FAQs: Phage Therapy at UC San Diego Health

What treatment did the patient receive?
Nov. 30 - Dec. 2, 2015
Doctors in Egypt initially diagnosed Patterson with pancreatitis — inflammation of the pancreas — but standard treatments, including pain relievers, intravenous fluids and antibiotics (gentamycin and a third generation cephalosporin), didn’t help.

Dec. 3-12, 2015
Patterson’s condition worsened and he was medevacked to Frankfurt, Germany, where doctors discovered a pancreatic pseudocyst. It was drained and the contents cultured, revealing an infection with A. baumannii. The only antibiotics with any effect proved to be a combination of meropenem, tigecycline and colistin, a drug of last resort because it often causes kidney damage, among other side effects. Patterson’s condition stabilized sufficiently for him to be airlifted Dec. 12, 2015 from Germany to the Intensive Care Unit at Thornton Pavilion at UC San Diego Health.

Dec. 2015 - March 2016
At Thornton Pavilion at UC San Diego Health, Patterson began to recover, moving from the ICU to a regular ward. By this time his isolate had become resistant to almost all known antibiotics, but researchers in the UC San Diego School of Medicine lab of Victor Nizet, MD, determined that, while not curative, a combination of the antibiotics azithromycin, rifampin and colistin could hold the infection at bay. Then, the day before Patterson was scheduled to be discharged to a long-term acute care facility, an internal drain designed to localize the infection slipped, spilling bacteria into his bloodstream. He quickly experienced septic shock, an overreaction of the immune system that can lead to organ failure. Patterson fell into a coma that lasted most of the next two months.

March 2016
On March 15, 2016, with emergency approval from the U.S. Food and Drug Administration (FDA), Patterson began treatment with bacteriophages (phages), viruses that infect only bacterial cells, in this case specifically Acinetobacter baumannii. The phages were introduced in cocktails through catheters into his abdominal cavity as well as intravenously, procedures that have rarely before been performed in the U.S., particularly since antibiotics were introduced in the 1940s.

Where did the phages come from?
Many researchers around the world were willing to help Patterson, but given the time constraints, only three were found to have suitable phages that were active against his particular bacterial infection: the Center for Phage Technology at Texas A&M University; the Biological Defense Research Directorate of the Naval Medical Research Center in Frederick, MD; and AmpliPhi, a San Diego-based biotech company specializing in bacteriophage-based therapies. Researchers at San Diego State University volunteered to purify the phage cocktails to ensure that they were met FDA guidelines for clinical use.

How does phage therapy work?
Phages are viruses that specifically dock on, invade and kill bacterial cells. There are trillions of phages in the world and each type infects only one or a few specific bacterial strains. To replicate, phages attach to a bacterium and insert their genetic material. Some phages then split open the cell to release new viral particles, killing the bacterium in the process.

Is phage therapy new?
No — phage therapy originated in the early 1900s, but fell out of favor in most parts of the world once antibiotics became commonplace. Phage therapy continued to be studied and tested throughout the 20th century in what is now Russia, Poland, and the Republic of Georgia, but trials were not controlled, randomized or blinded. While a few robust clinical trials in the 2000s have shown phage therapy to be generally safe, in all trials the phage cocktails were administered only topically on the skin or in the ear canal.

How does Tom Patterson’s case at UC San Diego Health differ from the case at Yale University, where researchers reportedly used a bacteriophage taken from a local pond to treat life-threatening bacterial infection in an 80-year-old man’s chest?
That case, described in the May 26, 2016 issue of Scientific Reports, is similar to the UC San Diego treatment of Patterson, but only in the sense that they both used bacteriophages to treat multidrug-resistant infections. Success in the Yale case appears to have relied upon the conversion of the bacteria (Pseudomonas aeruginosa) to an antibiotic-sensitive strain while in Patterson’s case at UC San Diego Health, phages were used to directly treat the A. baumannii bacterial infection.

Additionally, the Yale case involved direct application of phages to an open wound. As noted earlier, the UC San Diego phage treatment was administered systemically through an IV for several weeks.

Finally, the Yale treatment relied upon the perhaps serendipitous discovery of a pond phage that was effective against the patient’s particular bacterial infection. Such an approach would not be practical or reproducible if phage therapy were scaled up for widespread use. While still just one case, the UC San Diego effort reflects a longer term strategy: Development of a phage bank and rapid phage/pathogen matching system that would be applicable and effective to patient-specific infections in diverse situations. In the UC San Diego case, a second generation phage cocktail was developed within 10 days, once the first phage cocktails had generated resistance.

Will more patients now have access to this phage therapy?
Not yet. The FDA is still approving phage therapy only on a case-by-case basis, and only for patients who have exhausted all other treatment options and have a source of phage specific to the bacterial strain causing his or her infection. However, Tom Patterson’s successful case may accelerate clinical development and provide incentive for the development of a new regulatory framework that improves the accessibility of phage therapy over the next decade.

What are the benefits of phage therapy?
Phages may help overcome the three main drawbacks to today’s antibiotics: 1) resistance; 2) collateral damage to beneficial bacteria that make up our microbiomes; and 3) the long period of time it typically takes for new drugs to be developed. Though bacteria can develop resistance to phages (e.g., they can eventually shed the surface receptors that phages use to dock and enter the cells), this is not an insurmountable hurdle. Since there is a nearly inexhaustible supply of phages in nature, if resistance does occur, researchers can find new phages that use other receptors. In addition, phages are very specific about the bacteria they infect, so the collateral damage to other bacteria or human cells is minimal. In Tom Patterson’s case, after his bacteria were found to be resistant to the first cocktail of phages he received, a second generation phage cocktail was identified and prepared for use within 10 days. The potential for an ever-expanding phage library that can be used to match phages to patients’ specific bacterial infections is being explored by several teams worldwide.

What are the risks of phage therapy?
After decades of observational use in Russia and Eastern Europe, phage therapy appears to be generally safe, particularly when applied topically to the skin. However, lack of large, controlled, randomized, double-blind clinical trials means researchers don’t have a complete picture of phage therapy’s long-term safety, particularly when it is administered systemically. Many types of bacterial cells release endotoxins when broken open by phages. Endotoxins can trigger an overwhelming immune response (septic shock) and organ failure. Yet this is also a concern for some currently available antibiotics. In Tom Patterson’s case, no danger was posed from bacterial or phage endotoxins. A remaining safety issue to be resolved is the extent to which phages could transmit new toxin or antibiotic resistance genes to people during phage therapy. This hurdle can be overcome by selecting phages that have been carefully screened and for which the bacterium-phage relationship has been well studied.

Will phage therapy replace antibiotics?
Unlikely. Most experts agree that phage therapy will never completely replace antibiotics. Instead, this approach may be used in combination with antibiotics, or as the last line of defense for patients with infections that have not responded to antibiotics.