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.