Pilot RCT of Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Caused by AmpC Beta-lactamase Producing Enterobacter Spp., Citrobacter Freundii, Morganella Morganii, Providencia Spp. or Serratia Marcescens. in Low-risk Patients

Antibiotic resistance is a problem of immense public health significance. Effective antibiotics are essential to complex therapeutic interventions such as transplant medicine, critical care or major surgery. It is estimated that at least 2 million people acquire infections with bacteria that are resistant to standard therapy each year in the United States, with at least 23,000 deaths directly attributable to the infection. With few new antibacterial agents in late-stage development, it has been necessary to consider using existing generic agents in a more targeted approach. This might include revisiting therapeutic options that have previously been considered inferior.

Bloodstream infections caused by Gram negative bacteria are commonly encountered in clinical practice and can be associated with high rates of mortality. Outcomes may be dependent upon the timely administration of appropriate antibiotics, especially in septic shock. Bacteria that possess resistance mechanisms to commonly employed antibiotics are therefore of great concern and may contribute to further mortality.

Over the last 25 years, two antibiotic choices have predominated for intravenous management of these infections. These are combinations of beta-lactam antibiotics with beta-lactamase inhibitors (such as piperacillin/tazobactam) and third generation cephalosporins, such as ceftriaxone. However, some commonly encountered Gram negative organisms possess chromosomally encoded beta-lactamase enzymes, known as AmpC beta-lactamases, that may hydrolyse 3rd generation cephalosporins. Expression of AmpC may be inducible following beta-lactam exposure in some Enterobacteriaceae by loss of inhibitory effects from regulatory elements that control gene transcription. Furthermore, such inducible gene-expression can become constitutively 'de-repressed' by mutational loss of regulatory ampD or ampR genes, leading to high-levels of AmpC production and a phenotype that demonstrates in vitro resistance to most beta-lactams and beta-lactam/beta-lactamase inhibitor (BLBLI) combination agents, except cefepime or carbapenems. Such variants are usually present at low levels (e.g. between 10-5 to 10-7 of the total bacterial population) but may be rapidly selected for during antibiotic therapy.

As a result, AmpC-producing bacteria present particular problems for antibiotic susceptibility reporting and treatment. In vitro susceptibility may not correlate with clinical efficacy as resistance to beta-lactam antibiotics can emerge by selection of variants expressing high levels of AmpC. This has been best described in the context of Enterobacter bacteraemia and therapy with 3rd generation cephalosporins (3GCs). In a landmark study by Chow et al. in 1991, 129 patients with Enterobacter bacteraemia were prospectively examined. Prior cephalosporin use predicted a greater likelihood of identifying a multi-drug resistant isolate on initial blood culture, which was associated with higher subsequent mortality. Furthermore, emergence of resistance to cephalosporins developed during treatment in 6 (19%) of 31 bacteraemic episodes treated with cephalosporins. It is worth noting that this phenomenon was not seen in the small number of patients treated with piperacillin in this study, and that many of the Enterobacter isolates would now be reported as non-susceptible to 3GCs according to current breakpoints. Several other Gram-negative bacteria contain such inducible beta-lactamase genes with the capacity for de-repression. They have been informally labelled the 'ESCPM' group, and are variably described as comprising Enterobacter spp. (especially E. cloacae and E. aerogenes), Serratia marcescens, Citrobacter freundii, Providencia spp. and Morganella morganii.

Clinical studies have shown a variable risk of such emergent resistance and clinical failure occurring with beta-lactam therapy, particularly 3GCs, but when it occurs it has been associated with higher mortality and healthcare-related costs. As a result, 3GCs are usually not recommended as therapy for AmpC-producers, even when susceptible in vitro.