Population Pharmacokinetic Analyses for Arbekacin after Administration of ME1100 Inhalation Solution.

ME1100, an inhalation solution of arbekacin, an aminoglycoside, is being developed for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. The objective of these analyses was to develop a population pharmacokinetic model to describe the arbekacin concentration-time profile in plasma and epithelial lining fluid (ELF) following ME1100 administration. Data were obtained from a postmarketing study for an intravenous (i.v.) formulation of arbekacin, a phase 1 study of ME1100 in healthy volunteers, and a phase 1b study of ME1100 in mechanically ventilated subjects with bacterial pneumonia. Data from the postmarketing study were utilized to develop a population pharmacokinetic model following i.v. administration, and this model was subsequently utilized as the foundation for development of the model characterizing arbekacin disposition following inhalation of ME1100. The final model utilized two compartments for both plasma and ELF disposition, with movement of arbekacin between the ELF and plasma parameterized using linear first-order rate constants. A bioavailability term was included for the inhalational route of administration, which was estimated to be 19.5% for a typical subject. The model included normalized creatinine clearance (CLcrn) and weight as covariates on arbekacin clearance: CL = (weight/52.2)0.855·[(CLcrn-77)·0.0289 + 2.32]. The model simultaneously described arbekacin concentrations following both i.v. and inhaled administration and provided acceptable fits to the plasma and ELF data (r2 of 0.922 and 0.557 for observed versus fitted concentrations, respectively). The developed model will be useful for conducting future analyses to support ME1100 dose selection.

A Multicentre, Open label, Randomized, Comparative, Parallel Group, Active-controlled, Phase III Clinical Trial to Evaluate Safety and Efficacy of Arbekacin Sulphate Injection versus Vancomycin Injection in Patients Diagnosed with MRSA Infection.

BACKGROUND: Increasing resistance to currently available antimicrobials has led to the development of new agents. Arbekacin is aminoglycoside antibiotic currently used in Japan and Korea for the treatment of infections caused by multi-resistant bacteria including MRSA. Currently there is no published data available for use of Arbekacin in Indian patient population, thus the present study was conducted to evaluate the safety and efficacy of Arbekacin in Indian population. MATERIAL AND METHODS: The study was a phase III, multi-centre, open-label, randomised comparative, active control study. Subjects with microbiologically confirmed MRSA infection were randomized in the study to receive either Arbekacin sulphate 200 mg OD or Vancomycin hydrochloride 1000 mg BD for a period of 7 to 14 days. The primary endpoint was to evaluate the overall cure rate i.e. Clinical and microbiological cure during the study. RESULTS: A total of 162 patients were randomized in 2 treatment groups (i.e. 81 patients in each group). Out of these microbiologically confirmed MRSA patients, 153 patients were admitted for SSTI while 9 patients were admitted for CAP. Overall cure rate of MRSA infection (clinical as well as microbiological cure) was comparable in both the treatment groups i.e. 97.5% (79/81) in Arbekacin group and 100 % (79/79) in Vancomycin group (p value: 0.159). Both Arbekacin and Vancomycin were well tolerated by the patients during the study period. CONCLUSION: Arbekacin can be considered as safe and effective alternative to vancomycin in the management of MRSA infections.

Custom-made, antibiotic-loaded, acrylic cement spacers using a dental silicone template for treatment of infected hip prostheses.

PURPOSE: Antibiotic-loaded acrylic cement (ALAC) spacers are useful for treatment of infected prostheses in the course of a two-stage revision. Spacers are handmade or are made using a commercial template, with reportedly good treatment outcomes. This study aimed to confirm the usefulness of custom-made ALAC spacers shaped like bipolar hip prostheses using a dental silicone template for treatment of infected hip prostheses, and described their manufacture. METHODS: This study evaluated 10 patients who underwent two-stage revision for treatment of infected hip prostheses. Custom-made ALAC spacers were used in all patients. Templates were made with dental silicone. We investigated the following in treatment of the infected hip prostheses: bacterial pathogens; antibiotic-cement mixtures; waiting time to revision; dislocation, breakage, and migration of custom-made ALAC spacers; current hip status; progress during follow-up; presence or absence of recurrence; and walking ability. RESULTS: Dislocation, breakage, and migration were not observed in custom-made ALAC spacers. All patients recovered after two-stage revision without additional surgery and showed no recurrence during the follow-up period. CONCLUSION: Custom-made ALAC spacers shaped like bipolar hip prostheses using a template made of dental silicone may be useful for treatment of infected hip prostheses.

Efficacy and pharmacokinetics of ME1100, a novel optimized formulation of arbekacin for inhalation, compared with amikacin in a murine model of ventilator-associated pneumonia caused by Pseudomonas aeruginosa.

Background: Arbekacin is an aminoglycoside that shows strong antimicrobial activity against Gram-positive bacteria, including MRSA, as well as Pseudomonas aeruginosa . The therapeutic effectiveness of arbekacin is directly related to C max at the infection site. To maximize drug delivery to the respiratory tract and minimize the systemic toxicity, arbekacin optimized for inhalation, ME1100, is under development. In this study, we investigated the efficacy and pharmacokinetics of ME1100 in a murine model of ventilator-associated pneumonia caused by P. aeruginosa by using a customized investigational nebulizer system. Methods: The mice were treated for 5 min, once daily, with placebo, 3, 10 or 30 mg/mL ME1100 or 30 mg/mL amikacin. Results: In the survival study, the survival rate was significantly improved in the 10 and 30 mg/mL ME1100 treatment groups compared with that in the placebo group. The number of bacteria in the lungs was significantly lower in the 30 mg/mL ME1100 treatment group at 6 h after the initial treatment, compared with all other groups. In the pharmacokinetic study, the C max in the 30 mg/mL ME1100 treatment group in the epithelial lining fluid (ELF) and plasma was 31.1 and 1.2 mg/L, respectively. Furthermore, we compared the efficacy of ME1100 with that of amikacin. Although there were no significant differences in ELF and plasma concentrations between 30 mg/mL of ME1100 and 30 mg/mL of amikacin, ME1100 significantly improved the survival rate compared with amikacin. Conclusions: The results of our study demonstrated the in vivo effectiveness of ME1100 and its superiority to amikacin.

Population pharmacokinetics of arbekacin in different infectious disease settings and evaluation of dosing regimens.

The efficacy of arbekacin in patients with MRSA infections is influenced by the peak concentration (Cpeak)/MIC ratio (≧8). A daily arbekacin dose of 4-6 mg/kg is primarily used for the treatment of MRSA infection. However, clinical pharmacokinetic studies of arbekacin that evaluate changes in patients with different infectious diseases have been limited. This study was to evaluate the pharmacokinetics of arbekacin in different infectious diseases and to evaluate its dosing regimens. This work describes a single-centre, retrospective study. The pharmacokinetic parameters of arbekacin were calculated from individual serum-concentration data using WinNonlin ver. 6.3. A total of 331 serum samples were obtained from 170 patients. Our drug concentration-time data were well described by a two-compartment open model. The final model showed that drug clearance was related to creatinine clearance and that the total distribution volume (Vd) was related to actual body weight and the presence of bacteremia. The individual Vd in bacteremia patients was significantly higher than those of other patients (bacteremia: 29.7 ± 0.5 L, pneumonia: 20.8 ± 0.4 L, other infections: 21.4 ± 0.4 L; p < 0.05). Additionally, Monte Carlo simulation showed that target (Cpeak/MIC â‰§ 8) attainment was only 10.1%, even at a dose of 6 mg/kg, especially for MRSA bacteremia patients with an arbekacin MIC = 2 µg/mL. In conclusion, our study revealed that the Vd may be higher in bacteremia patients than in patients with other infectious diseases. Therefore, an increase in the daily dose of arbekacin should be considered for bacteremia patients.

Comparison of Arbekacin and Vancomycin in Treatment of Chronic Suppurative Otitis Media by Methicillin Resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of ear infections. We attempted to evaluate the clinical usefulness of arbekacin in treating chronic suppurative otitis media (CSOM) by comparing its clinical efficacy and toxicity with those of vancomycin. Efficacy was classified according to bacterial elimination or bacteriologic failure and improved or failed clinical efficacy response. Ninety-five subjects were diagnosed with CSOM caused by MRSA. Twenty of these subjects were treated with arbekacin, and 36 with vancomycin. The bacteriological efficacy (bacterial elimination, arbekacin vs. vancomycin: 85.0% vs. 97.2%) and improved clinical efficacy (arbekacin vs. vancomycin; 90.0% vs. 97.2%) were not different between the two groups. However, the rate of complications was higher in the vancomycin group (33.3%) than in the arbekacin group (5.0%) (P=0.020). In addition, a total of 12 adverse reactions were observed in the vancomycin group; two for hepatotoxicity, one for nephrotoxicity, eight for leukopenia, two for skin rash, and one for drug fever. It is suggested that arbekacin be a good alternative drug to vancomycin in treatment of CSOM caused by MRSA.

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.

The possibility of using fibrin-based collagen as an antibiotic delivery system.

PURPOSE: Collagen and fibrin are known to have potential use as a local drug-delivery system. This experimental study was designed to evaluate whether a fibrinogen-based collagen (FBC) fleece, coated with thrombin and aprotinin, can be used as an antibiotic delivery system. METHODS: In an in vitro study, gentamicin, fosfomycin, ampicillin, ciprofloxacin and dibekacin were absorbed by the FBC, Kirby-Bauer disks (KBDs), and expanded polytetrafluoroethylene. After washing with saline or phosphate buffer saline (PBS) 3 times for 6, 12 and 24 h, each sample was analyzed for antibiotic retention. In an in vivo study, we implanted the FBC onto mouse livers and dripped gentamicin and ciprofloxacin onto the FBC. The FBCs were subsequently collected and analyzed for their antibiotic activities. RESULTS: After irrigation with saline, each antibiotic showed different activities. After PBS washing, the FBC impregnated with each antibiotic had higher activity than the KBDs, and inhibited the bacterial growth by 60-80 % compared to the control. Gentamicin dripped onto the FBC could inhibit bacterial growth after 48 h in vivo without affecting the hemostatic properties of the FBC. However, the FBC treated with ciprofloxacin exhibited antibacterial activity for only 3 h. CONCLUSIONS: Some bases, including FBC, can retain antibacterial activities dependent on the ingredients of the base and the type of antibiotic. Gentamicin, but not ciprofloxacin, was retained in the FBC in vivo. These results suggest that absorbent FBC might be useful not only as hemostatic material, but also as a local drug-delivery system.

[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 usefulness of arbekacin compared to vancomycin.

The bacteriological efficacy response (improved, arbekacin vs. vancomycin; 71.2% vs. 79.5%) and clinical efficacy response (improved, arbekacin vs. vancomycin; 65.3% vs. 76.1%) were not statistically different between the two groups. The complication rate was significantly higher in the vancomycin group (32.9%) compared to the arbekacin group (15.1%) (p=0.019). Arbekacin was not inferior to vancomycin, and it could be a good alternative drug for vancomycin in methicillin-resistant Staphylococcus aureus (MRSA) treatment.

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.

Successful combination therapy with vancomycin and arbekacin against infective endocarditis caused by MRSA.

Infective endocarditis caused by methicillin-resistant Staphylococcus aureus (MRSA) is a serious disease and sometimes leads to poor prognosis. We should have several therapeutic options. Arbekacin is one of the aminoglycoside antibiotics, which is more active against MRSA and less nephrotoxic than gentamicin. Here we presented a successfully treated case of severe MRSA endocarditis without any adverse effect by monitoring therapeutic level of vancomycin and arbekacin.

[Evaluation of once a day of arbekacin administration to neonates as a new object of peak concentration].

Once a day of arbekacin (ABK) administrations based on a new object of peak concentration setting on 9-20 microg/mL were performed to 14 neonates. The gestational ages were 27.3 +/- 4.2 weeks. As to the preparing initial dosage, Therapeutic Drug Monitoring Program soft was used. Mean daily dose of 6.2 +/- 0.4 mg/kg bodyweight was administered every 24 to 48 h by 30 min intravenous infusion. Mean serum peak concentrations of ABK and those of trough concentrations were 15.2 +/- 4.3 microg/mL and 2.0 +/- 1.4 microg/mL respectively. The relationship between the measured values (y) and predicted values (x) showed the regression equation y = 0.969 + 0.931x (R2 = 0.769, n = 35), which suggested the usefulness of the dosage design. Overall clinical effectiveness was 78.9% (11/14). There were no obvious adverse effects including abnormal auto auditory brainstem responses and serum creatinine increase. Effectiveness rate and no adverse effects suggested that once a day of ABK therapy in neonate including extremely preterm infant was preferable regimen.

Pharmacokinetics and pharmacodynamics of once-daily arbekacin during continuous venovenous hemodiafiltration in critically ill patients.

This study examined the pharmacokinetics of arbekacin during continuous venovenous hemodiafiltration (CVVHDF) and assessed the pharmacodynamics to consider arbekacin dosage adaptation in CVVHDF. Arbekacin was administered by 0.5-h infusion once daily, using a polymethyl methacrylate membrane hemofilter, to three critically ill patients undergoing CVVHDF; the flow rates were 0.8 l/h for the filtrate and 0.6 l/h for the dialysate. The drug concentrations in plasma and in the filtrate-dialysate were determined using a fluorescence polarization immunoassay and analyzed pharmacokinetically. The average sieving coefficient of arbekacin was 0.739 and the average drug clearance by CVVHDF was 1.03 l/h. A pharmacokinetic model with three compartments (1, central; 2, peripheral; 3, filtrate-dialysate side hemofilter) accurately reflected the concentration-time data for both plasma and filtrate-dialysate. The pharmacokinetic model assessed the pharmacodynamic profile of arbekacin once-daily regimens (0.5-h infusions) at filtrate-dialysate flow rates of 1.4 and 2.8 l/h, and demonstrated that only the 150-mg and 200-mg regimens achieved an effective target range for C(max) (9-20 microg/ml), suggesting that empirical dosages lower than the usual 150-200 mg should be avoided in patients undergoing CVVHDF. The minimum regimens needed to achieve an effective pharmacodynamic target for the free C(max)/MIC ratio (>8) were 75 mg for an MIC of 0.5 microg/ml, 200 mg for an MIC of 2 microg/ml, and 400 mg for an MIC of 4 microg/ml. These results will help us to better understand the pharmacokinetics of arbekacin during CVVHDF, while also helping in the selection of the appropriate arbekacin regimens, based on a pharmacodynamic assessment, for patients receiving this renal replacement therapy.

[Analysis of factors affecting long-term administration of anti-methicillin resistant Staphylococcus aureus (MRSA) drugs].

In this study, we aimed to determine an index of anti-MRSA drugs for long-term treatment. We examined adult patients to whom the anti-MRSA drugs arbekacin sulfate (ABK), vancomycin hydrochloride (VCM), and teicoplanine (TEIC) had been administered in the St. Marianna University School of Medicine, Yokohama City Seibu Hospital, for 1, year. The number of patients treated for>or==14 days was 22 (31%) among 71 patients. Immunosuppressive agent positivity (p=0.07), albumin (ALB) level of or==10 mg/dl (p=0.01),%STAB >or==15% (p=0.11), and the period until the blood drug level is measured (p=0.06) were analyzed with respect to the differences between both groups by univariate analysis. An ALB level of

[Case with large abdominal abscess associated with a ventriculoperitoneal shunt].

Abdominal abscess is a rare shunt-related complication with few reported cases. A 6-year-old female presented with a large staphylococcal abdominal abscess manifesting as abdominal distension without significant clinical signs or blood and cerebrospinal fluid findings of infection. The patient had undergone repeated surgeries for craniopharyngioma at 2 years of age and had suffered central pontine and extrapontine myelinolysis during the clinical course, had severely impaired hypothalamic function, and was in a vegetative state on presentation. In addition, she had previously suffered epidural, subdural, and cerebral parenchymal abscesses, which had resolved completely. She underwent percutaneous irrigation drainage of pus and removal of the shunt coupled with intense antibiotic administration, which cured the abscess without recurrence. Culture revealed methicillin-resistant Staphylococcus aureus. We thought that preexisting intracranial infection, which had extended down into the abdominal cavity through the peritoneal tube of the shunt, coupled with the patient's impaired immune function, had probably caused the abdominal abscess. Abdominal abscess is a potential complication of ventriculoperitoneal shunting, and timely diagnosis and treatment may achieve a good outcome.

Influences of dosage regimen and co-administration of low-molecular weight proteins and basic peptides on renal accumulation of arbekacin in mice.

OBJECTIVES: The objectives of this study were to characterize renal accumulation of arbekacin, an aminoglycoside antibiotic for treatment of infections with methicillin-resistant Staphylococcus aureus, and to modulate renal uptake of arbekacin, leading to prevention of arbekacin-induced nephrotoxicity. METHODS: In vivo renal uptake studies were performed using mice. Renal concentrations of arbekacin after a bolus intravenous administration at various doses were analysed by HPLC. In addition, renal concentrations were investigated 24 h after an injection of arbekacin alone or in combination with low-molecular weight proteins and basic peptides. RESULTS: When administered by bolus injection at various doses, renal accumulation of arbekacin showed saturation kinetics with increasing dose. Renal concentration of arbekacin after a bolus administration remained constant from 4 to 24 h and subsequently decreased by a first-order process with a half-life of 42.7 h. The influences of three dosage regimens (a single injection of 4 mg/kg, two injections of 2 mg/kg and three injections of 1.33 mg/kg) were investigated. A single injection resulted in lower renal level of arbekacin than the multiple administrations. Co-administration of cytochrome c, lysozyme and N-WASP181-200 decreased renal accumulation of arbekacin in a dose-dependent manner. N-W(N1n), N-W(N1n,I2i,S3s) and N-W(N1n,K20k), in which the N- and/or C-terminal regions of N-WASP181-200 were substituted by one to three D-isomers, more potently decreased renal arbekacin accumulation than N-WASP181-200. CONCLUSIONS: These data may be useful for prevention of arbekacin-induced nephrotoxicity owing to reduction of renal accumulation of the aminoglycoside.

Prediction of aminoglycoside response against methicillin-resistant Staphylococcus aureus infection in burn patients by artificial neural network modeling.

OBJECTIVE: To predict the response of aminoglycoside antibiotics (arbekacin: ABK) against methicillin-resistant Staphylococcus aureus (MRSA) infection in burn patients after considering the severity of the burn injury by using artificial neural network (ANN). Predictive performance was compared with logistic regression modeling. METHODOLOGY: The physiologic data and some indicators of the severity of the burn injury were collected from 25 burn patients who received ABK against MRSA infection. A three-layered ANN architecture with six neurons in the hidden layer was used to predict the ABK response. The response was monitored using three clinical criteria: number of bacteria, white blood cell count, and C-reactive protein level. Robustness of models was investigated by the leave-one-out cross-validation. RESULTS: The peak plasma level, serum creatinine level, duration of ABK administration, and serum blood sugar level were selected as the linear input parameters to predict the ABK response. The area of the burn after skin grafting was the best parameter for assessing the severity of the burn injury in patients to predict the ABK response in the ANN model. The ANN model with the severity of the burn injury was superior to the logistic regression model in terms of predicting the performance of the ABK response. CONCLUSION: Based on the patients' physiologic data, ANN modeling would be useful for the prediction of the ABK response in burn patients with MRSA infection. Severity of the burn injury was a parameter that was necessary for better prediction.

Evaluation of the clinical application of cystatin C, a new marker of the glomerular filtration rate, for the initial dose-setting of arbekacin.

OBJECTIVE: Recent studies have shown that serum cystatin C is a better marker for measuring the glomerular filtration rate (GFR) than the conventional method, using serum creatinine concentration. The purpose of this study is to evaluate the clinical application of serum cystatin C as a marker of GFR to determine the initial dosage of arbekacin, an antibiotic primarily excreted via the kidneys. In this study, the predictability of serum arbekacin peak and trough concentrations were assessed using estimated population mean GFR values calculated from either serum creatinine (Cockcroft-Gault equation) or cystatin C (Sjöström equation) concentrations. METHOD: Ninety-five patients treated with arbekacin for methicillin-resistant Staphylococcus aureus infection were divided into three groups according to their GFR values estimated by the serum cystatin C concentration as follows: normal to mild (GFR > 70 mL/min, n = 40), moderate (30

Recommended dose of arbekacin, an aminoglycoside against methicillin-resistant Staphylococcus aureus, does not achieve desired serum concentration in critically ill patients with lowered creatinine clearance.

OBJECTIVE: To define the pharmacokinetics of arbekacin (ABK), an aminoglycoside, in patients with acutely lowered renal function. METHODS: We measured the serum concentrations of ABK, using fluorescence polarization immunoassay, in 10 critically ill patients (patient group) and six healthy volunteers (control group). Data were analysed with a two-compartment model and parameters were estimated by the Bayesian method. The Mann-Whitney U-test or chi-squared test was used as appropriate (P < 0.05). RESULTS: Creatinine clearance (CCR), measured or estimated using Cockcroft and Gault's formula of the patient group (CCR: 58 +/- 13 mL/min), was significantly lower than that of the control group (CCR: 99 +/- 8 mL/min). However, despite the low CCR, even the maintenance ABK dosage for normal CCR did not elevate the highest serum level (C(max)) to the effective range in the patient group. Although the ABK clearance (CL) did not differ between the groups, the patients' distribution volume (V(d)) increased significantly compared with the control. The transfer rate constant from central to peripheral compartment (k(12)) in the patient group was much higher than that in the control. CONCLUSION: In critically ill patients with lowered CCR, the ABK dose for normal CCR subjects does not elevate its serum concentration to effective levels because of augmented V(d) caused by increased k(12). The present results hypothesize that adjustment of antibiotic dosing according to CCR further lowers C(max) in critically ill patients with reduced CCR.