In vitro activity of antimicrobial combinations against multidrug-resistant Pseudomonas aeruginosa

Santos, Denissani Aparecida Ferrari dos; Nascimento, Margarida Maria Pásseri do; Vitali, Lúcia Helena; Martínez, Roberto

doi:10.1590/0037-8682-0012-2013

Cited by 22 publications

(11 citation statements)

References 23 publications

(18 reference statements)

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“…We tested combinations of Ag with different transition metals (Cu, Co, Zn, Ni and Cd) via a checkerboard assay, a widely used methodology to test synergistic effects between antimicrobial agents 38, 49–51 . The inhibitory effect of the different transition metal combinations with silver against E. coli is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Synergistic Antimicrobial Effects of Silver/Transition-metal Combinatorial Treatments

Garza-Cervantes

Chávez‐Reyes²,

Castillo

et al. 2017

Sci Rep

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Due to the emergence of multi-drug resistant strains, development of novel antibiotics has become a critical issue. One promising approach is the use of transition metals, since they exhibit rapid and significant toxicity, at low concentrations, in prokaryotic cells. Nevertheless, one main drawback of transition metals is their toxicity in eukaryotic cells. Here, we show that the barriers to use them as therapeutic agents could be mitigated by combining them with silver. We demonstrate that synergism of combinatorial treatments (Silver/transition metals, including Zn, Co, Cd, Ni, and Cu) increases up to 8-fold their antimicrobial effect, when compared to their individual effects, against E. coli and B. subtilis. We find that most combinatorial treatments exhibit synergistic antimicrobial effects at low/ non-toxic concentrations to human keratinocyte cells, blast and melanoma rat cell lines. Moreover, we show that silver/(Cu, Ni, and Zn) increase prokaryotic cell permeability at sub-inhibitory concentrations, demonstrating this to be a possible mechanism of the synergistic behavior. Together, these results suggest that these combinatorial treatments will play an important role in the future development of antimicrobial agents and treatments against infections. In specific, the cytotoxicity experiments show that the combinations have great potential in the treatment of topical infections.

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Section: Resultsmentioning

confidence: 99%

Synergistic Antimicrobial Effects of Silver/Transition-metal Combinatorial Treatments

Garza-Cervantes

Chávez‐Reyes²,

Castillo

et al. 2017

Sci Rep

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“…Using checkerboards/FICI, aminoglycosides, piperacillin-tazobactam, ceftazidime, cefepime, and ciprofloxacin were also synergistic with fosfomycin against CR P. aeruginosa strains (151). In one more study, in which the resistance profile of P. aeruginosa was not reported, synergy (using FICI) between fosfomycin and aminoglycosides was observed for 60% to 80% of tested strains, with amikacin and isepamicin demonstrating the higher synergy rates (27).…”

Section: Newer Studiesmentioning

confidence: 98%

Fosfomycin

et al. 2016

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SUMMARYThe treatment of bacterial infections suffers from two major problems: spread of multidrug-resistant (MDR) or extensively drug-resistant (XDR) pathogens and lack of development of new antibiotics active against such MDR and XDR bacteria. As a result, physicians have turned to older antibiotics, such as polymyxins, tetracyclines, and aminoglycosides. Lately, due to development of resistance to these agents, fosfomycin has gained attention, as it has remained active against both Gram-positive and Gram-negative MDR and XDR bacteria. New data of higher quality have become available, and several issues were clarified further. In this review, we summarize the available fosfomycin data regarding pharmacokinetic and pharmacodynamic properties, thein vitroactivity against susceptible and antibiotic-resistant bacteria, mechanisms of resistance and development of resistance during treatment, synergy and antagonism with other antibiotics, clinical effectiveness, and adverse events. Issues that need to be studied further are also discussed.

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“…Several in vitro SCTK and checkerboard studies have shown synergy for piperacillintobramycin against P. aeruginosa (35)(36)(37)(38)(39). A small number of dynamic HFIM and in vivo infection model studies conducted using other ␤-lactam plus aminoglycoside combinations have also demonstrated beneficial effects against P. aeruginosa (40)(41)(42)(43).…”

Section: Figmentioning

confidence: 99%

Optimization and Evaluation of Piperacillin-Tobramycin Combination Dosage Regimens against Pseudomonas aeruginosa for Patients with Altered Pharmacokinetics via the Hollow-Fiber Infection Model and Mechanism-Based Modeling

Yadav

Rogers

Bergen

et al. 2018

Antimicrob Agents Chemother

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Augmented renal clearance (ARC) in critically ill patients can result in suboptimal drug exposures and treatment failure. Combination dosage regimens accounting for ARC have never been optimized and evaluated against by use of the hollow-fiber infection model (HFIM). Using a isolate from a critically ill patient and static-concentration time-kill experiments (SCTKs), we studied clinically relevant piperacillin and tobramycin concentrations, alone and in combinations, against two inocula (10 and 10 CFU/ml) over 72 h. We subsequently evaluated the effects of optimized piperacillin (4 g every 4 h [q4h], given as 0.5-h infusions) plus tobramycin (5 mg/kg of body weight q24h, 7 mg/kg q24h, or 10 mg/kg q48h, given as 0.5-h infusions) regimens on killing and regrowth in the HFIM, simulating a creatinine clearance of 250 ml/min. Mechanism-based modeling was performed in S-ADAPT. In SCTKs, piperacillin plus tobramycin (except combinations with 8 mg/liter tobramycin and against the low inoculum) achieved synergistic killing (≥2 log versus the most active monotherapy at 48 h and 72 h) and prevented regrowth. Piperacillin monotherapy (4 g q4h) in the HFIM provided 2.4-log initial killing followed by regrowth at 24 h and resistance emergence. Tobramycin monotherapies displayed rapid initial killing (≥5 log at 13 h) followed by extensive regrowth. As predicted by mechanism-based modeling, the piperacillin plus tobramycin dosage regimens were synergistic and provided ≥5-log killing with resistance suppression over 8 days in the HFIM. Optimized piperacillin-tobramycin regimens provided significant bacterial killing and suppressed resistance emergence. These regimens appear to be highly promising for effective and early treatment, even in the near-worst-case scenario of ARC.

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In vitro activity of antimicrobial combinations against multidrug-resistant Pseudomonas aeruginosa

Cited by 22 publications

References 23 publications

Synergistic Antimicrobial Effects of Silver/Transition-metal Combinatorial Treatments

Synergistic Antimicrobial Effects of Silver/Transition-metal Combinatorial Treatments

Fosfomycin

Optimization and Evaluation of Piperacillin-Tobramycin Combination Dosage Regimens against Pseudomonas aeruginosa for Patients with Altered Pharmacokinetics via the Hollow-Fiber Infection Model and Mechanism-Based Modeling

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