Clinical Research: Clinical Evaluation of Ofloxacin on the Treatment of Male Non-Gonococcal Urethritis

Clinical Evaluation of Ofloxacin on the Treatment of

Male Non-Gonococcal Urethritis
C.F. Lai, T.K. Ng, P.K. Ip and S.T. Tam

ABSTRACT
Thirty-one male patients with uncomplicated Non-gonococcal urethritis (N.G.U.) were included into this study non-
selectively. Ofloxacin were given in the dose regimen of 200 mg b.i.d. orally for 10 consecutive days, i.e. 4 gm in total to each
patient. Clinical observations and laboratory monitorings were carried out at Day 0, Day 10 and Day 15 or after. The presence
of Chlamydia trachomatis (C.T.) was confirmed by both Chlamydiazyme and Microtrek serological techniques, and found to
be constituting 45% of the N.G. U. cases in this study. Most patients had either excellent or good response to this treatment
regime, especially for confirmed C.T. urethritis cases. Adverse reactions were rare, mild and self-limiting.
Keywords: Non-gonococcal Urethritis (N. G. U.) — Chlamydia Trachomatis (C. T.) — Ofloxacin — Chlamydiazyme — Microtrek
INTRODUCTION e) patients who refuse to be put into this trial.
Non-gonococcal urethritis (N.G.U.) is defined as urethritis Dose regimen:
not caused by Neisseria gonorrhoea, following venereal Ofloxacin is administered orally 200 mg twice daily after
exposure. The incidence of male N.G.U. has increased more breakfast and supper for 10 consecutive days, i.e. 4 gm in total
than double from 1,203 cases in 1984 to 2,680 cases in 1987 for each patient.
in the Government Social Hygiene Service. N.G.U., including Other concomitant drugs:
Chlamydia trachomatis (C.T.) urethritis, is notorious for its Preferably prohibited during treatment period. Necessary
resistance to treatment. Various drugs (such as tetracycline drugs would be recorded into the case record.
group and its derivatives, erythromycin, amoxicillin, co- Side effects:
trimoxazoles and rifampicin) and dosage regimens had been Patients were urged to report immediately to the phy-
tried in other countries. (1 — 5). Ofloxacin, a new broad- sician in-charge for any suspected side effects. The physician
spectrum quinolone known to be effective in its single-dose would record and decide on whether treatment was needed
treatment for P.P.N.G. gonorrhoea, was put on trial in this and whether Ofloxacin should be discontinued.
pilot study to evaluate its efficacy and safety in the treatment Clinical observations and laboratory monitoring:
of male N.G.U., especially for C.T. urethritis. At Day O, Day 10 and Day 15 or after patients were graded
for their clinical signs and symptoms and laboratory test
SUBJECTS AND METHODS results. They were instructed to come back for follow-up with
Patients were included non-selectively if: full bladders.
a) male patients over the age of 16; a).Symptoms: Grading
b) clinically diagnosed as uncomplicated N.G.U. on their i) micturition pain —absent
initial visits. The patient must satisfy at least 2 of the 3 ii) itching sensation in the urethra + present
criteria below: b) Signs:
i) presence of either micturition pain or itching sensation i) amount of urethral discharge
in the urethra; or — absent
ii) presence of urethral discharge on penile stripping; and + exudate in a small amount during penile strip-
iii) presence of polymorpho-nuclear leucocytes (P.M.N.L.) ping
on urethral smear, and absence of gram -ve gono- + + profusely excreted during penile stripping
coccal diplococci. + + + spontaneously excreted from the urethra
c) verbal consent obtained from the patient. ii) character of the discharge: serous or purulent.
Exclusion criteria: c) Microscopic examination of Gram-stained urethral smears
a) below the age of 16; for P.M.N.L. (polymorpho-nuclear leucocytes) under 1000
b) patients with severe cardiac, hepatic and renal dysfunction; x magnification (hpf)
c) patients who received previous treatment with other 0 0/hpf
antibiotics within the past 2 weeks; 1 1-4/hpf
d) patients with a past history of severe allergic reaction to the 2 5-9/hpf
quinolone family; 3 10-29/hpf
4 >/30/hpf
Social Hygiene Service, Sai Ying Pun Jockey Club Clinic, 2/f., Queen's Road W., d) Microbiological assay for Chlamydia trachomatis:
Hong Kong. Urethral mucosal scrapings were taken to test for the
C.F. Lai, M.R.C.P., Dip. Derm., Consultant Dermatologist
P.K. Ip, M.B.,B.S., Dip. Ven., Medical and Health Officer presence of C.T. antigen. During each visit, the first
S.T. Tarn, M.B.,B.S., Dip. Ven., Medical and Health Officer mucosal scrapings of each patient were tested by Enzyme-
Sai Ying Pun Pathology Institute, Medical and Health Department, Hong Kong
T.K. Ng, M.B.,B.S., M.R.C.Path., Senior Microbiologist
linked Immuno-sorbent assay (ELIZA) method, i.e.
Correspondence to: Dr. C.F. Lai Chlamydiazyme. The second scrapings that followed were
63
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tested by Immunofluorescence (IMF) technique, i.e. excellent = complete disappearance of clinical signs and
Microtrek for counter-checking, symptoms, plus bacteriological cure for C.T.U.
e) Blood tests for complete blood count, liver and renal patients
function tests on Day O, Day 10 to detect any abnormal good = improved but residual signs and symptoms still
change during treatment period. persist, plus bacteriological cure for C.T.U.
patients
RESULTS poor = persistence or worsening of symptoms and signs.
A total of 31 cases was tested. The diagnoses were Few side effects were encountered (Table 6). The skin
summarized in Table 1. One C.T.U. patient defaulted follow- rash presented as itchy generalized maculo-papular lesions at
up after initial visit and was not included in the overall Day 3 but subsided completely on Day 7 after taking piriton
assessment. One non-C.T.U. patient defaulted the last 4 mg three times daily. Nausea in one patient started at Day
follow-up. 2 and subsided spontaneously at Day 4. Both patients were
closely observed while Ofloxacin treatment continued.
Confirmed C.T. Urethritis 13 cases (41.9%)
+ gonococcal (on culture) 1 cases ( 3.2%) DISCUSSION
Non-C.T. Urethritis 17 cases (54.9%) Before the last decade, little was known about non-
gonococcal urethritis (N.G.U.) apart from it being the most
Table 1 Diagnoses and patient pool
frequently detected sexually transmitted diseases in Western
countries and its notorious resistance to treatment. Increasing
C.T.U. Non-C.T.U.
evidence in recent years have shown that Chlamydia
trachomatis (C.T.) infection constitute 40 - 70% of N.G.U.
Prostitute 23 cases (74.2%) 9 14 cases in both male and female patients (8). Other responsible
Acquaintance 4 cases (12.9%) 3 1
organisms include Ureaplasma urealyticum and Mycoplasma
Wife 3 cases ( 9.7%) 2 1
Others 1 cases ( 3.2%) 0 1
hominis but unidentified organisms still accounts for 20 —
40% of all N.G.U. patients.
Chlamydia trachomatis are obligatory intracellular bacteria
Table 2 Source of infection and are sexually transmissable. They replicate within the
The source of infection mainly came from the prostitutes cytoplasm of host cells, forming characteristic intracellular
and acquaintances (Table 2). Only 9.7% of patients claimed to inclusions. In men they commonly present as N.G.U. or post-
contact the urethritis from their wives. gonococcal urethritis (P.G.U.). Clinically, the urethral
The clinical findings, neutrophil counts in the urethral symptoms and discharge caused by most C.T. urethritis are
smear and the presence of C.T. antigen on Day 0, Day 10 and milder than acute gonococcal urethritis. Serous discharge,
Day 15 or after in C.T.U. and non-C.T.U. subjects were itchiness and mild pain on urination are the commonest
compared and summarized in Table 3 and Table 4 clinical presentations. Concomitant gonococcal and C.T.
respectively. urethritis will naturally mask the C.T. component. It was
Clinical effects (Table 5) were judged by the physician in- estimated 20 — 40% of patients presenting with gonococcal
charge as either excellent, good or poor with the following urethritis have concomitant C.T. urethritis (9). These patients
criteria: will present as Post-gonococcal urethritis (P.G.U.) on their

Before administration After administration

of Ofloxacin of Ofloxacin
D15 or
Day 0 D 10 after

Micturition pain: absent 2 10 12

present 12 3 1
Itching sensation: absent 3 10 11
of urethra present 11 3 2
Amount of discharge — 0 11 13
+ 13 2 0
++ 1 0 0
+ ++ 0 0 0
Character of discharge (if present)
serous 14 2 0
purulent 0 0 0
P.M.N.L. in urethral smear
0 0 0 2
1 4 11 11
2 5 2 0
3 5 0 0
4 0 0 0
C.T. antigen presence
positive Chlamydiazyme 14 0 0
positive Microtrek 14 0 0

Table 3 Patients with C.T. urethritis

64
 Clinical Research: Clinical Evaluation of Ofloxacin on the Treatment of Male Non-Gonococcal Urethritis

Before administration After administration

of Ofloxacin of Ofloxacin
D 15 or
Day 0 D10 after
Micturition pain: absent 3 12 14
present 14 5 2
Itching sensation: absent 5 9 13
of urethra present 12 8 3
Amount of discharge — 0 11 12
+ 15 5 3
++ 2 1 1
+++ 0 0 0
Character of discharge (if present)
serous 16 5 3
purulent 1 1 1
P.M.N.L. in urethral smear
0 0 0 0
1 3 9 12
2 8 3 4
3 6 5 0
4 0 0 0
C.T. antigen presence
positive Chlamydiazyme neg neg neg
positive Microtrek neg neg neg

Table 4 Patients with non-C.T. urethritis

Excellent Good Poor discrepancies as reported in other literatures. These

C.T.U. 12 1 0
Non C.T.U. 10 6 1
Table 5 Clinical effect judged by the physician in-charge
follow-up visits after eradication of the Neisseria gonorrhoea
by antibiotic treatment. Complications of C.T. infection in
male include proctitis, subacute or chronic prostatitis,
epididymits, conjunctivitis and Reiter syndrome. In female
patients C.T. infection usually present as non-specific
cervicitis and acute urethritis or urethral syndrome. Their
complications include bartholinitis, endometritis, acute and
chronic salpingitis leading to infertility and menorrhagia,
conjunctivitis and perihepatitis. Symptoms are either mild or
absent in most female sufferers. Newborns passing through
the birth canal of infected mother can suffer from ophthalmia
neonatorum due to C.T. organisms.
Diagnosis of C.T. infection depends on successful
culturing of the organism in the McCoy cells previously. Since
it is an obligatory intracellular bacteria, collecting mucosal
cellular scrapings for culture has a much higher yield than the
discharge specimen. Serological demonstrations of C.T.
antigens in the specimen collected at the infected sites by the
Enzyme-linked immunosorbent assay (Chlamydiazyme) and
direct immunofluorescence techniques (Microtrek) (6, 7) have
proved to be comparable to the culture results. In this trial,
Chlamydiazyme and Microtrek results did not reveal
serological methods are now commercially available and
require much less tedious working procedures. Detection of
antibodies in the blood and the local antibodies produced at
the infected areas are other promising aspects to aid in its
diagnosis. However, in contrast to the easy on-spot diagnosis
of gonorrhoea by Gram-stained urethral smear showing the
gram -ve diplococci, few centres in the world have the
facilities in their clinics to make an on-spot diagnosis of C.T.
infection.
In vitro studies have shown that C.T. is susceptible to
various antibiotics including Ofloxacin (10), the minimal
inhibitory concentration (M.I.C.) is 0.19 ug/ml and the
minimal lethal concentration (M.L.C.) is 0.78 ug/ml. Other
well susceptible antibiotics include tetracycline, doxycycline,
minocycline and rifampicin. Efficacy of these groups had been
confirmed clinically by trials conducted in other countries
(1 - 5).
In this study, the clinical efficacy of Ofloxacin was
evaluated using a dose regimen of 200 mg bid orally for 10
consecutive days. It was found that C.T. urethritis accounts
for nearly 50% of N.G.U. cases in Hong Kong and all these
patients had successful bacteriological cure with mark
improvement clinically. For N.G.U. with unidentifiable
organisms in this study (including Ureaplasma urealyticum,
Mycoplasma hominis because facilities for detection are not
yet available here), the results were not as good as C.T.
urethritis with 35% of patients still complaining of residual

Number of patient Start End Treatment

Nausea Day2 Day 4 Nil
Skin rash Day3 Day 7 Piriton

Table 6 Side effects reported

65

symptoms although subjective improvement had been
achieved. Side effects were rare and self-limiting. One patient
had nausea and another had a transient maculopapular rash.
Both recovered completely in 2 — 4 days without having to
stop the trial drug. No abnormalities of the blood tests
including complete blood counts, liver and renal function tests
were recorded.
The results are encouraging and comparable to other
clinical trials using doxycycline and minocycline in other
countries (1 — 5), Moreover, Ofloxacin has already been
proven to be effective in its single-dose treatment for
uncomplicated gonorrhoea. The current practice in
government social hygiene clinics is to give 400 mg stat dose
orally for males and 600 mg stat dose orally for female
patients, with an efficacy rate of 98%. Considering gonococcal
and C.T. urethritis may co-exist in 20 — 40% of all gonococcal
patients (9), a drug regimen that is effective against both
organisms may one day become the first line treatment for all
urethritis patients, especially in clinics where facilities for
66
Association Vol. 41, N
REFERENCES
1 Prentice MJ, et al. .Non-specific uretbritis a placebo-controlled trial of minocycline
in conjunction with laboratory investrigations. Br J Vener Dis, 1976; 52:269.
2 Taylor-Robinson D, Evans RT, Coufauk ED, Oates JK. Effect of short term Px of
N.G.U. with minocycline. Genito Med, 1986; 62:l9-23.
3. Oriel JO, et al. Comparison of erythromycin stearate and oxytetracycline in the
treatment of non-gonococcal urethritis, Scott Med J, 1977; 22:375.
4. Paavonen J, et al. Treatment with N.G.U. with trimethoprim-sulphadiazine and
with placebo: a double-blind partner-controlled study. Br 1 Vener Dis, 1980
56:101.
5. Bowie WR, et al. Eradication of chlamydia trachomatis from the urethra of men
with N.G.U. by treatment with amoxicillin. Sex Transm Dis, 1981; 879
6. Jones MF, South TF, Houglum AJ, Hermann JE. Detection of C.T. in genital
specimens by the chlamydiazyme test, J Clin Micro. 1.984; 20:465-466.
7. Teare EL, Sexton C, Lim F, McMnus T, Cuttley AH, Hodgson J. Conventional
tissue culture compared with rapid immunofluorescence for identifying C.T, in
specimens from patients attending a genitourinary clinic. Genito Med, 1985
61:379-382.
8. Terho P. Chlamydia trachomatis in N.G.U. Br J Vener Dis. 1978; 54:251.
9. Bowie WR, et al. Etiologies of postgonococcal urethritis in homosexual and
heterosexual men: roles of chlamydia trachomatis and ureaplasma urealyticum.
Sex Transm Dis, 1978; 5:151.
10. Katsuya Hirai, et al. Antichlamydial activity of ofloxacin. Microhol Immunol,
1986; 30(5):445-450.