Isepamicin Research Articles

Antimicrobial susceptibility analysis of isepamicin combination treatments in Mycobacterium abscessus species

This study evaluated the antimicrobial potency of the combination of isepamicin (ISP) for Mycobacterium abscessus species (MABS). 34 clinical MABS strains were isolated from clinical samples. Of them, 11 (32.4 %) were M. abscessus subsp. abscessus (Mab), 22 (64.7 %) were M. abscessus subsp. massiliense (Mma), and one (2.9 %) was M. abscessus subsp. bolletii (Mbo). We compared susceptibility to sitafloxacin (STFX)-ISP and clarithromycin (CLR)-ISP combinations with those of the antimicrobial agents alone, and synergistic effects were observed in 41.2 % and 17.6 % when treated with STFX-ISP and CLR-ISP. By hierarchical cluster analysis, the isolates divided into treatment-sensitive and treatment-resistant groups. Non-Mma or rough colony isolates were significantly likely to belong to the treatment-sensitive group (p = 0.024, p < 0.001, respectively). These results suggest that the ISP-containing combination could be a new therapeutic strategy for MABS, especially in cases of non-Mma: treatment-refractory subspecies, and rough morphotypes: high-virulence morphotypes.

Rapid determination of isepamicin by using SERS based on BSA-protected AgNPs modified by α-Fe2O3

A surface-enhanced Raman spectroscopy (SERS) method for the determination of isepamicin (ISE) using silver nanoparticles (AgNPs) protected by bovine serum albumin (BSA) and modified by α-Fe2O3 as an efficient substrate was established. The synthesized substrate was characterized and verified by transmission electron microscopy (TEM), ultraviolet visible spectroscopy (UV–vis), and fourier transform infrared spectroscopy (FT-IR). The conditions affecting the Raman signal of ISE were optimized by single factor and response surface experiments. Under optimized conditions, a standard curve ISERS = 43.08c + 63598.69 (c: nmol/L) with a linear relationship (r = 0.9976) was established between the SERS intensity and ISE concentration in the range of 20.00 – 2000.00 nmol/L. The limit of detection (LOD) for ISE was 16.58 nmol/L (S/N = 3). The recovery of ISE in the samples was 96.29 % – 104.12 %, with relative standard deviation (RSD) was 1.53 % – 3.43 % (n = 5). The SERS method was reliable and satisfactory for the quantitative analysis of ISE at low concentration.

Development of 6'-N-Acylated Isepamicin Analogs with Improved Antibacterial Activity Against Isepamicin-Resistant Pathogens.

The development of new aminoglycoside (AG) antibiotics has been required to overcome the resistance mechanism of AG-modifying enzymes (AMEs) of AG-resistant pathogens. The AG acetyltransferase, AAC(6′)-APH(2″), one of the most typical AMEs, exhibiting substrate promiscuity towards a variety of AGs and acyl-CoAs, was employed to enzymatically synthesize new 6′-N-acylated isepamicin (ISP) analogs, 6′-N-acetyl/-propionyl/-malonyl ISPs. They were all active against the ISP-resistant Gram-negative bacteria tested, and the 6′-N-acetyl ISP displayed reduced toxicity compared to ISP in vitro. This study demonstrated the importance of the modification of the 6′-amino group in circumventing AG-resistance and the potential of regioselective enzymatic modification of AG scaffolds for the development of more robust AG antibiotics.

Efficacy of combined prophylactic use of levofloxacin and isepamicin for transrectal prostate needle biopsy: A retrospective single-center study

PurposeTo assess the efficacy of a combined regimen of levofloxacin (LVFX) plus isepamicin (ISP) as prophylaxis for transrectal ultrasound-guided needle biopsy of the prostate (TRUSP-Bx). Materials and methodsOverall, 562 patients undergoing TRUSP-Bx were included in the present study. All patients were administered a single-dose of oral LVFX (500 mg) in the morning and intravenous ISP (400 mg) 60 min before biopsy. All biopsies were performed via TRUSP-Bx with an 18-gauge needle, and 12-core specimens were routinely obtained. Before initiating antibiotic treatment, urine and blood bacterial cultures were tested to determine the causative microorganisms in the patients with acute bacterial prostatitis. ResultsAcute bacterial prostatitis developed in three (0.53%) participants. The incidence rates of acute bacterial prostatitis in the low- and high-risk groups were 0.79% and 0.46%, respectively. These patients showed clinical symptoms of acute bacterial prostatitis 12–24 h after their biopsy. Escherichia coli (E. coli) was isolated in the urine or bladder cultures of all of patients. All three isolates were determined to be LVFX-resistant E. coli, although they had good sensitivity to aminoglycosides, cephalosporins, and carbapenems. All patients were administered antibiotic treatment (cephalosporin or carbapenem) immediately and were treated successfully with no evidence of further disease progression. ConclusionAntibiotic prophylaxis with LVFX plus ISP was effective, resulting in a lower incidence of acute bacterial prostatitis after TRUSP-Bx in both low- and high-risk patients.

Local irritation study with isepamicin

Local irritative effects of isepamicin (HAPA-B) were studied using muscle and blood vessel of Japanese White rabbits. Muscle irritation experiment was carried out with a single dosage of 100 mg HAPA-B, 100 mg amikacin (AMK), saline, 0.75% acetic acid or 6.0% acetic acid administered into musculus sacrospinalis. Vascular irritation experiment was carried out by allowing HAPA-B to remain in a sealed section of vena retroauricularis for 3 minutes after injection. In result, the muscular irritative activity of HAPA-B was less severe than 0.75% acetic acid but more than saline, and almost equal activity to AMK was observed. The HAPA-B caused very slight inflammation while thrombus was not formed. The vascular irritative activity was very little.

High performance liquid chromatography (HPLC) method coupled with resonance Rayleigh scattering detection for the determination of isepamicin

A simple and novel reversed-phase high performance liquid chromatography (HPLC) method coupled with resonance Rayleigh scattering (RRS) was developed to analyze isepamicin (ISP) in rat plasma. The chromatographic separation was achieved at 30 °C on a reverse phase column of Synergi Hydro-RP (150 mm × 4.6 mm; 4 μm), with (15 : 85, v/v) methanol–water (containing 0.15% TFA (v/v)) as the mobile phase. The flow rate was 0.4 mL min−1. The RRS signal was detected at λex = λem = 372 nm. Netilmicin (NTL) was used as the internal standard. The new analytical technique was validated for the intra- and inter-day variation, the linear range of the standard curve of ISP and the limit of detection (S/N = 3). The results indicated that HPLC coupled with RRS was a reliable and valuable technique for quantitative analysis of ISP in rat plasma. The method shows a better linear relationship and lower analysis time.

Resonance Rayleigh‐scattering spectral method for the determination of some aminoglycoside antibiotics using CdTe quantum dots as a probe

A novel method is used for the determination of some aminoglycoside antibiotics (AGs) such as etimicin (ETM), isepamicin (ISP) and amikacin (AMK). It is based on the resonance Rayleigh scattering (RRS) intensities enhanced by AGs-induced CdTe quantum dots aggregation. Under the optimum conditions, the increments in RRS intensity were directly proportional to the concentration of AGs in certain ranges. At the same time, the second-order scattering, the frequency-doubling scattering and the frequency-trebling scattering intensities were also enhanced and their increments were proportional to the concentration of AGs. Among them, the RRS method had the highest sensitivity; the linear ranges and detection limits for ETM, ISP and AMK were 0.085-7.2, 0.0067-1.2, 0.017-6.0 and 0.025, 0.0051, 0.0020 μg mL(-1) . This method was applied to the measurement of AGs in human serum and urine with satisfactory results. In addition, the reaction mechanism and the reasons for the enhancement of RRS are discussed using fluorescence, RRS, transmission electron microscope technology and quantum chemistry method.

LC Analysis of Isepamicin in Plasma Samples Post-Inhalation with Fluorescence Detection and Its Application to a Pharmacokinetic Study

A simple and novel LC method has been developed for determination of isepamicin (ISP) in rat plasma, an aminoglycoside antibiotic agent. After protein precipitation and clean-up procedure to remove lipophilic contaminants, ISP is derivatized by pre-column with 9-fluorenylmethyl chloroformate for fluorescence detection. Chromatographic separations are achieved using a C18 column and mobile phase consisting of water and acetonitrile (68/32, v/v). Amikacin was used as an internal standard. The calibration curve was linear over a concentration range of 0.625–15 μg mL−1. The limit of quantification was 0.45 μg mL−1. The intra- and inter-day variabilities of ISP were both less than 5%. Both derivatives were stable for at least a week at ambient condition. This assay procedure should have useful application in therapeutic drug monitoring of ISP. The limit of detection was 0.10 μg mL−1. The specificity, assay linearity, low level assay linearity and assay repeatability were also investigated. The established method provides a reliable bioanalytical method to carry out isepamicin pharmacokinetics in rat plasma.

Determination of Isepamicin in Human Plasma by HPLC with Fluorescence Detection after Derivatization Using 6-Aminoquinolyl-N-hydroxysuccinimidyl-carbamate

A simple and rapid high-performance liquid chromatographic method has been developed for determination in human plasma of isepamicin (ISP), an aminoglycoside antibiotic agent. After protein precipitation and clean-up procedure to remove lipophilic contaminants, ISP is derivatized pre-column with 6-aminoquinolyl-N-hydroxysuccinimidyl-carbamate for fluorescence detection. Chromatographic separations are achieved using C(18) column and mobile phase consisting of 20 mM KH(2)PO(4) containing 8 mM triethylamine (pH 7.0) and acetonitrile (78/22, v/v). Amikacin was used as an internal standard. The calibration curve was linear over a concentration range of 0.5-50 microg/ml. The limit of quantification was 0.5 microg/ml. The intra- and inter-day variabilities of ISP were both less than 17.5%. Both derivatives were stable for at least a week at ambient condition. This assay procedure should have useful application in therapeutic drug monitoring of ISP.

Oral Quinolone Switch after 8 Days of Aminoside Is an Efficient and Safe Antibiotherapeutic Strategy for Febrile Neutropenia after Hematopoetic Stem Cell Transplantation.

Management of febrile neutropenia is one of the important points during the management of autologous or allogeneic hematopoietic stem cell transplantation (HSCT). In this study, we prospectively evaluated the safety and effectiveness of an empiric antibiotherapeutic scheme that associated ticarcillin-clavulanic acid (TIM) and isepamycin (ISE) for 7 days followed by a switch at day 8 to TIM and ofloxacin (OFX), additional therapy (glycopeptide or antifungal therapy) was allowed according to clinical features or documented infection. All the steps of the strategy were evaluated. Ninety six patients (73 autologous HSCT and 23 allogeneic HSCT) were enrolled. Fifty three percents of the patients presented a Fever of Unknown Origin. Bacteriologically proven infections were documented in 32 patients mainly on blood cultures (66%) with an high frequency of gram positive bacterias (71%: 38% of coagulase negative staphylococci, 16% of streptococci, 6% of S. aureus). Median time to neutrophil recovery was 14 days and 24 days respectively for autologous and allogeneic HSCT. We observed an overall effectiveness of the strategy in 78% of the cases. First step strategy was successful in 64 patients (65%) but only 26 patients kept the TIM/ISE bi therapy alone (Glycopeptide and antifungal therapy added in 29 and 7 patients). Quinolone switch was performed in 57 patients (59%) and was effective in 35 patients (61%). The success rate of TIM/OFX after success of TIM/ISE was 95%. Forty five percents of the patient could keep an oral form of OFX. Glycopeptide and antifungal therapy were necessary in 58% and 16% of cases with an effectiveness of 79% and 57% respectively. Failures were mainly observed after front-line treatment (TIM/ISE: 34 Failures) with addition of other kind of antibiotics in 95% of the cases. In 11 patients (32%) the additional antibiotic was netromidazole for clinical symptoms conclusive with anaerobic bacteria. A significantly better effectiveness was found in short duration aplasia (<15days, p=0.008) and in autologous HSCT (p=0.0041). Tolerance was good with only 6 grade III toxicities, no severe nephrotoxicity (8 grade I events, 7 in allogeneic setting) and no infectious death was observed. These results showed(i) that the choice of the first-line beta lactamin molecule should be discussed(ii) that oral quinolone switch is safe and effective and(iii) furthermore pointed out the importance of different antibiotic strategies in autologous (and allogeneic HSCT using Reduced Intensity conditioning) in comparison to standard myeloablative allogeneic HSCT.

Comparison of two methods to obtain a desired first isepamicin peak in intensive care patients

A randomized multicenter study in intensive care unit (ICU) patients, evaluated the capacity of a Bayesian method to obtain an optimal first isepamicin (ISP) peak of 80 mg/L in comparison to a fixed loading dose (LD). Patients (n=236) over 18 years of age were enrolled from 6 September 1997 to 17 July 1999 and randomly assigned to received ISP in a calculated dose (CD) or a loading dose (LD) of 25 mg/kg body weight. The CD was estimated using a specific population model with Bayesian methodology implemented in the PKS program (Abbott PKS, Abbott Diagnostics, Rungis, France). The data required included age, body weight, height, gender and serum creatinine. ISP disposition is described by a one-compartment model. Blood samples were drawn 1 and 24 h after the start of infusion for fluorescence polarization immunoassay measurement of serum ISP concentrations. The predictive performance was assessed by computing bias and precision. Peak concentrations were significantly higher in CD group than the LD group (84.2 +/- 28.6 vs. 74.7 +/- 24.1 mg/L, respectively; P=0.008), but trough levels were comparable. The optimal ISP peak was attained by a significantly higher percentage of CD patients (P=0.018), and by significantly more CD patients on mechanical ventilation (P=0.025), and with simplified acute physiological scores (SAPS) > 35 (P=0.002). Pharmacokinetic parameters were similar for the two groups with large interindividual variations. Mean (+/- SD) volume of distribution of ventilated patients (72%) was significantly higher than of nonventilated patients (23.31 +/- 7.35 vs. 20.60 +/- 6.30 L, respectively; P=0.001). No relationship was found between the volume of distribution and SAPS. Total clearance was significantly correlated with estimated CLCR (creatinine clearance) (P=0.0001). Precision (RMSE) is better for CD than for LD strategy, respectively 27.96 and 28.66 mg/L. The Bayesian method was significantly more accurate and performed particularly well in ventilated patients and patients with high SAPS, compare to an LD of 25 mg/kg to obtain a first ISP peak of 80 mg/L in ICU patients. Therefore, a fixed dose of 28.5 mg/kg would be also adequate to reach a peak of 80 mg/L.

In vitro interaction of piperacillin and imipenem/cilastatin combined with aminoglycosides against Pseudomonas aeruginosa

The in vitro interactions of piperacillin (PIPC) and imipenem/cilastatin (IPM/CS) combined with 5 kinds of aminoglycosides (gentamicin, tobramycin, amikacin (AMK), isepamicin and netilmicin) were investigated against IPM/CS-susceptible (MIC of IPM/CS was < or = 3.13 micrograms/ml) and IPM/CS-resistant (MIC of IPM/CS was > or = 12.5 micrograms/ml) Pseudomonas aeruginosa. The following results were obtained. 1. In the checkerboard dilution studies, the combinations of PIPC with aminoglycosides showed synergistic effect for more than 50% of the each 54 strains of IPM/CS-susceptible and IPM/CS-resistant P. aeruginosa. The synergistic/additive effects of PIPC with aminoglycosides were demonstrated for all tested strains. 2. In the checkerboard dilution studies, the combinations of IPM/CS with aminoglycosides showed no antagonism against any strains. The synergistic effects of IPM/CS with aminoglycosides were demonstrated for 0 to 14.8%, and these values were smaller than the combinations of PIPC with aminoglycosides. 3. Corresponding to the results of checkerboard dilution studies, the combination of PIPC with AMK was more effective than the combination of IPM/CS with AMK on the killing curve for IPM-resistant P. aeruginosa. In conclusion, PIPC showed the synergistic effects in combinations with aminoglycosides against IPM/CS-resistant P. aeruginosa. These results suggest that the combination therapies of PIPC with aminoglycosides are useful for the clinical treatment of serious infections due to P. aeruginosa.

イセパマイシン１日１回投与法の有用性に関する検討

イセパマイシン１日１回投与法の有用性に関する検討

Selection of subpopulations resistant to amikacin and netilmicin of gentamicin-resistant clinical strains of Staphylococcus aureus and Staphylococcus epidermidis

Recently we have found several strains of Staphylococcus aureus and Staphylococcus epidermidis, which in spite of containing aminoglycoside-modifying enzymes (AMEs) remained susceptible to antibiotics such as netilmicin (NET) and amikacin (AN). Assuming an interest in this agent from a clinical point of view, the aim of this study was to determine if these strains became resistant after prolonged contact with such antibiotics. We found that minimal inhibitory concentrations (MICs) of the bacterial strains not only increased when using these two agents, but also when using other aminoglycosides such as gentamicin (GM), tobramycin (TM), amikacin (AN) and isepamicin (ISE). In order to see the effect of prolonged use of NET on enzyme production, three strains containing AMEs were selected and we could observe an increase in the enzyme levels after successive passages through media containing NET.

Reevaluation of current antimicrobials. Series 25: isepamicin

Reevaluation of current antimicrobials. Series 25: isepamicin

尿中濃度自動シミュレーター装置付属のin vitro複雑性膀胱炎モデルを用いたIsepamicinとPiperacillin併用療法の意義の検討

Isepamicin (ISP) and piperacillin (PIPC) were shifted to the urinary concentration by employing an in vitro complicated cystitis model operated by a computer-controlled automatic simulator for urinary concentration, and administrated to bacteria in the urinary bladder model (Pseudomonas aeruginosa: P. aeruginosa, initial cell concentration: 10(7) cfu/ml). In this case, effects by single treatment with ISP or PIPC on cell number curves were examined. Further, significance of the combined treatment with ISP and PIPC were investigated by changing the order of each treatment. And following the results were obtained. 1. In a single treatment with PIPC the cell concentration was minimum (10(4) cfu/ml) at 9th hour after its treatment and thereafter, regrowth to the same level as the initial concentration was observed at 16th hour. 2. In the case of single treatment with ISP, the cell concentration became minimum (10(2) cfu/ml) at 13th hour after the treatment and raised to the same concentration as the initial one at 25th hour. 3. In the combined treatment, the cell concentration was minimum (less than 10(1) cfu/ml) at 26th hour in the case of prior treatment with ISP. Thereafter, regrowth was observed and the cell concentration at 42nd hour reached to the initial cell concentration. 4. In simultaneous treatment with ISP and PIPC, the cell concentration at 24th hour was minimum (10(1) cfu/ml) and reached to the same level as the initial one after regrowth. From these results, it was found that the combined treatment with ISP and PIPC caused more reduction of the cell concentration than either single treatment. Further, regrowth of the cells was suppressed for longer duration.(ABSTRACT TRUNCATED AT 250 WORDS)

.GAMMA.-Lactam analogues of .BETA.-lactam antibiotics.

In vitro interactions between aztreonam (AZT) and 8 other antibiotics were studied using the agar dilution checkerboard technique against 88 clinical isolates of Escherichia coli, Proteus vulgaris, Serratia marcescens and Pseudomonas aeruginosa. Combinations of AZT with 8 other antibiotics were generally additive or indifferent. Synergism was occasionally seen against S. marcescens or P. aeruginosa with AZT plus isepamicin (ISP). Antagonism was observed only between AZT and latamoxef against P. vulgaris. In a phase-contrast microscopic study, synergistic effects between AZT and aspoxicillin or ISP were confirmed against E. coli 177 and P. aeruginosa 15846. AZT in combination with ISP demonstrated a synergy against experimental urinary tract infection in mice caused by P. aeruginosa 15846. We believe that combinations of several antibiotics with AZT should be considered for initial therapy of infections because synergism and additive action were observed and antagonism was rarely found in our study.

Combination antibacterial effects between aztreonam and eight other antibiotics

In vitro interactions between aztreonam (AZT) and 8 other antibiotics were studied using the agar dilution checkerboard technique against 88 clinical isolates of Escherichia coli, Proteus vulgaris, Serratia marcescens and Pseudomonas aeruginosa. Combinations of AZT with 8 other antibiotics were generally additive or indifferent. Synergism was occasionally seen against S. marcescens or P. aeruginosa with AZT plus isepamicin (ISP). Antagonism was observed only between AZT and latamoxef against P. vulgaris. In a phase-contrast microscopic study, synergistic effects between AZT and aspoxicillin or ISP were confirmed against E. coli 177 and P. aeruginosa 15846. AZT in combination with ISP demonstrated a synergy against experimental urinary tract infection in mice caused by P. aeruginosa 15846. We believe that combinations of several antibiotics with AZT should be considered for initial therapy of infections because synergism and additive action were observed and antagonism was rarely found in our study.

Ｂａｙｅｓｉａｎ法によるイセパマイシン（ＩＳＰ）の投与設計後の予測性の検討

Ｂａｙｅｓｉａｎ法によるイセパマイシン（ＩＳＰ）の投与設計後の予測性の検討

健常人におけるイセパマイシン（ＩＳＰ）の薬物動態の検討

健常人におけるイセパマイシン（ＩＳＰ）の薬物動態の検討