‘Oral is the new IV’: Another treatment dogma bites the dust?
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A lot of modern medicine is based on what Brad Spellberg, MD, and others call “inertial dogmas” — practices traced to decades-old evidence that are no longer supported by modern studies.
Spellberg helped popularize the “shorter is better” mantra for antibiotic prescribing. Perhaps lesser known is the effort by Spellberg and other clinicians to raise awareness of another longtime treatment dogma in infectious diseases that they believe deserves scrutiny: that IV-only therapy is the only way to treat certain conditions.
In fact, there are “overwhelming and concordant” data showing that oral therapy is at least as effective as IV-only therapy for three conditions — endocarditis, osteomyelitis and bacteremia — Spellberg told Healio | Infectious Disease News.
They have a name for this movement, too: “oral is the new IV.”
‘Myth and lore’
Spellberg, who is chief medical officer at the Los Angeles General Medical Center, is one of the authors of an article published late last year in Open Forum Infectious Diseases in which they argued that oral therapy for these three conditions has not been widely adopted because of historical dogmas.
“The historical practice derived from lack of good oral agents in the 1940s and 1950s, which led experts to publish opinions in an influential journal that grew to the status of myth and legend such that even when better oral agents became available, no one dared to question the myth and lore of the giants of yore,” Spellberg said.
Modern research has shown that, not only can oral antibiotic therapy be as effective as IV-only therapy for certain conditions, but it is also safer because of the variety of adverse events that are avoided by switching to oral therapy.
Spellberg said clinicians who have stuck with IV-only therapy for these conditions have done so out of fear, ego — “experts don’t want to admit they were wrong in the past” — and resistance to change. He forecasted that it could be another decade at least before practice changes.
“Medicine is a very hierarchical field. Dogmas become deeply entrenched,” Spellberg said. “The experts of today become defensive when the dogma of yesterday is challenged because it throws into question the very basis of expertise.”
In their article, Spellberg and colleagues traced the IV-only dogma for endocarditis and osteomyelitis to articles published in The New England Journal of Medicine in 1954 and 1970, respectively.
The conclusions of these papers, “amplified by the opinions of eminent experts,” led to the “nearly universal, fervently held belief that IV-only therapy must be used to treat these diseases,” Spellberg and colleagues wrote.
“Decades ago, when we first started to treat these types of infections with antibiotics, there were cases where oral antibiotics failed to cure the patient and IV antibiotics appeared to work better,” Emily G. McDonald, MD, MSc, a physician and associate professor of medicine at McGill University Health Center and co-author of the paper, told Healio | Infectious Disease News. “Thus, it became ingrained in practice. Since then, newer generations of oral antibiotics have been developed and we have a lot more effective options.”
Unchallenged opinions
For endocarditis, the historical practice of IV-only therapy originated in case series from the 1940s and 1950s that demonstrated cure rates of greater than 75% for IV penicillin and less than 30% for oral sulfanilamide, erythromycin or tetracycline, according to Spellberg and colleagues.
The 1954 New England Journal of Medicine review they cited in their paper was written by Maxwell Finland, MD, then a physician at Boston City Hospital and associate professor of medicine at Harvard Medical School, who Spellberg and colleagues described as “one of the giants of infectious diseases.” Spellberg himself called Finland “perhaps the single most influential figure in infectious diseases” in the United States during the 20th century.
In his review, Finland wrote that oral antibiotics are, “Presumably ... at times successful, particularly when a very early infection with a highly susceptible organism is being treated with massive doses; it is more likely, however, that such usage is responsible for many therapeutic failures since it may serve as an excuse for the delay in instituting adequate treatment, particularly when there is temporary improvement.”
“However, little of this type of experience is recorded, and therefore this assumption cannot be authenticated,” Finland wrote.
Similarly, in 1970, Francis A. Waldvogel, MD, and colleagues published an uncontrolled case series in The New England Journal of Medicine that examined 247 patients treated for osteomyelitis at Massachusetts General Hospital from 1963 to 1966.
“In our experience,” Waldvogel and colleagues concluded from their review, “clinically recurrent osteomyelitis is rarely controlled without the combination of careful, complete surgical debridement and prolonged (4 to 6 weeks) parenteral antibiotic therapy at high dosage.”
According to Spellberg and colleagues, the article is frequently cited as a supporting text for IV-only therapy for osteomyelitis, despite the fact that oral therapy was not attempted in any of the patients included in the case series.
“To be fair to them, there really weren’t good oral antibiotics at that time,” Spellberg said. “But because an opinion was published by a thought leader in The New England Journal of Medicine, it became dogma. No one ever tried to question it for decades.”
Modern research
According to Spellberg and colleagues, there are now a combined 55 observational studies showing that oral therapy is effective for endocarditis and osteomyelitis, and more than 20 combined randomized controlled trials demonstrating that oral therapy is at least as effective as IV-only therapy for endocarditis, osteomyelitis and bacteremia.
One such study, the POET trial, included 400 patients with left-sided infective endocarditis who were randomly assigned to continue IV therapy or switch to step-down treatment with oral antibiotics after at least 10 days of initial IV treatment. Five-year follow-up data reported in The New England Journal of Medicine last year continued to show a benefit from step-down therapy with oral antibiotics among clinically stabilized patients, including a lower incidence of death from any cause.
The 21 studies were identified by Spellberg and others in a systematic review and meta-analysis published last year in The American Journal of Medicine, in which the authors wrote that “guidelines should be modified to indicate that oral therapy is appropriate for reasonably selected patients with osteomyelitis, bacteremia, and endocarditis.”
“Twenty-one concordant randomized controlled trials show that oral therapy works for these three diseases, supported by concordant observational studies and concordant pharmacology data,” Spellberg emphasized.
In all these studies, Spellberg noted that the superiority of IV-only treatment was never demonstrated, and that by using oral therapy, potential side effects of IV treatment were avoided.
The side effects of long-term IV therapy include phlebitis, thrombosis and infection, according to Rachael A. Lee, MD, MSPH, a health care epidemiologist and associate professor of infectious diseases at the University of Alabama at Birmingham.
Lee, a co-author with Spellberg, McDonald and others of the 2022 Open Forum Infectious Diseases article, told Healio | Infectious Disease News that studies have also identified infusion reactions as a side effect of IV therapy, “particularly with medications such as vancomycin.”
‘Simpler for everyone’
In addition to reducing the risk for side effects, oral antimicrobial therapy is also easier and cheaper than IV-only treatment, experts said.
“From a hospital perspective, studies in bacteremia identified shorter lengths of stay, but what is not measured is the amount of time required for running a safe outpatient parenteral antimicrobial treatment (OPAT) program,” Lee said. “By safely limiting the number of patients required to have OPAT, this reduces direct costs to the health care system from providing infusion therapy at home.”
Kelly M. Percival, PharmD, BCPS, BCIDP, a clinical pharmacy specialist in infectious diseases at University of Iowa Hospitals & Clinics, said that oral therapy is also easier for both patients and clinicians.
“Taking an oral tablet is much easier than having to set up an IV line or put in a peripherally inserted central catheter line for long-term IV therapy,” Percival told Healio | Infectious Disease News.
Once a patient is discharged from the hospital on long-term IV therapy, they must either come to an infusion center every day or establish home health care, which includes a pump to run the IV, maintaining and caring for the line and being aware of potential secondary infections, Percival said.
“There’s definitely an advantage to oral therapy, for all of those reasons — you reduce risk of secondary infections and complications from having an IV line,” Percival said. “It’s simpler for everyone, especially for the patients when they’re doing it on their own.”
Still, clinicians need to feel confident that they are making the right treatment decision for their patients, Lee said.
“For me, it helped to have patients whom I treated in the hospital with oral antibiotics come to my clinic as follow up,” she said.
Not every patient will be a candidate for oral antibiotics. Spellberg said patients can be switched from IV to oral therapy if:
- they are hemodynamically stable;
- any source control procedure is completed and blood cultures are cleared or actively clearing;
- the patient can absorb medications;
- there is no psychosocial or economic reason to prefer IV therapy; and
- there is a published oral regimen with activity in vitro against the target bacteria.
McDonald noted that some patients with resistant or unusual bacteria may respond only to IV antibiotics, and some either cannot swallow pills or may not be able to reliably maintain an oral regimen.
‘Clinical inertia’
According to Spellberg, it has been only 4 years since the publication of the largest randomized clinical trials assessing oral therapy for osteomyelitis and endocarditis.
“Medical literature indicates that it takes about 15 to 20 years for doctors to change their practice from the time practice-changing studies are published,” he said. “So, it’s another 10 to 15 years before oral therapy becomes the norm.”
McDonald called it “clinical inertia.”
“Practice is starting to change but we still have a really long way to go to convince clinicians that this is safe and the best practice for some patients,” she said. “Doctors tend to practice according to how they’ve always done things. They practice according to how they learned. It takes time and advocacy to sway practice [and] many doctors still believe that IV is stronger and better.”
Aside from the comfort of experience, Percival said it also takes a long time for guidelines to be updated. Even when they are, providers sometimes remain cautious of new guidance.
Spellberg, Lee, McDonald and others have published their own guidelines for managing infective endocarditis and pyogenic osteomyelitis as part of the “WikiGuidelines” collaborative — an international, nonprofit group of researchers who crowdsource their topics. They published their first two guidelines in JAMA Network Open.
The goal of the collaborative is to create living guidelines “that are broadly applicable to ‘real world,’ practical settings, including outside of academic medical centers,” the group says on its website.
“Changing dogma is like turning a massive ship — it takes time and effort,” Lee said. “I believe that in some cases, many have been able to feel confident in safely changing practice, but it takes time to convince primary teams, patients and health care systems in general that we are doing the right thing.”
References:
- Davar K, et al. Open Forum Infect Dis. 2022;doi:10.1093/ofid/ofac706.
- Finland M. N Engl J Med. 1954;doi:10.1056/NEJM195403042500906.
- McDonald EG, et al. JAMA Netw Open. 2023;doi:10.1001/jamanetworkopen.2023.26366.
- Pries-Heje MM, et al. N Engl J Med. 2021;doi:10.1056/NEJMc2114046.
- Spellberg B, et al. JAMA Netw Open. 2022;doi:10.1001/jamanetworkopen.2022.11321.
- Wald-Dickler N, et al. Am J. Med. 2022;doi:10.1016/j.amjmed.2021.10.007.
- Waldvogel FA, et al. N Engl J Med. 1970;doi:10.1056/NEJM197001222820406.
- WikiGuidelines. WikiGuidelines Charter. https://www.wikiguidelines.com/en/charter. Published Nov. 21, 2022. Accessed Sept. 23, 2023.
For more information:
Rachael A. Lee, MD, MSPH, can be reached at ralee@uabmc.edu.
Emily G. McDonald, MD, MSc, can be reached at emily.mcdonald@mcgill.ca.
Kelly M. Percival, PharmD, BCPS, BCIDP, can be reached at kelly-percival@uiowa.edu.
Brad Spellberg, MD, can be reached at spellber@usc.edu.
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