Antibiotic synergy

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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]

Contents

Clinical interest

Clinical interest in synergism dates back to the early 1950s 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]

Related Research Articles

Antibiotic Antimicrobial substance active against bacteria

An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of such infections. They may either kill or inhibit the growth of bacteria. A limited number of antibiotics also possess antiprotozoal activity. Antibiotics are not effective against viruses such as the common cold or influenza; drugs which inhibit viruses are termed antiviral drugs or antivirals rather than antibiotics.

Antimicrobial resistance Ability of a microbe to resist the effects of medication

Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. Antibiotic resistance is a subset of AMR, that applies specifically to bacteria that become resistant to antibiotics.

Beta-lactamase Class of enzymes

Beta-lactamases, (β-lactamases) are enzymes produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems (ertapenem), although carbapenems are relatively resistant to beta-lactamase. Beta-lactamase provides antibiotic resistance by breaking the antibiotics' structure. These antibiotics all have a common element in their molecular structure: a four-atom ring known as a beta-lactam (β-lactam) ring. Through hydrolysis, the enzyme lactamase breaks the β-lactam ring open, deactivating the molecule's antibacterial properties.

Penicillin Group of antibiotics derived from Penicillium fungi

Penicillins are a group of antibiotics originally obtained from Penicillium moulds, principally P. chrysogenum and P. rubens. Most penicillins in clinical use are synthesised by P. chrysogenum using deep tank fermentation and then purified. A number of natural penicillins have been discovered, but only two purified compounds are in clinical use: penicillin G and penicillin V. Penicillins were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci. They are members of the β-lactam antibiotics. They are still widely used today for different bacterial infections, though many types of bacteria have developed resistance following extensive use.

Beta-lactam antibiotics Class of broad-spectrum antibiotics

β-lactam antibiotics are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and carbacephems. Most β-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics. Until 2003, when measured by sales, more than half of all commercially available antibiotics in use were β-lactam compounds. The first β-lactam antibiotic discovered, penicillin, was isolated from a strain of Penicillium rubens.

Drug resistance Pathogen resistance to medications

Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, resistance has evolved. Antimicrobial resistance and antineoplastic resistance challenge clinical care and drive research. When an organism is resistant to more than one drug, it is said to be multidrug-resistant.

Aminoglycoside Antibacterial drug

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer more generally to any organic molecule that contains amino sugar substructures. Aminoglycoside antibiotics display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli where resistance has not yet arisen but generally not against Gram-positive and anaerobic Gram-negative bacteria.

An antimicrobial is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria, and antifungals are used against fungi. They can also be classified according to their function. Agents that kill microbes are microbicides, while those that merely inhibit their growth are called bacteriostatic agents. The use of antimicrobial medicines to treat infection is known as antimicrobial chemotherapy, while the use of antimicrobial medicines to prevent infection is known as antimicrobial prophylaxis.

Carbapenem Class of highly effective antibiotic agents

Carbapenems are a class of very effective antibiotic agents most commonly used for the treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Similar to penicillins and cephalosporins, carbapenems are members of the beta lactam class of antibiotics, which kill bacteria by binding to penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. However, these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins. Furthermore, carbapenems are typically unaffected by emerging antibiotic resistance, even to other beta-lactams.

Amikacin Antibiotic medication

Amikacin is an antibiotic medication used for a number of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections. It is also used for the treatment of multidrug-resistant tuberculosis. It is used by injection into a vein using an IV or into a muscle.

Dicloxacillin Chemical compound

Dicloxacillin is a narrow-spectrum β-lactam antibiotic of the penicillin class. It is used to treat infections caused by susceptible (non-resistant) Gram-positive bacteria. It is active against beta-lactamase-producing organisms such as Staphylococcus aureus, which would otherwise be resistant to most penicillins. Dicloxacillin is available under a variety of trade names including Diclocil (BMS).

Fosfomycin

Fosfomycin, sold under the brand name Monurol among others, is an antibiotic primarily used to treat lower UTI. It is not indicated for kidney infections. Occasionally it is used for prostate infections. It is generally taken by mouth.

β-Lactamase inhibitor Family of enzymes

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. They act by breaking the beta-lactam ring that allows penicillin-like antibiotics to work. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

Arbekacin Antibiotic

Arbekacin (INN) is a semisynthetic aminoglycoside antibiotic which was derived from kanamycin. It is primarily used for the treatment of infections caused by multi-resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Arbekacin was originally synthesized from dibekacin in 1973 by Hamao Umezawa and collaborators. It has been registered and marketed in Japan since 1990 under the trade name Habekacin. Arbekacin is no longer covered by patent and generic versions of the drug are also available under such trade names as Decontasin and Blubatosine.

Ceftaroline fosamil

Ceftaroline fosamil (INN), brand name Teflaro in the US and Zinforo in Europe, is a cephalosporin antibiotic with anti-MRSA activity. Ceftaroline fosamil is a prodrug of ceftaroline. It is active against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria. It retains some activity of later-generation cephalosporins having broad-spectrum activity against Gram-negative bacteria, but its effectiveness is relatively much weaker. It is currently being investigated for community-acquired pneumonia and complicated skin and skin structure infection.

Plasmid-mediated resistance

Plasmid-mediated resistance is the transfer of antibiotic resistance genes which are carried on plasmids. The plasmids can be transferred between bacteria within the same species or between different species via conjugation. Plasmids often carry multiple antibiotic resistance genes, contributing to the spread of multidrug-resistance (MDR). Antibiotic resistance mediated by MDR plasmids severely limits the treatment options for the infections caused by Gram-negative bacteria, especially family Enterobacteriaceae. The global spread of MDR plasmids has been enhanced by selective pressure from antibiotic usage in human and veterinary medicine.

Antibiotic resistance in gonorrhea

Neisseria gonorrhoeae, the bacterium that causes the sexually transmitted infection gonorrhea, has developed antibiotic resistance to many antibiotics. The bacteria was first identified in 1879.

Enzybiotics

Enzybiotics are an experimental antibacterial therapy first described by Nelson, Loomis, and Fischetti. The term is derived from a combination of the words “enzyme” and “antibiotics.” Enzymes have been extensively utilized for their antibacterial and antimicrobial properties. Proteolytic enzymes called endolysins have demonstrated particular effectiveness in combating a range of bacteria and are the basis for enzybiotic research. Endolysins are derived from bacteriophages and are highly efficient at lysing bacterial cells. Enzybiotics are being researched largely to address the issue of antibiotic resistance, which has allowed for the proliferation of drug-resistant pathogens posing great risk to animal and human health across the globe.

Nanoparticles have been studied extensively for their antimicrobial properties in order to fight super bug bacteria. Several characteristics in particular make nanoparticles strong candidates as a traditional antibiotic drug alternative. Firstly, they have a high surface area to volume ratio, which increases contact area with target organisms. Secondly, they may be synthesized from polymers, lipids, and metals. Thirdly, a multitude of chemical structures, such as fullerenes and metal oxides, allow for a diverse set of chemical functionalities.

A combination antibiotic is one in which two ingredients are added together for additional therapeutic effect. One or both ingredients may be antibiotics.

References

  1. 1 2 3 4 Kohanski, Michael A.; Dwyer, Daniel J.; Collins, James J. (2010). "How antibiotics kill bacteria: from targets to networks". Nature Reviews Microbiology. 8 (6): 423–435. doi:10.1038/nrmicro2333. PMC   2896384 . 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. PMID   11155849.
  3. 1 2 3 4 Leekha, Surbhi; Terrell, Christine L.; Edson, Randall S. (2011). "General Principles of Antimicrobial Therapy". Mayo Clinic Proceedings. 86 (2): 156–167. doi:10.4065/mcp.2010.0639. PMC   3031442 . PMID   21282489.
  4. 1 2 Brown, David (2015). "Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void?". Nature Reviews Drug Discovery. 14 (12): 821–832. doi:10.1038/nrd4675. PMID   26493767. S2CID   22378623.
  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. PMID   26970828.
  6. ↑ Wang, Yao; Ding, Xiali; Chen, Yuan; Guo, Mingquan; Zhang, Yan; Guo, Xiaokui; Gu, Hongchen (2016). "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. PMID   27294538.
  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. PMID   27494437.
  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 . PMC   6273824 . PMID   26729075.
  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. Bibcode:2016EnST...50.8840D. doi:10.1021/acs.est.6b00998. ISSN   0013-936X. PMC   5300770 . PMID   27390928.
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