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Monotherapy versus beta-lactam-aminoglycoside combination therapy for gram-negative bacteremia

I read with interest the paper by Leibovici et al. which presented their prospective, observational study of monotherapy versus b-lactam–aminoglycoside combination treatment for gram-negative rod bacteremia (2). The authors should be commended because they presented important data on 2,165 patients with gram-negative rod bacteremia. I would like to point out some issues related to this report. First, although I understand the limitations in presenting summary results of complex analyses in a short text, I believe that some statements made in the abstract of the article should be clarified. Specifically, it is stated in the abstract that combination therapy showed no advantage over single b-lactam therapy except for neutropenic patients. However, it should be noted that a statistically significant association between combination treatment and improved survival was observed only in a subset analysis of 793 patients who were given combination treatment or a single b-lactam drug for both empirical (before results of blood cultures were known) and definitive (after the results of blood cultures were known) treatments. Specifically, the 95% confidence interval (95% CI) of odds ratio (OR) for mortality do not support any statistically significant advantage of empirical (OR, 0.8; 95% CI, 0.4 to 1.8; see Table 5 of reference 2) or definitive (OR, 0.6; 95% CI, 0.2 to 1.3; see Table 7 of reference 2) combination treatment over a single b-lactam for neutropenic patients. In addition, the OR for mortality in neutropenic patients treated with empirical combination over a single b-lactam (OR, 0.5; 95% CI, 0.2 to 1.3) that was presented in the abstract in reality refers to a subset of patients with neutropenia and an unknown source of infection, as reported in the text of the manuscript. Second, appropriate definitive b-lactam–aminoglycoside combination treatment was defined as treatment with the two drugs for more than 24 h during days 3 to 10 after the first blood specimen that was positive on culture was taken, if the pathogen was susceptible to both drugs. However, combination treatment for a longer period of time may be needed to see a clinically meaningful benefit. The authors should also analyze their data by using an alternative definition of combination treatment, e.g., at least 3 days of b-lactam–aminoglycoside combination treatment. Third, there is some evidence that supports the use of blactam–aminoglycoside combination treatment over a single b-lactam drug for patients with Enterobacter bacteremia (1, 3). It would be valuable for Leibovici et al. to look at this issue, because their study population included a significant number of patients (6% of 2,165) with Enterobacter bacteremia. Fourth, the headings of some columns of Tables 5 and 7 need to be corrected. The ORs in the fourth columns of Tables 5 and 7 refer to combination therapy versus b-lactam therapy and not to the reverse, as appeared in the published manuscript. Also, the ORs in the sixth column of Table 7 refer to aminoglycoside versus b-lactam therapy and not to b-lactam versus combination therapy, as appeared in the manuscript. Last but not least, a clinically and statistically significant difference in mortality between patients treated with appropriate and inappropriate empirical antibiotic treatment was noted in this study (mortality, 18 versus 34%, respectively; P , 0.0001). The authors may want to analyze their data to identify characteristics of patients who were treated with inappropriate empirical antibiotic treatment. Use of more appropriate empirical treatment (e.g., antibiotics with broader coverage) may decrease mortality in a well-defined subset of patients.