Overview of Synergy with Reference to Double Beta-Lactam Combinations

Abstract

Combination antimicrobial therapy is used to expand the bacterial coverage over a single agent, to prevent the emergence of resistant organisms, to decrease toxicity by allowing lower doses of both agents, or for synergy. Synergy is one of the most common of these reasons, especially in serious infections. The introduction of new broad-spectrum beta-lactam antimicrobials has led to their combination in the treatment of seriously ill patients. Whereas a combination of an aminoglycoside and a beta-lactam antimicrobial is frequently synergistic, much less is known about synergy between combinations of beta-lactams. In vitro testing shows most combinations of two beta-lactams to be indifferent or additive in their effects; rarely does synergy occur. Antagonism can sometimes be seen, particularly with combinations involving cefoxitin or imipenem, especially if the treated organism is Enterobacter or Pseudomonas. Results of clinical trials comparing double beta-lactam (DBL) therapy with aminoglycoside/beta-lactam combinations show no difference in clinical response rates. Highly active DBL combinations may substitute for standard aminoglycoside-containing regimens in certain situations, even though they are not reliably synergistic. However, in the treatment of seriously ill patients such combinations may be less desirable.

Dual beta-lactam therapy for serious Gram-negative infections: is it time to revisit?

“…Yet, to date, there has been little investigation into the exact mechanism of enhanced killing/synergy with dual beta-lactam combinations. One theory has proposed that combination beta-lactam therapy results in enhanced inhibition of the diverse penicillin-binding proteins (PBPs) found among Gram-negative pathogens (Gutmann et al, 1986;Hopefl, 1991;Moellering, 1979). Although there has been little evidence to support this claim, the current collection of in vitro and in vivo findings coupled with PBP data supports this as a plausible mechanism.…”

Use of in Vitro Critical Inhibitory Concentration, a Novel Approach to Predict in Vivo Synergistic Bactericidal Effect of Combined Amikacin and Piperacillin Against Pseudomonas aeruginosa in a Systemic Rat Infection Model

“…This mechanism of synergy is believed to result from the cellular uptake of the aminoglycoside by disruption of cell wall by the other antimicrobial. b-Lactam antibiotics have been shown to exert an effect on the permeability of the outer membrane of gram-negative bacteria (17,28). This increases the number of b-lactam molecules penetrating the periplasmic space, allowing greater saturation of their preferred PBPs and synergy.…”

“…Ratios of the concentrations required to produce a rapid rate of killing (1000-fold decrease over 5 h) were used in this study, as the rate of killing may be important in clinical situations (17). These ratios were chosen to determine if the killing effects and synergy are dependent not only on the concentrations of the antibiotics but also on the ratio in which these antibiotics are used and to observe the pattern of killing over a range of these ratios.…”

“…There have been varied reports on the killing effects of this combination. Whereas this combination has been shown to have in vitro synergy against some strains of bacteria, they have also shown additivity, indifference, or even antagonism against other strains of the same bacteria (17). These studies have also shown bacterial killing to be dependent on the concentration of the antibiotics used in the combination.…”

Toxicity of β-Lactam Antibiotics: Pathophysiology, Molecular Biology and Possible Recovery Strategies

“…This strategy has been able to increase the eiciency of the β-lactam antibiotics [91][92][93][94]. But clinicians should be aware that, because of a possibility of unexpected adverse efects, dialysis facilities should be available [95].…”