EFFICIENCY
OF SHORT AND LONG TERM ANTIMICROBIAL THERAPY IN TRANSRECTAL ULTRASOUND-GUIDED
PROSTATE BIOPSIES
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LEONARDO PETTEFFI, GUSTAVO P. TONIAZZO, GUILHERME B. SANDER, ALBERTO C. STEIN, WALTER J. KOFF
Division of Urology, Porto Alegre General Hospital, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
ABSTRACT
Objective:
Prostate biopsy is a frequent diagnostic measure to detect prostatic conditions,
including primarily prostate cancer. Its performance does not follow a
pattern, mainly regarding preparation for the examination through antimicrobial
prophylaxis. The aim of this study is to compare the efficiency of short
and long term antimicrobial prophylaxis in transrectal ultrasound-guided
prostate biopsies.
Materials and Methods: A clinical study
was conducted with a total of 140 patients submitted to prostate biopsy
with transrectal ultrasonographic control. Patients were randomly separated
in two groups: Group 1 receiving norfloxacin 400mg single dose before
the procedure and Group 2 receiving norfloxacin 400mg initiating before
the procedure and then bid up to 6 doses. Efficiency control was determined
by the incidence of urinary tract infection (UTI) and complications in
both groups after statistical analysis.
Results: The incidence of minor complications
in our study was 75%, consistent with data found in the literature. Among
the patients with diagnosis of simple UTI, 23% belonged to Group 1 and
8% to Group 2 (p=0.08). Among the patients with complicated UTI, 37% belonged
to Group 1 and none belonged to Group 2 (p=0.44).
Conclusions: Several advances made transrectal
ultrasound-guided prostate biopsies a useful and safe diagnostic tool
in the workup of urologic patients. There is no optimal prophylactic preparation
to the performance of this procedure. Long term antimicrobial prophylaxis
presents a trend toward lower incidence of infectious complications.
Key words:
prostate; biopsy; needle; ultrasonography; antibiotics
Int Braz J Urol. 2002; 28: 526-32
INTRODUCTION
Prostatic
conditions, including primarily prostate cancer, represent a significant
portion of urological practice nowadays. In its diagnostic workup, prostate
biopsy may be considered routine in outpatient urologic clinic in cases
where patients present alterations in rectal exam and in prostate specific
antigen (PSA) serum levels.
Use of transrectal ultrasound to guide prostate
biopsy supported improving the sensibility of this diagnostic procedure
standardized as transrectal ultrasound-guided prostate biopsies (TRPB)
(1).
Classified as an invasive diagnostic procedure,
TRPB may present complications, especially infectious, suggesting the
performance of an adequate preparation (2). Based on clinical trials,
antimicrobials prescriptions in these preparations became routine. The
role of the so-called antimicrobial prophylaxis has been responsible for
a significant reduction of infectious complications rates (3).
A standard regimen to prepare for TRPB performance
does not exist among urologists (4). Most regimens recommended in the
literature advocate antimicrobials use (5-9). The establishment of a rationale
for prescribing these agents aims preserving the benefits associated to
its therapeutic efficiency, for its indiscriminate use determines selection
of resistant bacterial strains (10,11).
In this context, the concept of short term
antimicrobial prophylaxis has been presenting increasing scientific evidence,
constituting a clinical practice extremely effective, showing good efficacy
in diagnostic and therapeutic procedures (12,13), and demonstrating an
economic impact reducing costs (7). Its superior efficiency compared to
conventional therapeutic regimens used is yet to be proven.
The aim of this study is to compare the
efficiency of short and long term antimicrobial prophylaxis in transrectal
ultrasound-guided prostate biopsies.
MATERIALS AND METHODS
Selection
of Patients and Study’s Profile
One hundred and forty patients from outpatient
general urology clinic presenting indication to TRPB for outpatient workup
of prostatic conditions were selected. This indication was primarily based
on anomalies at rectal exam or at PSA levels.
A clinical trial, simple-blind, controlled,
was designed. The study involved 140 patients randomly separated in two
groups of 70 patients: the short term antimicrobial prophylaxis group
(Group 1) and the long term antimicrobial prophylaxis group (Group 2).
Short term antimicrobial use was defined as a single dose of an antimicrobial
agent 1 hour before the TRPB procedure, and long term antimicrobial use
an initial antimicrobial dose 1 hour before TRPB procedure and maintenance
doses during 72 hours.
Norfloxacin was determined as antimicrobial
prophylaxis regimen, in therapeutic maintenance dose of 400mg PO, as single
dose or bid regimen. Factors as microbiologic efficiency, experience in
the use of the drug, and administration convenience of fluoroquinolones
were evaluated for its selection (5,6,13). The safety of short term antimicrobial
prophylaxis was established in a pilot study performed for the design
of this study.
Patients allergic to norfloxacin, using
long term indwelling catheter, with chronic or within less than 30 days
of antibiotic use, leucopenia with granulocytes count of less then 1,000mL,
with valvular cardiac conditions or valvular prosthesis, or still those
that did not wish voluntarily to participate in the study were all excluded.
After reassessing the number of patients according to the selection and
adequateness criteria to controls previously established, an analysis
of the 105 total patients that could participate in the study was performed,
with 51 patients in Group 1 and 54 patients on Group 2.
Method
and Evaluation Criteria
Before TRPB, patients were orally and by
written informed consent oriented about potentials risks and complications
of the method to be used, and this was approved by the Ethics Committee
of the Urologic Department of our hospital.
TRPB was performed through a needle puncture
biopsy guided by ultrasound control. Material used was: 18 Gauge x 20cm
Biopsy Cut (Core biopsy) – MD Tech ACN™ needle associated to
a biopty gun mechanism – Bard Biopty Gun and AI 5200 S Envision™
- Dornier ultrasound with 11mm 6.5 MHz Dornier end fire transducer. Following
the department’s routine, 12 prostate biopsies were performed, independently
of PSA values and prostate volume evidenced by rectal examination or ultrasound
findings.
All patients underwent a short bowel preparation
through diet and enema (sodium phosphate and di-sodium phosphate) –
Fleet™ enema type – Whitehall performed approximately 4 to 6
hours before the procedure.
For results control, patients underwent
medical and laboratorial control, still keeping secret about the groups.
Two exams were standardized involving complete blood count and urine culture
with resistance testing. The first drawing was performed seven days before
the procedure (previous to TRPB) and the second drawing was performed
between days 14 and 21 after the procedure (post-TRPB), except for those
patients who received emergency care.
Patients came to the revision visit on day
28 after the biopsy. In this visit the patients were interviewed according
to the review protocol including their symptoms and signs and requirements
for emergency care, and the laboratorial result were reviewed as well.
All patients presenting requiring urgent management were assessed in the
emergency room of a referenced hospital, and this management was appropriately
documented in the medical records.
Factors of interest assessed by the protocol
were whether symptoms and signs associated to TRPB were detected or not,
from minor complications (dysuria, hematuria, hematospermia) to major
complications (bacteremia, urinary retention, sepsis, death) considering
the patients’ medical management, as well as the occasional requirement
of hospitalization or initiating antimicrobials. In addition to the medical
history, patients underwent laboratorial control in order to objectively
document all cases of urinary tract infection (UTI), which constituted
the main interest. With this purpose we defined an UTI case according
to the criteria established by Carey & Korman (14), that attribute
simple UTI cases to patients presenting positive urinary culture, regardless
of the presence of urinary symptoms and, as complicated UTI cases patients
presenting positive urinary culture, systemic symptoms and alterations
in blood studies (complete blood count and/or blood culture). A positive
urinary culture is defined as presence of >100,000 colony forming units
(CFU) per milliliter of urine.
We analyzed still the presence of factors
that could potentially interfere in the analysis’ results as detecting
patients presenting diseases or conditions potentially immunosuppressive
(diabetes, neoplasia, AIDS or chronic corticosteroids use), and these
were defined as co-morbidities.
Statistical
Analysis
In
determining the efficiency of the treatments proposed we highlighted mean
comparisons and proportions of final events between both groups.
Factors of interest aiming to compare the
therapeutic efficiency between the groups were statistically analyzed
with Student’s t test to compare means in continuous variables. c-square,
Yates’ or Fisher’s tests were used to compare proportions in
categorical variables.
All tests were two-tailed and were considered
significant values attributed to p<0.05.
RESULTS
Results
were compared to 105 among 140 patients. Among these, 51 patients received
short term antimicrobial prophylaxis (Group 1) and 54 long term antimicrobial
prophylaxis (Group 2).
The population of patients valid for efficiency
analysis was similar in both groups regarding demographic aspects and
basal health profile (age, hematocrit, hemoglobin, total WBC and bands
percentage, presence of co-morbidities, and positive urine cultures).
The number of patients previously submitted to biopsy was also statistically
similar when compared between both groups (Table-1).
The incidence of minor complications was
statistically similar when both groups were compared (Group 1=78%, and
Group 2=74%), with a total of 75% for both groups.
Assessing the end-points for continuous
variables as hematocrit, hemoglobin, total WBC, and bands percentage,
no statistical difference was evidenced between the groups.
In the positive urine culture group determining
potential UTI we may observe that bacteriological analysis of the sample
detected a greater number o infections by Gram-negative bacteria (81%)
compared to Gram-positive (19%), and no infection by anaerobes was evidenced.
When assessing the end-points of categorical
events such as fever, urine culture, requirement of emergency management,
prescription of empirical antimicrobials and hospitalization post-biopsy,
patients in the group of short term antimicrobial prophylaxis (Group 1)
presented a trend towards major complications compared to the group receiving
long term antimicrobial prophylaxis (Group 2). For this the rates of fever
(Group 1=15% and Group 2=2%) (p=0.014), and urine cultures (Group 1=29%
and Group 2=7%) (p=0.006) statistically significant (Table-2).
By performing a selective analysis of patients
for the end-point positive urine culture post-TRPB, limited to patients
presenting negative urine culture previous to TRPB, evidence was that
Group 1 patients remained with a trend towards higher incidence, but this
values were not statistically significant (Group 1=23% and Group 2=8%)
(p=0.08). However, for patients presenting positive urine culture previous
to TRPB it was carefully determined the highest protraction of positive
cultures on Group 1 (Group 1=71% and Group 2=0%) (p=0.005) (Table-3).
Patients with identification of complicated
UTI, whether followed by urgent management or hospitalization or not,
were analyzed. A total of 10 patients were seen according to urgency criteria
or presenting systemic symptoms. Among these patients, 8 belonged to Group
1 and 2 belonged to Group 2. Among the 8 patients belonging to Group 1,
3 presented complicated UTI documented by urine culture, and among the
2 patients belonging to Group 2 none presented laboratorial documented
UTI. For this situation, Group 1 patients presented a trend to higher
incidence of complicated UTI (Group 1=37% and Group 2=0%), but this difference
was not statistically represented (p=0.44).
No complications such as sepsis of urinary
origin or deaths associated to the procedure were detected in both groups.
Two patients required hospitalization after the biopsy to undergo intravenous
antibiotic use, both from Group 1. In one case, treatment was initiated
empirically, regardless the result of the urine culture, that came to
be negative; the other case presented a positive urine culture previous
to the procedure with a multiresistent germ, so management was done based
on this previous result.
Based on patients’ selection as co-morbidities,
we pointed out that both groups presented a statistically similar proportion
of patients as co-morbidities present (Group 1=17% and Group 2=16%) (p=1).
Presence of co-morbidities did not influence the incidence of infectious
complications (Group 1=14% and Group 2=23%) (p=0.427). When a specific
selection of antimicrobial prophylaxis is done for these patients, despite
the small number of patients according to these criteria (6 patients in
Group 1 e 7 patients in Group 2), we have evidenced a trend towards a
higher incidence of infectious complications in Group 1 (Group 1=50% and
Group 2=0%) (p=0.07).
DISCUSSION
The
diagnosis of prostatic conditions collaborates to a great part of urological
practice today. Among these conditions, prostate cancer involves a significant
percentage, since it is the most commonly diagnosed neoplasia, and the
second greatest cause of death among cancers in American men, with an
approximate incidence of 185,000 cases/year (15).
The development of screening involving rectal
exam and PSA analysis, associated to the refinement of diagnostic methods,
promote early detection of this disease, offering conditions for a treatment
with the best results concerning survival. Regarding the diagnosis, we
must emphasize the role of prostate biopsy that provides an objective
substrate through histopathologic study for further staging and treatment
for the patients.
Prostate biopsy presented several improvement
stages. These went from perineal prostate fine-needle aspiration to transurethral
prostate biopsies, consolidating as prostate biopsies with core-biopsy-like
needles.
Historically, needle biopsy was performed
with higher gauge needles (14 gauge) compared to the ones used today (18-20
gauge), without firing mechanism, implying to patients in greater discomfort
and infectious complications (16). Associated to the improvement of biopsy
mechanisms and to confirmation of transrectal route, the use of transrectal
ultrasound as a guide in the biopsy region has helped to an increase in
efficiency of the conventional diagnostic method standardized as transrectal
ultrasound-guided prostate biopsies (TRPB).
According to Rodriguez Terris (2) and Carey
& Korman (14), TRPB presents a frequency of approximately 60 to 70%
of minor complications and 0.4 to 4.3% of major complications.
Nowadays, preparation methods to perform
TRPB aiming to minimize risks are advocated, but these, as well as the
technique of the exam itself, are not properly standardized (4).
Many papers try to settle an optimal framework
to prepare to perform TRPB, however few have a prospective design or present
control groups. The optimal prophylactic regimen and preparation should
be one of easy assimilation to the patient, cost-effective, efficacious
in preventing the infectious complications associated to the method, and
not inducing bacterial strains’ selection.
With this purpose, authors as Carey &
Korman (14) and Lindert et al. (17) assessed the efficacy of bowel preparation
with enema before TRPB, which did not show any difference in the rates
of complications associated to the procedure.
Studies to asses the efficiency of antimicrobial
prophylaxis in TRPB preparation were proposed. To determine the drug to
be used it is important to bear in mind some factors. The bacterial flora
involved in TRPB complications are Gram-negatives bacteria, primarily
represented by Escherichia coli, followed by Enterococos, Klebsiella,
Proteus and Pseudomonas; but anaerobes should be evidenced such as Bacteroides
fragilis and Clostridium sp., which accounts for deaths in some series,
despite an adequate antibiotic coverage (2). Tissue penetration, bioavailability
and clearance pattern should help defining the drug of choice (10).
Several prophylactic regimens using sulfas,
penicillins, cephalosporins, aminoglicosides, and anaerobicides, given
separately or in combinations, in single or multiple doses, by oral or
parenteral route, are proposed in the literature (6-11,16,18,19). In this
context, the quinolone group (norfloxacin, ciprofloxacin, and ofloxacin)
deserves emphasis due to its wide spectrum antimicrobial activity, high
and rapid bioavailability by oral route and capacity of high urinary and
prostate tissue concentrations (8,16).
From authors as Schein et al. (13), through
studies performed in urgent abdominal surgeries, the concept of short
term antimicrobial prophylaxis has been propagated. This practice aims
to rationalize the use of antibiotics, since its indiscriminate administration
may influence bacterial strains selection, risking the therapeutic efficiency
of these drugs and initiating a possible ecologic impact in the patients’
symbiotic flora. Strain selection was also evidence in patients submitted
to TRPB by authors such as Gilad et al. (11). We may estimated that the
use of short term therapies promotes better therapeutic efficiency due
to dosing convenience and its ability to reduce in approximately 60% patients’
direct costs (7). Nevertheless, in this analysis we should assume that
the proposed prophylaxis shall present an adequate efficiency in order
that the initial savings do not become diluted in further personal or
social costs with treatments or hospital stays (8).
Based on results obtained in our study,
we observed that minor complications rate was 75%, consistent with data
reported in the literature (14,17).
In positive urine culture rates we could
find that bacteriologic analysis of the samples has detected a higher
number of infections by Gram-negative bacteria (81%) compared to Gram-positive
(19%), and this data is consistent with the flora usually associated to
UTIs. No anaerobe infection was observed in our study.
Our study could document that patients submitted
to short time antimicrobial prophylaxis (Group 1) presented a higher statistical
rate of simple UTI documented by urine culture positive after biopsies,
nevertheless this data may be assumed as a trend since when a control
was performed to patients with incidental simple UTI figures did not show
statistical significance (p=0.08). Yet it was established that for patients
presenting urine culture documented UTI before TRPB, prophylactic long
term therapy is superior in efficiency (p=0.005).
According to the analysis of complications
incidence values considered as complicated UTI, it was not statistically
different in the groups analyzed. The difference in documented complicated
UTI in higher incidence in Group 1 may be deduced as a trend. Also, hospitalizations
observed did not imply in direct interference of TRPB performance. Maybe
further major studies performance should be necessary in order to attain
a more definitive conclusion.
Factors such as biopsies numbers, PSA values,
grade of obstructive symptoms, prostate volume, and cancer detection were
not directly correlated to the incidence of UTI after TRPB (17). According
to Griffith et al. (9), immunosuppressive conditions, such as diabetes
mellitus and recent corticosteroid use may be determined as potential
risk factors for this, suggesting the use of long term antimicrobial prophylaxis
regimens. This data corroborates our study’s results for the incidence
of infectious complications in patients presenting co-morbidities.
CONCLUSIONS
The
long term antimicrobial prophylaxis established by our study – six
doses of norfloxacin 400mg, bid, initial dose one hour before the exam
– seems to determine a lower simple and complicated UTI incidence.
It is important, however, to perform further
studies aiming at testing new prophylactic regimens, in order to determine
an optimal preparation regimen for the performance of transrectal ultrasound-guided
prostate biopsies.
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______________________
Received: August 27, 2002
Accepted after revision: December 2, 2002
_______________________
Correspondence address:
Dr. Leonardo Petteffi
Hospital de Clínicas de Porto Alegre, sala 835
Rua Ramiro Barcelos, 2350
Porto Alegre, RS, 90035-003, Brazil
Fax: + 55 51 3316-8775