Excess Mortality in CRKp: A Non-Randomized (Fortunately) Trial

Understanding the burden of antimicrobial resistance is critically important if we are to appropriately target research and clinical resources. For years, lack of proper estimates of the morbidity, mortality and costs associated with multidrug-resistant bacteria greatly limited the attention paid to these pathogens. This changed with the 2013 CDC Antibiotic Resistance Threats Report which provided the public with the number 23,000.  In the report, carbapenem-resistant Klebsiella pneumoniae (CRKp) was estimated to cause 7,900 infections and 520 deaths per year. But questions remain: Is the 6.5% (520/7900) mortality estimate high or low and how can we estimate the burden of resistance since we can't (fortunately) perform randomized trials where we randomly infect patients?

To answer these important questions, a group of investigators formed The Consortium on Resistance against Carbapenems in K. pneumoniae (CRACKLE) and just published a cohort study in Clinical Microbiology and InfectionThis group, of what appears to be 18 Great Lakes hospitals, prospectively collected CRKp BSI (N=90), pneumonia (N=49), and UTI (N=121) isolates along with a control group (N=223) of patients with CRKp urinary tract colonization. The use of patients colonized but not infected with the pathogen as controls is interesting. The authors explain that they chose these controls since "non-infection-associated contribution to overall mortality is relatively larger in patients colonized with CRKp compared with patients colonized with more susceptible organisms, since risk factors for mortality such as chronic and acute illness, overlap with risk factors for CRKp colonization. An estimate of this non-infection-related mortality may be approximated in patients who are colonized, but not infected with CRKp." This is another way of saying that they wanted to isolate the attributable mortality risk of infection, not underlying disease.

The primary outcome was time-to-hospital-mortality from the time of the first positive CRKp culture as calculated by an adjusted hazard ratio using Cox proportional hazard models. I've included the unadjusted outcomes below. The full paper includes separate models and Kaplan-Meier curves for each infection, which don't differ greatly from the unadjusted outcomes.

As you can see, 39% of both BSI and pneumonia patients died or were transferred to hospice care compared to 12% of controls giving an attributable mortality of 27% for CRKp infection. In the Cox models, the adjusted hazard ratio was 2.59 (1.52-4.50) for BSI and 3.44 (1.80-6.48) for pneumonia. In contrast CRKp UTI was protective in both the unadjusted (3% lower mortality) and adjusted (aHR=0.68, p=0.33) analyses. This is further evidence that we need to rethink our definitions and focus on UTI.

Overall, a very nice study that utilized a novel control group of patients colonized but not infected with the organism of interest. It is likely that this approach when coupled with multivariable analysis reduced the effects of measured and unmeasured confounders. And it looks like CDC should increase the attributable mortality from 6.5% in their 2013 report to something a bit higher - say 27%.


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