Risk of bacteremia was cut in half with levofloxacin (Levaquin) prophylaxis given to children with acute leukemias during intensive chemotherapy treatment, a multicenter phase III trial found.
In 195 acute myeloid leukemia (AML) or relapsed acute lymphoblastic leukemia (ALL) patients, the primary endpoint of bacteremia occurred in 21.9% of those in the levofloxacin arm compared with 43.4% in the control arm (risk difference 21.6%, 95% CI 8.8%-34.4%, P=0.001), Sarah Alexander, MD, of the Hospital for Sick Children in Toronto, and colleagues reported.
"These children also experienced fewer episodes of fever and less exposure to therapeutic antibiotics," Alexander told 鶹ý. "The findings indicate the implementation of levofloxacin prophylaxis should be a standard component of supportive care for these leukemia patients, who are at very high risk for bacterial blood infections."
In 418 patients receiving hematopoietic stem cell transplantation (HSCT), levofloxacin showed a numerical advantage in bacteremia reduction (11.0% versus 17.3% with no prophylaxis), but this did not reach significance (risk difference 6.3%, 95% CI 0.3%-13.0%, P=0.06), as reported in .
The authors noted that with the low number of events, the HSCT arm was possibly underpowered, with the few events possibly "explained, in part, by a shorter duration of neutropenia in the HSCT group."
Alexander and colleagues noted that bacteremia was chosen as the main endpoint due to its association with sepsis, deaths from infections, and increased use of healthcare.
The secondary endpoint of fever and neutropenia, among all patients in the study, occurred in 71.2% of those on levofloxacin compared with 82.1% of those who received no prophylaxis (risk difference 10.8%, 95% CI 4.2%-17.5%, P=0.002). And fewer patients on levofloxacin needed therapeutic antibiotics (68.6% versus 85.7%), for an adjusted OR of 0.36 (95% CI 0.24-0.55, P<0.001).
Only a small group of centers in North America currently use prophylactic antibiotic treatment as standard supportive care for pediatric AML patients being treated with chemotherapy, according to Alexander, and its use in transplant patients is more variable.
Concerns over bacterial resistance, musculoskeletal adverse events, and Clostridium difficile-associated diarrhea has limited the support for regular use of antibiotics in this setting.
Alexander's group cautioned that antibiotic prophylaxis can lead to resistance and noted that in adult patients an increase in fluoroquinolone resistance has been reported during breakthrough bacteremia, suggesting "that patients receiving levofloxacin prophylaxis who develop fever and neutropenia should not receive an empirical antibiotic regimen that relies on fluoroquinolones."
No significant differences were seen among other secondary endpoints studied in all patients, and outside of invasive fungal disease (2.9% with levofloxacin versus 2.0% without), most were numerically reduced in the levofloxacin group compared with the no prophylaxis group: musculoskeletal adverse events at baseline (5.9% versus 10.0%), 2 months (11.4% versus 16.3%), or 12 months (10.1% versus 14.4%); severe infection (3.6% versus 5.9%); and C. difficile-associated diarrhea (2.3% versus 5.2%).
"A surprising finding from the study was that prophylaxis decreased the likelihood of having a positive test for C. difficile, which may have been related to decreased exposure to therapeutic antibiotics for those who received prophylaxis," said Alexander.
A post-hoc analysis of all patients revealed that 7.8% of the levofloxacin-treated patients tested positive for C. difficile compared with 14.0% of the control patients (adjusted OR 0.52, 95% CI 0.31-0.89, P=0.02).
From 2011 to 2016 (across 76 sites in the U.S. and Canada), the randomized 200 acute leukemia patients to 2 cycles of intensive chemotherapy with or without levofloxacin, and 424 patients receiving HSCT to levofloxacin or no prophylaxis.
Patients ranged in age from 6 months to 21 years. Grade 4 adverse events were similar between levofloxacin-treated patients (23 events among 8 patients). Overall there was 1 death among the levofloxacin-treated patients (not attributed to the study drug) and 4 deaths among patients who received no prophylaxis.
Disclosures
The study was funded in part by the Children's Oncology Group, and grants from the Community Clinical Oncology Program, and the National Cancer Institute (NCI)-supported Quality of Life Studies Program.
Alexander reported no conflicts of interest. Co-authors disclosed relationships with Bristol-Myers Squibb, Chimerix, the Children's Oncology Group, and Jazz Pharmaceuticals.
Primary Source
JAMA
Alexander S, et al “Effect of levofloxacin prophylaxis on bacteremia in children with acute leukemia or undergoing hematopoietic stem cell transplantation: A randomized clinical trial” JAMA 2018; 320(10):995-1004.