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Comparative study of tosufloxacin tosilate fine granules
15% for pediatrics: MEIJI® versus Ozex®
SOICHIRO ANDO
Ando Clinic(Received for publication December 14, 2016)

In this study, we compared the efﬁcacy, adverse event incidences, and medication
compliance of MEIJI® (T group) with those of Ozex® (O group) tosuﬂoxacin tosilate
ﬁne granules. Tosuﬂoxacin tosilate ﬁne granule was effective in all but one case(32/33) while the time to defervescence was within 2 days of drug administration inboth groups (T and O groups, 1.31 and 1.92 days, respectively). The time to coughimprovement was within 3 days of drug administration in both groups (T and O
groups, 2.27 and 2.64 days, respectively). Adverse events were observed in 7.3%
and 14.1% of the T and O groups (6/82 and 10/71), respectively. The medication
compliance was good in both groups and, overall, the mean rate of administration of
the T and O groups was 93.8% and 97.0%, respectively. The rate of complete
administration was 87.8% (72/82) and 91.5% (65/71) in the T and O groups,
respectively. No signiﬁcant changes were observed between the two groups inefficacy, adverse event incidences, and medication compliance. Therefore,
tosuﬂoxacin tosilate ﬁne granule 15% for pediatrics (MEIJI®) may be equivalent to
tosuﬂoxacin tosilate hydrate 15% for pediatrics (Ozex®) in efﬁcacy, adverse event
incidences, and medication compliance.

Introduction
Tosuﬂoxacin tosilate ﬁne granule 15% for pediatrics (MEIJI®) is a generic formulation of the
drug Ozex® (tosuﬂoxacin tosilate hydrate 15% for pediatrics), which was released on June 19,
2015, in Japan. Generic drugs are thought to have the same effectiveness and incidences of adverse events. However, factors affecting patient drug compliance (the taste and frequency of medicine administration) may differ between the original brand and generic drugs, particularly forchildren and, therefore, their effectiveness and adverse event incidences may also differ. Tosuﬂoxacin tosilate is the only new quinolone that can be used for treating pediatric pneumonia andotitis media and is usually used against other antibiotic-resistant pathogens. It also is thought to86（ 2 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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decrease hospitalization due to pneumonia in children1). Therefore patient compliance to drugs isthought to be extremely important to avoid increasing the incidence of antibiotic-resistant bacteria.
The effectiveness and incidence of adverse events of Ozex® have been reported previously2, 3),
but not that of MEIJI®. In addition, only one study comparing the effectiveness of MEIJI® withthat of Ozex® in vitro and in vivo (mice pneumonia model) has been reported4). Therefore, thepurpose of this study was to investigate the effectiveness and incidences of adverse events of
MEIJI® and subsequently compare it with those of Ozex® in a population of Japanese children.

Patients and Methods
This study was conducted according to the Helsinki Declaration and performed after the
written informed consent of patients, their parents, or both was obtained. The study design wasapproved by the appropriate ethics review board of our clinic (the approval code: AC1501).

1)
2)
3)

Eligibility Criteria
The eligibility criteria were as follows:
Age: 1–14 years
Clinically diagnosed with bacterial pneumonia, otitis media, or both.
Induction of tosuﬂoxacin tosilate therapy was considered appropriate.
a) Previous antibiotic therapies were not effective, and atypical pneumonia could not bedenied.
b) First-line drugs (e.g., macrolides) could not be used because of the existence of drug allergies, severe adverse events, or administration difﬁculties.
c) The family members of the patients exhibited a similar clinical course as that describedin a).

Exclusion Criteria
1) A history of allergy to tosuﬂoxacin tosilate.
2) Use of other generic tosuﬂoxacin tosilate ﬁne granule drug formulations (e.g., Takada and
Sawai).
Epilepsy and arthralgia were not excluded with the condition that the merit of medication
use outweighed the demerits of use and informed consent was acquired from the patients, theirparents, or both.
Bacterial pneumonia
Bacterial pneumonia was deﬁned as follows:Apr. 2017

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1)
2)

Typical clinical symptoms such as fever, cough, and sputum.
Inﬁltrates observed in chest X-rays.
Fulﬁllment of both 1) and 2) above or:3) Patients who exhibited a similar clinical course to that of a family member already diagnosed with pneumonia.
4) Cases of viral infection with a suspicion of mixed bacterial infection as evidenced by signs
such as prolonged clinical course, productive cough, dense inﬁltrates (i.e., “consolidation”)
visible on diagnostic imaging scans such as chest X-rays.
However, since viral pneumonia may be included using these criteria, the evaluation of efﬁcacy was done for only pathogen-identiﬁed cases.

1)2)

Otitis media
Otitis media was deﬁned as follows:
Typical clinical symptoms such as ear pain, fever, and discolored nasal discharge.
Conﬁrmation of eardrum infection using an otoscope.
Fulﬁllment of both 1) and 2).

Detection of pathogens
1) Culture of respiratory secretions including sputum as well as ear and nasal cavity secretions.
2) Mycoplasma pneumoniae:
Positive reactions using antigen detection kits (Ribotest, Asahi Kasei Pharma Co.).
Single serum antibody (particle agglutination method): × >3205)
3) Streptococcus pneumoniae:
Positive culture with respiratory secretion.
Positive reaction using urine antigen detection kit (BinaxNOW Streptococcus pneumoniae
test, Alere Medical Co., Ltd.)
4) Bordetella pertussis (Pertussis, diagnosed later):Single serum antibody (PT-IgG): >100 EU/mL6).
Other viral antigen detection kits also were used (respiratory syncytial virus [RSV], human
metapneumovirus, inﬂuenza virus, and adenovirus).
Efﬁcacy
The efﬁcacy was evaluated according to the criteria of the Japanese Society of Chemother7)
apy . However, fever and cough were evaluated separately.
Namely, fever: the effectiveness was deﬁned as the occurrence of defervescence within 3days from starting tosuﬂoxacin tosilate ﬁne granule treatment.
Cough: the effectiveness was deﬁned as cough improvement occurring within 7 days from

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starting tosuﬂoxacin tosilate ﬁne granule treatment because cough improvement is usually delayed.
“Overall effectiveness” was deﬁned as positive conﬁrmations using either clinical symptoms(fever, cough, wheezing, and dyspnea) or clinical examination (X-rays and otoscope). The performance of an X-ray re-examination when either inﬁltrates or consolidation regressed was deﬁned
as an effective response. As mentioned above, the efﬁcacy was evaluated only in pathogen-identiﬁed cases.
Adverse events
The adverse events were also evaluated according to the criteria of the Japanese Society of
Chemotherapy7), which were classiﬁed into the following ﬁve groups:
・No medication/complete: No treatments for adverse events was needed, and medication
could be administered completely.
・Medication <4 days/complete: Treatment of adverse events was needed within 3 days, but
medication could be administered completely.
・Medication ≥4 days/complete: Treatment for an adverse event was needed over 3 days,
but medication could be administered completely.
・Drug discontinuation/no medication: Tosuﬂoxacin tosilate ﬁne granule had to be discontinued because of incidences of adverse events, but no treatments were needed.
・Drug discontinuation/medication needed: Tosuﬂoxacin tosilate ﬁne granule had to be discontinued because of incidences of adverse events and medication was needed.
Medication compliance
Patient medication compliance was evaluated according to the criteria of the Japanese Society of Chemotherapy7), based on the following four classiﬁcation groups:
・Complete (100%): This group consisted of patients who could take the complete tosuﬂoxacin tosilate ﬁne granule regimen.
・Almost 100% complete: This group included patients who were sometimes unwilling to takethe tosuﬂoxacin tosilate ﬁne granule but could take it almost completely for the most part.
・Impossible to administer: The group included patients who could not take the tosuﬂoxacin
tosilate ﬁne granules.
・Discontinuation due to ineffectiveness or adverse events: This group included cases of patients who had to stop tosuﬂoxacin tosilate ﬁne granule because of its ineffectiveness orincidences of adverse events.
The projected number of cases was at least 100 for each group, and the allocation was equivalently performed but was based on the willingness of patients, their parents, or both.

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89（ 5 ）The effectiveness and adverse event evaluations were determined during the patientsʼ revisit
or using the questionnaire or telephone interview. The cases that used generic drugs of other pharmaceutical companies were also excluded by similar way.
Statistical analysis
The student t-test and chi-square (χ2) test were used to compared the groups treated withMEIJI® and Ozex® (tosuﬂoxacin tosilate hydrate 15% for pediatrics). When confounding factors
were observed, the logistic regression analysis was included and a two-sided P < 0.05 was considered signiﬁcant.
Statistical analysis was performed using the JMP® 13 (Statistical Analysis Software, SAS Institute Inc., Cary, NC, USA).

Results
Patient characteristics
From June 2015 to September 2016, 206 patients were enrolled (male : female patients,
105 : 101). However, since some cases had bronchial asthma and complicated bronchial asthma
attacks or were in a condition of asthmatic bronchitis at their presentation, steroid use was necessary. Steroid therapy affects fever and cough and, therefore, we excluded cases that used steroid
therapy. Finally, 153 patients were treated with MEIJI® and Ozex® (T and O groups, 82 and 71
cases, respectively) and their characteristics are listed in Table 1. Among the clinical factors, age
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was signiﬁcantly lower in the T group than it was in the O group (mean 4.6±0.36 and 6.2±0.39
years, respectively, P=0.0017). The other clinical factors were equivalent between the twogroups. Clinical diagnoses consisted of 137 cases of pneumonia, six cases of otitis media, andnine cases of both pneumonia and otitis media. Underlying diseases were observed in 13 cases,
and bronchial asthma was the most commonly seen (69.2% [9/13]). Previous viral infection wasobserved in three cases (two cases of RSV infections and one case of human metapneumovirus
infection). Furthermore, 88 cases were pretreated with antibiotics (macrolides: 60, cephems: 15,
penicillins: 10, cephems plus macrolides: three).
Efﬁcacy
The efﬁcacy evaluation is summarized in Table 2. The responsible pathogens were identiﬁed
in 33 cases. The identiﬁed pathogens are as follows; Pneumonia/Mycoplasma pneumoniae: 11,
Streptococcus pneumoniae: 2, S. pneumoniae plus Branhamella catarrhalis: 2, Haemophilus inﬂuenzae: 1, S. pneumoniae+H. inﬂuenzae: 1, S. pneumoniae+H. inﬂuenzae (β-lactamase-negative
ampicillin-resistant, BLNAR): 1, S. pneumoniae+H. inﬂuenzae+B. catarrhalis: 1, Bordetella pertussis: 1; pneumonia plus otitis media/S. pneumoniae: 2, H. inﬂuenzae: 1, B. catarrhalis: 1, methicillin-sensitive Staphylococcus aureus (MSSA): 1, Corynebacterium sp.: 1, H. inﬂuenzae+B. catarrhalis: 1, H. inﬂuenzae+Corynebacterium sp.: 1; and otitis media/H. inﬂuenzae: 3, MSSA: 2.
Among the pneumonia-inducing pathogens, M. pneumoniae was the most frequent (33.3%,
11/33). Infection by macrolide-resistant M. pneumoniae, which was deﬁned as being clinically resistant to improvement despite at least 3 days of administration of a macrolide, occurred in 45.5%(5/11, consisting of three and two patients administered clarithromycin and azithromycin hydrate,
respectively). The tosuﬂoxacin tosilate ﬁne granule formulation was effective against macrolideresistant M. pneumoniae (in 100%, 5/5). Furthermore, one case of pertussis was identiﬁed, whichwere subsequently diagnosed based on high serum titer (PT-IgG: 160). The tosuﬂoxacin tosilate
ﬁne granule formulation was effective in this case with pertussis. Although the number of pathogen-identiﬁed cases was low, all cases were effectively treated, except one. The rate of efﬁcacy
did not differ signiﬁcantly between both groups (T and O groups, 94.4% and 100%, respectively).
The fever declined rapidly, and the time to defervescence was within 2 days of drug administration in both groups (T and O groups, 1.31 and 1.92 days, respectively). Time to cough improvement was within 3 days of drug administration in both groups (T and O groups, 2.27 and 2.64
days, respectively). Further the only patient considered as “not effectively treated” who was evaluated as a case of M. pneumoniae infection, also showed a regression of symptoms following
tosuﬂoxacin tosilate treatment (since he needed other therapy for complete resolution, he was
evaluated as “not effective”). For otitis media, both drugs were effective in all but one case,which could not be followed-up.

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Table 2. Efﬁcacy proﬁlesApr. 2017

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Adverse events
The adverse event incidences summarized in Table 3 were observed in 7.3% and 14.1% of
the T (6/82) and O (10/71) group patients, respectively but overall, no signiﬁcant differences wereobserved (corrected P=0.2544). Although the number of cases with medication ≥4 days/completegroup was signiﬁcantly higher in the O group than it was in the T group (T and O groups, 0%[0/82] and 4.2% [3/71], respectively, corrected P=0.0241), its clinical signiﬁcance appears to beunclear (because of the small population number). Although adverse events were observed, the rate
or number of cases with drug discontinuation was low (T and O groups, 4.9% [4/82] and 2.8%
[2/71], respectively). Among the adverse events, gastrointestinal effects were the most common
Table 3. Incidence of adverse events

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(68.8%, 11/16). All adverse events were reversible and not severe, and no cases were sent to amajor hospital.
Medication compliance
The medication compliance was extremely good with both drugs, and no signiﬁcant changes
were observed between the two groups (Table 4). Overall, the mean rates of administration in the
T and O groups were 93.8% and 97.0%, respectively. In approximately 90% of cases, the drug
regimen administration was complete (T and O groups, 72/82 [87.8%] and 65/71 [91.5%], respectively).

Discussion
This study compared the proﬁles of MEIJI® and Ozex®. Although the number of evaluatedcases was small, the rate of efﬁcacy was approximately 100%. The fever declined within 2 days
from drug administration in both groups. Time to cough improvement was within 3 days of drug
administration in both groups. This result is comparable to that of previous studies (pneumonia,
100%, otitis media, 97.7%2), and M. pneumoniae, 94.0%3)). The tosuﬂoxacin tosilate ﬁne granule
formulation was effective against macrolide-resistant M. pneumoniae (100%, 5/5). Incidentally,
one case of pertussis was included and diagnosed later. This patient may have had complicatedmixed infections since the X-rays showed dense inﬁltrates. However, the tosuﬂoxacin tosilate ﬁne
granule formulation was also effective in this case of pertussis. Furthermore, 88 cases were pretreated with antibiotics and tosuﬂoxacin tosilate ﬁne granule formulation was also effective forthese cases. It was also in agreement with results of previous reports, which showed the effectiveness of tosuﬂoxacin tosilate in antibiotic-resistant infections3, 8, 9).
The adverse events of both drugs were also comparable, and the overall rate of adverse
events was 10.5% (16/153). Although this rate was slightly higher than those of previous reports(2.77%2) and 3.6%3)), it was thought to be attributable to the small sample size of this study. Furthermore, no severe adverse events were observed, and the administration of the drug regimen
was completed in almost cases (89.5%, 137/153). Almost all adverse events were gastrointestinal(68.8%, 11/16) but drug discontinuation and medication were needed in only three cases (2.0%,
3/153). All cases recovered without sequelae. In addition, the medication compliance of bothdrugs was good and equivalent. Overall, the percentage of cases that had to discontinue the drug
because it was impossible to take, ineffective, or induced adverse events was low (8.5%, 13/153).
Finally, this study has several limitations that are worth mentioning. First, the diagnosis ofbacterial pneumonia was uncertain. The diagnosis was based on clinical examinations (clinicalsymptoms and X-rays), but dense inﬁltrates could not always be diagnosed as bacterial pneumonia. The rate of pathogen identiﬁcation was low (21.6%, 33/153). In addition, the pathogens iden-THE JAPANESE JOURNAL OF ANTIBIOTICS

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95（ 11 ）tiﬁed using cultures of respiratory secretion could not be conclusively identiﬁed as pathogens(particularly in pneumonia). Second, for the diagnosis of M. pneumoniae, the detection of a single serum antibody (particle agglutination method) and rapid antigen test were used. The rapid
antigen test showed a sensitivity and speciﬁcity of 57.1% and 92.2%, respectively compared tothe throat swab culture (package insert ﬁrst edition, April 2014, Ribotest, Asahi Kasei PharmaCo.) and, therefore, its sensitivity was low. Third, whether administration of the tosuﬂoxacin tosilate ﬁne granule formulation was adequate is questionable under the conditions described above.
However, tosuﬂoxacin tosilate ﬁne granules were effective in almost cases in this study; its efﬁcacy was rapid and the clinical course clearly improved in almost cases. Numerous cases in thisstudy used previous antibiotic therapy (57.5%, 88/153), and other cases were considered as moderate grade pneumonia induced by an antibiotic-resistant pathogen (e.g., cases with a similar clinical course to that of a family member already diagnosed with antibiotic-resistant pneumonia) 5).
Finally, the evaluation of efﬁcacy and adverse events was based mainly on the clinical course andfew examinations were performed (such as blood sampling). Particularly, multiple blood sampling had not been done in almost case (it is hard to take multiple blood samples from children
for medical practitioner). Therefore, there were limitations associated with the evaluation of efﬁcacy and adverse events.
In conclusion, the tosuﬂoxacin tosilate ﬁne granule 15% for pediatrics (MEIJI®) may beequivalent to tosuﬂoxacin tosilate hydrate 15% for pediatrics (Ozex®), in efﬁcacy, adverse events,and medication compliance. Both drugs are extremely effective and safe, particularly for treating
bacterial pneumonia and otitis media, as well as other antibiotic-resistant infection. However,their unregulated use should be discouraged to avoid increasing multi-antibiotic-resistant bacterial infections. To the best of our knowledge, this study is the ﬁrst report showing the efﬁcacy, adverse event incidences, and medication compliance of tosuﬂoxacin tosilate ﬁne granule 15% forpediatrics MEIJI® and the comparison to Ozex®.
Conﬂict of interest (COI) of the author: No potential COI to disclose.

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