(Below I discuss the POET study at some length. If you’re not interested, skip to the bottom of this post for links to this month’s articles)
I have an ID-related confession.
The way I treat MRSA endocarditis in my patients is not the way I would want my MRSA endocarditis to be treated.
The 2015 IDSA-endorsed AHA guideline on the treatment of infective endocarditis in adults states that native valve endocarditis due to methicillin-resistant Staphylococcus aureus should be treated with six weeks of either IV vancomycin or daptomycin. This is how I treat my patients. I respect S. aureus, I respect endocarditis, I know that poor outcomes in MRSA endocarditis commonly occur even with excellent care, and frankly I worry that if I deviated from the standard of care without a darn good reason and my patient had one of those poor outcomes, it would be tough to defend that choice in court.
But honestly, if I had MRSA endocarditis, I would want vancomycin or daptomycin until I was doing better (blood cultures negative, leukocytosis downtrending, fever broken), and then I would want to go home with a big bottle of linezolid. As a patient, dogma about the innate superiority of bactericidal versus bacteriostatic antibiotics (an archaic laboratory definition of questionable clinical relevance) and the innate superiority of IV versus oral antibiotics (IMO implausible so long as we’re talking about highly bioavailable drugs) would matter a lot less to me than avoiding a PICC line for a month and a half. PICC lines are associated with thrombophlebitis and thrombosis, serve as a nidus for bloodstream infections, and remind me of that one poor minion of the Baron Harkonnen. No thanks!
Well, good news: on Tuesday NEJM published the POET study, a randomized controlled trial on the subject of oral versus IV antibiotics for completion of endocarditis treatment (no, it didn’t include MRSA, though it did include MSSA treated with linezolid). This study has been immensely controversial; I’ve never seen so many hot takes about a single study across the ID twitterverse! Let’s do a deep dive.
The Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis (POET) trial randomized 400 patients with left-sided streptococcus, S. aureus, or E. faecalis endocarditis who had received at least 10 days of IV antibiotic therapy, including at least 7 days of antibiotics after any valve surgeries performed, to either continue IV antibiotics or switch to one of several prespecified oral antibiotic regimens. MRSA was not specifically excluded, but all cases of S. aureus enrolled were due to methicillin and/or penicillin-susceptible strains. The primary outcome of interest was treatment failure, defined as a composite of all-cause mortality and evidence of relapsed infection (unplanned need for cardiac surgery, clinically evidence embolic events, or recurrent bacteremia with the original pathogen).
This was a multicenter study in Denmark that enrolled clinically stable adults (e.g. those who had had a good response to initial IV therapy) who fulfilled modified Duke criteria and who had had a prerandomization TEE demonstrating no abscess or valve pathology indicating need for (additional) surgery. Nearly 80% of screened patients were excluded, which has been a big point of contention, but let's look at the primary reasons: 28% did not fulfill Duke criteria, 19% were unable or unwilling to give consent, and only 17% were excluded because they had not had a good response to initial therapy (e.g. they had persistently high temperature, CRP, or WBC count, or evidence of abscess).
Importantly, only 22 patients (1.4%) were excluded on account of concern they would not adhere to therapy, and only 1.3% used IV drugs. This is potentially a problem for generalizing these results to American patients with staphylococcal endocarditis due to ongoing intravenous opiate abuse.
Back to the methods. Patients kept on IV therapy had to stay in the hospital, whereas those switched to oral antibiotics could be discharged at the physician’s discretion and seen in clinic 2-3 times a week; 80% of the patients in the switch group were discharged before finishing therapy. The IV antibiotic regimens used were not given, but the oral regimens used are included in the supplementary materials. For MSSA (some of which were penicillin-susceptible) and CONS, they used either amoxicillin or dicloxacillin (each 1g four times a day) or linezolid plus either rifampin (600mg twice daily) or fusidic acid. For E. faecals and streptococcus with a penicillin MIC <1mg/L they gave either amoxicillin or linezolid plus either rifampin or moxifloxacin, and for streptococcus with reduced penicillin susceptibility they gave linezolid plus rifampin or moxifloxacin plus either rifampin or clindamycin. Note those big doses of rifampin, and also that fusidic acid is not commercially available in the US right now.
All patients received therapeutic drug monitoring with antibiotic dose adjustment as needed. In the results section, the authors mention that while 7 of the patients in the oral switch group had suboptimal levels of one antibiotic, none had their regimens changed and none experienced treatment failure (so in the end, did the patients on oral antibiotics really need drug monitoring?). Patients also received a TEE at the end of therapy to confirm a satisfactory response to treatment, and were followed for another 4 visits over the next six months.
The two groups were similar; 38% had required valve surgery and 35 patients had an implanted cardiac device, which I suspect is why nearly all of the oral regimens included rifampin or fusidic acid (recently repurposed as another adjunctive “biofilm” agent for prosthetic device infections). Patients received a median 17 days of IV antibiotics before being randomized to all-IV or oral therapy, and they were treated a median 17 days (oral group) to 19 days (IV group) afterward. Only 4 patients (2%) in the oral group were switched back to IV – one for new infection with a different pathogen, one for nausea, and two at the patient’s request; for comparison, 22% of patients in the IV group switched to another IV regimen, and 12% in the oral group switched to another oral regimen.
So, how did the patients do? At 6 months, treatment failure had occurred in 12.1% of the patients given all-IV therapy and 9% of the oral group, meeting the prespecified threshold for non-inferiority. All-cause mortality was similar between groups with a trend in favor of oral therapy (6.5% in the IV group versus 3.5% in the oral group, HR 0.53 with 95% CI 0.21 to 1.32). I noted that the outcomes in IV versus oral treatment of MSSA endocarditis were equivalent (e.g. 2/40 died in the IV group vs 2/47 died in the oral group). Intravenous and oral therapies were equally well tolerated, with adverse events occurring in 6% of the IV arm and 5% of the oral arm; bone marrow suppression accounted for a significant portion of the AEs in the oral arm, probably due to extended use of linezolid. Tedizolid might actually be the drug of choice for this indication – though I’m wasn't able to find data to support the claim, I’ve been told that anecdotally it’s better tolerated than linezolid over long periods.
What’s the bottom line? In a population of care-adherent patients with streptococcal, MSSA, or E. faecalis endocarditis and a good response to an initial 2-3 weeks of IV therapy, completing treatment with oral antibiotics and intensive outpatient monitoring was as good as continued IV therapy and hospitalization.
Now I want to specifically discuss three of the talking points that have come up around this study:
This study isn’t generalizable to endocarditis in non-adherent American IV drug abusers.
Fair point. Choosing IV antibiotics can be a means to improve adherence, either by keeping the patient institutionalized or by setting them up with an OPAT program where an RN goes to their home to “touch the patient” several times a week and ensure they're getting their medications. May I also point out, though, that clinicians in the TB world have had great success ensuring adherence to oral antibiotics by using directly observed therapy? And that six weeks of DOT would probably be no more expensive than OPAT and way cheaper than six weeks of inpatient or skilled nursing facility care?
This study isn’t generalizable to my practice because my hospital can’t provide therapeutic drug monitoring of oral antibiotics or perform two TEEs before and after treatment.
I'm not sure this matters. What in the study’s results indicated that either practice was actually necessary to facilitate the use of oral antibiotics? The prerandomization TEE was done to rule out an abscess or valvular lesions indicating further need for surgery. Well, if there is a myocardial abscess or major valve pathology, neither IV nor oral antibiotics alone are appropriate therapy, right? You need a CT surgeon. The posttreatment TEE had no bearing on the primary outcome (which again, was a composite of mortality, embolic event, unplanned surgery, and recurrent bacteremia), so that shouldn't be an issue. As for the therapeutic drug monitoring, the authors mention that suboptimal drug levels were observed in a minority of patients (3.5%), that none of those levels led to a change in the patient’s regimen, and that none of those patients experienced treatment failure. So, what did drug monitoring really add to the oral antibiotic recipients’ care?
This study isn’t generalizable to MRSA endocarditis.
Outcomes of MSSA treated with regimens including an oral beta-lactam definitely aren’t generalizable to MRSA, and these constituted 74% of the MSSA cases (see Table S10). But for the dozen cases who received some combination of linezolid, rifampin, fusidic acid, and moxifloxacin (given off protocol), why shouldn’t we generalize the applicability of those outcomes to MRSA? The best argument, I think, is that this is a now a tiny sample size and the author's don't provide outcomes data stratified by the type of oral regimen used. Keep in mind, though, that older data also supports the use of these alternative agents, including their oral formulations, for staphylococcal endocarditis (see 14986244 2572799 and even 1503330 for MRSA, though I’d probably be hesitant to use TMP/SMX without a second agent like rifampin due to the poor performance of TMP/SMX monotherapy in this trial).
Admittedly, I don’t know if I’m ready to risk prescribing oral mop-up therapy for MRSA endocarditis (though I’ve read some clinicians are already doing so) and I hope the POET trial inspires future studies looking at oral versus IV treatment in patients who use IV drugs and have MRSA endocarditis. But I think it’s what I’d want for myself.
All that said, here are my favorite papers from August 2018:
Antimicrobial Agents research included data on inoculum effects in MSSA and E. faecium, antimicrobial regimens for carbapenem-resistant Acinetobacter pneumonia, ceftaz-avi for OXA-type CRE infections, and new dosing regimens for oral fosfomycin.
ID Diagnostics research included two new rapid pathogen identification and susceptibility tests (Unyvero and Accelerate Pheno) and a paper showing that none of these fancy gizmos matter if you don't have a stewardship program.
General ID topics included rifampin versus INH for latent TB, outcomes of prosthetic joint infections managed with implant retention, and whether long surgeries need additional doses of cefazolin to maintain adequate surgical site infection prophylaxis.
Onc and Transplant ID research included a meta-analysis comparing antifungal prophylaxis strategies for hematologic cancer patients, a multicenter description of toxoplasmosis across the various types of transplant recipients, immune-mediated allograft injuries after HCV treatment, and adjunctive sulfamethoxazole to improve azole treatment of Candida auris.
HIV and STD research included more good news about PrEP, the adequacy of doxycycline for syphilis, the benefits of switching to much-maligned rilpivirine, and the dethroning of tuberculosis by histoplasmosis as the deadliest opportunistic infection in Latin America.
Antimicrobial Stewardship and Infection Control research topics included history of ESBL and future infection risk, amoxicillin for non-pneumonia LRTI, enhanced patient room disinfection techniques to stop the spread of MDROs, and two dogs that shouldn't quit their day jobs.