INTRODUCTIONOver the past decade, rates of central line-associated bloodstream infections
(CLABSIs) have been reduced by over 50% among hospitalized patients through the
implementation of standardized infection prevention strategies1,2.
However, CLABSIs remain common in patients with hematologic malignancy and are
associated with significant morbidity and mortality, including an increased risk of
acute graft-versus host disease (GVHD), prolonged lengths of stay, and up to a
7-fold increased risk of death3–8. In patients
undergoing autologous stem cell transplant (SCT), rates of CLABSIs have been
estimated to be as high as 20–40%6,9.
Patients undergoing SCT are at increased risk of infection due to their
underlying malignancy, frequent hospitalizations, chemotherapy-induced immune
suppression, and neutropenia. The majority of patients require prolonged use of
central venous access devices for the receipt of chemotherapy and transfusion of
blood products. In addition, myeloablative regimens prior to SCT result in
neutropenia of days to weeks and typically result in mucosal barrier injury in the
gastrointestinal tract10.
Translocation of gut bacteria can then result in primary bloodstream infections, an
infection termed mucosal barrier injury laboratory confirmed bloodstream infection
(MBI-LCBI) for surveillance purposes by Centers for Disease Control and Preventions
(CDC)’s National Healthcare Safety Network (NHSN)11. Importantly, these MBI-CLABSI events may
not be preventable with common infection prevention strategies such as aseptic
catheter insertion, chlorhexidine gluconate bathing, and optimal central line
care12. However,
MBI-CLABSIs are associated with similar morbidity and mortality as CLABSIs
associated with typical, non-MBI pathogens and as such, represent a critical target
for prevention in hospitalized patients5,11.
Two randomized trials of levofloxacin prophylaxis among cancer patients
conducted more than a decade ago demonstrated conflicting results for the prevention
of bloodstream infections and were limited by inclusion of patients with both solid
and hematologic malignancy and varied timing and duration of prophylaxis
regimens13–15. Since these studies, the utility
of antibiotic prophylaxis has become less clear, due in part to increasing rates of
fluoroquinolone resistance and the risk of Clostridium difficile
infection associated with these agents16–18.
Additionally, the complexity of these patients and delivery of care (e.g.,
chemotherapy regimens) have significantly increased. Given the paucity of evidence
for the impact of routine antibiotic prophylaxis in patients undergoing autologous
SCT, there has been a lack of standardized recommendations from hematology oncology
society guidelines, as well as significant variation in application by cancer
treatment programs19–21. Thus, we aimed to investigate not
only the benefit of levofloxacin prophylaxis for the prevention of CLABSIs, but also
potential risks in a current group of patients undergoing autologous SCT at a
tertiary care center.
METHODSStudy design and setting.We performed a retrospective cohort study of autologous SCT patients
admitted to the Hospital of the University of Pennsylvania (HUP) from January
13, 2015 to January 12, 2017. HUP is a 776-bed tertiary care medical center and
a National Cancer Institute Comprehensive Cancer Care designated center.
Study population.Levofloxacin prophylaxis in patients undergoing autologous SCT was
initiated on January 13, 2016 as an infection prevention initiative. Prior to
January 13, 2016 no routine antibiotic prophylaxis was provided to these
patients. With the initiation of levofloxacin prophylaxis, patients undergoing
autologous SCT were prescribed levofloxacin 500 mg oral daily (with dosing
adjustments made based on creatinine clearance), from the date of SCT (day 0)
until day 13, engraftment (absolute neutrophil count (ANC) >500
cells/mm3), or neutropenic fever (ANC<500
cells/mm3 with oral temperature >100.4˚ F),
whichever occurred earliest. With the onset of neutropenic fever, patients were
switched to cefepime or meropenem as per institutional neutropenic fever
guidelines. No alternative antibiotics were provided for prophylaxis in the
setting of an allergy or contraindication to fluoroquinolones (e.g., prolonged
QT interval). During the entire study period, there was also an ongoing
infection prevention educational campaign to improve adherence to daily
chlorhexidine gluconate (CHG) bathing. There were no additional co-occurring
interventions targeted towards the reduction of CLABSIs during the study period.
Additionally, no routine surveillance cultures were performed. The group of
patients who received levofloxacin prophylaxis during the year after initiation
of this intervention (January 13, 2016 to January 12, 2017) were compared to
those who did not receive prophylaxis in the previous year (January 13, 2015 to
January 12, 2016). Therefore, the exposure of interest for this cohort study was
the receipt of levofloxacin prophylaxis. The study was reviewed and approved by
the University of Pennsylvania institutional review board (IRB).
Data collection.Clinical data were collected via electronic medical record review,
including demographics and comorbidities. Specific oncology data were
ascertained, including type of malignancy, history of relapsed or recurrent
primary malignancy, the chemotherapy regimen received during autologous SCT,
duration of neutropenia, development of mucositis, inpatient medications, and
adherence to CHG bathing. CHG bathing adherence was measured as the number of
days with documented completion in the nursing flowsheet during the day of SCT
and the following seven days (day 0 to day 7).
Study outcomes.The primary outcome of interest was incidence of CLABSI, including both
MBI and non-MBI primary bloodstream infection events. CLABSI events had been
previously ascertained by standardized review by the Department of Healthcare
Epidemiology and Infection Prevention utilizing NHSN surveillance
criteria11, defined as
a primary BSI with the presence of a central venous catheter. Within the
definition of CLABSI, these events may be classified as either MBI or non-MBI
depending on the pathogen (i.e. intestinal organisms) and clinical
characteristics of the patient (e.g. neutropenia, diarrhea, or GVHD of the gut).
Secondary BSIs were attributed when there was a known primary site of infection
(e.g., pneumonia). Secondary outcomes included in-hospital mortality,
requirement for medical intensive care unit (ICU) transfer, C.
difficile infection, bloodstream infection other than primary
CLABSI, neutropenic fever, and broad-spectrum antibiotic utilization, all within
30 days of SCT. Inpatient antibiotics were reviewed from patient charts and
recorded as days of therapy (DOT). Additional outcomes included total length of
stay following SCT and readmission to any University of Pennsylvania Health
System hospital within 30 days from discharge.
All blood cultures were performed in the Hospital of the University of
Pennsylvania Clinical Microbiology Laboratory using the BACTEC™ FX system
(Becton Dickinson, Franklin Lakes, NJ), organism identification using the Vitek
MS Matrix Assisted Laser Desorption/Ionization (MALDI-TOF) (bioMérieux,
Durham, NC), and antibiotic susceptibilities using the Vitek 2 automated
platform (bioMérieux, Durham, NC) with Clinical and Laboratory Standards
Institute (CLSI) breakpoints22. C. difficile testing was performed using a
commercial EIA for detection of toxin A, B, and glutamate dehydrogenase (GDH) (C
Diff Quik Check Complete, Alere, Waltham, MA). Samples negative for toxin A and
B but positive for GDH were subsequently tested using PCR for toxin genes (BD
MAX Cdiff Assay, Becton Dickinson, Franklin Lakes, NJ).
Statistical analysis.Primary outcome analysis was conducted using survival analysis to
determine the association between levofloxacin prophylaxis and time to
development of a CLABSI. Time zero for all patients was defined as the day of
SCT (day 0). The failure event was defined as development of CLABSI. Patients
who did not develop a CLABSI were censored at death, discharge, or day 30 of
hospital stay. Evaluation of the time to development of CLABSI was assessed with
the Kaplan-Meier product-limit survival curve estimates and the log-rank
statistic for comparison of multiple hazard ratios (HRs) for unadjusted
comparison of groups and Cox-proportional hazards regression covariate
adjustment. Multivariable Cox-proportional hazards regression analysis was
performed to determine the adjusted association between levofloxacin prophylaxis
and time to development of CLABSI. This multivariable model was developed
beginning with the primary risk factor of interest, admission during the time
period following routine antibiotic prophylaxis with levofloxacin. A manual
stepwise selection procedure was used, with variables with a P
value of <0.25 on bivariable analysis considered as candidate variables
and maintained in the final model if their inclusion was statistically
significant on likelihood ratio testing. Underlying malignancy was a
priori selected for inclusion in the model regardless of
significance on bivariable analysis due to its clinical importance. The
proportional hazards assumption was assessed visually using a log-log plot and
by plotting Kaplan-Meier survival against predicted survival. Primary analysis
was performed per protocol and an intention-to-treat analysis was performed as a
secondary analysis. Additionally, subanalysis was performed using a bivariable
Cox proportional hazard regression model to evaluate the differential impact of
levofloxacin prophylaxis on MBI-CLABSIs vs non-MBI CLABSIs. In this subanalysis,
all patients were censored at time of CLABSI, with separate failure events of
MBI-CLABSI and non-MBI-CLABSI. Two tailed P values <0.05
were considered statistically significant.
Categorical secondary outcomes were analyzed using logistic regression.
To determine the strength of the association between receipt of levofloxacin and
the categorical secondary outcomes, an odds ratio (OR) and 95% confidence
interval (CI) were calculated. The association between receipt of levofloxacin
and the continuous secondary outcomes, length of stay and antibiotic duration,
was assessed using linear regression. All analyses were performed using STATA
v.14.2 (StataCorp, College Station, Texas).
RESULTSStudy population.A total of 324 patients received an autologous SCT during the 2-year
study period, with 174 patients included in the baseline group, and 150 patients
in the levofloxacin prophylaxis group. Baseline characteristics were similar in
both groups (Table 1). In the total
population, the median age was 59 years (interquartile range (IQR),
52–65), 194 (60%) were male, and 83 (26%) were categorized as non-white
race. Comorbidities were common in the study population, with 83 (26%) of
patients with acute kidney injury, and 207 (64%) of patients with mucositis.
There was a greater proportion of patients with multiple myeloma in the
levofloxacin prophylaxis group (n=121; 81%) compared to the baseline group that
did not receive antibiotic prophylaxis (n=126; 72%) (P=0.01).
Rates of relapsed or recurrent hematologic malignancy were similar between the
levofloxacin and the baseline group, 22 (13%) and 15 (10%), respectively
(P=0.46). Adherence to CHG bathing was lower in the
baseline group, with 140 (80%) patients receiving CHG on <50% of days,
compared to 71 (47%) in the levofloxacin group
(P<0.001).
Primary outcome.The incidence of CLABSI was 18.4% (32 episodes) in the baseline group
and 6.0% in the levofloxacin group (9 episodes). MBI-CLABSI represented 67% of
all CLABSIs in the baseline group and 56% in the intervention group. On
bivariable analysis, receipt of levofloxacin prophylaxis was associated with a
significant reduction in the hazard of CLABSI (HR 0.30, 95% CI 0.14–0.62,
P <0.001) (Table
2). CLABSI-free survival from autologous SCT is shown in Figure 1. On multivariable analysis adjusting
for age, and underlying malignancy, receipt of levofloxacin significantly
decreased the hazard of CLABSI with an adjusted HR of 0.33 (95% CI
0.16–0.69, P =0.003) (Table 2). On subanalysis, receipt of levofloxacin prophylaxis was
associated with a significant reduction in MBI-CLABSI (HR 0.24, 95% CI
0.09–0.64, P=0.004) but not non-MBI-CLABSI (HR 0.42, 95%
CI 0.13–1.37, P=0.15).
On intention-to-treat analysis, an additional eight patients were
included who did not receive levofloxacin during the intervention period.
Reasons for withholding levofloxacin prophylaxis included reported levofloxacin
allergy (n=2), prolonged QT interval at baseline (n=2), history of tendon injury
(n=1), history of foot drop (n=1), and ongoing treatment with broad-spectrum
gram-negative antibiotics (n=2). On intention-to-treat analysis, there was a
similar reduction in hazard of CLABSI with levofloxacin on multivariable
analysis, with a HR of 0.34 (95% CI 0.17–0.70,
P=0.003).
Secondary outcomes.Receipt of levofloxacin was associated with a significant reduction in
neutropenic fever (OR 0.23, 95% CI 0.14–0.39,
P<0.001) and a trend towards a significant reduction in
ICU transfer for sepsis (OR 0.33, 95% CI 0.09–1.234,
P=0.10) (Table 3). There
was no significant association of levofloxacin prophylaxis with in-hospital
mortality, hospital readmission, or C. difficile infection.
Of the primary and secondary BSIs, there were a total of 61 organisms
identified among 50 infections in both groups; 33 (67%) were gram-negative
organisms and 16 (33%) were gram-positive organisms in the baseline group
compared to 4 (33%) and 8 (67%) respectively in the levofloxacin group. Among
gram-negative organisms, the susceptibility rate to levofloxacin was 94% in the
baseline group compared to 0% in the levofloxacin group. In the baseline group,
the majority of blood culture isolates were levofloxacin-susceptible
Klebsiella species (35%), Pseudomonas
aeruginosa (12%), and Escherichia coli (12%). In
the levofloxacin prophylaxis group, most isolates were levofloxacin-resistant or
non-susceptible organisms including Escherichia coli (33%) and
Enterococci (25%).
Mean total days of levofloxacin therapy was greater in the levofloxacin
group versus the baseline group (mean 9.2 vs 0.9 days, respectively;
P<0.001). However, the levofloxacin group compared
to the baseline group demonstrated significant reductions in the use of cefepime
(mean 3.1 vs 4.7 days, respectively; P<0.001), and
piperacillin-tazobactam (mean 0.1 vs 0.8 days, respectively;
P=0.001) (Table 4).
There was also a trend toward a decrease in the use of aminoglycosides (mean 0.2
vs 0.4 days, P=0.07) and intravenous vancomycin (mean 1.1 vs
1.7 days, P=0.06) in the levofloxacin prophylaxis group.
DISCUSSIONIn this study, we demonstrated that receipt of levofloxacin prophylaxis was
associated with a significant reduction in the incidence of CLABSI in patients
undergoing autologous SCT. Additionally, the use of levofloxacin resulted in a
reduction in neutropenic fever and a trend toward reduced ICU transfers for sepsis,
without an increase in rates of C. difficile infection. These
findings suggest that the use of routine levofloxacin prophylaxis in autologous SCT
patients may be beneficial in certain settings where rates of CLABSIs are
particularly high. The results of our study are strengthened by a large sample size,
use of a current cohort, and detailed collection of both patient characteristics and
concomitant interventions (e.g., CHG bathing) that may have impacted the risk of
CLABSI.
CLABSIs are associated with significant morbidity and mortality in patients
with hematologic malignancy5. Our
study demonstrated a 67% reduction in hazard of CLABSI with receipt of levofloxacin
prophylaxis. To our knowledge, our study is only the second to date to investigate
the utility of antibiotic prophylaxis in patients undergoing autologous SCT, and the
first to include patients receiving autologous SCT for all malignancy
diagnoses9. A previous
study also found a reduction in bloodstream infections (BSIs) with the use of
levofloxacin prophylaxis (41.2% to 14.7%), but was restricted to autologous SCT
patients with multiple myeloma and focused on a composite outcome of primary and
secondary BSIs9. We were primarily
interested in the ability of antibiotic prophylaxis to prevent CLABSIs due to high
rates in this population and prior studies demonstrating increased mortality with
these infections5,23,24.
We demonstrated that the greatest reduction in BSI with levofloxacin prophylaxis was
the prevention of MBI-CLABSI. This distinction is important because it suggests that
antibiotic prophylaxis, in concert with traditional methods to reduce CLABSI such as
central line care and CHG bathing, may be a particularly beneficial strategy in
institutions that provide care for oncology populations.
Our study also demonstrated a substantial reduction of 77% in the odds of
neutropenic fever with the use of routine levofloxacin prophylaxis. Neutropenic
fever results in prolonged lengths of stay and cost, with an average length of stay
of 20 days and a cost of $38,000 per episode25–27. Thus,
strategies for the prevention of neutropenic fever are important in this population
independent of reductions in bloodstream infections. Additionally, prior studies
have demonstrated that episodes of neutropenic fever result in over three weeks of
antibiotic use per patient28.
Exposure to broad-spectrum antibiotics, including vancomycin and aminoglycosides,
increase the risk of antibiotic resistance, C. difficile, and other
antibiotic-associated adverse events (e.g. renal failure) which could potentially be
limited by use of prophylactic antibiotic therapy. While levofloxacin use increased
in our intervention, there was a corresponding reduction in the exposure to
broad-spectrum antibiotic therapy, as well as a trend towards decreased transfers to
the ICU for neutropenic sepsis. Antibiotic stewardship programs will need to balance
the potential benefits of levofloxacin prophylaxis with other factors such as local
antibiotic resistance patterns and ongoing interventions that may restrict
fluoroquinolone use.
In patients with hematologic malignancy, gut microbiome diversity has been
associated with important clinical outcomes including mortality29. Prior studies have shown a differential
impact of antibiotic classes on microbiome measures, and that the impact of
fluoroquinolones is of shorter duration and less severity than beta-lactam
antibiotics30–34. Thus, it possible that exposure
to fluoroquinolone prophylaxis may result in less disruption of the gut microbiome
if patients are spared subsequent broad-spectrum beta-lactam antibiotic exposure for
neutropenic fever. Further studies are needed to investigate the impact of
prophylactic antibiotics versus those administered for the treatment of neutropenic
fever on the gut microbiome in this population.
The use of fluoroquinolones has previously been associated with an over
two-fold increased risk of C. difficile infection among
hospitalized adult patients35–37. However,
we found no increase in the rate of C. difficile in among
autologous SCT patients receiving levofloxacin prophylaxis. These results are
similar to a previous study evaluating fluoroquinolone prophylaxis in multiple
myeloma patients undergoing autologous SCT, where rates of C.
difficile were 7% and 3% in the intervention versus baseline groups,
respectively (P=0.75)9. It is likely that our intervention did not result in an
increase in C. difficile rates due to the reduction in
broad-spectrum antibiotics used for neutropenic fever, which have also been
implicated in C. difficile infection38.
Not surprisingly, in our study, we saw an overall shift in the proportion of
levofloxacin-resistant gram-negative organisms isolated from blood cultures with
receipt of levofloxacin prophylaxis. However, the absolute increase was small (2
isolates in the baseline group versus 4 in the levofloxacin group). This is similar
to the prior study in this population where the investigators found an increase in
the rate of BSIs due to levofloxacin-resistant Enterobacteriaceae from 1% to 5% with
the introduction of levofloxacin prophylaxis9. These findings suggest a relatively low rate of
levofloxacin-resistant bloodstream infections in our population. However, rates of
levofloxacin resistant gram-negative organisms should be systematically monitored in
institutions where levofloxacin prophylaxis is used. Future studies should also
focus on rates of gastrointestinal colonization with fluoroquinolone-resistant
Enterobacteriaceae with the introduction of fluoroquinolone prophylaxis.
There are potential limitations to our study. First, a retrospective study
design was used, which can lead to greater misclassification of variables. However,
we performed detailed medical record review of patient factors including
comorbidities, medications, and laboratory results, rather than utilizing diagnostic
or billing codes. Second, while the impact of antibiotic prophylaxis on rates of
detection of C. difficile was assessed, we were unable to ascertain
if positive C. difficile tests represented colonization or active
infection, as approximately 65% of cases were associated only with a positive
molecular assay for toxin gene and not with detectable C. difficile
toxin in the stool specimen. However, colonization with toxigenic C.
difficile remains a clinically important outcome as colonization with
C. difficile increases the risk of infection and contributes to
transmission in the hospital setting18,39. Third, while
rates of fluoroquinolone resistance were tracked in bloodstream isolates, we did not
perform patient screening for gastrointestinal colonization with
fluoroquinolone-resistant gram-negative organisms. Fourth, while we were powered to
detect a difference in our primary outcome, we may not have had sufficient power to
detect a difference in our less common secondary outcomes, including ICU transfer
for sepsis. Finally, this study was conducted in a tertiary care center, and may not
be generalizable to other centers performing autologous SCT that may have different
patient characteristics, prevention practices, or risk of
C.difficile infection.
In conclusion, we found that levofloxacin prophylaxis significantly reduced
rates of CLABSI and neutropenic fever in patients undergoing autologous SCT. Further
studies are needed to identify individual patient factors, and patient groups, at
highest risk of MBI-CLABSI who would benefit most from antibiotic prophylaxis.