This study analyzed data from 2,673 men who underwent rectal culture before transrectal prostate biopsy at six institutions between 2007-2013. The study found that 20.5% of rectal cultures showed fluoroquinolone resistant (FQR) bacteria. Men with positive FQR cultures had higher rates of post-biopsy infection (6.6% vs 1.6%) and hospitalization (4.4% vs 0.9%) compared to men with negative cultures. Logistic regression showed that positive FQR culture was associated with significantly increased risk of both post-biopsy infection and hospitalization. The findings suggest that rectal culture can help identify men at high risk for infectious complications following prostate biopsy.
2. INFECTIOUS complications from transrectal prostate
biopsy have increased and have caused widespread
concerns about the safety of the most common pro-
cedure for the histological diagnosis of prostate
cancer.1e3
Reports have shown infectious complica-
tion rates of 3.6% to 5.0% and sepsis rates of 0.3% to
3.1%, largely attributed to fluoroquinolone resistant
bacteria.4e7
FQ antibiotic prophylaxis is used in the majority
of nearly 2 million prostate biopsies performed in
North America and Europe each year.8
The emer-
gence of FQR bacteria has led the urological com-
munity to question the continued use of FQ for
prophylaxis. A recent survey noted that as a result
of this concern more than 20% of U.S. urologists are
already using combination therapy.9e11
However,
the identification of high risk groups to guide such
antibiotic augmentation has not been definitive.12
Rectal culture guided prophylaxis has been
shown to reduce the incidence of post-TRPB infec-
tious complications in nonrandomized studies.13e15
Unfortunately, current studies have a limited sam-
ple size to provide associations due to the low event
rate of biopsy infection. Thus, we formed an inter-
national, multi-institutional collaboration to inves-
tigate the natural history of FQR rectal colonization
and its association with prostate biopsy infection,
which could justify the incorporation of preoperative
rectal cultures in routine clinical care.
MATERIALS AND METHODS
Patients
All men underwent TRPB as part of routine care and were
enrolled in an institutional review board approved study
at 1 of 6 institutions (supplementary table 1, http://
jurology.com/). All institutions had a university affilia-
tion. Subjects were eligible regardless of the antibiotic
used for prophylaxis but documentation of antibiotic se-
lection was required. Rectal culture was obtained before
TRPB from all patients in the study, but in no patient did
the culture direct the selection of antibiotic regimen in
order to investigate the natural history of fecal carriage of
fluoroquinolone resistant organisms. Therefore, we are
able to determine the risk of infection with empiric, non-
targeted prophylaxis and its correlation to the culture
results performed in the context of previously institu-
tional review board approved clinical studies. Patient
followup was achieved with direct interview or chart
review. Infection was defined as a fever, urinary tract
infection, any additional antibiotic therapy, emergency
room consultation for infectious purposes or hospital
admission for infection.
Rectal Culture and Antimicrobial Resistance
Due to the retrospective nature of this multi-institutional
study, methods of obtaining and processing cultures were
not standardized across institutions. Rectal culture was
obtained with a culturette before or at the time of TRPB
(supplementary table 1, http://jurology.com/). Isolation of
fluoroquinolone resistant organisms included the use of
selective media with ciprofloxacin infused agar or a
nonselective media with antibiotic discs. All sites but one
used the Clinical and Laboratory Standards Institute
guidelines, with susceptible defined as a ciprofloxacin
minimum inhibitory concentration of 1 mg/ml or less and
resistance defined as a ciprofloxacin minimum inhibitory
concentration of 4 mg/ml or greater.16
One site (England)
used the British Society for Antimicrobial Chemotherapy
definition of resistance as a 16 mm or less zone of inhi-
bition around a ciprofloxacin disk.17
Study Design
Institutional review board approval was obtained at the
University of California, San Diego for the concept and
use of a secure, open source, electronic sharing network
named iDASH (integrating Data for Analysis, Anonym-
ization, and SHaring) housed at the San Diego Super-
computer Center. Seven institutions that had published
studies involving rectal cultures taken before TRPB were
identified by literature search. Of these institutions
6 agreed to participate and contribute data through
iDASH (supplementary table 1, http://jurology.com/). All
institutions were required to sign a data contribution and
data use agreement. Additionally, all institutions were
required to provide documentation of institutional review
board approval to participate in the study. Before sharing
the data the institutions were asked to review them for
accuracy. However, after the data were shared, other in-
stitutions did not have access to the source data.
Statistical Analysis
Sample size or power analysis was not performed due to
the retrospective study design. However, to detect a 50%
reduction in infection rates, studies would need to enroll
1,700 to 2,000 patients. Due to the multiple institutions
with various data sets, missing data were a significant
limitation. Therefore, for this study we included only
variables with a sample size of 2,000 patients to avoid
partial data being influenced heavily by a particular
institution. The primary outcome was any infection
attributed to the TRPB and the secondary outcome was
hospitalization after TRPB because of infection.
We classified patients as FQR colonized or not based on
results of rectal cultures regardless of how they were
obtained. Using these 2 groups a chi-square analysis was
performed to determine if there was an increased risk of
infection in the culture positive group. Any potential
associations with demographic parameters were investi-
gated to identify at risk or protective features from
infection. We performed a logistic regression to determine
the degree of risk that FQR colonization had on post-
TRPB infection and hospital admission from infection.
Statistical significance was set at p ¼ 0.05.
RESULTS
A total of 2,673 men were included in the study with
a median age of 66 years (range 27 to 89) who un-
derwent rectal culture before TRPB between January
1, 2007 and September 12, 2013 at 6 institutions
1674 FLUOROQUINOLONE RESISTANT RECTAL COLONIZATION AND RISK OF POST-BIOPSY INFECTION
3. (supplementary table 1, http://jurology.com/). The
majority of patients (93%; 2,474 of 2,673) received a
fluoroquinolone before biopsy and 24% (643 of 2,673)
received more than 1 antibiotic. FQ selective media
was used in 43% of cultures (1,151 of 2,673). Only
2 of 6 study sites (1,054 of 2,673 patients; 39.4%)
performed prospective studies including telephone
followup.
FQR bacteria were isolated from 20.5% of rectal
cultures (549 of 2,673). The overall infection rate
was 2.6% (69 of 2,673) and the hospital admission
rate for infection was 1.6% (44 of 2,673). Post-biopsy
infection was noted in 1.6% (33 of 2,091) of patients
with a negative FQR culture vs 6.6% (36 of 549)
of men with positive cultures for FQR bacteria
(p <0.001). Patients who had a positive culture yet
only received FQ prophylaxis had an 8.2% (28 of
343) infection rate compared to 1.8% (28 of 1,533) in
those with a negative culture (see figure). When
patients with a FQR positive culture were given
combined therapy the infection risk decreased
from 8.2% to 6.2%, but this was not statistically
significant (p¼0.651).
Hospitalization for infection occurred in only
0.9% (24 of 2,224) of men with a negative culture for
FQR bacteria vs 4.4% (20 of 549) of those with a
positive FQR culture (p <0.001). In patients who
presented with infection after TRPB, 76% of positive
cultures grew E. coli. More patients were identified
with an infectious complication if they received a
telephone call compared to retrospective chart
review (62.3% vs 35.6%, p <0.001, supplementary
table 1, http://jurology.com/).
Univariate analysis of these variables is dis-
played in table 1. Followup was significantly
different as verbal confirmation will likely find more
infections than chart review. The only clinically
significant factor that varied between those who had
an infectious complication after TRPB and those
who did not was FQR rectal culture (52.2% vs
19.7%, p <0.001).
In previous studies diabetes has been recognized
as being associated with infection and was selected
for multivariate analysis.18
We also included anti-
biotic augmentation and bowel preparation as these
have suggested a reduced risk of infection.9
Four
multivariate models were used to determine the
association of rectal culture with infection and
hospital admission in the overall cohort and in a
subset of patients who only received FQ prophylaxis
(table 2). The FQ only group excluded those who did
not take a FQ before biopsy or those who received
a second antibiotic. The odds ratios of infection
in patients with a positive FQR culture were 3.98
Proportion of patients with infectious complications after TRPB based on clinical history of FQ exposure and rectal culture results
FLUOROQUINOLONE RESISTANT RECTAL COLONIZATION AND RISK OF POST-BIOPSY INFECTION 1675
4. (95% CI 2.37e6.71, p <0.001) for the entire cohort
and 4.71 (95% CI 2.75e8.07, p <0.001) for the FQ
only group. The odds ratios for patients who had a
hospital admission related to prostate biopsy were
4.77 (95% CI 2.50e9.10, p <0.001) for the entire
cohort and 5.67 (95% CI 3.00e10.90, p <0.001) for
the FQ only group.
The most common bacteria isolated from rectal
culture were E. coli (83.7%, supplementary table 2,
http://jurology.com/). Of the FQR organisms many
had resistance to multiple antibiotics. The most
commonly used antibiotics to supplement FQ pro-
phylaxis were gentamicin, amikacin, trimethoprim/
sulfamethoxazole and ceftriaxone. However, FQR
bacteria were also resistant to these antibiotics in
27%, 41% and 21% of cases, respectively. Imipenem,
meropenem and amikacin had the lowest
co-resistance rates. Clinical isolates were recovered
in 42% of those with infection, the majority being
E. coli (76%), of which 79% were FQR.
DISCUSSION
Patients harboring FQR organisms on rectal culture
before TRPB have a greater than threefold higher
risk of infection and of subsequent hospitalization
than men without FQR organisms. Moreover, if
a patient has a positive rectal culture and only
receives FQ prophylaxis, he has a nearly sixfold
higher risk of hospital admission for infectious
complications. Patients with a negative culture are
adequately treated with the current standard FQ
prophylaxis and have a risk of infection of approxi-
mately 1% (see figure). We confirm the major source
of infectious complications from TRPB is FQR
E. coli, which can be multidrug resistant.8,19
Broad
spectrum antibiotics should be initiated with po-
tential assistance from infectious disease physicians
if post-prostate biopsy infection is encountered.
The current FQ based prophylaxis before TRPB
has come under scrutiny due to a substantial
increase in post-TRPB infections due to FQR
bacteria.20
Concern about infection has led in-
vestigators to attempt to identify new means to
prevent post-TRPB infections, including steriliza-
tion of the rectum, antibiotic augmentation and
transperineal biopsy.7,13e15,21e24
These studies have
shown incremental improvements in preventing
infection. However, they have not led to changes in
current clinical practice.
Perhaps the most refined and promising method
is the use of targeted prophylaxis, which uses rectal
culture to tailor the antibiotic prophylaxis regimen
to specific bacterial resistance patterns.13
Deter-
mining the optimal prophylaxis regimen based on
culture results would be the next step in developing
this strategy. However, we argue that the first step
in the process of reducing infection is to identify
those men at high risk.
Table 2. Multivariate analysis
Overall Risk of Infection Risk of Hospitalization
OR (95% CI) p Value OR (95% CI) p Value
Entire cohort (all antibiotic combinations, 2,052):
Diabetes 1.40 (0.75e2.61) 0.292 1.73 (0.84e3.55) 0.134
Antibiotic augmentation (2 or more antibiotics) 0.35 (0.08e1.78) 0.152 0.26 (0.04e1.95) 0.191
Bowel preparation (enema or suppository) 0.85 (0.41e1.77) 0.669 0.58 (0.26e1.28) 0.176
FQR pos rectal culture 3.98 (2.37e6.71) <0.001 4.77 (2.50e9.10) <0.001
FQ only prophylaxis (1,794):
Diabetes 1.40 (0.73e2.67) 0.311 1.58 (0.74e3.35) 0.238
Bowel preparation 0.844 (0.39e1.83) 0.688 0.62 (0.27e1.44) 0.276
FQR pos rectal culture 4.71 (2.75e8.07) <0.001 5.67 (3.00e10.90) <0.001
Table 1. Demographics
No Infection Infection
p
Value
Sample
Size
No. pts 2,604 69
Median pt age (IQR) 66 (61e71) 66 (60e71) 0.549 2,669
Median ng/ml prostate
specific antigen (IQR)
5.81 (4.0e8.3) 5.7 (4.0e8.49) 0.814 1,967
Median mm3
prostate
size (transrectal
ultrasound)(IQR)
43 (29e63) 44 (23.8e65.8) 0.778 1,989
No. race/ethnicity (%): 0.504 1,290
White/Caucasian 857 (68.0) 24 (82.8) 881
Black/African-American 118 (9.4) 2 (6.9) 120
Hispanic/Latino 52 (4.1) 0 (0) 52
Asian 156 (12.4) 2 (6.9) 158
Other 78 (6.2) 1 (3.4) 79
No. diabetes (%): 0.849 2,059
Yes 315 (15.8) 10 (16.7)
No 1,684 (84.2) 50 (83.8)
No. antibiotic
augmentation (2 or
more antibiotics)(%):
0.109 2,669
Yes 632 (24.3) 11 (15.9)
No 1,968 (75.7) 58 (84.1)
No. bowel preparation
(enema or
suppository)(%):
0.259 2,661
Yes 1,749 (67.5) 51 (73.9)
No 843 (32.5) 18 (26.1)
No. followup (%): <0.001 2,672
Pt contact 927 (35.6) 43 (62.3)
Chart review 1,676 (64.4) 26 (37.7)
No. FQR rectal culture (%): <0.001 2,673
Yes 513 (19.7) 36 (52.2)
No 2,091 (80.3) 33 (47.8)
1676 FLUOROQUINOLONE RESISTANT RECTAL COLONIZATION AND RISK OF POST-BIOPSY INFECTION
5. Recent commentary suggests that the current
universal approach by which every patient receives
the same empiric antibiotic(s) is not likely to be the
future of prophylaxis before TRPB.25,26
The universal
augmentation approach does not account for vari-
ability in resistance rates at various locations and
resistance changes over time. While many urologists
advocate adding a second empiric antibiotic, our data
suggest that FQR organisms are also often resistant
to other common antibiotics (supplementary table 2,
http://jurology.com/). Moreover, this approach may
have unforeseen consequences such as side effects of
antibiotics not well-known by urologists, increased
resistance and increased cost.
Effective prophylactic antibiotic selection is
difficult even assuming that all drugs are equally
effective for TRPB prophylaxis. Moreover, indis-
criminate use of additional antibiotics may promote
further drug resistance, affecting future antibiotic
effectiveness in the face of the limited development
of new antibiotics.27
Prospective clinical trials
are needed to determine the use of rectal culture
performed weeks before prostate biopsy, which
antimicrobials will be effective and the cost-
effectiveness of this approach.
Other risk factors associated with post-TRPB
infection include a history of diabetes, indwelling
urethral catheter, recent hospitalization, recent
travel to high risk countries and recent use of
antibiotics (especially fluoroquinolones).12,28
Our
study had limited data on the clinical history of
patients in terms of recent antibiotic use. However,
clinical history may be an imperfect tool for esti-
mating risk due to recall bias. Future investigations
will include optimizing test characteristics (sensi-
tivity and specificity) and performing predictive
modeling using clinical history to further risk
stratify patients.
Limitations of this study include the retrospec-
tive nature of the data collection, in which the main
bias pertained to the various methods of data
collection and culture techniques. However, varia-
tion in the collection from a wide range of patient
populations may add to the generalizability of the
study. By collecting the raw data our study can be
informative as we were able to investigate the risk
of infection in men with FQR rectal colonization
who only received FQ prophylaxis, which would not
have been possible with a meta-analysis. Physicians
may have chosen to alter or augment prophylaxis
for high risk patients based on clinical factors or
medical history, which would have likely selected
out high risk individuals biasing the results.
Nonselective media may be less likely to capture
FQR organisms than selective media, and the yield
of FQR organisms should be tested in the same
population and ideally from the same culture swab.
Moreover, the interpretation of resistance may
vary among institutions. Some institutions con-
tacted patients directly and some only performed
chart review to identify complications, which may
bias the data toward a lower rate of infection. To
include a more definitive outcome we used hospital
admission as a secondary outcome because it has a
higher likelihood of being captured on retrospective
chart review, thereby yielding a more strict defini-
tion of infection. Moreover, hospital admission is an
important factor for severity of infection and overall
cost of the complication.
We cannot exclude the possibility that patients
were hospitalized at institutions other than where
the biopsy was performed. Again, this would lead to
an underestimation of risk. We focused on the nat-
ural history of FQR organisms in the rectum. Most
cultures were obtained at the time of biopsy and we
would not have been able to change clinical practice.
One previous small study showed concordance
among cultures obtained in the office at the time of
biopsy.29
However, a larger cohort is needed.
Another limitation is that we were unable to
obtain many of the sensitivity profiles of the clinical
infection isolates. The small number of patients
(7%) who did not have FQ prophylaxis was included
in the overall analysis with the augmentation group
to obtain the overall infection risk in all patients.
Then we selected out those with FQ prophylaxis
only as shown in the figure and provided analysis
for both groups. The lack of infection isolates
was significant but consistent with other studies
showing difficulty in capturing cultures on read-
mission due to hospital location, receipt of antibi-
otics before culture or the specimen not being
obtained. The univariate analysis was limited due
to missing documentation in the majority of studies.
We are currently investigating predictive models
that include infection history adjusting for missing
data, which is beyond the scope of this study. Our
findings coincide with the current literature sug-
gesting that the majority of post-biopsy infections
are related to FQR organisms, mainly E. coli.
CONCLUSIONS
Fecal carriage of FQR organisms poses a significant
increased risk of TRPB infectious complications.
The risk is increased in those patients who carry the
resistant organisms and only have FQ prophylaxis.
We suggest further investigation of rectal culture
performed before biopsy to identify high risk
individuals who may need altered prophylaxis.
ACKNOWLEDGMENTS
J. Kellogg Parsons, Florin Vaida and Theodore
Ganiats provided critical review of the manuscript.
FLUOROQUINOLONE RESISTANT RECTAL COLONIZATION AND RISK OF POST-BIOPSY INFECTION 1677
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