Comparative analysis of azithromycin and ciprofloxacin in the

International Journal of Antimicrobial Agents 21 (2003) 457 /462
www.ischemo.org
Comparative analysis of azithromycin and ciprofloxacin in the
treatment of chronic prostatitis caused by Chlamydia trachomatis
Višnja Škerk a,*, Slavko Schönwald a, Ivan Krhen b, Arthur Banaszak c, Josip Begovac a,
Jadranka Strugar c, Zvonimir Strapac c, Renata Vrsalovic a, Jacinta Vukovic c,
Margita Tomas c
a
University Hospital for Infectious Diseases ‘Dr. Fran Mihaljevic’, Mirogojska 8, 10 000 Zagreb, Croatia
b
Clinical Hospital Centre Rebro, Zagreb, Croatia
c
PLIVA Pharmaceutical Company, Zagreb, Croatia
Received 19 June 2002; accepted 10 September 2002
Abstract
A total of 89 patients, ( /18 years), with symptoms of chronic prostatitis and inflammatory findings as well as the presence of
Chlamydia trachomatis confirmed by DNA/RNA DIGENE hybridization method and/or by isolation, McCoy culture and Lugol
stain in expressed prostatic secretion or in voided bladder urine collected immediately after prostatic massage, were examined. The
patients were randomized to receive a total of 4.5 g of azithromycin for 3 weeks, given as a 3-day therapy of 1 /500 mg weekly or
ciprofloxacin 500 mg b.i.d. for 20 days. Patients’ sexual partners were treated at the same time. Clinical and bacteriological efficacy
were evaluated 4 /6 weeks after the end of therapy. Significantly higher eradication (36/45: 17/44; P/0.0002) and a significantly
higher clinical cure (31/45: 15/44; P /0.0021) were achieved in the group of patients treated with azithromycin than in the
ciprofloxacin group.
# 2003 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved.
Keywords: Prostatitis; Chlamydia trachomatis ; Treatment; Azithromycin; Ciprofloxacin
1. Introduction
Prostatitis is a disease entity that is diagnosed by
symptoms, the microscopy of expressed prostatic secretion (EPS) and the culture of EPS and segmented urine
samples [1]. According to the duration of symptoms,
prostatitis is described as either acute or, where symptoms are present for at least three months, chronic [1].
What was previously denoted ‘prostatitis’ is today
referred to as ‘prostatitis syndrome’ [1].
Basic factors for the classification of prostatitis
syndrome include clinical symptoms and signs as well
as the presence of bacteria and leukocytes in both
selectively collected urine samples and expressed pro-
* Corresponding author. Tel.: /385-1-4603-222; fax: /385-1-4678235.
E-mail address: bfm@bfm.hr (V. Škerk).
static secretion determined using Meares and Stamey
localization technique [2]. Classification of prostatitis
according to Drach et al. differentiates between: (1)
acute bacterial prostatitis; (2) chronic bacterial prostatitis; (3) chronic abacterial prostatitis; (4) prostatodynia
[3]. In 1995, the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK) of the National Institute of Health recommended new classification of the prostatitis syndrome: (1) acute bacterial
prostatitis; (2) chronic bacterial prostatitis; (3) chronic
pelvic pain syndrome; (3A) inflammatory chronic pelvic
pain syndrome; (3B) non-inflammatory chronic pelvic
pain syndrome; (4) asymptomatic inflammatory prostatitis [4].
The aim of this prospective, comparative, randomized
study was to compare the efficacy and tolerability of
azithromycin and ciprofloxacin in the treatment of
chronic prostatitis caused by Chlamydia trachomatis .
0924-8579/03/$30 # 2003 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved.
doi:10.1016/S0924-8579(03)00056-6
458
V. Škerk et al. / International Journal of Antimicrobial Agents 21 (2003) 457 /462
2. Patients and methods
Since the beginning of 1999, as part of two scientificresearch projects of the Ministry of Science and
Technology of the Republic of Croatia, we have
prospectively been investigating prostatitis syndrome
and urogenital infections caused by C. trachomatis at
the University Hospital for Infectious Diseases ‘Dr.
Fran Mihaljevic’, Zagreb. In the period March 1, 1999/
February 28, 2002, we performed quantitative segmental
bacteriological localization cultures and microscopy of
EPS, as described by Meares and Stamey, on a total of
1352 males older than 18 years of age. The presence of
C. trachomatis was looked for using a urethral swab and
EPS specimens of all patients. C. trachomatis was
confirmed by the DNA/RNA DIGENE hybridization
method and/or by isolation, McCoy culture and Lugol
stain. The majority of patients came to the Outpatient
Department for Urogenital Infections and Sexually
Transmitted Diseases because of symptoms of urogenital infection; only a few came because of symptoms and
laboratory findings of their sexual partner, reactive
arthritis or fear from having contracted a sexually
transmitted disease. Of the 1352 patients, /10 WBC/
hpf in EPS was detected in 902 patients, and C.
trachomatis in EPS of 324 patients. Some results from
this study are currently in press [5].
This prospective, comparative, randomized study,
part two scientific-research project of the Croatian
Ministry of Science and Technology, was conducted at
the Outpatient Department for Urogenital Infections
and Sexually Transmitted Diseases, University Hospital
for Infectious Diseases ‘Dr. Fran Mihaljevic’, Zagreb,
Croatia, between January 1, 2001 and December 31,
2001. The Ethics Committee of the University Hospital
for Infectious Diseases ‘Dr. Fran Mihaljevic’, Zagreb,
approved the study.
2.1. Patients
We examined a total of 89 patients, older than 18
years of age, with inflammatory finding as well as the
presence of C.trachomatis in expressed prostatic secretion (EPS) or in voided bladder urine collected immediately after prostatic massage (VB3). In all patients
clinical symptoms were present for at least 3 months.
There was no evidence of structural or functional
abnormalities of genitourinary tract in these patients.
2.2. Diagnostic criteria
The inclusion criteria for C. trachomatis prostatitis
were the presence of ten or more WBC/hpf in EPS or
VB3, presence of C. trachomatis in EPS or VB3, absence
of C. trachomatis in urethral swabs and absence of other
possible pathogens of chronic prostatitis in urethral
swab specimens, VB1, VB2, EPS or VB3.
Patients with hypersensitivity to macrolides or fluoroquinolones, severe renal or hepatic impairment (AST
and/or ALT levels twice above the upper limit) as well as
patients who had received any oral antibiotic 2 weeks
prior to study enrolment and patients with chronic
diarrhoeal diseases or other gastrointestinal conditions
which could affect drug absorption, were excluded.
2.3. Methods
The following data were obtained for each patient:
medical history, clinical status including digitorectal
prostatic examination, urethral swab specimens and
selective samples of urine and EPS, according to the 4glass localization test.
Urethral swab specimens were examined for C.
trachomatis , Trichomonas vaginalis , Ureaplasma urealyticum and Mycoplasma hominis . In segmented samples
of urine and EPS the number of leukocytes were
determined and the number of Gram-positive and
Gram-negative bacteria in 1 ml of sample.
EPS and urine sample collected immediately after
prostatic massage were examined for the presence of C.
trachomatis , U. urealyticum , M. hominis and T.
vaginalis .
Quantitative segmented cultures and bacterial identification in three voided urine samples and EPS as well as
bacteriological analysis of urethral swabs were performed at the Laboratory for Clinical Microbiology of
the University Hospital for Infectious Diseases ‘Dr.
Fran Mihaljevic, Zagreb, Croatia, using standard microbiological methods.
Diagnosis of urogenital mycoplasma was confirmed
by semi quantitative culturing and antimicrobial susceptibility test, Mycoplasma duo 62740, Sanofi, Diagnostic Pasteur. Diagnosis of T. vaginalis was confirmed
by culture on Diamond modified medium. C. trachomatis was demonstrated in urethral swabs/EPS/VB3
using DNA/RNA hybridization method and/or by
isolation, McCoy culture and Lugol stain. The isolation
of C. trachomatis was performed at the Croatian
Institute for Public Health, Zagreb, Croatia.
2.4. Antimicrobial treatment
Patients were randomized according to a computerized randomization list to receive a total dose of 4.5 g of
azithromycin given as a 3-day therapy of 1/500 mg
weekly for 3 weeks or ciprofloxacin 500 mg b.i.d. for 20
days. Patients’ sexual partners were treated at the same
time. Female partners with asymptomatic urogenital
chlamydial infection and those with infection symptoms
lasting longer than three weeks were treated with total
dose of 3.0 g of azithromycin, while those with acute
V. Škerk et al. / International Journal of Antimicrobial Agents 21 (2003) 457 /462
459
Table 1
Age of patients with chronic chlamydial prostatitis
Age
Patients treated with azithromycin
Patients treated with ciprofloxacin
Total
18 /19
20 /29
30 /39
40 /49
50 /59
60 /69
1
7
13
12
11
1
2
7
13
11
10
1
3
14
26
23
21
2
Total
45
44
89
Median9/S.D.
40.899/11.96
infection were given a single dose of 1.0 g of azithromycin.
Clinical efficacy and tolerability of administered drug
as well as possible adverse events were evaluated during,
at the end and 4 /6 weeks after completion of therapy.
Bacteriological efficacy of administered drug was evaluated 4 /6 weeks after completion of therapy, using
methods identical to those used during study enrolment.
2.5. Statistics
Statistical significance of observed differences between treatment groups was assessed by Yates corrected
chi-square test or Fisher‘s exact test when appropriate.
Differences in continuous variables were assessed by
Student’s t -test.
3. Results
A total of 89 patients with chronic prostatitis caused
by C. trachomatis were available for this study. Treatment groups did not differ regarding age (Table 1, t/
0.538717).
Distribution of particular clinical symptoms (Table 2)
was not statistically different between two therapeutic
groups of patients (urethral P /0.9999, prostatic P /
0.6905, sexual P /0.9999, other P /0.9794).
39.489/12.75
Treatment groups did not differ according to digotorectal prostatic examination of the prostate gland (Table
3; P /0.9472).
One patient treated with azithromycin had nausea as
well as serum transaminases elevated on the level below
three times of the upper limit immediately after completion of therapy. After two weeks serum transaminases
were within normal range.
Bacteriological evaluation of azithromycin and ciprofloxacin in the treatment of patients with chronic
prostatitis caused by C. trachomatis is shown in Table 4.
A significantly higher eradication was achieved in the
group of patients treated with azithromycin (P /
0.0002).
Clinical evaluation of azithromycin and ciprofloxacin
efficacy in the treatment of chronic chlamydial prostatitis is shown in Table 5.
A significantly higher clinical cure rate was achieved
in the group of patients treated with azithromycin than
in ciprofloxacin group (P /0.0021).
4. Discussion
C. trachomatis is the most frequent cause of epididymitis in patients up to 35 years of age and according to
recent literature data and results of our study of a total
of 1352 patients, C. trachomatis is a common bacterial
pathogen causing prostatitis [5,6]. Chlamydia tracho-
Table 2
Incidence of clinical symptoms in patients with chronic chlamydial prostatitis
Clinical symptoms
Patients treated with azithromycin
Patients treated with ciprofloxacin
Total
Urethral
Prostatic
Sexual
17
31
9
16
32
8
33
63
17
2
3
5
Other
V. Škerk et al. / International Journal of Antimicrobial Agents 21 (2003) 457 /462
460
Table 3
Digitorectal examination of patients with chronic chlamydial prostatitis
Prostate finding
Patients treated with azithromycin
Patients treated with ciprofloxacin
Total
Normal
Soft and tender
Hard
33
10
2
31
11
2
64
21
4
Total
45
44
89
matis is causally linked to acute and chronic prostatitis
[7 /19]. Acute prostatitis is a disease entity where
symptoms are present for less than 3 months, while
symptoms in chronic prostatitis are present for at least 3
months [1]. Other diagnostic criteria, the microscopy of
EPS and the culture of EPS and segmented urine
samples, are identical in both acute and chronic
prostatitis with the exception of acute bacterial prostatitis when prostatic massage is contraindicated [1,2]. On
the other hand, the European Association of Urology
‘Guidelines on urinary and male genital tract infections
for 2002’, and many review articles about prostatitis
syndrome, state that the role of C. trachomatis in
chronic prostatitis is unclear and controversial [1,20/
22]. We believe that the cause of these disagreements is
the fact that EPS was not adequately analyzed for the
presence of C. trachomatis .
C. trachomatis is an intracellular Gram-negative
bacteria with particular life cycle of development and
growth which is complex and dimorphic [23]. It is the
most common bacterial pathogen of sexually transmitted diseases causing acute and chronic recurrent but
also persistent infections [24]. More than half of the
infected persons have an aysmptomatic form of infection or a very mild clinical course [25] making it very
difficult to determine when C. trachomatis infection
started. For this reason, the classification of symptomatic Chlamydial infection of the prostate into acute
and chronic is made on the basis of the duration of
clinical symptoms present.
Antimicrobial drugs used in the treatment of prostatitis caused by C. trachomatis must fulfill two main
criteria: high susceptibility of C. trachomatis to these
Table 4
Bacteriological evaluation of azithromycin and ciprofloxacin efficacy
in the treatment of chronic chlamydial prostatitis
drugs, and accumulation in prostatic tissue and secretion during chronic inflammation for 2 /4 weeks [26].
C. trachomatis has good in vitro susceptibility to
tetracycline, doxycycline, erythromycin, azithromycin,
clarithromycin, rifampicin, ofloxacin and clindamycin
[13]. In vitro susceptibility testing of urogenital isolates
of C. trachomatis demonstrated isolates simultaneously
resistant to tetracycline, doxycycline, erythromycin,
sulphamethoxazole and clindamycin, but sensitive to
rifampicin, ciprofloxacin and ofloxacin [27].
Azithromycin is a new member of macrolide group of
antimicrobial drugs. It is well absorbed after oral use,
quickly distributed throughout the body achieving high
concentrations in tissues and slowly eliminated from
them [28]. The extensive tissue uptake of azithromycin
has been attributed to cell uptake into lysosomes. MIC90
for C. trachomatis is 0.12 /0.25 mg/l [28]. In clinical
study as well as in clinical practice azithromycin has
shown efficacy in the treatment of chlamydial prostatitis
and other urogenital, sexually transmitted infections
[29,30].
Ciprofloxacin is a highly active fluoroquinolone.
Following oral dose it is rapidly absorbed and distributed throughout the body achieving concentrations in
prostate tissues up to 2.3-fold higher than those in serum
[31,32]. The MIC90 for C. trachomatis is 1 /1.3 mg/l [31].
Ciprofloxacin is retained in cells for a short period of
time, localized in the cytoplasma outside lysosomes and
phagosomes [31]. Ciprofloxacin administered in dose
2 /500 mg for 7 days achieved cure in 21.4 /61.5% of
patients with chlamydial urethritis [33 /35]. Cure was
recorded in 15 of 16 patients with pelvic inflammatory
disease caused by C. trachomatis and receiving ciprofloxacin 2 /750 mg for 2 weeks [36]. Ciprofloxacin is
Table 5
Clinical efficacy of azithromycin and ciprofloxacin in the treatment of
chronic chlamydial prostatitis
Efficacy
Efficacy
Patients treated with azithromycin (n/45)
Eradication 36 (80%)
Persistence
9 (20%)
Patients treated with ciprofloxacin (n/44)
17 (38.64)
27 (61.36)
Patients treated with azithromycin (n /45)
Cure
31 (68.9%)
Improvement 4 (8.9%)
Failure
10 (22.2%)
Patients treated with ciprofloxacin (n/44)
15 (34.1%)
7 (15.9%)
22 (50%)
V. Škerk et al. / International Journal of Antimicrobial Agents 21 (2003) 457 /462
the drug of choice for patients with inflammatory
chronic pelvic pain syndrome (chronic abacterial prostatitis), meaning in patients in whom prostatitis pathogens cannot be detected in EPS by using standard
microbiological methods [1,26]. It is possible that in
some of these patients C. trachomtis is the pathogen
causing prostatitis and that these are cases of chronic
bacterial prostatitis caused by C. trachomatis .
Our study has shown a correlation between results of
in vitro study of the efficacy of ciprofloxacin against C.
trachomatis and its efficacy in patients with chronic
chlamydial prostatitis. Significantly higher eradication
(36/45:17/44) and significantly higher clinical cure (31/
45:15/44) were achieved in the group of patients treated
with azithromycin compared with the the ciprofloxacin
group.
In patients with prostatitis caused by C. trachomatis ,
the drug of choice is azithromycin. In patients with
chlamydial prostatits and in patients with inflammatory
chronic pelvic pain syndrome, in case C. trachomatis is
suspected, ciprofloxacin is not recommended.
Acknowledgements
This research is part of two scientific research projects
of the Ministry of Science and Technology of the
Republic of Croatia: ‘Urogenital infections caused by
Chlamydia trachomatis ’ (no. 143004) and ‘Etiology and
treatment of chronic prostatitis’ (no. 0108149). Cofinanced by PLIVA Pharmaceutical Company, Zagreb,
Croatia.
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