Vol 13 No 01 January-February 2016 2471Vol 13 No 01 January-February 2016 2533
A Prospective Randomized Trial Comparing a Combined Regimen of Ami-
kacin and Levofloxacin to Levofloxacin Alone as Prophylaxis in Transrec-
tal Prostate Needle Biopsy.
Yu Miyazaki,1,3 Shusuke Akamatsu,1,3* Sojun Kanamaru,2 Yuki Kamiyama,2 Atsushi Sengiku,1 Ryo Iguchi,2
Takeshi Sano,2 Akira Takahashi,1 Masaaki Ito,1 Jun Takenawa,2 Noriyuki Ito,2 Keiji Ogura1
Purpose: We investigated whether addition of amikacin to levofloxacin-based antimicrobial prophylaxis reduces
febrile urinary tract infections after transrectal ultrasound-guided prostate needle biopsy (TRUSB).
Materials and Methods: A total of 447 patients undergoing TRUSB were prospectively randomized into two
groups. The 230 patients in Group A were given one oral dose of levofloxacin 400 mg prior to TRUSB; the 217
patients in Group B each received the same dose of levofloxacin and one 200 mg intravenous dose of amikacin.
Patients’ characteristics were assessed prior to TRUSB and their symptoms were checked after the TRUSB.
Results: Both regimens were well tolerated with no side effects. No statistically significant difference in patients’
characteristics, or in incidence of inflammation- or infection-related symptoms was seen between the two groups;
nor any significant difference among those who developed fever and those who did not. Two Group A patients and
one Group B patient developed febrile urinary tract infections. Accountable pathogens determined by urine and
blood cultures were fluoroquinolone-resistant E.coli and extended-spectrum β-lactamase-producing E.coli. All
pathogens isolated were levofloxacin-resistant, amikacin-susceptible species.
Conclusion: Although the present study was under-powered by unexpectedly low overall incidence of febrile uri-
nary tract infections, addition of one intravenous administration of amikacin to one oral administration of levoflox-
acin showed no advantage compared with levofloxacin alone as antimicrobial prophylaxis in TRUSB. Strikingly,
all pathogens isolated from febrile patients were sensitive to amikacin in vitro. Therefore, further understanding of
amikacin’s drug kinetics in the prostate is necessary to develop a more efficient drug delivery system for amikacin.
Keywords: antibiotic prophylaxis; methods; bacterial infections; prevention & control; prostatic neoplasms; diag-
nosis; anti-bacterial agents; administration & dosage.
INTRODUCTION
Currently, transrectal ultrasound-guided prostate needle biopsy (TRUSB) is accepted as a standard
procedure for pathologic diagnoses of prostate cancer.
However, TRUSB is an invasive procedure with com-
plications such as pain, dysuria, hematuria, hemato-
spermia, rectal bleeding, urinary retention, non-febrile
and febrile urinary tract infection (UTI), and sepsis. In-
fectious complications, especially acute prostatitis and
sepsis may result in severe morbidity, and even death.
(1) Hence, antibiotic prophylaxis is routinely admin-
istered to lower incidence of infectious complications
after TRUSB.(2-4) Fluoroquinolone (FQ) antimicrobi-
al agents are widely used as prophylaxis due to their
broad spectrum of activity against gram-positive and
gram-negative bacteria. Moreover, FQs are available
orally, have a widely acceptable safety profile, and pen-
etrate well into the prostatic cytosol.(5-7) Until the early
2000s, multiple randomized studies have shown FQs
to be effective in lowering the incidence of infectious
complications after TRUSB.(2,8-10) However, wide use of
FQs has led to development of FQ-resistant bacteria,
such as extended-spectrum β-lactamase (ESBL)-pro-
ducing coliforms.(11) A number of studies during the last
decade have shown a trend of increasing FQ resistance
in cases of bacterial infections after TRUSB.(11-13) Sev-
eral studies have tested alternative antibiotic prophylax-
is regimens, or combinations of other antibiotics with
FQs to lower the incidence of these complications. The
American Urological Association (AUA) guideline for
antimicrobial prophylaxis for TRUSB recommends
1 Department of Urology, Japanese Red Cross Otsu Hospital, 1-35 Nagara 1-Chome Otsu City, Shiga, 520-8511, Japan.
2 Department of Urology, Nishi-Kobe Medical Center, 7-1 Kojidai 5-Chome, Nishi-Ku, Kobe City, Hyogo, 651-2273, Japan.
3 Department of Urology, Kyoto University Graduate School of Medicine, 54 Shougoin Kawahara-cho, Sakyo-ku, Kyoto,
606-8507, Japan.
*Correspondence: Department of Urology, Kyoto University Graduate School of Medicine, 54 Shougoin Kawahara-cho,
Sakyo-ku, Kyoto, 606-8507, Japan.
Tel: +81 75 7513325 . Fax: +81 75 7613441. E-mail: akamats@kuhp.kyoto-u.ac.jp.
Received: May 2015 & Accepted: October 2015
UROLOGICAL ONCOLOGY
FQs or cephalosporins as the agents of first choice, and
lists aminoglycosides, aztreonam, or trimethoprim-sul-
famethoxazole (TMP-SMX) as alternatives to FQs.(14)
Aminoglycosides have also been recommended as al-
ternative antimicrobials for preoperative prophylaxis
for a number of other surgical procedures in the guide-
line. Amikacin (AMK) is a low-cost aminoglycoside
drug available in Japan, and has a good sensitivity pro-
file against ESBL-producing coliforms.(12,15) However,
there is no report of a prospective randomized study on
the combined use of AMK and FQs for TRUSB. The
aim of this prospective study is to assess whether the
addition of AMK to levofloxacin (LVFX)-based antimi-
crobial prophylaxis reduces febrile UTI after TRUSB.
MATERIALS AND METHODS
Study Patients
From November 2007 to December 2009, patients un-
dergoing TRUSB at Nishi-Kobe Medical Center and
Japanese Red Cross Otsu Hospital, two tertiary refer-
ral hospitals 80 km apart, were recruited to the study.
These patients had standard indications for TRUSB,
such as abnormal findings on digital rectal examination
and/or elevated serum prostate specific antigen (PSA)
levels. Patients with indwelling urethral catheters, un-
treated UTI, current use of antibiotics, severe heart dis-
ease, abnormal liver function (aspartate transaminase
(AST) and alanine transaminase (ALT) > × 2.5 upper
limit of normal), abnormal renal function (serum creati-
nine > 1.2 mg/dL), immunosuppressive status, or histo-
ries of hypersensitivity to FQs or aminoglycosides were
excluded. We calculated that with a two-sided alpha of
0.05, a power of 0.8, and expected reduction in inci-
dence of febrile UTI from 2% in the Group A control
arm to 0.5% in the Group B, we needed 201 samples
for each arm. All Patients were sufficiently informed of
the aims of this trial and all possible complications. The
447 patients who agreed to this trial gave written con-
sent documents to be enrolled in this study, which was
approved by Institutional Review Boards at each hos-
pital (IRB Approval Number 200904 for Nishi-Kobe
Medical Center, and 109-2009 for Japanese Red Cross
Otsu Hospital).
Methods
Patients were prospectively randomized into two groups
using a computer-generated random number table.
Group A received a single oral administration of LVFX
(400 mg), two hours before TRUSB. Group B received
the same dose of LVFX two hours before TRUSB and
a single intravenous administration of AMK (200 mg),
30 minutes before TRUSB. This trial was performed
as a single blind trial: the patients were not informed
of the group they were randomized to. Patient charac-
teristics, including age, serum PSA, prostate volume,
International Prostate Symptom Score (IPSS), quality
of life (QoL) score, presence of dysuria, comorbidi-
ties, history of previous TRUSB, use of anticoagulant
agents, antimicrobials, or steroid drugs, were assessed
prior to TRUSB. For analgesia, each patient had a di-
clofenac sodium suppository (50 mg) 30 minutes be-
fore the procedure. We established an intravenous line
before each TRUSB to prepare for hypotensive side ef-
fects, and performed each TRUSB using a disposable
automated biopsy gun with 18-gauge biopsy needles.
All biopsies were carried out using a systematic ap-
proach in which 10 specimens were taken from each
patient. Of note, the method of bowel preparation was
not predetermined in the current study. As a result, all
the patients who underwent TRUSB at the Nishi-Kobe
Medical Center took sennoside orally (24 mg, before
sleep), and were administered an enema (glycerine en-
ema 120 mL, under 70 years old/ glycerine enema 60
mL over 71 years old) on the day of TRUSB, whereas
the patients at Japanese Red Cross Otsu Hospital did
not receive any bowel preparation. All the other pro-
cedures were identical between the two institutions.
Patients were instructed to record symptoms associated
with their TRUSBs, including pain at TRUSB, gross
hematuria, rectal bleeding, hematospermia, perineal
discomfort, urination pain, difficulty voiding, urinary
retention, fever, and symptomatic adverse drug events,
using provided check sheets, which were collected at
2-4 weeks after each TRUSB. Patients were instructed
to contact the office immediately if any problems occur,
especially febrile symptoms (body temperature higher
than 38.0°C). Urine and blood cultures were collected
immediately from patients who developed febrile symp-
toms, and the patients were immediately treated with
meropenem. Antimicrobial susceptibility was evaluated
by Clinical and Laboratory Standards Institute (CLSI)
broth microdilution method, and a bacterial isolate was
considered non-susceptible to an antimicrobial agent
when it tested resistant, intermediate, or non-suscepti-
ble. Multiple drug resistance was defined as acquired
non-susceptibility to at least one agent in three or more
antimicrobial categories. The primary endpoint of the
present study was incidence of febrile UTI in each
group. Secondary endpoints were incidence of non-fe-
brile symptoms, tolerability, and safety of the combined
regimen, and determination of variables associated with
febrile UTI. Results were analyzed using JMP 9 soft-
ware (SAS Institute Inc, Cary, North Carolina, USA); P
Amikacin and Levofloxacin for Prophylaxis in Prostate Biopsy-Miyazaki et al.
Urological Oncology 2534
Vol 13 No 01 January-February 2016 2535
values were calculated with Student’s t-test, chi-square
test and Fisher’s exact test, and P < .05 was considered
significant.
RESULTS
There was no significant difference in incidences of
non-infectious complications after TRUSB, such as
pain at TRUSB, gross hematuria, rectal bleeding, and
hematospermia. Moreover, we could not detect any sig-
nificant difference in incidences of symptoms related
to inflammation or infection including perineal discom-
fort, micturition pain, difficulty voiding, urinary reten-
tion, and fever (Table 1). Two patients from Group
A and one patient from Group B developed febrile
symptoms. Urine and blood cultures were collected
immediately from these patients, and the patients were
promptly treated with intravenous administration of
meropenem. Table 2 shows details of the three patients
and results of their urine and blood cultures. The history
of previous TRUSB is reported as one of the significant
risk factors of febrile UTI. In the present study, 46/230
(20.0%) in group A, and 38/217 (17.5%) in group B
had prior TRUSB, however, the three patients who de-
veloped febrile symptoms had not undertaken TRUSB
previously.
All three patients were diagnosed with acute prostati-
tis; none progressed to septic shock, and all were cured
with intravenous meropenem. Accountable pathogens,
as determined by urine and blood cultures were FQ-re-
sistant E.coli in two cases and ESBL-producing E.coli
in another. All pathogens isolated were LVFX-resist-
ant, AMK-susceptible species (Table 2). Both regimens
were well tolerated with no side effects. No patient had
deterioration of renal function. No patient was lost to
follow up. There was no statistically significant differ-
ence in patients’ characteristics between the two groups
before TRUSBs (Table 3). Overall, prostate cancer was
detected in 208 (46.5%) cases by TRUSB. Prostate can-
cer detection rates were similar between the two groups
(105 [45.6%] of 230 in group A, 103 [47.4%] of 217 in
group B).
The survey of urine culture results from all the symp-
tomatic UTI patients in the two hospitals between 2006
and 2009 showed that the detection rate of LVFX-resist-
Amikacin and Levofloxacin for Prophylaxis in Prostate Biopsy-Miyazaki et al.
Table 1. Complications after transrectal ultrasound-guided prostate needle biopsy.
Variables Group A Group B P Value
Single-dose LVFX Single-dose LVFX + AMK iv.
(n = 230) (n = 217)
Pain at TRUSB, no. 40 28 .160 †
Hematuria, no. 77 72 .865 †
(mean duration of symptoms, days) 3.64 3.32
Rectal bleeding, no. 40 44 .464 †
(mean duration of symptoms, days) 1.33 1.33
Hematospermia, no. 13 11 .812 †
Perineal discomfort, no. 34 25 .265 †
(mean duration of symptoms, days) 1.38 1.62
Urination pain, no. 9 9 .933 ††
(mean duration of symptoms, days) 4.33 2.89
Feeling of residual urine, no. 19 17 .903 †
(mean duration of symptoms, days) 4 3.35
Difficulty voiding, no. 3 8 .179 ††
(mean duration of symptoms, days) 1 1
Urinary retention, no. 3 2 .935 ††
(mean duration of symptoms, days) 4.33 3
Fever > 38°C 2 1 .950 ††
(mean duration of symptoms, days) 3.5 5
Symptomatic adverse drug event, no. 0 0 -----
Abbreviations: TRUSB, transrectal ultrasound-guided prostate needle biopsy; LVFX, levofloxacin; AMK, amikacin; iv, intravenous.
† Chi-square test; †† Fisher’s exact test.
ant E.coli among all E.coli had increased from 17.2% in
2006 to 22.2% in 2009, and that of ESBL-producing
E. coli from 3.80% to around 10% (Figure 1). AMK
showed a very high sensitivity rate (99.0%) to coliforms
from urine cultures of all UTI patients. Furthermore,
AMK showed almost similar sensitivity rate (97.1%) to
ESBL producing E.coli (Figure 2).
DISCUSSION
Introduction of PSA testing into clinical practice led
Table 2. Characteristics of the patients who developed febrile urinary tract infection, and results of urine / blood cultures.
Variables Patient 1 Patient 2 Patient 3 P Value
(vs. afebrile patients)
Group A A B –-----
Age, years 78 68 75 .282 †
PSA, ng/ml 6.88 14.1 13.7 .00106 †
Prostate volume, cc 35 45.8 62.4 .636 †
Antimicrobial history –----- –----- –----- .850 ††
Comorbidities Re-biopsy Dysuria Dysuria; use of anticoagulant agents; –-----
diabetes mellitus; hypertension
Complications after TRUSB Hematuria; feeling of Urination pain Urination pain; –-----
residual urine
urinary retention
Prostate cancer detection + + + 0.0625 ††
Interval from biopsy to febrile symptom, days 1 3 1 –-----
Organism isolated E. coli (urine) E. coli ESBL-producing E. coli –-----
(source)
(urine and blood)
(urine)
Antimicrobial sensitivity
Levofloxacin Resistant Resistant Resistant –-----
Amikacin Sensitive Sensitive Sensitive –-----
Abbreviations: TRUSB, transrectal ultrasound-guided prostate needle biopsy; E. coli, Escherichia coli.
† Chi-square test; †† Fisher’s exact test.
Figure 1. Ratios of LVFX-resistant E.coli and ESBL-producing E.coli
to all E.coli isolated from urine cultures of patients with UTI at the two
hospitals.
Abbreviations: LVFX, levofloxacin; E. coli, Escherichia coli; ESBL, ex-
tended-spectrum β-lactamase; UTI, urinary tract infection.
Figure 2. Drug susceptibility of extended-spectrum β-lactamase produc-
ing E.coli at the two hospitals.
Abbreviations: AMK, amikacin; LVFX, levofloxacin; MINO: minocy-
cline; S/T, sulfamethazine /trimethoprim.
Amikacin and Levofloxacin for Prophylaxis in Prostate Biopsy-Miyazaki et al.
Urological Oncology 2536
Vol 13 No 01 January-February 2016 2471Vol 13 No 01 January-February 2016 2537
to a dramatic increase in TRUSBs. About 700,000 pa-
tients are diagnosed with prostate cancer worldwide
annually.(16) E.coli is the major cause of symptomatic
infection after TRUSB.(17) Although prophylactic an-
timicrobial administrations lower the risk of infection
after TRUSB,(18) no standard antimicrobial prophylaxis
regimen has been established, and a variety of antimi-
crobial prophylaxis regimens are administered without
clear evidence,(4,19) FQs are the most widely used anti-
microbial in TRUSB, and is recommended as a first-
line agent for prophylaxis in both AUA and European
Association of Urology (EAU) guidelines.(14,20) In the
United States and Europe, ciprofloxacin (CPFX) is
commonly used, whereas in Japan LVFX is popular.
Increasing resistance to FQs and wide emergence of
ESBL-producing E.coli has been reported,(11-13) which
would pose more patients receiving FQs alone as
prophylaxis before TRUSB at risk of developing fe-
brile UTIs. Because of these increases in FQ-resistant
coliforms, the urgent need to develop new prophylac-
tic strategies have been emphasized.(21-23) Batura and
colleagues examined resistance rates of organisms
which were isolated from rectal swab during TRUSBs
to CPFX, co-amoxiclav, and AMK, and found AMK
to have the lowest resistance rate (0.22%) compared to
CPFX (10.6%) and co-amoxiclav (13.3%).(15) Further-
more, a recent survey of 3000 patients who underwent
TRUSB in France showed that the resultant pathogen
for acute bacterial prostatitis were 95% resistant to
FQs, and only 5% resistant to AMK.(24) The resistance
rates of these pathogens to third-generation cephalo-
sporin, gentamicin, and imipenem were 25%, 55%,
and 0% respectively. These results suggest the possible
advantage of adding AMK to conventional FQ-based
regimen, although it has never been tested in a prospec-
tive randomized controlled trial. Batura and colleagues
have retrospectively reviewed the addition of AMK
to their conventional regimen (CPFX + co-amoxiclav
+ metronidazole) and reported decreased incidence of
febrile infections, from 3.9% to 1.4%.(23) However, two
patients in their study, who received AMK as a part of
combined regimen, also developed febrile infections
from AMK-sensitive coliforms. In the present study, al-
though all organisms isolated from patients developing
Table 3. Patient characteristics.
Variables Group A Group B P Value
Single-dose LVFX Single-dose LVFX + AMK iv.
(n = 230) (n = 217)
Age, years (mean ± SD) 69.4 ± 7.82 69.5 ± 7.38 .994 †
PSA, ng/mL (median) 7.90 (IQR 5.38-13.85) 7.51 (IQR 5.58-14.25) .771 †
Prostate volume, cc (mean ± SD) 41.3 ± 22.7 41.0 ± 24.2 .886 †
IPSS score (mean ± SD) 12.2 ± 7.60 11.5 ± 7.16 .543 †
QoL score (mean ± SD) 3.28 ± 1.54 3.17 ± 1.56 .916 †
Presence of previous TRUSB 46 38 .465 ††
Dysuria 73 69 .924 ††
Use of anticoagulant agents 30 24 .557 ††
Long term use of antimicrobials 1 4 .334 †††
Use of steroid drugs 5 1 .0856 †††
Diabetes mellitus 21 31 .106 ††
Hypertension 69 63 .807 ††
Cardiovascular disease 21 18 .656 ††
Respiratory disease 5 9 .486 †††
Liver disease 2 3 .667 †††
Renal disease 2 3 .667 †††
Cerebrovascular disease 11 6 .363 †††
Number of prostate cancers detected 105 103 .603 ††
Abbreviations: TRUSB, transrectal ultrasound-guided prostate needle biopsy; LVFX, levofloxacin; AMK, amikacin; PSA, prostate specific antigen;
QoL, Quality of Life; SD, standard deviation; IPSS, International Prostate Symptom Score; IQR, interquartile range; iv, intravenous.
† Student’s t-test; †† chi-square test; ††† Fisher’s exact test.
Amikacin and Levofloxacin for Prophylaxis in Prostate Biopsy-Miyazaki et al.
acute prostatitis were resistant to LVFX and sensitive to
AMK, patients with combined regimen also developed
acute prostatitis, and there was no overall benefit of the
combined regimen. These results underscore the theo-
retical efficacy of AMK to LVFX-resistant E.coli, how-
ever, the clinical ineffectiveness of combining AMK to
LVFX in prophylaxis of TRUSB associated febrile UTI
suggests suboptimal drug delivery or tissue penetrance
of AMK to prostate tissue.
There is no report on the optimal dosage or administra-
tion method of AMK as prophylaxis in TRUSB. Goto
and colleagues reported a high concentration of AMK
in the prostate tissue after a single dose (200 mg, intra-
muscularly).(25) However, Özden and colleagues report-
ed ESBL-producing isolates had a significant reduction
in activity for most antimicrobial agents, including FQs
and AMK.(11) Further studies to elucidate the precise
drug kinetics of AMK in the prostate could lead to a
more efficient drug delivery method for AMK.
The reported incidence of febrile infection is similar
between CPFX and LVFX: 0.1–3% in CPFX,(2,3,26) and
0.6–5% in LVFX.(27-29) Although we expected the in-
cidence of febrile UTI to be 2% in the LVFX group
(group A) in power calculation, in the present study,
only 3 (0.67%) of 447 cases developed febrile UTI.
This low incidence of overall febrile UTI in the present
study lowered the power of the study, and might partial-
ly explain the lack of significant difference between the
two groups. Increasing sample size may detect smaller
difference due to addition of AMK; however, at the cost
of a larger number needed to treat (NNT), which would
limit its clinical benefit.
Prostate volume, history of previous TRUSB, and use
of antimicrobials have been reported to be associated
with febrile UTIs after TRUSB;(12,13,30) however, we
could not detect any clinical variables statistically asso-
ciated with febrile UTIs except PSA, which was higher
in the febrile patients (Table 2).
Although there was no difference in clinical variables
between the two hospitals, all febrile UTIs occurred in
patients at Japanese Red Cross Otsu Hospital. To iden-
tify any possible cause, we reviewed all the maneuvers
associated with TRUSB at the two hospitals, and found
that the only difference was the way of bowel prepara-
tion prior to TRUSB. All the patients who developed
acute prostatitis did not receive any bowel preparation.
The combined antimicrobial prophylaxis protocol was
adopted for one year following the end of patient re-
cruitment for this study. During this one-year period,
another four febrile UTI cases occurred, exclusively in
the patients not receiving any bowel preparation, sug-
gesting a possible prophylactic role of bowel prepara-
tion in TRUSB. Kim and colleagues reported that using
enemas significantly decreased the incidence of acute
prostatitis (15 [1.6%] of 913 in enema group, and 3
[30%] of 10 in no enema group).(31) On the contrary,
Carey and colleagues have retrospectively reviewed
the usefulness of enemas in TRUSB, and found no sig-
nificant difference in the incidence of acute prostatitis
(10 [4.4%)] of 225 in enema group, 6 [3.2%] of 185 in
no enema group).(32) Therefore, a well-designed rand-
omized study is necessary to confirm the role of bowel
preparation in TRUSB.
FQ resistant E-coli continue to be a growing threat for
patients undergoing TRUSB. The rate of LVFX resistant
E-coli among all the E-coli isolated from urine samples
has been increasing even after 2009 at Japanese Red
Cross Otsu Hospital, and is approaching 35% in 2015
(Figure 3). Considering the cost of treating TRUSB in-
duced sepsis, newer prophylactic methods are certain-
ly needed, and multiple studies to improve efficacy of
prophylaxis including personalized approach based on
pre-biopsy rectal swab are underway.
CONCLUSIONS
There is a strong rationale to add AMK to conventional
FQ-based regimens, since FQ-resistant coliforms show
strong sensitivity to AMK in vitro. However, in the
present randomized control study, addition of a single
Figure 3. Ratios of LVFX-resistant E.coli and ESBL-producing E.coli to
all E.coli isolated from urine cultures of patients with UTI between 2002
and 2015 at Japanese Red Cross Otsu Hospital.
Abbreviations: LVFX, levofloxacin; E. coli, Escherichia coli; ESBL, ex-
tended-spectrum β-lactamase; UTI, urinary tract infection.
Amikacin and Levofloxacin for Prophylaxis in Prostate Biopsy-Miyazaki et al.
Urological Oncology 2538
Vol 13 No 01 January-February 2016 2539
intravenous administration of AMK to single oral ad-
ministration of LVFX did not show any advantage com-
pared with LVFX alone as an antimicrobial prophylaxis
in TRUSB. More strikingly, all the pathogens isolated
from febrile patients were sensitive to AMK. Therefore,
further understanding of drug kinetics of AMK in the
prostate is necessary to develop a more efficient drug
delivery method for AMK. Factors other than antimi-
crobial prophylaxis, such as bowel preparation, should
also be considered in the future studies.
CONFLICTS OF INTEREST
None declared.
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