Discussion
Patients undergoing HSCT are particularly prone for infections in the period preceding engraftment [18]. Neutrophils are important first defence against bacterial infections. Both severity and duration of neutropenia are important for risk assessment. AGIHO regards patients with expected neutrophil count of <0.5 for more than 7 days to be high risk [19]. Patients undergoing BMT are at high risk for complicated infections [20]. Prevention of febrile neutropenia is of utmost importance as after onset it is associated with 25 to 30% rate of major complications like hypotension, renal failure along with 11% mortality [21]. Antibiotic prophylaxis has been shown to reduce the risk of life-threatening infections in neutropenic patients albeit with the risk of developing antimicrobial resistance, alteration of gut microbiome, drug toxicity and increased cost [22].
IDSA /ASCO guidelines published in 2018, suggest antibiotic prophylaxis in patients undergoing myeloablative conditioning regimen [11]. Zeigler et al reported reduction in central line related blood stream infections from 18.4% to 6.0% with levofloxacin prophylaxis [23].
Overall incidence of blood stream infections in our study was 22.8%. This is similar to most published literature. In most studies published, gram-positive BSI has been the most common cause of bacteremia [24]. In our study, we found an overwhelming majority of GNB infection seen in 28.7% of all patients. Gram-positive infection was observed in 9.13% of all patients. In a single center retrospective study, gram-positive bacteria accounted for 57% and gram-negative rods bacteria for 37% of bacteremia [25]. Over time the author had been a decrease in GPC/GNB ratio with use of fluroquinolone prophylaxis.
In a randomised study done by GIMEMA group, the duration of fever, microbiologically documented infections, BSI and single-agent gram-negative BSI were significantly lower in the levofloxacin group than in the placebo group. This, however, did not include HSCT patients. Mortality and tolerability were similar in the two groups [26].Similar to our results, Clemmons et al reported reduced incidence of bacteremia in both autologous and allogeneic HSCT with flouroquinolone prophylaxis. They reported no difference in mortality in autologous subgroup with trend towards lower mortality in AlloSCT patients [27]. Modi et al also reported reduction in the incidence of neutropenic fever and antibiotic use in ASCT group with fluoroquinolone prophylaxis without any impact on mortality or morbidity [28].  In our study antibiotic prophylaxis was found to reduce gram negative sepsis and carbapenem resistance without any impact on mortality. However, the incidence of bacteremia, gram positive sepsis and duration of fever was not affected. Increasing rates of CRE over time is related to stopping antibiotic prophylaxis is non-intuitive as these outcomes are likely to be influenced by time. This association has been matched with greater antibiotic utilization over the past decade [29].   Fever could be due to a lot of non-infectious causes in a transplant patient. On the other hand, Heindenrech et al reported day 100 mortality and BSI in their cohort of 47 patients undergoing allogeneic HSCT and concluded that bacterial prophylaxis was not required [30].
Averbuch et al reported more MDR infections in allogeneic BMT group vs autologous BMT [31].  They also reported a high 18% mortality in CRE group vs 4% in carbapenem sensitive GNB. A multicenter Italian study reported CRE infection-related mortality rates of 16% and 64.4% in autologous and allogeneic groups respectively [32]. Multidrug resistant (MDR) GNB infection are associated with high mortality. A recent study reported 79% mortality in post HSCT setting and MDR pseudomonas infection [33]. Our findings are somewhat surprising as we noted more carbapenem resistant gram-negative bacteria in no-prophylaxis group. This is difficult to explain. It is possible that during the study period (2012-2019) overall incidence of CRE was rising. Even though CRE did not impact mortality in ASCT group, it was a major contributor to mortality in allogeneic BMT group. Increased mortality in no-prophylaxis group in our study was largely driven by mortality in AlloSCT group. Median age in this group was higher compared to prophylaxis group. Even if mortality in HSCT was not affected, antibiotic prophylaxis is likely to reduce use of carbapenem antibiotics and thereby reduce cost.
Quinolones have been shown to be associated with Clostridium difficile diarrhea, tendinopathy, decrease in seizure threshold and QT prolongation. We did not observe any such adverse effect in our study. Retrospective nature of our study may have led to under-reporting of these adverse effects. In children less than 7 years old quinolones are contraindicated as they may cause cartilage damage [34]. In our study we used amoxicillin as an antibiotic prophylaxis to overcome these effects. Overall, we did not observe any significant toxicity due to quinolones in our patients.
Resistance to fluoroquinolones have been reported in 50% of gram-negative isolates in patients receiving fluoroquinolone prophylaxis. In a study by Miles-Jay A et al, the rates of fluoroquinolone resistance has been found to be static over 10 years of prophylaxis [35].
Limitations of present study are that to some extent such data are available in literature. However, data on correlation with carabapenem resistance are not easily available. Our study was limited by retrospective nature performed on patients treated over a period of 8 years. The inclusion of both autologous and allogeneic patients, heterogeneity of underlying diseases and transplantation type (matched related, matched unrelated, haploidentical) does take away some shine from the analysis of total patients compared to the non-prophylaxis group. One may argue that results may differ based on these factors. However, we are reliably able to document role of antibiotic prophylaxis in prevention of gram-negative infection and carbapenem resistance in this high-risk population.
Based on results of this data, we now routinely use antibiotic prophylaxis for all our HSCT patients. This paper contributes to scientific literature by provide data from India which is scarce.
Conclusion : Antibiotic prophylaxis reduces documented bacterial infections and incidence of carbapenem resistance. Antibiotic prophylaxis does not reduce mortality in patients undergoing hematopoietic stem cell transplant.