Results from this study indicated that initially inadequate antimicrobial treatment was significantly associated with antibiotic resistant Gram-negative bacteria, mainly P. aeruginosa and ESBL producing bacteria. Previous antibiotic exposure to a 3rd generation cephalosporin was identified as the independent risk factor for initially inadequately treated bacteremias before blood culture results and antibiotic susceptibilities were available. The possible explanation could be that broad-spectrum cephalosporin exposure caused selection of drug-resistant bacteria, which further resulted in inadequately treated bacteremias if alternatively more effective antibiotics were not prescribed. The adverse outcomes were the significantly higher rates of infectious complications and overall mortality (within 30 days) than adequately treated patients.
Several factors have been found for inadequate treatment in other settings, e.g. hospital admission in the 90 days prior to the current admission, admission to surgery, nosocomial infection, polymicrobial infection [16, 24, 25], which were not found in the present study. In the present study, we found that antibiotic exposure to broad-spectrum cephalosporin was associated with a significantly higher risk of infection caused by antibiotic-resistant bacteria, which was consistent with previous reports [26–29]. Although some other broad-spectrum antibiotics, such as carbapenem or fluoroquinolones [28, 30], are also found to cause antibiotic resistance in Gram-negative bacteria, these antibiotics were much less prescribed in our cohort. We found initially inadequately treated Gram-negative bacteremias seemed inevitable since it was difficult to differentiating non-resistant bacteremia from drug-resistant bacteremias by both the clinical presentations and laboratory data. Some other factors may exist and explain why these bacteremias were inadequately treated, including initial partial response of these inadequately treated bacteremias masked the requirement of antibiotic modification, or clinically worsening progression has been ignored by the clinicians.
The appropriateness of initial antibiotics depends on the empirical antibiotic prescribed and the local antibiotic susceptibility patterns. It seemed reasonable that the lower the rate of drug resistant organisms in the NICU, the lower the rate of initially inadequate antimicrobial therapy. Therefore, the issue how to reduce antimicrobial resistance in the ICU [31, 32] is important but not fully studied in the neonatal settings. For example, in contrast to previous studies that S. marcescens and A. baumannii causing bacteremias were multidrug resistant and associated with high mortality or morbidity in the NICU [33, 34], all of the S. marcescens and most of the A. baumannii isolates in our cohort were susceptible to aminoglycoside or cefotaxime, so they were not difficult to treat. The significantly higher mortality of inadequately treated Gram-negative bacteremias may partially explained by the pathogens themselves, and P. aeruginosa and ESBL-producing bacteria, the major causative organisms of this study, have been found to be more likely to cause fulminant illness or early mortality [35, 36].
In the present study, Gram-negative bacteremias without initially adequate antimicrobial therapy had a significantly higher risk of overall mortality, prolonged illness, progression to severe sepsis and infectious complications but not early mortality within seven days of onset. It seemed that in neonates, Gram-negative bacteremias without initially adequate antimicrobial therapy did not cause early mortality within seven days of onset but they caused a prolonged illness, major organs damage, infectious complications and then led to clinical deterioration, which subsequently resulted in final in-hospital mortality.
There are some limitations in this study. This study was observational and not randomized; therefore the choices of initial empirical antibiotic depended on attending physicians instead of the researchers. We failed to account for some important confounders that might influence the decision of attending physician in modifying antibiotics, such as the clinical progression on the first day of bacteremia. Besides, the data were derived from a single center; therefore our conclusions are necessarily limited in generalizability to other settings and institutions.