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Reimbursements for pharmacist interventions and infectious disease teams have recently been introduced in Japan. Arbekacin (ABK) is used to treat pneumonia and sepsis caused by methicillin-resistant Staphylococcus aureus, and therapeutic drug monitoring (TDM) is recommended. This study aimed to clarify the trend in TDM implementation for ABK over time and the factors associated with TDM implementation using a claims database.Data of patients aged ≥15 years who received ABK for ≥3 consecutive days between 2010 and 2019 were extracted from a large Japanese medical claims database. The proportion of reimbursements claimed for TDM, pharmacist interventions, and the setup of infectious disease teams for each year were calculated. The factors associated with TDM implementation were identified using multivariate logistic regression analysis.The proportion of TDM implementation for ABK increased by 9.1% from 2010 to 2019, but it remained less than 40% throughout this period. The proportion of TDM implementation was higher in patients who claimed reimbursements for pharmacist interventions than in patients who did not. Logistic regression analysis showed that the stationing of pharmacists in wards and long-term ABK treatment were significantly associated with TDM implementation.From 2010 to 2019, the proportion of TDM implementation for ABK was significantly low. Moreover, the factors associated with TDM implementation were clarified. An environment wherein pharmacists can help implement TDM for patients receiving ABK would be beneficial.

To overcome serious methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa infections, we synthesized TS2037, 5,4″-diepi-arbekacin, a novel aminoglycoside antibiotic, and evaluated its biological properties. TS2037 showed broad-range, as well as robust antibacterial activities against Gram-positive and Gram-negative bacteria. The MIC50 and MIC90 of TS2037 against clinical isolates of MRSA (n = 54) were both 0.25 µg/mL, and no resistant strain was observed. The MIC50 and MIC90 of TS2037 against clinical isolates of P. aeruginosa (n = 54) were 1 and 4 µg/mL, respectively. TS2037 and arbekacin, anti-MRSA aminoglycoside, were more stable against AAC(6′)-APH(2″), aminoglycoside-6′-N-acetyltransferase and 2″-O-phosphotransferase, produced by resistant S. aureus than gentamicin. Therapeutic efficacies of TS2037 in the mouse models of systemic infection with MRSA were superior to those of arbekacin, vancomycin, and linezolid. The efficacy of TS2037 against systemic infection caused by P. aeruginosa producing AAC(6′)-II was superior to those of arbekacin and amikacin. In the nephrotoxicity risk screening, the release of free N-acetyl-β-d-glucosaminidase from the kidney epithelial cell line after treatment with TS2037 at 2.5 and 5.0 μM were 2.0 and 2.1 (U/L), respectively, which were about two times higher than those of arbekacin. In conclusion, TS2037 exhibited the most potent antibacterial activity among aminoglycosides tested against both MRSA and P. aeruginosa in vitro and in vivo, although its nephrotoxicity risk remains to be improved.

This study describes highly aminoglycoside-resistant Klebsiella pneumoniae and Klebsiella oxytoca clinical isolates obtained from an inpatient in Okinawa, Japan, with no known record of traveling overseas. The minimum inhibitory concentrations of amikacin and arbekacin against these strains were >1024 μg/ml. Whole-genome sequencing analysis revealed that these isolates harbored armA, which encodes a 16S rRNA methylase, ArmA, that confers pan-aminoglycoside resistance. This is the second report of K. pneumoniae harboring armA and the first report of K. oxytoca harboring a 16S rRNA methylase encoding gene in Japan.

Aminoglycoside 2″-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci. We describe a novel aminoglycoside 2″-phosphotransferase from the Gram-negative pathogen Campylobacter jejuni , which shares 78% amino acid sequence identity with the APH(2″)-Ia domain of the bifunctional aminoglycoside-modifying enzyme aminoglycoside (6′) acetyltransferase-Ie/aminoglycoside 2″-phosphotransferase-Ia or AAC(6′)-Ie/APH(2″)-Ia from Gram-positive cocci, which we called APH(2″)-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin, but not to any of the 4,5-disubstituted antibiotics tested. Steady-state kinetic studies demonstrated that GTP, and not ATP, is the preferred cosubstrate for APH(2″)-If. The enzyme phosphorylates the majority of 4,6-disubstituted aminoglycosides with high catalytic efficiencies ( k cat / K m = 10 5 to 10 7 M −1 s −1 ), while the catalytic efficiencies against the 4,6-disubstituted antibiotics amikacin and isepamicin are 1 to 2 orders of magnitude lower, due mainly to the low apparent affinities of these substrates for the enzyme. Both 4,5-disubstituted antibiotics and the atypical aminoglycoside neamine are not substrates of APH(2″)-If, but are inhibitors. The antibiotic susceptibility and substrate profiles of APH(2″)-If are very similar to those of the APH(2″)-Ia phosphotransferase domain of the bifunctional AAC(6′)-Ie/APH(2″)-Ia enzyme.

Synthesis and antibacterial activity of 1- N -[( S )-ω-amino-2-hydroxyalkyl] derivatives of dibekacin, 5-deoxydibekacin, 3′-deoxykanamycin A and gentamicin B

Aminoglycosides are mainly distributed in the extracellular fluid, so when they are given to neonates who have a large amount of extracellular fluid, their distribution is increased. In our data, the volume of distribution (Vd) of Arbekacin in the neonates was twice that of the adults, 0.54 l/kg. Therefore, the dose per weight of aminoglycosides to the neonates should be increased more than to the adults. In the renal function of the neonates, differentiation of the nephron is completed within 36 weeks after conception, but it is functionally immature. In our data, renal drug excretion increased rapidly in the post-conceptional ages (PCAs) of 34-35 weeks. Consequently, we based the Arbekacin administration schedule for the neonates on the PCAs. There is excellent correlation between serum level of vancomicin (VCM) and dose x serum creatinine (Scr)/weight in the haemodialysis patients, suggesting that we can use weight and Scr to set the VCM administration schedule for these patients. We also established on administration schedule of Teicoplanin for the haemodialysis patients. In this article, we present the TDM analysis result of the antibiotics in our hospital.

To investigate the exact isolation frequency of 16S rRNA methylase–producing, gram-negative pathogenic bacteria, we tested 87,626 clinical isolates from 169 hospitals. Twenty-six strains from 16 hospitals harbored 16S rRNA methylase genes, which suggests sparse but diffuse spread of pan-aminoglycoside–resistant microbes in Japan.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteria have acquired stable resistance against most clinically available antibiotics. At present, MRSA infection is treated mainly with vancomycin. However, clinical isolates of S. aureus with reduced susceptibility to vancomycin, known as glycopeptide-intermediate S. aureus or vancomycin-intermediate S. aureus have recently been reported in Japan, the United States, and Europe (5, 16, 20). On the other hand, in Japan, arbekacin has been successfully used to treat MRSA infections for more than 10 years. Arbekacin, a derivative of dibekacin, is active against MRSA and both gram-positive and gram-negative bacteria (8). Moreover, arbekacin is not affected by the inactivating enzymes produced by MRSA (9). A killing curve study demonstrated that the bactericidal activity of arbekacin depended critically on its concentration (1). As with other aminoglycosides, arbekacin is eliminated exclusively into the urine as the unchanged form via glomerular filtration and tubular reabsorption. There is a linear relationship between arbekacin pharmacokinetics and the glomerular filtration rate (4). Although therapeutic drug monitoring (TDM) of arbekacin has become a common practice to maintain drug concentrations within a therapeutic range, the target concentrations of arbekacin used to monitor efficacy and toxicity are determined simply on the basis of knowledge of other aminoglycosides, such as gentamicin, amikacin, and tobramycin (12, 15, 22). To date, the exposure-response relationship for arbekacin in patients infected with MRSA has not been established. For aminoglycosides, there is evidence that the efficacy in patients with gram-negative bacterial infections is influenced by the early onset of a high peak concentration/MIC ratio (3, 6, 7, 11). In these studies, to estimate the correlation of pharmacokinetic-pharmacodynamic indices with therapeutic outcomes in patients receiving aminoglycosides, the peak concentration was obtained from measurements 1 h after infusion (11) or extrapolated from the actual concentration obtained approximately 30 min after the end of a 30-minute infusion (3, 6, 7). In the companion article (21), we reported the population pharmacokinetic parameters of arbekacin for patients infected with MRSA. Once population pharmacokinetic parameters have been obtained, the Bayesian forecasting method is applicable for predicting the serum drug concentration-time curve in each patient on the basis of a limited number of drug concentration measurements. These predicted serum drug concentration profiles are useful to estimate individual exposure parameters to arbekacin and to analyze the relationship between exposure and response. In the present study, we analyzed the pharmacokinetic-pharmacodynamic relationship of arbekacin to determine the drug exposure parameters that correlate with the efficacy and safety of this drug and to obtain the optimal target values of these parameters. (This work was presented in part at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois, 14 to 17 September 2003.)

Arbekacin, a derivative of dibekacin, is an aminoglycoside developed and widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). The population pharmacokinetics of arbekacin was investigated in the Japanese, using 353 patients infected with MRSA and 50 healthy or renally impaired volunteers. The age of the study population ranged from 8 to 95 years, and weight ranged from 10.8 to 107 kg. In total, 1,581 serum arbekacin concentrations were measured (primarily from routine patient care) and used to perform the present pharmacokinetic analysis. Drug concentration-time data were well described by a two-compartment open model. Factors influencing arbekacin pharmacokinetics were investigated using a nonlinear mixed-effect model analysis. The best-developed model showed that drug clearance (CL) was related to creatinine clearance (CL CR ), age, and body weight (WT), as expressed by CL (liter/h) = 0.0319CL CR + (26.5/age) (CL CR < 80 ml/min) and CL (liter/h) = 0.0130 CL CR + 0.0342WT + (26.5/age) (CL CR ≥ 80 ml/min). The volume of distribution for the central and peripheral compartments was different in healthy subjects and infected patients, and this difference was more pronounced among disease types. The elderly subjects (aged 80 years or over) exhibited, on average, a 19% greater volume for the central compartment. The volumes for the peripheral compartment were 50.6 liters in patients with pneumonia and 24.3 liters in patients with sepsis. The population pharmacokinetic parameters of arbekacin obtained here are useful for optimal use of this aminoglycoside in the treatment of MRSA-infected patients.

A total of 472 clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) isolated in Japan between 1979 and 2000 were investigated for resistance to 8 aminoglycosides, 4 aminoglycoside-modifying enzyme gene profiles, and AluI-restriction fragment length polymorphism of the coagulase gene determined by polymerase chain reaction assay. The majority of MRSA strains tested belonged to 4 groups based on coa-RFLP: L21, L22, L31, and M22. About 90% of recent isolates belonged to type L21, indicating the spread of a specific type of MRSA in Japan. Of the type L21 strains, 41.9% included the aac(6')/aph(2") gene, which was one of the risk factors of arbekacin (ABK) resistance, but only 5.5% were resistant to ABK. In contrast, all of the type M22 strains carried aac(6')/aph(2") and 70.1% showed ABK resistance. Among the other types, less than 20% of strains showed ABK resistance. These results suggested that ABK has maintained potent activity. If the predominance of type L21 continues, there will be no progression to ABK resistance in MRSA. However, it may be necessary to monitor the trends in type M22 continuously.

An extract from ginger (root of Zingiber officinale) reduced the minimum inhibitory concentrations (MICs) of aminoglycosides in vancomycin-resistant enterococci (VRE). The effective compound was isolated and identified as [10]-gingerol. In the presence of [10]-gingerol at 1/10 concentration of its own MIC, the MIC of arbekacin was lowered by 1/32 to 1/16. [10]-Gingerol also reduced the MICs of other aminoglycosides, and of bacitracin and polymixin B, but not of other antimicrobial agents tested. Because [10]-gingerol reduced the MICs of several aminoglycosides both in strains possessing or lacking aminoglycoside-modification enzymes, it seems that the effect of [10]-gingerol is not related to these enzymes, which mainly confer bacterial resistance against aminoglycosides. It seemed that a detergent-like effect of [10]-gingerol potentiated the antimicrobial activity of the aminoglycosides. In fact, some detergents such as sodium dodecyl sulfate (SDS) and Triton X-100 reduced the MICs of aminoglycosides, bacitracin and polymixin B in VRE. Since the intrinsic resistance to aminoglycosides in enterococci is due to low level of entry of the drugs into the cells, increase in the membrane permeability caused by [10]-gingerol will enhance the influx of aminoglycosides into enterococcal cells.

Aminoglycoside-modifying enzymes (AMEs) are major factors that confer aminoglycoside resistance to enterococci. In an epidemiologic study on distribution of 12 AME genes in 534 recent clinical strains isolated from a Japanese hospital, two uncommon AME genes, ant(9)-Ia and a novel aph(2") allele, aph(2")-Ie, were detected. ant(9)-Ia had been reported only in Staphylococcus aureus and encodes spectinomycin adenylyltransferase ANT(9)-I, which confers resistance to spectinomycin. The ant(9)-Ia gene was detected in three strains, a single strain each of Enterococcus faecalis, E. faecium, and E. avium. Nucleotide sequences of ant(9)-Ia from these three enterococcal species were identical to that reported for S. aureus and considered to be located on Tn 554. The new aph(2") allele, designated aph(2")-Ie, was identified in three E. faecium strains. The aph(2")-Ie allele was genetically close to aph(2")-Id reported in E. casseliflavus (93.7% amino acid sequence identity; 96.3% similarity), while distant from aph(2")-Ia, aph(2")-Ib, or aph(2")-Ic (26.3-29.5% amino acid sequence identity). Sequence divergence between APH(2")-Id and APH(2")-Ie was mostly located in amino-terminal half. In contrast, sequences corresponding to the three motifs required for aminoglycoside phosphotransferase were conserved except for a single amino acid. Three E. faecium strains having aph(2")-Ie showed high-level resistance to gentamicin and streptomycin, but not to kanamycin, dibekacin, and tobramycin, unlike enzyme specificity described for aph(2")-Id in E. casseliflavus. Such a difference in resistance phenotype was suggested to be related to amino acid sequence divergence between APH(2")-Id and APH(2")-Ie.

Biofilms are a major concern for clinicians in the treatment of infectious disease because of the resistance to a wide range of antibiotics. Using a rat air pouch model, methicillin-resistant Staphylococcus aureus (MRSA) growing as a biofilm was treated with a combination of fosfomycin (FOM) and arbekacin (ABK) or by the agents alone. This model has the advantage of permitting frequent sampling of exudates for bacterial counts and anti-bacterial activity, and morphological examination of the biofilm structure and inflammatory process in the pouch tissues. A clear synergistic effect was observed in the rats treated with a combination of fosfomycin and arbekacin. Morphological studies using scanning electron microscopy and histological staining showed dramatic changes of the biofilm structure as well as the inflammatory response in the rats. These results suggested an enhancement of bactericidal activity of arbekacin penetrating through the biofilm layer by virtue of fosfomycin. A possible mechanism of the synergistic effect is discussed.

Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem. Eighty-three neonates received arbekacin ( n = 41), vancomycin ( n = 19), or panipenem ( n = 23). The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g. A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis. In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution ( V ) was BW. The final formulas for the population pharmacokinetic parameters are as follows: CL arbekacin = 0.0238 × BW/serum creatinine level for PCAs of arbekacin = 0.0367 × BW/serum creatinine level for PCAs of ≥33 weeks, V arbekacin = 0.54 liters/kg, CL vancomycin = 0.0250 × BW/serum creatinine level for PCAs of vancomycin = 0.0323 × BW/serum creatinine level for PCAs of ≥34 weeks, V vancomycin = 0.66 liters/kg, CL panipenem = 0.0832 for PCAs of panipenem = 0.179 × BW for PCAs of ≥33 weeks, and V panipenem = 0.53 liters/kg. When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of

Biofilms are a major concern for clinicians in the treatment of infectious disease because of their resistance to a wide range of antibiotics. Arbekacin, an aminoglycoside antibiotic, is the drug of choice for the treatment of infection caused by methicillin-resistant Staphylococcus aureus (MRSA). However, it has not yet been defined whether arbekacin tends to penetrate into the biofilm structure induced by MRSA infection. In this study, we treated a biofilm mode of MRSA growth with arbekacin, using a rat air-pouch model. The model has the advantage of permitting frequent sampling of exudates for bacterial counts and antibacterial activity. A clear dose-dependent bactericidal effect was detected in rats treated with arbekacin at con-centrations between 0.3 and 10 mg/kg, but 0.1 mg/kg of arbekacin was ineffective against the experimental MRSA infection in rats. Morphological studies using scanning electron microscopy and histochemical staining demonstrated that an effective dosage of arbekacin induced dramatic changes in the biofilm membranous structure as well as in the inflammatory response, resulting in eradication of the biofilm structure and resolution of inflammation.

We have clinically isolated a methicillin-resistant Staphylococcus aureus (MRSA) K-1 which exhibits enhanced arbekacin (Abk) resistance. In this study, we investigated a molecular mechanism for the overproduction of a bifunctional enzyme catalyzing both 2″-O-phosphorylation and 6′-N-acetylation of aminoglycoside antibiotics that is encoded by aacA-aphD and designated [AAC(6′)/APH(2″)] and is expressed in MRSA K-1. The sequence analysis of the 5′-adjacent region of the aacA-aphD structural gene in MRSA K-1 showed that 12 bp are deleted from the aacA-aphD promoter region when compared with that in MRSA B-26, which exhibits lower resistance to Abk than K-1. By artificially deleting the 12 bp from the corresponding region in MRSA B-26, we confirmed that the strain increases Abk resistance to the same level as seen in MRSA K-1, which suggests that the 12 bp deletion from the 5′-adjacent region of the aacA-aphD structural gene created a strong promoter to overexpress the bifunctional enzyme.

Background: This is a retrospective study on the efficacy and safety of arbekacin (ABK), an aminoglycoside antibiotic, for acquired staphylococcal infection in the neonatal intensive care nursery. Patients and methods: Subjects were 29 infants treated with ABK in a tertiary care neonatal center. They were 23−39 (median 28) weeks’ gestation, 530−3334 (median 930) grams at birth, and 3−157 (median 17) days of age. Diagnosis of staphylococcal infection was made by clinical signs and laboratory findings. Sensitivity of the isolated organisms to ABK was tested by the microliquid dilution method. Serum ABK level was monitored to achieve the therapeutic range during the treatment. Effectiveness was defined by improving clinical signs and laboratory findings within 3 days. Effectiveness was studied in relation to type of infection and other antibiotics administered. Auditory brainstem response and serum creatinine changes were studied for ototoxicity and nephrotoxicity assessment, respectively. Results: Twenty-seven (93.1%) cases of infection were attributed to methicillin-resistant Staphylococcus aureus (MRSA) and two (6.9%) were attributed to coagulase-negative staphylococci (CNS). The rate of in vitro sensitivity to ABK was 85.2% for MRSA and 100.0% for CNS. The overall clinical effeciveness rate was 79.3% (23/29) with no difference associated with types of infection. Combination of ABK with sulbactam/ampicillin showed greater effectiveness (100.0%) than with other antibiotics (64.3%) (P

The aacA29b gene, which confers an atypical aminoglycoside resistance pattern to Escherichia coli , was identified on a class 1 integron from a multidrug-resistant isolate of Pseudomonas aeruginosa . On the basis of amino acid sequence homology, it was proposed that the gene encoded a 6′- N -acetyltransferase. The resistance gene was cloned into the pET23a(+) vector, and overexpression conferred high-level resistance to the usual substrates of the aminoglycoside N- acetyltransferase AAC(6′)-I, except netilmicin. The level of resistance conferred by aacA29b correlated perfectly with the level of expression of the gene. The corresponding C-terminal six-His-tagged AAC(6′)-29b protein was purified and found to exist as a dimer in solution. With a spectrophotometric assay, an extremely feeble AAC activity was detected with acetyl coenzyme A (acetyl-CoA) as an acetyl donor. Fluorescence titrations of the protein with aminoglycosides demonstrated the very tight binding of tobramycin, dibekacin, kanamycin A, sisomicin ( K d , ≤1 μM) and a weaker affinity for amikacin ( K d , ≈60 μM). The binding of netilmicin and acetyl-CoA could not be detected by either fluorescence spectroscopy or isothermal titration calorimetry. The inability of AAC(6′)-29b to efficiently bind acetyl-CoA is supported by an alignment analysis of its amino acid sequence compared with those of other AAC(6′)-I family members. AAC(6′)-29b lacks a number of residues involved in acetyl-CoA binding. These results lead to the conclusion that AAC(6′)-29b is able to confer aminoglycoside resistance by sequestering the drug as a result of tight binding.

Background: The objective of the present study was to determine pharmacokinetic variables and to characterize a new initial dosing regimen of arbekacin (ABK) for preterm and term newborn infants. Patients and methods: Subjects were 40 infants treated with ABK in a tertiary care neonatal unit over a period of 18 months. At birth, the infants were 23 5/7−40 0/7 weeks and weighed 530−3428 g. Serum ABK concentration was measured at two points in a course of treatment. Data were analyzed by a one-compartment model to obtain volume of distribution (Vd) and clearance (CL) of ABK. These variables were correlated with the patients’ demographic and laboratory data. The new initial dosing regimen was determined based on these data. Results: Sixty pairs of blood samples were taken from the infants. They were divided into three groups: preterm early (PE), gestational age (GA)

Infected hip prosthesis, a serious complication of primary total hip arthroplasty (THA), can have severe consequences. We report the treatment outcome of two-stage revision THA for infected hip arthroplasty, including hemiarthroplasty, using an antibiotic-impregnated cement spacer for the interval between the first and second stages. Between 1996 and 2000 we performed this procedure on nine hips in eight patients. Cementless revision THA was performed as the second-stage procedure. Bone defects were restored with frozen allografts. The outcome was evaluated using the hip score of the Japanese Orthopaedic Association (JOA hip score). The mean duration of follow-up was 35.7 months (range 10–55 months). The mean JOA hip score at follow-up improved from 30.1 (range 10–74) to 73.2 (24–96). The mean interval between the first and second stages was 10.1 weeks (range 6–19 weeks). Eight of the nine hips achieved a successful outcome. One hip, with methicillinresistant Staphylococcus aureus infection, experienced recurrence 4 months after revision THA. This patient was successfully treated 14 months after the first revision THA with a second two-stage procedure using a vancomycin- and arbekacin-impregnated cement spacer and beads. These results suggest that two-stage revision THA using an antibiotic-impregnated cement spacer is a useful technique for treating infected hip arthroplasty.

Purpose To describe the incidence and clinical management of corneal infections with methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE). Methods The incidence of methicillin-resistant Staphylococcus (MRS) at the Department of Ophthalmology, Kyoto Prefectural University of Medicine, was reviewed during the 5-year period from January 1996 to December 2000. Clinical aspects of MRS colonization or infection in the eye were investigated. Results Methicillin-resistant S. aureus or MRSE was detected from 30 eyes with ocular diseases; post-keratoplasty (11 eyes), ocular surface disorders without operation (9 eyes), and others (10 eyes). Among the 30 eyes, 12 manifested keratitis. Eight cases (8 eyes) occurred after keratoplasty, including four postoperative cases in patients with Stevens-Johnson syndrome, and two bilateral cases (4 eyes) in patients with acute-phase Stevens-Johnson syndrome. The degree of MRS keratitis was classified into 4 groups: asymptomatic carrier or conjunctivitis, intraepithelial infiltrations, superficial keratitis, and severe keratitis leading to corneal perforation. All cases of keratitis were treated successfully with topical ofloxacin (OFLX), vancomycin (VCM), or arbekacin (ABK). Conclusion Factors associated with ocular MRS colonization were long-term use of antibiotics and/or steroids, and hospitalization. Patients who had undergone keratoplasty or who had Stevens-Johnson syndrome were at increased risk of MRS keratitis. Superficial stromal infiltrations, minimal melting, and minimal stromal scarring are characteristic of MRS keratitis. Therapy for MRS keratitis is summarized. Ofloxacin, VCM, and ABK are effective in the treatment of MRS keratitis. Vancomycin eye ointment is effective as the final choice in serious cases.

An aminoglycoside-modifying enzyme in arbekacin-resistant methicillin-resistant Staphylococcus aureus (MRSA), exhibiting 4'''-N-acetylation, was examined. Although the MRSA strain with AAC(4''') had no AAC(6')-APH(2") activity, a DNA fragment of the AAC(6')-APH(2") gene was amplified by PCR and the purified N-terminal 30-amino acid sequence of this AAC(4''') was identical to AAC(6')-APH(2"). Direct DNA sequencing of this 'silent' AAC(6')-APH(2") gene revealed a single point mutation leading to a substitution of Gly for Asp80, through which the secondary structure is affected. A change in protein conformation could lead to a cleavage and a change of the enzymatic activity. We propose a new aminoglycoside-resistance mediated by AAC(4''') is caused by a mutation-modified AAC(6')-APH(2").

Daptomycin, a lipopeptide antibiotic, has broad activity against gram-positive organisms, similar to vancomycin; however, its mechanism of action differs, resulting in interference with cell membrane transport and a more rapid bactericidal activity. In light of increasing need for alternative treatments against intermediate-resistant Staphylococcus aureus , there is revitalized interest in this antibiotic. We, therefore, evaluated the activity of daptomycin alone or in combination in an in vitro infection model against two glycopeptide intermediate-resistant S. aureus (GISA) isolates. Newly designed regimens of daptomycin at 4 and 6 mg/kg of body weight every 24 h (q24h) were compared to the previous regimen of 3 mg/kg q12h. Daptomycin MICs and minimal bactericidal concentrations (MBCs) (MIC/MBC) for Mu-50, HIP5836 (992), and MRSA-67 were 0.5/1.0, 0.5/1.0, and 0.125/0.5 μg/ml, respectively. MICs and MBCs of arbekacin for the three strains were 2.0/8.0, 0.125/0.5, and 0.125/0.25 μg/ml, respectively. Vancomycin and gentamicin MICs and MBCs for the three strains were 8.0/8.0, 8.0/8.0, and 0.5/1.0 μg/ml and 128/128, 0.5/1.0, and 0.25/0.5 μg/ml, respectively. Our experience with daptomycin in an in vitro infection model has shown significant kill against the two GISA strains (Mu-50 and 992) ( P < 0.03). We also noted that kill was related to a total dose effect for 992, in which simulated daptomycin in vivo dosages of 6 mg/kg q24h and 3 mg/kg q12h produced similar kill and 4 mg/kg q24h resulted in significant regrowth ( P ≤ 0.05). Combination therapy with arbekacin resulted in synergistic activity against Mu-50. Daptomycin area under the concentration-time curve/MIC and C max /MIC ranges for GISA isolates were 80 to 116 and 6 to 12, respectively, and ranges for MRSA-67 were 320 to 461 and 24 to 48, respectively, and appeared to have an association with kill (i.e., decreased CFU/milliliter) at 24 and 48 h. Therefore, these experiments suggest that daptomycin alone or in combination could provide an alternative for the treatment of GISA.

Fourteen different aminoglycoside antibiotics (AGs) were challenged with aminoglycoside acetyltransferases (AACs) of actinomycete origin in order to examine their 'double stage activity' that is arbitrarily defined as antibiotic activity retainable after enzymatic modification. In kanamycin (KM)-group AGs tested [KM, dibekacin (DKB), amikacin and arbekacin (ABK)], ABK retained activity after acetylations by AAC(3), AAC(2') and AAC(6'). DKB also retained a weak activity after acetylation by AAC(2'). In gentamicin (GM)-group AGs tested [GM, micronomicin, sisomicin (SISO), netilmicin (NTL) and isepamicin], GM, SISO and NTL retained activites after acetylation by AAC(2'). In neomycin (NM)-group AGs tested [ribostamycin, NM, paromomycin], NM retained activity after acetylation by AAC(6') and AAC(2'). None of astromicin (ASTM)-group AGs tested (ASTM and istamycin B) retained activity after acetylation by AAC(2') and AAC(6'). The activities of acetylated ABK derivatives by AAC(3) and AAC(2') were distinctively high, compared to the others. Streptomyces lividans TK21 containing the cloned aac genes were markedly sensitive to AGs that retained activities after acetylation, indicating the substantial effect of 'double stage activity'.

Emergence of the newly identified 16S rRNA methylases RmtA, RmtB, and ArmA in pathogenic gram-negative bacilli has been a growing concern. ArmA, which had been identified exclusively in Europe, was also found in several gram-negative pathogenic bacilli isolated in Japan, suggesting global dissemination of hazardous multiple aminoglycoside resistance genes.

Aminoglycoside antibiotics (AGs) with a free 2'-amino group were subjected to enzymatic N-acetylation using a cell free extract that contained an aminoglycoside 2'-N-acetyltransferase, AAC (2'), derived from a kasugamycin-producing strain of Streptomyces kasugaensis. TLC and antibiotic assay of the incubated reaction mixtures revealed that a modified compound retaining substantial antibiotic activity was formed from arbekacin (ABK), while modification of the other AGs resulted in the marked decrease in antibiotic activity. Structure determination following isolation from a large scale reaction mixture showed the modified ABK to be 2'-N-acetyl ABK. In addition, 2',6'-di-N-acetyl ABK was formed as a minor product. The same conversion also occurred with dibekacin (DKB) resulting in the formation of 2'-N-acetyl DKB and 2',6'-di-N-acetyl DKB. MIC determination showed antibacterial activity (1.56 approximately 3.13 micrograms/ml) of 2'-N-acetyl ABK against a variety of organisms. By contrast, 2'-N-acetyl DKB showed no substantial antibiotic activity. We believe 2'-N-acetyl ABK has the highest and broadest antibacterial activity, compared with known N-acetylated AGs.

Pseudomonas aeruginosa NCGM1588 has a novel chromosomal class 1 integron, In151, which includes the aac(6′)-Iaj gene. The encoded protein, AAC(6′)-Iaj, was found to consist of 184 amino acids, with 70% identity to AAC(6′)-Ia. Escherichia coli transformed with a plasmid containing the aac(6′)-Iaj gene acquired resistance to all aminoglycosides tested except gentamicin. Of note, aac(6′)-Iaj contributed to the resistance to arbekacin. Thin-layer chromatography revealed that AAC(6′)-Iaj acetylated all aminoglycosides tested except gentamicin. These findings indicated that AAC(6′)-Iaj is a functional acetyltransferase that modifies the amino groups at the 6′ positions of aminoglycosides and contributes to aminoglycoside resistance of P. aeruginosa NCGM1588, including arbekacin.

As part of a study on fluorination--toxicity relationships for aminoglycoside antibiotics, 5,3'-dideoxy-5-epifluorokanamycin B (10), 5,3',4'-trideoxy-5-epifluorokanamycin B (11), 1-N-[(S)-4-amino-2-hydroxybutanoyl]-5-deoxy-5-epifluorotobramyc in (19), 5-deoxy-5-epifluoroarbekacin (20), and 5-deoxy-5-epifluoroamikacin (21) have been prepared. The acute toxicities of these three 5-deoxy-5-epifluoro compounds showed values almost identical or similar to those for arbekacin (ABK) and amikacin (15), making a sharp contrast with the toxicities of the corresponding 5-deoxy-5-fluoro derivatives. This fact is explained on the basis of basicity changes (retention for the 5-epifluoro derivatives and reduction for the 5-fluoro derivatives) at the H2N-3 groups of the fluorinated compounds compared to the parent compounds; this hypothesis was substantiated by the pKa values at the H3N(+)-1, 3 groups (determined by the shift changes depending on pD values at C-2 and C-4, 6 in their 13C NMR spectra) of 2,5-dideoxy-5-epifluorostreptamine (23) and 2,5-dideoxy-5-fluorostreptamine (24), chosen as model compounds, and 2-deoxystreptamine (DST).

Arbekacin (1-N-((S)-4-amino-2-hydroxybutyryl)-3',4'-dideoxykanamycin B) was active against 54 strains of methicillin-resistant Staphylococcus aureus from 16 different countries, all of which were resistant to > or = 32 mg/L amikacin. MICs of arbekacin ranged from 1 to 16 mg/L, the MIC50 was 3.2 mg/L and the mode geometric mean MICs were 4 and 4.5 mg/L respectively.

Arbekacin (ABK) is a newly developed aminoglycoside in Japan which can cause bactericidal effects on methicillin-resistant Staphylococcus aureus (MRSA). However, details of the mechanism on effective antibacterial activity of this drug in host patients has not been completely elucidated. We studied the modulating effects on some functional activities of immunocompetent cells in in vitro and in vivo mouse experimental systems. 1. (i) ABK stimulated the phagocytic activity against S. aureus into mouse phagocytic cells in a dose-dependent manner. 2. (ii) ABK enhanced oxygen radical generation with chemiluminescence in mouse phagocytic cells. 3. (iii) ABK exhibited a stimulatory effect on interleukin 1α release from mouse adherent cells. 4. (iv) Injection with ABK into mice showed an adjuvant activity which stimulated antibody production against sheep red blood cells and S. aureus . These experimental results indicate the possibility that ABK has not only a direct antibacterial activity but also a modulating activity for immunocompetent cells to enhance host defense against S. aureus infection.

A novel drug delivery system was developed for osteomyelitis using porous hydroxyapatite blocks (HA-b) that were impregnated with antibiotics by a centrifuge method. For the experimental study, a 10 mm3 HA-b was placed in a container, mixed with an antibiotic solution and centrifuged at 1500 rpm for 15 min for the purpose of impregnating antibiotics into the pores. The slow release activity of antibiotic (Arbekacin sulfate [1-N-(S)-4 amino-2-hydroxybutyryl dibekacin]) from the HA-b was tested. An evaluation was made of the slow-releasing capabilities of the ABK from HA-b which was still maintained at 0·5 μg/ml within 21 exchanges of PBS after 42 days. Consequently, seven patients with osteomyelitis, including one with tuberculosis and two with infected hip arthroplasty, have been treated. On a follow-up study, all of the foci had completely healed by the end of the follow-up period without complications. This new method is simple and can be performed safety as a one-stage operation.

The respiratory depression effect of aminoglycoside antibiotics was studied by a toxicokinetic approach, and species differences in drug susceptibility were elucidated based on plasma concentrations. An allometric relationship was obtained between total body clearance of arbekacin, a novel aminoglycoside antibiotic, and animal body weight. The power was 0.714, less than unity, which means smaller animals have higher ability to eliminate the drug from the body and need higher doses to attain a certain steady-state plasma concentration. When the infusion rate of arbekacin was altered, the total dose required to cause the toxicologic endpoint for respiratory depression (60 per cent loss of respiratory rates) changed greatly, but the plasma concentration of arbekacin at the toxicologic endpoint remained at almost a constant level. The concentration at the toxicologic endpoint was similar for all of the animal species examined and was 650-950 micrograms ml-1, even though the total dose required to cause the toxicologic endpoint varied greatly among the animal species. These findings suggest that the toxicologic effect compartment for respiratory depression is indistinguishable from the plasma compartment, and that species differences in the total dose are due to differences in pharmacokinetics of the drug, mainly in the total body clearance, but not to differences in intrinsic susceptibility to the drug.

Only a limited number of strains of methicillin-resistant Staphylococcus aureus (MRSA) moderately resistant to arbekacin (ABK) have been isolated clinically. Three inactivated products of ABK have been obtained by reaction with excess amounts of a crude enzyme preparation extracted from an ABK-resistant MRSA strain (MIC, 25 micrograms/ml). The 2"-O-phosphate was the major product together with small amounts of the 6'-N-acetate and the double modification product. The structures of these modification products were determined by MS and NMR spectral analyses.

Out of 110 strains of Staphylococcus aureus isolated from 1985 to 1990, isolation rate of methicillin-resistant S. aureus (MRSA) was investigated. Nineteen strains of 59 S. aureus from outpatients and 20 strains of 51 S. aureus from inpatients were determined as MRSA. Isolation frequency of MRSA from inpatients was increasing in the recent two years. Coagulase type, enterotoxin type and production of toxic shock syndrome toxin-1 (TSST-1) were examined in 22 strains of MRSA. Coagulase type II (86%), enterotoxin type C (68%) and TSST-1 positive strain was most dominant. Susceptibility of MRSA to 4 antimicrobial agents were measured, MRSA were sensitive to vancomycin (VCM), arbekacin (ABK) and minocycline, but resistant to flomoxef. Thirty-four patients from whom MRSA was isolated including 20 patients from urine, 13 from pus and 1 from blood, were analyzed clinically. Pyuria was not recognized in some cases in whom MRSA was isolated from their urine. Concomitant polymicrobial infection was frequently noted in those patients with MRSA in their urinary tract. These facts show that the pathogenic role of MRSA in the urinary tract infection was not significant. On the other hand, when MRSA was isolated from pus or blood, serious infections could be caused by MRSA, especially in compromised host. Regarding the treatment in these cases, administration of VCM or ABK was though to be necessary.

We determined the in vitro MIC of arbekacin against 200 Acinetobacter isolates recovered from wounded soldiers. The median MIC was 2 μg/ml (range, 0.5 to >64 μg/ml). A total of 97.5% of the isolates had arbekacin MICs of P = 0.7239). Synergy testing suggested an enhanced effect of arbekacin-carbapenem combinations.

A conjugative aminoglycoside resistance plasmid pST2 has been isolated from Escherichia coli K-12 14R525, which was mated with a clinical isolate of Salmonella typhimurium S24. A novel resistance gene of aminoglycoside 6'-N-acetyltransferase[AAC(6')] was cloned from plasmid pST2 on a 1,393 kilobase (kb) of SphI-SalI fragment into vector pACYC184 and pUC18. This novel AAC(6') gene in plasmid pST2 acetylated kanamycin, amikacin, dibekacin, tobramycin, gentamicin, netilmicin, and sisomicin. The complete nucleotide sequence of the novel AAC(6') gene and its neighboring sequences were also determined. Minicell experiments detected only one protein of 24.7 kilodaltons (kDa) translated from an open reading frame of the 618 base pairs (bp) gene.

The combination of ampicillin plus arbekacin produced synergistic killing against 8 of 13 vancomycin-, ampicillin-, gentamicin-, and streptomycin-resistant Enterococcus faecium isolates that possess the high-level gentamicin resistance gene, aph(2")-Id. This combination may prove useful in treating infections caused by multiresistant enterococci.

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.

A high-performance liquid chromatographic method for the measurement of isepamicin, a new aminoglycoside, in plasma, urine and dialysate is reported. The assay utilizes a simple extraction of isepamicin in plasma using commercially available Cyano solid-phase cartridges and dilution of urine and dialysate samples. The separation is performed on a Hypersil C18 column (15 cm X 4.6 mm I.D., 5 microns particle size) and utilizes a mobile phase consisting of 10% methanol and 90% buffer solution containing 0.01 M sodium hexanesulfonate, 0.1 M sodium sulfate and 17 mM acetic acid. The flow-rate is 1.1 ml/min. Dibekacin is used as the internal standard. Isepamicin is derivatized post-column with o-phthalaldehyde for spectrofluorometric detection. The method can also be used for the measurement of other aminoglycosides, i.e. tobramycin, kanamycin, netilmicin and gentamicin. The assay is fast, accurate and has a quantitation limit of 100 ng/ml isepamicin in plasma and 50 ng/ml in urine and dialysate.

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.

5-Deoxy-5-episubstituted arbekacin derivatives have been designed and efficiently synthesized. The synthetic compounds showed potent antibacterial activity against both Staphylococcus aureus , including methicillin-resistant S. aureus , and Pseudomonas aeruginosa . In particular, these derivatives were superior to arbekacin against MRSA strains expressing the bifunctional aminoglycoside-modifying enzyme AAC(6′)-APH(2″). The antibacterial activity of the 5-deoxy-5-episubstituted arbekacin derivatives against Pseudomonas aeruginosa was markedly influenced by the efflux system of MexXY/OprM. The 6′- N -methyl derivative of the 5-epi arbekacin was effective against Pseudomonas aeruginosa expressing the aminoglycoside-modifying enzyme AAC(6′).

The VraSR two-component regulatory system is involved in glycopeptide resistance in Staphylococcus aureus . We examined the relationship between VraS mutation and susceptibility to various antimicrobial agents in 400 clinical isolates of methicillin-resistant S. aureus (MRSA) from Cancer Institute Hospital between 1998 and 2004. The prevalence of MRSA isolates with teicoplanin minimum inhibitory concentrations (MICs) of 4–8μg/mL rose between 2000 and 2002 (52% in 2000). Among the isolates displaying reduced susceptibility to teicoplanin (78 isolates), 99% harboured the Ile5Asn (I5N) mutation in VraS. In addition, MICs of oxacillin and imipenem tended to be higher for I5N mutants compared with those for non-I5N isolates. By contrast, no significant change was noted in susceptibility to arbekacin or vancomycin. In this hospital, I5N mutants emerged at an early stage after the introduction of teicoplanin and thereafter declined in number upon increased usage of arbekacin instead of glycopeptides. Outcomes from 18 patients who were infected with MRSA with reduced susceptibility to teicoplanin were analysed microbiologically in a retrospective manner. Teicoplanin was effective in 50% of the patients treated with this drug. On the other hand, arbekacin and vancomycin were effective in all cases. The results indicate the relationship between antimicrobial susceptibility and therapeutic effect.

Given the increasing prevalence of mycobacterial resistance to aminoglycoside antibiotics, we examined the susceptibility of 76 clinical isolates of mycobacteria to arbekacin, amikacin, gentamicin, kanamycin, tobramycin and streptomycin using an agar dilution method. Only arbekacin and amikacin showed excellent therapeutic potential (minimum inhibitory concentrationis (MICs)or =0.25-4 microg/ml) against 30 isolates of rapidly growing mycobacteria, including Mycobacterium fortuitum, M. chelonae and a related organism, Nocardia asteroides. The MIC(90)of tobramycin against 23 isolates of M. avium complex was 8 microg/ml, while that of the other 5 aminoglycosides ranged from 64-256 microg/ml. Of the 23 M. tuberculosis isolates tested, 5 showed aminoglycoside resistance (MICs 128 toor =1,024 microg/ml), while the others were variably susceptible (MICsor =0.25-32 microg/ml) to all 6 aminoglycosides. The chemotherapeutic potential of arbekacin, amikacin and streptomycin as treatment of tuberculosis was apparent; however, proper patient management would be required to control against the emergence of the drug-resistant strains during prolonged treatment.

We compared the results of two typing methods for 678 strains of methicillin-resistant Staphylococcus aureus and methicillin-susceptible S. aureus . PCR-restriction fragment length polymorphism typing of the coagulase gene was a more reliable method than coagulase serotyping from the viewpoint of arbekacin resistance.

It is generally accepted that methicillin-resistant Staphylococcus aureus (MRSA) is also resistant to aminoglycoside antibiotics. We investigated trends of gentamicin and arbekacin susceptibilities and the prevalence of the genes encoding aminoglycoside-modifying enzymes (AMEs) for a total of 218 strains of MRSA isolated from blood specimens obtained from 1978 through 2002 in one hospital. The minimum inhibitory concentrations of gentamicin at which 50% of the strains were inhibited (MIC(50)) wereor =128 and 32 microg/ml for isolates obtained from 1978 to 1984 and from 1985 to 1989, respectively, and 0.5 microg/ml for isolates obtained from 1990 to 2002. The MIC(90) of gentamicin was consistentlyor =128 microg/ml. Investigation of the occurrence of AME revealed that the MIC(50) of gentamicin was highly correlated with the presence of aac(6')/aph(2'') encoding aminoglycoside acetyl/phosphotransferase. The MIC(50) of arbekacin was 2 microg/ml for strains isolated in 1978-1984 and/=0.5 microg/ml for strains isolated from 1985 to 2002. The MIC(90) of arbekacin was 8 microg/ml for the strains isolated in 1978-1989 and 1 to 2 microg/ml for strains isolated in 1990-2002. Though it has been established that AAC(6')/APH(2'') modifies arbekacin, the trend of arbekacin resistance was not necessarily consistent with the presence of this enzyme. However, the prevalence of both aac(6')/aph(2'') and aph(3')-III in the strains isolated from 1978 through 2002 was correlated with the MIC(90) values of arbekacin. Thus, it is most likely that APH(3')-III, in addition to AAC(6')/APH(2''), is somehow involved in arbekacin resistance in S. aureus. Our results imply that gentamicin- and arbekacin-resistant MRSAs have consistently decreased for the past 25 years and that this finding is, most likely, attributable to the declining prevalence of genes encoding for AMEs.

The bacterial strains isolated from 490 patients diagnosed as having urinary tract infections (UTIs) in 14 institutions in Japan were collected between August 2004 and July 2005. The susceptibilities of them to many kinds of antimicrobial agents were measured. Of them, 577 strains were estimated as causative bacteria and used for the measurement. The strains consisted of 156 gram-positive bacterial strains (27.0%) and 421 gram-negative bacterial strains (73.0%). Against Staphylococcus aureus, arbekacin (ABK), vancomycin (VCM) showed the strongest activity and prevented the growth of all strains with 2 microg/mL. Against Enterococcus faecalis, ampicillin (ABPC) and VCM showed a strong antibacterial activity. The antibacterial activity of cephems to Escherichia coli was generally good, and especially cefozopran (CZOP) and cefpirome (CPR) showed the strongest activity (MIC90:or = 125 microg/mL). Quinolone resistant E. coli [MIC of ciprofloxacin (CPFX):or = 4 microg/mL] was detected at frequency of 18.8%, which was higher than that in the last year. Against Klebsiella pneumoniae, CZOP, meropenem (MEPM), and carumonam (CRMN) showed the strongest activity and prevented the growth of all strains with 0.125 microg/mL or less. The antibacterial activity of the other cephems was relatively good, and decrease in their activity observed in the last year study was not recognized. Against Serratia marcescens, imipenem (IPM) and gentamicin (GM) had the strongest antibacterial activity. Against Proteus mirabilis, CRMN showed the strongest activity and prevented the growth of all strains with 0.125 microg/mL or less. MEPM prevented the growth of all strains with 0.25 microg/mL. Next, cefmenoxime (CMX), ceftazidime (CAZ), CZOP, cefixime (CFIX), cefpodoxime (CPDX), and cefditoren (CDTR) showed a strong activity. The antibacterial activity of the drugs to Pseudomonas aeruginosa was generally low, and MIC90 of all the drugs was ranged from 32 to128 microg/mL except IPM and MEPM having 16 microg/mL. The antibacterial activities of CZOP and CAZ were considered to be relatively good on MIC50 comparison (MIC50: 2 microg/mL).

This study was undertaken to evaluate the in vitro activities of arbekacin-based combination regimens against vancomycin hetero-intermediate Staphylococcus aureus (hetero-VISA). Combinations of arbekacin with vancomycin, rifampin, ampicillin-sulbactam, teicoplanin, or quinipristin-dalfopristin against seven hetero-VISA strains and two methicillin-resistant S. aureus strains were evaluated by the time-kill assay. The combinations of arbekacin with vancomycin, teicoplanin, or ampicillin-sulbactam showed the synergistic interaction against hetero-VISA strains. Data suggest that these arbekacin-based combination regimens may be useful candidates for treatment options of hetero-VISA infections.