Comparable Efficacy and Better Safety of Double β-Lactam Combination Therapy versus β‑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 metaanalysis 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 ϭ 0.0338) and ototoxicity (0.7 versus 3.1%, P ϭ 0.0137). Other adverse events were largely comparable. Overall, empirically designed DBL showed comparable clinical and microbiological responses across different Gramnegative 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.

Synergistic Efficacy of β-Lactam Combinations against Mycobacterium abscessus Pulmonary Infection in Mice

“…Dual ␤-lactam therapies are often avoided in clinical practice due to concern for potential toxicity. However, a recent meta-analysis of 13 randomized controlled trials assessed the efficacy and safety profiles of dual ␤-lactams compared to ␤-lactam plus aminoglycoside combinations against Gram-negative infections (80). This study found that dual ␤-lactams achieved slightly better clinical and microbiological responses, while conferring significant decreases in nephrotoxicity and ototoxicity compared to aminoglycoside-containing regimens, with the rates of other adverse events being largely comparable.…”

Novel Cassette Assay To Quantify the Outer Membrane Permeability of Five β-Lactams Simultaneously in Carbapenem-ResistantKlebsiella pneumoniaeandEnterobacter cloacae

“…This allowed us to employ the LC-MS/MS assay in cassette and discrete modes and to demonstrate a lack of influx-related drug-drug interactions for the five ␤-lactams. Therefore, this assay enables characterization of the rate of OM permeability of double ␤-lactam combinations (12). The ranking of OM permeability coefficients matched between the discrete and cassette assay, and the results were comparable ( Table 1).…”

“…Double ␤-lactam combination therapy has shown promising efficacy in early clinical trials for patients with infections by susceptible Klebsiella spp. (12,34,35); this topic has received increasing attention. When each ␤-lactam inactivates its highest affinity PBP target, double ␤-lactam combination therapy offers the potential to inactivate an optimal set of PBPs.…”

“…The relative rates of these processes determine the target site concentration of ␤-lactams and ultimately the extent of inactivation of the PBPs (i.e., transpeptidases) in the periplasm. Simultaneous combinations of two ␤-lactams (i.e., double ␤-lactam therapy) have been evaluated with promising results in large clinical trials in the 1970s and 1980s (12). For such combinations, it is important to assess that both of the ␤-lactams can efficiently penetrate through OM porin(s) at the same time.…”

Double-carbapenem therapy in the treatment of multidrug resistant Gram-negative bacterial infections: a systematic review and meta-analysis

“…Novel beta-lactam/beta-lactamase inhibitors (such as ceftazidime/avibactam) may be available treatment options, while poor use and rapid emergence of resistance restrict their application [16,17]. With less effective monotherapy and increasing resistance, evidence of retrospective studies on combination therapy of Gramnegative bacterial infections is increasing [18][19][20]. Many combination therapies have shown better survival and mortality reduction compared with monotherapy regimens, especially patients with a high predicted mortality [21][22][23].…”