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Updated: Apr 20, 2026
Multiplex Therapeutic Drug Monitoring by Isotope-dilution HPLC-MS/MS of Antibiotics in Critical Illnesses
Published on: August 30, 2018
Multi-drug resistance, inappropriate initial antibiotic therapy and mortality in Gram-negative severe sepsis and
Marya D Zilberberg1,2, Andrew F Shorr3, Scott T Micek4
1EviMed Research Group, LLC, PO Box 303, Goshen, MA, 01032, USA. evimedgroup@gmail.com.
Introduction:
The impact of in vitro resistance on initially appropriate antibiotic therapy (IAAT) remains unclear. We elucidated the relationship between non-IAAT and mortality, and between IAAT and multi-drug resistance (MDR) in sepsis due to Gram-negative bacteremia (GNS).
Methods:
We conducted a single-center retrospective cohort study of adult intensive care unit patients with bacteremia and severe sepsis/septic shock caused by a gram-negative (GN) organism. We identified the following MDR pathogens: MDR P. aeruginosa, extended spectrum beta-lactamase and carbapenemase-producing organisms. IAAT was defined as exposure within 24 hours of infection onset to antibiotics active against identified pathogens based on in vitro susceptibility testing. We derived logistic regression models to examine a) predictors of hospital mortality and b) impact of MDR on non-IAAT. Proportions are presented for categorical variables, and median values with interquartile ranges (IQR) for continuous.
Results:
Out of 1,064 patients with GNS, 351 (29.2%) did not survive hospitalization. Non-survivors were older (66.5 (55, 73.5) versus 63 (53, 72) years, P = 0.036), sicker (Acute Physiology and Chronic Health Evaluation II (19 (15, 25) versus 16 (12, 19), P < 0.001), and more likely to be on pressors (odds ratio (OR) 2.79, 95% confidence interval (CI) 2.12 to 3.68), mechanically ventilated (OR 3.06, 95% CI 2.29 to 4.10) have MDR (10.0% versus 4.0%, P < 0.001) and receive non-IAAT (43.4% versus 14.6%, P < 0.001). In a logistic regression model, non-IAAT was an independent predictor of hospital mortality (adjusted OR 3.87, 95% CI 2.77 to 5.41). In a separate model, MDR was strongly associated with the receipt of non-IAAT (adjusted OR 13.05, 95% CI 7.00 to 24.31).
Conclusions:
MDR, an important determinant of non-IAAT, is associated with a three-fold increase in the risk of hospital mortality. Given the paucity of therapies to cover GN MDRs, prevention and development of new agents are critical.
Insights
Multi-drug resistance (MDR) significantly impacts Gram-negative bacteremia (GNS) outcomes. Non-initially appropriate antibiotic therapy (non-IAAT) due to MDR increases hospital mortality risk by three-fold.
Area of Science:
- Infectious Diseases
- Critical Care Medicine
- Pharmacology
Background:
- The clinical significance of in vitro antibiotic resistance on initially appropriate antibiotic therapy (IAAT) in Gram-negative bacteremia (GNS) is not fully understood.
- Investigating the link between non-IAAT and mortality, and IAAT and multi-drug resistance (MDR) in GNS is crucial for improving patient outcomes.
Purpose of the Study:
- To determine the relationship between non-IAAT and mortality in patients with GNS.
- To examine the association between IAAT and MDR in GNS.
- To identify predictors of hospital mortality and the impact of MDR on non-IAAT.
Main Methods:
- A single-center retrospective cohort study was conducted on adult ICU patients with GNS.
- IAAT was defined as antibiotics active against the identified pathogen within 24 hours of infection onset.
- Logistic regression models were used to analyze mortality predictors and the impact of MDR on non-IAAT.
Main Results:
- Out of 1,064 patients with GNS, 351 (29.2%) died during hospitalization.
- Non-IAAT was an independent predictor of hospital mortality (adjusted OR 3.87).
- MDR was strongly associated with receiving non-IAAT (adjusted OR 13.05).
Conclusions:
- MDR is a key factor determining non-IAAT and is linked to a threefold increase in hospital mortality risk.
- Given limited treatment options for Gram-negative MDR infections, prevention and new therapeutic agent development are critical.
