Multidrug Resistance of F. tularensis subsp. holarctica, Epizootiological and Epidemiological Analysis of the Situation on Tularemia in the Russian Federation in 2022 and Forecast for 2023

The review provides concise information on the innate ability of cells of the tularemia pathogen, Francisella tularensis subsp. Holarctica, to resist antimicrobials through a variety of mechanisms, leading to its multi-resistance. In total, taking into account new territories, 120 cases of human infection were registered in the Russian Federation in 2022. Epizootic manifestations of the infection of varying degrees of intensity were detected in 58 constituent entities. Against this background, sporadic cases of tularemia in humans were reported in 18 regions of the country. An outbreak of tularemia occurred in the Stavropol Territory; the disease of mild and moderate severity was found in 76 people. The increased incidence of tularemia persists in the Republic of Karelia with severe cases of the disease in the absence of immunoprophylaxis of this infection in the region. A total of 61 cultures of the tularemia pathogen F. tularensis subsp. holarctica, out of which 20 erythromycin-resistant strains were isolated in the Stavropol Territory. In addition, 8 cultures of F. tularensis subsp. mediasiatica from a silt sample and mites Dermacentor silvarum and Haemaphysalis concinna caught in the Republic of Altai were isolated. On the territory of the Russian Federation in 2022, 930 999 people were vaccinated and revaccinated against tularemia. Based on the analysis of the data obtained in 2022, epidemic complications in 2023 in the form of sporadic cases of the disease among the unvaccinated population are most likely to occur in the territories of the Central Federal District – in the Vladimir, Ryazan and Smolensk Regions; Northwestern Federal District – in the Arkhangelsk Region and the Republic of Karelia; Southern Federal District – in the Volgograd and Rostov Regions. The situation in the North Caucasian Federal District will remain tense in the Stavropol Territory; in the Volga Federal District – in the territories of the Saratov Region, as well as in the Kirov Region and the Republic of Mordovia; Ural Federal District – in Khanty-Mansi and Yamalo-Nenets Autonomous Districts; Siberian Federal District – in certain territories of Omsk, Kemerovo, Tomsk, Novosibirsk, Irkutsk Regions, Altai, Krasnoyarsk Territories; in the Far Eastern Federal District, the most intense epizootic activity of natural tularemia foci is in Primorsky Krai.

1. Challacombe J.F., Pillai S., Kuske C.R. Shared features of cryptic plasmids from environmental and pathogenic Francisella species. PLoS One. 2017; 12(8):e0183554. DOI: 10.1371/journal.pone.0183554.

2. Martinez J.L. General principles of antibiotic resistance in bacteria. Drug Discov. Today. 2014; 11:33–9. DOI: 10.1016/j.ddtec.2014.02.001.

3. Cox G., Wright G.D. Intrinsic antibiotic resistance: mechanisms, origins, challenges and solutions. Int. J. Med. Microbiol. 2013; 303(6-7):287–92. DOI: 10.1016/j.ijmm.2013.02.009.

4. Soto S.M. Role of efflux pumps in the antibiotic resistance of bacteria embedded in a biofilm. Virulence. 2013; 4(3):223–9. DOI: 10.4161/viru.23724.

5. Bina X.R., Wang C., Miller M.A., Bina J.E. The Bla2 betalactamase from the live-vaccine strain of Francisella tularensis encodes a functional protein that is only active against penicillin-class beta-lactam antibiotics. Arch. Microbiol. 2006; 186(3):219–28. DOI: 10.1007/s00203-006-0140-6.

6. Antunes N.T., Frase H., Toth M., Vakulenko S.B. The class A β-lactamase FTU-1 is native to Francisella tularensis. Antimicrob. Agents Chemother. 2012; 56(2):666–71. DOI: 10.1128/AAC.05305-11.

7. Biswas S., Raoult D., Rolain J.M. A bioinformatic approach to understanding antibiotic resistance in intracellular bacteria through whole genome analysis. Int. J. Antimicrob. Agents. 2008; 32(3):207–20. DOI: 10.1016/j.ijantimicag.2008.03.017.

8. Bodey G.P. Penicillins, monobactams, and carbapenems. Tex. Heart Inst. J. 1990; 17(4):315–29.

9. Llewellyn A.C., Zhao J., Song F., Parvathareddy J., Xu Q., Napier B.A., Laroui H., Merlin D., Bina J.E., Cotter P.A., Miller M.A., Raetz C.R.H., Weiss D.S. NaxD is a deacetylase required for lipid A modification and Francisella pathogenesis. Mol. Microbiol. 2012; 86(3):611–27. DOI: 10.1111/mmi.12004.

10. Li Y., Powell D.A., Shaffer S.A., Rasko D.A., Pelletier M.R., Leszyk J.D., Scott A.J., Masoudie A., Goodlett D.R., Wang X., Raetz C.R.H., Ernst R.K. LPS remodeling is an evolved survival strategy for bacteria. Proc. Natl Acad. Sci. USA. 2012; 109(22):8716–21. DOI: 10.1073/pnas.1202908109.

11. Stephens M.D., Hubble V.B., Ernst R.K., van Hoek M.L., Melander R.J., Cavanagh J., Melander C. Potentiation of Francisella resistance to conventional antibiotics through small molecule adjuvants. Medchemcomm. 2016; 7(1):128–31. DOI: 10.1039/C5MD00353A.

12. Karlsson E., Golovliov I., Lärkeryd A., Granberg M., Larsson E., Öhrman C., Niemcewicz M., Birdsell D., Wagner D.M., Forsman M., Johansson A. Clonality of erythromycin resistance in Francisella tularensis. J. Antimicrob. Chemother. 2016; 71(10):2815–23. DOI: 10.1093/jac/dkw235.

13. Pérez-Castrillón J.L., Bachiller-Luque P., Martin-Luquero M., Mena-Martin F.J., Herreros V. Tularemia epidemic in northwestern Spain: clinical description and therapeutic response. Clin. Infect. Dis. 2001; 33(4):573–6. DOI: 10.1086/322601.

14. Boisset S., Caspar Y., Sutera V., Maurin M. New therapeutic approaches for treatment of tularaemia: a review. Front. Cell. Infect. Microbiol. 2014; 4:40. DOI: 10.3389/fcimb.2014.00040.

15. Caspar Y., Maurin M. Francisella tularensis susceptibility to antibiotics: a comprehensive review of the data obtained in vitro and in animal models. Front. Cell. Infect. Microbiol. 2017; 7:122. DOI: 10.3389/fcimb.2017.00122.

16. Caspar Y., Siebert C., Sutera V., Villers C., Aubry A., Mayer C., Maurin M., Renesto P. Functional characterization of the DNA gyrases in fluoroquinolone-resistant mutants of Francisella novicida. Antimicrob. Agents Chemother. 2017; 61(4):e02277-16. DOI: 10.1128/AAC.02277-16.

17. Jaing C.J., McLoughlin K.S., Thissen J.B., Zemla A., Gardner S.N., Vergez L.M., Bourguet F., Mabery S., Fofanov V.Y., Koshinsky H., Jackson P.J. Identification of genome-wide mutations in ciprofloxacin-resistant F. tularensis LVS using whole genome tiling arrays and next generation sequencing. PLoS One. 2016; 11(9):e0163458. DOI: 10.1371/journal.pone.0163458.

18. Sutera V., Hoarau G., Renesto P., Caspar Y., Maurin M. In vitro and in vivo evaluation of fluoroquinolone resistance associated with DNA gyrase mutations in Francisella tularensis, including in tularaemia patients with treatment failure. Int. J. Antimicrob. Agents. 2017; 50(3):377–83. DOI: 10.1016/j.ijantimicag.2017.03.022.

19. Sutera V., Levert M., Burmeister W.P., Schneider D., Maurin M. Evolution toward high-level fluoroquinolone resistance in Francisella species. J. Antimicrob. Chemother. 2014; 69(1):101–10. DOI: 10.1093/jac/dkt321.

20. Enderlin G., Morales L., Jacobs R.F., Cross J.T. Streptomycin and alternative agents for the treatment of tularemia: review of the literature. Clin. Infect. Dis. 1994; 19(1):42–7. DOI: 10.1093/clinids/19.1.42.

21. Maurin M., Mersali N.F., Raoult D. Bactericidal activities of antibiotics against intracellular Francisella tularensis. Antimicrob. Agents Chemother. 2000; 44(12):3428–31. DOI: 10.1128/AAC.44.12.3428-3431.2000.

22. Gil H., Platz G.J., Forestal C.A., Monfett M., Bakshi C.S., Sellati T.J., Furie M.B., Benach J.L., Thanassi D.G. Deletion of TolC orthologs in Francisella tularensis identifies roles in multidrug resistance and virulence. Proc. Natl Acad. Sci. USA. 2006; 103(34):12897–902. DOI: 10.1073/pnas.0602582103.

23. Loughman K., Hall J., Knowlton S., Sindeldecker D., Gilson T., Schmitt D.M., Birch J.W.-M., Gajtka T., Kobe B.N., Florjanczyk A., Ingram J., Bakshi C.S., Horzempa J. Temperaturedependent gentamicin resistance of Francisella tularensis is mediated by uptake modulation. Front. Microbiol. 2016; 7:37. DOI: 10.3389/fmicb.2016.00037.

24. Chen L.F., Kaye D. Current use for old antibacterial agents: polymyxins, rifamycins, and aminoglycosides. Med. Clin. North Am. 2011; 95(4):819–42, viii–ix. DOI: 10.1016/j.mcna.2011.03.007.

25. Ahmad S., Hunter L., Qin A., Mann B.J., van Hoek M.L. Azithromycin effectiveness against intracellular infections of Francisella. BMC Microbiol. 2010; 10:123. DOI: 10.1186/1471-2180-10-123.

26. Hightower J., Kracalik I.T., Vydayko N., Goodin D., Glass G., Blackburn J.K. Historical distribution and host-vector diversity of Francisella tularensis, the causative agent of tularemia, in Ukraine. Parasit. Vectors. 2014; 7:453. DOI: 10.1186/s13071-014-0453-2.

27. Prilutsky A.S., Rogovaya Yu.D., Zubko V.G. [Tularemia: etiology, epidemiology, vaccinal prevention]. Universitetskaya Klinika [University Clinic]. 2017; 13(2):231–39.

28. Rubis L.V. [Epizootiological and epidemiological situation on tularemia in the Republic of Karelia]. Problemy Osobo Opasnykh Infektsii [Problems of Particularly Dangerous Infections]. 2021; (4):105–11. DOI: 10.21055/0370-1069-2021-4-105-111.