Tosufloxacin Research Articles

Effects of early-life tosufloxacin tosilate hydrate administration on growth rate, neurobehavior, and gut microbiota at adulthood in male mice.

Reportedly, antibiotics, which are frequently prescribed in children, have long-term effects owing to gut microbiota dysregulation. Tosufloxacin tosilate hydrate (TFLX) is the first orally administered new quinolone with high efficacy and broad-spectrum action approved as an antibacterial agent for pediatric use in Japan. However, studies on the effects of its early-stage administration are limited. Therefore, we aimed to analyze the later effects of its developmental administration by monitoring growth rate, neurobehavior, and gut microbiota in mice. The TFLX was administered via drinking water at a dose of up to 300 mg/kg for two consecutive weeks during the developmental period (4-6 weeks of age) or adulthood (8-10 weeks of age). Thereafter, the body weights of the mice were measured weekly to monitor growth rate. Behavioral tests were also conducted on 11-12-week-old mice to examine the neurobehavioral effects of the treatment. Further, to examine the effects of the treatment on microbiota, fecal samples were collected from the rectum of mice dissected at 12 weeks of age, and 16s rRNA analysis was conducted. Our results showed increased body weights after TFLX administration, without any long-term effects. Behavioral analysis suggested alterations in anxiety-like behaviors and memory recall dysregulation, and gut microbiota analysis revealed significant differences in bacterial composition. These findings indicated that TFLX administration during the developmental period affects mice growth rate, neurobehavior, and gut microbiota structure. This is the first study to report that TFLX is potentially associated with the risk of long effects.

Recent Trend of Antimicrobial Susceptibility among Mycoplasma pneumoniae Isolated from Japanese Children.

Macrolide-resistant Mycoplasma pneumoniae (MRMP) infections have become increasingly prevalent, especially in East Asia. Whereas MRMP strains have point mutations that are implicated in conferring resistance, monitoring the antibiotic susceptibility of M. pneumoniae and identifying mutations in the resistant strains is crucial for effective disease management. Therefore, we investigated antimicrobial susceptibilities among M. pneumoniae isolates obtained from Japanese children since 2011. To establish the current susceptibility trend, we analyzed the minimum inhibitory concentrations (MICs) of M. pneumoniae in recent years (2017-2020) in comparison with past data. Our observation of 122 M. pneumoniae strains suggested that 76 were macrolide-susceptible M. pneumoniae (MSMP) and 46 were macrolide-resistant. The MIC ranges (µg/mL) of clarithromycin (CAM), azithromycin (AZM), tosufloxacin (TFLX), and minocycline (MINO) to all M. pneumoniae isolates were 0.001->128, 0.00012->128, 0.25-0.5, and 0.125-4 µg/mL, respectively. None of the strains was resistant to TFLX or MINO. The MIC distributions of CAM and AZM to MSMP and MINO to all M. pneumoniae isolates were significantly lower, but that of TFLX was significantly higher than that reported in all previous data concordant with the amount of recent antimicrobial use. Therefore, continuation of appropriate antimicrobial use for M. pneumoniae infection is important.

Drug-induced crystalluria attributable to tosufloxacin in children.

Drug-induced crystalluria is reportedly caused by a large number of drugs. Tosufloxacin (TFLX), a second-generation fluoroquinolone antibiotic, is reported to cause kidney injury and crystalluria. We retrospectively analyzed patients with crystalluria caused by TFLX to clarify the clinical course of TFLX-induced crystalluria in children. This study was designed as a retrospective case series using the database of the National Center for Global Medicine covering the period from January 1, 2020 to March 31, 2021. We enrolled pediatric patients aged 15 years or younger with crystalluria attributable to TFLX treated in our pediatric department and collected clinical data. Thirteen patients were diagnosed with crystalluria attributable to TFLX. The median age of the patients at diagnosis was 4.0 years (range, 0.8-15 years; interquartile range=1.2-8.8 years), and five patients (38%) were male. Six patients (46%) had gastrointestinal symptoms such as vomiting and abdominal pain, and 12 patients (92%) had decreased oral intake. The median time to diagnosis after TFLX administration was 4 days (range, 2-7 days; interquartile range=3-6 days). All patients received TFLX at the appropriate dose. Two patients (17%) were diagnosed with acute kidney injury, and both had gastrointestinal symptoms such as vomiting and abdominal pain. Crystalluria induced by TFLX occurred despite administration of the appropriate dose of TFLX. Physicians should recognize crystalluria and renal injury attributable to TFLX. It may be possible to prevent renal injury by discontinuing drug therapy.

Comparison between antimicrobial stewardship program and intervention by infection control team for managing antibiotic use in neurogenic bladder-related urinary tract infection patients: A retrospective chart audit

BackgroundAntimicrobial prescriptions are relatively common in urologic outpatients. Therefore, it is necessary to investigate the impact of antimicrobial stewardship program (ASP) interventions. MethodsIn urology outpatients, antimicrobial use density (AUD), antimicrobial agent costs, isolation of urinary tract infection (UTI)-causing organisms and their antimicrobial susceptibilities were compared between intervention by infection control team (ICT) era (pre-2014) and ASP era (post-2014) in 2739 patients with lower urinary tract symptoms, including neurogenic bladder patients with UTI or suspected UTI, from 2011 to 2020. ResultsIn the ASP, overall AUD (P<.001), cefotiam (CTM) (P=.0013), 2nd-generation cephalosporins (P=.026), cefdinir (CFDN) (P<.001), levofloxacin (LVFX) (P<.001), sitafloxacin (STFX) (P=.0016), and tosufloxacin (TFLX) (P=.0044) showed a significant decrease, but cefaclor (P=.019) showed a significant increase. Regarding antimicrobial agent costs, overall (P=.016), CTM (P=.021), 2nd-generation cephalosporins (P=.033), CFDN (P=.016), LVFX (P=.016), STFX (P=.033), and TFLX (P=.033) showed a significant decrease in the ASP. UTI-causing antimicrobial susceptibilities, CTM (P=.035), LVFX (P=.026) and sulfamethoxazole/trimethoprim (P=.048) in E. coli, and minocycline (P=.026) in K. pneumoniae showed a significant improve in the ASP. ConclusionASP contributed to decrease AUD and antimicrobial agent costs, and to improve antimicrobial susceptibilities of E. coli and K. pneumoniae to several antibiotics, compared to ICT. Further prospective studies are necessary for definitive conclusions.

Emergence of Haemophilus influenzae with low susceptibility to quinolones isolated from pediatric patients in Japan

IntroductionIn 2010, oral fluoroquinolone tosufloxacin (TFX) granules were released as the first oral respiratory quinolone for children in Japan. MethodsTo investigate the recent trend of H. influenzae strains with low susceptibility to quinolones in children, we analyzed the gene sequences of quinolone resistance-determining regions (QRDRs) of gyrA, gyrB, parC, and parE of 23 clinical isolates from 15 patients aged <15 years with an MIC of ≥0.5 μg/mL for TFX from 2010 to 2018. ResultsAmino acid substitutions were observed in both GyrA and ParC in 13 strains (81%, 13/16), except two strains with a TFX MIC of 0.5 μg/mL with amino acid substitution in only GyrA and one strain with a TFX MIC of 1 μg/mL with no amino acid substitution. Four ST422 strains were observed in 2018, the detection age range was wide (0–7 years), and the residential city was varied. A total of 3/15 patients had a clear history of TFX treatment. ConclusionsEven for the strain with an MIC of 0.5 μg/mL for TFX, it is highly possible that it harbors a mutation in gyrA, which is the first step toward quinolone resistance, and it may also harbor mutations in both gyrA and parC. Furthermore, several specific sequence type quinolone-resistant H. influenzae strains, particularly ST422, may be widespread among children in Japan. It is necessary to investigate changes in resistance both at the MIC and gene levels. The continuous monitoring of strains and the use of antimicrobial drugs in treatment should be carefully observed.

Acute Kidney Injury after Administration of Tosufloxacin Tosilate in Children with &lt;i&gt;Mycoplasma pneumoniae &lt;/i&gt;Pneumonia

Acute Kidney Injury after Administration of Tosufloxacin Tosilate in Children with &lt;i&gt;Mycoplasma pneumoniae &lt;/i&gt;Pneumonia

Drug-induced tubulointerstitial nephritis in a retrospective study using spontaneous reporting system database.

IntroductionTubulointerstitial nephritis (TIN) is a problem in clinical settings because drug therapy is the cause in most cases. Patients often present with nonspecific symptoms, which can lead to delays in the diagnosis and treatment of the disease. The purpose of this study was to clarify the rank-order of the association of TIN with the causative drugs using a spontaneous reporting system database.Materials and methodsData were extracted from the Japanese Adverse Drug Event Report database of the Pharmaceuticals and Medical Devices Agency (Japan). Based on 5,195,890 reports of all adverse reactions, we obtained 3,088 reports of TIN caused by all drugs and calculated the reporting odds ratio (ROR) and 95% CI for TIN.ResultsThe 5 drugs with the highest RORs were gliclazide (ROR, 30.5; 95% CI, 17.4–53.2), tosufloxacin tosilate hydrate (ROR, 29.5; 95% CI, 21.3–41.0), piperacillin–tazobactam (ROR, 24.3; 95% CI, 19.4–30.5), cefteram pivoxil (ROR, 23.5; 95% CI, 12.5–44.2), and mefenamic acid (ROR, 22.5; 95% CI, 13.4–37.7). No sex-related difference was observed in drug-induced TIN. Most of the reports about TIN onset following the administration of culprit drugs were recorded within 12 weeks.ConclusionBased on the results, a comprehensive study using a pharmacovigilance database enabled us to identify the dugs that most frequently induced TIN, so these drugs should be used carefully in clinical practice to avoid TIN.

JAID/JSC Guidelines for Infection Treatment 2015-Intestinal infections.

JAID/JSC Guidelines for Infection Treatment 2015-Intestinal infections.

Killing kinetics of minocycline, doxycycline and tosufloxacin against macrolide-resistant Mycoplasma pneumoniae

Macrolide-resistant Mycoplasma pneumoniae (MRMP) has emerged and is increasing worldwide. In a 2011 outbreak of MRMP infections in Japan, symptoms failed to improve in many patients who initially received macrolides; the therapeutic agent was then changed to minocycline (MIN), doxycycline (DOX) or tosufloxacin (TFX). In this study, the bactericidal effects of these three agents against MRMP were evaluated. Time–kill kinetics against MRMP and macrolide-susceptible M. pneumoniae (MSMP) were determined for 5 days at concentrations corresponding to the respective minimum inhibitory concentration (MIC) and 2 × MIC, i.e. 1 µg/mL and 2 µg/mL for MIN, 0.5 µg/mL and 1 µg/mL for DOX, and 0.5 µg/mL and 1 µg/mL for TFX. The post-antibiotic effects (PAE) of these agents in culture against MRMP were also examined based on their pharmacokinetic parameters in children. Following exposure of MRMP and MSMP to up to twice the respective MICs of MIN, DOX and TFX, viable cells initially numbering 106 CFU/mL had decreased similarly to 103 CFU/mL after 4 days. Clarithromycin and azithromycin showed good bactericidal action against MSMP but not against MRMP. PAEs against MRMP appeared superior with MIN and DOX compared with TFX. In infection with M. pneumoniae having a generation time exceeding 6 h, a therapeutic agent must be selected in consideration of pharmacokinetic parameters, not MICs alone.

Emergence of quinolone-resistant strains in Streptococcus pneumoniae isolated from paediatric patients since the approval of oral fluoroquinolones in Japan.

Tosufloxacin (TFLX) is a fluoroquinolone antimicrobial agent. TFLX granules for children were initially released in Japan in 2010 to treat otitis media and pneumonia caused by drug-resistant bacteria, e.g. penicillin-resistant Streptococcus pneumoniae and beta-lactamase-negative, ampicillin-resistant Haemophilus influenzae. The evolution of bacterial resistance since TFLX approval is not known. To clarify the influence of quinolones administered to children since their approval, we examined the resistance mechanism of TFLX-resistant S.pneumoniae isolated from paediatric patients as well as patient clinical characteristics. TFLX-resistant strains (MIC≥2mg/L) were detected among clinical isolates of S.pneumoniae derived from children (≤15 years old) between 2010 and 2014. These strains were characterised based on quinolone resistance-determining regions (QRDRs), i.e. gyrA, gyrB, parC, and parE. In addition, the antimicrobial susceptibility, serotype, and multilocus sequence type of strains were determined, pulsed-field gel electrophoresis was performed, and patient clinical characteristics based on medical records were assessed for cases with underling TFLX-resistant strains. Among 1168 S.pneumoniae isolates, two TFLX-resistant strains were detected from respiratory specimens obtained from paediatric patients with frequent exposure to TFLX. Both strains had mutations in the QRDRs of gyrA and parC. One case exhibited gradual changes in the QRDR during the clinical course. This is the first study of quinolone-resistant S.pneumoniae isolated from children, including clinical data, in Japan. These data may help prevent increases in infections of quinolone-resistant S.pneumoniae in children; specifically, the results emphasise the importance of administering fluoroquinolones only in appropriate cases.

Biological safety evaluation of the modified urinary catheter.

The purpose of this study was to evaluate in vitro safety of the novel tosufloxacin (TOS)-treated catheters with the prolonged antimicrobial activity. The test samples of silicone latex catheter were prepared by the immobilization of TOS on chitosan (CHIT)-coated catheter by means of covalent bonds and non-covalent interactions. Each step of the modification process of catheter surface was observed using ATR-Fourier transform infrared spectroscopy. In vitro cytotoxicity of the modified and unmodified catheters was assessed by direct and indirect tests in accordance with ISO standards using green monkey kidney (GMK) cell line. The MTT, lactate dehydrogenase activity (LDH), WST-8, Sulforhodamine B (SRB) test results and microscopic observation clearly indicated that unmodified silicone latex catheters decrease cell metabolic activity, act as a cytotoxic agent causing cell lysis and induce cell death through necrotic or apoptotic process. We suggest that chitosan coat with TOS immobilized limits leaching of harmful agents from silicone latex material, which significantly enhances survivability of GMK cells and therefore is quite a good protection against the cytotoxic effect of this material.

小児マイコプラズマ感染症の治療期間に影響を与える要因の探索

Mycoplasma pneumonia is caused by infection of Mycoplasma pneumoniae, and is a frequently occurring infectious disease transmitted from children to young adults. Macrolides are recommended as first-line drugs, minocycline (MINO) and tosufloxacin (TFLX) are used for the second-line drugs. In this study, we investigated the factors affecting the treatment period of mycoplasma pneumonia.We compared the effects of azithromycin (AZM), TFLX and MINO. The duration from hospitalization to defervescence was shorter in the MINO group than in the TFLX group. We then attempted to identify the factors that affect the treatment period of mycoplasma pneumonia. Patients who were treated in accordance with the Guidelines for the Management of Respiratory Infectious Diseases in Children in Japan 2011 (Guideline) showed shorter duration of fever and disease duration as compared with patients who were not treated in accordance with the guidelines.In the case macrolides are ineffective, quickly switching to other drugs showed higher efficiency. In the light of these results, as treatment is carried out in accordance with the Guidelines, the disease and fever periods are shortened, and prolonged treatment in children could be prevented. These results also suggest that MINO is more effective for the treatment of mycoplasma pneumonia than TFLX.

A study on the distribution of T-3262 (tosufloxacin tosilate) in salivary glands of rats using microautoradiography

The distribution of T-3262 (tosufloxacin tosilate) in salivary glands of rats was investigated with frozen-microautoradiography. One and 4 hours after oral administration of 14C-T-3262 at 100 mg/kg to rats submandibular glands, parotid glands and sublingual glands were removed, and a microautoradiogram of each was made. In the submandibular gland and the parotid gland 14C-T-3262 was distributed at high levels throughout the glands taken at 1 and 4 hours after administration, but lower levels than the other glands were found in the sublingual gland at 1 hour. The results of this study suggested that T-3262 penetrates effectively into the saliva, because 14C-T-3262 is distributed well into glandular acinus, striated duct and excretory duct. The microautoradiography was a useful and reliable method for investigating the distribution of antimicrobial agents in salivary glands.

総説 [最新の抗菌薬XXXV] Tosufloxacin tosilate

総説 [最新の抗菌薬XXXV] Tosufloxacin tosilate

急性歯性感染症に対するAzithromycinの薬効評価 Tosufloxacin tosilateを対照とした二重盲検群間比較試験

To objectively assess azithromycin (AZM) for its clinical efficacy, safety and usefulness in the treatment of acute odontogenic infections (periodontitis, pericoronitis and osteitis of the jaw), a double-blind, randomized, multi-center trial was conducted in which tosufloxacin tosilate (TFLX) was used as the control drug. AZM was administered to 90 patients at a once-daily 500 mg dose for 3 days, while TFLX was given to 90 patients at a 150 mg t.i.d. dose for 7 days. 1. The clinical efficacy rates calculated according to evaluation at an endpoint set on the 3rd day of treatment by a committee of experts were 85.9% (73/85) in the AZM group and 78.9% (71/90) in the TFLX group. No statistically significant difference between the treatment groups was detected, and clinical equivalence was verified (p = 0.002). 2. The clinical efficacy rates according to evaluations made by investigators at the end-of-tail point was 87.1% (74/85) in the AZM group and 73.3% (66/90) in the TFLX group. The efficacy rate in the AZM group was higher than that in the TFLX group, and the difference was statistically significant (p = 0.006). 3. The bacteriological elimination rate in the AZM group was 97.5% (39/40) and that in the TFLX group was 85.7% (30/35), but the difference was deemed statistically not significant. 4. Adverse reactions were observed in 11 of 88 cases (12.5%) in the AZM group and 5 of 90 cases (5.6%) in the TFLX group. Six of 85 cases (7.1%) in the AZM group and 5 of 85 cases (5.9%) in the TFLX group showed laboratory abnormalities. However, neither adverse reactions nor laboratory abnormalities showed any differences in statistical significance between the treatment groups. 5. The safety rates, expressed as percentages of cases with no adverse events and no laboratory abnormalities, was 84.1% (74/88) in the AZM group and 90.0% (81/90) in the TFLX group. The difference between the two groups was found to be statistically insignificant. 6. The usefulness rates, the ratio of cases rated as either "Very useful" or "Useful", was 83.9% (73/87) in the AZM group, and it was statistically higher (p = 0.025) than 72.2% (65/90) obtained for TFLX group. Judging from the above results, it has been concluded that AZM is as useful as TFLX in the treatment of acute dental infections.

トシル酸トスフロキサシン (TFLX) の食後単回・連続投与時の副鼻腔粘膜・組織内濃度の検討

トシル酸トスフロキサシン (TFLX) の食後単回・連続投与時の副鼻腔粘膜・組織内濃度の検討

Moxifloxacin is more effective than tosufloxacin in reducing chemotherapy-induced febrile neutropneia in patients with hematological malignancies

Recent studies have shown the prophylactic efficacy of fluoroquinolones against infections in patients with chemotherapy-induced neutropenia. However, little is known about the differences between fluoroquinolones, and there are some concerns about the emergence of resistant bacteria. In this retrospective study, we compared the prophylactic efficacy of moxifloxacin (MFLX) and tosufloxacin (TFLX) for chemotherapy-induced febrile neutropenia. The cumulative incidences of febrile neutropenia were 74.7% (59 of 79) in the MFLX group and 81.1% (219 of 270) in the TFLX group (log-rank test p = 0.044). Subgroup analysis revealed a more prominent prophylactic advantage of MFLX in patients with acute myeloid leukemia (AML) or long duration of neutropenia (p = 0.013 and 0.008, respectively). There were no significant differences in the incidences of adverse events and fluoroquinolone resistant bacteria in both groups. This study indicates that prophylaxis with MFLX is more beneficial to reduce febrile neutropenia episodes than TFLX, especially in patients with high-risk disease.

The efficacy of sequential therapy using pazufloxacin followed by oral fluoroquinolones for treatment of pyelonephritis

The efficacy of sequential therapy of pazufloxacin (PZFX), which is a parenteral fluoroquinolone, followed by oral fluoroquinolones [tosufloxacin tosilate (TFLX) or levofloxacin (LVFX)] for treatment of pyelonephritis, was evaluated. Patients with pyelonephritis who had fever (≥37.5°C), pyuria (≥10 white blood cells/high-power field), and bacteriuria (≥10(4) colony-forming units/ml) were eligible for this study. PZFX (500mg) was given intravenously twice a day for at least 3days. If the patients were clinically improved, TFLX (150mg) or LVFX (100mg) was then administered orally three times a day for at least 5days. Patients underwent clinical and microbiological evaluation at 5-9days after final drug administration. Clinical and microbiological efficacy could be assessed in 21 of 25 cases enrolled. Both clinical and microbiological efficacy rates were 81.0% (17/21 cases). In the effective cases, the mean administration time was 4.2days for PZFX and 6.0days for oral fluoroquinolones. The mean time to defervescence was 3.4days for the effective cases. In the four treatment failure cases, three quinolone-resistant Escherichia coli and a quinolone-resistant Enterococcus faecalis were isolated. This sequential therapy seemed to be clinically effective in the treatment of pyelonephritis; however, the prevalence of quinolone-resistant E. coli should be taken into account.

Rapid Effectiveness of Minocycline or Doxycycline Against Macrolide-Resistant Mycoplasma pneumoniae Infection in a 2011 Outbreak Among Japanese Children

Mycoplasma pneumoniae is a major pathogen causing community-acquired pneumonia in children and young adults. Outbreaks typically occur at intervals of several years. In 2011, a widespread outbreak was associated with macrolide-resistant M. pneumoniae (MRMP) in Japanese children, often those of school age. Two hundred fifty-eight children were diagnosed with M. pneumoniae-associated pneumonia based on chest radiography, real-time polymerase chain reaction (PCR), and antibody titers between January and December 2011. Mycoplasma pneumoniae cultures obtained from nasopharyngeal samples using appropriate broth were subjected to real-time PCR, by which decreases in M. pneumoniae in patients treated with minocycline (MIN), doxycycline (DOX), or tosufloxacin (TFX) were calculated. Mutations of the 23S ribosomal RNA gene that confer high resistance to macrolides in M. pneumoniae were identified by DNA sequencing. Among 202 M. pneumoniae isolates from M. pneumoniae-associated pneumonia patients, 176 (87.1%) were MRMP. Macrolide-resistant M. pneumoniae infection was significantly related to school age (P < .01) and initial administration of macrolides (P < .01). Minocycline or DOX (n = 125) or TFX or levofloxacin (n = 15) was used for definitive treatment of MRMP patients. Minocycline or DOX was significantly more effective than TFX (P ≤ .05) in achieving defervescence within 24 hours and in decreasing numbers of M. pneumoniae DNA copies 3 days after initiation. Macrolides are inappropriate as first-choice agents against MRMP in terms of shortening the clinical course and decreasing M. pneumoniae. Control and prevention of MRMP outbreaks in children require early decreases in M. pneumoniae as well as improvement of clinical findings.

Clinical Efficacy of Tosufloxacin Tosilate Hydrate for the Treatment of Acute Otitis Media in Children

Special attention has been focused on the recent problem of pediatric acute otitis media. The increase in the number of pediatric patients with intractable acute otitis media has been a serious problem in the clinical setting of ENT clinics and hospitals. Such a change in the clinical figures of otitis media may be due to the social environment, including the tendency for more very young children to be looked after at nurseries, and the increase in drug-resistant bacteria. In the clinical guidelines for the treatment of pediatric acute otitis media, published in 2006 and revised in 2009, a classification of severity according to scoring of symptoms and tympanic membrane findings was proposed and a severity-oriented treatment algorithm was recommended. In response to the proliferation of drug-resistant bacteria, we have also emphasized the importance of the proper use of antimicrobials and have promoted a correct assessment of the clinical efficacy of various antimicrobial agents according to the scoring system recommended by the guidelines. In this study, we employed this severity classification by the scoring system to examine the usefulness and bacteriological efficacy of tosufloxacin (TFLX) fine granules (6 mg/kg bid), a novel pediatric quinolone antimicrobial, in 106 children aged 15 or under diagnosed with moderate or severe acute pediatric otitis media. We obtained the following results. The clinical response rate to TFLX was 98.1% (104/106) according to the score-oriented evaluation and 97.2% (103/106) as conventionally judged by the treating physicians. Bacterial pathogens detected in this study were Haemophilus influenzae 37.7% (40/106), Streptococcus pneumoniae 32.1% (34/106) and Moraxella catarrhalis 6.6% (7/106). At the time of completion of TFLX administration, the rate of bacterial elimination was 95.8% (69/72). Only one patient experienced mild diarrhea as an adverse drug reaction.