ARTICLE
Auteur(s) : Gerd
Plewig1, Keith T Holland2, Pietro
Nenoff3
1Klinik und Poliklinik für Dermatologie und
Allergologie, Ludwig-Maximilians-Universität München, Frauenlobstr.
9-11, D-80337 München, Germany
2Skin Research Centre, School of Biochemistry and
Microbiology, Faculty of Biological Sciences, University of Leeds,
Leeds LS2 9JT, UK
3Laboratorium für medizinische Mikrobiologie, Strasse
des Friedens 8, D-04579 Mölbis, Germany
accepté le 31 Août 2005
Acne vulgaris is a chronic inflammatory skin disorder affecting the
sebaceous follicles that commonly occurs in adolescence and young
adulthood. The pathogenesis of acne is complex and involves
stimulation of sebaceous gland secretion by androgens, abnormal
follicular keratinisation and obstruction of the follicle, and
ductal colonisation with P. acnes, which induces immune reactions
and perifollicular inflammation [1-4]. The clinical presentation of
acne can range from a mild comedonal form to severe inflammatory
cystic acne of the face, chest, and back.Antimicrobials have been a
mainstay of inflammatory acne treatment for more than 30 years,
with topical and systemic agents [5]. The choice between topical
and systemic antibiotics is generally based on the presence, extent
and severity of inflammatory lesions. Thus, while systemic
antibiotics are indicated for moderate-to-severe inflammatory acne,
topical antibiotics are indicated for mild-to-moderate inflammatory
acne.At the time of this study, antibiotic-resistant
propionibacteria had been isolated with increased frequency and
associated with failure to respond to antibiotic therapy [6, 7].
The widespread incidence of erythromycin-resistant propionibacteria
may limit the further usefulness of this antibiotic as a
therapeutic agent for acne [8], and also there is concern that
associated antibiotic resistance of resident cutaneous
staphylococci may pass the resistance genes onto Staphylococcus
aureus, which is a transient coloniser of skin. This is a concern
for all topical antibiotics used in acne therapy.Nadifloxacin 1%
(w/v) cream (Nadixa®) is an anti-infective drug for the
topical cutaneous treatment of inflammatory mild-to-moderate
(papulo-pustular) forms of acne vulgaris. Nadifloxacin is a
synthetic bactericidal fluoroquinolone with a broad spectrum of
antibacterial activity against aerobic Gram-positive and
Gram-negative and anaerobic bacteria, including P. acnes and S.
epidermidis [9, 10]. Nadifloxacin showed potent antibacterial
activity against methicillin-resistant and -sensitive
Staphylococcus aureus (MRSA and MSSA), with no cross-resistance
with any other antibiotic or with another fluoroquinolone [9, 10].
Additionally, in several clinical studies, topical application of
nadifloxacin cream exhibited excellent efficacy and tolerability,
and did not induce resistance in P. acnes strains [11-14].In this
pivotal, phase III European study, nadifloxacin 1% cream was
assessed for clinical and bacteriological efficacy and compared
with erythromycin 1% cream in patients with predominantly inflamed
slight-to-moderate acne vulgaris.
Material and methods
Study population
To be included, patients had to be 16 to 35 years of age and have
slight-to-moderate, predominantly inflamed acne vulgaris with at
least 15 papules/pustules on the face. All patients were required
to understand the nature of the study and the procedures to be
followed, as well as to provide written informed consent prior to
entry to the trial. For patients under the legal age, the informed
consent was additionally obtained from a parent or legal guardian.
Patients were not included if they had severe concomitant
disease; if they had severe acne which required more than topical
treatment (nodular facial acne); if they used another
investigational drug in the previous 6 months; if they had any
specific topical acne treatment in the 3 weeks prior to the study
or any systematic acne treatment, oral antibiotics or oral hormones
that could influence the acne in the 4 weeks prior the study
(except for patients of childbearing potential who had been taking
hormonal contraceptives for at least 6 months). Patients were also
excluded if they had used a systemic retinoid anti-acne therapy
during the last 12 months; had chronic alcohol or drug abuse; had
chronic or transient use of mood-altering or hallucinatory drugs;
were pregnant or lactating; or were women not using
contraception.
Patients who were included in the study could be withdrawn at
any time due to insufficient compliance, unacceptable adverse
events, any other protocol violation or withdrawal of consent.
Study design
This was a pivotal, multinational, double-blind, phase III study,
in which the patients were randomly assigned to be treated with
nadifloxacin 1% (w/v) cream or erythromycin 2% (w/v) cream during a
12-week treatment period. Randomization was carried out in blocks
of 4 patients within each study center, where each block included
the two different treatment groups twice. Erythromycin 2% (w/v)
cream was used as a reference, being the only available cream
formulation of a topical antibacterial anti-acne treatment. The
dose of nadifloxacin 1% (w/v) cream was selected on the basis of a
dose investigational, double-blind, phase II study of 96 patients
which was conducted in Japan [15]. The patients were instructed to
apply both study drugs to the affected skin after washing the face
with a standard soap. Creams were applied twice daily, in the
morning and in the evening, over 30 seconds, and without use of any
concomitant drugs. At 2, 4, 6, 8, 10 and 12 weeks of treatment, the
patients were observed for clinical response and occurrence of
adverse reactions as well as for treatment compliance and use of
cosmetics or concomitant medications. Minimal inhibitory
concentration (MIC) of both antibiotics, hematology, urinalysis,
clinical chemistry analysis and plasma concentrations of
nadifloxacin were performed in selected centers at the baseline
visit and after 12 weeks of treatment. Safety variables
(hematology, urinalysis and clinical chemistry) were first analyzed
for changes in region (below, within or above normal range) at week
12 compared with pretreatment (“changes in region analysis”).
Secondly, only changes greater than 50% of the normal values were
examined (“large change analysis”). Data from all 474 patients
enrolled into the study were used in the analysis of safety
variables. The plasma concentrations of nadifloxacin were
determined using a sensitive enzyme immunoassay (EIA) with a
nadifloxacin-specific antibody, which has been confirmed to be a
very reliable means of measurement of nadifloxacin concentration
with regard to specificity, sensitivity, accuracy and
reproducibility [16, 17].
This study was conducted in compliance with the good clinical
practice guidelines of the EU and the Association of the British
Pharmaceutical Industry (ABPI) guidelines for good clinical
practice and clinical trial compensation, the German Drug Law (AMG)
[18-20] and the German principles of the proper conduct of clinical
trials [21]. These were the valid guidelines at the time the study
was performed. Additionally, the study was performed in accordance
with the standards of the responsible institutional committees on
human experimentation and conditions, as set down in the
Declaration of Helsinki by the World Medical Association amended in
1989 in Hong Kong [22].
Outcome measures
The primary endpoints in this study were the standard counting of
inflamed lesions (papules and pustules) on the face, the overall
judgment of efficacy and tolerability, and the overall judgment of
the therapeutic effect of both formulations by the physician at the
end of the study. At the follow-up visits, each physician’s
response regarding efficacy and tolerability, compared with the
baseline condition, was assessed on a 3-step scale as “very good”,
“good”, and “unsatisfactory”. The investigator’s judgment of the
therapeutic effect of the drug on the acne lesions was made
according to the following scale: excellent (> 90%
improvement), very good (76-90% improvement), good (51-75%
improvement), slight (25-50% improvement), unchanged (< 25%
improvement), or deteriorated (increased number of acne lesions).
The secondary endpoints encompassed the standard counting of the
non-inflamed lesions (open and closed comedones and nodules <
1 cm), the judgment of the drug effect and the evaluation of
the satisfaction with the application and the consistency of the
cream by the patients after the 12-week study period using a
100 mm visual analogue scale. Moreover, the MIC examinations
for Propionibacterium acnes and coagulase-negative staphylococci
(CNS) were performed at the beginning and the end of the study
using two different methods.
Microbiological analysis
In Leeds (UK), samples were taken from 92 patients at baseline and
from 90 patients at week 12 from a defined area
(6.1 cm2) on the left cheek by using the detergent
scrub wash technique of Williamson and Kligman [23]. Serial decimal
dilutions of the samples were prepared to perform the total
bacterial plate counts and the number of erythromycin- and/or
nadifloxacin-resistant P. acnes and CNS using the Miles and Misra
method [24]. The method employed in this center to enumerate the
total viable and antibiotic-resistant microflora allowed the
resistant bacteria to be enumerated with the sensitivity limit of 3
CFU cm–2 of skin. Total viable propionibacteria were
enumerated by plating onto Reinforced Clostridial Agar (Oxoid)
containing 2 μg ml–1 of furazolidone (Sigma) (RCAF) to
inhibit the growth of staphylococci. Plates were incubated at
37 °C for 7 days under an anaerobic atmosphere containing 10%
CO2, 10% H2, 80% N2. Total viable
CNS were enumerated using IsoSensitest agar and were incubated at
37 °C for 48 hours. The propionibacteria and CNS populations
resistant were determined by plating out the samples onto media
containing two-fold serial dilutions of nadifloxacin (0.025 to
204.8 μg ml–1) or erythromycin (0.1 to 819.2 μg
ml–1).
In the selected centers in Germany, Switzerland and France
(13/31), to determine the MIC, the content of three inflamed
lesions was extracted with a sterile comedo extractor. Samples were
analyzed in three microbiological laboratories in Germany, France
and Switzerland. From those samples, P. acnes and Staphylococcus
species were isolated to assess their susceptibility to both
nadifloxacin and erythromycin. The susceptibility of clinical
isolates to the test materials was determined according to the
following standard method. The bacteria were preincubated using
modified GAM agar broth as the medium. The inoculum size was
106 CFU/ml and 108 CFU/ml, respectively,
prepared with an agar plate containing McFarland No I over 48
hours. Before assessment of the antibacterial potency and the MIC
of nadifloxacin and erythromycin, the organisms were cultured for a
further 48 hours.
Statistical analysis
The sample size estimate was based on attaining 80% power to detect
a difference of 10% in the total lesion count between the treatment
groups, valid for two-tailed non-parametric testing. Analyses were
performed on the intention-to-treat (ITT) population that included
all patients enrolled in the study and per protocol (PP)
considering data from patients who completed 12 weeks of treatment
according to the protocol. P-values were obtained using
Mann-Whitney U-test, the Wilcoxon signed rank test, the
Mantel-Haenszel test or Pearson’s + McNemar X2 test, as
appropriate. Results were considered significantly different if p ≤
0.05.
For primary and secondary response variables, analyses from all
patients who were treated for at least 2 weeks were included in the
analysis. The end-of-study analyses were performed by using the
last observation carried forward for patients who did not complete
the study. There were principally two types of analysis considering
the changes from baseline in number of lesions both within and
between groups for all follow-up time points.
The method of bacteria sampling and MIC determination performed,
allowed the analysis within and between groups not only for the
quantitative change of microflora on the skin after 12 weeks of
treatment and the number of patient bearers of resistant strains,
but also the proportion of antibiotic-resistant bacteria carried by
an individual. Based upon previous studies, a MIC value ≥ 50 μg/ml
was chosen to distinguish nadifloxacin/erythromycin-sensitive or
-resistant strains [25]. Patients in each of the treatment groups
were divided into those who did not carry resistant strains (NR,
< 50 μg/ml) and those bearers of resistant strains of P. acnes
or CNS (R, value > 50 μg/ml) to be compared within (week 12) and
between (baseline vs. week 12) groups by the McNemar X2
test and the Fisher’s exact statistics test, respectively.
Differences between groups in the global judgment of efficacy
and therapeutic effect were analyzed after treatment by the
X2 statistic test. The safety evaluation was based on
all patients who took at least one dose of the assigned study
medications. Fisher’s exact test and the McNemar X2 test
were used to evaluate the differences in adverse events between
treatment groups.
Results
Patients
A total of 474 in- or out-patients with slight-to-moderate acne
vulgaris and who fulfilled the selection criteria were enrolled in
31 European medical centers in Germany, Switzerland, France and
Great Britain. There were 234 patients in the nadifloxacin group
and 240 in the erythromycin group. Analysis of the demographic
variables listed in table 1( Table 1 )
indicated no significant differences between the treatment groups
at baseline. Although two patients in the erythromycin group were
beyond the age limit of 16-35 years (one below and another over the
upper age limit) and four patients in the nadifloxacin were below
the lower age limit for inclusion, they were included into the
study since they were considered suitable for participation. At the
end of the study, 426 patients completed the 12-week treatment
according to the protocol. There were 26 dropouts in the
nadifloxacin group and 22 dropouts in the erythromycin group. The
most common reasons for discontinuation were due to lost to
follow-up (9 patients in the nadifloxacin and 8 in the erythromycin
group), deterioration or no improvement of acne (5 patients in the
nadifloxacin and 6 in the erythromycin group), adverse events (4
patients in the nadifloxacin and 3 in the erythromycin group),
protocol violations (4 patients in the nadifloxacin and 2 in the
erythromycin group), patient withdrawal of consent (3 patients in
the nadifloxacin and 2 in the erythromycin group), and other
reasons (1 patient in each group). Furthermore, of the 474
recruited patients, 37 were excluded from the main analysis of
response variables because of protocol violations. Thus, at week
12, data from 394 patients – 204 in the nadifloxacin group and 190
in the erythromycin group – were included in response variable
analysis. The majority of patients in both groups had received
previous treatments for acne and showed similar acne severity at
baseline following Plewig classification.
Table 1 Summary of demographic characteristics at
baseline of the intent-to-treat population
|
|
Nadifloxacin group
|
Erythromycin group
|
|
(n = 234)
|
(n = 240)
|
|
Sex
|
Male
|
120
|
116
|
|
Female
|
114
|
124
|
|
Age
|
Mean ± SEM (Years)
|
21.1 ± 0.3
|
21.9 ± 0.3
|
|
Range (Years)
|
14-34
|
15-36
|
|
Height
|
Mean ± SEM (cm)
|
173.4 ± 0.6
|
172.6 ± 0.7
|
|
Range (cm)
|
145-202
|
133-198
|
|
Weight
|
Mean ± SEM (kg)
|
65.3 ± 0.6
|
66.4 ± 0.8
|
|
Range (kg)
|
42-96
|
42-108
|
|
Race
|
Caucasian
|
220
|
236
|
|
Asian
|
9
|
4
|
|
Negroid
|
4
|
-
|
|
Eurasian
|
1
|
-
|
|
Severity
|
Plewig score 1
|
15
|
17
|
|
Plewig score 2
|
166
|
160
|
|
Plewig score 3
|
46
|
49
|
|
Plewig score 4
|
7
|
14
|
Lesion counts
Table 2( Table 2 ) presents the effect
of 12 weeks of treatment with either nadifloxacin 1% cream or
erythromycin 2% cream on the number of inflammatory lesions
(papules and pustules) and non-inflammatory acne lesions (open and
closed comedones). In both treatment groups, within group analysis
showed a significant reduction in all acne lesions that was noted
at all follow-up visits from week 2 onwards. ( Figure 1 ) shows the within
group analysis of both nadifloxacin and erythromycin cream, which
was associated with an improvement of inflamed acne lesions and a
significant reduction in the percentage change from baseline on
inflamed lesions at any follow-up visit. There was no significant
difference between the two treatment groups or between the
different centers (Leeds versus all others) at any time point.
Analysis of nodule data was not performed because only a minority
of patients had nodules, which in all cases were present in very
small numbers.
Table 2 Mean lesion count at week 0 (baseline) and mean
differences from baseline in lesion count at weeks 2, 6, 10 and
12
|
Week
|
Nadifloxacin 1% cream
|
Erythromycin 2% cream
|
|
n
|
Median ± SEM*
|
Range
|
n
|
Median ± SEM*
|
Range
|
|
Papules
|
|
|
|
|
|
|
|
0
|
190
|
23.1 ± 1
|
-
|
204
|
22.8 ± 0.9
|
-
|
|
2
|
190
|
4.5 ± 0.7
|
– 19 to 85
|
203
|
5 ± 0.7
|
– 20 to 51
|
|
6
|
190
|
8 ± 0.8
|
– 41 to 81
|
202
|
8 ± 0.7
|
– 17 to 57
|
|
10
|
186
|
12 ± 0.7
|
– 17 to 120
|
203
|
10 ± 0.7
|
– 17 to 57
|
|
12
|
190
|
12.5 ± 0.8
|
– 36 to 119
|
204
|
12 ± 0.6
|
– 16 to 65
|
|
Pustules
|
|
|
|
|
|
|
|
0
|
190
|
9.2 ± 0.6
|
-
|
204
|
10 ± 0.7
|
-
|
|
2
|
190
|
2 ± 0.5
|
– 13 to 27
|
203
|
2 ± 0.6
|
– 21 to 29
|
|
6
|
190
|
4 ± 0.3
|
– 10 to 38
|
202
|
4 ± 0.5
|
– 22 to 52
|
|
10
|
186
|
4 ± 0.3
|
– 10 to 40
|
203
|
5 ± 0.4
|
– 18 to 55
|
|
12
|
190
|
5 ± 0.3
|
– 13 to 45
|
204
|
5 ± 0.3
|
– 9 to 57
|
|
Open comedones
|
|
|
|
|
|
|
|
0
|
190
|
17.7 ± 1.9
|
-
|
204
|
13.6 ± 1.2
|
-
|
|
2
|
190
|
0 ± 1.7
|
– 29 to 46
|
203
|
1 ± 1.0
|
– 15 to 48
|
|
6
|
190
|
1 ± 1.7
|
– 22 to 47
|
202
|
2 ± 0.8
|
– 13 to 53
|
|
10
|
186
|
2 ± 1.6
|
– 14 to 54
|
203
|
2 ± 0.8
|
– 56 to 48
|
|
12
|
190
|
3 ± 1.6
|
– 75 to 73
|
204
|
2.5 ± 0.7
|
– 25 to 72
|
|
Closed comedones
|
|
|
|
|
|
|
|
0
|
190
|
26.5 ± 1.8
|
-
|
204
|
22.7 ± 1.6
|
-
|
|
2
|
190
|
2 ± 1.8
|
– 60 to 58
|
203
|
1 ± 1.6
|
– 80 to 60
|
|
6
|
190
|
2 ± 1.9
|
– 104 to 69
|
202
|
2 ± 1.4
|
– 80 to 87
|
|
10
|
186
|
6 ± 1.7
|
– 92 to 81
|
203
|
4 ± 1.0
|
– 43 to 94
|
|
12
|
190
|
5 ± 1.7
|
– 106 to 141
|
204
|
5 ± 1.2
|
– 62 to 113
|
Treatment evaluations
The overall evaluation of the therapeutic effect of both
formulations by the physicians at the end of the study was judged
as “excellent” or “very good” in 23 and 38 patients, respectively,
in the nadifloxacin group and in 14 and 29 patients, respectively,
in the erythromycin group (table 3( Table
3 )). A difference close to significant (p = 0.066) was
found between groups in favor of nadifloxacin 1% cream. However,
when five categories were gathered into two main categories
(Category I: excellent and very good; Category II: good, slight,
unchanged, and deteriorated), the therapeutic effect was
significantly better for nadifloxacin 1% cream (p < 0.01,
X2 test). As the result of the global judgment of
efficacy (table 3) and tolerability by the physicians at week 12,
there was a close to significance between group difference (p =
0.071) favoring nadifloxacin 1% cream. The efficacy and
tolerability endpoints of treatment with nadifloxacin and
erythromycin creams was attributed to be “very good”, “good” or
“unsatisfactory” in 18.7, 56.7 and 24.6%, and in 28.4, 48.4 and
23.2% of cases, respectively. Additionally, by the end of 12 weeks
there were no significant differences between the two groups in the
patients’ overall judgment of treatment. There was a significant
difference between treatment groups in the patients’ judgment of
the consistency of the cream, favoring nadifloxacin 1% cream (p
< 0.002, X2 test) (table 4( Table
4 )).
Table 3 Results of global judgment by the physicians
regarding the therapeutic effect of both drugs at the end of the
study
|
Treatment
|
Excellent
|
Very good
|
Good
|
Slight
|
Unchanged
|
Deteriorated
|
Total
|
|
Nadifloxacin 1% cream
|
14 (6.9%)
|
29 (14.3%)
|
83 (41%)
|
43 (21.2%)
|
29 (14.3%)
|
5 (2.5%)
|
203
|
|
Erythromycin 2% cream
|
23 (12.1%)
|
38 (20%)
|
56 (29.5%)
|
42 (22.1%)
|
22 (11.6%)
|
9 (4.7%)
|
190
|
Table 4 Judgment of satisfaction with consistency of
the creams by the patients at week 12 of the study
|
Treatment
|
Very satisfied
|
Satisfied
|
Moderately satisfied
|
Unsatisfied
|
Very unsatisfied
|
Total
|
|
Nadifloxacin 1% cream
|
22 (11%)
|
83 (41.3%)
|
72 (35.8%)
|
21(10.4%)
|
3 (1.5%)
|
201
|
|
Erythromycin 2% cream
|
33 (17.6%)
|
102 (54.5%)
|
40 (21.4%)
|
10 (5.3%)
|
2 (1.1%)
|
187
|
Bacteriological evaluations
The data from those patients who dropped out or who were excluded
from the analysis of the primary response variables were omitted
from the analysis.
In Leeds (UK), P. acnes and CNS were sampled from 92 patients at
week 0 and from 90 patients at week 12. However, the
microbiological analysis data from 86 patients had been used (43
patients in each group) [26]. When numbers of P. acnes and CNS were
compared before and after treatment, logarithmically transformed P.
acnes populations (mean ± SD) were reduced in the nadifloxacin
group from 5.43 ± 0.28 to 4.92 ± 0.39 and in the erythromycin group
from 5.21 ± 0.33 to 4.68 ± 0.39. In both groups the decrease was
significant (p < 0.0001; Wilcoxon signed rank test).
Additionally, there was no significance between group difference in
the number of P. acnes at either week 0 or week 12. Viable CNS
populations expressed as a logarithmic mean (mean ± SD) were
reduced in the nadifloxacin group from 4.39 ± 0.14 at baseline to
2.37 ± 0.47 after treatment. This decrease in CNS was significant
(p < 0.0001; Wilcoxon signed rank test). In the erythromycin
group the mean number of viable CNS at baseline was 4.38 ± 0.20 and
4.59 ± 0.26 after treatment. The increase in CNS was significant as
analyzed by Wilcoxon signed rank test (p < 0.048). Although at
week 0 there was no significance between group differences in the
number of viable CNS, at week 12 a significant difference in the
number of viable CNS between nadifloxacin and erythromycin groups
was observed (p < 0.0001; Mann-Whitney U-test and independent
t-test).
Within group comparison demonstrated that in all 43 patients the
total P. acnes population was sensitive to nadifloxacin before and
after treatment, whereas in the erythromycin group 5 patients
carried P. acnes resistant to treatment at baseline and in
additional 7 patients P. acnes developed resistance to erythromycin
at week 12. The remaining 29 patients in the erythromycin group had
P. acnes populations sensitive to erythromycin before and after
treatment. Regarding CNS, in the nadifloxacin group, 1 patient
carried a proportion of CNS resistant to the treatment at baseline
and in none of the patients did CNS develop resistance to
nadifloxacin throughout the study period. In the remaining 42
patients the total of CNS was sensitive to nadifloxacin before and
after treatment. Seven of those patients had no CNS detected after
12 weeks of treatment. In the erythromycin group, 24 patients had
resistant CNS and in 18 patients CNS developed resistance to
erythromycin during the study period; meanwhile only 1 patient in
the total CNS population was sensitive to erythromycin before and
after treatment (p < 0.001; McNemar X2 test).
Furthermore, between group comparison showed that both at baseline
and end of the study, patients in the erythromycin group had a
larger population of resistant strains of P. acnes and CNS (table
5( Table 5 )).
After 12 weeks of treatment with nadifloxacin, there were
significant changes in the sensitivity pattern of P. acnes and CNS,
but these changes were without biological significance as they
occurred within regions of high microbial susceptibility (0.05
μg/ml and 0.2 μg/ml) (( figures 2A and 2B) ). In
the erythromycin group, at week 12 there were significantly more P.
acnes (> 10%) that grew on a media containing concentrations of
erythromycin as high as 409.6 μg/ml and 819.2 μg/ml. At the end of
the study, 80% of the CNS were not inhibited at a concentration of
819.2 μg/ml of erythromycin compared to 20% of CNS not inhibited at
baseline (( figures 3A
and 3B) ).
In Germany, Switzerland and France, a total of 107 samples were
taken at baseline and 90 samples at week 12. At week 12, MIC data
for nadifloxacin and erythromycin were analyzed for the patients
treated with nadifloxacin and erythromycin, respectively. The
sensitivity of the clinical isolates of P. acnes and CNS within the
nadifloxacin and erythromycin groups are listed in table 6( Table 6 ). To perform the between group
comparison, only the patients treated with erythromycin were
compared with those treated with nadifloxacin in order to detect
any differences in resistance between both test drugs. Both at
baseline and after 12 weeks of treatment, none of the P. acnes
sampled from the patients in the nadifloxacin group was resistant
to nadifloxacin at week 0 and at week 12. However, P. acnes sampled
from 3 (6.8%) and 1 (7.7%) patients from the erythromycin group
were resistant to erythromycin before and after treatment,
respectively. In regard to resistance of viable CNS, none of the
CNS sampled was resistant to nadifloxacin, whereas CNS samples
taken from 47 patients (64.4%) were resistant to erythromycin
therapy at baseline (p < 0.0001; Fisher’s exact test). At the
end of the study, 1 (4.5%) CNS sample from the nadifloxacin group
and 28 (80%) samples taken from patients treated with erythromycin
were resistant to nadifloxacin and erythromycin treatment,
respectively (p < 0.001; Fisher’s exact test).
Table 5 Between group comparison of treatments with
nadifloxacin and erythromycin at baseline and the end of the study
(week 12)
|
Treatment
|
Bacteria
|
Baseline (Week 0)
|
End of study (Week 12)
|
|
|
Category
|
Category
|
|
|
Not resistant
|
Resistant
|
Not resistant
|
Resistant
|
- Nadifloxacin 1% cream
- (n = 43)
|
P. acnes
|
43 (100%)
|
0
|
43 (100%)
|
0
|
- Erythromycin 2% cream
- (n = 43)
|
36 (83.7%)
|
7 (16.3%)***
|
31 (72.1%)
|
12 (27.9%)***
|
- Nadifloxacin 1% cream
- (n = 43)
|
CNS
|
42 (97.7%)
|
1 (2.3%)
|
43 (100%)
|
0
|
- Erythromycin 2% cream
- (n = 43)
|
19 (44.2%)
|
24 (55.8%)***
|
1 (2.3%)
|
42 (97.7%)***
|
Table 6 Susceptibility of isolated P. acnes and CNS
strains to nadifloxacin and erythromycin treatment at baseline
(week 0) and after 12-week treatment
|
Treatment
|
Bacteria
|
Week
|
≤ 0.024
|
0.05
|
0.1
|
0.2
|
0.4
|
0.8
|
1.6
|
3.2
|
6.4
|
12.8
|
25.6
|
> 50
|
Σ
|
ng
|
|
Nadifloxacin 1% cream
|
P. acnes
|
Week 0
|
|
|
11 (57.9%)
|
7 (36.9%)
|
1 (5.3%)
|
|
|
|
|
|
|
|
19
|
30
|
|
Week 12
|
|
|
5 (45.5%)
|
6 (54.5%)
|
|
|
|
|
|
|
|
|
11
|
30
|
|
CNS
|
Week 0
|
10 (29.4%)
|
11 (32.4%)
|
8 (23.5%)
|
5 (14.7%)
|
|
|
|
|
|
|
|
|
34 (%)
|
16 (%)
|
|
Week 12
|
7 (31.8%)
|
4 (18.2%)
|
4 (12.8%)
|
|
|
2 (9.1%)
|
|
1 (4.5%)
|
|
1 (4.5%)
|
2 (9.1%)
|
1 (4.5%)
|
22
|
18
|
|
Erythromycin 2% cream
|
P. acnes
|
Week 0
|
19 (76%)
|
3 (12%)
|
|
|
2 (8%)
|
|
|
|
|
|
|
1 (4%)
|
25
|
24
|
|
Week 12
|
12 (92.3%)
|
|
|
|
|
|
|
|
|
|
|
1 (7.7%)
|
13
|
30
|
|
CNS
|
Week 0
|
|
5 (12.5%)
|
|
6 (15%)
|
|
|
|
|
|
|
|
29 (72.5%)
|
40 (%)
|
9 (%)
|
|
Week 12
|
|
|
5 (14.3%)
|
1 (2.9%)
|
|
|
|
|
|
|
1 (2.9%)
|
28 (80%)
|
35 (%)
|
9 (%)
|
Safety evaluation
Fifty-four patients in the nadifloxacin group and 64 patients in
the erythromycin group reported adverse events that were judged as
possible, probable or almost certainly drug related. The frequency
and new incidence of adverse events decreased towards the end of
the study in both treatment groups. Table 7( Table 7 ) presents the frequencies of the adverse
events with the highest incidence per group (p < 0.05; Fisher’s
test). None of the adverse events in the nadifloxacin group were
judged as severe (severe: 0; moderate: 30; light: 99), while 7
severe adverse events were reported in patients in the erythromycin
group (severe: 7; moderate: 28; light: 129). Group means for
hematology, clinical chemistry and urinalysis parameters were
within the normal range at both time points for all the
variables.
Table 7 Incidence of adverse events (≥ 1)
|
Event
|
Erythromycin 2% cream
|
Nadifloxacin 1% cream
|
|
n (%)
|
n (%)
|
|
Pruritus
|
13 (5.4)
|
11 (4.7)
|
|
Erythema
|
46 (19.2)
|
32 (15)
|
|
Burning skin
|
13 (5.4)
|
10 (4.3)
|
|
Warm skin
|
7 (2.9)
|
10 (4.3)
|
|
Skin peeling
|
10 (4.2)
|
7 (3)
|
|
Dry skin
|
28 (11.7)
|
21 (9)
|
|
Feeling tense
|
3 (1.25)
|
0
|
Plasma levels of nadifloxacin
From 18 selected centers the mean plasma concentration from the 122
patients was 1.23 ng/ml (± 1.546 STD). In 31 patients (25.4%) the
concentration of nadifloxacin was below the detection limit. There
was no significant correlation between the amount of cream applied
per day and plasma concentration of nadifloxacin. Moreover,
nadifloxacin plasma concentration correlated significantly
negatively with the number of inflamed lesions at the end of the
study (p < 0.017) and positively with the decrease from baseline
of inflamed lesions (p < 0.024).
Discussion
Over the 20 years before this study, concern has grown about the
gradual worldwide increase in the prevalence of
antibiotic-resistant P. acnes strains due to extensive use of
antibiotic therapy in the treatment of bacterial infections
[27-29]. Among patients treated for prolonged periods, the use of
topical and systemic antibiotics has been linked to decreased
sensitivity to antibiotics and the emergence of clinically
resistant strains of P. acnes in approximately 25% of cases leading
to therapeutic failure [8]. The widespread incidence of
antibiotic-resistant P. acnes may limit the future usefulness of
antibiotic agents for acne. Hence, use of a new antibiotic with
proven clinical improvements in acne lesions, which inhibits P.
acnes, has a low potential for the development of
antibiotic-resistant microorganisms present on human skin and has a
good safety profile, may awaken interest for antibiotic treatment
of acne vulgaris.
As previously reported by Bojar and coworkers [26], in this
population the association between the number of patients carrying
antibiotic-resistant microorganisms and overall treatment results
was not straightforward as both nadifloxacin and erythromycin cream
had similar clinical benefits, whilst the proportion of resistant
propionibacteria and CNS isolated from the erythromycin-treated
group was significantly increased. Noteworthy is that no resistant
strains of propionibacteria or CNS to nadifloxacin were found after
12 weeks of treatment. Direct assessment of the extent and level of
antibiotic resistance to both agents and the number of patients
carrying resistant strains, as well as the quantitative change of
microflora on the skin, allowed for a more accurate evaluation and
prediction of final clinical effect.
The safety results of the present study have demonstrated that
used twice daily, nadifloxacin 1% cream is a safe and
well-tolerated topical treatment for moderate, papulo-pustular
acne. Previous data on tolerance of nadifloxacin was collected in
several studies after single and repeated topical application of
0.5 to 1% nadifloxacin cream to healthy volunteers. There were no
complaints of skin irritation, redness or any other dermatological
symptoms, nor were any adverse events or abnormal clinical
laboratory parameters reported, thus confirming the good safety
profile of the drug [17]. Furthermore, based on skin irritation and
phototoxicity studies, it was concluded that the 1% nadifloxacin
formulation did not exhibit any irritation and sensitization
potential, nor phototoxic or photosensitization potential under the
patch tests [30].
In conclusion, this study, which ended in 1994, has demonstrated
that topical nadifloxacin and erythromycin are equally clinically
effective. At the time no significant resistance to nadifloxacin
was detected amongst the skin microflora and to the present time no
loss of sensitivity has been noted [31-38]. This encouraging result
needs to be confirmed at the present time when antibiotic resistant
patterns of cutaneous bacteria may have altered.
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