There are a series of clinical trials published this year that challenge long-held notions in the treatment of infectious diseases.
When I was a trainee, we routinely prescribe high-dose intravenous antibiotics for prolonged periods of 4 to 6 weeks for infective endocarditis (infection of the heart valves), because the conventional understanding was that high concentrations of antibiotics was required to penetrate the avascular vegetations and inhibit/kill the bacteria within, hence an intravenous antibiotic was virtually mandatory for the entire course of treatment.
In a large study from Denmark published in the NEJM in January this year, 400 patients with endocarditis were randomized to either IV treatment for the entire course of treatment, or switched to oral antibiotics after approximately 17 days (range of 13 to 23 days). Outcomes were similar in both arms.
In the case of osteomyelitis (bone infections), including those where prosthetic implants are in place, intravenous antibiotics for a significant part of the course – if not the complete course – of therapy has been the norm. Again this is because of the perceived need for high concentrations of antibiotics to target bacteria in slow-growth/stationary growth phase hiding within the ischaemic infected bone or implant. Prolonged intravenous antibiotics for osteomyelitis and prosthetic joint infections has in fact been the primary driver for outpatient antibiotic therapy (OPAT) units that have proliferated both locally and internationally.
The use of oral antibiotics in this setting has been less controversial than in endocarditis however. In acute osteomyelitis, the use of oral antibiotics is well established. Back in 2013, Cochrane reviewers had studied the evidence comparing oral vs. intravenous antibiotics in osteomyelitis, and reached the conclusion that route of administration of antibiotics did not affect outcomes, although the quality of evidence was low. However, there was no large-scale well-organized randomized clinical trial performed until the OVIVA trial, which was also published in NEJM in January.
In this trial, 1,054 subjects were randomized to either receiving oral antibiotics within 7 days after the start of treatment/surgery or completing at least 6 weeks of intravenous antibiotics. Of note, the majority (76.7%) received antibiotics beyond 6 weeks, with a few being treated for more than a year. The results were clear – switching to oral antibiotics early was not inferior to continuing intravenous antibiotics for at least 6 weeks.
Finally, a Singapore study was just published in Clinical infectious Diseases evaluating oral vs long-term intravenous antibiotics for Klebsiella pneumoniae liver abscess. The “invasive Klebsiella syndrome” – caused by hypervirulent clones of Klebsiella pneumoniae – occurs primarily in Asia and Asian patients, and is also relatively prevalent in Singapore. Conventionally, these liver abscesses have generally been treated with long-term intravenous antibiotics (particularly ceftriaxone), although the basis for using an intravenous route has never been clear, unlike the case of endocarditis or osteomyelitis.
In a multi-centre study led by infectious disease physicians from the National University Hospital, 152 subjects with Klebsiella liver abscess were recruited and randomized to receiving either oral antibiotics (mostly ciprofloxacin) within a week after initiating treatment or continuing with intravenous antibiotics. Again, non-inferiority was demonstrated.
These studies collectively challenge the existing paradigm of prolonged intravenous antibiotics for chronic infections, and should lead to more cost-effective care if implemented in practice. It is great that one of these paradigm-shifting trials was performed in Singapore. Of note, patients on long-term oral antibiotics should still be monitored closely as the adverse effects reported in the oral arms of all three studies was equivalent to those on the intravenous arms.