Clinical and economic impact of bacteraemia with extended-spectrum-β-lactamase producing Enterobacteriaceae

Schwaber MJ, Navon-Venezia S, Kaye KS, et al. Antimicrob Agents Chemother 2006;50:1257–1262.

Summary:

Extended spectrum β-lactamases (ESBLs) are a major source of antimicrobial resistance among Gram-negative pathogens. Their presence in bacteria is associated with broad-spectrum resistance to penicillins, cephalosporins and aztreonam. In addition, plasmids coding for ESBLs often confer resistance to numerous non-β-lactam agents, including fluoroquinolones, aminoglycosides, trimethoprim/sulfamethoxazole and β-lactam/β-lactamase-inhibitor combinations. Carbapenems remain the antibiotic of choice for managing these infections, and the new agent tigecycline is also active in vitro against these pathogens.

The present article was a retrospective cohort study that evaluated health and economic outcomes in 99 patients with bacteraemia caused by ESBL-producing Enterobacteriaceae. Data was obtained from inpatients with bacteremia caused by ESBL-producing Escherichia coli, Klebsiella spp., or Proteus spp. (cases). These were compared against outcomes in 99 patients with bacteraemia caused by non-ESBL producers (controls) of the same genera. Important demographic characteristics and comorbidities were evaluated in order to control for their potential confounding impact on health and economic outcomes.

Outcomes reported included mortality, mortality due to infection, length of stay (LOS), delay in appropriate therapy (DAT) and hospital cost. For each of these endpoints, univariate findings were described and a multivariate model was constructed to evaluate the independent impact of ESBL production on the dependent outcome. The average age of patients was 74 ± 14 years and the average number of comorbid conditions was 2 (most commonly cardiovascular disease [73%], malignancy [34%] and diabetes [30%]. Primary sources of bacteraemia were urinary tract (37%), primary bacteraemia (25%) and pneumonia (16%).

Consistent with studies evaluating risks for multidrug-resistant pathogens, cases were more likely than controls to have had a central (45% versus 20%) or urinary (81% versus 60%) catheter, require mechanical ventilation (30% versus 11%), be in the intensive care unit (22% versus 8%), and to have received dialysis (13% versus 4%) or a surgical intervention (31% versus 11%) (all p<0.01). More cases than controls came from an institution rather than from home (27% versus 14%) or had nosocomial infection (62% versus 27%) p<0.05 for both and more had recently received antibiotics (66% versus 17%); p<0.001. Collectively these findings support the definition of ‘health-care associated infection’ and emphasise that these risk factors place patients at high risk of infection with a resistant pathogen, including ESBLs.

In terms of primary outcome measures, in all analyses, a patient with an ESBL- producing strain of bacteria fared worse than those patients who were infected with a bacterial strain susceptible to antibiotic treatment. Thirty-five percent of cases died versus 18% of controls (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.3 – 4.7; p=0.01). Thirty percent of cases died due to infection versus 16% of controls (OR, 2.3; 95% CI, 1.1 – 4.5; p=0.03). The median LOS after bacteraemia for cases was 11 days (interquartile range, 5 – 21 days) versus 5 days for controls (interquartile range, 3 – 9 days) (p<0.001). DAT occurred in 66% of cases versus 7% of controls (OR, 25.1; 95% CI, 10.5 – 60.2; p<0.001). After adjusting for differences between groups by using multivariate analyses, ESBL production remained a significant predictor of mortality (OR, 3.6; 95% CI, 1.4 – 9.5; p=0.008), increased LOS (1.56-fold; p=0.001), DAT (OR, 25.1; 95% CI, 10.5 – 60.2; p<0.001), and increased cost (1.57-fold; p=0.003).

The average hospital cost for cases was 65,509 Israeli shekels, versus 23,538 shekels for controls (p<0.001). At the time of the study, 1 Israeli shekel was worth US $0.717. The mean increase in equivalent cost attributable to ESBL production was $9,620.

Clearly in all evaluations, ESBL production was associated with severe adverse outcomes, including higher overall and infection-related mortality, increased LOS, delay in therapy and higher costs. Patients at risk for multidrug-resistant pathogens must be anticipated using consideration of patient-specific risk factors. Only then may early, appropriate therapy be provided in the hope of reversing many of the adverse outcomes described in this study, where use of appropriate therapy was low in patients with ESBL- producing bacteria.

AIM core principles supported:

Patient outcomes

• Select the most appropriate antibiotic depending on the patient, risk factors, suspected infection and resistance.

Antibiotic choice

• It is important to start with the appropriate empiric antibiotic first in nosocomial infections

Resistance

• Recognise that prior antimicrobial administration is a risk factor for the presence of resistant pathogens.

Infection control

• Remove indwelling devices as soon as they are no longer indicated.