Sparing meropenem 101: what alternatives exist for the treatment of ESBL-producers?

Guest post: Patrick Harris, Staff Specialist in Microbiology, Central Laboratory, Pathology Queensland, Brisbane

In a previous post we looked at bacteria that produce AmpC-type beta-lactamases, such as Enterobacter spp.  Perhaps a more familiar, and increasingly common, problem is presented by species such as E. coli or K. pneumoniae, which have acquired extended-spectrum beta-lactamase enzymes (or ‘ESBLs’).  A key feature of these enzymes is their ability to hydrolyse and inactivate third-generation cephalopsorins (3GCs) – a class of antibiotics including important drugs such as ceftriaxone or ceftazidime. The genes that code for these enzymes are usually found on highly mobile plasmids (small circular packages of DNA) that can be easily transmissible between strains or across species.  In recent years, a new group of ESBLs called CTX-M have rapidly emerged, and are now the dominant type in many parts of the world.  The spread of these genes is strongly associated with a successful epidemic strain of uropathogenic E. coli termed ST-131. These are now increasingly encountered in community-acquired infections, with prevalence rates of more than 50% in some countries in our region.  In Australia, the prevalence of ESBL-producers has remained relatively low, but is increasing each year. HNE Local health District data on ESBLs will be published in May.

So how should ESBLs be treated – are carbapenems always best? For significant infections caused by ESBL-producers, the predominant view has been that carbapenems (such as meropenem) are considered optimal therapy. There are many good reasons for this: stability to the hydrolysis effects of ESBLs, low MICs in vitro and some older observational data showing a mortality benefit (especially in comparison to 3GCs or fluoroquinolones). However, the inexorable rise in ESBL prevalence is driving a massive global increase in carbapenem use, which in turn is providing selection pressure for the new threat of carbapenem resistance in Gram-negative bacteria.

As such, we need to consider alternative strategies for treating ESBL infections.  One microbiological oddity is that many ESBL-producers remain susceptible to piperacillin-tazobactam, or even amoxicillin-clavulanate in vitro.  Indeed, the laboratory definition of an ESBL-producer is by confirming the effect of beta-lactamase inhibitors neutralising the ESBL and restoring the activity of 3GCs.  However, until recently there was scant clinical data to support the use of beta-lactamase inhibitor combination antibiotics in patients. There is now an increasing body of observational data to suggest that piperacillin-tazobactam may be just as effective as meropenem for ESBL-producers, even for bacteraemia.

This is probably most acceptable for less serious presentations such as patients with a urinary or biliary tract focus, when source control has been achieved. Whether this strategy remains effective in more critical infections (e.g. neutropenia, severe sepsis, infection with a complex focus) is less well established.  There is also one recent study from the US suggesting that carbapenems for empirical therapy (i.e. before you know the susceptibility profile) of ESBL-producers is associated with lower mortality when compared with piperacillin-tazobactam.

So who is right? There is an Australian-led international randomised controlled trial (RCT) comparing piperacillin-tazobactam with meropenem in bloodstream infections caused by ESBL-producers, which will be the first time these have been compared head-to-head for these infections. In the meantime, if you are treating an infection caused by an ESBL-producer, and it remains susceptible to piperacillin-tazobactam in vitro, I would argue that it might be a reasonable alternative option in selected cases – but data from an RCT would be the best way to settle this uncertainty.

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