Freedom from antibiotic purgatory? Salvage phage therapy for cure of spinal hardware infection

PHAVES #16, a seminar by Dr. Laura Damioli and Dr. Greg Canfield (May 12, 2021)

YouTube video

Overview and highlights

The patient case

• 80 year old patient, complaints of wound dehiscence (wound separation) following spinal hardware surgery to correct kyphoscoliosis (abnormal curve of the spine).
• The patient also had medical co-morbidities, including recurrent UTIs, which placed a higher risk of infection following hardware surgery.
• Cultures from the open wound found to grow 3 colony variants Pseudomonas aeruginosa, all with similar antibiotic sensitivity patterns.
• A lack of wound healing after wound vacuuming, antibiotic treatment, and subsequent wound wash-out and muscle flap surgery. The drainage from the wash-out cultured Pseudomonas aeruginosa.

Challenges

• Hardware infections are hard to treat due to Pseudomonas aeruginosa biofilms
• Antibiotics aren't good at sterilising the hardware, and the patient was not a good candidate for hardware extraction.
• Quinolones are the only oral antibiotic with activity against Pseudomonas aeruginosa, however, the patient was a poor candidate for quinolones. Additionally, previous data shows that 36% of patients had intolerability to quinolones following prosthetic joint infections, with 43.3% of these experiencing adverse reactions

Options for the patient

1. IV antibiotics for 6-12 months, followed by hardware extraction if infection resolved.
2. Antibiotics + phage therapy
3. Hospice care

The patient chose option 2.

Option 2: Phage Therapy

• The three Pseudomonas aeruginosa strains isolated from the patient were sent to Paul Turner's Lab (Ben Chan & Jon Koff) at Yale University.
• Multiple lytic phages were found to lyse the clinical isolates of Pseudomonas aeruginosa, however, the 3 strains showed varying degrees of phage sensitivity.
• 5 phages were chosen based on qualitative (spot test) and quantitative (killing kinetics, EOP etc.,) characterisation.

The treatment plan

• Over an 8-week period, 4 different phage regimens were administered, either singly or in a phage cocktail combination (1 x 10^9 - 5 x 10^10). Between 5-100 mL of the phage formulation was administered, either into the patient's catheter or spinal drain.
• 2 hours after phage therapy, antibiotics were administered (as previous literature has shown that the order of phages/antibiotics matters).
• New phages were chosen every 2 weeks (as it has been shown previously there is a fitness trade-off between phage resistance and antibiotic resistance).

Patient monitoring

• Inflammatory tests (Biomarker of resolving infection)
• Organ monitoring
• CT scans of the spine

Results

• Successful resolution of Pseudomonas aeruginosa infections. No sign of hardware of infection 60 days after treatment.
• Recurrent UTIs on-going and C. difficile diarrhea.

June 2021 update: The patient is off all antibiotics, with no signs of recurrence of the hardware infection.

Audience question highlight

Q: The propagation strain of Pseudomonas aeruginosa harboured 7 prophages. Did you check to see if these excised and were present? Do you see this as a problem?

A: Yes this a potential problem, but was NOT observed in this study. Given the potential of induced prophages to horizontally transfer antibiotic resistance and toxin-associated associated genes to susceptible bacterial hosts, it might be important to use prophage-less bacterial strains for lytic phage amplification.

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Thanks to Atif Khan for help finding and summarizing this week's job posts!