Dataset Information

Combination Therapy of Phage vB_KpnM_P-KP2 and Gentamicin Combats Acute Pneumonia Caused by K47 Serotype Klebsiella pneumoniae.

ABSTRACT: Klebsiella pneumoniae (K. pneumoniae) is an important nosocomial and community acquired opportunistic pathogen which causes various infections. The emergence of multi-drug resistant (MDR) K. pneumoniae and carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) has brought more severe challenge to the treatment of K. pneumoniae infection. In this study, a novel bacteriophage that specifically infects K. pneumoniae was isolated and named as vB_KpnM_P-KP2 (abbreviated as P-KP2). The biological characteristics of P-KP2 and the bioinformatics of its genome were analyzed, and then the therapeutic effect of P-KP2 was tested by animal experiments. P-KP2 presents high lysis efficiency in vitro. The genome of P-KP2 shows homology with nine phages which belong to "KP15 virus" family and its genome comprises 172,138 bp and 264 ORFs. Besides, P-KP2 was comparable to gentamicin in the treatment of lethal pneumonia caused by K. pneumoniae W-KP2 (K47 serotype). Furthermore, the combined treatment of P-KP2 and gentamicin completely rescued the infected mice. Therefore, this study not only introduces a new member to the phage therapeutic library, but also serves as a reference for other phage-antibiotic combinations to combat MDR pathogens.

SUBMITTER: Wang Z

PROVIDER: S-EPMC8100603 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Combination Therapy of Phage vB_KpnM_P-KP2 and Gentamicin Combats Acute Pneumonia Caused by K47 Serotype Klebsiella pneumoniae.

Wang Zijing Z Cai Ruopeng R Wang Gang G Guo Zhimin Z Liu Xiao X Guan Yuan Y Ji Yalu Y Zhang Hao H Xi Hengyu H Zhao Rihong R Bi Lanting L Liu Shanshan S Yang Li L Feng Xin X Sun Changjiang C Lei Liancheng L Han Wenyu W Gu Jingmin J

Frontiers in microbiology 20210422

Klebsiella pneumoniae (K. pneumoniae) is an important nosocomial and community acquired opportunistic pathogen which causes various infections. The emergence of multi-drug resistant (MDR) K. pneumoniae and carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) has brought more severe challenge to the treatment of K. pneumoniae infection. In this study, a novel bacteriophage that specifically infects K. pneumoniae was isolated and named as vB_KpnM_P-K ...[more]

PMID: 33968007

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Project description:We isolated and characterized a novel phage from hospital sewage, P13, able to lyse ST11 K47 carbapenem-resistant Klebsiella pneumoniae (CRKP), a major CRKP lineage. P13 formed a large lytic plaque (3.0 to 6.0 mm in diameter) in double-layer LB agar after overnight coculture with its host bacterial strain. A translucent halo formed when the culture was prolonged to 48 h. P13 showed a narrow host range only lysing ST11 K47 CRKP with a burst size of around 167 PFU/cell and exhibited broad pH and thermal stability. Genome sequencing showed that P13 contains no virulence, lysogenic or antimicrobial resistance genes, making this lytic phage a potential agent for phage therapy. Transmission electron microscopy showed that P13 exhibited typical morphology of the family Podoviridae with an isometric head and a short noncontracted tail. Genomic analysis showed that P13 belongs to a novel species of the genus Przondovirus, subfamily Studiervirinae, family Autographiviridae. P13-resistant mutants of bacteria emerged after 4 h exposure to the phage. Interruptions of wbaP (encoding capsule polysaccharide synthesis) by insertion sequence IS903B mediated P13 resistance. The rapid emergence of resistant mutants represents a disadvantage for P13 as a therapeutic phage and highlights the need for recovery of a range of phages binding to different surface receptors of host bacteria to further extend their utility as a potential tool against CRKP. IMPORTANCE Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a major challenge for infection control and clinical management. Alternative therapies to antimicrobial agents are urgently needed and bacteriophages (phages) are an attractive option. However, more novel lytic phages and more studies to reveal phage-resistant mechanisms are needed to overcome phage resistance. In this study, we isolated and characterized a novel species of lytic phage active against CRKP. We found this phage exhibited delayed formation of halo, which is atypical compared to other characterized similar phages, and we provide an explanation for this phenotype based on genomic analysis. We also identified mechanisms mediating resistance to the phage.

Project description:This research focused on evaluating the clinical results of patients suffering from pneumonia caused by carbapenem-resistant Klebsiella pneumoniae (CRKP), who received treatment with either ceftazidime-avibactam (CZA) alone or in combination with other antibiotics. From January 2020 to December 2023, we retrospectively analyzed CRKP-related pneumonia patients treated in two Chinese tertiary hospitals. Mortality was measured at 14 and 30 days as the primary outcome. Secondary outcomes included the 14-day microbiological cure rate and the 14-day clinical cure rate. Factors contributing to clinical failure were evaluated via both univariate analysis and multivariate logistic regression. To account for confounding factors, propensity score matching (PSM) was utilized. Among the 195 patients with CRKP infections, 103 (52.8 %) received CZA combination therapy, and 92 (47.2 %) patients received CZA monotherapy. The combination therapy group exhibited superior clinical and microbiological cure rates compared to the monotherapy group, with a 14-day clinical cure rate of 60.1 % vs. 45.7 % (P = 0.042) and a 14-day microbiological cure rate of 72.8 % vs. 58.6 % (P = 0.038), respectively. Combination therapy reduced mortality rates at 14 days (7.8 % vs. 17.4 %, P = 0.041), but not at 30 days (14.6 % vs. 25.0 %, P = 0.066). Even after using PSM, the group treated with the CZA combination continued to had a lower mortality rate at 14 days (5.9 % vs. 17.6 %, P = 0.039). The 14-day clinical cure rate for the combination therapy group was 63.2 %, and the 14-day microbial cure rate was 77.9 %. Both of these statistics were notably greater than those observed in the monotherapy group. Furthermore, the multivariate logistic regression model indicated a significant link between combination therapy and a decrease in clinical failure. Carbapenems were noted to be the most effective class of concomitant agents. Our findings indicate that patients with pneumonia due to CRKP benefit from combination treatment of CZA rather than monotherapy; administering carbapenem in combination with CZA in the early stages could provide considerable survival benefits.

Project description:BackgroundPresence of capsule enhances the virulence of bacteria that cause pneumonia, meningitis, cystic fibrosis, dental caries, periodontitis. Capsule is an important virulence factor for Klebsiella pneumoniae and infections due to this pathogen have been associated with high mortality rates. In the present study, use of an Aeromonas punctata derived capsule depolymerase against K. pneumoniae, to reinstate the efficacy of gentamicin during pneumonia and septicemia was investigated.MethodsDepolymerase was administered in mice intraperitoneally (50 μg) alone as well in combination with gentamicin (1.5 mg/kg), 24 h post infection during acute lung infection and 6 h later during septicemia. Bacterial load, neutrophil infiltration and cytokine levels were estimated. The immunogenicity of protein was also studied.ResultsIn comparison to groups treated with gentamicin alone, combination treatment with depolymerase and gentamicin significantly reduced (P < 0.01) bacterial titer in the lungs, liver, kidney, spleen and blood of experimental animals. Highly significant reduction in neutrophil infiltration and levels of pro-inflammatory and anti-inflammatory cytokines was also observed. This indicated an efficient capsule removal by the enzyme, that improved gentamicin efficacy in vivo. Although the enzyme was found to be immunogenic, but no significant reduction in treatment efficacy was observed in the preimmunized as well as naïve mice. In addition, as confirmed through flow cytometry, the hyperimmune sera raised against the enzyme did not neutralize its activity.ConclusionThe results confirm that administration of enzyme 'depolymerase' along with gentamicin not only checked the virulence of K. pneumoniae in vivo but it also increased its susceptibility to gentamicin at a lower concentration. Such a strategy would help to avoid exposure to higher concentration of gentamicin. Moreover, since this decapsulating protein does not possess a lytic activity therefore there would be no chances of development of bacterial resistance against it. Therefore, it should be studied further for its successful inclusion in our prophylactic/therapeutic regimes.

Dataset Information

Combination Therapy of Phage vB_KpnM_P-KP2 and Gentamicin Combats Acute Pneumonia Caused by K47 Serotype Klebsiella pneumoniae.

Publications

Combination Therapy of Phage vB_KpnM_P-KP2 and Gentamicin Combats Acute Pneumonia Caused by K47 Serotype <i>Klebsiella pneumoniae</i>.

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