Application of the Hartford Hospital Nomogram for Plazomicin Dosing Interval Selection in Patients with Complicated Urinary Tract Infection.

Plazomicin is a new FDA-approved aminoglycoside antibiotic for complicated urinary tract infections (cUTI). In the product labeling, trough-based therapeutic drug management (TDM) is recommended for cUTI patients with renal impairment to prevent elevated trough concentrations associated with serum creatinine increases of ≥0.5 mg/dl above baseline. Herein, the utility of the Hartford nomogram to prevent plazomicin trough concentrations exceeding the TDM trough of 3 µg/ml and optimize the area under the curve (AUC) was assessed. The AUC reference range was defined as the 5th to 95th percentile AUC observed in the phase 3 cUTI trial (EPIC) (121 to 368 µg · h/ml). Observed 10-h plazomicin concentrations from patients in EPIC (n = 281) were plotted on the nomogram to determine an eligible dosing interval (every 24 h [q24h], q36h, q48h). Based on creatinine clearance (CLcr), a 15- or 10-mg/kg of body weight dose was simulated with the nomogram-derived interval. The nomogram recommended an extended interval (q36h and q48h) in 31% of patients. Compared with the 15 mg/kg q24h regimen received by patients with CLcr of ≥60 ml/min in EPIC, the nomogram-derived interval reduced the proportion of patients with troughs of ≥3 µg/ml (q36h, 27% versus 0%, P = 0.021; q48h, 57% versus 0%, P = 0.002) while significantly increasing the number of patients within the AUC range. Compared with the 8 to 12 mg/kg q24h regimen (received by patients with CLcr of >30 to 59 ml/min in EPIC), the nomogram-derived interval significantly reduced the proportion of troughs of ≥3µg/ml in the q48h cohort (72% versus 0%, P < 0.001) while maintaining a similar proportion of patients in the AUC range. Simulated application of the Hartford nomogram optimized plazomicin exposures in patients with cUTI while reducing troughs to <3 µg/ml.

A Simulated Application of the Hartford Hospital Aminoglycoside Dosing Nomogram for Plazomicin Dosing Interval Selection in Patients With Serious Infections Caused by Carbapenem-Resistant Enterobacterales.

PURPOSE: In the Phase III Study of Plazomicin Compared With Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CARE), plazomicin was studied for the treatment of critically ill patients with infections caused by carbapenem-resistant Enterobacterales. Initial plazomicin dosing was guided by creatinine clearance (CrCl) and subsequent doses adjusted by therapeutic drug monitoring to achieve AUC0-24 exposures within a target range (210-315 mg∙h/L). We applied the Hartford nomogram to evaluate whether this clinical tool could reduce plazomicin troughs levels and increase the proportion of patients within the target AUC range. METHODS: Thirty-seven patients enrolled in cohorts 1 or 2 of CARE were eligible for analyses. Observed 10-hour concentrations after the initial dose were plotted on the Hartford nomogram to determine an eligible dosing interval group (q24h, q36h or q48h). On the basis of baseline CrCl, a 15- or 10-mg/kg dose was simulated with the nomogram-recommended dosing interval. The proportion of patients in each dosing interval group with a trough ≥3 mg/L (trough threshold associated with serum creatinine increases ≥0.5 mg/dL in product label) was quantified. Simulated interval-normalized AUC0-24 was compared with the target AUC range. FINDINGS: Among the 28 patients with a CrCl ≥60 mL/min, the nomogram recommended every-24-hour dosing in 61% and an extended-interval (q36h or q48h) in 39% of patients. For patients with a CrCl ≥30-59 mL/min (n = 9), the nomogram recommended every-24-hour dosing and an extended-interval in 22% and 78% of patients, respectively. Among both renal function cohorts, exposure simulation with the nomogram significantly reduced the proportion of patients with trough concentrations ≥3 mg/L (CrCl ≥60 mL/min cohort: 91% vs 9%, P < 0.001; CrCl ≥30-59 mL/min cohort, 100% vs 0%, P < 0.001). Relative to the observed mean (SD) AUC0-24 of 309 mg∙h/mL (96 mg∙h/mL), simulation of extended intervals resulted in a mean interval-normalized AUC0-24 of 210 mg∙h/mL (40 mg∙h/mL) in all patients eligible for an extended interval, resulting in a similar proportion (49% vs 54%) of patients within the target AUC0-24 range after the first dose. IMPLICATIONS: Application of the Hartford nomogram successfully reduced the likelihood of elevated plazomicin trough concentrations while improving AUC exposures in these patients with carbapenem-resistant Enterobacterales infections.

A Phase 1 Study of Intravenous Plazomicin in Healthy Adults to Assess Potential Effects on the QT/QTc Interval, Safety, and Pharmacokinetics.

Plazomicin is an aminoglycoside with in vitro activity against multidrug-resistant Enterobacteriaceae. A phase 1, randomized, double-blind, crossover study assessed the potential effects of plazomicin on cardiac repolarization (NCT01514929). Fifty-six healthy adults (24 men, 32 women) received a single therapeutic dose of plazomicin (15 mg/kg administered by 30-minute intravenous infusion), a single supratherapeutic dose of plazomicin (20 mg/kg administered by 30-minute intravenous infusion), placebo, or oral moxifloxacin (400 mg). The primary end point was the baseline-adjusted, placebo-corrected QTc interval using the Fridericia formula (ΔΔQTcF). Assay sensitivity was concluded if the lower limit of a 1-sided 95%CI (adjusted for multiplicity using the Hochberg procedure) for moxifloxacin ΔΔQTcF was >5 milliseconds at ≥1 prespecified time points. No QT prolongation effect for plazomicin was concluded if the largest mean effect was <5 milliseconds, and the upper limit of a 2-sided 90%CI for plazomicin ΔΔQTcF was <10 milliseconds at all time points. Assay sensitivity was demonstrated based on moxifloxacin ΔΔQTcF. No QT prolongation effect for plazomicin was concluded because the largest mean ΔΔQTcF for plazomicin was 3.5 milliseconds, and the highest upper limit was 5.6 milliseconds. No clinically relevant changes were observed in electrocardiograms. For the 15- and 20-mg/kg dose levels of plazomicin, mean peak plasma concentration values were 76.0 and 96.6 mg/L, and mean values of the area under the concentration-time curve over 24 hours were 263 and 327 mg·h/L, respectively. Model-derived pharmacokinetic parameters and safety findings were generally consistent with previously reported plazomicin studies. In conclusion, therapeutic and supratherapeutic doses of plazomicin had no clinically significant effect on cardiac repolarization and were generally well tolerated.

A Phase 1 Study To Assess the Pharmacokinetics of Intravenous Plazomicin in Adult Subjects with Varying Degrees of Renal Function.

Plazomicin is an FDA-approved aminoglycoside for the treatment of complicated urinary tract infections. In this open-label study, 24 adults with normal renal function or mild, moderate, or severe renal impairment (n = 6 per group) received a single 7.5-mg/kg of body weight dose of plazomicin as a 30-min intravenous infusion. Total clearance declined with renal impairment, resulting in 1.98-fold and 4.42-fold higher plazomicin exposures, as measured by the area under the concentration-time curve from 0 h to infinity, in subjects with moderate and severe impairment, respectively, than in subjects with normal renal function. (This study has been registered at ClinicalTrials.gov under identifier NCT01462136.).

Development of a non-derivatization high-performance liquid chromatography method with resonance Rayleigh scattering detection for the detection of sisomicin in rat serum.

A resonance Rayleigh scattering (RRS) detection approach was developed to detect sisomicin (Siso) in rat serum following chromatographic separation. The detection principle is based on the enhancement of RRS intensity of ion-association complex formed from aminoglycosides and pontamine sky blue (PSB) used as molecular recognition probe. The high-performance liquid chromatography (HPLC) coupled with RRS detection scheme was implemented post-column by mixing a PSB solution with the column eluent prior to detection. The RRS signal was detected by fluorescence detector at lambda(ex)=lambda(em)=365 nm. Separation and detection conditions were optimized. Siso and etimicin (Eti) chosen as the internal standard (IS) were separated on a C(18) reversed phase column with the mobile phase consisting of a ternary mixture of 20mM sodium acetate aqueous solution-methanol (92:8, v/v) containing 0.22% TFA (v/v). The limit of detection (S/N=3) for Siso was 18 ng. A calibration curve ranged from 25 ng to 700 ng shown to be linear. The presented method was applied for the determination of Siso in rat serum and used for the pharmacokinetics study of Siso in rat.

Distribution and serum concentration of sisomicin released from fibrin glue-sealed dacron graft in the rat and human.

We investigated whether or not fibrin glue (FG) used as a sealant in vascular prostheses to prevent leakage might be useful as a carrier of antibiotics for the prevention of local graft infection. Sisomicin (SISO) was incorporated into fibrin glue (SISO-FG) and evaluated as to its safety and pharmacokinetics. SISO (1.75 mg) -FG Dacron grafts were implanted subcutaneously in the anterior abdominal region of Sprague-Dawley rats, and then the changes in SISO concentrations in the serum and in the tissue around the implantation sites were compared with those same sites in rats that had had intravenous injection of SISO (1.75 mg). The serum SISO concentrations were significantly lower in the SISO-FG Dacron graft group than they were in the intravenous injection group. However, until 4 h after implantation the SISO concentrations in the tissues around the implantation sites were significantly higher in the SISO-FG Dacron group than they were in the iv injection group, and the peak concentrations during that time were 5.8 times higher for the SISO-FG Dacron group than they were for the intravenous injection group. The ratio of the area under the tissue concentration time curve of SISO (AUC tissue) after implantation of the SISO-FG Dacron graft to that after intravenous injection of SISO was 13.08. Therefore, FG was considered to control the release of SISO into the serum and to maintain a high SISO concentration in the tissue around the implantation site. Clinically, SISO (45 mg) -FG was applied directly to the Dacron grafts implanted in 10 patients who underwent prosthetic vascular reconstruction. No graft infection was observed in any of the patients who received SISO-FG Dacron grafts. The mean serum concentration of SISO was 0.65+/-0.17 microg/mL after 1 h and 0.33+/- 0.21 microg/mL after 3 h. The results of these clinical applications are in close correlation with those of the animal experiment and suggest that FG is useful as a carrier of SISO, allowing its controlled release for the prevention of local infection.

Sensitive high-performance liquid chromatographic assay for aminoglycosides in biological matrices enables the direct estimation of bacterial drug uptake.

Following the development of a sensitive high-performance liquid chromatographic (HPLC) assay for gentamicin in biological matrices, the utility of this assay for the determination of other clinically important aminoglycosides (neomycin, netilmicin and sisomicin) in bacterial culture media or plasma is demonstrated. The high sensitivity of the assay enables direct measurement of the aminoglycoside content of bacterial cells cultured in the presence of unlabelled drug.

[Pharmacokinetic monitoring of aminoglycoside therapy: an optimal method of administration of individualized doses of gentamicin and sisomicin]. / Farmakokineticheskii monitoring pri lechenii aminoglikozidami: optimal'nyi sposob individualizatsii dozirovaniia gentamitsina i sizomitsina.

One of the most promising approaches to design the optimal schedule for TDM provides a single determination of a drug content in the blood specimen being collected at the "ideal" sampling time equaled to the inverse value of the elimination rate constant. Three versions of the one-point method when the specimen was collected at the "ideal" time point (3 h after a single i.m. drug administration), as well as at the times of "maximum" (1 h after injection) and "minimum" (6 h after injection) concentrations were compared by the retrospective analysis of the routine TDM data obtained with HPLC-techniques in 47 patients treated with gentamicin or sisomicin. As optimal individualized doses were considered ones calculated on the base of three subsequent determinations of the aminoglycoside concentrations, i.e. 1, 3 and 6 h after injection, and the estimation of individual clearance values (Cli). The optimal doses (DCl) were calculated according to equation DCl = Dp.Cli/Clp, where Dp and Clp are population values of the dose (1 mg/kg) and Cl 72.4 ml/(h.kg), respectively. The approximate values of the individual doses (D) were calculated according to equation D = Dp.Cp/Ci, where Ci is the individual drug serum concentration 1, 3 or 6 h after administration and Cp is the corresponded population value (4.8, 1.9 and 0.8 mg/l, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of the aminoglycoside antibiotics sisomicin and netilmicin in dried blood spots on filter discs, by high-performance liquid chromatography with pre-column derivatization and fluorimetric detection.

A simple method for the determination of the aminoglycoside antibiotic sisomicin or its 1-N-ethyl derivative, netilmicin in whole blood, using dried blood spots (DBSs) on filter-paper punched discs has been developed. Sisomicin or netilmicin in the DBSs were recovered most effectively in 0.5 M Na2HPO4 using ultrasonication. The eluates from the DBSs were treated by ultrafiltration for deproteinization and subjected to pre-column fluorescent derivatization using o-phthalaldehyde and beta-mercaptopropionic acid in 0.05 M KH2PO4-borate buffer (pH 9.0), followed by determination by reversed-phase high-performance liquid chromatography. The detection limits of sisomicin and netilmicin in the DBSs on punched discs (10.1 microliters of whole blood) were 0.053 and 0.50 micrograms per ml of whole blood, respectively (signal-to-noise ratio greater than or equal to 2). The method permits a simple collection of blood at the microlitre level and should prove particularly useful for monitoring sisomicin and netilmicin in blood at therapeutic levels in geriatric and paediatric patients.

Determination of sisomicin in eluate from dried blood spot on filter paper disc for monitoring of blood level in rat, by reversed-phase high-performance liquid chromatography after pre-column fluorimetric derivatization.

About 20 microliters of whole blood obtained by venipuncture from rat tail vein was spotted onto a filter paper and the blood spot was punched out (5 mm diameter). Sisomicin (SISO) in the dried blood spot (DBS) was extracted effectively into 0.5 M Na2HPO4 solution by ultrasonication and determined by reversed-phase high-performance liquid chromatography with pre-column derivatization using o-phthalaldehyde and beta-mercaptopropionic acid. This method could be used for the pre-clinical study of SISO blood levels of a number of mice or rats without killing. The results were identical with those for SISO in serum, if corrected for hematocrit values, and were used for the calculation of pharmacokinetic parameters for individual rats. The detection limit of SISO in DBS (10.1 microliters of whole blood) was 1.0 microgram per ml of whole blood.

Pre-column derivatization of sisomicin with o-phthalaldehyde-beta-mercaptopropionic acid and its application to sensitive high-performance liquid chromatographic determination with fluorimetric detection.

The stability of the o-phthalaldehyde (OPA) derivatives of sisomicin obtained using beta-mercaptopropionic acid was investigated by reversed-phase high-performance liquid chromatography. One of the fluorescent derivatives of sisomicin was stable at least for 6 h in 50% methanol under the optimal conditions used (OPA concentration, pH and temperature). When plasma samples spiked with sisomicin were analysed, the response was linear in the calibration range 136-900 pg of sisomicin per injected volume (40 microliters). As little as 0.06 micrograms of sisomicin per 1 ml of plasma could be detected with signal-to-noise ratio greater than or equal to 2. For plasma samples spiked with 0.2 micrograms/ml sisomicin, the recovery was 97.1 +/- 6.6% (mean +/- S.D., n = 5) with a within-run coefficient of variation of 6.8% and a day-to-day coefficient of variation of 7.2%. The method was also applied to plasma samples from rabbit after a subcutaneous injection of 1 mg/kg sisomicin.

[Effectiveness of the new aminoglycoside sisomicin in surgery]. / Effektivnost' novogo aminoglikozida sizomitsina v khirurgii.

Antimicrobial activity of sisomicin against causative agents of wound infections was studied. It was shown that by its antimicrobial activity and the rate of bactericidal effect attainment sisomicin is superior to other aminoglycosides, such as gentamicin and tobramycin. Individual variability of the pharmacokinetics of sisomicin on its intravenous and intramuscular injection to patients with wound infections was observed. For prediction of the treatment efficacy it is suggested that the drug be used under the control of its blood levels in comparison to the MTC for the isolated causative agent.

[Kinetics of the antimicrobial effect in a dynamic system: the microcalorimetric recording method and choice of parameters for characterizing kinetic curves]. / Kinetika antimikrobnogo éffekta v dinamicheskoi sisteme: mikrokalorimetricheskii metod registratsii i vybor parametrov dlia kharakteristiki kineticheskikh krivykh.

The kinetics of the in-vitro antimicrobial effect of sisomicin on E. coli, A 20363 was studied microcalorimetrically in a dynamic model simulating the pharmacokinetic profiles (intramuscular administration in a dose of 1 mg/kg) of the antibiotic obeying the one-compartmental model with first-order absorption. The microcalorimetric method was more accurate than the count of the colony forming units (CFU). Unlike the CFU method, it permits continuous recording of the process and unlike the turbidimetric method, it is more sensitive and selective. For quantitative characteristic of the curves of the antimicrobial effect kinetics it is suggested to use a new parameter, the effect duration (Td) which is determined by the difference in the moment of the antibiotic administration into the dynamic model (Tin) and the moment (Tout) when the rate of heat production or the number of the CFU or the optical density during the microbial secondary growth was the same as that at Tin. It was shown that the values of Td estimated in experiments with recording of the antimicrobial effect by different methods are similar. Evaluation of Td may be useful in predicting the optimal dosing intervals.

[Clinical evaluation of sisomicin following intravenous drip infusion in respiratory tract infections].

The efficacy, safety and utility of sisomicin (SISO) followed intravenous infusion were evaluated in 35 cases with various respiratory infections. For many cases, SISO was given at a daily dosage of 100 mg, and a single dose was infused over about 1 hour. Clinical efficacy was evaluable in 28 cases including pneumonia (14 cases), bronchitis (8 cases), bronchiectasis (4 cases), pulmonary suppuration (1 case) and pulmonary abscess plus pyothorax (1 case). Almost cases had diagnosis of serious infection associated with various diseases. Clinical efficacy was evaluated as "excellent" in 2 cases, "good" in 15 cases, "fair" in 5 cases and "poor" in 6 cases, and efficacy rate in total case was 60.7%. Efficacy rate stratified by disease was calculated as 57.1% in pneumonia, 87.5% in bronchitis, 50.0% in bronchiectasis. Responses against pulmonary suppuration or pulmonary abscess with pyothorax were little or not. Bacteriologically, organisms isolated from sputum cleared in 7 out of 15 evaluable cases, thus the responses rate was 46.7%. Adverse reaction probably due to treatment observed in 2 cases with hepatic dysfunction. Blood levels of SISO at the end of infusion were ranged from 2.1 to 6.4 micrograms/ml, and no tendency of accumulation in blood after repeated infusion was showed.

Serum concentration of sisomicin by intravenous infusion and its clinical response as a single agent.

SISO in doses of 1.0 to 1.8 mg/kg was administered by a 30-minute intravenous infusion every 12 hours to 10 patients with infections, 9 of whom had underlying diseases including malignant diseases, diabetes mellitus, and diabetes insipidus with indwelling FOLEY catheter. The serum concentration of SISO was around 6.75 micrograms/ml in the end of infusion, and less than 1.0 micrograms/ml at 8 to 12 hours after infusion. SISO was given to the patients as a single agent for at least 3 to 5 days and all patients experienced an excellent to good response clinically, and causative organisms which showed a minimal inhibitory concentration of less than 1.56 micrograms/ml disappeared after the treatment associated with clinical improvement. There were no untoward effects noted in this study.

The single-dose pharmacokinetics of 5-epi-sisomicin (Sch 22591) in human volunteers.

5-epi-sisomicin was given as a single 1 mg/kg intramuscular injection to six adult male volunteers. No adverse effects were observed and the pharmacology was very similar to that of sisomicin. The extended spectrum of 5-epi-sisomicin and its enhanced antipseudomonal activity prompt further clinical evaluation of this agent.

[Immunological assay of sisomycin by fluorescence polarization]. / Dosage immunologique de la sisomicine, par polarisation de fluorescence.

Fluorescence polarization immunoassays (FPIA) of aminoglycoside antibiotics (gentamicin, tobramycin and amikacin) in plasma have been described. The use of sisomicin, a structural analogue of a C1a gentamicin fraction, is an alternative to gentamicin therapy for economical reasons. We have tested a therapeutic monitoring of this drug bases on FPIA using its croos reaction with gentamicin. Tracer (gentamicin labelled with fluorescein) and antisera were purchased from Abbott S.A. (gentamicin kit). Standard curves were obtained with sisomicin standard plasma samples. Within run and run-to-run precisions expressed as coefficient of variation were lower than 9.2 p. cent. The measurement of concentrations as low as 0.15 mg/l are possible. In order to evaluate specificity of this assay in clinical situation, we compared FPIA and liquid chromatography results.