A multidisciplinary intervention to reduce infections of ESBL- and AmpC-producing, gram-negative bacteria at a University Hospital

Abstract

In response to a considerable increase in the infections caused by ESBL/AmpC-producing Klebsiella pneumonia in 2008, a multidisciplinary intervention, with a main focus on antimicrobial stewardship, was carried out at one university hospital. Four other hospitals were used as controls. Stringent guidelines for antimicrobial treatment and prophylaxis were disseminated throughout the intervention hospital; cephalosporins were restricted for prophylaxis use only, fluoroquinolones for empiric use in septic shock only, and carbapenems were selected for penicillin-allergic patients, infections due to ESBL/AmpC-producing and other resistant bacteria, in addition to their use in severe sepsis/septic shock. Piperacillin-tazobactam ± gentamicin was recommended for empiric treatments of most febrile conditions. The intervention also included education and guidance on infection control, as well as various other surveillances. Two year follow-up data on the incidence rates of patients with selected bacterial infections, outcomes, and antibiotic consumption were assessed, employing before-and-after analysis and segmented regression analysis of interrupted time series, using the other hospitals as controls. The intervention led to a sustained change in antimicrobial consumption, and the incidence of patients infected with ESBL-producing K. pneumoniae decreased significantly (p<0.001). The incidences of other hospital-associated infections also declined (p's<0.02), but piperacillin-tazobactam-resistant Pseudomonas aeruginosa and Enterococcus faecium infections increased (p's<0.033). In wards with high antimicrobial consumption, the patient gut carrier rate of ESBL-producing bacteria significantly decreased (p = 0.023). The unadjusted, all-cause 30-day mortality rates of K. pneumoniae and E. coli were unchanged over the four-year period, with similar results in all five hospitals. Although not statistically significant, the 30-day mortality rate of patients with ESBL-producing K. pneumoniae decreased, from 35% in 2008-2009, to 17% in 2010-2011. The two-year follow-up data indicated that this multidisciplinary intervention led to a statistically significant decrease in the incidence of ESBL/AmpC-resistant K. pneumoniae infections, as well as in the incidences of other typical hospital-associated bacterial infections.

Figure 1. Monthly consumption of antimicrobials.

Bold lines show the monthly consumption at the intervention hospital. Dashed lines represent the predicted usage. Grey shaded bands illustrate the range of the monthly use at the four control hospitals. DDD = defined daily doses; OBD = occupied bed-days. The consumption of ciprofloxacin did not changed significantly, but shifts in levels of consumptions of cefuroxime (p<0.001), ertapenem (p = 0.001), and piperacillin-tazobactam (p<0.001) at the intervention hospital were statistically significant, as indicated by segmented regression analysis of interrupted time series.

Figure 2. The monthly proportions of ESBL/AmpC-producing isolates of K. pneumoniae in patient clinical samples at Bispebjerg Hospital.

The average proportion per six months is shown as grey lines. The arrow indicates the start of the intervention.

Figure 3. Annual incidences of patients infected with various bacterial species.

The annual incidences of patients, as number per 1000 occupied bed days (OBD), infected with various bacterial species at (a) Bispebjerg Hospital and (b) the four control hospitals. At Bispebjerg Hospital (a), the incidence of infections decreased for ESBL/AmpC producing K. pneumoniae (p<0.001), Enterococcus sp. (p<0.0001), E. cloacae (p = 0.002), and Candida sp. (p = 0.018). The Incidences of infections with non-ESBL/AmpC K. pneumonia, ESBL/AmpC producing E. coli, S. aureus and P. aeruginosa were unchanged (p’s>0.063), and the incidence of infections increased for non-ESBL/AmpC producing E. coli (p<0.001). At the other hospitals (b) the incidence of infections with S. aureus, and Enterococus sp. increased significantly (p’s<0.015), the incidences of infections with Candida sp, ESBL/AmpC producing E. coli, non-ESBL/AmpC producing E.coli, P. aeruginosa, E. cloacae, were unchanged (p’s>0.06).

Figure 4. Annual incidences of patients infected with ESBL/AmpC-producing bacteria.

The number of new patients with ESBL- or AmpC- producing K. pneumoniae (upper panel) and E. coli (lower panel) per 1000 occupied bed days (OBD) per month. The dashed line represents the predicted incidence given that the intervention had not taken place. Grey shaded bands illustrate the range at the four control hospitals.

Figure 5. Annual incidences of patients infected with C. difficile.

The annual incidence of patients with Clostridium difficile associated diarrhea, as number per 1000 occupied bed days (OBD), per year, at the different hospitals.