Use of Phage Cocktail BFC 1.10 in Combination With Ceftazidime-Avibactam in the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Femur Osteomyelitis—A Case Report

Abstract

High-energy trauma with severe bone fractures can be complicated by infection, leading to the development of osteomyelitis. Pseudomonas aeruginosa is an important causative agent of such infections because of its high virulence profile and ability to develop resistance against a wide range of antimicrobials quickly. P. aeruginosa biofilms cause treatment failure and relapsing infections. Bacteriophages are viruses that can be used to treat biofilm-associated infections. Moreover, the combination of phages with certain antimicrobials have demonstrated synergistic and additive effects. We present a case of a 21-year-old patient with relapsing multidrug-resistant (MDR) P. aeruginosa femur osteomyelitis that developed after a road accident, with a proximal right femoral Grade III B open fracture and severe soft tissue damage. Despite extensive antimicrobial treatment and multiple surgical interventions with wound debridement, the infection persisted, with subsequent development of femoral osteomyelitis with a fistula. Patient care management included femoral head excision with wound debridement, intravenous (IV) ceftazidime-avibactam, and the local application of the lytic Pseudomonas bacteriophage cocktail BFC 1.10. Nine months after the intervention, the patient did not show any clinical, radiological, or laboratory signs of inflammation; therefore, hip replacement was performed. Nevertheless, recurrent P. aeruginosa infection evolved at the distal side of the femur and was successfully treated with conventional antimicrobials. In this case, wound debridement combined with antibiotics and bacteriophages resulted in bacterial eradication of proximal femoral segment, avoiding leg amputation, but failed to treat osteomyelitis in distal bone segment. An in vitro assessment of the isolated MDR P. aeruginosa strain for biofilm formation and phage susceptibility was performed. Additionally, the antimicrobial effects of ceftazidime-avibactam and BFC 1.10 were determined on planktonic cell growth and bacterial biofilm prevention was evaluated. The isolated bacterial strains were susceptible to the bacteriophage cocktail. Strong biofilm formation was detected 6 h after inoculation. Ceftazidime-avibactam combined with BFC 1.10 was most effective in preventing planktonic cell growth and biofilm formation. In both cases, the required concentration of ceftazidime-avibactam decreased two-fold. This study demonstrates the possible use of bacteriophages and antibiotics in difficult-to-treat bone and soft tissue infections, where the additive effects of phages and antibiotics were observed.

Antimicrobial Treatment of Pseudomonas aeruginosa Severe Sepsis

“…Phage therapy was also combined with antibiotics (phage-antibiotic synergy) to increase bacterial killing of MDR P. aeruginosa in vitro [ 138 , 139 ]. There are several case reports of a combination of antibiotics with phage therapy to treat resistant P. aeruginosa infections, particularly in cases of chronic infections: antibiotics in various reports consisted of ceftazidime in endovascular infection with bacteremia [ 140 ]; meropenem, tobramycin, and polymyxin B in endovascular infection with bacteremia [ 141 ]; cefiderocol in cranial osteomyelitis [ 142 ], meropenem and colistin in UTI [ 143 ], CAZ/AVI in femur osteomyelitis [ 144 ], piperacillin/tazobactam, tobramycin, and colistin in lung transplant recipients [ 145 ], and other conventional antibiotics for empyema [ 146 ]. However, to date there is no data on the efficacy of phage therapy in sepsis.…”

Ceftazidime-Avibactam as Osteomyelitis Therapy: A Miniseries and Review of the Literature

“…Clinical data on CAZ–AVI’s efficacy in treating BJIs are limited. Nonetheless, several reports mentioned that patients with osteomyelitis or arthritis caused by MDR/XDR-GNB were successfully treated with CAZ–AVI [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”

“…Thirteen case reports that described fourteen patients with BJI treated with CAZ–AVI which were published between 2017 and 2022 were selected for the analysis [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. The characteristics of the retrieved patients are shown in Table 3 , together with those of the three patients we previously described.…”

Antibiofilm approaches as a new paradigm for treating infections

“…Aside from antibiotics, new therapies such as bacteriophage cocktails, are also emerging. Recent studies, for example, have demonstrated the efficacy of bacteriophages against MRSA, especially in association with daptomycin and ceftaroline with a >3 log 10 CFU ml −1 reduction (Kebriaei et al 2022), and against P. aeruginosa in difficult-to-treat bone and soft tissue infections in combination with low ceftazidimeavibactam concentrations (two-fold lower than the standalone needed concentrations) (Racenis et al 2022).…”