Antibiotic synergy

Antibiotic synergy is one of three responses possible when two or more antibiotics are used simultaneously to treat an infection. In the synergistic response, the applied antibiotics work together to produce an effect more potent than if each antibiotic were applied singly.[1] Compare to the additive effect, where the potency of an antibiotic combination is roughly equal to the combined potencies of each antibiotic singly, and antagonistic effect, where the potency of the combination is less than the combined potencies of each antibiotic.[1]

Clinical Interest

Clinical interest in synergism dates back to the early 1950’s when practitioners noted that patients with enterococcal endocarditis experienced a high relapse rate when penicillin G alone was used for treatment and a demonstrably lower relapse rate when streptomycin was combined with penicillin G to combat the infection.[2] Since that time the research community has conducted numerous studies regarding the effects and possibilities of antibiotic combinations. Today, combination therapy is recognized as providing a broad spectrum of antibiotic coverage, effectively fighting polymicrobial infections, minimizing selection for antibiotic resistant strains, lowering dose toxicity where applicable, and in some cases providing synergistic activity.[2][3]

Desirability

Antibiotic synergy is desirable in a clinic sense for several reasons. At the patient level, the boosted antimicrobial potency provided by synergy allows the body to more rapidly clear infections, resulting in shorter courses of antibiotic therapy.[3] Shorter courses of therapy in turn reduce the effects of dose-related toxicity, if applicable.[3] Additionally, synergy aids in total bacterial eradication, more completely removing an infection than would be possible without synergy.[2] At a higher level, synergistic effects are useful for combating resistant bacterial strains through increased potency and for stalling the spread of bacterial resistance through the total eradication of infections, preventing the evolutionary selection of resistant cells and strains.[2][3]

Current Research Directions

Current research on antibiotic synergy and potential therapies is moving in three primary directions. Some research is devoted to finding combinations of extant antibiotics which when combined exhibit synergy. A classic example of this effect is the interaction between β-lactams, which damage the bacteria cell membrane, and aminoglycosides, which inhibit protein synthesis.[1] The damage dealt to the cell wall by β-lactams allows more aminoglycoside molecules to be taken up into the cell than would otherwise be possible, enhancing cell damage.[1] In some cases, antibacterial combinations restore potency to ineffective drugs.[4] Other research has been devoted to finding antibiotic resistance breakers (ARB’s) which enhance an antibiotic’s potency. This effect is mediated through direct antibacterial activity of the ARB, targeting and destroying mechanisms of bacterial resistance thereby allowing the antibiotic to function properly, interacting with the host to trigger defensive mechanisms, or some combination thereof.[4] The third direction of research involves combining traditional antibiotics with unconventional bactericides such as silver nano particles. Silver nano particles have strong non-specific interactions with bacterial cells that result in cell wall deformation and the generation of damaging reactive oxygen species (ROS) in the presence of cellular components. These effects are thought to weaken bacterial cells, making them more susceptible to assault from conventional antibiotics.[5][6][7][8][9]

References

  1. 1 2 3 4 Kohanski, Michael A.; Dwyer, Daniel J.; Collins, James J. "How antibiotics kill bacteria: from targets to networks". Nature Reviews Microbiology. 8 (6): 423–435. doi:10.1038/nrmicro2333. PMC 2896384Freely accessible. PMID 20440275.
  2. 1 2 3 4 Acar, Jacques F. (2000-11-01). "ANTIBIOTIC SYNERGY AND ANTAGONISM". Medical Clinics of North America. 84 (6): 1391–1406. doi:10.1016/S0025-7125(05)70294-7.
  3. 1 2 3 4 Leekha, Surbhi; Terrell, Christine L.; Edson, Randall S. "General Principles of Antimicrobial Therapy". Mayo Clinic Proceedings. 86 (2): 156–167. doi:10.4065/mcp.2010.0639. PMC 3031442Freely accessible. PMID 21282489.
  4. 1 2 Brown, David. "Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void?". Nature Reviews Drug Discovery. 14 (12): 821–832. doi:10.1038/nrd4675.
  5. ↑ Panáček, Aleš; Smékalová, Monika; Večeřová, Renata; Bogdanová, Kateřina; Röderová, Magdaléna; Kolář, Milan; Kilianová, Martina; Hradilová, Šárka; Froning, Jens P. (2016-06-01). "Silver nanoparticles strongly enhance and restore bactericidal activity of inactive antibiotics against multiresistant Enterobacteriaceae". Colloids and Surfaces B: Biointerfaces. 142: 392–399. doi:10.1016/j.colsurfb.2016.03.007.
  6. ↑ Wang, Yao; Ding, Xiali; Chen, Yuan; Guo, Mingquan; Zhang, Yan; Guo, Xiaokui; Gu, Hongchen. "Antibiotic-loaded, silver core-embedded mesoporous silica nanovehicles as a synergistic antibacterial agent for the treatment of drug-resistant infections". Biomaterials. 101: 207–216. doi:10.1016/j.biomaterials.2016.06.004.
  7. ↑ Zheng, Kaiyuan; Setyawati, Magdiel I.; Lim, Tze-Peng; Leong, David Tai; Xie, Jianping (2016-08-23). "Antimicrobial Cluster Bombs: Silver Nanoclusters Packed with Daptomycin". ACS Nano. 10 (8): 7934–7942. doi:10.1021/acsnano.6b03862. ISSN 1936-0851.
  8. ↑ Panáček, Aleš; Smékalová, Monika; Kilianová, Martina; Prucek, Robert; Bogdanová, Kateřina; Večeřová, Renata; Kolář, Milan; Havrdová, Markéta; Płaza, Grażyna Anna (2015-12-28). "Strong and Nonspecific Synergistic Antibacterial Efficiency of Antibiotics Combined with Silver Nanoparticles at Very Low Concentrations Showing No Cytotoxic Effect". Molecules. 21 (1): 26. doi:10.3390/molecules21010026.
  9. ↑ Deng, Hua; McShan, Danielle; Zhang, Ying; Sinha, Sudarson S.; Arslan, Zikri; Ray, Paresh C.; Yu, Hongtao (2016-08-16). "Mechanistic Study of the Synergistic Antibacterial Activity of Combined Silver Nanoparticles and Common Antibiotics". Environmental Science & Technology. 50 (16): 8840–8848. doi:10.1021/acs.est.6b00998. ISSN 0013-936X.
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