Bacteriophage therapy for critical infections related to cardiothoracic surgery

Bacterial resistance to conventional antibiotic therapy represents an increasingly significant challenge for human health worldwide. The objective is to investigate whether bacteriophage therapy could supplement conventional antibiotic therapy in critical cases of bacterial infections related to cardiothoracic surgical procedures or represent a viable alternative to it.

Since September 2015, eight patients with multi-drug resistant or particularly persistent infections involving Staphylococcus aureus, Enterococcus faecium, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli were treated with bacteriophage preparations as a last resort therapy in accordance with Article 37 of the Declaration of Helsinki. The patients had infections associated with immunosuppression following organ transplantation, or infections of vascular grafts, implanted medical devices, and surgical wounds. Individualized phage preparations were administered locally, orally, or by inhalation for varying durations depending on the case. All patients continued to receive conventional antibiotics during the bacteriophage treatment.

Results: The patients ranged in age from 13 to 66 years (average 48.5 ± 16.7), consisting of seven men and one woman. Eradication of the target bacteria was achieved in seven out of eight patients. No serious adverse side effects were observed. (4) Conclusions: Phage therapy can effectively treat bacterial infections related to cardiothoracic surgery when conventional antibiotic therapy fails.
Keywords: phage therapy; bacterial infection; cardiothoracic surgery; implant-associated infection; graft-associated infection; surgical site infection

Patients who have undergone cardiothoracic surgery are at a particularly high risk for life-threatening infectious complications. Surgical site infections contribute significantly to postoperative morbidity and mortality.
Implant-associated infections often become chronic, as bacteria growing on artificial surfaces tend to form biofilms that are highly tolerant of antibiotics. Furthermore, drug-induced immunosuppression makes heart and lung transplant patients particularly vulnerable to life-threatening infections. Given these challenges and the worldwide increase in bacterial resistance to conventional antibiotics, there is an urgent need for new antibacterial agents and strategies.
Bacteriophages (or phages) are viruses that specifically infect bacteria. With the advent of antibiotics, the idea of using bacteriophages to treat clinical infections was neglected for nearly a century, except in some Eastern European countries and the former USSR [1,2]. In recent years, the revival of using lytic phages for difficult-to-treat bacterial infections has gained significant interest; however, relatively few phages have demonstrated clinical efficacy. Nonetheless, several recent case studies have reported success with local [3] and parenteral [4] phage therapy using natural bacteriophages as well as genetically modified bacteriophages [5].
Here we report on a case series of implant- and graft-associated multi-drug resistant or refractory infections that were successfully treated with individualized bacteriophages. The current case series includes patients treated with our recently described strategy of phage application in combination with fibrin glue. Fibrin glue is a two-component hemostat, sealant, and tissue adhesive consisting of fibrinogen and thrombin. In this case, half of the thrombin solution is replaced by phage suspension [6] and the mixture is applied intraoperatively to act as a phage-containing biocompatible scaffold or coating. This unique approach enables the sustained release of phages at infected sites. These results demonstrate that modern phage therapy represents a powerful alternative or viable support to standard antibiotic therapy in severe infections.

Clinical outcome

Patient 1: After the second phage application, Staphylococcus aureus, Enterococcus faecium, and Pseudomonas aeruginosa were no longer detected and phage therapy was stopped. The bacteria were not detected for 16 days following the final phage application, and phage therapy was concluded. Unfortunately, 17 days after the phage therapy, the patient developed a subsequent infection caused by P. aeruginosa and E. coli, which was treated with conventional antibiotic therapy in another hospital only one month later. It is not known whether the second P. aeruginosa isolate was identical to the first P. aeruginosa isolate; however, it had a different antibiogram than the first isolate, which would suggest a separate infection.

Patient 2: Following phage therapy, Klebsiella pneumoniae was not detected in bronchial lavage samples, but it was found in stool samples. However, in contrast to the pan-resistant strain that caused the lung infection, the K. pneumoniae strain isolated from the patient’s stool was susceptible to antibiotics.

Patient 3: After the final phage application, blood culture samples were free of S. aureus. A positron emission tomography/computed tomography (PET-CT) scan performed seven months after phage therapy showed no signs of graft infection.
Antibiotics 09 00232 g001 550Figure 1. PET-CT scans of Patient 3 before (A) and seven months after (B) phage therapy in the area of the aortic graft, and of Patient 4 before (C) and two months after (D) phage therapy in the area of the left ventricular assist device (LVAD) and pleural cavity empyema. The yellow emission indicates the level of accumulation of the tracer substance (2-[18F]fluoro-2-deoxy-D-glucose), which corresponds to inflammation.

Patient 4: Following phage therapy, no bacteria were detected in wound swabs. The left ventricular assist device (LVAD) was not infected, as shown on a PET-CT scan two months after phage therapy (Figure 1D). Patient 4 showed no further signs of bacterial infection; however, this patient died 20 months after the conclusion of phage therapy due to graft failure. It is extremely unlikely that the graft failure and subsequent death were related to the previously resolved infection or to the phage therapy.

Patient 5: The in vitro activity of the phages was tested during phage therapy, and there was no evidence of bacterial resistance to the bacteriophage strains used. After the first dose, viable phages were consistently detected in the drainage fluid (≥104 pfu/mL) before subsequent phage applications were performed. Up to two weeks after phage application, there were no signs of bacteriophage-neutralizing antibodies in the patient’s serum. Nevertheless, moderate but steady concentrations of S. aureus were detected in the drainage fluid. To potentially improve the delivery of phages to the infection site, a surgical procedure was offered but was declined by the patient.
In patients 6-8, the intraoperative application of fibrin glue-bacteriophage preparations to target devices or tissue led to the sustained release of bacteriophages.

Patient 6: S. aureus was not detected after phage therapy. Observation of the pump 1.5 months after phage application showed no signs of infection or remnants of the fibrin glue.

Patient 7: The wound healed completely and E. coli was no longer detected after phage therapy.

Patient 8: The wound healed completely, and P. aeruginosa was no longer detected after phage therapy.

Details at: https://www.mdpi.com/2079-6382/9/5/232/htm

Machine translation of the source: Bacteriophage Therapy for Critical Infections Related to Cardiothoracic Surgery