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. 2021 Jan 25:10:608402.
doi: 10.3389/fcimb.2020.608402. eCollection 2020.

Heterogeneous Klebsiella pneumoniae Co-infections Complicate Personalized Bacteriophage Therapy

Jinhong Qin  1   2   3 , Nannan Wu  2 , Juan Bao  4 , Xin Shi  1 , Hongyu Ou  5 , Shanke Ye  6 , Wei Zhao  7 , Zhenquan Wei  8 , Jinfeng Cai  9 , Lisha Li  10 , Mingquan Guo  2   9 , Jingyan Weng  11 , Hongzhou Lu  6 , Demeng Tan  2 , Jianzhong Zhang  11 , Qin Huang  6 , Zhaoqin Zhu  9 , Yejing Shi  2 , Chunlan Hu  2 , Xiaokui Guo  2   3 , Tongyu Zhu  2   4   12
Affiliations

Heterogeneous Klebsiella pneumoniae Co-infections Complicate Personalized Bacteriophage Therapy

Jinhong Qin et al. Front Cell Infect Microbiol. .

Abstract

Multidrug-resistant (MDR) organisms have increased worldwide, posing a major challenge for the clinical management of infection. Bacteriophage is expected as potential effective therapeutic agents for difficult-to-treat infections. When performing bacteriophage therapy, the susceptibility of lytic bacteriophage to the target bacteria is selected by laboratory isolate from patients. The presence of a subpopulation in a main population of tested cells, coupled with the rapid development of phage-resistant populations, will make bacteriophage therapy ineffective. We aimed to treat a man with multifocal urinary tract infections of MDR Klebsiella pneumoniae by phage therapy. However, the presence of polyclonal co-infectious cells in his renal pelvis and bladder led to the failure of three consecutive phage therapies. After analysis, the patient was performed with percutaneous nephrostomy (PCN). A cocktail of bacteriophages was selected for activity against all 21 heterogeneous isolates and irrigated simultaneously via the kidney and bladder to eradicate multifocal colonization, combined with antibiotic treatment. Finally, the patient recovered with an obviously improved bladder. The success of this case provides valuable treatment ideas and solutions for phage treatment of complex infections.

Clinical trial registration: www.chictr.org.cn, identifier ChiCTR1900020989.

Keywords: heterogeneous cells; multidrug-resistant Klebsiella pneumoniae; percutaneous nephrostomy; phage therapy; urinary tract infection.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Cystoscope of the inner wall of the bladder. (A) The inner wall of the bladder before phage treatment. The bladder mucosa was hyperemic with local ulceration and pseudomembrane attachment; bilateral ureteral openings were not clearly observed. (B) The inner wall of the bladder post phage treatment. Bladder mucosa was smooth and complete; bilateral ureter openings were clear.
Figure 2
Figure 2
Time course of clinical treatment. (A) Timeline beginning with patient hospitalization and ending with recovery. Major treatment during the course is indicated above the line. Surgery during the course is indicated below the line. (B) Laboratory culture event and culture result during the course.
Figure 3
Figure 3
Transmission electron microscopy image of phages. (A) phage ФJD902. (B) phage ФJD905. (C) phage ФJD907. (D) phage Ф JD908. (E), phage ФJD910.
Figure 4
Figure 4
Phylogenetic trees of K. pneumoniae isolates. (A) The genome-wide SNP-based phylogenetic trees of 21 sequenced K. pneumoniae ST15 isolates and 4 completely sequenced ST15 K. pneumoniae isolates currently available at GenBank (PMK1, BR, Kp-Geo-39795, and Kp36). (B) The genome-wide SNP-based phylogenetic trees of 21 sequenced K. pneumoniae isolates by this study. The phylogeny scheme based on parsimony was generated from 9,170 SNPs for all genomes and 2,795 SNPs for 21 genomes by this study using kSNP3 with k = 21 and displayed by iTOL with midpoint rooting.
Figure 5
Figure 5
Phage susceptibilities of clinical isolates. (A) K. pneumoniae strains isolated before phage therapy. (B) K. pneumoniae strains isolated post ФJD902 therapy. (C) K. pneumoniae strains isolated post Ф902+Ф905 therapy. (D) K. pneumoniae strains isolated post Ф905+Ф907+Ф908 therapy. Phages were serially diluted 10-fold and spotted onto 21 K. pneumoniae as indicated. These assays were repeated three times with similar results and a representative experiment is shown.
See this image and copyright information in PMC

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