Antibiotic prophylaxis and the gastrointestinal resistome in paediatric patients with acute lymphoblastic leukaemia: a cohort study with metagenomic sequencing analysis

Abstract

Background Although antibiotic prophylaxis with levofloxacin can reduce the risk of serious infection in immunocompromised patients, the potential contribution of prophylaxis to antibiotic resistance is a major drawback. We aimed to identify the effects of levofloxacin prophylaxis, given to paediatric patients with acute lymphoblastic leukaemia to prevent infections during induction chemotherapy, on antibiotic resistance in gastrointestinal microbiota after completion of induction and consolidation therapy. Methods This prospective, single-centre (St Jude Children's Research Hospital, Memphis, TN, USA) cohort study included children (≤18 years) receiving therapy for newly diagnosed acute lymphoblastic leukaemia and who received either primary levofloxacin prophylaxis or no antibacterial prophylaxis (aside from Pneumocystis jirovecii prophylaxis with trimethoprim-sulfamethoxazole) and provided at least two stool samples, including one after completion of induction therapy. We used metagenomic sequencing to identify bacterial genes that confer resistance to fluoroquinolones, trimethoprim-sulfamethoxazole, or other antibiotics, and to identify point mutations in bacterial topoisomerases (gyrA, parC) that confer resistance to fluoroquinolones. We then used generalised linear mixed models to compare the prevalence and relative abundance of antibiotic resistance gene groups after completion of induction and consolidation therapy between participants who had received levofloxacin and those who received no prophylaxis.

Effectiveness of Quinolone Prophylaxis in Pediatric Acute Leukemia and Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-analysis

“…Eight of the included studies reported data on the impact of fluoroquinolone PPX on the development of antibiotic resistance in colonizing microorganisms and/or in bacteria isolated from blood [ 29 , 32 , 33 , 36 , 37 , 40 , 41 , 43 ]; the results are summarized in Table 5 . Among patients with AL receiving fluoroquinolone PPX, 3 studies found an increased incidence of gram-negative bacteria resistant to fluoroquinolone in intestinal microflora [ 29 , 40 ] and isolated from blood [ 33 ].…”

“…Among patients with AL receiving fluoroquinolone PPX, 3 studies found an increased incidence of gram-negative bacteria resistant to fluoroquinolone in intestinal microflora [ 29 , 40 ] and isolated from blood [ 33 ]. Similarly, in the study by Margolis et al, the prevalence of topoisomerase point mutations, known to confer fluoroquinolone resistance, increased during induction chemotherapy for ALL in participants receiving LVX but not those receiving no PPX [ 32 ]. Conversely, in the 2 works of Yeh et al, CPFX [ 43 ] and amikacin [ 37 ] resistance to the most common gram-negative bacilli at the study institution was significantly reduced during the PPX period, with a concomitant rising of cefuroxime and imipenem resistance [ 37 ].…”

“…Although studies reported variable results, an increase in fluoroquinolone resistance was generally reported in patients undergoing PPX [ 41 ]. Interestingly, this increase seems to be related to the acquisition of topoisomerase mutations known to confer resistance to fluoroquinolones [ 32 ]. Furthermore, the emergence of new antibiotic resistance in bacterial microflora was noted in some studies, reporting an increase in ceftazidime and cefuroxime resistance [ 29 , 37 ].…”

“…Moreover, this risk is significantly higher in relapsed patients [ 9 ]. Among the meta-analyzed studies on AL patients, in all cases PPX was prescribed during a period of intensive chemotherapy, differently but quite consistently defined, namely, during induction for ALL [ 39 , 40 ] or during regimens that are predicted to cause prolonged neutropenia [ 32 , 33 , 41 , 42 ]. Moreover, 4 of 6 studies included patients with AML [ 33 , 37 , 41 , 42 ] and 2 of 6 included patients with rALL [ 33 , 41 ].…”

The Gut Resistome during Hematopoietic Stem Cell Transplantation in Children

“…On the contrary, in a study of 49 children with acute lymphoblastic leukemia, levofloxacin prophylaxis was associated with an increase in the prevalence of fluoroquinolone resistance, while a rise in collateral antibiotic resistance from other ARG classes was not detected. 34 As levofloxacin prophylaxis is becoming more common in pediatric centers, further research is needed to determine the effect of levofloxacin on the resistome.…”