ESBL Infections: A Conundrum Yet to be Figured Out

Extended spectrum-beta lactamase producing organisms are those gram negatives that make beta-lactamases that inhibit third and fourth generation cephalosporins. As such, things such as piperacillin-tazobactam tends to show up as susceptible in antibiograms, however there has been a push lately towards the use of carbapenems as therapy for infections with these organisms. It seems kind of like a backwards thing to suggest out of infectious disease; indeed, we tend to tell people to “narrow” antibiotics once we known an organism is susceptible, but like vancomycin and its MIC of 2, carbapenems may just reign supreme for ESBL gram negative infections. In this post, we will look at the role of carbapenems in empiric therapy and then its role for definitive therapy. Then, we will look at how the once a day, ertapenem, may play a role in OPAT (outpatient parenteral antibiotic therapy).

Data for Empiric Therapy

This is what we think about when starting antibiotics especially in those who are colonized with ESBL organisms or have risk factors for them. Should you start someone upfront with carbapenems pending cultures? In a cohort of 213 patients, of which 48% received empiric PTZ for ESBL bacteremia, multivariate logistic regression models were used to calculated 14-day mortality which was higher for the empiric PTZ group than in the carbapenem group (1):

Notably, all these patients received definitive carbapenem upon receipt of susceptibility report. Despite this, other studies suggest that, at worst, piperacillin-tazobactam is as good as carbapenems. One retrospective cohort study of 394 patients from Singapore compared empiric therapy for ESBL E.coli or K. pneumo bacteremia (2). In this cohort, after propensity score matching, empiric piperacillin-tazobactam was not associated with higher 30-day mortality when compared to carbapenem:

Interestingly, empiric carbapenem was the only factor associated with higher likelihood of acquiring MDRO infections from either fungi or bacteria:

In a 8-year cohort study (3) of possible ampC producer organisms evaluated carbapenem and pip-tazo empiric therapy and found that empiric therapy with piperacillin-tazobactam was associated with a lower likelihood of treatment response (OR 0.29, 95% CI 0.16-0.53). Empiric carbapenem use was associated with higher likelihood of treatment response (OR 1.62, 95% CI 0.97-2.70) though this was not statistically significant. While in general different organisms (i.e. the SPICE organisms), it adds on to the evidence of the utility of both antibiotics with similar patterns of resistance to that of E.coli. 

What about cefepime? In a cohort of 109 patients with hematological malignancy, cefepime therapy was not associated with higher 14-day mortality when compared to carbapenem in multivariate cox analysis (4):

Notably, however, time to defervescence was shorter in those treated with carbapenem (1.5 days vs 2 days), as well as less likely to have persistent bacteremia (5% vs 36%) when compared to cefepime, however these should be taken with a grain of salt. 

Definitive Therapy

This is the more important topic of the two, as therapy with definitive therapy tends to make up the vast majority of the time under antibiotic therapy. Early observational therapy suggests a benefit of carbapenems over other antibiotics. For instance, a prospective observational study of 85-bacteremic episodes with K. pneumo found that therapy with carbapenem was independently associated with lower 14-day and 28-day mortality via multivariate analysis (5):

In a retrospective, multicenter cohort study of non-bacteremic UTI with ESBL-organisms evaluated 141 patients treated with definitive carbapenems and 39 treated with definitive PTZ (6). Patients treated with PTZ were more likely to be in the ICU, though also more likely to have E.coli isolated from their urine. There was no difference in primary outcome between groups (i.e clinical response):

A meta-analysis of 14 studies (7) did not find any difference for mortality in those patients with ESBL bacteremia with Enterobacteracea when either BL/BLI or carbapenems were used for definitive therapy (RR 1.05, 95% CI 0.83-1.37). This also was seen in those who had E. coli bacteremia (RR 1.01, 95% CI 0.49-2.10). The most well-known, randomized trial randomized patients who had ESBL E.coli or K. spp bacteremia into piperacillin-tazobactam or meropenem in a 1:1 ratio. Here, the primary outcome was all-cause mortality at 30 days, with 379 patients being randomized. Patients who received meropenem tended to be more likely to have diabetes, a urinary source of infection, higher APACHE scores, while those who got piperacillin-tazobactam were more likely to be immunocompromised or have a shorter time to get appropriate therapy. At 30 days, 12.3% of patients in the PTZ group achieved the primary outcome compared to 3.7% of the MER group (risk difference 8.6%, p=0.90 for non-inferiority). This was also true in subgroup analysis, suggesting superiority of meropenem over PTZ:

Where does this leave us? It is difficult to say, actually. Most retrospective data seems to go back and forth and one meta-analysis composed of mostly retrospective data suggest no benefit, yet a randomized trial found that carbapenems were superior. Sure, it is one trial but its sister trial, the MERINO 2 attempts to answer a similar question but to other AmpC producers such as Enterobacter spp, Serratia marcescens, Morganella morganii among others (9). The pilot randomized 79 patients, and there was no difference in the primary outcome of death, microbiological failure, clinical failure, or microbiological relapse when comparing piperacillin-tazobactam (29%) and meropenem groups (21%, risk difference 8%, 95% CI -12 to 28%). All in all, I would take it as carbapenems being the superior drug as of the time of writing this.

Utility of Ertapenem

When it comes to carbapenems, the one that sticks out like a sore thumb is ertapenem. This once a day antibiotic does not have any pseudomonas activity, yet it is used in outpatient antibiotic programs due to its ease of dosing and relatively good safety profile. Susceptibility to ertapenem may portend some prognostic utility. A retrospective study evaluated over 250 patients who were treated for ESBL-producing organism bacteremia with carbapenems and fond that ertapenem resistance (or as they call it here, non-susceptibility) was associated with higher mortality (10):

Most of the data here comes from several case series where it was used as consolidative therapy or for OPAT. For instance, a case series of 22 patients found that it was fairly useful for consolidation therapy, where only two had clinical failure (11). In another, ertapenem was used as first-line therapy in 73 patients with failure occurring in 8% of cases (12). In a case series of 11 OPAT patients who received ertapenem for ESBL urinary tract infections, the estimated number of inpatient bed days avoided totaled 238 days (13). 

When compared to other carbapenems, ertapenem tends to do as well depending on the study which tend to involve vastly different patient populations. You will see what I mean. A single-center retrospective cohort of 261 patients who had ESBL-producing E.coli or K. pneumoniae infections compared those who received consolidative ertapenem with those who got other carbapenems (14). There was no significant difference in in-hospital mortality or 90-day mortality between groups, however those who got other carbapenems were more likely to be immunosuppressed, require ICU stay, or more likely to have septic shock at onset of ESBL isolation:

A multicenter, retrospective study compared ertapenem with other carbapenems for therapy of ESBL bacteremia (15). Crude mortality was higher in those treated with other carbapenems (23%) compared to those treated with ertapenem (3.1%), however those treated with other carbapenems tended to require ICU admission more often as well as more likely to have septic shock. After propensity score matching, ertapenem was not associated with worse outcome:

Here, meropenem and imipenem were more likely to be used in sicker patients compared to ertapenem, which makes sense as the latter is used in relatively stable patients who need some sort of outpatient IV therapy. As such, it seems like ertapenem is a reasonable consolidative therapy in those with ESBL infections that require prolonged therapy as outpatient rather than upfront, empiric therapy where meropenem may do better. 

TL;DR

• ESBL = resistance to 3rd and 4th gen cephalosporins
• Piperacillin-tazobactam, despite being susceptible in vitro, may actually have worse outcomes compared to the carbapenems in terms of mortality and infection recurrence
• For serious ESBL infections, meropenem and impinenem are better than piperacillin-tazobactam
• For stepdown or transitioning to outpatient therapy, ertapenem is a reasonable option

References:

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2. Ng TM, Khong WX, Harris PN, De PP, Chow A, Tambyah PA, Lye DC. Empiric Piperacillin-Tazobactam versus Carbapenems in the Treatment of Bacteraemia Due to Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae. PLoS One. 2016 Apr 22;11(4):e0153696. doi: 10.1371/journal.pone.0153696. PMID: 27104951; PMCID: PMC4841518.
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