Studies on Antibiotic Synergism and Antagonism: The Effect in Vitro of Combinations of Antibiotics on Bacteria of Varying Resistance to Single Antibiotics

Gunnison, J. B.; Shevky, Marian C.; Bruff, J. A.; Coleman, Virginia R.; Jawetz, Ernest

doi:10.1128/jb.66.2.150-158.1953

Cited by 14 publications

(3 citation statements)

References 13 publications

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“…Our results showed that when the ranges of concentrations of pairs of antibacterial agents are studied, it is possible that just a narrow range can show synergistic in their action. Besides, in resistant bacterial isolates, the additive, and synergistic concentration ranges are wider than the sensitive isolates ( Gunnison et al, 1953 ). In conclusion, this study presented a modified chequerboard technique and confirmed a significant correlation between FIC and FBC indices for bactericidal agents whilst it is not good predictive when one of the pairs is a bacteriostatic agent.…”

Section: Discussionmentioning

confidence: 99%

Highly Synergistic Effects of Melittin With Vancomycin and Rifampin Against Vancomycin and Rifampin Resistant Staphylococcus epidermidis

et al. 2022

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Methicillin-resistant Staphylococcus epidermidis (MRSE) strains are increasingly emerging as serious pathogens because they can be resistant to many antibiotics called multidrug resistance (MDR) that limit the therapeutic options. In the case of vancomycin- and rifampin-resistant MDR-MRSE, the physicians are not allowed to increase the doses of antibiotics because of severe toxicity. Accordingly, we investigated the synergistic activity of melittin antimicrobial peptide with vancomycin and rifampin against vancomycin-resistant, and rifampin-resistant MDR-MRSE isolates. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), fractional inhibitory concentration index (FICi), and fractional bactericidal concentration index (FBCi) of antimicrobial agents against isolates were determined. Coagulate activities and serum and salt stability as well as melittin cytotoxicity on the human embryonic kidney (HEK) 293 cells and human red blood cells (RBCs) at their synergistic concentrations. MIC and MBC values for melittin were in the range of 0.312–2.5 and 0.312–5, respectively. Results also showed that the interaction of melittin with drugs was highly synergistic in which the geometric means of FICi and FBCi were < 0.5. Induced synergism led to a decrease in melittin, rifampin, and vancomycin concentrations by 8–1,020, 2–16, and 4–16-folds, respectively. This phenomenon caused a reduction in melittin toxicity by which the synergistic concentration of melittin needed to kill bacteria did not show cytotoxicity and hemolytic activity. Besides, no coagulation activity was found for the synergistic and alone concentrations of melittin in both Prothrombin Time (PT) and Partial Thromboplastin Time (PTT). Interestingly, the antibacterial activity of melittin in Mueller Hinton Broth (MHB) containing human serum did no significant differences between MIC and MBC values of melittin in MHB and MHB containing 10% human serum. The present findings showed that the therapeutic index of melittin was improved by 32.08- and 12.82-folds when combined with vancomycin and rifampin, respectively. Taken together, the obtained data show that melittin alone was effective against MDR-MRSE isolates and this antimicrobial peptide showed highly synergistic effects with vancomycin and rifampin without causing toxicity. Therefore, the combination of melittin and traditional antibiotics could be a promising strategy for the treatment of infections caused by MDR-MRSE.

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Section: Discussionmentioning

confidence: 99%

Highly Synergistic Effects of Melittin With Vancomycin and Rifampin Against Vancomycin and Rifampin Resistant Staphylococcus epidermidis

et al. 2022

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“…The aminoglycoside antibiotic amikacin also displayed synergy when combined with colistin, but its therapeutic benefits in treating clinical infections are challenging due to excessive renal toxicity [ 25 ]. On the other hand, certain combinations of antibiotics have long been believed to be more effective than using a single antibiotic; however, the real effectiveness of those antibiotics’ combinations is not clear as the resistance mechanisms continue to evolve [ 22 , 26 ]. Therefore, the effectiveness of those antibiotics pairs or any emerging alternative strategy in multi-drug environments should be continuously assessed to combat AMR [ 27 ].…”

Section: Conventional Antibiotics To Combination Therapymentioning

confidence: 99%

Progress in Alternative Strategies to Combat Antimicrobial Resistance: Focus on Antibiotics

et al. 2022

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Antibiotic resistance, and, in a broader perspective, antimicrobial resistance (AMR), continues to evolve and spread beyond all boundaries. As a result, infectious diseases have become more challenging or even impossible to treat, leading to an increase in morbidity and mortality. Despite the failure of conventional, traditional antimicrobial therapy, in the past two decades, no novel class of antibiotics has been introduced. Consequently, several novel alternative strategies to combat these (multi-) drug-resistant infectious microorganisms have been identified. The purpose of this review is to gather and consider the strategies that are being applied or proposed as potential alternatives to traditional antibiotics. These strategies include combination therapy, techniques that target the enzymes or proteins responsible for antimicrobial resistance, resistant bacteria, drug delivery systems, physicochemical methods, and unconventional techniques, including the CRISPR-Cas system. These alternative strategies may have the potential to change the treatment of multi-drug-resistant pathogens in human clinical settings.

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“…First, the "Antagonistic effect", where the potency of the combination is less than the combined potencies of each antibiotic or even less than the more active single agent; second, the "Additive effect", where the potency of an antibiotic combination is roughly equal to the combined potencies of each antibiotic singly; and third, the "Synergistic effect", where the applied antibiotics work together to produce an effect more potent than the combined potencies of each antibiotic applied singly. 12,13 Combination therapies are commonly employed, considering their possibility of synergistic effect despite little laboratory guidance as to the efficacy of this approach. 14 Combination therapy could be a better option than high-dose monotherapy as well, for the reason that it also decreases the dose toxicity to the patient.…”

Section: Introductionmentioning

confidence: 99%

In vitro Antimicrobial Synergy Testing of Extensively Drug-Resistant Clinical Isolates at an Organ Transplant Center in Nepal

Karki¹,

Lamichhane²,

Basnet³

et al. 2021

IDR

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Purpose Inappropriate use of broad-spectrum antibiotics contributes to the emergence of multidrug-resistant (MDR) bacteria. Finding novel antimicrobial agents and strategies based on synergistic combinations are essential to combat MDR infections. This study was designed to determine in vitro synergy of different antimicrobials against extensively drug-resistant (XDR) Gram-negative clinical isolates. Methods A descriptive, cross-sectional study was conducted at Human Organ Transplant Center, Nepal, for five months. Clinical isolates were checked for their drug-resistance properties including extended-spectrum beta-lactamase- (ESBL-) and metallo-beta-lactamase- (MBL-) production. The XDR isolates were further tested for antimicrobial synergy, and the results were interpreted as synergistic, additive, indifferent or antagonistic determining fractional inhibitory concentration of the antibiotics. Results Out of total 1155 clinical samples, 308 showed significant growth. Escherichia coli was the most common isolate (n=142) followed by Klebsiella pneumoniae, Acinetobacter calcoaceticus baumannii (Acb) complex, Pseudomonas aeruginosa and miscellaneous bacteria. Out of the culture positive isolates, 21.4% were MDR and 10.06% were XDR. The XDR population comprised K. pneumoniae (18.42%), E. coli (9.86%), Acb complex (7.41%) and P. aeruginosa (4.17%). Among the culture positive isolates, 4.5% and 5.8% were ESBL- and MBL-producers, respectively. Colistin, polymyxin B, and tigecycline were the antibiotics effective in majority of MDR isolates as compared to carbapenems. The combination of antibiotics – meropenem and colistin showed the highest proportion of “synergy” among all XDR E. coli whereas the combination of amikacin and colistin showed synergistic effect in XDR K. pneumoniae . Conclusion A significant proportion of isolates were MDR among which a large fraction was XDR. The combination of meropenem, amikacin and colistin with one another in pair showed beneficial activity in vitro. Such combinations can be utilized as effective therapy for XDR infections. Further studies are required to confirm these findings, and accordingly treatment protocols should be developed in the management of such infections.

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Studies on Antibiotic Synergism and Antagonism: The Effect in Vitro of Combinations of Antibiotics on Bacteria of Varying Resistance to Single Antibiotics

Abstract: Earlier studies on combined antibiotic action from this laboratory have resulted in the formulation of a scheme for combined antibiotic action.

Cited by 14 publications

References 13 publications

Highly Synergistic Effects of Melittin With Vancomycin and Rifampin Against Vancomycin and Rifampin Resistant Staphylococcus epidermidis

Highly Synergistic Effects of Melittin With Vancomycin and Rifampin Against Vancomycin and Rifampin Resistant Staphylococcus epidermidis

Progress in Alternative Strategies to Combat Antimicrobial Resistance: Focus on Antibiotics

In vitro Antimicrobial Synergy Testing of Extensively Drug-Resistant Clinical Isolates at an Organ Transplant Center in Nepal

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