The Shift in the Treatment of Native Valve Enterococcal Endocarditis

Older males with a subacute presentation tends to be a clue to Enterococcal spp bacteremia. With the new murmur, the suspicion for enterococcal endocarditis should go up. The prevalence of enterococcal infections in older patients is going up, with it being a major cause of nosocomial infections. While classified as a type of streptococcus, enterococcus is actually quite unique, for the wrong reasons. The major reason involves its intrinsic resistance to the antibiotics that are generally used for streptococcal infections (read: the penicillins, 1). Whereas you can kill a viridans strep with a beta-lactam, this does not hold true for enterococcus. That is not to say you cannot use them. For instance, ampicillin and amoxicillin are frequently used for these types of infections. Yet, cephalosporins and the semi-synthetic penicillins are not used due to its intrinsic resistance (1). This is because these bacteria expressed a low-affinity PBP5 in E. faecium and PBP4 in E. faecalis which binds weakly to the beta-lactams (2), with enterococci being up to 100-fold less susceptible to beta-lactams when compared to streptococci (3). Indeed, at the same concentration of beta-lactam of other streptococci, the PBP in enterococci can continue to build up the cell wall. This resulted in a lack of bactericidal options for Enterococci (for a foray into the difference between -static and -cidal, look here). Furthermore, E. faecalis have an ability to form biofilms, at a higher rate than E. faecium (87-95% vs 16-29%, respectively, 4). As a result, deep seated infections such as infective endocarditis require dual therapy for synergy. I should note, the post deals with Enterococcus faecalis, which is more pathogenic than E. faecium but tends to be more susceptible in general. 

The Aminoglycosides

The idea behind this is explained in the 2005 AHA guidelines (5). Ampicillin binds to PBP4/5, which allows aminoglycosides to penetrate the cell wall, reaching its intracellular target. Given the lack of bacteriocidal activity of the penicillins against enterococcus, the search for a synergistic combination lead to the finding that streptomycin had synergistic activity when combined with penicillin (6). Indeed, the addition of gentamicin to ampicillin in the treatment of IE has been in the AHA guidelines since 1995, however there is little in the way of clinical data to support its use. One of the earliest studies from 1947 was a case series of 18 patients with bacterial endocarditis, where streptomycin was added to penicillin resulting in cure of 8 patients (7).  A larger study from 1984 evaluated 36 patients receiving penicillin G/streptomycin and 20 patients receiving penicillin/gentamicin (the latter patients had resistance to streptomycin, 8), however the conclusions draw form this study concerned the duration of therapy depending on the length of symptoms (i.e. those who had symptoms for more than 3 months would benefit from a 6 week duration of therapy vs 4 weeks in those who were symptomatic for fewer than 3 months). So not exactly revealing in terms of the efficacy of gentamicin in addition to penicillins. In fact, most of this comes from in vitro studies (9). As a result of the toxicities associated with aminoglycosides, there has been a push towards alternatives. 

One alternative proposed has been the shortening of duration of the aminoglycoside component from 4-6 weeks down to 2 weeks. This was evaluated in a Danish prospective study, which evaluated 84 patients with native valve left sided infective endocarditis (10). Patients were treated with ampicillin in combination with 3mg/kg of gentamicin per day, divided 1-3 times daily, with primary outcome being 12-month event free survival. Patients admitted prior to 2007 received 4-6 weeks while those after 2007 were treated for 2 weeks. There was no statistically significant differences between groups in terms of primary outcome, with 66% in the 4-6 week group and 69% in the 2 week group achieving the primary end point (p-value 0.75). Furthermore, there was no statistical difference in mortality between groups, though it trended towards benefiting the longer duration group:

Not surprisingly, those with longer duration of gentamicin were more likely to have changes in eGFR:

Despite this, with more data coming in from a dual-beta lactam combination approach, the frequency with which aminoglycosides are used is dropping. This was seen in a retrospective study from Spain, where 69 cases of IE were evaluated. From 1996-2011, the trend was towards using ampicillin and ceftriaxone (11):

The “Other” Beta-Lactam

So I mentioned in the introduction that enterococci are inherently resistant to cephalosporins. So why is there a push towards using ceftriaxone (besides the fact its nicer to the kidneys)? An in vitro study found the MIC of 10 different Enterococcal strains that were aminoglycoside resistant significantly decreased in the presence of both, ampicillin and ceftriaxone, despite the high MIC to ceftriaxone (12):

Furthermore, this same experiment found a significant improvement in both, vegetation size and CFU/g of vegetation when comparing ampicillin and amp/CTX in an experimental model of endocarditis:

Therefore, it seems there is some sort of synergism between these 2 beta-lactam antibiotics. Indeed, this seems to be true for other extended-spectrum beta lactams. An in vitro analysis found that the combination of ampicillin with ceftaroline and cefepime had similar activity to that of ampicillin-ceftriaxone in a pharmacodynamic model of E. faecalis (13):

So its odd that an antibiotic that is ineffective in enterococcus should pair up nicely with an aminopenicillin, so this begs the question of what is happening? A proposed mechanism (14) is that ampicillin saturates PBP 4 and 5 (at least partially) while ceftriaxone binds PBP 2 and 3, leading to a less effective cell wall synthesis and thus, bactericidal activity. 

Clinical data seems to favor the combination of ampicillin/CTX over that of ampicillin/gentamicin. In a retrospective analysis of 69 patients treated with both combinations (11), found the rate of in-hospital mortality and 1 year mortality between the groups was not statistically different:

Not surprisingly, the rate of renal failure was higher in the gentamicin group (GFR at end of treatment 21 in gent vs 65 in CTX group), and there was a higher rate of discontinuation in the gent group compared to the CTX group:

Of course, there is a relative time difference between when each group was treated (pre 2007 vs post 2007), leading to potential bias in the results. A larger, prospective multicenter trial evaluated the two combinations in a similar population, with 291 patients evaluated (15). 159 were treated with Amp/CTX while 87 were treated with amp/gentamicin. There was no difference between groups in the rate of relapse, death during treatment, or death during 3 month follow up. More patients in the Amp/Gent group had side effects leading to treatment discontinuation:

This efficacy also held true despite high-level aminoglycoside resistant strains. In one open-label, observational study (16) evaluating the amp/CTX combination in those with HLAR- and non-HLAR-Enterococcal IE, outcomes were not statistically different between the 2 groups, with an overall failure rate of 32.6% (28.6% in HLAR vs 36.4% in non-HLAR Enterococcal IE). Though this study was small and observational in nature, the rates of failure were similar to that of other case series, suggesting the combination is a reasonable option given its higher tolerability. The length of combination therapy is generally recommended to be 6 weeks, however a prospective cohort study found similar outcomes in patients treated with 4 weeks of combination therapy (17). The GAMES registry evaluated patients treated with combination Amp/CTX for four weeks (39 patients) vs 6 weeks (70 patients). Notably, those with 6 weeks theray had a longer duration of symptoms prior to diagnosis (21 days vs 7) and were more likely to have perivalvular abscess (6 vs 0) or valve perforation (17 vs 4). In-hospital and one year mortality was similar between both groups:

This suggests that in patients who have been symptomatic for about a week and who do not have any perivalvular abscess on TTE/TEE may safely be treated with a 4 week course.

TL;DR

• Enterococcus spp is common cause of infective endocarditis in older patients, typically left sided
• Enterococcus tends to be resistant to many penicillins, with ampicillin/amoxicillin being bacteriostatic and cephalosporins having no activity
• Amp/Gent is a reasonable combination for synergy in severe infections, especially native valve endocarditis, with 2 weeks being as efficacious as 4-6 weeks.
• Ceftriaxone and other extended spectrum beta-lactams (3rd and 4th gen cephs) in combination with ampicillin have demonstrated similar results for mortality/failure compared to ampicillin/gentamicin, with less treatment discontinuation due to adverse events
• 4 weeks of amp/CTX in those without complications (abscess/valve rupture) and with <7 days of symptoms is a reasonable approach. Beyond that, everyone who can should get amp/CTX.

References:

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2. Gagetti P, Bonofiglio L, Garcia Gabarrot G, et al,Resistance to β-lactams in enterococci,Revista Argentina de Microbiología, Volume 51, Issue 2,2019, Pages 179-183, ISSN 0325-7541,https://doi.org/10.1016/j.ram.2018.01.007.
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