When Does 2 Plus 2 Equal 5? A Review of Antimicrobial Synergy Testing

Doern, Christopher D.

doi:10.1128/jcm.01121-14

Cited by 328 publications

(306 citation statements)

References 24 publications

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“…This discrepancy has been documented by different investigators. 38,39) The lack of correlation between the checkerboard and killing-curve methods is also observed in this study. Nevertheless, the checkerboard method was used with the aim of selecting adequate concentrations to be assayed by time-kill studies.…”

Section: Resultssupporting

confidence: 51%

“…Furthermore, comparison of results between them is not possible due to variations in techniques and the criteria to classify the interactions. 6,37,38) It should be noted that the checkerboard method assesses bacteriostatic activity only, while time-kill studies test both bacteriostatic and bactericidal activities. This discrepancy has been documented by different investigators.…”

Section: Resultsmentioning

confidence: 99%

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Cooperative Behavior of Fluoroquinolone Combinations against Escherichia coli and Staphylococcus aureus

Vitorino

Becerra

Barrera

et al. 2017

Biological & Pharmaceutical Bulletin

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The effects of different combinations of ciprofloxacin (CIP) and norfloxacin (NOR) against Escherichia coli and Staphylococcus aureus were studied using checkerboard, fractional inhibitory concentration (FIC) and time-kill analysis methods. Results obtained by the checkerboard method showed that the more effectives combinations against Escherichia coli were 0.0009 µg/mL CIP 0.0312 µg/mL NOR and 0.0037 µg/mL CIP 0.0075 µg/mL NOR with a FIC index of 0.62. For Staphylococcus aureus, the combination of 0.0625 µg/mL CIP 0.2500 µg/mL NOR showed a synergistic effect, with a FIC index of 0.50. The results of the time-kill method demonstrated either indifference or additivity of the combinations 0.0009 µg/mL CIP 0.0312 µg/mL NOR, 0.0018 µg/mL CIP 0.0312 µg/mL NOR, 0.0037 µg/mL CIP 0.0075 µg/mL NOR and 0.0037 µg/mL CIP 0.0156 µg/mL NOR at 24 h against E. coli. The combination 0.0037 µg/mL CIP 0.0312 µg/mL NOR showed synergistic activity. All the analyzed combinations evidenced bactericidal effects at 4 h. The combinations 0.0625 µg/mL CIP 0.2500 µg/mL NOR and 0.0625 µg/mL CIP 0.0625 µg/mL NOR showed indifference or additivity against S. aureus. None of them generated bactericidal effect at 4 h. Moreover, this last equimolecular combination (equivalent to 1/4 minimum inhibitory concentration (MIC) CIP 1/16 MIC NOR) generated higher reduction of nitro blue tetrazolium than drugs alone. By another way, combinations not equimolecular of CIP and NOR assayed, generated less levels of reactive oxygen species (ROS) than the components alone.

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Section: Resultssupporting

confidence: 51%

Section: Resultsmentioning

confidence: 99%

Cooperative Behavior of Fluoroquinolone Combinations against Escherichia coli and Staphylococcus aureus

Vitorino

Becerra

Barrera

et al. 2017

Biological & Pharmaceutical Bulletin

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“…The combination also promoted sustained bacterial killing when assessed using a time-kill methodology. Due to the degree of heterogeneity in methodology and the interpretation of in vitro synergy studies, there is still debate about the relevance of these data to clinical practice (27). This applies also to our findings, although it should be noted that, when using SBPI as a marker for useful synergy, values many magnitudes above the theoretical pharmacodynamic breakpoint were observed.…”

Section: Discussionmentioning

confidence: 53%

Colistin and Fusidic Acid, a Novel Potent Synergistic Combination for Treatment of Multidrug-Resistant Acinetobacter baumannii Infections

Phee

Betts

Bharathan

et al. 2015

Antimicrob Agents Chemother

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bThe spread of multidrug-resistant Acinetobacter baumannii (MDRAB) has led to the renaissance of colistin (COL), often the only agent to which MDRAB remains susceptible. Effective therapy with COL is beset with problems due to unpredictable pharmacokinetics, toxicity, and the rapid selection of resistance. Here, we describe a potent synergistic interaction when COL was combined with fusidic acid (FD) against A. baumannii. Synergy in vitro was assessed against 11 MDRAB isolates using disc diffusion, checkerboard methodology (fractional inhibitory concentration index [FICI] of < 0.5, susceptibility breakpoint index [SBPI] of >2), and time-kill methodology (>2 log 10 CFU/ml reduction). The ability of FD to limit the emergence of COL resistance was assessed in the presence and absence of each drug alone and in combination. Synergy was demonstrated against all strains, with an average FICI and SBPI of 0.064 and 78.85, respectively. In time-kill assays, COL-FD was synergistic and rapidly bactericidal, including against COL-resistant strains. Fusidic acid prevented the emergence of COL resistance, which was readily selected with COL alone. This is the first description of a novel COL-FD regimen for the treatment of MDRAB. The combination was effective at low concentrations, which should be therapeutically achievable while limiting toxicity. Further studies are warranted to determine the mechanism underlying the interaction and the suitability of COL-FD as an unorthodox therapy for the treatment of multidrug-resistant Gram-negative infections. Infections due to the Gram-negative bacterium Acinetobacter baumannii are increasingly challenging to treat and control. The organism has emerged worldwide as a major nosocomial pathogen in critical care units responsible for bloodstream, respiratory, skin and soft tissue, and device-related infections (1). Clinical isolates are often resistant to multiple antimicrobial drugs and belong to successful epidemiologically defined clones that, once established, are extremely difficult to eradicate from the hospital environment (2). As a result, outbreaks are common, typically last for months, and may cost institutions in excess of $500,000 to curtail (3). Treatment of infected individuals is equally hampered by a seemingly endless capacity of the organism to acquire and maintain large numbers of antimicrobial resistance genes (4). Carbapenems, once considered the treatment of choice, are increasingly found to be ineffective, leaving polymyxins (polymyxin B and colistin [COL]) as the treatment of last resort (5).Although polymyxins have been widely employed in the treatment of A. baumannii infections, there are still concerns about their efficacy and safety. These include the unreliable methods for performing susceptibility testing, inadequate population pharmacokinetic data, uncertainties around appropriate dosing regimens, and the availability of the licensed formulations of colistin only as the inactive prodrug colistimethate sodium (6).Despite this, polymyxins have frequently been s...

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“…We next investigated the mechanism by which this combination of compounds with different modes of action achieved its negative effect on bacterial cells. Time-kill assays, as defined by the National Committee for Clinical Laboratory Standards, are a favored methodology for distinguishing between bacteriostatic and bactericidal activities, as well as if an effect of this type is synergistic or additive (33). When examined in this fashion, all of the combinatorial antibiotics except CTX for E. coli (four for E. coli and two for S. aureus), when in the presence of DFP, reduced the cell number below that of the starting inoculum over time and proved more potent at reducing the overall density of the population relative to each individual drug at 24 h ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Escherichia coli Free Radical-Based Killing Mechanism Driven by a Unique Combination of Iron Restriction and Certain Antibiotics

Gao

Maresso

2015

J Bacteriol

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Bacterial resistance to antibiotics is precipitating a medical crisis, and new antibacterial strategies are being sought. Hypothesizing that a growth-restricting strategy could be used to enhance the efficacy of antibiotics, we determined the effect of FDA-approved iron chelators and various antibiotic combinations on invasive and multidrug-resistant extraintestinal pathogenic Escherichia coli (ExPEC), the Gram-negative bacterium most frequently isolated from the bloodstreams of hospitalized patients. We report that certain antibiotics used at sublethal concentrations display enhanced growth inhibition and/or killing when combined with the iron chelator deferiprone (DFP). Inductively coupled plasma optical emission spectrometry reveals abnormally high levels of cell-associated iron under these conditions, a response that correlates with an iron starvation response and supraphysiologic levels of reactive oxygen species (ROS). The high ROS level is reversed upon the addition of antioxidants, which restores bacterial growth, suggesting that the cells are inhibited or killed by excessive free radicals. A model is proposed in which peptidoglycan-targeting antibiotics facilitate the entry of lethal levels of iron-complexed DFP into the bacterial cytoplasm, a process that drives the generation of ROS. This new finding suggests that, in addition to restriction of access to iron as a general growth-restricting strategy, targeting of cellular pathways or networks that selectively disrupt normal iron homeostasis can have potent bactericidal outcomes. IMPORTANCEThe prospect that common bacteria will become resistant to all antibiotics is challenging the medical community. In addition to the development of next-generation antibiotics, new bacterial targets that display cytotoxic properties when altered need to be identified. Data presented here demonstrate that combining subinhibitory levels of both iron chelators and certain antibiotics kills pathogenic Escherichia coli. The mechanism of this effect is the production of supraphysiologic levels of reactive oxygen species, likely powered by the excessive import of iron. These findings were consistent for both clinically relevant and no longer clinically used antibiotics and may extend to Staphylococcus aureus as well.A ntibiotics are compounds that inhibit or kill bacteria and may have saved more lives than any other medical intervention, aside from vaccination (1). However, the development of strains resistant to antibiotics is precipitating a medical crisis. It is estimated that each year in the United States there are 900,000 cases of antibiotic-resistant infections, with an estimated cost of over 20 billion U.S. dollars (2). Several factors contribute to resistance, including the over-and misuse of these drugs (which generates evolutionary pressure that selects for resistant strains), horizontal gene transfer (which allows elements that confer resistance to be transferred among species or genera), and the high level of genetic diversity generated from de novo muta...

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When Does 2 Plus 2 Equal 5? A Review of Antimicrobial Synergy Testing

Cited by 328 publications

References 24 publications

Cooperative Behavior of Fluoroquinolone Combinations against <i>Escherichia coli</i> and <i>Staphylococcus aureus</i>

Cooperative Behavior of Fluoroquinolone Combinations against <i>Escherichia coli</i> and <i>Staphylococcus aureus</i>

Colistin and Fusidic Acid, a Novel Potent Synergistic Combination for Treatment of Multidrug-Resistant Acinetobacter baumannii Infections

Escherichia coli Free Radical-Based Killing Mechanism Driven by a Unique Combination of Iron Restriction and Certain Antibiotics

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