Bacteriophage Treatment Rescues Mice Infected with Multidrug-Resistant Klebsiella pneumoniae ST258

Abstract

Severe infections caused by multidrug-resistant Klebsiella pneumoniae sequence type 258 (ST258) highlight the need for new therapeutics with activity against this pathogen. Bacteriophage (phage) therapy is an alternative treatment approach for multidrug-resistant bacterial infections that has shown efficacy in experimental animal models and promise in clinical case reports. In this study, we assessed microbiologic, histopathologic, and survival outcomes following systemic administration of phage in ST258-infected mice. We found that prompt treatment with two phages, either individually or in combination, rescued mice with K. pneumoniae ST258 bacteremia. Among the three treatment groups, mice that received combination phage therapy demonstrated the greatest increase in survival and the lowest frequency of phage resistance among bacteria recovered from mouse blood and tissue. Our findings support the utility of phage therapy as an approach for refractory ST258 infections and underscore the potential of this treatment modality to be enhanced through strategic phage selection. IMPORTANCE Infections caused by multidrug-resistant K. pneumoniae pose a serious threat to at-risk patients and present a therapeutic challenge for clinicians. Bacteriophage (phage) therapy is an alternative treatment approach that has been associated with positive clinical outcomes when administered experimentally to patients with refractory bacterial infections. Inasmuch as these experimental treatments are prepared for individual patients and authorized for compassionate use only, they lack the rigor of a clinical trial and therefore cannot provide proof of efficacy. Here, we demonstrate that administration of viable phage provides effective treatment for multidrug-resistant K. pneumoniae (sequence type 258 [ST258]) bacteremia in a murine infection model. Moreover, we compare outcomes among three distinct phage treatment groups and identify potential correlates of therapeutic phage efficacy. These findings constitute an important first step toward optimizing and assessing phage therapy’s potential for the treatment of severe ST258 infection in humans.

Advances in Phage Therapy: Targeting the Burkholderia cepacia Complex

“…This principle is well established in modern phage therapy, since it is identical to the one that has been used to guide the successful development of chemical antimicrobial and antiviral cocktails since at least the late 1980s [ 232 , 233 ]. Consequently, the field is rife with phage therapy trials employing polyphage cocktails, including several successful human trials, with authors consistently reporting the predictable superiority of these cocktails over monophage therapy [ 135 , 172 , 182 , 187 , 193 , 195 , 196 , 213 , 234 , 235 , 236 , 237 , 238 ]. Despite the criticisms levelled against temperate phages by a number of authors, polyphage cocktails that combine temperate phages with more virulent types also appear to be highly effective [ 165 , 172 , 187 ].…”

Microencapsulated phages show prolonged stability in gastrointestinal environments and high therapeutic efficiency to treat Escherichia coli O157:H7 infection

“…Phages are very effective and have been successfully used to prevent and treat bacterial infections in animals [ 14 – 16 ]. Although phages can be administered in a variety of ways, including via parenteral, topical, oral and inhaled routes, by lavage and through eye and nose drops [ 13 , 17 ], the current problem is that phages lack suitable dosage forms.…”

Successful Treatment of Staphylococcus aureus Prosthetic Joint Infection with Bacteriophage Therapy

“…Even though intra-articular and IV phage was administered in both BT courses, the second course also included hardware removal and physical washout of the infected joint cavity leading to a reduction in organism and biofilm burden; this most likely played a role in the resolution infection. Previous cases of BT for PJI include long IV courses of phage as well as local joint injection along with drainage of the infected joint (via arthroscopy, local drain placement and/or surgical debridement) [ 8 , 14 , 23 , 24 , 25 ]. Additionally, the concentration of phage was different in both cycles as well—10 8 PFU/mL in the first and 10 10 PFU/mL in the second; this higher concentration may have played a role in the successful outcome, as seen in another successful case in which 6.3 × 10 10 PFU/mL was used [ 8 ].…”

“…It is not surprising that phages stimulate an adaptive immune response, which could potentially affect BT [ 25 , 29 ]. One mouse model study noted development of humoral activity against S. aureus phages delivered orally [ 30 ].…”