Combination Antibiotics: Viva la resistance!

4. July 2013

Antibiotic-resistant bacteria are developing into a problem. The fact that combination therapies promote the emergence of resistant bacteria has now been shown by researchers. They call for a rethink when considering the use of antibiotics. A stress protein could be one therapeutic approach.

It seems to be like a race, which we have been running against bacteria for decades. With each newly developed antibiotic we give ourselves a short-lived feeling of superiority. Yet the evolution of these ever-threatening unicellular creatures is so fast that we can no longer stay apace with them by developing new antibiotics. For each antibiotic in clinical use there is now at least one resistant strain of bacteria, this development becoming a growing problem for humanity. How did it come to this?

Effective drugs increase selection pressure

Standard therapy ensures that a pathogenic bacterium is treated with antibiotics. It’s during this process that resistance first appears, which spreads throughout the general bacterial population and remains established there. The more efficient the agent, the greater the selection pressure for resistant bacteria and the faster the resistance is manifested within the population. According to medical and pharmaceutical textbooks, there’s only one way to help: “hit early, hit hard!” The bacterial invaders should be fought as soon and as aggressively as possible in order to avoid the emergence of resistant bacteria. In addition physicians ideally combine two antibiotics together synergistically in order to achieve a stronger effect in killing bacteria. To not only rely on a weapon of defence in the instance of attack by a life-threatening enemy seems really obvious and this rule is part of everyday medical practice: combination therapies have been employed for over 70 years in the fight against bacteria, viruses and also cancer.

Combination therapy promotes proliferation of resistant bacteria

It has now been vividly shown by scientists at the University of Kiel and Exeter that this approach can be extremely counter-productive, at least in the fight against pathogenic bacteria, if not all of them are done away with as a result of the first “attack”. The scientists studied the therapeutic approach under controlled laboratory conditions, in which two antibiotics are used in combination to increase their efficiency. “We are talking here about synergistic antibiotics, which together have a higher efficacy than the individual antibiotics applied in the same amount. Thus if antibiotic A and B used alone inhibit 50% of the growth at a certain concentration, the combination of ½ A and ½ B would be more efficient than the monotherapies although as a total the same amount of antibiotic agent is used. The combination, not the concentration, increases the efficiency of antibiotics”, Dr. Jansen says in explaining why the researchers tested various combinations of two antibiotics. Their experiments showed that apparently the combination therapy itself can result in a greater number of resistant bacteria in a shorter time than if only one antibiotic were employed alone.

E. coli with Erythromycin and Doxycycline

E. coli K12 (MC4100) was used as test bacterium, which the scientists treated over five days with 16 different combinations of treatments of Erythromycin (a macrolide), and Doxycycline (a tetracycline). Earlier studies had already shown that the combination of the two antibiotics is particularly effective against E. coli. The scientists observed something astonishing: “We were completely surprised by the speed with which the resistance developed anew”, says Schulenburg, head of the study at the Christian-Albrechts-University of Kiel. The resistance appears in particular together with the especially effective combination therapies. “The phenomenon occurred exactly with the combination of concentrations that was the most efficient in killing bacteria”, according to Dr. Jansen in regard to the maximum synergistic therapy.

However, with regard to new treatment it is still too soon to be making recommendations. “Our data so far apply only to E. coli. It might however be that they are also applicable to other types of bacteria”, says Dr. Gunther Jansen, Head of Ecology and Evolutionary Genetics at the Christian-Albrechts-University of Kiel. On this point however, further studies are needed.

The subsequent complete genomic study of the bacteria used has brought to light an unusual evolutionary mechanism: the rapid development of resistance resulting from the duplication of specific genomic regions in which a large number of resistance genes are located. It is clear that the bacterium seems to defend itself against the attack from antibiotics. “This is the principle that more is better'”, says Dr. Jansen “the more resistance gene there are in the genome, the higher the resistance”. The molecular reasons for this phenomenon are not yet known to scientists. Much more importantly, the researchers identified a genomic portion with whose help the bacterium can pump the antibiotic out of the cells. When just this section was removed from the genetic tissue of the bacterium, the effect disappeared. “Then the combination therapy was effective even after 5 days”, states Dr. Jansen explaining the importance of this genome sequence.

Monotherapy more effective in the long term

Additional mathematical calculations confirm that resistance in combination therapy can generally occur very quickly. “Therefore, the use of single antibiotics is more effective in the long term”, concludes Beardmore, leader of the study in Exeter. In established medical considerations, therapies would generally be classified via short-term experiments as efficient or non-efficient. “Evolution, the ability of germs to adapt, is ignored”, adds Schulenburg. “This is obviously a mistake.” “Our work shows that one should think about the antibiotics currently used in therapies”, says Dr. Jansen. Because in the tested case the combination therapy was more devastating than the monotherapy. “Although combination therapy can be very successful in the short term, we want to raise awareness that the long-term consequences can be threatening. One should think about that”, says Dr. Jansen.

Practical investigations follow

The working groups from Kiel and Exeter are currently further building on the experimental approach developed thus far, in order to specifically investigate the effectiveness of different antibiotic therapies. They also base themselves on agents which are actually combined together in everyday medical practice. By doing this they hope to be able to get more information on how treatment strategies for people can be optimised in the future.

Even low doses of antibiotics can promote resistant bacteria

Another approach, which could curb the spread of antibiotic-resistant bacteria, is currently being pursued by French scientists, because even extremely low doses of antibiotics can contribute to the development of resistant germs. As part of their study the scientists treated among others the cholera pathogen Vibriocholerae and the cause of lung inflammation Klebsiellapneumoniae with commonly used antibiotics such as gentamicin, streptomycin or neumycin, all belonging to the group of aminoglycosides. Unlike in the above study, already at a hundred-fold dilution of fatal dose level there is creation of antibiotic resistant bacteria from among numerous bacteria.

“SOS” response triggers formation of resistance genes

Scientists explain this phenomenon as a stress reaction in the bacteria by which they protect their DNA from danger. Already at low doses of antibiotic some bacteria activate a so-called “SOS” response, in which on the one hand via an increased number of mutations they build resistance genes in the genome, and on the other hand they activate a protein called integrase. Integrases are capable of stably integrating resistance genes into the genome.

New pharmacological approach plausible

Yet this mechanism does not operate in all bacteria. E. coli, for example, showed no SOS reactions to aminoglycosides. In contrast to other bacteria, E. Coli appears to have a built-in stress regulator that prevents a SOS response being triggered. If it were possible to combine this stress protein in the future with antibiotics, the formation of resistance genes could be able to be averted.

“We will always need antibiotics”, says Dr. Jansen. The problem resides somewhat more in the spread of resistant bacteria. “We cannot prevent the development of resistance. That’s biology. However we need to think about how we can minimise its occurrence.”

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