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Adaptation but no resistance

13 June 2018

Even under most disadvantageous laboratory conditions, octenidine remains antimicrobi-ally effective

Hardly a day goes by without antibiotics failing to serve. Antibiotics-resistant pathogens have been spreading in hospitals for years. Severe infections can be the result. The once sharp weapons are increasingly blunted. The consequence: Therapeutic options are becoming more and more limited. In view of this situation, in 2014 the WHO even predicted the beginning of a post-antibiotics era [1].

Antiseptics are also suspected over and over again of inducing resistance in pathogens, as antibiotics do. Until recently, however, relatively nonspecific, locally acting antiseptics were a reassuring exception.

However, now this absolute certainty cannot be maintained anymore. For example, for chlorhexidine, one of the most important antiseptic agents in the world, concerns about the first clinically evident resistances have been raised [2, 3]. The user rightly asks whether resistance to octenidine dihydrochloride (octenidine) is also to be expected? Octenidine is used mainly in wound care and for decontamination of patients with multidrug-resistant pathogens. It is reassuring that, in contrast to the situation for chlorhexidine, resistance with loss of efficacy is still unknown for octenidine.

Now a systematic, extensive study has shown experimentally that even under extreme laboratory conditions octenidine as an antimicrobial agent does not induce any resistance. In the end, test bacteria did indeed tolerate higher concentrations of the active substance, but the preparations containing octenidine remained fully effective [4].

The research group exposed clinical isolates of the Gram-negative pathogen Pseudomonas aeruginosa to increasing concentrations (2 mg / L to 64 mg / L) of octenidine. Bacteria growing at a low octenidine concentration were transferred to the next higher, i.e. double concentration every two days. In this way, the strains had the opportunity to slowly and steadily adapt to higher concentrations of octenidine. The germs were thus selected for survival and growth in the presence of octenidine. As a result, in this “breeding” of germs for resistance, there was merely adaptation of the strains to 25 – 50 % of the octenidine concentration contained in the tested products (e.g. octenisept). Complementary studies under real-world conditions in effusions with a diluted octenidine-containing surfactant solution resulted in significantly lower maximally tolerated octenidine concentrations. In this experiment with real-world, i.e. changing antiseptic burdens, the adaptations were not permanent either and were lost when octenidine was no longer present. The virulence of the adapted strains generally showed no difference to the parent strains.

These investigations under worst-case conditions were confirmed by results of other publications with octenidine. Under similar experimental conditions, Gram-positive MRSA isolates developed only very minor adaptations to elevated octenidine concentrations. The maximally tolerated levels increased only from 2 mg / L to 8 mg / L after octenidine exposure [5]. In a recent paper [6] these results were confirmed with a variety of MRSA strains partially isolated from English hospitals. 90 percent of the strains exposed to octenidine during decontamination showed a minimal bactericidal concentration (MBC90) up to 1 mg / L. This value was just a slight increase from the 0.5 mg/L of the reference strains. Due to this low increase in concentration no practical relevance is foreseen.

Clinically, these results could be verified. Thus, octenidine washings in an intensive care unit did not alter the sensitivity of MRSA strains (MIC values <4 mg / L) before and after patient decontamination [7].

Therefore, the authors of the new study [4] conclude that only incorrect use may cause a risk that strains can adapt to octenidine. Proper use as intended thus ensures that patients will be untroubled by resistances to octenidine products in the future as well.

References

[1] WHO (2014).http://www.who.int/mediacentre/news/releases/2014/amr-report/en/
(retrieved on 17-MAY-2018)

[2] Poovelikunnel T, Gethin G, Humphreys H. Mupirocin resistance: clinical implications and potential alternatives for the eradication of MRSA. J. Antimicrob. Chemother. (2015) 70 (10): 2681-2692. doi: 10.1093/jac/dkv169

[3] Kampf G. (2016). Acquired resistance to chlorhexidine – is it time to establish an ‘antiseptic stewardship’ initiative? J. Hosp. Infect. 94 (2016) 213-227. 

[4] Shepherd MJ, Moore G et al. Pseudomonas aeruginosa adapts to octenidine in the laboratory and a simulated clinical setting, leading to increased tolerance to chlorhexidine and other biocides. J. Hosp. Infect. (2018), doi: 10.1016/j.jhin.2018.03.037.

[5] Al-Doori Z et al. Low-level exposure of MRSA to octenidine dihydrochloride does not select for resistance. J. Antimicrob. Chemother. 59 (2007) 1280-2.

[6] Hardy K, Sunnucks K et al. Increased usage of antiseptics is associated with reduced suscep-tibility in clinical isolates of Staphylococcus aureus. mBio 9(3) (2018), e00894-18

[7] Ang B, See T, Poh BF et al. Chlorhexidine and octenidine bathing for methicillin-resistant Staphylococcus aureus does not lead to development of resistance. ePoster EV0699, ESCMID Copenhagen 2015. https://www.escmid.org/escmid_publications/escmid_elibrary/material/?mid=21757
(retrieved on 18-MAY-2018)