Empiric combination therapy using a beta-lactam antibiotic plus an aminoglycoside is no more beneficial than empiric monotherapy using an appropriately broad-spectrum beta-lactam antibiotic alone for children suspected of having gram-negative bacteremia, according to a report published online April 7 in Pediatrics.
Routine use of the combination therapy neither reduced 10-day mortality nor decreased the duration of bacteremia, compared with monotherapy, in a retrospective cohort study involving 452 patients aged 3 months and older, said Dr. Anna C. Sick of the University of Pittsburgh Medical Center and her associates.
The exception to this rule was children who were at risk for multidrug-resistant gram-negative bacteremia, who did appear to benefit from the addition of an aminoglycoside, they noted.
The investigators assessed the role of empirical combination therapy because it has not been well studied in this patient population, so its usefulness "remains unsettled."
CDC/ Janice Haney Carr
For pediatric patients suspected of having gram-negative bacteremia such as Pseudomonas aeruginosa, empiric monotherapy without an aminoglycoside may be enough.
In addition, later generations of beta-lactam antibiotics have broader spectrums of activity, which may obviate any benefit offered by adding aminoglycosides. And unnecessary exposure to aminoglycosides should be avoided because the drugs are known to cause ototoxicity and nephrotoxicity; they require drug monitoring; and they require frequent administration, which can lead to complex treatment schedules and possible adverse interactions with other drugs, Dr. Sick and her associates said.
They reviewed the medical records of all 714 children hospitalized at a single tertiary-care hospital – the Johns Hopkins Charlotte R. Bloomberg Children’s Center, Baltimore – during an 8-year period who had signs and symptoms suggestive of infection and who were found to have monomicrobial gram-negative bacteremia. After propensity-score matching, 226 well-balanced pairs were identified, and they formed the study cohort of 452 patients.
Overall, 35 (7.7%) of these patients died within 10 days of diagnosis.
The primary outcome measure, 10-day mortality, was 8.4% among children who received combination therapy and 7.1% among those who received monotherapy. This difference was not significant, the researchers reported (Pediatrics 2014 April 7 [doi: 10.1542/peds.2013-3363]).
These mortality risks did not change appreciably after the data were adjusted to account for the presence or absence of a central line. There also was no survival benefit for adding an aminoglycoside to a beta-lactam antibiotic among children who had the most severe illness, such as those who had PRISM (Pediatric Risk of Mortality) scores of 15 or higher or those who had absolute neutrophil counts of 100 cells or fewer per milliliter.
However, in the subgroup of 46 patients who proved to have multidrug-resistant gram-negative bacteremia, those given combination therapy were more likely to receive an empirical agent with in vitro activity against their pathogen (54.3%) than those given monotherapy (45.6%). Therefore, combination therapy "appears prudent" for patients at risk for multidrug resistance, such as children with a history of either colonization or infection with a resistant organism, children who have received broad-spectrum antibiotic therapy during the preceding month, children whose current hospitalization has been prolonged, and children residing in a community with a high prevalence of resistant pathogens.
The median duration of bacteremia also was not significantly different between the two treatment groups, even after the data were adjusted to account for the time until removal of a central line and the time for drainage of an intraabdominal abscess.
Taken together, the study findings indicate that "selecting an appropriate beta-lactam antibiotic for empirical therapy may be more important than the reflexive addition of an aminoglycoside to all patients who have gram-negative bacteremia," Dr. Sick and her associates said.
This study was supported by a Thrasher Research Foundation Award. Dr. Sick reported no financial conflicts of interest; two of her associates reported receiving grants from Pfizer for work unrelated to this study.