Escherichia coli is a leading cause of intra-abdominal, urinary tract, and bloodstream infections encountered in routine clinical practice (1). It is a recognized pathogen for causing both community acquired and nosocomially acquired infections (1, 2). Over the past two decades, antibiotic-resistant strains that produce extended spectrum β-lactamases (ESBL) have emerged among the Enterobacteriaceae, predominantly in E. coli and Klebsiella pneumoniae (2-4). ESBLs are a group of hydrolyzing enzymes that provide resistance to third generation cephalosporins and aztreonam, but can in turn be hydrolyzed by clavulanic acid (5). Several epidemiological studies have investigated the prevalence of ESBLs and their clinical impact (2, 3, 6). There is considerable geographic variability in the prevalence of ESBLs with the prevalence being highest in from Latin America and Asia Pacific region followed by Europe and North America (4). In a recently conducted meta-analysis from Pakistan, the pooled prevalence of ESBL producing Enterobacteriaceae was reported to be 40% (7). This is similar to proportions reported from neighbouring countries of China (8) and India (9) and considerably higher than US and developed countries from Europe (5). Hence, Pakistan is a country with high endemicity of community acquired ESBL producing Enterobacteriaceae with major public health implications (10, 11).
Since ESBL-producing organisms are frequently resistant to multiple antimicrobial agents therapeutic options for these infections are severely limited (12). Moreover infections caused by ESBL producing organisms have been associated with high morbidity and mortality (13). Studies have shown high Pitt Bacteremia score and Charlson co-morbidity index to be predictive of death in patients with sepsis secondary to ESBL producing organisms (14). Bacteremia with ESBL producing organisms has been associated with a delay in the initiation of appropriate treatment regimens and leads to an increase in the hospital length of stay and cost of overall treatment (14, 15). Carbapenems have been considered as drugs of choice for treating severe infections caused by ESBL producing Enterobacteriaceae as they are not affected by ESBLs in vitro and clinical efficacy has been demonstrated in several observational studies as well as clinical trials (5, 16, 17). A large multi-country open label non-inferiority randomized controlled (MERINO) trial which compared piperacillin tazobactam with meropenem as definitive treatment for Ceftriaxone resistant E.coli or K.pneumoniae bloodstream infection found significantly higher long term mortality in patients randomized to piperacillin tazobactam arm (16). However, prolonged use of carbapenems places the community at risk of development of carbapenem resistance due to antibiotic selection pressure (18). Thus it is imperative to find alternatives for treatment. Beta lactam/beta lactam inhibitor combinations (BL/BLI) have been widely studied both as empiric and definitive choice of antibiotics and while some studies have reported no difference in clinical outcomes with use of BL/BLI combination compared to carbapenem (19); pooled data from meta-analysis have recommended their use for only clinically stable patients with urinary tract infections as the source (17).
Existing studies from Pakistan have shown that ESBL producing strains of Enterobacteriaceae show greater than 90 percent susceptibility for BL/BLI and hence may be an effective alternative (10, 11). Carbapenem use has severe cost constraints in a low middle country like Pakistan and is reserved for very severe infections. Despite the high endemicity of ESBL producing organisms, data on risk factors for mortality and the optimal choice of antibiotic therapy is lacking. Our study aims to determine the risk factors for in-hospital mortality in patients with ESBL E.coli bacteremia using Ceftriaxone resistance as a marker of ESBL presence; with emphasis on difference in outcome when patients were treated with a Carbapenem compared to beta lactam/beta lactam inhibitor combination at a tertiary care hospital in Pakistan.