Bloodstream Infections Clinical Trial
Official title:
Randomized Controlled Trial of Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Due to Ceftriaxone Non-susceptible E. Coli and Klebsiella Species.
No randomized controlled trials (RCTs) have yet been performed comparing different treatment
options for AmpC or ESBL-producing Enterobacteriaceae. During the last 10 years we have seen
an exponentially increasing rate of carbapenem resistance worldwide, including Australia and
New Zealand. The investigators urgently need data from well-designed RCTs to guide clinicians
in the treatment of antibiotic resistant Gram-negative infections. The investigators face a
situation where a commonly used antibiotic for these infections (meropenem) may be driving
carbapenem resistance. For this reason, the investigators are seeking to compare a
carbapenem-sparing regimen with a carbapenem for the treatment of these infections. Formal
evaluation of safety and efficacy of generic antibiotics in the treatment of infection is of
immense clinical and public health importance, and no formal trial has yet been conducted to
address these issues. The international collaboration between teams of clinician researchers,
some of whom are leaders in their field, makes it highly likely that the outcomes of this
trial will have a significant impact on clinical practice.
The investigators' hypothesis is that piperacillin/tazobactam (a carbapenem-sparing regimen)
is non-inferior to meropenem (a widely used carbapenem) for the definitive treatment of
bloodstream infections due to third-generation cephalosporin non-susceptible E. coli or
Klebsiella species.
Escherichia coli and Klebsiella spp. are common causes of bacteraemia, and may acquire genes
encoding extended-spectrum beta-lactamases (ESBLs) or AmpC beta-lactamases (1). ESBL or AmpC
producers are typically resistant to third generation cephalosporins such as ceftriaxone, but
susceptible to carbapenems (1). Observational studies have been performed evaluating
antibiotic choices for ESBL producers (2-9). In no study has the outcome of treatment for
serious infections for ESBL producers been significantly surpassed by carbapenems (2-9).
Despite the potential advantages of carbapenems for treatment of ceftriaxone non-susceptible
organisms, widespread use of carbapenems may cause selection pressure leading to
carbapenem-resistant organisms. This is a significant issue since carbapenem-resistant
organisms are treated with "last-line" antibiotics such as colistin. Some new beta-lactam
antibiotics and beta-lactamase inhibitors, which are active against ESBL, AmpC and some
carbapenemase producing organisms, are in advanced clinical development (10). However, these
antibiotics are likely to be expensive and may best be held in reserve for infections where
there are no alternatives. Therefore, we see a need for establishing the efficacy of a
generically available alternative to carbapenems for serious infections.
The susceptibility of ESBL producers and AmpC producers to piperacillin/tazobactam is less
predictable than that of carbapenems. By definition, ESBLs are inhibited by beta-lactamase
inhibitors such as tazobactam (1). However, E. coli or Klebsiella may produce multiple
beta-lactamase types some of which are resistant to inhibition by tazobactam. Additionally,
in some cases outer membrane protein loss may contribute to resistance to tazobactam. By
definition, AmpC is not inhibited by beta-lactamase inhibitors such as tazobactam. However,
despite these limitations, approximately 50% or more of ceftriaxone non-susceptible E. coli
or Klebsiellae remain susceptible in vitro to piperacillin/tazobactam (1).
No randomised controlled trials have yet been performed comparing different treatment options
for ceftriaxone resistant Enterobacteriaceae. The largest observational study with an
analysis by treatment outcome was published in February 2012 by Rodriguez-Bano and colleagues
(9). They performed a post-hoc analysis of six published cohorts of patients with bacteraemia
due to ESBL producing E. coli. Two nonmutually exclusive cohorts (empirical therapy and
definitive therapy) were constructed and analysed separately. In both cohorts, carbapenems
were not superior to beta-lactam/beta-lactamase inhibitor combinations (BLBLIC).
Specifically, in the definitive therapy cohort, mortality rates at 30 days were not
significantly different - 9.3% for those who received a BLBLIC and 16.7% for those who
received a carbapenem (p>0.20) (9).
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