patrick Harris, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
The number needed to harm with PTZ treatment was 12, said Dr. Harris of the University of Queensland, Australia.
“This was really not the result we wanted. We were expecting to show noninferiority, but the answer we did get was quite compelling. We have to say that in patients with these kinds of bloodstream infections, the use of piperacillin-tazobactam is definitely not supported.”
The signal came on strongly and quickly in the 32-country MERINO trial, he said. An independent data safety monitoring board stopped the study at 75% recruitment after reviewing the alarming interim results last summer.
The trial was designed to test a seemingly sound hypothesis. PTZ is an effective weapon against increasingly extended spectrum beta-lactamase–producing (ESBL) Escherichia coli and Klebsiella infections. These have long been treated with carbapenems, including meropenem, but the widespread global use of that class is putting heavy environmental pressure on these bacteria and creating carbapenem resistance, Dr. Harris said.
“Carbapenems have for many years been the top therapy for these infections, but it may well be a strong selection driver for carbapenem resistance in Gram negative bacilli. We should be thinking about carbapenem-sparing therapy, and it seemed that piperacillin-tazobactam could be useful here.”
Some observational studies do suggest a use for it in this setting but the combination had never been formally investigated. MERINO was designed to do so; investigators hoped to show that PTZ would be noninferior to meropenem in patients with septicemias caused by ESBL E. coli and K. pneumoniae.
The enrollment target for MERINO was 454 patients. Between 2014 and 2017, the study enrolled 391, of whom 379 were included in the final analysis. Patients had to start treatment with the study drugs within 72 hours of confirmatory blood culture. Both arms underwent 4 days of treatment with either PTZ 4.5 g every 6 hours or meropenem 1 g every 8 hours.
The study’s primary outcome was 30-day all-cause mortality. Secondary outcomes were days to clinical and microbiological resolution, clinical and microbiological success at day 4, relapsing septicemia or secondary infection with a PTZ- or meropenem-resistant organism, or Clostridium difficile infection.
The mean age of the patients was 66 years. Most (86%) were infected with resistant strains of E. coli; the rest had K. pneumoniae. About 60% of the infections were acquired in a health care or hospital setting, and about 50% originated in the urinary tract. APACHE II scores were different between the meropenem and PTZ groups (21 vs. 17.9). More patients in PTZ arm had immune compromise (27% vs. 21%).
By 30 days, 23 of those randomized to the combination therapy (12.3%) and seven (3.7%) of those randomized to meropenem had died – a significant 8.6% difference. This translated to more than a threefold increase in the risk of death for those taking the combination (RR 3.4; P = .002). The number needed to harm was just 12.
All of the secondary endpoints also favored meropenem, although the differences were not statistically significant. Patients taking meropenem experienced clinical and microbiological improvement a mean of 1 day sooner (2 vs. 3 days). Microbiological relapse occurred in 2% of those taking meropenem compared with 4.8% of those taking PTZ. The meropenem group was also less likely to develop a multidrug resistant organism or C. difficile infection (4.2% vs. 8%).
The investigators performed several subgroup analyses looking for other trends in 30-day mortality. The difference remained significant no matter how the groups were analyzed.
“Patients with urinary tract infections had a slightly lower risk of mortality, but even after adjusting for risk in several multivariate regression models, the increased risk of 30-day mortality remained,” Dr. Harris said.
The Australasian Society for Antimicrobials and the International Society for Chemotherapy funded the work. Dr. Harris reported having no financial declarations.
MADRID – A study designed to test the benefit of piperacillin-tazobactam in cephalosporin-resistant bloodstream infections has showed just the opposite: The combination can be fatal for these patients, conferring a threefold increased risk of death compared with meropenem.
The piperacillin-tazobactam combination (PTZ) was associated with a significantly higher 30-day mortality than that of meropenem (12.3% vs. 3.7%; RR 3.4), Patrick Harris, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
The number needed to harm with PTZ treatment was 12, said Dr. Harris of the University of Queensland, Australia.
“This was really not the result we wanted. We were expecting to show noninferiority, but the answer we did get was quite compelling. We have to say that in patients with these kinds of bloodstream infections, the use of piperacillin-tazobactam is definitely not supported.”
The signal came on strongly and quickly in the 32-country MERINO trial, he said. An independent data safety monitoring board stopped the study at 75% recruitment after reviewing the alarming interim results last summer.
The trial was designed to test a seemingly sound hypothesis. PTZ is an effective weapon against increasingly extended spectrum beta-lactamase–producing (ESBL) Escherichia coli and Klebsiella infections. These have long been treated with carbapenems, including meropenem, but the widespread global use of that class is putting heavy environmental pressure on these bacteria and creating carbapenem resistance, Dr. Harris said.
“Carbapenems have for many years been the top therapy for these infections, but it may well be a strong selection driver for carbapenem resistance in Gram negative bacilli. We should be thinking about carbapenem-sparing therapy, and it seemed that piperacillin-tazobactam could be useful here.”
Some observational studies do suggest a use for it in this setting but the combination had never been formally investigated. MERINO was designed to do so; investigators hoped to show that PTZ would be noninferior to meropenem in patients with septicemias caused by ESBL E. coli and K. pneumoniae.
The enrollment target for MERINO was 454 patients. Between 2014 and 2017, the study enrolled 391, of whom 379 were included in the final analysis. Patients had to start treatment with the study drugs within 72 hours of confirmatory blood culture. Both arms underwent 4 days of treatment with either PTZ 4.5 g every 6 hours or meropenem 1 g every 8 hours.
The study’s primary outcome was 30-day all-cause mortality. Secondary outcomes were days to clinical and microbiological resolution, clinical and microbiological success at day 4, relapsing septicemia or secondary infection with a PTZ- or meropenem-resistant organism, or Clostridium difficile infection.
The mean age of the patients was 66 years. Most (86%) were infected with resistant strains of E. coli; the rest had K. pneumoniae. About 60% of the infections were acquired in a health care or hospital setting, and about 50% originated in the urinary tract. APACHE II scores were different between the meropenem and PTZ groups (21 vs. 17.9). More patients in PTZ arm had immune compromise (27% vs. 21%).
By 30 days, 23 of those randomized to the combination therapy (12.3%) and seven (3.7%) of those randomized to meropenem had died – a significant 8.6% difference. This translated to more than a threefold increase in the risk of death for those taking the combination (RR 3.4; P = .002). The number needed to harm was just 12.
All of the secondary endpoints also favored meropenem, although the differences were not statistically significant. Patients taking meropenem experienced clinical and microbiological improvement a mean of 1 day sooner (2 vs. 3 days). Microbiological relapse occurred in 2% of those taking meropenem compared with 4.8% of those taking PTZ. The meropenem group was also less likely to develop a multidrug resistant organism or C. difficile infection (4.2% vs. 8%).
The investigators performed several subgroup analyses looking for other trends in 30-day mortality. The difference remained significant no matter how the groups were analyzed.
“Patients with urinary tract infections had a slightly lower risk of mortality, but even after adjusting for risk in several multivariate regression models, the increased risk of 30-day mortality remained,” Dr. Harris said.
The Australasian Society for Antimicrobials and the International Society for Chemotherapy funded the work. Dr. Harris reported having no financial declarations.
REPORTING FROM ECCMID 2018
Key clinical point: PTZ more than tripled the risk of 30-day mortality in patients with cephalosporin-resistant bloodstream infections.
Major finding: Compared with meropenem, PZT increased the risk of death by 3.4, with a number needed to harm of 12.
Study details: The study randomized 391 patients.
Disclosures: The Australasian Society for Antimicrobials and the International Society for Chemotherapy funded the work. Dr. Harris has no financial declarations.
Source: Harris et al. ECCMID 2018, abstract O1121.