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US-12622919-B2 - Methods for treating hypervirulent Klebsiella pneumoniae infection

US12622919B2US 12622919 B2US12622919 B2US 12622919B2US-12622919-B2

Abstract

Methods of treating a hypervirulent Klebsiella pneumoniae (hvKp) infection in a subject in need thereof, the method involving co-administering a therapeutically effective amount of an antibiotic and a non-steroidal anti-inflammatory drug or a signal transducer and activator of transcription 1 inhibitor to the subject.

Inventors

  • Sheng Chen
  • Guan Yang
  • Qi Xu
  • Xiaoxuan Liu

Assignees

  • CITY UNIVERSITY OF HONG KONG

Dates

Publication Date
20260512
Application Date
20230323

Claims (11)

  1. 1 . A method of treating a hypervirulent Klebsiella pneumoniae (hvKp) infection in a subject in need thereof, the method comprising co-administering a therapeutically effective amount of an antibiotic and a signal transducer and activator of transcription 1 (STAT1) inhibitor to the subject, wherein the antibiotic is a carbapenem or a cephalosporin.
  2. 2 . The method of claim 1 , wherein the hvKp comprises a pLVPK-like virulence plasmid or a pK2044-like virulence plasmid.
  3. 3 . The method of claim 1 , wherein the hvKp comprises one or more carbapenemase genes selected from the group consisting of bla KPC-2 , bla VIM , bla IMP , bla OXA-48 , bla SPM , bla AIM , bla DIM , bla GIM , bla SIM , and bla NDM-1 .
  4. 4 . The method of claim 2 , wherein the hvKp comprises one or more carbapenemase genes selected from the group consisting of bla KPC-2 , bla VIM , bla IMP , bla OXA-48 , bla SPM , bla AIM , bla DIM , bla GIM , bla SIM , and bla NDM-1 .
  5. 5 . The method of claim 1 , wherein the hvKp infection causes increased expression in the subject of one or more genes selected from the group consisting of Nlrp3, Caspase-1, Caspase-11, Gsdmd, and Il1b.
  6. 6 . The method of claim 1 , wherein the STAT1 inhibitor is epigallocatechin-3 gallate, nifuroxazide, fludarabine, or a pharmaceutically acceptable salt thereof.
  7. 7 . The method of claim 1 , wherein the antibiotic is cefotaxime, cefpodoxime, ceftizoxime, ceftriaxone, ceftazidime, cefoperazone, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, ceftolozane, or a pharmaceutically acceptable salt thereof.
  8. 8 . The method of claim 1 further comprising the step of co-administering a β-lactamase inhibitor.
  9. 9 . The method of claim 8 , wherein the β-lactamase inhibitor is sulbactam, tebipenem, clavulanic acid, tazobactam, avibactam, relebactam, vaborbactam, or a pharmaceutically acceptable salt thereof.
  10. 10 . The method of claim 1 , wherein the hvKp comprises one or more of a pLVPK-like virulence plasmid and a carbapenemase genes selected from the group consisting of bla KPC-2 , bla VIM , bla IMP , bla OXA-48 , bla SPM , bla AIM , bla DIM , bla GIM , bla SIM , and bla NDM-1 ; and the method further comprises co-administering avibactam or a pharmaceutically acceptable salt thereof.
  11. 11 . The method of claim 1 , wherein the method further comprises the step of providing a sample comprising the hvKp or suspected of comprising the hvKp from the subject; and determining whether the hvKp comprises one or more of a pLVPK-like virulence plasmid and a carbapenemase genes selected from the group consisting of bla KPC-2 , bla VIM , bla IMP , bla OXA-48 , bla SPM , bla AIM , bla DIM , bla GIM , bla SIM , and bla NDM-1 prior to the step of co-administering a therapeutically effective amount of the antibiotic and the STAT1 inhibitor to the subject.

Description

TECHNICAL FIELD The present disclosure relates to methods for treating hypervirulent Klebsiella pneumoniae infections in a subject. BACKGROUND Klebsiella pneumoniae (Kp) is a Gram-negative commensal and opportunistic bacterium of the Enterobacteriaceae family. Certain Kp strains have acquired exogenous antibiotic resistance genes or virulence genes and have become multidrug-resistant. An notable example is the carbapenem-resistant Kp (CR-Kp) strains that cause a wide range of infections such as urinary tract infection, pneumonia, bloodstream infection, and pneumonic sepsis, primarily among the elderly, immunocompromised, critically ill and cancer patients. Hypervirulent Kp (hvKp) is currently the most common pathotype that can be differentiated from classic Kp (cKp) due to carriage of a cluster of virulence factors located in a virulence plasmid or other mobile genetic elements that can be integrated into the chromosome. The threat posed by these strains has been compounded by the fact that they undergo evolution continuously, rendering them resistant to carbapenems and various other antibiotics. Evidence gathered in our laboratory and others showed that emergence of carbapenem-resistant hvKp (CR-hvKp) was due to acquisition of a pLVPK-like virulence plasmid by the carbapenem resistant strains, or plasmids containing various carbapenemase genes such as blaKPC-2, blaVIM, or blaNDM-1 harbored by the hvKp strains. Therapeutic options for infections caused by CR-hvKp, which simultaneously exhibit multidrug resistance and hypervirulence, are extremely limited, resulting in extremely high mortality among the infected patients. In the current scenario of rapidly emerging phenotypic antimicrobial resistance in Kp, the need to hunt for novel antibiotics is urgent, so are new therapies for infections caused by the hvKp strains. For instance, phage therapy was found to exhibit promising therapeutic potential in managing Kp infection. Drug combination therapies, such as usage of econazole in combination with colistin, or the polymyxin B and zidovudine combination, was shown to be successful in treatment of Kp infection. An ideal treatment protocol should address the immune responses elicited by Kp infection. Comprehensive understanding of hvKp-host interaction, especially the hvKp-mediated immune responses, is necessary. Although Kp-host interaction has been studied for more than 20 years, most research showed that pro-inflammatory signaling was crucial to Kp clearance in the host, without providing evidence to explain why hvKp causes a high rate of death. There thus exists a need to develop improved methods of treating hvKp infections in a subject in need thereof. SUMMARY The results presented herein demonstrate that hvKp-induced a type of immune response strikingly different from that induced by cKp in a mouse sepsis model, especially the reactions elicited in monocyte-derived macrophages (MDMs) and neutrophils. Notably, we it was found that hvKp induced expression of a signal transducer and activator of transcription 1 (STAT1)-dependent cytokine storm, which can be suppressed by STAT1 inhibitors or acetylsalicylic acid (ASA). Significantly, combination of antibiotic and ASA could protect mice from death, providing a therapeutic strategy for acute hvKp infection. These findings indicate that hvKp infection can be readily treated by suppressing specific host immune responses, drastically reducing the mortality rate of patients infected by hvKp. In a first aspect, provided herein is a method of treating a hypervirulent Klebsiella pneumoniae (hvKp) infection in a subject in need thereof, the method comprising co-administering a therapeutically effective amount of an antibiotic and a non-steroidal anti-inflammatory drug (NSAID) or a signal transducer and activator of transcription 1 (STAT1) inhibitor to the subject. In certain embodiments, the hvKp comprises a pLVPK-like virulence plasmid or a pK2044-like virulence plasmid. In certain embodiments, the hvKp comprises one or more carbapenemase genes selected from the group consisting of blaKPC-2, blaVIM, blaIMP, blaOXA-48, blaVIM, blaSPM, blaAIM, blaDIM, blaGIM, blaSIM, and blaNDM-1. In certain embodiments, the hvKp comprises one or more carbapenemase genes selected from the group consisting of blaKPC-2, blaVIM, blaIMP, blaOXA-48, blaVIM, blaSPM, blaAIM, blaDIM, blaGIM, blaSIM, and blaNDM-1. In certain embodiments, the hvKp infection causes increased expression in the subject of one or more genes selected from the group consisting of Nlrp3, Caspase-1, Caspase-11, Gsdmd, and Il1b. In certain embodiments, the NSAID is acetylsalicylic acid, naproxen, or a pharmaceutically acceptable salt thereof. In certain embodiments, the STAT1 inhibitor is epigallocatechin-3 gallate, nifuroxazide, fludarabine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the antibiotic is an aminoglycoside, a cephalosporin, a quinolone, or a carbapenem. In certain embodiments, the