International Journal of Antimicrobial Agents 32 (2008) 145–153

Oral levofloxacin 500 mg once daily in the treatment

of chronic bacterial prostatitis
K.G. Naber a,∗ , K. Roscher b , H. Botto c , V. Schaefer d
a Technical University of Munich, Munich, Germany
b Medical Affairs, Sanofi-Aventis Deutschland GmbH, Potsdamer Str. 8, 10785 Berlin, Germany
c Hôpital Foch, 40 rue Worth, BP 36, 92151 Suresnes, France
d Institute of Medical Microbiology, University of Frankfurt, Paul-Ehrlich-Str. 40, 60596 Frankfurt, Germany
Received 10 November 2007; accepted 25 March 2008

Abstract
The aim of this study was to confirm further the efficacy and safety of levofloxacin in patients with chronic bacterial prostatitis (CBP) in
Europe. Men with a history of CBP were enrolled in a prospective, multinational (eight countries), open-label study to receive levofloxacin
500 mg once daily per os (p.o.) for 28 days. Patients were followed for 6 months. A total of 117 patients were treated. Gram-negative bacteria
were identified in 57/106 patients (mainly Escherichia coli (n = 37)) and Gram-positive bacteria in 60/106 patients (mainly Enterococcus
faecalis (n = 18) and Staphylococcus epidermidis (n = 14)). Among the intention-to-treat population (n = 116), the clinical success rate (cured
and improved patients) was 92% (95% confidence interval (CI) 84.8–96.5%), 77.4% (95% CI 68.2–84.9%), 66.0% (95% CI 56.2–75.0%) and
61.9% (95% CI 51.9–71.2%) at 5–12 days, 1 month, 3 months and 6 months post treatment. The microbiological eradication rate according
to evaluation scheme II was 82/98 (83.7%, 95% CI 74.8–90.4%) at 1 month and the continued eradication rate was 52/57 (91.2%, 95% CI
80.7–97.1%) at 6 months post treatment. Comparison of four classification schemes showed similar results. Thus, the present investigation is
suitably comparable in methods and results to previous studies. Levofloxacin was well tolerated. Four patients (3.4%) discontinued therapy
due to adverse events and 15 patients (12.8%) experienced at least one adverse event. Levofloxacin 500 mg p.o. once daily for 28 days is
clinically and microbiologically effective in the treatment of CBP caused by susceptible pathogens and is well tolerated.
© 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Keywords: Chronic bacterial prostatitis; Levofloxacin

1. Introduction CBP is traditionally diagnosed by the Meares–Stamey

Chronic prostatitis is the most common urological condi-
tion in men under 50 years of age. It is diagnosed in ca. 7%
of all men at some time, and histological signs of prostatitis
are present in one-half of prostates removed for carcinoma of
the prostate and in nearly all tissue diagnosed as benign pro-
static hypertrophy [1]. According to the National Institutes
of Health, prostatitis has been classified as acute bacterial
prostatitis (category I), chronic bacterial prostatitis (CBP)
(category II), chronic pelvic pain syndrome (category III) and
asymptomatic inflammatory prostatitis (category IV) [2,3].
∗ Corresponding author. Present address: Karl-Bickleder-Str. 44c, D-
94315 Straubing, Germany. Tel.: +49 9421 33369.
E-mail address: kurt@nabers.de (K.G. Naber).
(M&S) four-glass test [4,5] or the simpler two-glass test
[6,7], by which a positive culture can be localised to the
prostate. Among Gram-negative bacteria, Escherichia coli
is the most common aetiological agent, followed by other
Enterobacteriaceae and sometimes also non-fermenters such
as Pseudomonas aeruginosa. The frequency of Gram-
positive bacteria, such as enterococci, staphylococci and
streptococci, varies widely from study to study [8–16] and
their role as pathogens is disputed [17]. To cope with this
problem, the Japanese guidelines [18] recommend differ-
ent thresholds for inclusion: ≥103 colony-forming units
(CFU)/mL for Gram-negative bacteria and ≥104 CFU/mL
for Gram-positive bacteria.
A previous clinical study in the USA [12] demonstrated
satisfactory efficacy and safety of levofloxacin 500 mg per

0924-8579/$ – see front matter © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
doi:10.1016/j.ijantimicag.2008.03.014
146 K.G. Naber et al. / International Journal of Antimicrobial Agents 32 (2008) 145–153
os (p.o.) once daily compared with ciprofloxacin 500 mg
twice daily for 4 weeks in the treatment of CBP. To sup-
port the outcome of the abovementioned comparative study
and to gain additional data on a prolonged post treatment
phase, this open, non-comparative study of CBP patients with
4 weeks treatment and a comprehensive 6-months follow-
up was undertaken. The primary endpoint of the study was
microbiological eradication 1 month after completion of 28
days of levofloxacin treatment.
2. Material and methods
2.1. Patients
Men with a history of CBP, clinical signs and symp-
toms, and laboratory evidence of CBP were enrolled in this
prospective, multinational (eight countries, 21 centres), open-
label, non-comparative study to receive levofloxacin 500 mg
p.o once daily for 28 days. In accordance with local legal
requirements, the clinical study protocol, informed consent
document and any other appropriate documents were sub-
mitted to the Independent Ethics Committee/Institutional
Review Board and, if applicable, to the competent authorities
before the start of the study. Eligible patients were included
after having signed the informed consent document.
History of CBP was defined as a clinical diagnosis of at
least one previous episode lasting for at least 4 weeks, or
two or more episodes during the previous 12 months. Clini-
cal diagnosis of CBP required one or more of the following
signs and symptoms: dysuria; suprapubic discomfort; painful
ejaculation; low back pain; perineal discomfort; frequency,
urgency, hesitancy, decreased urinary stream or urinary reten-
tion; tender prostate on digital rectal examination without
suspicion of prostate cancer; and perineal tenderness with
or without fever. Laboratory evidence included a positive
M&S four-glass test [5] including first voided urine (VB1),
midstream urine (VB2), expressed prostatic secretion after
prostatic massage (EPS) and urine after prostatic massage
(VB3) with pathogens with or without white blood cells
(WBCs) (see classification schemes). All investigators were
trained and had been provided with a teaching video to
perform the M&S test correctly. Thus, the procedure was
standardised in all participating centres.
WBCs in urine and EPS were counted microscopi-
cally either per high-power field (HPF) with a threshold
of 10 WBCs/HPF or in a chamber with a threshold of
1000 cells/mL. For bacterial counting, 100 ␮L of urine or
10 ␮L of prostatic secretion were immediately plated on agar
plates routinely used by the local laboratory followed by
identification of the cultured bacteria by standard methods.
A dense suspension of each bacterial isolate was prepared
(density ca. 109 CFU/mL) in the cryopreservative solution
of a MicrobankTM bead storage cryovial. The cryovial was
frozen and stored below –20 ◦ C. Bacterial isolates were trans-
ported in MicrobankTM cryovials on dry ice to the Central
Laboratory (Medical Microbiology of the University of
Frankfurt, Frankfurt, Germany) for re-identification and sus-
ceptibility testing. Vials with 1 mL of sample from VB1 and
VB3 for detection of sexually transmitted infections (STIs),
such as Chlamydia, Mycoplasma and gonococci, by poly-
merase chain reaction (PCR) were also stored at −20 ◦ C and
shipped to the Central Laboratory together with the bacterial
strains on dry ice in the same shipment.
In the Central Laboratory, all strains were re-identified
with the API System (bioMérieux, Nürtingen, Germany)
and the levofloxacin minimum inhibitory concentration
(MIC) was determined using Etest (Viva Diagnostika, Köln,
Germany). MIC breakpoints were defined according to
the Clinical and Laboratory Standards Institute [19] for
Staphylococcus spp. as susceptible ≤1 mg/L, intermediately
susceptible >1 mg/L to <4 mg/L and resistant ≥4 mg/L; for
all other strains breakpoints were susceptible ≤2 mg/L, inter-
mediately susceptible >2 mg/L to <8 mg/L and resistant
≥8 mg/L. Patients were followed for 6 months. Clinical signs
and symptoms were evaluated 5–12 days and then 1, 3 and 6
months post treatment. The microbiological eradication rate
was determined by the M&S test at 1 month post treatment
and patients with clinical success (cure and improvement) and
microbiological eradication at 1 month were also evaluated
clinically and microbiologically at 6 months post treatment.
Fig. 1 provides an overview of clinical and microbiolog-
ical assessments during the study. Spontaneously reported
adverse events (AEs) were collected.
2.2. Evaluation criteria for microbiological diagnosis
Patients were classified according to four commonly used
microbiological classification schemes. This allowed direct
comparison with previous studies [12] and also to investigate
which microbiological classification scheme best predicts the
clinical outcome of CBP (category II).
Classification scheme I was mainly based on a previous
study [12] conducted in the USA. A pathogen was considered
Fig. 1. Schedule of visits: treatment and follow-up period and the assess-
ments performed during the study.
 K.G. Naber et al. / International Journal of Antimicrobial Agents 32 (2008) 145–153 147

an original pathogen if: at Visit 1 its CFU count in EPS or, discordant results) and +1 (only concordant results). A value
if EPS is not available, in VB3 was at least 10 times higher of zero indicates no association between clinical success and
than in VB2 or, if VB2 is not available, in VB1; and EPS microbiological eradication. The Wilcoxon two-sample test
or VB3 specimen contains 102 CFU/mL or more of a single (two-sided) using normal approximation and continuity cor-
strain specimen if VB2 or, if VB2 is not available, if VB1 is rection was used for pairwise comparison of MIC values
sterile (<102 CFU/mL). WBCs are not considered. between pathogens classified as eradicated, persistent/early
Classification scheme II (based on a previous study in recurrence and re-infection/superinfection.
Germany [10]) corresponds to the CFU criterion of scheme To obtain 60 patients who were microbiologically evalu-
I except 103 instead of 102 CFU/mL or more at species level able according to classification scheme I at Visit 5, i.e. 1
is required for classification of the pathogen to be contained month post treatment, it was planned to recruit 120 patients.
in the EPS or VB3 specimen. WBCs are not considered. Based on a sample size of 60 patients, a two-sided 95% CI
In classification scheme III, in addition to the criteria extends by less than 10 percentage points from the observed
of scheme II, WBCs in EPS or VB3 ≥1000 WBCs/mL proportion for an expected microbiological eradication rate
or ≥10 WBCs/HPF are required for classification of the of ≥85%.
pathogen; or WBCs in EPS or, if EPS is not available, in
VB3 are at least 10 times higher than in VB2 or, if VB2 is
not available, than in VB1. 3. Results
Classification scheme IV (based on the proposed Japanese
guidelines [18]) corresponds to scheme III, except 104 instead 3.1. Demographic and baseline characteristics
of 103 CFU/mL or more at species level of Gram-positive
bacteria are required for classification of the pathogen to be A total of 117 patients were treated and 116 patients were
contained in the VB3 or EPS specimen. evaluable according to the intention-to-treat (ITT) principle.
The average (±standard deviation) age was 45.8 ± 14.6 years
(median 45.0 years). On average, patients were suffering from
2.3. Efficacy evaluation
CBP for 72.3 ± 71.2 months (median 48.0 months). Accord-
ing to scheme I, Gram-negative bacteria were identified in
The primary efficacy variable was the microbiological
57 patients (mainly E. coli (n = 37)) and Gram-positive bac-
response at one month post treatment. Clinical response and
teria in 60 patients (mainly Enterococcus faecalis (n = 18)
microbiological efficacy at six months post treatment were
and Staphylococcus epidermidis (n = 14)) among 106 patients
secondary efficacy variables.
with baseline pathogens. With progressing stringency of the
Clinical response was assessed as cure (disappearance of
evaluation criteria, the number of patients with pathogens
all pre treatment symptoms), improvement (without worsen-
decreased from scheme I to scheme IV. The number of
ing of any symptoms), failure (no change or worsening of
patients with a microbiological diagnosis is summarised for
symptoms) and unable to evaluate. Clinical success included
each evaluation scheme and for the bacterial strains cultured
cure and improvement.
in Table 1. Most of the baseline strains were susceptible to
Microbiological response was evaluated in terms of both
levofloxacin, expect for five strains that were resistant (two
subject and pathogen. Outcome for each pathogen was
assessed as eradicated, persisted, relapsed (same species)
or re-/superinfected (new species) according to the thresh-
olds used in the classification schemes I–IV. Patients without
microbiological assessment were included as patients with
presumed eradication or persistence/relapse if they showed
continued clinical success without clinical sign of relapse or
with failure/relapse, respectively.
A medical expert team validated the clinical and microbi-
ological endpoints in a blinded setting, i.e. only with regard to
the data needed for the evaluation criteria as described above.

2.4. Statistical analysis

The statistical analysis consisted of point estimates for

proportions of subjects and corresponding 95% confidence
intervals (CIs) calculated using Pearson–Clopper values as
well as Kendall’s τ b with 95% CIs to analyse the association
Fig. 2. Eradication rate per patient (with 95% confidence intervals) 1 month
between clinical success and eradication. Kendall’s τ b is a after 28 days of treatment with levofloxacin in the four overlapping popu-
measure of association between clinical success and micro- lations with microbiological diagnosis according to classification schemes
biological eradication and can have values between −1 (only I–IV. Patients with presumed eradication were included.
148 K.G. Naber et al. / International Journal of Antimicrobial Agents 32 (2008) 145–153

Table 1
Number of pathogens at baseline (N) and eradication per pathogen (n) at 1 month post treatment according to classification schemes I–IVa,b
Classification scheme
I II III IV
Patients with baseline pathogens 106 100 86 75
Patients with baseline pathogens and microbiologically 104 98 84 73
assessable at 1 month post treatment
(n/N) (n/N) (n/N) (n/N)
Enterococcus faecalis 10/18 9/13 7/10 5/6
Staphylococcus epidermidis 10/14 8/11 6/9 5/7
Staphylococcus haemolyticus 10/11 9/9 9/9 7/7
Streptococcus agalactiae 3/5 3/5 3/4 2/2
Staphylococcus saprophyticus 3/3 2/2 2/2 2/2
Staphylococcus, NOS 2/3 2/2 2/2 2/2
Staphylococcus aureus 3/3 2/2 2/2 1/1
Corynebacterium, NOS 2/3 2/2 1/1 1/1
Gram-positive coccus 1/2 1/2 1/2 2/2
Corynebacterium renale 1/1 1/1 1/1 1/1
Streptococcus intermedius 1/1 1/1 1/1 1/1
Haemophilus parainfluenzae 0/1 0/1 0/1 0/1
␣-Haemolytic streptococcus 1/1 1/1 1/1 1/1
Aerococcus urinae 1/1 1/1 1/1 1/1
Streptococcus anginosus 0/1 0/1 0/1 0/1
Streptococcus sanguis 1/1 1/1 1/1
Staphylococcus hominis 1/1 1/1 1/1
Lactobacillus, NOS 1/1 1/1 1/1
Enterococcus, NOS 1/1
Total Gram-positive pathogens 52/72 (72.2%) 45/57 (78.9%) 40/50 (80.0%) 31/36 (86.1%)
Escherichia coli 30/36 30/35 23/27 23/27
Proteus mirabilis 8/9 8/9 8/8 8/8
Pseudomonas aeruginosa 3/3 3/3 3/3 3/3
Enterobacter cloacae 3/3 3/3 3/3 3/3
Morganella morganii 2/2 2/2 2/2 2/2
Klebsiella pneumoniae 2/2 2/2 2/2 2/2
Citrobacter, NOS 2/2 2/2 1/1 1/1
Citrobacter freundii 1/1 1/1 1/1 1/1
Gardnerella vaginalis 1/1 1/1 1/1 1/1
Klebsiella oxytoca 1/1 1/1 1/1 1/1
Klebsiella pneumoniae ss. ozaenae 1/1
Total Gram-negative pathogens 54/61 (88.5%) 53/59 (89.8%) 45/49 (91.8%) 45/49 (91.8%)
Total pathogens 106/133 (79.7%) 98/116 (84.5%) 85/99 (85.9%) 76/85 (89.4%)
NOS, not otherwise specified.
a In the absence of microbiological assessment, eradication was presumed if patients showed continued clinical success and no clinical sign of relapse.
b More than one pathogen per patient possible.

E. coli, one S. epidermidis, one Proteus mirabilis and one
Corynebacterium renale) and two strains that were intermedi-
ately susceptible (one Lactobacillus, not otherwise specified
(NOS) and one Streptococcus sanguinis). Nine baseline
pathogens were untested.
One hundred and four patients were tested for STIs using
PCR. At baseline, six patients showed positive tests (VB1 or
VB3 sample) for Neisseria gonorrhoeae and three patients
for Chlamydia trachomatis.
3.2. Efficacy parameters
Microbiological eradication 1 month post treatment was
observed in 82/104 (78.8%, 95% CI 69.7–86.2%), 82/98
(83.7%, 95% CI 74.8–90.4%), 71/84 (84.5%, 95% CI
75.0–91.5%) and 65/73 (89.0%, 95% CI 79.5–95.1%)
patients analysed according to schemes I–IV. The four differ-
ent classification schemes showed similar results regarding
pathogen eradication per patient (Fig. 2). However, eradica-
tion rates at 1 month post treatment tended to be higher the
more stringent the definition for the presence of pathogens
(increasing from scheme I to scheme IV).
Continued eradication 6 months post treatment was
observed in 46/50 (92.0%, 95% CI 80.8–97.8%), 52/57
(91.2%, 95% CI 80.7–97.1%), 47/51 (92.2%, 95% CI
81.1–97.8%) and 49/53 (92.5%, 95% CI 81.8–97.9%)
patients in the ITT data set analysed according to schemes
I–IV with microbiologically demonstrated eradication at 1
month post treatment or presumed eradication. The contin-
ued eradication rates were comparable in all four analysis
groups. The pathogens at baseline and the eradication rate
per pathogen at 1 month post treatment as well as new
 K.G. Naber et al. / International Journal of Antimicrobial Agents 32 (2008) 145–153 149

Table 2
Microbiological diagnosis 1 month post treatment: pathogens and number
of patients with new pathogens detected 1 month post treatment according
to classification schemes I–IVa
Classification scheme

I II III IV
Patients with new pathogens 39 32 32 23
Enterococcus faecalis 15 15 15 10
Staphylococcus saprophyticus 5 1 1 1
Staphylococcus epidermidis 4 3 3 3
Streptococcus agalactiae 3 3 3 3
Staphylococcus, NOS 2 3 3 1
Corynebacterium, NOS 2 2 2 1
Gram-positive coccus 2 2 2
Enterococcus, NOS 2 1 1 1
Staphylococcus haemolyticus 2 Fig. 3. Minimum inhibitory concentrations (MICs) of pathogens classi-
Streptococcus, NOS 1 1 1 1 fied according to dilution steps by microbiological assessment according
Streptococcus, group F 1 1 1 to classification scheme I at 1 month after treatment (including presumed
Streptococcus pyogenes 1 assessments). Displayed values are the MIC of the pathogen at baseline in the
␤-Haemolytic streptococcus 1 case of eradication or persistence/early recurrence and the MIC of the new
Total Gram-positive pathogens 41 32 32 21 pathogen 1 month after treatment in the case of re-infection/superinfection.
Escherichia coli 3 2 2 2
Pseudomonas aeruginosa 2 2 2 2
Klebsiella pneumoniae 2 2 2 2 ceptible at baseline were cultured but not tested at 1 month
Total Gram-negative pathogens 7 6 6 6 post treatment.
Total pathogens 48 38 38 27 Five pathogens presumed persistent at 1 month post treat-
NOS, not otherwise specified. ment had been tested susceptible at baseline.
a More than one pathogen per patient possible.
For two pathogens assessed as persistent (Corynebac-
terium, NOS (cultured) and Gram-positive coccus (presumed
persistent)) at 1 month post treatment, no MIC was avail-
pathogens cultured at 1 month and 6 months post treatment able at baseline and 1 month post treatment. From the two
are listed in Tables 1–3. According to scheme I, 22/104 pathogens tested resistant at baseline, one became susceptible
patients showed 27 persistent or early relapsing pathogens (E. coli MIC = 8 mg/L at baseline and 0.47 mg/L 1 month post
at 1 month post treatment (20 Gram-positive and 7 Gram- treatment) and the other remained resistant (S. epidermidis
negative pathogens) (Table 1). Thirteen of these pathogens MIC > 32 mg/L at baseline and 1 month post treatment).
were susceptible at baseline and remained susceptible 1 One month after completion of a 28-day treatment of
month post treatment, with MICs ranging from 0.023 mg/L to CBP (category II) with levofloxacin, 39/109 (35.8%), 32/104
1.5 mg/L. Two pathogens initially susceptible became resis- (30.8%), 32/94 (34.0%) and 23/82 (28.0%) patients had
tant at 1 month post treatment: S. epidermidis (16 mg/L) and acquired (irrespective of the presence of a baseline pathogen)
Staphylococcus, NOS (24 mg/L). Three pathogens tested sus- a new pathogen according to schemes I–IV, in most cases E.
faecalis (Table 2). A total of 48 new pathogens occurred in
those 39 patients with new pathogen according to scheme I,
Table 3
Microbiological diagnosis 6 months post treatment: pathogens and number
with 29 of them sensitive, 11 resistant and 8 untested.
of patients with new pathogens detected 6 months post treatment according The 11 resistant strains occurred in nine patients (three
to classification schemes I–IVa patients with E. faecalis, two patients each with Staphylococ-
Classification scheme cus saprophyticus and S. epidermidis and one patient each
with Corynebacterium jeikeium, Klebsiella pneumoniae,
I II III IV
Staphylococcus haemolyticus and Staphylococcus, NOS).
Patients with new pathogens 8 7 6 3 Except for the two S. epidermidis strains that had MICs of
Gram-positive coccus 2 2 2
Enterococcus faecalis 2 1 1
6 mg/L and 12 mg/L, all pathogens showed a MIC > 32 mg/L.
Micrococcus, NOS 1 1 1 1 Eight of 50 patients without a prior new pathogen acquired
Enterococcus faecium 1 1 eight new pathogens according to scheme I at 6 months post
Staphylococcus haemolyticus 1 1 1 treatment (Table 3). Five of these pathogens were susceptible
Micrococcus luteus 1 1 1 and the others were left untested.
Total Gram-positive pathogens 6 7 6 3
Escherichia coli 2 1 1 1
The correlation of numbers of isolates between the
Total Gram-negative pathogens 2 1 1 1 MIC of pathogens classified according to dilution steps
Total pathogens 8 8 7 4 and microbiological assessment according to classification
NOS, not otherwise specified. scheme I at 1 month after treatment (including presumed
a More than one pathogen per patient possible. assessments) is shown in Fig. 3. Displayed values are the
150 K.G. Naber et al. / International Journal of Antimicrobial Agents 32 (2008) 145–153

Table 4
Clinical success rates (cure + improvement) at 1 month post treatment: number of patients with clinical success depending on microbiological diagnosis
according to classification schemes I–IV
Classification scheme

I II III IV
Patients with clinical success/total number of patientsa 77/94 (81.9%) 74/90 (82.2%) 67/78 (85.9%) 60/68 (88.2%)
Patients with clinical success and eradication/total number of patients 65/94 (69.1%) 66/90 (73.3%) 60/78 (76.9%) 56/68 (82.4%)
Clinical success/patients with eradication 65/77 (84.4%) 66/78 (84.6%) 60/68 (88.2%) 56/62 (90.3%)
Eradication/patients with clinical success 65/77 (84.4%) 66/74 (89.2%) 60/67 (89.6%) 56/60 (93.3%)
The clinical success rate is given (from top to bottom) in relation to the total number of patients with assessment, diagnosis of microbiological eradication and
total number of patients with clinical success. Only eradication and persistence regarding baseline pathogens is considered.
a All patients with baseline pathogen and assessment for clinical success and microbiological eradication at 1 month post treatment.

MIC of the pathogen at baseline in the case of eradica-
tion or persistence/early recurrence and the MIC of the
new pathogen 1 month after treatment in the case of
re-infection/superinfection. There was no statistically signif-
icant difference between the MIC distribution of pathogens
eradicated versus persistence/early recurrence (P = 0.1422).
In contrast, re-infecting/superinfecting pathogens showed
significantly higher MIC values compared with eradicated
strains (P < 0.0001) as well as persistent/early recurrent
strains (P = 0.0050).
The clinical success rate (cured and improved subjects) as
assessed independently from the microbiological classifica-
tion schemes was 92/100 (92%, 95% CI 84.8–96.5%) on Days
5–12 post treatment (Visit 4). Long-term clinical success
showed a continuous decline during follow-up: 1 month post
treatment (Visit 5), 82/106 (77.4%, 95% CI 68.2–84.9%);
3 months post treatment (Visit 6), 70/106 (66.0%, 95% CI
56.2–75.0%); and 6 months post treatment (Visit 7), 65/105
(61.9%, 95% CI 51.9–71.2%).
Table 4 compares clinical success with eradication as
determined according to classification schemes I–IV at 1
month post treatment. Similar to the eradication rate, the
long-term success was slightly better in the subgroups with
more stringent microbiological assessment. Persistence of
the primary pathogen or infection with a new pathogen at
1 month post treatment was observed in 15/17, 13/16, 9/11
and 5/8 patients with clinical failure as analysed according
to classification schemes I–IV, respectively.
Table 5 summarises the concordance between clinical
success and microbiological eradication as well as between
clinical failure and the detection of persistent or new
pathogens. Based on the percentage of concordant pairs, con-
cordance of clinical outcome and microbiological eradication
was lowest in Group I and highest in Group IV. The main fea-
ture responsible for this outcome was the high rate of patients
with clinical success despite the observation of pathogens at
1 month post treatment in Group I (30/77 patients with clin-
ical success) and the comparatively low rate of such patients
in Group IV (12/60 patients with clinical success).
Prominent presence of leukocytes in prostate
secretion at baseline (WBC count rate EPS(VB3)/
VB2(VB1) ≥10/HPF) was associated with a compara-
tively high rate of clinical long-term success 1 month post
treatment (43/53 patients; 81.1%) compared with patients
with a lower WBC ratio (16/26 patients; 61.5%).
At 6 months post treatment, no systematic relationship
between stringency of microbiological classification and
long-term success was observed. All subgroups showed
approximately the same long-term success in patients with
continued eradication (38/42 (90.5%), 44/49 (89.8%), 40/44
(90.9%) and 41/46 (89.1%) patients classified according
to schemes I–IV). At the end of the follow-up phase, no
pathogen could be identified in the majority of patients with
clinical failure. This involved 2/4, 3/5, 2/4 and 5/6 patients
classified according to schemes I–IV, respectively, with clin-
ical failure after 6 months follow-up.

Table 5
Concordance of clinical success and microbiological eradication at 1 month post treatment: number of patients with clinical success (yes/no) versus microbio-
logical eradication (yes/no) depending on microbiological assessment according to classification schemes I–IV
Microbiological eradication (yes) vs. new infection and/or persistence (no)

I II III IV

Yes No Yes No Yes No Yes No

Clinical success
Yes 47 (50.0%) 30 (31.9%) 53 (58.9%) 21 (23.3%) 48 (61.5%) 19 (24.4%) 48 (70.6%) 12 (17.6%)
No 2 (2.1%) 15 (16.0%) 3 (3.3%) 13 (14.4%) 2 (2.6%) 9 (11.5%) 3 (4.4%) 5 (7.4%)
Concordance 62/94 (66.0%) 66/90 (73.3%) 57/78 (73.1%) 53/68 (77.9%)
Kendall’s τ b (95% CI) 0.3797 (0.2211–0.5382) 0.4169 (0.2313–0.6026) 0.3879 (0.1849–0.5908) 0.3162 (0.0465–0.5859)
Persistence of the primary pathogen and new infections were both considered as microbiological failure. Concordance is calculated as the number of patients
with matching clinical and microbiological outcome in relation to the total number of patients with assessments. CI, confidence interval.
 K.G. Naber et al. / International Journal of Antimicrobial Agents 32 (2008) 145–153
One month post treatment, 7/74, 2/74 and 1/74 tested
patients were positive for N. gonorrhoeae, C. trachomatis
and Mycoplasma hominis. New infections were observed in
4/7, 2/2 and 1/1 of these patients diagnosed with N. gon-
orrhoeae, C. trachomatis and M. hominis at 1 month post
treatment. At the end of the study (6 months post treatment),
only 3/52 tested subjects who acquired the infection after
baseline presented positive PCR tests for N. gonorrhoeae.
3.3. Safety observations
The spectrum of observed AEs was as expected for
the study drug: 15 patients (12.8%) experienced treatment-
emergent AEs (i.e. AEs occurring during the treatment period
+7 days). Treatment-emergent AEs mostly concerned the
gastrointestinal system (seven patients, 6.0%) as well as mus-
culoskeletal and connective tissue disorders (six patients,
5.1%). Six patients (5.1%) experienced treatment-emergent
AEs with possible relation to the study medication. Six
patients (5.1%) discontinued the study due to AEs (dur-
ing the treatment or follow-up phase). Four patients (3.4%)
discontinued study medication due to AEs. One serious
treatment-emergent AE was observed (intestinal bleeding)
that was not assessed as possibly related to the study medi-
cation.
Abnormal laboratory values were rare and laboratory
safety data for haematology and blood chemistry showed
no changes that could be attributed to the administration of
levofloxacin.
One abnormal laboratory value was considered an AE
(hyperlipidaemia) but was not assessed as possibly related
to the study drug. Physical examination showed a transitory
increase in pathological findings affecting the musculoskele-
tal system and connective tissue, but these findings were
already recorded as AEs affecting musculoskeletal and con-
nective tissue. No effect on vital signs was observed.
No patient died during the study. Evaluation of labora-
tory safety parameters, vital signs and physical examination
revealed no further side effects of the study medica-
tion.
4. Discussion
The bacterial spectrum and the composition of subjects
included in the current study represent the clinical conditions
of CBP (category II) in Europe. In general, fluoroquinolone
antimicrobials are recommended as the drugs of choice
because they cover the bacterial spectrum of CBP and pene-
trate best into the prostate compartments [20]. As equivalent
efficacy of levofloxacin in the treatment of CBP was demon-
strated in a previous comparative study with ciprofloxacin
[12], which is the fluoroquinolone for which most clinical
experience has been gathered in the past [20], the objec-
tive of this study was to confirm these previous results in
terms of clinical success and eradication rate and to pro-
151
vide additional data on the long-term efficacy over a period
of 6 months. Comparative pharmacokinetics in plasma and
urine, including urinary bactericidal titres, have been exten-
sively characterised in previous studies [21,22]. These studies
have demonstrated that pharmacokinetic/pharmacodynamic
parameters of an oral dosage of levofloxacin 500 mg once
daily are comparable (even superior for Gram-positive
strains) with a dosage of ciprofloxacin 500 mg twice daily
or ciprofloxacin extended-release 1000 mg once daily for the
treatment of urinary tract infections. For the treatment of CBP,
however, the antibiotic concentrations in prostatic tissue and
secretion and probably also in seminal secretion might also
be of importance. Patients undergoing transurethral resection
of the prostate showed a (mean) penetration ratio of 2.96.
Using these results for a 1000-subject Monte Carlo simu-
lation, >70% of the population had a penetration ratio in
excess of 1.0 [23]. In a study of volunteers [24] in which
ciprofloxacin and levofloxacin were compared after simulta-
neous oral administration of 250 mg, after 3 h levofloxacin
showed significantly higher (median) concentrations in
plasma (3.10 mg/L vs. 1.37 mg/L) and prostatic secretion
(0.89 mg/L vs. 0.16 mg/L) and similar concentrations in
seminal secretion (3.25 mg/L vs. 2.59 mg/L). From the two
studies it can be assumed that an oral dosage of levofloxacin
500 mg once daily exhibits concentrations in prostatic tissue
and secretion sufficiently high for the treatment of susceptible
pathogens.
The relationship between in vitro susceptibility in gen-
eral and eradication of the pathogen could not be studied
because there were only a few pathogens at baseline inter-
mediately susceptible or resistant. The MIC distribution
of eradicated versus persisting/early relapsing strains was
also not statistically significantly different, but the re-
infecting/superinfecting strains showed significantly higher
MIC values compared with eradicated as well as persist-
ing/early relapsing strains. These results demonstrate the
complexity of this disease. In vitro susceptibility of a
pathogen is probably only one prerequisite for eradica-
tion. Other anatomical or functional factors, such as biofilm
infection [25], may be as important. Since no bacterial typ-
ing was performed in the study, it is not known whether
some of the cases rated as persistence/early recurrence are
in fact new infections with different, probably less vir-
ulent, strains that are only colonisers but not pathogens.
The higher MIC values of re-infecting/superinfecting
strains may, however, be interpreted as a selection
process.
There was a significant correlation between microbiolog-
ical success (eradication of the baseline pathogen without
re-infection/superinfection) and clinical success on the one
hand and microbiological non-success and clinical failure
on the other, with increasing concordance according to the
stringency of the microbiological diagnosis. This result is
expected if an infection is effectively treated by an antimi-
crobial agent. However, despite this positive correlation,
approximately one-third (scheme I) to one-sixth (scheme
152 K.G. Naber et al. / International Journal of Antimicrobial Agents 32 (2008) 145–153
IV) of the patients with microbiological non-success also
showed clinical success depending on the stringency of the
microbiological diagnosis. This discrepancy makes the inter-
pretation of microbiological results very difficult, because up
to now there are no validated criteria to differentiate between
pathogens and colonisers. In contrast, only a few patients
(2.1–4.4%) with microbiological success showed clinical
non-success.
The efficacy of levofloxacin demonstrated in this study
is in line with results of a previous clinical trial [12]. For
better comparison with published studies, four classifica-
tion schemes for microbiological diagnosis were used in
the current investigation. The overall effect of the different
classification schemes on the assessment of microbiological
eradication and clinical success was minor. The eradication
rate showed an increase with increasing stringency of micro-
biological diagnosis. This effect was even more pronounced
if the proportion of patients with clinical success and bacterial
eradication are considered in the study populations classified
according to the four schemes. On the other hand, the clinical
success rate 1 month post treatment was largely indepen-
dent of the classification scheme. These findings may have
implications for future study designs, whether the primary
aim is to compare bacterial eradication, e.g. in comparative
antimicrobial studies, or clinical efficacy. Altogether, it can be
concluded that the mentioned clinical studies and the present
investigation produce fairly comparable results and support
each other.
5. Conclusion
Evaluation of efficacy and safety parameters indicates
that levofloxacin treatment is generally well tolerated and
shows convincing efficacy in CBP caused by susceptible
pathogens in terms of symptoms, clinical success and micro-
biological eradication. Observed efficacy and safety results
are in line with previous studies. The spectrum of observed
pathogens and the observed efficacy of levofloxacin conforms
with the current state of clinical practice in the treatment of
CBP.
Funding: This study was supported by an unrestricted
grant from Sanofi-Aventis Deutschland, Berlin, Germany.
Competing interests: Kurt G. Naber: Bayer (Investiga-
tor, speaker at scientific meetings), Combinature/MerLion
(Investigator, consultant), Daiichi (speaker at scientific meet-
ings), Mucos Pharma (Consultant, speaker at scientific
meetings), OM Pharma (Investigator, scientific publication),
Ocean Spray cranberries (Investigator), Peninsula/Johnson
& Johnson/Janssen-Cilag (Investigator, speaker at scientific
meetings, scientific publication), Sanofi-Aventis (Investiga-
tor, speaker at scientific meetings) and Zambon (Investigator,
speaker at scientific meetings).
Ethical approval: Ethical Committee of the Bayerische
Landesärztekammer, Munich, Germany (Ref. No. 02186).
Clinicaltrials.gov identifier: NCT00277511.
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