Using local clinical and microbiological data to develop an institution specific carbapenem-sparing strategy in sepsis: a nested case-control study

Abstract

Background: From a stewardship perspective it is recommended that antibiotic guidelines are adjusted to the local setting, accounting for the local epidemiology of pathogens. In many settings the prevalence of Gram-negative pathogens with resistance to empiric sepsis therapy is increasing. How and when to escalate standard sepsis therapy to a reserve antimicrobial agent, is a recurrent dilemma. The study objective was to develop decision strategies for empiric sepsis therapy based on local microbiological and clinical data, and estimate the number needed to treat with a carbapenem to avoid mismatch of empiric therapy in one patient (NNTC).

Methods: We performed a nested case control study in patients (> 18 years) with Gram-negative bacteremia in 2013-2016. Cases were defined as patients with Gram-negative bacteremia with in vitro resistance to the combination 2nd generation cephalosporin AND aminoglycoside (C-2GC + AG). Control patients had Gram-negative bacteremia with in vitro susceptibility to cefuroxime AND/OR gentamicin, 1:2 ratio. Univariate and multivariable analysis was performed for demographic and clinical predictors of resistance. The adequacy rates of empiric therapy and the NNTC were estimated for different strategies.

Results: The cohort consisted of 486 episodes of Gram-negative bacteremia in 450 patients. Median age was 66 years (IQR 56-74). In vitro resistance to C-2GC + AG was present in 44 patients (8.8%). Independent predictors for resistance to empiric sepsis therapy were hematologic malignancy (adjusted OR 4.09, 95%CI 1.43-11.62, p < 0.01), previously cultured drug resistant pathogen (adjusted OR 3.72. 95%CI 1.72-8.03, p < 0.01) and antibiotic therapy during the preceding 2 months (adjusted OR 12.5 4.08-38.48, p < 0.01). With risk-based strategies, an adequacy rate of empiric therapy of 95.2-99.3% could be achieved. Compared to treating all patients with a carbapenem, the NNTC could be reduced by 82.8% (95%CI 78.5-87.5%) using the targeted approaches.

Conclusions: A risk-based approach in empiric sepsis therapy has the potential to better target the use of reserve antimicrobial agents aimed at multi-resistant Gram-negative pathogens. A structured evaluation of the expected antimicrobial consumption and antibiotic adequacy rates is essential to be able to weigh the costs and benefits of potential antibiotic strategies and select the most appropriate approach.

Keywords: Antibiotic stewardship; Antimicrobial resistance; Empiric therapy; Gram-negative bacteremia; Guideline-development; Sepsis.

Fig. 1

Odds ratio for resistance to empiric therapy related to time since the last drug resistant pathogen (DRP) was cultured. Legend. M = months. C-2GC + AG = Combination 2nd generation cephalosporin and aminoglycoside. Prior-DRP = drug resistant pathogen(s) isolated from any body site: Vancomycin resistant enterococci, multi resistant Staphylococcus aureus, Enterobacteriaceae with in vitro resistance to aminoglycosides, second and/or third generation cephalosporin’s (including ESBL positive Enterobacteriaceae) and/or quinolones, Pseudomonas aeruginosa with resistance to third generation cephalosporin’s, aminoglycosides or quinolones. Odds ratio for infection with cefuroxime and gentamicin resistant Gram-negative pathogen, for patients with prior-DRP isolated compared to patients without prior-DRP isolates, for different time intervals in months since the last DRP was cultured. Note that the y-axis is on a logarithmic scale

Fig. 2

Estimation of the effect of the different empiric strategies on effective therapy rate and consumption of carbapenems, differentiated by a priori probability of bacteremia and compared to other strategies for selection of empiric therapy. Legend. NNTC = number of patients needed to treat with a carbapenem instead of cefuroxime/gentamicin to avoid mismatch of empiric therapy in one patient. C-2GC + AG = 2nd generation cephalosporin/aminoglycoside combination therapy. DRP = drug resistant pathogen(s) isolated from any body site: Vancomycin resistant enterococci, multi resistant Staphylococcus aureus, enterobacteriaceae with in vitro resistance to aminoglycosides, second and/or third generation cephalosporin’s (including ESBL positive Enterobacteriaceae) and/or quinolones, Pseudomonas aeruginosa with resistance to third generation cephalosporins, aminoglycosides or quinolones.. Current clinical practice: 2GC + AG as standard therapy, escalation to a carbapenem according to judgment of treating physician. The percentages (91.2–99.0%) indicate the proportion of patients with bacteremia that would receive adequate treatment if the strategy was implemented. For example: if all patients were to be treated with a carbapenem, the overall rate of adequate therapy in patients with bacteremia would be 99.0%. In case of an a priory risk of bacteremia of 10%, the corresponding NNTC is 128 patients