Synergistic activity of fosfomycin, β-lactams and peptidoglycan recycling inhibition against Pseudomonas aeruginosa

Ceftazidime-avibactam is a combination of β-lactam/β-lactamase inhibitor, the use of which is restricted to some clinical cases, including cystic fibrosis patients infected with multidrug-resistant , in which mutation is the main driver of resistance. This study aims to predict the mechanisms of mutation-driven resistance that are selected for when is challenged with either ceftazidime or ceftazidime-avibactam. For this purpose, PA14 was submitted to experimental evolution in the absence of antibiotics and in the presence of increasing concentrations of ceftazidime or ceftazidime-avibactam for 30 consecutive days. Final populations were analyzed by whole-genome sequencing. All evolved populations reached similar levels of ceftazidime resistance. In addition, they were more susceptible to amikacin and produced pyomelanin. A first event in this evolution was the selection of large chromosomal deletions containing (involved in pyomelanin production), (involved in β-lactams resistance), and (involved in aminoglycoside resistance). Besides mutations in and that regulate β-lactamase expression, mutations related to MexAB-OprM overexpression were prevalent. Ceftazidime-avibactam challenge selected mutants in the putative efflux pump and and in a two-component system ( and ), likely regulating its expression. All populations produced pyomelanin and were more susceptible to aminoglycosides, likely due to the selection of large chromosomal deletions. Since pyomelanin-producing mutants presenting similar deletions are regularly isolated from infections, the potential aminoglycoside hypersusceptiblity and reduced β-lactam susceptibility of pyomelanin-producing should be taken into consideration for treating infections caused by these isolates.

Section: Discussionmentioning

confidence: 99%

Mutation-Driven Evolution of Pseudomonas aeruginosa in the Presence of either Ceftazidime or Ceftazidime-Avibactam

Sanz-García

Hernando-Amado

Martínez

2018

“…There are several resistance mechanisms capable of reducing the sensitivity of fosfomycin (29). Hamou-Segarra et al evaluated P. aeruginosa mutant isolates defective in several components of the peptidoglycan recycling system exposed to fosfomycin and imipenem alone or in combination and showed that the hyperproduction of AmpC significantly increased susceptibility to fosfomycin (30). Using a hollow-fiber infection model, Drusano et al evaluated the activity of meropenem and fosfomycin against P. aeruginosa at a high inoculum (8.18 log 10 CFU/ml) and demonstrated that the combination resulted in significant synergism and was also able to contain the amplification of the subpopulation of mutants resistant to both antimicrobials; the authors speculated that the different mechanisms of action of the agents and the AmpC hyperproduction, commonly expressed in the presence of carbapenems, could be responsible for these positive effects (31).…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic Attainment of the Synergism of Meropenem and Fosfomycin Combination against Pseudomonas aeruginosa Producing Metallo-β-Lactamase

Albiero

Mazucheli

Barros

et al. 2019

Fosfomycin combined with other antimicrobials has shown good efficacy against multidrug-resistant (MDR) bacteria in both in vitro and clinical studies; however, the activity of fosfomycin combined with other antimicrobials against metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa strains has not been tested. The objective of this study was to determine the synergism and optimal intravenous dosing regimens of fosfomycin with meropenem against MDR and MBL-producing P. aeruginosa strains. The MICs of both antimicrobials were determined by the checkerboard method and analyzed by two synergism tests with 19 clones of P. aeruginosa isolates, 10 of which were MBL producers. A pharmacodynamic (PD) analysis was performed for meropenem (administered at 1 g every 8 h [q8h], 1.5 g every 6 h [q6h], and 2 g q8h) and fosfomycin (administered at 4 g q8h, 4 g q6h, 6 g q8h, and 8 g q8h) regimens with a dose reduction for renal impairment by determining the probability of target attainment (PTA) for target PD indices of meropenem (the percentage of the time in a 24-h duration at which the free drug concentration remains above the MIC [fT>MIC], ≥40%) and fosfomycin (the ratio of the area under the free drug concentration-versus-time curve over 24 h and the MIC [fAUC/MIC], ≥40.8). The combination reduced the MIC50 and MIC90 by 8-fold. Seven (44%) isolates with MICs in the intermediate or resistant ranges became sensitive to meropenem. For the MBL-producing isolates, the combination resulted in 40% of isolates becoming sensitive to meropenem. The meropenem regimens reached a PTA of ≥90% (MIC = 4 μg/ml) in 6 (32%) isolates when they were used as monotherapy and 13 (68%) isolates when they were combined with fosfomycin. None of the fosfomycin monotherapy regimens reached the PTA of ≥90% (MIC = 16 μg/ml). When combined with meropenem, the fosfomycin regimens reached the PTA of ≥90% in 14 (74%) isolates. The increase in pharmacodynamic activities resulting from the synergistic action of meropenem with fosfomycin demonstrates the potential relevance of this combination to fight infections caused by MDR and MBL-producing P. aeruginosa strains.

“…␤-Lactams mainly act on a late stage in cell wall synthesis by preventing the transpeptidation of peptidoglycan. It is important to recognize that ampC overexpression results in a change in susceptibility to fosfomycin (11). Hamou-Segarra demonstrated this clearly (11), but it should be recognized this demonstration was with an isolate with inactivation of the three ampD amidases.…”

Section: Discussionmentioning

confidence: 99%

“…It is important to recognize that ampC overexpression results in a change in susceptibility to fosfomycin (11). Hamou-Segarra demonstrated this clearly (11), but it should be recognized this demonstration was with an isolate with inactivation of the three ampD amidases. Meropenem and other carbapenems are strong inducers of ampC production, and this may be another mechanism by which there is meropenem/fosfomycin synergy.…”

Section: Discussionmentioning

confidence: 99%

The Combination of Fosfomycin plus Meropenem Is Synergistic for Pseudomonas aeruginosa PAO1 in a Hollow-Fiber Infection Model

Drusano

Neely

Yamada

et al. 2018

Treating high-density bacterial infections is a challenging clinical problem. We have a paucity of new agents that can address this problem. Pseudomonas aeruginosa is a particularly difficult pathogen to treat effectively because of the plethora of resistance mechanisms it carries. Fosfomycin is an agent discovered circa 40 years ago. Recently, it has been resurrected in the United States and studied for intravenous therapy. We hypothesized that, to maximize its utility, it would require combination chemotherapy when used in a clinical circumstance in high-bacterial-burden infections. We chose to examine the combination of meropenem plus fosfomycin. These agents were studied in the hollow-fiber infection model. We utilized a fully factorial study design, looking at 2 doses of meropenem alone (1 and 2 g 8-hourly) and two doses of fosfomycin alone (6 and 8 g 8-hourly), as well as all possible combinations plus a no-treatment control. We used a high-dimensional model of 5 inhomogeneous differential equations with 5 system outputs to analyze all data simultaneously. Combination therapy outperformed all monotherapy regimens, with all combinations driving >6 log10 CFU/ml of bacterial killing. Combination therapy was able to counterselect resistance emergence (meropenem mutants being killed by the combination, as well as fosfomycin mutants being killed by the combination) in all regimens studied. The analysis demonstrated that the combination was significantly synergistic for bacterial cell killing and resistance suppression. Meropenem plus fosfomycin is a promising combination for therapy of high-burden Pseudomonas aeruginosa infections and requires further study.