Comparable Efficacy and Better Safety of Double -Lactam Combination Therapy versus -Lactam plus Aminoglycoside in Gram-Negative Bacteria in Randomized, Controlled Trials

Yuanyuan Jiao, Bartolome Moya, Mong Jen Chen, Alexandre P. Zavascki, Hsinyin Tsai, Xun Tao, Dhruvitkumar S. Sutaria, Arnold Louie, John D. Boyce, Deanna Deveson Lucas, Tae Hwan Kim, Brian T. Tsuji, Robert A. Bonomo, George L. Drusano, Jürgen B. Bulitta

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

There is a great need for efficacious therapies against Gram-negative bacteria. Double -lactam combination(s) (DBL) are relatively safe, and preclinical data are promising; however, their clinical role has not been well defined. We conducted a meta-analysis of the clinical and microbiological efficacy of DBL compared to -lactam plus aminoglycoside combinations (BLAG). PubMed, Embase, ISI Web of Knowledge, and Cochrane Controlled Trials Register database were searched through July 2018. We included randomized controlled clinical trials that compared DBL with BLAG combinations. Clinical response was used as the primary outcome and microbiological response in Gram-negative bacteria as the secondary outcome; sensitivity analyses were performed for Pseudomonas aeruginosa, Klebsiella spp., and Escherichia coli. Heterogeneity and risk of bias were assessed. Safety results were classified by systems and organs. Thirteen studies evaluated 2,771 cases for clinical response and 665 cases for microbiological response in various Gram-negative species. DBL achieved slightly, but not significantly, better clinical response (risk ratio, 1.05; 95% confidence interval [CI], 0.99 to 1.11) and microbiological response in Gram-negatives (risk ratio, 1.11; 95% CI, 0.99 to 1.25) compared with BLAG. Sensitivity analyses by pathogen showed the same trend. No significant heterogeneity across studies was found. DBL was significantly safer than BLAG regarding renal toxicity (6.6% versus 8.8%, P 0.0338) and ototoxicity (0.7 versus 3.1%, P 0.0137). Other adverse events were largely comparable. Overall, empirically designed DBL showed comparable clinical and microbiological responses across different Gram-negative species, and were significantly safer than BLAG. Therefore, DBL should be rationally optimized via the latest translational approaches, leveraging mechanistic insights and newer -lactams for future evaluation in clinical trials.

Original languageEnglish
Article numbere00425-19
Number of pages15
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number7
DOIs
Publication statusPublished - Jul 2019

Keywords

  • Beta-lactamase inhibitor
  • Combination therapy
  • Double beta-lactam
  • Gram-negative bacteria
  • Meta-analysis
  • Randomized controlled clinical trial

Cite this

Jiao, Yuanyuan ; Moya, Bartolome ; Chen, Mong Jen ; Zavascki, Alexandre P. ; Tsai, Hsinyin ; Tao, Xun ; Sutaria, Dhruvitkumar S. ; Louie, Arnold ; Boyce, John D. ; Lucas, Deanna Deveson ; Kim, Tae Hwan ; Tsuji, Brian T. ; Bonomo, Robert A. ; Drusano, George L. ; Bulitta, Jürgen B. / Comparable Efficacy and Better Safety of Double -Lactam Combination Therapy versus -Lactam plus Aminoglycoside in Gram-Negative Bacteria in Randomized, Controlled Trials. In: Antimicrobial Agents and Chemotherapy. 2019 ; Vol. 63, No. 7.
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title = "Comparable Efficacy and Better Safety of Double -Lactam Combination Therapy versus -Lactam plus Aminoglycoside in Gram-Negative Bacteria in Randomized, Controlled Trials",
abstract = "There is a great need for efficacious therapies against Gram-negative bacteria. Double -lactam combination(s) (DBL) are relatively safe, and preclinical data are promising; however, their clinical role has not been well defined. We conducted a meta-analysis of the clinical and microbiological efficacy of DBL compared to -lactam plus aminoglycoside combinations (BLAG). PubMed, Embase, ISI Web of Knowledge, and Cochrane Controlled Trials Register database were searched through July 2018. We included randomized controlled clinical trials that compared DBL with BLAG combinations. Clinical response was used as the primary outcome and microbiological response in Gram-negative bacteria as the secondary outcome; sensitivity analyses were performed for Pseudomonas aeruginosa, Klebsiella spp., and Escherichia coli. Heterogeneity and risk of bias were assessed. Safety results were classified by systems and organs. Thirteen studies evaluated 2,771 cases for clinical response and 665 cases for microbiological response in various Gram-negative species. DBL achieved slightly, but not significantly, better clinical response (risk ratio, 1.05; 95{\%} confidence interval [CI], 0.99 to 1.11) and microbiological response in Gram-negatives (risk ratio, 1.11; 95{\%} CI, 0.99 to 1.25) compared with BLAG. Sensitivity analyses by pathogen showed the same trend. No significant heterogeneity across studies was found. DBL was significantly safer than BLAG regarding renal toxicity (6.6{\%} versus 8.8{\%}, P 0.0338) and ototoxicity (0.7 versus 3.1{\%}, P 0.0137). Other adverse events were largely comparable. Overall, empirically designed DBL showed comparable clinical and microbiological responses across different Gram-negative species, and were significantly safer than BLAG. Therefore, DBL should be rationally optimized via the latest translational approaches, leveraging mechanistic insights and newer -lactams for future evaluation in clinical trials.",
keywords = "Beta-lactamase inhibitor, Combination therapy, Double beta-lactam, Gram-negative bacteria, Meta-analysis, Randomized controlled clinical trial",
author = "Yuanyuan Jiao and Bartolome Moya and Chen, {Mong Jen} and Zavascki, {Alexandre P.} and Hsinyin Tsai and Xun Tao and Sutaria, {Dhruvitkumar S.} and Arnold Louie and Boyce, {John D.} and Lucas, {Deanna Deveson} and Kim, {Tae Hwan} and Tsuji, {Brian T.} and Bonomo, {Robert A.} and Drusano, {George L.} and Bulitta, {J{\"u}rgen B.}",
year = "2019",
month = "7",
doi = "10.1128/AAC.00425-19",
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publisher = "American Society for Microbiology",
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Jiao, Y, Moya, B, Chen, MJ, Zavascki, AP, Tsai, H, Tao, X, Sutaria, DS, Louie, A, Boyce, JD, Lucas, DD, Kim, TH, Tsuji, BT, Bonomo, RA, Drusano, GL & Bulitta, JB 2019, 'Comparable Efficacy and Better Safety of Double -Lactam Combination Therapy versus -Lactam plus Aminoglycoside in Gram-Negative Bacteria in Randomized, Controlled Trials', Antimicrobial Agents and Chemotherapy, vol. 63, no. 7, e00425-19. https://doi.org/10.1128/AAC.00425-19

Comparable Efficacy and Better Safety of Double -Lactam Combination Therapy versus -Lactam plus Aminoglycoside in Gram-Negative Bacteria in Randomized, Controlled Trials. / Jiao, Yuanyuan; Moya, Bartolome; Chen, Mong Jen; Zavascki, Alexandre P.; Tsai, Hsinyin; Tao, Xun; Sutaria, Dhruvitkumar S.; Louie, Arnold; Boyce, John D.; Lucas, Deanna Deveson; Kim, Tae Hwan; Tsuji, Brian T.; Bonomo, Robert A.; Drusano, George L.; Bulitta, Jürgen B.

In: Antimicrobial Agents and Chemotherapy, Vol. 63, No. 7, e00425-19, 07.2019.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Jiao, Yuanyuan

AU - Moya, Bartolome

AU - Chen, Mong Jen

AU - Zavascki, Alexandre P.

AU - Tsai, Hsinyin

AU - Tao, Xun

AU - Sutaria, Dhruvitkumar S.

AU - Louie, Arnold

AU - Boyce, John D.

AU - Lucas, Deanna Deveson

AU - Kim, Tae Hwan

AU - Tsuji, Brian T.

AU - Bonomo, Robert A.

AU - Drusano, George L.

AU - Bulitta, Jürgen B.

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N2 - There is a great need for efficacious therapies against Gram-negative bacteria. Double -lactam combination(s) (DBL) are relatively safe, and preclinical data are promising; however, their clinical role has not been well defined. We conducted a meta-analysis of the clinical and microbiological efficacy of DBL compared to -lactam plus aminoglycoside combinations (BLAG). PubMed, Embase, ISI Web of Knowledge, and Cochrane Controlled Trials Register database were searched through July 2018. We included randomized controlled clinical trials that compared DBL with BLAG combinations. Clinical response was used as the primary outcome and microbiological response in Gram-negative bacteria as the secondary outcome; sensitivity analyses were performed for Pseudomonas aeruginosa, Klebsiella spp., and Escherichia coli. Heterogeneity and risk of bias were assessed. Safety results were classified by systems and organs. Thirteen studies evaluated 2,771 cases for clinical response and 665 cases for microbiological response in various Gram-negative species. DBL achieved slightly, but not significantly, better clinical response (risk ratio, 1.05; 95% confidence interval [CI], 0.99 to 1.11) and microbiological response in Gram-negatives (risk ratio, 1.11; 95% CI, 0.99 to 1.25) compared with BLAG. Sensitivity analyses by pathogen showed the same trend. No significant heterogeneity across studies was found. DBL was significantly safer than BLAG regarding renal toxicity (6.6% versus 8.8%, P 0.0338) and ototoxicity (0.7 versus 3.1%, P 0.0137). Other adverse events were largely comparable. Overall, empirically designed DBL showed comparable clinical and microbiological responses across different Gram-negative species, and were significantly safer than BLAG. Therefore, DBL should be rationally optimized via the latest translational approaches, leveraging mechanistic insights and newer -lactams for future evaluation in clinical trials.

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KW - Combination therapy

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KW - Gram-negative bacteria

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