For Bay Area born and raised Derek Amanatullah, joining Stanford School of Medicine was a dream. When his first bid to come to Stanford as a medical student didn’t materialize, he pursued his training elsewhere, but kept his sites on Stanford. From Los Angeles to New York, Davis to Minnesota and even the UK, Amanatullah amassed a wealth of knowledge and experience. He studied molecular and cell biology while conducting research on chromatin repressor proteins, imagining a career in oncology. But a shoulder injury and subsequent surgery led him to orthopaedic surgery.
When it came time to meld his interest in basic science with his passion for clinical care, he once again pursued Stanford, this time successfully joining its faculty in October 2014 as an Assistant Professor of Orthopaedic Surgery. The collaborative, cross-disciplinary environment at Stanford is the perfect breeding ground for Amanatullah, who splits his time 80/20 between clinical practice and research. Today, he is one of a small group of MD/PhDs in Orthopaedic Surgery in the nation addressing what he considers one of the fundamental challenges of his specialty—post-surgical infections after joint replacement surgery.
“One of the biggest problems in joint replacement surgery is peri-prosthetic joint infection,” Amanatullah said. Over half of his practice is revising failed joint replacements, and over half of those revisions are due to peri-prosthetic joint infections. “It [peri-prosthetic joint infection] is the number one cause of revision surgery for knee replacements and the third leading cause of revision hip replacements.”
Of the one million joint replacements conducted in the US in 2018, 10 percent will need a revision, estimates Amanatullah, and of those revisions, 25 percent will be due to infection. By 2030, the number of joint replacement surgeries conducted in the U.S. is expected to jump to over 1.7 million, paving the way for an increasingly larger number of peri-prosthetic joint infections.
“Infection of orthopaedic implants is a rare problem for infectious disease doctors, but a very common problem for orthopaedic surgeons,” said Amanatullah. Eradicating peri-prosthetic joint infections at their earliest onset would be a game changer for joint replacement surgery. Current treatment is a largely morbid undertaking that involves removing all or part of the joint replacement, debriding the infection site, delivering antibiotics directly to the affected area with antibiotic-laden bone cement, and placing the patient on intravenous antibiotics.
“Surgery alone cannot solve the peri-prosthetic joint infection crisis,” said Amanatullah. Nor can antibiotics. After repeated exposure to antibiotics, bacteria can become less metabolically active persister cells. “We’re trying to develop therapies that target these bacterial persister cells,” he said, “and we know that those solutions cannot be antibiotics.”
To address this problem, Amanatullah has teamed up with Robert Manasherob, PhD, a staff microbiologist; Paul Bollyky, MD, PhD, an infectious disease specialist; David Lowenberg, MD, an orthopaedic surgeon specializing in musculoskeletal infections; and Annelise Barron, PhD, an expert in molecular synthesis. Together they are looking at ways to disrupt bacteria’s natural ability to protect itself and proliferate.
In one area of study, Amanatullah and his team are using bacteriophages. Bacteriophage is a natural predator of bacteria, a bacteria-specific virus that will infect the infection. A second area has been in developing more resilient antibiotics, called peptoids, which are non-degradable. The peptoid’s protein molecules are modified so that enzymes in the body cannot break them down. In a third area of study, the team is looking at non-specific phage-derived therapies, using chemicals or properties of the bacteriophages, to attack the infection and make antibiotics more effective. The fourth area of research is in developing drugs that can interfere with bacteria’s ability to communicate with each other. Most of the studies being done in this area involve quorum quenching, getting bacteria to act as if it has not amassed enough partner bacteria to attack, basically keeping an infection silent. But Amanatullah’s idea is to coax bacteria to do just the opposite; to express virulence before it has the numbers to overwhelm the innate immune system, leading to auto-sterilization of the implant.
“We would like to stimulate the bacteria to express virulence with very few bacteria around, so your body can auto-eradicate or auto-sterilize a wound or implant even if small amounts of bacterial contamination are present,” he said. Rather than quorum quenching, Amanatullah is looking at forcing quorum stimulation. “We want to expose any underlying contaminant to the body’s immune system before the bacteria has time to make biofilm or become a persister cell.”
“Over the next decades, if we don’t find some novel solutions for peri-prosthetic joint infections, we will not have addressed the central challenge facing orthopaedic surgery,” said Amanatullah. “This is the problem my generation of surgeons has to solve over the next 20 years.”