Appropriate antimicrobial therapy in the era of multidrug-resistant human pathogens

Abstract

The past decade has brought a significant rise in antimicrobial resistance, and the ESKAPE pathogens have become a significant threat to public health. Three epidemiological features that negatively impact patients, which are consistently seen with the ESKAPE pathogens, are the following: 1) there has been a rise in incidence of these organisms as causative human pathogens, 2) there has been a significant increase in antimicrobial resistance in these bacterial species, and 3) the infections caused by these resistant strains are associated with worse outcomes when compared with infections caused by their susceptible counterparts. Significant delays in time to appropriate antimicrobial therapy of up to 5 days have been reported in infections due to these organisms and this is the strongest predictor of mortality with ESKAPE pathogens, particular in critically ill patients, where every hour delay has an incremental survival disadvantage for patients. Strategies to decrease these delays are urgently needed. Although routine broad-spectrum empiric coverage for these organisms would ideally limit this delay, agents with activity against these organisms are sometimes less effective, have significant toxicity risk, and their use can result in the development of resistance. Therefore, strategies to optimize therapy, although limiting unnecessary use of broad-spectrum antimicrobials, are urgently needed. This review will discuss potential strategies to optimize empiric therapy in the age of multi-drug resistance, the limitations of these strategies, and will discuss future directions and opportunities.

Molecular β-Lactamase Characterization of Aerobic Gram-Negative Pathogens Recovered from Patients Enrolled in the Ceftazidime-Avibactam Phase 3 Trials for Complicated Intra-abdominal Infections, with Efficacies Analyzed against Susceptible and Resistant Subsets

“…In addition to the high prevalence rates, reports of antimicrobial resistance in Gram-negative pathogens causing community-acquired infections and HAI have increased (6,7). Carbapenem-resistant Enterobacteriaceae (CRE) strains and ceftriaxoneresistant Enterobacteriaceae strains have been reported to account for 35,000 HAI each year in U.S. hospitals (6), and the percentage of CRE among U.S. medical centers increased from 1.2% in 2001 to 4.2% in 2011 (8).…”

In Vitro Activity of Imipenem-Relebactam against Gram-Negative ESKAPE Pathogens Isolated by Clinical Laboratories in the United States in 2015 (Results from the SMART Global Surveillance Program)

“…Gram-negative ESKAPE pathogens act as important reservoirs and transmitters of resistance and are responsible for the increased reporting of antimicrobial-resistant nosocomial infections worldwide (11)(12)(13)16). There are very few new antimicrobial agents in development to treat Gram-negative ESKAPE pathogens despite the well-recognized need (11)(12)(13)17).…”

“…ESKAPE pathogens are known to "escape" the effects of currently marketed antimicrobial agents, are frequently multidrug resistant, and are associated with poor patient outcomes, because patients infected with ESKAPE pathogens often receive inappropriate empirical antimicrobial therapy that leads to unfavorable clinical outcomes, high case fatality rates, and opportunities for the pathogen to spread to other patients (11,(13)(14)(15)(16). Gram-negative ESKAPE pathogens act as important reservoirs and transmitters of resistance and are responsible for the increased reporting of antimicrobial-resistant nosocomial infections worldwide (11)(12)(13)16). There are very few new antimicrobial agents in development to treat Gram-negative ESKAPE pathogens despite the well-recognized need (11)(12)(13)17).…”

An Immunocompromised Child with Bloodstream Infection Caused by Two Escherichia coli Strains, One Harboring NDM-5 and the Other Harboring OXA-48-Like Carbapenemase

“…Invasive infections due to CRE are often associated with mortality rates exceeding 50%, with the worst outcomes being seen in the most vulnerable patient populations, such as the case presented here. High mortality rates in patients with CRE infections are driven by significant delays in the time to implementation of appropriate antimicrobial therapy, in addition to patient-specific characteristics (such as age and severity of illness) (19). In some instances, due to delays in processing antimicrobial susceptibility results, appropriate antimicrobial therapy will not be initiated until day 5 of treatment or later, and these "appropriate" treatment options come with significant limitations.…”