Impact of Combination Antimicrobial Therapy on Mortality Risk for Critically Ill Patients with Carbapenem-Resistant Bacteremia

Abstract

There are limited treatment options for carbapenem-resistant Gram-negative infections. Currently, there are suggestions in the literature that combination therapy should be used, which frequently includes antibiotics to which the causative pathogen demonstrates in vitro resistance. This case-control study evaluated risk factors associated with all-cause mortality rates for critically ill patients with carbapenem-resistant Gram-negative bacteremia. Adult patients who were admitted to an intensive care unit with sepsis and a blood culture positive for Gram-negative bacteria resistant to a carbapenem were included. Patients with polymicrobial, recurrent, or breakthrough infections were excluded. Included patients were classified as survivors (controls) or nonsurvivors (cases) at 30 days after the positive blood culture. Of 302 patients screened, 168 patients were included, of whom 90 patients died (53.6% [cases]) and 78 survived (46.4% [controls]) at 30 days. More survivors received appropriate antibiotics (antibiotics with in vitro activity) than did nonsurvivors (93.6% versus 53.3%; P < 0.01). Combination therapy, defined as multiple appropriate agents given for 48 h or more, was more common among survivors than nonsurvivors (32.1% versus 7.8%; P < 0.01); however, there was no difference in multiple-agent use when in vitro activity was not considered (including combinations with carbapenems) (87.2% versus 80%; P ‫؍‬ 0.21). After adjustment for baseline factors with multivariable logistic regression, combination therapy was independently associated with decreased risk of death (odds ratio, 0.19 [95% confidence interval, 0.06 to 0.56]; P < 0.01). These data suggest that combination therapy with multiple agents with in vitro activity is associated with improved survival rates for critically ill patients with carbapenem-resistant Gram-negative bacteremia. However, that association is lost if in vitro activity is not considered. Carbapenem resistance among Gram-negative bacteria has been increasingly reported (1). Between 2004 and 2008, the proportion of Klebsiella pneumoniae isolates resistant to meropenem in the United States increased from 0.6% to 5.6% (2). In certain geographic areas, such as New York City, prevalence rates are substantially higher and carbapenem resistance is considered endemic (3). Additionally, carbapenem resistance is a significant problem for critically ill patients admitted to an intensive care unit (ICU), as an ICU stay has consistently been shown to be an independent predictor of the acquisition of a carbapenem-resistant Gram-negative infection (4, 5).Furthermore, outcomes of carbapenem-resistant Gram-negative bacteremia are known to be poor. Infections with carbapenem-resistant Gram-negative organisms are associated with increased mortality rates, compared to carbapenem-susceptible organisms, and mortality rates are exceedingly high for these infections (4-8). In fact, attributable mortality rates for carbapenem-resistant Klebsiella pneumoniae bacteremia are as high as 50% (9). Additional...

Improving outcomes of severe infections by multidrug-resistant pathogens with polyclonal IgM-enriched immunoglobulins

“…The present study provides promising data supporting the use of polyclonal IgM-enriched immunoglobulin preparations as adjunctive of antimicrobial treatment for the management of severe infections caused by MDR Gram-negative bacteria. These pathogens progressively emerge in critically ill patients, causing infections with reported mortality even exceeding 50% [18,19]. A prospective randomized trial is warranted to prove the role of polyclonal IgM-enriched preparations as an adjunctive therapeutic strategy for severe infections by MDR Gramnegative bacteria.…”

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016

“…A number of other recent observational studies and some small, prospective trials also support initial combination therapy for selected patients with specific pathogens (e.g., severe pneumococcal infection, multidrug-resistant gram-negative pathogens) [172,[176][177][178][179][180][181][182]. Unfortunately, in most cases and pending the development of rapid bedside pathogen detection techniques, the offending pathogen is not known at the time of presentation.…”

“…Therefore, specifying combination therapy to specific identified pathogens is useful only if more prolonged targeted combination therapy is contemplated. In addition, with respect to multidrug-resistant pathogens, both individual studies and meta-analyses yield variable results depending on the pathogen and the clinical scenario [179][180][181][182][183][184]. Infectious diseases consultation may be advisable if multidrug-resistant pathogens are suspected.…”

Association between infections caused by multidrug-resistant gram-negative bacteria and mortality in critically ill patients

“…In eight studies patients infected with a MDR strain were compared to those with a susceptible one or to those without any infection. Comparative data on the appropriateness of empirical antibiotic treatment were provided by only seven [48,50,51,52,54,55] out of twenty-four studies.…”