A Case of Type I Food Allergy Induced by Monosodium Glutamate.

Monosodium glutamate (MSG), a salt form of a non-essential amino acid, is widely used as a food additive, particularly in Asian cuisines, due to its unique flavor-enhancing qualities. Type I allergic reactions to MSG have not previously been reported. Our patient, a 21-year-old woman, was 14 years old when she first noticed swelling of her tongue (but no oral itching, diarrhea, or abdominal pain) after eating various snack foods. Current skin prick testing elicited a weak positive reaction to MSG. We then performed an oral challenge test during which our patient ingested potato snacks. Subsequent histology showed telangiectasia of the buccal mucosa, interstitial edema in the subepithelial submucosa, and mast cell infiltration. Oral mucosal challenge tests using sodium glutamate confirmed oral swelling in this patient. This report is the first to confirm a case of type 1 allergy to MSG by combining pathology findings with the results of challenge testing.

Intravenous cyclophosphamide and immunoglobulin ameliorated visual field defects in a patient with eosinophilic granulomatosis with polyangiitis.

Treating ocular involvement in eosinophilic granulomatosis with polyangiitis (EGPA) can be challenging. We present the case of a 37-year-old woman with EGPA who had severe bilateral visual field defects. Laboratory results showed leukocytosis (17,500 WBC/µL, 25.8 % eosinophils), negative MPO-ANCA titer, and elevated PR3-ANCA level (33.2 IU/mL). Diffusion-weighted MRI revealed bilateral hyperintense occipital lesions, which were more prominent on the left. Her therapy initially included a steroid pulse, followed by daily prednisolone, but her visual field defects remained refractory. The addition of intravenous cyclophosphamide (5 courses) and intravenous immunoglobulin decreased her optic neuropathy and resolved her visual field defects.

Dupilumab suppresses relapsing chronic eosinophilic pneumonia with severe asthma.

Dupilumab-induced hypereosinophilia is mediated by blockade of the IL-4/IL-13 pathway, which reduces eosinophil migration from peripheral blood. The increase in peripheral blood eosinophils may lead to chronic eosinophilic pneumonia (CEP) and/or eosinophilic granulomatosis with polyangiitis, but a direct causal connection between dupilumab and eosinophilic lung diseases has not been established. A 33-year-old Japanese woman with bronchial asthma since age three was treated with fluticasone propionate plus salmeterol twice daily after several asthma exacerbations at age 17. Her course was complicated by CEP at age 33 which resolved without the need for systemic steroids. However, in the four months following resolution of her CEP, the patient had three asthma exacerbations, and a recurrence of CEP, with blood leukocytes of 8500/µL, of which 25.0% were eosinophils. She was treated with prednisolone 50 mg/day, but she could not continue this dose due to the onset of myalgia. Then she had relapsing CEP twice within three months. She was treated with prednisolone 15 mg/day for CEP, but she had persistent asthma for more than one month; dupilumab was added at 600 mg, followed by 300 mg every two weeks. In the first month of treatment with dupilumab, the patient's asthma symptoms resolved completely, and she had only one relapse of CEP. In 12 months of follow-up, she had neither an asthma exacerbation nor another relapse of CEP. Dupilumab may be a promising treatment for patients with refractory asthma complicated by recurring CEP and undesirable steroid side effects.

Eosinophilic granulomatosis with polyangiitis and severe cardiac involvement in a patient surviving for 34 years.

INTRODUCTION: Many studies have reported a poor prognosis for eosinophilic granulomatosis with polyangiitis (EGPA) patients with cardiac involvement. CASE STUDY: A woman developed EGPA at 37 years of age, with weight loss, numbness in the right upper and lower extremities, muscle weakness, skin rash, abdominal pain, chest pain, an increased peripheral blood eosinophil count (4165/µL), and necrotizing vasculitis on peroneal nerve biopsy. The patient was treated with prednisolone, immunosuppressants, intravenous immune globulin, and mepolizumab, but she experienced many relapses, with chest pain, abdominal pain, numbness, and paralysis, over a long period. The patient died from aspiration pneumonia at 71 years of age after undergoing left total hip arthroplasty for left hip neck fracture. RESULTS: Autopsy showed bronchopneumonia in the lower lung lobes on both sides, as well as infiltration of inflammatory cells, including neutrophils and lymphocytes. There was no evidence of active vasculitis in either the lung or colon. At autopsy the heart showed predominantly subendocardial fibrosis and fatty infiltration, but no active vasculitis or eosinophilic infiltration. CONCLUSION: To our knowledge, there have been no autopsy reports of EGPA patients who have survived for 34 years with recurrent cardiac lesions. In this case, the cardiac involvement (active vasculitis and eosinophilic infiltration) had improved by the time of death.

Long-term mepolizumab treatment reduces relapse rates in super-responders with eosinophilic granulomatosis with polyangiitis.

BACKGROUND: The mainstay of treatment for eosinophilic granulomatosis with polyangiitis (EGPA) is systemic corticosteroid therapy; some patients also receive intravenous immunoglobulins, other immunosuppressive agents, and biologics. Mepolizumab, an anti-interleukin-5 monoclonal antibody, induces remission and decreases the daily corticosteroid dose; however, the clinical efficacy of mepolizumab in EGPA and the prognosis with long-term treatment with this drug are unknown. METHODS: Seventy-one EGPA patients were treated at Hiratsuka City Hospital, Japan, between April 2018 and March 2022. We administered mepolizumab for a mean of 2.8 ± 1.7 years to 43 patients in whom remission could not be induced by conventional treatment. After excluding 18 patients who had received mepolizumab for less than 3 years, we classified 15 patients into a "super-responder group" (the daily dose of corticosteroids or other immunosuppressant could be decreased, or the interval between IVIG treatments could be prolonged) and 10 patients into a "responder group" (neither of these changes was achievable). Eosinophil numbers, serum IgG levels, daily doses of corticosteroids and other immunosuppressants, Birmingham Vasculitis Activity Score (BVAS), and relapse frequency before and after mepolizumab initiation were determined. RESULTS: Blood eosinophil count at diagnosis and the lowest serum IgG level before mepolizumab treatment were significantly higher in super-responders than in responders (p < 0.05). In super-responders, the prednisolone dose at last visit on mepolizumab treatment was lower than that before treatment (p < 0.01) and lower than that at last visit in the responders (p < 0.01). In both groups, peripheral blood eosinophil numbers and BVAS were lower after starting mepolizumab than before (p < 0.01). BVAS before mepolizumab (p < 0.05) and at last visit (p < 0.01) were lower in super-responders than in responders. Relapse rates every year after the start of mepolizumab were lower in super-responders than in responder groups (p < 0.01). In super-responders, relapse rates were lower during the 3 years following mepolizumab initiation (p < 0.01) and at last visit (p < 0.01) were significantly lower than after 1 year of treatment. CONCLUSION: Mepolizumab treatment of super-responders sustainably reduced the relapse rate.

Complications of cerebral air embolism associated with pleural lavage for empyema.

Standard initial treatment for acute empyema involves antibiotic administration and chest tube drainage; however, pleural lavage with saline is another treatment that mitigates the need for surgical drainage. Although this treatment is recognised as non-invasive and safe, the complications of cerebral air embolism are less recognised.In this case, a man in his late 40s was diagnosed with acute empyema and treated with chest tube (28 Fr) drainage and antibiotics. Empyema remained on follow-up chest imaging; thus intrapleural fibrinolytic therapy (urokinase 120 000 units/day for a total of 3 days) and pleural lavage (0.9% saline 1000 mL/day daily) were administered. During the 10th pleural lavage, the patient suddenly became unconscious. Head imaging revealed a cerebral air embolism. Consequently, he received urgent hyperbaric oxygen therapy and improved without any neurological sequelae.Clinicians should be aware of the complications of sudden cerebral air embolism due to pleural lavage for empyema.

Correlations among age, sex, axial length, and subfoveal choroidal thickness in the choriocapillaris structure analyzed using multiple en face image averaging optical coherence tomography angiography.

PURPOSE: To analyze the structure of the choriocapillaris in healthy eyes by using averaged en face images acquired using swept source optical coherence tomography angiography and to examine the changes in the macular profile in relation to age, sex, axial length, and choroidal thickness. METHODS: This prospective, cross-sectional study included 81 eyes of 81 subjects without ophthalmologic or systemic diseases who underwent a full ophthalmologic examination, including 3 × 3-mm macular optical coherence tomography angiography. Four to nine choriocapillaris en face images were registered and averaged. The averaged images were then binarized and analyzed. RESULTS: The averaged choriocapillaris images showed a continuous capillary meshwork, whereas the unaveraged images had a granular appearance. The mean total area and size of flow voids were 0.99 ± 0.20 mm2 and 567.8 ± 201.5 µm2, respectively, and these values correlated positively with age (p = 0.002, R = 0.336 and p = 0.026, R = 0.247, respectively). Age-related gains in the mean total area and flow void size were 4.20 × 10-3 mm2 and 3.07 µm2 per year, respectively. However, the mean total area and flow void size had no significant correlation with axial length, subfoveal choroidal thickness, or sex. CONCLUSIONS: Multiple averaged en face swept source optical coherence tomography angiography is more effective than a single optical coherence tomography angiography scan for better visualizing the choriocapillaris. The total area and size of flow voids within a 3 × 3-mm macular area positively correlated with age. This technique can be useful for investigating the changes arising in macular diseases.

Nivolumab-induced Vogt-Koyanagi-Harada-like Syndrome and Adrenocortical Insufficiency with Long-term Survival in a Patient with Non-small-cell Lung Cancer.

A 58-year-old man was diagnosed with lung adenocarcinoma with a tumor proportion score of 10%. After six cycles of second-line chemotherapy with nivolumab, he achieved a complete response (CR) but developed uveitis and sensorineural hearing disorder, which were consistent with Vogt-Koyanagi-Harada (VKH)-like syndrome. Simultaneously, pituitary adrenocortical insufficiency was identified. Nivolumab discontinuation and systemic corticosteroid administration resolved these immune-related adverse events (irAEs). The patient has maintained a CR without any chemotherapy for approximately two years. We herein report a patient with a long-term progression-free survival despite chemotherapy discontinuation due to irAEs, including VKH-like syndrome, which were appropriately managed.

Efficacy and safety of carboplatin and pemetrexed followed by maintenance with pemetrexed for elderly patients with advanced non-squamous non-small cell lung cancer: A single-arm, open-label, multicenter, phase II study.

PURPOSE: Carboplatin plus pemetrexed followed by maintenance pemetrexed is expected to be well-tolerated by the elderly. This multicenter, prospective study examined the efficacy and tolerability of the regimen in elderly patients with previously untreated advanced non-squamous non-small cell lung cancer. METHODS: The primary endpoint was the 1-year survival rate, with secondary endpoints of response rate (RR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse event rate. Efficacy was compared between patients with performance status (PS) 0 and 1. RESULTS: Forty-one patients were enrolled between March 2011 and April 2016. Median age was 76.0 years. The 1-year survival rate was 73% (95% confidence interval (CI), 56-84%). RR was 44%, DCR was 81%, median PFS was 7.2 months (95%CI, 3.98-9.20 months), and median OS was 17.4 months (95%CI, 13.60-22.83 months). Twenty-one patients (51%) transitioned to maintenance therapy. Toxicities of grade ≥ 3 during the induction phase included anemia (37%), thrombocytopenia (29%), neutropenia (22%), appetite loss (15%), nausea (10%), bacterial pneumonia (7%), febrile neutropenia (5%), and interstitial pneumonia (2%). Treatment was discontinued in two patients with interstitial pneumonia, but no deaths were encountered. During the maintenance phase, one patient needed dose reductions due to phlegmon. No significant difference in efficacy was seen between PS 0 and PS 1. CONCLUSION: Carboplatin and pemetrexed followed by maintenance pemetrexed for non-squamous non-small cell lung cancer in elderly patients appear effective and tolerable.

MicroRNA-200b is a potential biomarker of the expression of PD-L1 in patients with lung cancer.

BACKGROUND: Advanced non-small cell lung cancer (NSCLC) has a high mortality rate and poor prognosis. However, outcomes have gradually improved after the introduction of novel immunotherapies, including immune checkpoint inhibitors (ICIs). Although programmed death-ligand 1 (PD-L1) expression in tumor tissues is a known biomarker for guiding ICI treatment of NSCLC, challenges such as difficulty of liquid biopsy and heterogeneous results during treatment persist. This study evaluated the potential of miR200b as a surrogate biomarker for PD-L1 expression. METHODS: We used the human lung cancer cell lines H226, H460, H520, A549, and H1975. miR200b expression in blood and bronchoscopy specimens of NSCLC patients was evaluated using reverse-transcription-quantitative PCR. Using flow cytometry, PD-L1 expression in vitro, as well as in tumor tissues, was evaluated after transfection with a mimic miR200b or siRNA. RESULTS: miR200b expression negatively correlated with PD-L1 expression in all cell lines. The induction or knockdown of miR200b also altered PD-L1 expression in vitro. The patient group with a PD-L1 tumor proportion score ≥ 50% had significantly lower miR200b expression in the bronchoscopy specimens (P = 0.025) and serum-derived exosomes (P = 0.022) than that with PD-L1 tumor proportion score < 50%. CONCLUSIONS: miR200b can regulate PD-L1 expression in lung cancer cells, and miR200b expression in clinical specimens negatively correlated with PD-L1 expression. Thus, miR200b may be a useful surrogate biomarker for PD-L1 expression in lung cancer patients. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: High PD-L1 expression was linked to low miR200b expression, whereas low PD-L1 expression was linked to high miR200b expression in human lung cancer patients. Thus, miR200b overexpression or silencing can control PD-L1 expression in cancer cells. What this study adds We demonstrated the potential of miR200b as a surrogate biomarker for PD-L1 expression in lung cancer patients.

Analysis of targeted somatic mutations in pleomorphic carcinoma of the lung using next-generation sequencing technique.

BACKGROUND: Pleomorphic carcinoma (PC) of the lung is a rare type of lung cancer with aggressive characteristics and a poor prognosis. Because it is rare, the molecular characteristics of PC remain unclear. METHODS: A gene mutation analysis was performed using next-generation sequencing (NGS) in patients with PC of the lung who had undergone surgical resection. RESULTS: A total of nine patients were enrolled in the study. All the patients were male and eight had a history of smoking. Eight tumors contained spindle cells and three contained giant cells. Mutations considered significant were found in eight of the nine patients: in TP53 in five patients, in MET in two patients, and in ALK, ERBB2, PIK3CA, APC, NF1, and CDKN2A in one patient each. No EGFR mutation was detected in our analysis. Co-mutations were detected in three patients: TP53 with MET and NF1, TP53 with ERBB2, and PIK3CA with CDKN2A. CONCLUSIONS: TP53 mutations were detected most frequently in PC of the lung with NGS analysis. Different co-mutations were seen in several specimens. KEY POINTS: Significant findings of the study This study demonstrates that mutations in the TP53 gene are frequently found and co-mutations are sometimes found in pleomorphic carcinoma of the lung using genomic profiling analysis. What this study adds Our results will help to analogize the genetic characteristics and potential target of molecular-targeted agents of pleomorphic carcinoma of the lung.

Afatinib + bevacizumab combination therapy in EGFR-mutant NSCLC patients with osimertinib resistance: Protocol of an open-label, phase II, multicenter, single-arm trial.

INTRODUCTION: As most patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) develop progressive disease after treatment with osimertinib, it is important to develop more effective treatment options. Afatinib has been shown to be more effective in in vitro studies than osimertinib when used in cancer cell lines containing some specific EGFR mutations. Therefore, afatinib may be an effective solution, especially when used in combination with an anti-VEGF agent such as bevacizumab. METHODS: A phase II multicenter, open-label, single-arm trial has been initiated to evaluate the efficacy and safety of afatinib and bevacizumab combination as salvage therapy for EGFR-mutated lung cancer in patients previously treated with osimertinib. The primary endpoint will be the objective response rate (ORR) and secondary endpoints are progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs). DISCUSSION: A previous study indicated that afatinib inhibits lung cancer cells with specific EGFR mutations more effectively than other EGFR-TKIs such as osimertinib. Therefore, we expect that combination therapy using afatinib and bevacizumab will be effective in patients previously treated with osimertinib (registration no. jRCTs031190077).

Neuroleptic malignant syndrome as part of an akinetic crisis associated with sepsis in a patient with Lewy body disease.

A 65-year-old Japanese woman with Parkinson's disease, later diagnosed with Lewy body disease, presented with a 2-day history of systemic tremors. She also had fever without rigidity or creatine kinase (CK) elevation. She was diagnosed with sepsis caused by pyelonephritis with acute kidney injury and parkinsonism exacerbation. Although antibiotic and fluid therapy improved her pyuria and renal function, her fever and tremors persisted. On the fourth day, her symptoms worsened and resulted in cardiopulmonary arrest; however, quick resuscitation allowed the return of spontaneous circulation. Simultaneously, hyperthermia, altered consciousness, extrapyramidal symptoms, dysautonomia and CK elevation were noted. Thus, dantrolene administration was initiated with a tentative diagnosis of neuroleptic malignant syndrome (NMS). This caused her fever to subside, and her symptoms gradually improved. It was difficult to distinguish between parkinsonism exacerbation associated with sepsis and NMS. Physicians should consider NMS early on, even if the patient does not fulfil the diagnostic criteria.

Persistent metamorphopsia associated with branch retinal vein occlusion.

PURPOSE: To investigate longitudinal changes in metamorphopsia associated with branch retinal vein occlusion. METHODS: In this prospective observational case series, we included 32 eyes (32 patients) with branch retinal vein occlusion and acute macular edema. Eyes were treated as needed with intravitreal ranibizumab injections for 12 months. At baseline and 1, 6, and 12 months after initiating treatment, metamorphopsia was quantified using M-CHARTS. Retinal morphology was examined through optical coherence tomography. RESULTS: Logarithm of the minimum angle of resolution visual acuity progressively improved from 0.342 ± 0.304 (Snellen equivalent: 20/44) at baseline to 0.199 ± 0.259 (20/32) and 0.118 ± 0.195 (20/26) at 1 and 12 months, respectively (both P < 0.001). The M-CHARTS score significantly decreased from 0.63 ± 0.61 at baseline to 0.45 ± 0.50 at 1 month (P = 0.044), but no further improvement was achieved with 1 year of additional treatment (6 months: 0.47 ± 0.53 [P = 0.094] and 12 months: 0.50 ± 0.44 [P = 0.173]). Three (13.6%) of 22 eyes with baseline metamorphopsia had complete metamorphopsia resolution. At 12 months, the M-CHARTS score was correlated with baseline foveal thickness (r = 0.373, P = 0.035) and the baseline M-CHARTS score (r = 0.503, P = 0.003). A multiple regression analysis revealed that only the baseline M-CHARTS score was correlated with the 12-month M-CHARTS score (ß = 0.460, P = 0.027). CONCLUSIONS: Eyes with branch retinal vein occlusion often have persistent metamorphopsia, even when visual acuity and retinal morphology improve. Metamorphopsia at 12 months was correlated with metamorphopsia and foveal thickness at baseline.

One-year outcomes of fixed treatment of intravitreal aflibercept for exudative age-related macular degeneration and the factor of visual prognosis.

The aim of this study was to investigate the efficacy of periodic intravitreal aflibercept (IVA) in exudative age-related macular degeneration, and to explore the predictive factors for visual outcome.This is a prospective interventional case series.Fifty-two eyes of 52 treatment-naïve age-related-macula-degeneration patients were enrolled. All participants received IVA bimonthly following 3 monthly loading dose. The primary endpoint was change in best corrected visual acuity (BCVA) and central retinal thickness (CRT), and the secondary outcomes included changes in subfoveal choroidal thickness (SCT), macular atrophy (MA), and retinal average sensitivity (AS) determined by microperimetry at 12 months compared with baseline. The predictive factors for the change of BCVA were examined.Of 52 enrolled patients, 4 patients were drop out. Remaining 48 patients were examined. Mean logMAR BCVA significantly improved from 0.42 ±â€Š0.37 at baseline to 0.29 ±â€Š0.34 at 12 months (P = .008). Mean CRT and SCT significant reduced from 285.6 ±â€Š135.2 µm, 247.9 ±â€Š96.7 µm at baseline to 233.4 ±â€Š98.0 µm, 208.1 ±â€Š94.6 µm at 12 months, respectively (P < .001). At 12 months, 35 eyes of 48 eyes (72.3%) were archived dry macula. MA occurred in 7 eyes of 35 eyes with dry macula at 12 months (20.0%). AS was significant improved (P = .027) between baseline (median: 15.7 dB) and 12 months (median: 19.5 dB). The BCVA of the cases with MA involved fovea was significant worse. Age was significantly predicted for the BCVA at 12 months.IVA administered over 1 year improved BCVA, AS, and morphological findings, and the predictive factors for BCVA were age and MA-involved fovea.

Necrotising soft tissue infection without systemic toxicity in a patient with rheumatoid arthritis treated with tocilizumab.

A Japanese woman aged 76 years with rheumatoid arthritis treated with prednisolone and tocilizumab presented with a 2-day history of redness and pain in her right thigh. She was hospitalised with a primary diagnosis of cellulitis and antimicrobial therapy was initiated. She had been stable until the fourth day of admission, when the swelling of her right thigh rapidly worsened and demonstrated purpura; she was subsequently unable to walk because of the pain. A diagnosis of necrotising soft tissue infection (NSTI) was made and extensive debridement was performed. Over the next 4 months, additional debridement was performed four times. Her condition improved significantly and she was able to walk later. Physicians should recognise that tocilizumab can mask systemic toxicities and inflammatory findings even in severe infections. To avoid delays in diagnosis and surgical intervention, clinicians should consider NSTIs when they encounter patients treated with tocilizumab, even if it mimics cellulitis.

Clinical Course of Eosinophilic Cellulitis.

The patient was a previously healthy 23-year-old woman who made an outpatient visit to our hospital's Department of General Internal Medicine after developing pain and edema of the lower legs a week earlier. The patient was diagnosed with eosinophilic cellulitis (EC) based on an increased eosinophil count of 5,418/mm3 and the results of a skin biopsy of the lower leg that showed eosinophilic infiltration of the dermal tissue. Her condition improved after oral prednisone therapy. EC presents clinically as edema and eosinophilia. Therefore, in many cases, patients make an outpatient visit to the internal medicine department. In the present study, the clinical course of nine patients diagnosed with EC as outpatients at our Department of General Internal Medicine over the past 10 years was examined.

A Case of Overwhelming Postsplenectomy Infection Caused by Streptococcus pneumoniae with Fulminant Purpura.

Severe infection in patients who have lost splenic function is called overwhelming postsplenectomy infection (OPSI). Untimely treatment of patients with OPSI results in critical conditions with mortality rates as high as 50 %-70 %. For patients who undergo a splenectomy, vaccination is recommended for the prevention of OPSI. However, in Japan, the vaccination utilization rates are low. Herein, we report a case of OPSI caused by Streptococcus pneumoniae with a fulminant purpura resulting in multi-organ failure, which could be reversed by intensive care.

Paravascular inner retinal abnormalities in healthy eyes.

PURPOSE: To investigate the prevalence and characteristics of paravascular inner retinal abnormalities in healthy eyes. MATERIALS AND METHODS: In this prospective observational case series, we included 178 healthy eyes (178 patients) with no ocular diseases. Eyes with co-existing ocular diseases, e.g., epiretinal membrane, glaucoma, or high myopia, were excluded from the current study. The posterior pole and paravascular areas of the temporal arcade vessels were comprehensively examined by dense radial scanning of optical coherence tomography (OCT) with the extended field imaging technique. RESULTS: On fundus photography, no inner retinal abnormalities were detected along the temporal arcade vessels. On OCT sections, paravascular inner retinal abnormalities were seen in 77 (43.3%) eyes. In 71 (39.9%) eyes, inner retinal cystoid or fissure-like spaces that had no connection to the vitreous cavity were seen adjacent to the temporal arcade vessels. Most of these lesions were detected only on several consecutive OCT sections. In four (2.2%) eyes, inner retinal cleavages with openings to the vitreous cavity were seen adjacent to the temporal arcade vessels. These lesions were more frequently detected in the inferior hemisphere and along the major retinal veins. No eyes showed typical broad defects of the inner retinal tissue. There were no significant differences in age, gender, visual acuity, refractive error, or axial length between eyes with or without paravascular inner retinal abnormalities. CONCLUSIONS: Paravascular cystoid or fissure-like spaces were frequently seen in the inner retina of healthy eyes. However, we detected no typical paravascular inner retinal defects in healthy eyes.

Assessment of urinary pharmacokinetics and pharmacodynamics of orbifloxacin in healthy dogs with ex vivo modelling.

PURPOSE: The aim of this study was to investigate the urinary pharmacokinetics (PK) of orbifloxacin (OBFX) administered at 5 mg kg-1 in six healthy dogs. A further aim was to use an ex vivo model to evaluate the urinary PK and pharmacodynamics (PD) of OBFX to determine its urinary bactericidal titre (UBT), which represents the maximal dilution of urine allowing bactericidal activity. METHODOLOGY: Fourteen urinary tract infection (UTI) pathogenic strains of five bacterial species (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis and Staphylococcuspseudintermedius) were used. Urine samples were obtained every 4 h for the first 24 h after OBFX administration, for measurement of urine drug concentration and UBT.Results/Key findings. The urine OBFX concentration peaked at 0-4, 4-8 or 4-8 h after administration, with a maximum concentration of 383±171 µg ml-1. Overall, the fluctuation in median UBT closely correlated with that of the mean urine OBFX concentration. In addition, the median areas under the UBT-time curves (AUBTs) were significantly inversely correlated with the MICs for OBFX in the tested strains (P<0.01). Notably, median UBTs and AUBTs were extremely low (0-0.5 and 2-5, respectively) in OBFX-resistant E. coli strains with MIC ≥8 µg ml-1. CONCLUSION: The fluctuation of UBTs closely correlated with that of urine concentration, and UBT values depended on the susceptibility of the bacterial strains to OBFX. We believe that ex vivo modelling to determine UBTs is useful to evaluate the urinary PK/PD of antimicrobials indicated for UTIs in dogs.