Nearly a generation of medical dogma on Lyme disease may be slowly unraveling as new test tube research shows that antibiotics long endorsed as curative do not kill what scientists call "persister" cells -- and may even promote their growth.
The corkscrew Lyme spirochete, known as Borrelia burgdorferi, had been shown in previous research to hide beneath slimy shields called biofilms and shape-shift into "round bodies," persisters that survive lethal drugs and may repopulate later.
But emerging science implicates the antibiotics long used to treat the tick-borne illness, including the predominant doxycycline, as a potential key to persistent infection: While killing most pathogens, the antibiotics commonly prescribed for Lyme disease have been shown in test tubes to leave behind a smattering of remarkably resilient Lyme bacteria. As the bacteria's growth slows under antibiotic assault, these persister cells increase, sometimes dramatically, three research groups found, providing a plausible explanation for a problem that has bedeviled Lyme disease care.
While most patients are treated successfully with go-to antibiotics, some 10 to 20 percent remain sick. With an estimated 300,000 U.S. Lyme cases annually,
that means 30,000 to 60,000 people every year develop lingering neurological, arthritic or other symptoms, some for months or years. Many are told their symptoms are "subjective," even psychological, and aren't tied to Lyme disease.
Care guidelines challenged
Ying Zhang, a Johns Hopkins University researcher, said his and other test-tube research "clearly demonstrates Borrelia persisters are not killed by the current Lyme antibiotics." Scientists have tried stronger and combined antibiotic treatments in test-tube experiments and found many to be more effective than those in common use. They say funding is desperately needed to prove that persisters are causing illness in people -- the "missing link," said one scientist -- yet there is little money and huge resistance. In fact, Lyme disease placed 202nd in 2015 in a ranking of federal funding by disease -- this though the disease costs the healthcare system up to$1.3 billion a year.
The debate over Lyme disease, one of the most vicious and polarized in medicine, pits a small medical society founded by Lyme practitioners, the International Lyme and Associated Diseases Society, against the hugely powerful and connected Infectious Diseases Society of America, whose guidelines have ruled Lyme patient care since 2001. Patient advocates say the protocols are rigid in limiting antibiotic courses, rely on diagnostic tests that often fail, and do not reflect other studies, some years before these latest ones, that have shown the Lyme spirochete survives antibiotic treatment.
The IDSA guidelines, recently taken off the National Guidelines Clearinghouse as out of date, say that single, short courses of doxycycline, amoxicillin and, sometimes, intravenous ceftriaxone are almost always enough to kill the Lyme spirochete in people, and their authors and supporters have sought to debunk and challenge research that calls them into question.
But in perhaps 20 papers since 2012, scientists from major research centers demonstrate their considerable, often frustrating, efforts to eradicate Lyme spirochetes in animals and test tubes, and, in particular, the persisters that survived initial antibiotic onslaught.
- A University of California, Davis, team gave ceftriaxone to Lyme-infected mice and was "stunned," the lead author said, to see the infection resurge after 12 months to the same level as in untreated mice.
- A Northeastern University team found the bacteria's persisters were so ironclad that it took four "pulsed" doses of ceftriaxone or a single dose of a highly toxic anticancer drug, not recommended for Lyme patients, to kill them.
- A Tulane University experiment found the Lyme spirochete was more likely to form persisters if it had been treated with doxycycline at a certain phase in the bacteria's growth -- as did the Northeastern study -- and hitting the bacteria in repeated pulses of doxycycline did not stop growth or reduce the persisters.
- And last May, a Johns Hopkins University team reported that 23 drugs were more effective in the test tube against persisting "round body" forms of the Lyme spirochete than the two pillars of human treatment, amoxicillin or doxycycline.
Although the cause of post-treatment illness "is unclear," Hopkins researchers reported, "one possibility is the presence of bacterial persisters not effectively cleared by the current Lyme antibiotics."
Treatment guidelines of the smaller ILADS group -- which, unlike the IDSA's protocols, have the Guidelines Clearinghouse imprimatur -- allow for longer and repeated antibiotic courses. The rapidly emerging research doesn't go as far as to support that, at least yet, because the experiments have mostly been done on animals or in test tubes -- limitations that fail to convince IDSA supporters that the case has been made.
"The newer research still leaves the problem that it is not known to be modeling phenomena that occur in human disease," said Dr. Paul Lantos, a medical instructor at Duke University School of Medicine who has challenged the notion that Lyme disease can be chronic.
IDSA: No comment
Officials of the IDSA did not respond to requests for comment; two guideline authors also did not respond, while lead author Gary Wormser declined comment. Guideline authors and proponents have generally maintained that lingering spirochetes have been genetically impaired and are noninfectious, and that ongoing complaints of Lyme patients may be caused by some other illness or Lyme-related tissue damage or inflammation.
Nonetheless, the fast accumulating evidence that Lyme spirochetes survive antibiotic assault may be more difficult for naysayers to dismiss. For one, it is emanating from respected research centers, like Johns Hopkins, Northeastern, Tulane, UC Davis, and Tufts University. It has also produced breakthroughs, scientists say. At a small Lyme lab at the University of New Haven, in the shadow of Yale University, a scrappy scientist named Eva Sapi has shown why the Lyme spirochete is so resilient: in a word, biofilms, complex extracellular aggregates that shield the bug from the strongest drugs.
"She has shown unequivocally that Borrelia burgdorferi sensu stricto can form biofilms in vitro," said Garth Ehrlich, executive director of the Center for Advanced Microbial Processing at Drexel University who is renowned for research on biofilms in other bacteria. "And she has additional strong suggestive evidence that it can form biofilms in vivo," namely in people. In one experiment, Sapi found biofilm-encased spirochetes in archived biopsies from Lyme-infected patients.
These results "strongly indicate the presence of persistent, viable, but uncultivable spirochetes." -- California researcher
Emir Hodzic, a professor and director of the Real-time PCR Research and Diagnostic Core Facility at UC Davis, led a team that treated Lyme-infected mice with antibiotics and found a resurgence in infection 12 months later. However, Hodzic couldn't cultivate the organisms; Lyme tests currently diagnose -- and often fail to diagnose -- the disease by finding Lyme antibodies and proteins in the blood of patients.
The lack of cultured spirochetes "gives the denialist the reason to deny such a condition (as post-treatment syndrome) ever exists," said Hopkins' Dr. Zhang. Indeed, Wormser, the IDSA guidelines author, reported several months after Hodzic's publication that he cultured spirochetes in untreated mice that were infected with the Lyme bug but not in treated mice, findings that "further document the effectiveness of antibiotic therapy."
Nonetheless, Hodzic, who tracked his mice for 12 months against Worsmer's three, found lingering infection in other ways: Uninfected ticks that fed on the treated mice actually acquired the spirochetes; the ticks later fed on and infected other mice. Tissue transplanted from treated to uninfected mice wound up infecting them. And spirochetal DNA was found in the treated mice.
These results "strongly indicate the presence of persistent, viable, but uncultivable spirochetes," Hodzic wrote in an email, noting "culture cannot be relied upon as a gold standard of viability."
Research money short
Tufts scientists showed in another way that infection could survive antibiotic treatment. Lyme patients who had been treated with antibiotics agreed to have uninfected ticks feed on them -- and, in a reversal of the Lyme norm, ticks from two of 21 patients acquired the Lyme bug from their human hosts. The study said there was "insufficient evidence, however, to conclude that viable spirochetes were present in either patient."
"I remain open to evidence about whether there is chronic infection in the patient populations." -- Critic of 'chronic' Lyme diagnosis
That's why researchers who believe spirochetes survive antibiotic treatment want more money for studies, and question why it is so difficult to get. Lyme disease researchers got a mere $25 million from the National Institutes of Health in 2015, far less than many illnesses with lower case counts.
The Lyme debate has seemed to teeter before in favor of a new view on treatment, for example, in 2008 when then-Connecticut State Attorney General Richard Blumenthal, now a U.S. senator, charged that some on the Infectious Diseases Society of America panel that crafted the Lyme guidelines had "undisclosed financial interests" and forced their reconsideration. Nothing substantive came of the review, however.
But there may, nonetheless, be movement afoot. A longtime critic of the notion of chronic Lyme infection, Paul Auwaerter, is among the authors of three Johns Hopkins papers on the spirochetes' stubborn ability to persist after treatment, results he interpreted with caution.
"These experiments with drug combinations were in vitro only which means in a test tube," Auwaerter wrote through email when asked about the experiments. "Whether this approach will assist is unclear in my mind ... I remain open to evidence about whether there is chronic infection in the patient populations that hope antibiotics will fix them."
Patients: Find a solution
To be sure, Lyme patients want to be fixed. But what they really want, after years of being told that Lyme disease is easy to diagnose and cure, is for medicine to recognize the problem of post-treatment or chronic Lyme -- whatever it may be called -- and devote the resources needed to find a treatment that works. Many patients say they cannot get doctors to care for them because the doctors simply do not know what to do. And some doctors have been professionally censured or lost licenses for treating outside of the prevailing Lyme guidelines.
"I was stunned as I started learning about all of this," said Drexel's Ehrlich, who referred several times in an interview to a "cabal" of powerful physicians who he said is unwilling to acknowledge that Lyme disease treatment needs re-examination.
"Lyme disease has somehow been so politicized," he said. "That's one reason we're so bad at it."
Another may very well be the tools we are using to fight Lyme disease: Several scientists said doxycycline alone was a poor choice as a frontline Lyme antibiotic. And their experiments show why.
"We do know that the spirochetes can remain in animals following doxycycline treatment," said Monica Embers, a Tulane researcher whose ground-breaking study in 2012 found live spirochetes in Lyme-infected Rhesus monkeys after they were dosed with antibiotics.
The next step is to sort out whether the disease itself, along with the Lyme bug, survives antibiotic therapy, as scientists suspect. "I just want to figure out how to biologically rid individuals of the spirochetes," Embers said.