Levofloxacin prophylaxis cuts bacteremia in pediatric acute leukemias

Levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias receiving intensive chemotherapy, according to results of a multicenter, randomized phase 3 trial.

Risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children undergoing hematopoietic stem cell transplantation (HSCT), although a post hoc analysis accounting for time at risk did show a significant difference, according to results of this Children’s Oncology Group (COG) trial.

The reduction in risk for children with acute leukemias was similar to findings of adult studies showing the benefit of prophylactic antibiotics in patients with cancer-related neutropenia, said Sarah Alexander, MD, of the division of hematology/oncology, the Hospital for Sick Children, Toronto, and her coinvestigators.

Before this COG study, data on prophylactic antibiotics in children with cancer were limited to several small, single-group observational studies, Dr. Alexander and her coauthors wrote in JAMA.

Bacteremia was the primary outcome of the COG study, according to the investigators, because of its link to sepsis, increased health care utilization, and infection-related mortality. “Consequently, this outcome is meaningful to both clinicians and patients,” the investigators noted.

The multicenter, randomized, open-label phase 3 trial (ACCL0934) enrolled patients aged 6 months to 21 years, including 200 with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were to receive at least two intensive chemotherapy cycles, and 424 who were to receive a myeloablative autologous or allogeneic HSCT.

In the final analysis of the acute leukemias group, which included 195 patients, likelihood of bacteremia was 21.9% for those randomized to levofloxacin prophylaxis, versus 43.4% for no prophylaxis (P = 0.001).

In the final analysis of the HSCT group, which included 418 patients, likelihood of bacteremia was not significantly different, at 11.0% for levofloxacin prophylaxis, versus 17.3% for no prophylaxis (P = 0.06).

“Levofloxacin prophylaxis was effective at reducing the risk of bacteremia among patients with acute leukemia, but not among patients undergoing HSCT,” Dr. Armstrong and her coauthors said.

A post hoc analysis accounting for time at risk, however, showed a significant difference in favor of prophylaxis in both groups and a similar effect size between groups, according to investigators.

For the acute leukemias group, the rate of bacteremic episodes in that post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and no prophylaxis arms, respectively (P = 0.008). In the HSCT group, the rate was 5.3 versus 10.0 bacteremias per 1,000 patient-days in the prophylaxis and no prophylaxis arms (P = .02).

The similar effect size suggests that in the primary analysis, there was reduced power to detect a significant difference in the HSCT group because of fewer events, driven partly by a shorter duration of neutropenia in that group, Dr. Armstrong and her associates said.

“However, it is also plausible that the leukemia and HSCT groups had different supportive care measures or were infected with pathogens that had differential sensitivity to levofloxacin resulting in different efficacy of levofloxacin in the 2 groups,” they added.

Levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several Gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests that other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk, the investigators said.

Further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits, according to the investigators, who reported 23 serious adverse events in 8 patients, 11 of which were considered unrelated or unlikely to be related to levofloxacin.

“The adoption of antibacterial prophylaxis is tempered by potential negative consequences including Clostridium difficile-associated diarrhea, bacterial resistance, and musculoskeletal toxicities,” Dr. Armstrong and her colleagues noted.

The research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

SOURCE: Alexander S, et al . JAMA. 2018;320(10):995-1004.

Levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias receiving intensive chemotherapy, according to results of a multicenter, randomized phase 3 trial.

Risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children undergoing hematopoietic stem cell transplantation (HSCT), although a post hoc analysis accounting for time at risk did show a significant difference, according to results of this Children’s Oncology Group (COG) trial.

The reduction in risk for children with acute leukemias was similar to findings of adult studies showing the benefit of prophylactic antibiotics in patients with cancer-related neutropenia, said Sarah Alexander, MD, of the division of hematology/oncology, the Hospital for Sick Children, Toronto, and her coinvestigators.

Before this COG study, data on prophylactic antibiotics in children with cancer were limited to several small, single-group observational studies, Dr. Alexander and her coauthors wrote in JAMA.

Bacteremia was the primary outcome of the COG study, according to the investigators, because of its link to sepsis, increased health care utilization, and infection-related mortality. “Consequently, this outcome is meaningful to both clinicians and patients,” the investigators noted.

The multicenter, randomized, open-label phase 3 trial (ACCL0934) enrolled patients aged 6 months to 21 years, including 200 with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were to receive at least two intensive chemotherapy cycles, and 424 who were to receive a myeloablative autologous or allogeneic HSCT.

In the final analysis of the acute leukemias group, which included 195 patients, likelihood of bacteremia was 21.9% for those randomized to levofloxacin prophylaxis, versus 43.4% for no prophylaxis (P = 0.001).

In the final analysis of the HSCT group, which included 418 patients, likelihood of bacteremia was not significantly different, at 11.0% for levofloxacin prophylaxis, versus 17.3% for no prophylaxis (P = 0.06).

“Levofloxacin prophylaxis was effective at reducing the risk of bacteremia among patients with acute leukemia, but not among patients undergoing HSCT,” Dr. Armstrong and her coauthors said.

A post hoc analysis accounting for time at risk, however, showed a significant difference in favor of prophylaxis in both groups and a similar effect size between groups, according to investigators.

For the acute leukemias group, the rate of bacteremic episodes in that post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and no prophylaxis arms, respectively (P = 0.008). In the HSCT group, the rate was 5.3 versus 10.0 bacteremias per 1,000 patient-days in the prophylaxis and no prophylaxis arms (P = .02).

The similar effect size suggests that in the primary analysis, there was reduced power to detect a significant difference in the HSCT group because of fewer events, driven partly by a shorter duration of neutropenia in that group, Dr. Armstrong and her associates said.

“However, it is also plausible that the leukemia and HSCT groups had different supportive care measures or were infected with pathogens that had differential sensitivity to levofloxacin resulting in different efficacy of levofloxacin in the 2 groups,” they added.

Levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several Gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests that other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk, the investigators said.

Further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits, according to the investigators, who reported 23 serious adverse events in 8 patients, 11 of which were considered unrelated or unlikely to be related to levofloxacin.

“The adoption of antibacterial prophylaxis is tempered by potential negative consequences including Clostridium difficile-associated diarrhea, bacterial resistance, and musculoskeletal toxicities,” Dr. Armstrong and her colleagues noted.

The research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

SOURCE: Alexander S, et al . JAMA. 2018;320(10):995-1004.

Levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias receiving intensive chemotherapy, according to results of a multicenter, randomized phase 3 trial.

Risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children undergoing hematopoietic stem cell transplantation (HSCT), although a post hoc analysis accounting for time at risk did show a significant difference, according to results of this Children’s Oncology Group (COG) trial.

The reduction in risk for children with acute leukemias was similar to findings of adult studies showing the benefit of prophylactic antibiotics in patients with cancer-related neutropenia, said Sarah Alexander, MD, of the division of hematology/oncology, the Hospital for Sick Children, Toronto, and her coinvestigators.

Before this COG study, data on prophylactic antibiotics in children with cancer were limited to several small, single-group observational studies, Dr. Alexander and her coauthors wrote in JAMA.

Bacteremia was the primary outcome of the COG study, according to the investigators, because of its link to sepsis, increased health care utilization, and infection-related mortality. “Consequently, this outcome is meaningful to both clinicians and patients,” the investigators noted.

The multicenter, randomized, open-label phase 3 trial (ACCL0934) enrolled patients aged 6 months to 21 years, including 200 with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were to receive at least two intensive chemotherapy cycles, and 424 who were to receive a myeloablative autologous or allogeneic HSCT.

In the final analysis of the acute leukemias group, which included 195 patients, likelihood of bacteremia was 21.9% for those randomized to levofloxacin prophylaxis, versus 43.4% for no prophylaxis (P = 0.001).

In the final analysis of the HSCT group, which included 418 patients, likelihood of bacteremia was not significantly different, at 11.0% for levofloxacin prophylaxis, versus 17.3% for no prophylaxis (P = 0.06).

“Levofloxacin prophylaxis was effective at reducing the risk of bacteremia among patients with acute leukemia, but not among patients undergoing HSCT,” Dr. Armstrong and her coauthors said.

A post hoc analysis accounting for time at risk, however, showed a significant difference in favor of prophylaxis in both groups and a similar effect size between groups, according to investigators.

For the acute leukemias group, the rate of bacteremic episodes in that post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and no prophylaxis arms, respectively (P = 0.008). In the HSCT group, the rate was 5.3 versus 10.0 bacteremias per 1,000 patient-days in the prophylaxis and no prophylaxis arms (P = .02).

The similar effect size suggests that in the primary analysis, there was reduced power to detect a significant difference in the HSCT group because of fewer events, driven partly by a shorter duration of neutropenia in that group, Dr. Armstrong and her associates said.

“However, it is also plausible that the leukemia and HSCT groups had different supportive care measures or were infected with pathogens that had differential sensitivity to levofloxacin resulting in different efficacy of levofloxacin in the 2 groups,” they added.

Levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several Gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests that other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk, the investigators said.

Further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits, according to the investigators, who reported 23 serious adverse events in 8 patients, 11 of which were considered unrelated or unlikely to be related to levofloxacin.

“The adoption of antibacterial prophylaxis is tempered by potential negative consequences including Clostridium difficile-associated diarrhea, bacterial resistance, and musculoskeletal toxicities,” Dr. Armstrong and her colleagues noted.

The research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

SOURCE: Alexander S, et al . JAMA. 2018;320(10):995-1004.