Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, March 1998, p. 579-582, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Reduced Clinical Efficacy of Pazufloxacin against
Gonorrhea Due to High Prevalence of Quinolone-Resistant Isolates
with the GyrA Mutation
Masatoshi
Tanaka,1,*
Tetsuro
Matsumoto,1
Misao
Sakumoto,1
Koichi
Takahashi,1
Takeshi
Saika,2
Intetsu
Kabayashi,2
Joichi
Kumazawa,1 and
The
Pazufloxacin Std
Group
Department of Urology, Faculty of Medicine,
Kyushu University, Fukuoka,1 and
Chemotherapy Division, Mitsubishi-kagaku BCL,
Tokyo,2 Japan
Received 14 July 1997/Returned for modification 12 September
1997/Accepted 19 December 1997
 |
ABSTRACT |
Forty-two men with gonococcal urethritis were treated with an oral
dosage of 200 mg of pazufloxacin, a new fluoroquinolone, three times
daily for 3 days. Only 28 of the 42 men (66.7%) had negative culture
results for Neisseria gonorrhoeae during follow-up. Of the
42 isolates, 41 could be recultured for antibiotic susceptibility testing and DNA sequencing. In 26 of the 41 isolates (63.4%), GyrA
mutations with or without ParC mutations were identified. Among the 26 isolates, 23 contained a single GyrA mutation, 1 contained two GyrA
mutations, and 2 contained three mutations including double GyrA and
single ParC mutations. A single Ser-91-to-Phe mutation, which was
detected in 14 of the 26 isolates, was the most common GyrA mutation,
followed by an Ala-75 to Ser mutation and an Asp-95 to Asn or Gly
mutation in GyrA. All three isolates with two or three mutations
contained the Ser-91-to-Phe GyrA mutation. Eleven of the 14 isolates
with the single Ser-91-to-Phe mutation within GyrA and all 3 isolates
with two or three mutations persisted after pazufloxacin treatment. On
the other hand, all 15 wild-type and 9 mutant isolates with a
substitution at codon Ala-75 or Asp-95 were eradicated. The mean MIC of
pazufloxacin for mutants with the single Ser-91-to-Phe mutation in GyrA
was 66-fold higher than that for the wild type. The results obtained in
this study suggest that a high prevalence of fluoroquinolone-resistant
gonococcal isolates with the Ser-91-to-Phe mutation in GyrA reduced the
efficacy of pazufloxacin as treatment for gonococcal urethritis.
| |
INTRODUCTION |
The increasing frequency of
occurrence of Neisseria gonorrhoeae isolates with plasmid-
and chromosome-mediated resistance to penicillin or tetracycline is a
serious problem worldwide. Fluoroquinolones such as norfloxacin,
ofloxacin, and ciprofloxacin demonstrate excellent in vitro
activities against N. gonorrhoeae, including penicillin- and
tetracycline-resistant strains, and are highly effective for the
oral treatment of gonococcal infections caused not only by strains
sensitive to penicillin or tetracycline but also by strains
resistant to these antibiotics (4, 6, 20). Therefore, over
the past decade, fluoroquinolone regimens have increasingly been used
in various countries for the treatment of gonococcal infections.
Although the emergence of isolates of N. gonorrhoeae showing
reduced susceptibility to fluoroquinolones has recently been reported
in several countries including Japan (3, 5, 7, 9-12, 22,
23), high failure rates for fluoroquinolone treatment of
gonococcal urethritis have not yet been reported.
Pazufloxacin (T-3761) is a new orally administered fluoroquinolone
which has excellent in vitro activity against 
-lactamase-producing and -nonproducing clinical isolates of N. gonorrhoeae, with
an MIC at which 50% of isolates are inhibited (MIC50) of
<0.006 µg/ml and an MIC90 of 0.1 µg/ml
(16). A single oral dose of 200 mg of pazufloxacin results
in a mean peak level in plasma of 2.0 µg/ml in 1.2 h, with the
half-life averaging 1.9 h (17). These data
suggest that pazufloxacin might be effective for the treatment of
gonococcal urethritis in men. An open clinical trial was undertaken to
assess the efficacy and safety of pazufloxacin in men with acute
urethritis caused by N. gonorrhoeae. However, a
high failure rate was obtained for the treatment of gonococcal
urethritis with pazufloxacin. Thus, we examined the prevalence of
clinically fluoroquinolone-resistant N. gonorrhoeae isolates
with mutations in the GyrA protein with or without mutations
in the ParC protein, both of which confer quinolone resistance (2,
24), and investigated the relationship between the clinical
efficacy of pazufloxacin and mutations within the GyrA and ParC
proteins of these bacteria.
| |
MATERIALS AND METHODS |
Study population and design.
Forty-seven men who presented
with urethral discharge and whose urethral discharge showed
gram-negative intracellular diplococci upon Gram staining and five or
more polymorphonuclear leukocytes per high-power field were enrolled in
this study. The men ranged in age from 19 to 47 years (mean age, 30.3 years). The diagnosis of gonococcal urethritis was confirmed by
recovery of N. gonorrhoeae by culture. All participants
provided oral or written informed consent before they were enrolled in
the study.
Patients were treated with an oral dosage of 200 mg pazufloxacin three
times daily for 3 days and were asked to return for reexamination on
days 4 and 7 after the initiation of treatment. At each visit, patients
were examined, urethral smears were collected for microscopy and the
detection of N. gonorrhoeae, and first-void urine specimens
were also obtained for the detection of the Chlamydia trachomatis antigen.
Microbiological examination.
Two urethral specimens for the
detection of N. gonorrhoeae and a first-void urine
sample for the detection of the C. trachomatis antigen were
collected from each patient. The detection of N. gonorrhoeae
was performed by recovery by culture and a DNA probe test (Gen Probe).
A commercial kit (IDEIA; Dako, Cambrigeshire, United Kingdom) was used
for the C. trachomatis antigen assay. Specimens for
culture of N. gonorrhoeae were immediately inoculated onto
Thayer-Martin agar (Beckton Dickinson). The culture plates were
incubated at 35°C for 24 to 48 h in a 5% CO2
atmosphere. N. gonorrhoeae was identified by
colony morphology, oxidase reaction, and appearance upon Gram
staining and was confirmed by sugar utilization reactions.
-Lactamase production was assayed by the chromogenic cephalosporin
technique (15, 18).
N. gonorrhoeae isolates were stored at 
70°C until
antibiotic susceptibility testing. The MICs for all isolates were
determined by an agar dilution technique with a GC agar base containing
1% IsoVitaleX (Beckton Dickinson) and twofold dilutions of the
antibiotic (8). The plates were inoculated with 5 µl of
106 CFU of each isolate per ml with a multipoint
inoculator. The plates were incubated at 35°C for 24 h in a 5%
CO2 atmosphere. The MICs were defined as the lowest
antibiotic concentration that inhibited bacterial growth. Three
fluoroquinolones were tested: pazufloxacin (Toyama Chemical Company,
Tokyo, Japan), norfloxacin (Kyorin, Tokyo, Japan), and ciprofloxacin
(Bayer, Osaka, Japan).
Molecular biology-based study.
PCR and direct DNA sequencing
were performed to identify mutations in the gyrA and
parC genes of the gonococcal strains isolated before and
after treatment. Chromosomal DNA was extracted by standard methods
(1) and was subjected to PCR. The oligonucleotide primers for the PCR amplification were as follows: for the gyrA gene
the forward primer was 5'-CGGCGCGTACTGTACGCGTTGAC-3' and the
reverse primer was 5'-AATGTCTGCCAGCATTTCATGTGAGA-3', and for
the parC gene the forward primer was
5'-ATGCGCGATATGGGTTTGAC and the reverse primer was
5'-GGACAACAGCAATTCCGCAA. These primers were produced with
a DNA synthesizer and were based on the sequences previously reported by Belland et al. (2). The gyrA gene
sequence was determined from nucleotides 160 to 439, which correspond
to amino acids 54 to 147 of the GyrA protein. This includes the
quinolone resistance-determining region (amino acids 55 to 110 of the
gonococcal GyrA protein) (2). The parC gene
sequence was also determined from nucleotides 166 to 420, which
correspond to amino acids 56 to 140 of the gonococcal ParC
protein. This includes the quinolone resistance-determining region of
the ParC protein (amino acids 66 to 119 of the gonococcal ParC protein)
(2).
PCR amplification was performed with 25 µl of a reaction mixture
which contained 2.5 µl of 10×
Taq polymerase
buffer (500
mM KCl, 100 mM Tris-HCl [pH 8.3], 15 mM
MgCl
2, 0.1% gelatin),
0.25 µl of each of the two primers
(25 pmol/µl), 0.5 µl of each
of the four deoxynucleotide
triphosphates (10 mM), 0.2 µl of
Taq DNA polymerase
(5 U/µl; Takara, Shiga, Japan), 2.5 µl of Triton
X-100 (2 mg/ml), and 1.0 µl of template DNA (100 ng/µl). Thirty-five
cycles were performed for each reaction. Each cycle consisted
of
30 s at 93°C, 1 min at 52°C, and 1 min at 72°C.
The PCR amplification products were directly sequenced by the
dideoxy-chain termination method (
13) with the Taq DyeDeoxy
Terminator Cycle Sequencing Kit and a model 373A autosequencer
(ABI).
| |
RESULTS |
Clinical results.
Of the 47 men enrolled in the study and
treated with pazufloxacin, 5 could not be evaluated due to protocol
violation. Among the 42 patients evaluated, only 1 had been treated
with another fluoroquinolone before this study. The remaining 41 patients were not treated with any antimicrobial agent before
pazufloxacin treatment. Seven were infected with
penicillinase-producing N. gonorrhoeae strains. N. gonorrhoeae was not detected again in only 28 of the 42 patients
(66.7%) during follow-up. Thus, the response rate to pazufloxacin
treatment of gonococcal urethritis was very low. Table
1 presents the relationship between the
MICs of pazufloxacin for N. gonorrhoeae isolates and the
bacteriological responses. Forty-one isolates could be recultured for
antibiotic susceptibility testing. All 23 isolates for which the MICs
of pazufloxacin were 0.1 µg/ml or less were eradicated by treatment.
Of the 11 isolates for which the MICs of pazufloxacin ranged from 0.2 to 0.78 µg/ml, only 4 were eradicated. All seven isolates for which
the pazufloxacin MICs exceeded 1.56 µg/ml were persistent. The MIC of
pazufloxacin for an isolate from the patient treated with another
fluoroquinolone before this study was 1.56 µg/ml. These results
indicate that the gonococcal isolates for which the MICs of
pazufloxacin were higher than 0.2 µg/ml are possibly clinically
resistant to pazufloxacin treatment. C. trachomatis was also
present in 8 of the 42 patients (19.0%). The C. trachomatis
antigen was not detected again in five of these eight patients during
follow-up. One patient from whom C. trachomatis was
eradicated had been given 200 mg of pazufloxacin three times daily for
7 days.
The treatment was well tolerated. No side effects related to the
treatment were observed in these patients.
Prevalences of the gyrA and parC gene
mutations.
Table 2 lists the
mutations within the gyrA and parC genes of 41 gonococcal strains isolated before treatment. In 26 of the 41 isolates
(63.4%), GyrA mutations with or without ParC mutations were
identified. Among these 26 isolates, 23 (56.1%) contained a single
GyrA mutation, 1 (2.4%) contained two GyrA mutations, and 2 (4.9%)
contained three mutations including double GyrA and single ParC
mutations. A Ser-91-to-Phe mutation was the most common GyrA mutation,
followed by an Ala-75-to-Ser mutation and an Asp-95-to-Asn or -Gly
mutation in GyrA. The detected mutations within ParC were a
Ser-88-to-Pro mutation and a Glu-91-to-Gly mutation. One type of silent
mutation was frequently detected: the DNA sequence was substituted at
codon 131, but the ParC protein sequence was unchanged.
Of the 41 strains, 18 were isolated in Tokyo and the remaining 23 were
isolated in Fukuoka city, located in the northern part
of Kyushu
Island, which is far from Tokyo. There was no significant
difference in
the incidence of isolates with GyrA mutations between
Fukuoka (69.6%)
and Tokyo (61.1%). It seems that fluoroquinolone-resistant
gonococci
carrying GyrA mutations are widespread in Japan. We
did not know
whether the isolates carrying the Ser-91-to-Phe GyrA
mutation or the
double mutations were clonal.
We also analyzed the DNA sequences of isolates not eradicated by
pazufloxacin treatment. All 14 strains which were isolated
after
treatment with pazufloxacin had GyrA mutations with or without
ParC
mutations. However, there were no differences in the GyrA
and ParC
mutation patterns or in susceptibility to pazufloxacin
between
pretherapy and posttherapy isolates from the same patient.
Bacteriological responses of mutants to pazufloxacin.
The
relationships between mutations in GyrA and ParC and the
bacteriological responses to pazufloxacin are presented in Table 3. All 15 wild-type isolates, 5 containing the Ala-75-to-Ser mutation in GyrA and 4 containing the
Asp-95-to-Asn or -Gly mutation in GyrA, were eradicated by pazufloxacin
treatment. On the other hand, of the 14 isolates containing the single
Ser-91-to-Phe mutation, only 3 (21.4%) were eradicated. Moreover,
all three isolates with the double mutations in GyrA or the triple
mutations involving both GyrA and ParC were persistent. These three
mutants contained the Ser-91-to-Phe mutation in GyrA. These results
indicate that although the mutants with the Ala-75-to-Ser,
Asp-95-to-Asn, or Asp-95-to-Gly substitution in GyrA were still
clinically susceptible to pazufloxacin treatment, the mutants
containing the Ser-91-to-Phe substitution in GyrA with or without
another substitution were clinically resistant to this treatment.
Susceptibilities of the mutants to fluoroquinolones.
Table
4 describes relationships between
mutations in GyrA and ParC and the pazufloxacin MICs for N. gonorrhoeae. The mean MICs of pazufloxacin for the mutants with
the Ala-75-to-Ser, Ser-91-to-Phe, Asp-95-to-Asn, and Asp-95-to-Gly
substitutions in GyrA were 0.08, 0.86, 0.2, and 0.075 µg/ml,
respectively, while that for the wild-type isolate was 0.013 µg/ml.
This result indicates that gonococcal isolates which acquired the
single Ser-91-to-Phe mutation are more resistant to pazufloxacin than
the other mutants with a single GyrA substitution. The mutants with
double GyrA substitutions or triple substitutions involving GyrA and
ParC were extremely resistant to pazufloxacin compared to the level of
resistance of the wild type. These mutants were cross-resistant to
other fluoroquinolones: norfloxacin and ciprofloxacin.
| |
DISCUSSION |
Until recently, fluoroquinolones have been shown to have excellent
antimicrobial activities against N. gonorrhoeae isolates. Thus, fluoroquinolone regimens have increasingly been used in Japan.
The emergence of gonococcal isolates showing reduced susceptibility to
fluoroquinolones in vitro has recently been reported in Japan (22,
23). However, the widespread existence of gonococcal isolates
clinically resistant to treatment with fluoroquinolones has not yet
been recognized.
In this study, we evaluated the clinical efficacy of pazufloxacin, a
new fluoroquinolone, for the treatment of gonococcal urethritis. This
treatment eradicated N. gonorrhoeae isolates from only
66.7% of patients with gonococcal urethritis. This response rate would
appear to be very low, because until recently the effectiveness rates
of various fluoroquinolones for the treatment of uncomplicated gonorrhea were approximately 100% (4, 6, 14, 19-21). To determine the cause of this high rate of failure of pazufloxacin treatment, we investigated the frequency of occurrence of isolates with
mutations in GyrA and ParC proteins which confer fluoroquinolone resistance on these bacteria. Surprisingly, in 26 (63.4%) of the 41 isolates tested, GyrA mutations with or without ParC mutations were
identified. The identified mutations in GyrA were Ala-75-to-Ser, Ser-91-to-Phe, Asp-95-to-Asn, and Asp-95-to-Gly substitutions. Of these
mutations, the Ser-91-to-Phe mutation was the most common GyrA
mutation, and it was detected in 17 (65.4%) of the 26 isolates with
GyrA substitutions. Among these 17 isolates, 14 contained the single
Ser-91-to-Phe GyrA mutation, 1 contained two GyrA mutations, and 2 contained three mutations including double GyrA and single ParC
mutations. The eradication rate for the isolates with the Ser-91-to-Phe
mutation was only 17.6% (3 of 17 isolates), while that for wild-type
isolates or isolates containing the other GyrA mutations was 100% (24 of 24 isolates). These results indicate that the Ser-91-to-Phe mutation
in GyrA is a critical mutation which confers on N. gonorrhoeae clinical resistance to fluoroquinolones. Antibiotic
susceptibility tests of these mutants corroborated the clinical
significance of the Ser-91-to-Phe mutation in GyrA. The mean MICs of
pazufloxacin for the mutants with the Ser-91-to-Phe substitution were
increased 66-fold compared to that for the wild type. However, the
level of reduction of the susceptibility of the mutants with
substitutions at codon Ala-75 or Asp-95 was 6- or 15-fold less,
respectively, than that of the wild type.
The ParC mutation was identified in only 2 of the 41 isolates. The
double GyrA mutations coexisted in the two isolates with the ParC
mutation. No isolates contained the ParC mutation without the
simultaneous presence of at least one GyrA mutation. The mutants with
both GyrA and ParC mutations were extremely resistant to fluoroquinolones. The ParC mutation may be essential for the bacteria to acquire high-grade fluoroquinolone resistance.
In this study we were not able to compare pazufloxacin therapy with
ciprofloxacin therapy, because this study was undertaken as an open
clinical trial. Treatment failure with ciprofloxacin has been reported
for isolates for which MICs are 
0.05 or 0.06 µg/ml (7,
9). Therefore, the isolates containing a single Ser-91-to-Phe
GyrA mutation, double GyrA mutations, or triple mutations within GyrA
and ParC may be refractory to ciprofloxacin treatment, because the
ciprofloxacin MICs for these mutants ranged from 0.1 to 3.13 µg/ml.
To our knowledge, this is the first study to examine the relationship
between the clinical efficacies of fluoroquinolones against gonorrhea
and mutations involving the GyrA and ParC proteins of these bacteria.
The high prevalence of fluoroquinolone-resistant N. gonorrhoeae isolates with the GyrA mutation limits the clinical efficacy of pazufloxacin against gonococcal infections in
Japan.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Urology, Faculty of Medicine, Kyushu University, 3-1-1, Maidashi,
Higashi-ku, Fukuoka 812, Japan. Phone: 81-92-642-5603. Fax:
81-92-642-5618. E-mail: masatosh{at}uro.med.kyushu-u.ac.jp.
| |
REFERENCES |
| 1.
|
Ausubel, F. M.,
R. Brent,
R. E. Kingston,
D. D. Moore,
J. G. Seidman,
J. A. Smith, and K. Struhl.
1989.
Current protocols in molecular biology.
Greene Publishing and Wiley-Interscience, New York, N.Y.
|
| 2.
|
Belland, R. J.,
S. G. Morrison,
C. Ison, and W. M. Huang.
1994.
Neisseria gonorrhoeae acquires mutations in analogous regions of gyrA and parC in fluoroquinolone resistant isolates.
Mol. Microbiol.
14:371-380[Medline].
|
| 3.
|
Bogaerts, J.,
W. M. Tello,
J. Akingeneye,
V. Mukantabana,
E. Van Dyck, and P. Piot.
1993.
Effectiveness of norfloxacin and ofloxacin for treatment of gonorrhoea and decrease of in vitro susceptibility to quinolones over time in Rwanda.
Genitourin. Med.
69:196-200[Medline].
|
| 4.
|
Bryan, J. P.,
S. K. Hira,
W. Brady,
N. Luo,
C. Mwale,
G. Mpoko,
R. Krieg,
E. Siwiwaliondo,
C. Reichart,
C. Waters, and P. Perine.
1990.
Oral ciprofloxacin versus ceftriaxone for the treatment of urethritis from resistant Neisseria gonorrhoeae in Zambia.
Antimicrob. Agents Chemother.
34:819-822[Abstract/Free Full Text].
|
| 5.
|
Clendennen, T. E., III,
C. S. Hames,
E. S. Kees,
F. C. Price,
A. B. Andrada,
G. E. Espinosa,
G. Kabrerra, and F. S. Wignall.
1992.
In vitro antibiotic susceptibilities of Neisseria gonorrhoeae isolates in the Philippines.
Antimicrob. Agents Chemother.
36:277-282[Abstract/Free Full Text].
|
| 6.
|
Covino, J. M.,
M. Cummings,
B. Smith,
S. Benes,
K. Draft, and W. M. McCormack.
1990.
Comparison of ofloxacin and ceftriaxone in the treatment of uncomplicated gonorrhea caused by penicillin-producing and non-penicillin-producing strains.
Antimicrob. Agents Chemother.
34:148-149[Abstract/Free Full Text].
|
| 7.
|
Gransden, W. R.,
C. A. Warren,
I. Phillips,
M. Hodges, and D. Barlow.
1990.
Decreased susceptibility of Neisseria gonorrhoeae to ciprofloxacin.
Lancet
335:51[Medline].
|
| 8.
|
Japanese Society of Chemotherapy.
1981.
Revision of methods for determining minimum inhibitory concentrations.
Chemotherapy (Tokyo)
29:76-79.
|
| 9.
|
Jephcott, A. E., and A. Turner.
1990.
Ciprofloxacin resistance in gonococci.
Lancet
335:165[Medline].
|
| 10.
|
Kam, K. M.,
K. K. Lo,
K. Y. Ho Ng, and M. M. Cheung.
1995.
Rapid decline in penicillinase-producing Neisseria gonorrhoeae in Hong Kong associated with emerging 4-fluoroquinolone resistance.
Genitourin. Med.
71:141-144[Medline].
|
| 11.
|
Knapp, J. S.,
R. Ohye,
S. W. Neal,
M. C. Parekh,
H. Higa, and R. J. Rice.
1994.
Emerging in vitro resistance to quinolones in penicillinase-producing Neisseria gonorrhoeae strains in Hawaii.
Antimicrob. Agents Chemother.
38:2200-2203[Abstract/Free Full Text].
|
| 12.
|
Knapp, J. S.,
J. A. Washington,
L. J. Doyle,
S. W. Neal,
M. C. Parekh, and R. J. Rice.
1994.
Persistence of Neisseria gonorrhoeae strains with decreased susceptibilities to ciprofloxacin and ofloxacin in Cleveland, Ohio, from 1992 through 1993.
Antimicrob. Agents Chemother.
38:2194-2196[Abstract/Free Full Text].
|
| 13.
|
Messing, J.
1983.
New M13 vectors for cloning.
Methods Enzymol.
101:20-78[Medline].
|
| 14.
| Mogabgab, W. 1991. Single-dose oral temafloxacin
versus parenteral ceftriaxone in the treatment of gonococcal
urethritis/cervicitis. JAMA 91(Suppl.
6A):145S-149S.
|
| 15.
|
Montgomery, K.,
L. Raymundo, Jr., and W. L. Drew.
1979.
Chromogenic cephalosporin spot test to detect to direct beta-lactamase in clinically significant bacteria.
J. Clin. Microbiol.
9:205-207[Abstract/Free Full Text].
|
| 16.
| Muratani, T., S. Mitsuhashi, and M. Inoue. 1995. In
vitro activity of pazufloxacin, a new fluoroquinolone. Jpn. J. Chemother. 43(Suppl. 2):1-11.
|
| 17.
| Nakashima, M., K. Kosuge, and T. Uematsu. 1995. Phase I clinical study of pazufloxacin. Jpn. J. Chemother.
43(Suppl. 2):143-163.
|
| 18.
|
O'Callaghan, C. H.,
A. Morris,
S. M. Kirby, and A. H. Shingler.
1972.
Novel method for detection of -lactamases by using a chromogenic cephalosporin substrate.
Antimicrob. Agents Chemother.
1:283-288[Abstract/Free Full Text].
|
| 19.
|
Pabst, K. M.,
N. A. Siegel,
S. Smith,
J. R. Black,
H. H. Handsfield, and E. W. Hook, III.
1988.
Multicenter, comparative study of enoxacin and ceftriaxone for treatment of uncomplicated gonorrhea.
Sex. Transm. Dis.
16:148-151.
|
| 20.
|
Romanowski, B.,
H. Wood,
J. Draker, and M. C. Tsianco.
1986.
Norfloxacin in the therapy of uncomplicated gonorrhea.
Antimicrob. Agents Chemother.
30:514-515[Abstract/Free Full Text].
|
| 21.
|
Smith, B. L.,
M. Cummings,
S. Benes,
K. Draft, and W. M. McCormack.
1989.
Evaluation of difloxacin in the treatment of uncomplicated urethral gonorrhea in men.
Antimicrob. Agents Chemother.
33:1721-1723[Abstract/Free Full Text].
|
| 22.
|
Tanaka, M.,
J. Kumazawa,
T. Matsumoto, and I. Kobayashi.
1994.
High prevalence of Neisseria gonorrhoeae strains with reduced susceptibility to fluoroquinolones in Japan.
Genitourin. Med.
70:90-93[Medline].
|
| 23.
|
Tanaka, M.,
T. Matsumoto,
I. Kobayashi,
U. Uchino, and J. Kumazawa.
1995.
Emergence of in vitro resistance to fluoroquinolones in Neisseria gonorrhoeae isolated in Japan.
Antimicrob. Agents Chemother.
39:2367-2370[Abstract].
|
| 24.
|
Tanaka, M.,
M. Otsuki,
T. Nishino,
I. Kobayashi I,
T. Matsumoto, and J. Kumazawa.
1997.
Mutation in DNA gyrase of norfloxacin-resistant clinical isolate of Neisseria gonorrhoeae.
Genitourin. Med.
70:253-255.
|
Antimicrobial Agents and Chemotherapy, March 1998, p. 579-582, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Allen, G. P., Hankins, C. D.
(2009). Evaluation of the mutant selection window for fluoroquinolones against Neisseria gonorrhoeae. J Antimicrob Chemother
64: 359-363
[Abstract]
[Full Text]
-
Shultz, T. R., Tapsall, J. W., White, P. A.
(2001). Correlation of In Vitro Susceptibilities to Newer Quinolones of Naturally Occurring Quinolone-Resistant Neisseria gonorrhoeae Strains with Changes in GyrA and ParC. Antimicrob. Agents Chemother.
45: 734-738
[Abstract]
[Full Text]
-
Mavroidi, A., Tzouvelekis, L. S., Tassios, P. T., Flemetakis, A., Daniilidou, M., Tzelepi, E.
(2000). Characterization of Neisseria gonorrhoeae Strains with Decreased Susceptibility to Fluoroquinolones Isolated in Greece from 1996 to 1999. J. Clin. Microbiol.
38: 3489-3491
[Abstract]
[Full Text]
-
Tanaka, M., Nakayama, H., Haraoka, M., Saika, T., Kobayashi, I., Naito, S.
(2000). Antimicrobial Resistance of Neisseria gonorrhoeae and High Prevalence of Ciprofloxacin-Resistant Isolates in Japan, 1993 to 1998. J. Clin. Microbiol.
38: 521-525
[Abstract]
[Full Text]
-
Tanaka, M., Nakayama, H., Haraoka, M., Saika, T., Kobayashi, I., Naito, S.
(2000). Susceptibilities of Neisseria gonorrhoeae Isolates Containing Amino Acid Substitutions in GyrA, with or without Substitutions in ParC, to Newer Fluoroquinolones and Other Antibiotics. Antimicrob. Agents Chemother.
44: 192-195
[Abstract]
[Full Text]
-
Ison, C. A., Woodford, P. J., Madders, H., Claydon, E.
(1998). Drift in Susceptibility of Neisseria gonorrhoeae to Ciprofloxacin and Emergence of Therapeutic Failure. Antimicrob. Agents Chemother.
42: 2919-2922
[Abstract]
[Full Text]
Top
Abstract
Introduction
