Clinical efficacy and safety of arbekacin sulfate in patients with MRSA sepsis or pneumonia: a multi-institutional study.

Arbekacin (ABK) is an aminoglycoside and widely used in Japan for treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). Although, ABK has concentration-dependent antibacterial activity, the peak serum concentration (C (peak)) of ABK has not yet been fully investigated as an indicator of the efficacy of ABK. The present study was conducted in patients admitted to hospitals affiliated with the ABK Dose Finding Study Group, between October 2008 and June 2011, who had pneumonia or sepsis, the cause of which was identified or suspected to be MRSA. The initial target C (peak) was set at 15-20 µg/mL and therapeutic drug monitoring was conducted. Then the relationship between serum concentration and efficacy/safety of ABK was prospectively examined to obtain sufficient clinical efficacy. In total, 89 patients from 11 clinical sites in Japan were enrolled and 29 of these patients were subjected to efficacy analysis. The mean initial dose and C (peak) were 306.9 mg/day and 16.2 µg/mL, respectively. The efficacy rate was 95 % (19/20 patients) at 5-6 mg/kg or higher, 87.5 % (7/8) for sepsis and 90.5 % (19/21) for pneumonia, and the overall efficacy rate was 89.7 % (26/29). There was no increase in the incidence of adverse events. In conclusion, we recommend the initial dose of ABK at 5-6 mg/kg or higher and the dosage regimen should be adjusted to achieve C (peak) at 10-15 µg/mL or higher in the treatment of patients with pneumonia or sepsis caused by MRSA. This strategy would surely achieve low incidence of adverse events while obtaining high clinical efficacy.

[Safety and pharmacokinetics of 400 and 600 mg arbekacin sulfate to healthy male volunteers].

We assessed the safety and pharmacokinetics of arbekacin sulfate (ABK, brand name: Habekacin injection) in single and 7-day multiple administration of ABK 400 and 600 mg as potency to healthy male volunteers. In the single administration of ABK 400 and 600 mg (over 30 min, drip infusion), C(max) values were 41.0 +/- 3.6 microg/mL and 63.0 +/- 9.9 microg/mL, respectively. Serum ABK concentrations at 60 min (C(peak)) after the start of administration were 23.2 +/- 2.9 microg/mL and 38.5 +/- 3.3 microg/mL, respectively, and the mean serum ABK concentrations at 24 hr (C(trough)) after the start of administration were less than 0.4 microg/mL (LOQ: limited of quantitation). C(max), Cpeak and AUC(0-infinity) were increased with doses, and t1/2, CL(tot), CL(r) V(ss) and urinary excretion were comparable at both doses. In the multiple administration of ABK 400 and 600 mg (over 30 min, drip infusion) once a day for 7 days, C(max0, C(peak) and AUC(0-infinity) were comparable from the 1st day through to 7th day and increased with doses. After the administration, the serum ABK concentrations were decreased with time, and the means of C(trough) were 0.4 microg/mL (LOQ) -0.5 microg/mL, which showed ABK has no tendency toward accumulation. In addition, t1/2, CL(tot), CL(r) V(ss) and urinary excretion were constant throughout administration days at either dose, and CL(tot) containing CL(r) was not decreased. There were no notable changes in the functions of the kidney, auditory organs, etc. Based on the above-mentioned results, when ABK 400 or 600 mg was intravenously administered over 30 min once or once a day for 7 days to the healthy male volunteers with normal renal clearance, it is suggested there were no problems in terms of safety, and C(max) were 36.7-54.1 and 44.2-78.5 microg/mL, respectively. In addition, C(trough) was 0.5 microg/mL or lower at either doses and ABK was not accumulated in multiple administration of ABK. ABK was, therefore, expected to have good safety profile and favorable pharmacokinetics.

The efficacy and safety of high-dose arbekacin sulfate therapy (once-daily treatment) in patients with MRSA infection.

The efficacy and safety of once-daily high-dose arbekacin sulfate therapy for methicillin-resistant Staphylococcus aureus (MRSA) infection were evaluated, with analysis of their relationship to blood drug levels. The study was conducted in patients with pneumonia or sepsis, the cause of which was suspected to be MRSA, who were admitted to the Nagasaki University Hospital or its affiliated hospitals between January 2009 and December 2010. The initial drug dose was set at a level expected to yield the goal peak of 20 µg/ml and a trough level of less than 2 µg/ml, using the Habekacin Therapeutic Drug Monitoring analysis software. Thirteen patients were enrolled: 10 patients had pneumonia and 3 patients had sepsis. Patient mean age was 72.0 years; mean initial drug dose was 269.2 mg. Clinical efficacy at completion of treatment and bacterial eradication-reduction were achieved in 66.7% (6/9) and 62.5% (5/8) of patients, respectively. Incidence of adverse reactions was 38.5% (5/13). In analysis of efficacy in relationship to serum drug levels, the peak drug level was 22.7 ± 5.50 µg/ml, on average, and 15 µg/ml or higher in all 6 responders. Also, in patients with renal dysfunction, it seemed to be essential to ensure a certain peak drug level and to control the trough level appropriately. Although the number of patients was limited, once-daily high-dose arbekacin sulfate therapy may be highly effective, without posing any major safety problems. Further larger-scale studies are needed.

[Analysis of factors in selecting anti-methicillin-resistant Staphylococcus aureus drugs by doctors].

Three types of medication, Arbekacin, Vancomycin, and Teicoplanin, are used primarily to treat MRSA infections. These medications differ in their respective anti-bacterial actions, antibacterial spectrums, and pharmacokinetics. Proper use and dosage is required, and is based on patient background and the conditions of infection, among other factors. This study was conducted for a period of over one year at St. Marianna University School of Medicine, Yokohama City Seibu Hospital. It was designed to compare the conditions as they related to why doctors ordered a certain drug, the background, and their clinical examination values. The tendency to avoid selection of Arbekacin Sulfate (ABK) for patients who had kidney dysfunction was recognized, although there were a few exceptions made. Other than that, there were not any standard criteria set in selecting which medication to prescribe. Therefore, it is necessary to examine the appropriateness of the selection since ordering anti-MRSA medication seemed to depend on each doctor's own experience. Serum concentration was measured in order to avoid any side effects. Moreover, cases of young people, normal renal function and malignant tumor patients were recognized in which serum concentration of the anti-MRSA medications was not within the therapeutic range of therapeutic drug monitoring (TDM). This was to show that there is a possibility the medications involved were not sufficiently effective. Therefore, in the future it will be necessary to ensure that proper dosing instructions are followed.

Clinical efficacy and safety of arbekacin for high-risk infections in patients with hematological malignancies.

We performed a clinical trial to investigate the efficacy and safety of arbekacin (ABK), a unique aminoglycoside with activity against methicillin-resistant Staphylococcus aureus (MRSA), in patients with hematological malignancies complicated by high-risk infections. ABK was administered intravenously at a dose of approximately 5 mg/kg with various broad-spectrum ß-lactams, followed by therapeutic drug monitoring (TDM). A total of 54 febrile or infectious episodes were registered, and TDM was performed in 44 (81%) cases. The absolute neutrophil count was below 500/µl in 49 (91%) cases, and cytotoxic chemotherapy was being administered in 47 (87%) cases. Before initiation of ABK, 52 (96%) patients had received fluoroquinolones (n = 37) and/or broad-spectrum ß-lactams (n = 34). There were 10 cases of documented infections including one of MRSA pneumonia, and 44 cases of febrile neutropenia. The efficacy at the end of treatment was 80% for all patients, and efficacy was significantly higher in patients attaining maximum concentrations ≥ 16 µg/ml or receiving TDM-guided dose-adjustment of ABK (n = 19, 95 vs. 71%, P = 0.039). Renal toxicity was observed in six cases (11%) but was generally acceptable. This study demonstrated that TDM-guided ABK administration may be applicable under limited conditions for patients with hematological malignancies.

Binding of 3',4'-dideoxykanamycin B to ATP and its related compounds.

The interactions of aminoglycoside, 3',4'-dideoxykanamycin B(DKB) with ATP and its related compounds were investigated. ATP, ADP, cyclic AMP and FAD bound to the DKB-conjugated Sepharose 4B column. The binding of DKB to ATP was also confirmed by equilibrium gel filtration. In the acidic pH region, the fluorescence of nucleotides was quenched by DKB. The Stern-Volmer plots showed that the molar ratios of the complexes were 1:1. The apparent stability constant was dependent on the number of the phosphate groups of nucleotides and was in the order of ATP greater than ADP greater than AMP.

Comparative vestibular toxicity of dibekacin, habekacin and cisplatin.

The vestibular toxicity of two aminoglycoside antibiotics, dibekacin sulfate and habekacin sulfate, and of a drug with potent antimitotic activity, cisplatin (cis-diamminedichloroplatinum) has been investigated in both rats and frogs. In rats, chronic intraperitoneal injection of a saline solution of dibekacin (50 mg/kg/day), habekacin (50 mg/kg/day), cisplatin (0.5 mg/kg/day) for 4 weeks and of cisplatin (1 mg/kg/day) for 5 weeks, produced no behavioral vestibular disorders and the righting reflex could be elicited at any time. In frogs, the spontaneous discharge was recorded from individual fibres of the ampullary nerve of the horizontal semicircular canal before and after acute administration of the drugs, dissolved in Ringer, into the perilymph of the inner ear near the horizontal ampulla. Following injection of 1 microliter of solutions containing 10 micrograms or 20 micrograms of dibekacin, 20 micrograms or 50 micrograms of habekacin, 0.5 micrograms, 2.5 micrograms or 10 micrograms of cisplatin, the spontaneous discharge decreased in a number of fibres and was sometimes completely abolished. The vestibular toxicity of the three drugs tested is discussed with respect to that of aminosides whose ototoxicity is well known.

Control by the evoked potential of the brain stem of the administration of dibekacine in premature infants.

The administration of dibekacine to 10 newborn carriers of a germ infection--or staphylococcus, was controlled for auditory tolerance. The auditory threshold was controlled by the evoked potential of the brain stem. Medication never caused the threshold to change. The evolution of latency in waves J1, J3 and J5 could not be seen except in wave 1 where latency decreased, as can be seen in other premature infants of babies born at term.

[Retinal toxicity caused by intravitreous injection of an aminoglycoside. Apropos of a case]. / Toxicité rétinienne secondaire à l'injection intravitréenne d'un aminoside. A propos d'un cas.

The authors present a case of severe retinal ischemia associated with Dibekacin intraocular injection. This aminoglycoside was used, at an inadvertent dose, for the treatment of a postoperative endophthalmitis. The prominent finding at ocular ophthalmoscopy was oedematous retina with hemorrhages in the macular area. Fluorescein angiography revealed severe retinal vascular non perfusion. The eye subsequently developed neovascular glaucoma. Precautions are necessary to prevent such a catastrophic event; the injectable solution must be prepared on the surgical field, the injection should be performed slowly in the anterior vitreous without exceeding 0.2 mg when Gentamicin is used.

[Nationwide investigation in Japan of the status of MRSA infections and usefulness of arbekacin].

A clinical investigation on MRSA infections, and the determination of the efficacy and usefulness of arbekacin (ABK) were performed an "MRSA Forum" composed of 18 groups including 115 institutions in Japan. Patients with infectious diseases clearly related with MRSA, a total of 348 (males: 237, females: 111), were evaluated, 74/274 patients were treated with ABK alone/combination with ABK. Most of them (94.6%/96.4%) had underlying diseases and they had pneumonia (38/175), sepsis (6/35) or other infections (30/64). Infections by MRSA alone were noted in 41/159 and polymicrobial infections including with MRSA were in 33/115. 53.6%/56.4% of MRSA were eradicated and bacteriological clinical efficacies were 75.6%/67.9% in single infections and 63.6%/71.3% in polymicrobial infections. The clinical efficacies were obtained in 70.3%/69.3% of total and in 60.5%/72.0% of pneumonia and in 90.0%/80.8% of the patients pretreated with other drugs within 3 days previously. Efficacy rates were 78.6%/71.4% in 30 minute's div and 63.2%/66.4% in 60 minute's div. Adverse effects were found in 4.76%/5.70% including renal function disorder (2/11) but no case was serious. Abnormal laboratory test results were noted in 15.4%. ABK is effective against MRSA infections.

[Evaluation of once-daily administration of arbekacin. Experimental study and determination of pharmacokinetic properties in man].

Experimental and phase I clinical studies were performed to evaluate the efficacy and safety of once-daily administration of arbekacin (ABK). The results obtained were as follows: 1. ABK displayed dose-dependent, excellent antibacterial activity and post-antibiotic effects (PAE) against MRSA. 2. No significant difference was found between once-daily and divided administration regimens in protection against an experimental MRSA infection in mice. 3. There was no significant difference between once-daily and twice-daily administration of ABK in ototoxicity in guinea pigs or in nephrotoxicity in rats. 4. In the phase I clinical study using 200 mg single daily administration of ABK, no abnormal laboratory test results or symptoms were observed. 5. In the phase I clinical study of 5-day repeated administration of 200 mg/day of ABK, headache and increase in WBC sediment in the urine was noted in 1 volunteer; however these were not confirmed to be attributable to ABK. No abnormal laboratory test results were obtained other than increases in beta 2-microglobulin, NAG and gamma-GTP levels, each of which returned to normal after the completion of ABK administration. No abnormality was observed in the audiometry examination. 6. Maximum serum concentration (Cmax), serum half-life (T1/2 beta) and urinary recovery rate (0-48 hours) after single administration of 200 mg of ABK, were 13.20 micrograms/ml, 2.30 hours and 86.75%, respectively. There were no significant differences in pharmacokinetic parameters or urinary recovery rates between day 1 and day 5 in the 5-day repeated administration study. These findings suggest that once-daily administration regimen of ABK may be as effective and safe as divided administration regimen for the treatment of MRSA infection. Further clinical evaluation is required, however.

[Clinical efficacy of arbekacin on MRSA infections].

Clinical efficacy of arbekacin (ABK) was examined on patients with MRSA infection during hospitalization in Nagoya University Hospital. A total of 15 analysed cases of 5 sepsis, 3 pneumonias, 6 wound infections and one abdominal abscess. ABK was administered intravenously by drip infusion of 200 mg per day divided into 2 doses with or without other antibiotics. Overall clinical efficacy rate was 76.9%, and eradication rate for the MRSA was 54.5%. Adverse effects were noted in 3 cases (one each case of urticaria, disorder of liver function, and renal disorder). The renal disorder was found in the case where ABK was used in combination with vancomycin.

[Clinical efficacy of arbekacin on MRSA pneumonia].

Arbekacin sulfate (ABK) was administered by intravenous drip to pneumonia patients infected with methicillin-resistant Staphylococcus aureus (MRSA), and the efficacy and the safety were objectively evaluated by the executive committee. The daily dose was determined in principle as 150-200 mg, two times a day, 30-90 minutes drip infusion, and the dose was to be changed at each special occasion. Combined therapy with other antibiotics was scheduled in severe cases at a decision of the physician in charge. Data of 18 cases were accumulated. The efficacy could be evaluated for 12 cases (4 cases with ABK alone, and 8 cases with combined therapy), and the safety was evaluated for 18 cases. The clinical efficacy was: excellent, 1; good, 4; fair, 5; and poor, 2. The efficacy rate was 41.7%. The bacteriological effect was: eradicated, 2 (16.7%); decreased, 2; and no change, 8. There found no side effects except 3 cases of abnormal laboratory data, two abnormal renal functions(11.1%) and one abnormal hepatic function (5.5%). In one of the renal disorders, decreased dose of ABK improved the function. In the other case, the impaired renal function lasted until death by heart failure. In the case of abnormal function, discontinuing the ABK therapy improved the hepatic function. In the 4 out of 5 cases that showed excellent or good clinical efficacy, patients recovered within relatively early days of ABK therapy. The average days for recovery was 7.8.

[An evaluation study on arbekacin for MRSA-infectious diseases including pneumonia, septicemia and others].

Availability of arbekacin (ABK) was analyzed in the chemotherapy of 24 MRSA-infected patients with symptoms of pneumonia (12), sepsis (6) and others (6). Most patients had background diseases such as malignant tumors or cerebrovascular disorders. 47% (7/15) of them were immunologically abnormal. 17 of them had been previously treated with cephems, imipenem, minocycline or fosfomycin. The ABK therapy was performed with doses ranging 50-400 mg a day, divided into 1-3 times (mostly 100 mg x 2), and for 5-24 days. (18 patients were treated between 5 and 14 days). 14 patients (58%) received combined therapy with other antibiotics (mostly with beta-lactams, 12). The clinical efficacy rate of the ABK therapy was 62% (good, 13; fair, 4; ineffective, 4; unknown, 3). The bacteriological efficacies were: eradicated, 7 (44%); decreased, 4; no change, 5; unknown, 8. Side effects were found in 3 patients (oliguria, 2; eruption due to drug, 1) and one case resulted in serious renal disorder. Abnormal laboratory data were found in 7 cases. Above results have indicated that ABK is a useful antibiotic in chemotherapy of MRSA-infections.

[Clinical efficacy of arbekacin on MRSA infections with hematopoietic disorders. The Hanshin Study Group of Hematopoietic Disorders and Infections].

Arbekacin (ABK) was administered to 17 patients with MRSA infections that complicated underlying hematopoietic disorders, and the efficacy and safety were evaluated. The underlying diseases included acute myelocytic leukemia (8 cases), acute lymphocytic leukemia (1) myelodysplastic syndrome (3), chronic myelocytic leukemia (1), non-Hodgkin's lymphoma (2), Hodgkin's disease (1) and adult T cell leukemia (1). The infections consisted of septicemia (5 cases), pneumonia (4), upper respiratory tract infections (6) and urinary tract infections (2). ABK was administered by i.v. drip infusion in daily doses of 150-200 mg, given in two divided dosages. The therapeutic efficacies were: excellent in 2 (2 septicemias), good in 7 (1 septicemia, 4 upper respiratory infections, 2 urinary tract infections), fair in 2 (septicemia and pneumonia) and poor in 6 (1 septicemia, 3 pneumonias, 2 upper respiratory infections). As a side effect, reversible renal dysfunction was detected in four cases. Causative bacteria were isolated from six cases. They were all coagulase type II and MIC's of ABK were from 0.25 microgram/ml to 4.0 micrograms/ml. Arbekacin therapy was found to be effective even in patients with hematopoietic disorders accompanied by MRSA infections.

[Clinical efficacy of arbekacin in deep MRSA infection. Including follow-up study after the termination of chemotherapy].

We analyzed the efficacy of arbekacin (ABK) using monotherapy or combined therapy on deep MRSA infection to find the most adequate usage of the drug. We also followed-up the isolation incidence of MRSA after the end of chemotherapy. The results are summarized as follows: 1. Clinical efficacy of ABK on 29 pneumonia and 3 septicemia due to MRSA was 42.9% in ABK monotherapy (9 patients), 62.5% in combined therapy with ABK and minocycline (9 patients), 100% with ABK and imipenem/cilastatin (IPM/CS) (7 patients), and 100% with ABK and other drugs (7 patients). 2. As for microbiological efficacy, combined therapy with ABK and IPM/CS or other drug was superior to other methods. Among patients from whom two or more species of bacteria were isolated, causative bacteria persisted in many cases, and some replacements occurred. 3. Kidney functions deteriorated in two patients that underwent monotherapy or combined therapy with ABK and IPM/CS, but they recovered when therapy was completed the completion. 4. In the three month follow-up study after ABK therapy, we found four cases of renewed infections after disappearance of MRSA. When just decreases in the number of MRSA resulted upon the chemotherapy, the relapse occurred in all cases. 5. Above results indicate that ABK is effective in MRSA infection, and combined therapy with beta-lactams is superior to other methods in serious MRSA infections. We also suggest that chemotherapy should be continued until the complete disappearance of MRSA is achieved.