Comparison of amikacin lung delivery between AKITA® and eFlow rapid® nebulizers in healthy controls and patients with CF: A randomized cross-over trial.

INTRODUCTION: Nebulization plays a key role in the treatment of cystic fibrosis. The Favorite function couple to jet nebulizers (AKITA®) emerged recently. The aim of this study was to assess the efficiency of the lung delivery by the AKITA® by comparing the urinary concentration of amikacin after nebulization with the AKITA® and the eFlow rapid®, in healthy subjects and patients with CF (PwCF). METHOD: The two samples (healthy subjects and PwCF) were randomized (cross-over 1:1) for two nebulizations (500 mg of amikacin diluted in 4 mL of normal saline solution), with the AKITA® and with the eFlow rapid®. The primary endpoint was the amount of urinary excretion of amikacin over 24 h. The constant of elimination (Ke) was calculated based on the maximal cumulative urinary amikacin excretion plotted over time. RESULTS: The total amount of urinary amikacin excretion was greater when AKITA® was used in PwCF (11.7 mg (8.2-14.1) vs 6.1 mg (3.7-13.3); p = 0.02) but not different in healthy subjects (14.5 mg (11.7-18.5) vs 12.4 mg (8.0-17.1); p = 0.12). The duration of the nebulization was always shorter with eFlow rapid® than with AKITA® (PwCF: 6.5 ± 0.6 min vs 9.2 ± 1.8 min; p = 0.001 - Healthy: 4.7 ± 1.3 min vs 9.7 ± 1.6 min; p = 0.03). The constant of elimination was similar between the two modalities in CF subjects (0.153 (0.071-0.205) vs 0.149 (0.041-0.182); p = 0.26) and in healthy subjects (0.166 (0.130-0.218) vs 0.167 (0.119-0.210), p = 0.25). CONCLUSION: the Favorite inhalation is better to deliver a specific amount of drug than a mesh nebulizer (eFlow rapid®) in PwCF but not in healthy subjects.

Specific fluorometric assay for direct determination of amikacin by molecularly imprinting polymer on high fluorescent g-C3N4 quantum dots.

Here, a specific and reliable fluorometric method for the rapid determination of amikacin was developed based on the molecularly imprinting polymer (MIP) capped g-C3N4 quantum dots (QDs). g-C3N4 QDs were obtained by facile and one-spot ethanol-thermal treatment of bulk g-C3N4 powder and showed a high yield fluorescence emission under UV irradiation. The MIP layer was also created on the surface on QDs, via usual self-assembly process of 3-aminopropyl triethoxysilane (APTES) functional monomers and tetraethyl ortho-silicate (TEOS) cross linker in the presence of amikacin as template molecules. The synthesized MIP-QDs composite showed an improved tendency toward the amikacin molecules. In this state, amikacin molecules located adjacent to the g-C3N4 QDs caused a remarkable quenching effect on the fluorescence emission intensity of QDs. This effect has a linear relationship with amikacin concentration and so, formed the basis of a selective assay to recognize amikacin. Under optimized experimental conditions, a linear calibration graph was obtained as the quenched emission and amikacin concentration, in the range of 3-400 ng mL-1 (4.4-585.1 nM) with a detection limit of 1.2 ng mL-1 (1.8 nM). The high selectivity of MIP sites as well as individual fluorescence properties of g-C3N4 QDs offers a high specific and sensitive monitoring method for drug detection. The method was acceptably applied for the measurement of amikacin in biological samples.

Aerosol delivery to the lung is more efficient using an extension with a standard jet nebulizer than an open-vent jet nebulizer.

BACKGROUND: Open-vent jet nebulizers are frequently used to promote drug deposition in the lung, but their clinical efficacy and indications are not clear. Our study compared lung deposition of amikacin using two different configurations of a jet nebulizer (Sidestream(®)): one vented (N1) and one unvented with a corrugated piece of tubing (N2). METHODS: In vitro nebulizer performance was assessed by laser diffraction and filtering. Lung delivery was evaluated by scintigraphy in baboons as a child model, and by amikacin urinary drug concentration in seven healthy spontaneously breathing volunteers. Subjects were randomly assigned to the two nebulizer systems (N1 and N2). RESULTS AND CONCLUSIONS: In vitro results showed a higher efficiency of N2 than N1 in terms of lung deposition prediction (95±3 mg vs. 70±0 mg; p<0.0001). Radioactivity deposition in the baboons' lungs was lower with N1 than with N2 (1.8% vs. 4.7% of nebulizer charge; p<0.05). The total daily amount of amikacin urinary excretion was lower with N1 than with N2 (29.5 mg vs. 40.1 mg; p<0.01). Conversely, in vivo drug output rate was higher with N1 than with N2 (3.1 mg/min vs. 2.2 mg/min; p<0.05). Using a corrugated piece of tubing with standard jet nebulizers delivers higher doses to the lungs than open-vent jet nebulizers. The open-vent jet nebulizer might be recommended for rapid administration of a lower dose to the lungs and the standard jet nebulizer with corrugated piece of tubing for a higher dose in the lungs.

Delivery efficacy of a vibrating mesh nebulizer and a jet nebulizer under different configurations.

BACKGROUND: Jet nebulizers coupled to spacers are frequently used to promote drug lung deposition, but their clinical efficacy has not been established. Few in vivo studies have been performed with mesh nebulizers, commonly used to nebulize antibiotics. Our study compared inhaled mass and urinary drug concentration of amikacin by using three different nebulizer delivery configuration systems: a standard unvented jet nebulizer (Sidestream(®)) used alone or coupled to a 110-mL corrugated piece of tubing and a vibrating mesh nebulizer (e-Flow rapid(®)). METHOD: The inhaled mass of amikacin was assessed using the residual gravimetric method. Delivery efficacy was evaluated by assessing amikacin urinary drug concentration in six healthy spontaneously breathing volunteers. Urinary amikacin was monitored by fluorescent polarization immunoassay then cumulative excreted amount and antibiotic elimination rate were calculated. RESULTS AND CONCLUSIONS: The total daily amount of amikacin urinary excretion (Cu) was almost twice as high with eFlow rapid(®) compared to Sidestream(®) used alone; intermediate values being observed when the device was coupled to a corrugated piece of tubing. The latter configuration was also associated with a higher total daily amount of amikacin urinary excretion. In vivo drug output rate was around threefold higher with the eFlow Rapid(®) than with the Sidestream(®) used in any configuration. These results were concordant to those obtained with in vitro analysis comparing inhaled mass of amikacin for the three nebulizers. The elimination constant (Ke) and the mass median aerodynamic diameter (MMAD) did not differ between the three devices. In conclusion, the vibrating mesh nebulizer is more efficient, promoting larger urinary drug concentration and drug output. Coupling a corrugated piece of tubing to the standard jet nebulizer favors delivery efficacy.

Effect of continuous positive airway pressure combined to nebulization on lung deposition measured by urinary excretion of amikacin.

UNLABELLED: Continuous positive airway pressure (CPAP) is frequently used in patients attending emergency units. Its combination with nebulization is sometimes necessary in those patients presenting with a CPAP dependency. STUDY OBJECTIVE: To compare lung deposition of amikacin delivered by a classical jet nebulizer (SideStream; Medic-Aid; West Sussex, UK) used alone (SST) or coupled to a CPAP device (Boussignac; Vygon; Belgium). METHOD: Amikacin (1g) was nebulized with both devices in six healthy subjects during 5 min on spontaneous breathing. A 1-week wash-out period between each nebulization was applied. Lung deposition was indirectly assessed by urinary monitoring of excreted amount of amikacin. RESULTS: Total daily amount of amikacin excreted in the urine was significantly lower with CPAP than with SST (1.97% initial dose versus 4.88% initial dose, p<0.001) with a corresponding mean ratio CPAP/SST of 0.41. The residual amount of amikacin in the nebulizer was higher with CPAP than with SST (607 mg versus 541 mg) but the difference was not significant (p=0.35). CONCLUSION: These data suggest that the amount of amikacin delivered to healthy lungs is 2.5-fold lower with CPAP than with SST for the same nebulization time and that the nebulization time when using CPAP should be increased to reach the same amount of drug delivered with a classical jet nebulizer.

Determination of amikacin in body fluid by high-performance liquid-chromatography with chemiluminescence detection.

A simple and sensitive method was developed for the quantification of amikacin in human plasma and urine samples. The method involves centrifugation of body fluid plasma after dilution with an ethanol/sodium carbonate mixture, and then an aliquot of the supernatant is directly injected into the chromatograph. After separation on a reversed-phase C18 column (runtime 20 min), aminoglycoside is detected on the basis of its complex formation reaction with Cu(II), the catalyst of the luminol/hydrogen peroxide chemiluminescence system. Using a volume of 500 microl biological sample, linearity is established over the concentration range 0.15-2.0 microg/ml and the limit of detection (LOD) is ca. 50 microg/l in plasma or urine. The intra-day and inter-day precision (measured by relative standard deviation, R.S.D.%) are always less than 9%, and relative recoveries are found to be over 92%.

Comparison of lung deposition of amikacin by intrapulmonary percussive ventilation and jet nebulization by urinary monitoring.

The intrapulmonary percussive ventilation (IPV), frequently coupled with a nebulizer, is increasingly used as a physiotherapy technique; however, its physiologic and clinical values have been poorly studied. The aim of this study was to compare lung deposition of amikacin by the nebulizer of the IPV device (Percussionaire; Percussionaire Corporation; Sandpoint, ID) and that of standard jet nebulization (SST; SideStream; Medic-Aid; West Sussex, UK). Amikacin was nebulized with both devices in a group of five healthy subjects during spontaneous breathing. The deposition of amikacin was measured by urinary monitoring. Drug output of both devices was measured. Respiratory frequency (RF) was significantly lower when comparing the IPV device with SST (8.2 +/- 1.6 breaths/min vs. 12.6 +/- 2.5 breaths/min, p < 0.05). The total daily amount of amikacin excreted in the urine was significantly lower with IPV than with SST (0.8% initial dose vs. 5.6% initial dose, p < 0.001). Elimination halflife was identical with both devices. Drug output was lower with IPV than with SST. The amount of amikacin delivered to the lung is sixfold lower with IPV than with SST, although a lower respiratory frequency was adopted by the subjects with the IPV. Therefore, the IPV seems unfavorable for the nebulization of antibiotics.

Pharmacokinetic interactions of ceftazidime, imipenem and aztreonam with amikacin in healthy volunteers.

The common usage of extended spectrum beta-lactams co-administered with amikacin in everyday clinical practice for infections by multidrug-resistant isolates has created the need to search for pharmacokinetic interaction. Eighteen healthy volunteers were enrolled in the study; six were administered 1g of ceftazidime singly intravenously or combined with 0.5 g of amikacin; six received 0.5 g of imipenem singly or combined with 0.5 g of amikacin and six 1g of aztreonam singly or combined with 0.5 g of amikacin. Blood and urine samples were collected at regular time intervals and apparent serum levels were determined by a microbiological assay. Co-administration of ceftazidime and amikacin resulted in higher C(max) and AUC for amikacin than when administered alone. Co-administration of imipenem and amikacin resulted in higher C(max) for imipenem than when administered alone. The tested interactions did not affect plasma half-life (t(1/2)) and clearance rate of any antimicrobial compared with its single administration. All tested drugs were mainly eliminated by glomerular filtration. It is concluded that co-administration of ceftazidime, imipenem or aztreonam with amikacin in healthy volunteers might affect C(max) and AUC without influencing any other pharmacokinetic parameter. The probable clinical endpoint is that giving ceftazidime, imipenem or aztreonam with amikacin might result in a transient elevation of beta-lactam serum levels without further affecting the complete pharmacokinetic profile of each drug as obtained after administration of the drug alone.

A simple tool for monitoring nebulized amikacin treatments based on a single urine assay.

Aerosolized aminoglycosides have demonstrated their efficacy in the treatment of P. aeruginosa pneumonia in cystic fibrosis (CF) patients. There is wide interpatient variability in the deposited and systemic drug doses that depend on both the nebulization and inhalation conditions and result in a risk of inefficacy or toxicity. We have developed a tool to provide a simple method for individual dose monitoring by estimating the total quantity of amikacin excreted, which corresponds to the dose absorbed systemically. It is based on a single urine assay. Thirty-seven urinary pharmacokinetic time courses in healthy volunteers (groups A and B) or in CF patients (groups C and D) were used. The rules for extrapolating the total dose excreted on the basis of 6-, 8-, 10-, and 12-h urine samples, were determined from group A. The accuracy of these rules was then tested in the other three groups. The total amount excreted was poorly predictable, with a coefficient of variation (CV) of 36 and 30% in the healthy volunteers, and of 48 and 82% in the CF group, whereas the CV of the estimated amount, based on 8- to 12-h samples, was only 10-15% in the healthy volunteers and 4-8% in the CF patients. Collecting a single sample over an 8- to 12-h period requires overnight sampling. The very low circadian variations in renal function, ranging from -2% to +5%, demonstrated the absence of any significant bias resulting from overnight sampling. A single urine assay can therefore be proposed as a simple, noninvasive, low cost, and reliable method for the clinical monitoring of nebulized amikacin in CF patients. Further studies are needed before this method can be extended to aerosol treatments with other aminoglycosides.

Pharmacokinetics of amikacin in lactating goats.

The pharmacokinetics of amikacin was studied in five lactating goats after single intravenous and intramuscular administrations of 7.5 mg kg-1 body weight. After intravenous injection, the plasma concentration-time curve of amikacin was characteristic of a two-compartment open model with a distribution half-life of 11.03 min and an elimination half-life of 114.81 min. The mean residence time was 142.96 min and the volume of the central compartment was 0.061 kg-1. Following intramuscular injection, amikacin was rapidly absorbed with an absorption half-life of 20.39 min. The peak plasma concentration was 34.48 micrograms ml-1 and was attained at 62.15 min. The elimination half-life of amikacin after intramuscular administration was 122.86 min and the corresponding mean residence time was 205.51 min. The systemic bioavailability of amikacin after intramuscular administration was 98.27%. Amikacin was not bound to plasma and milk proteins in vitro. Amikacin was detected only at low concentrations in the goat's milk 2-6 h after intravenous and intramuscular injections. Amikacin urine concentrations were much higher than those of plasma. Thus, amikacin is likely to be efficacious in the eradication of many Gram-negative urinary tract pathogens.

A population approach to the forecasting of amikacin plasma and urinary levels using a prescribed dosage regimen.

We retrospectively analyzed amikacin pharmacokinetics in 19 critically ill patients who received amikacin intravenously. Fourteen subjects (577 serum amikacin concentrations, 167 urine measurements) were studied to obtain data for population modeling, while 5 patients (267 serum amikacin concentrations, 68 urine measurements) were studied for the assessment of predictive performance. The population analysis was performed using serum and urine amikacin measurements; the renal clearance of amikacin was expressed as a function of creatinine clearance. A two-compartment model was fitted to the population data by using NONMEM. The population characteristics of the pharmacokinetic parameters (fixed and random effects) were estimated using the FOCE method. The population pharmacokinetic parameters with the interindividual variability (CV%) were as follows: slope (0.254, 126%) and intercept (3 l/h, 59.6%) of the linear model which relate the amikacin renal clearance to the creatinine clearance, initial volume of distribution (17.1 l, 22.2%), intercompartment clearance (5.22 l/h, 104%), steady state volume of distribution (55.2 l, 64.1%) and urinary elimination (67.5%, 36.3%). The Bayesian approach developed in this study accurately predicts amikacin concentrations in serum and urine and allows for the estimation of amikacin pharmacokinetic parameters, minimizing the risk of bias in the prediction.

Pharmacokinetics and urinary excretion of amikacin in low-clearance unilamellar liposomes after a single or repeated intravenous administration in the rhesus monkey.

Liposomal aminoglycosides have been shown to have activity against intracellular infections, such as those caused by Mycobacterium avium. Amikacin in small, low-clearance liposomes (MiKasome) also has curative and prophylactic efficacies against Pseudomonas aeruginosa and Klebsiella pneumoniae. To develop appropriate dosing regimens for low-clearance liposomal amikacin, we studied the pharmacokinetics of liposomal amikacin in plasma, the level of exposure of plasma to free amikacin, and urinary excretion of amikacin after the administration of single-dose (20 mg/kg of body weight) and repeated-dose (20 mg/kg eight times at 48-h intervals) regimens in rhesus monkeys. The clearance of liposomal amikacin (single-dose regimen, 0.023 +/- 0.003 ml min-1 kg-1; repeated-dose regimen, 0.014 +/- 0.001 ml min-1 kg-1) was over 100-fold lower than the creatinine clearance (an estimate of conventional amikacin clearance). Half-lives in plasma were longer than those reported for other amikacin formulations and declined during the elimination phase following administration of the last dose (from 81.7 +/- 27 to 30.5 +/- 5 h). Peak and trough (48 h) levels after repeated dosing reached 728 +/- 72 and 418 +/- 60 micrograms/ml, respectively. The levels in plasma remained > 180 micrograms/ml for 6 days after the administration of the last dose. The free amikacin concentration in plasma never exceeded 17.4 +/- 1 micrograms/ml and fell rapidly (half-life, 1.47 to 1.85 h) after the administration of each dose of liposomal amikacin. This and the low volume of distribution (45 ml/kg) indicate that the amikacin in plasma largely remained sequestered in long-circulating liposomes. Less than half the amikacin was recovered in the urine, suggesting that the level of renal exposure to filtered free amikacin was reduced, possibly as a result of intracellular uptake or the metabolism of liposomal amikacin. Thus, low-clearance liposomal amikacin could be administered at prolonged (2- to 7-day) intervals to achieve high levels of exposure to liposomal amikacin with minimal exposure to free amikacin.

The disposition kinetics, urinary excretion and dosage regimen of amikacin in cross-bred bovine calves.

The disposition kinetics, urinary excretion and dosage regimen of amikacin after a single intravenous administration of 10 mg/kg was investigated in six cross-bred bovine calves. At 1 min, the concentration of amikacin in the plasma was 116.9 +/- 3.16 micrograms/ml and the minimum therapeutic concentration was maintained for 8 h. The elimination half-life and volume of distribution were 3.09 +/- 0.27 h and 0.4 +/- 0.03 L/kg, respectively. The total body clearance (ClB) and T/P ratio were 0.09 +/- 0.002 L/kg/h and 4.98 +/- 0.41, respectively. Approximately 50% of the total dose of amikacin was recovered in the urine within 24 h after administration. Amikacin in concentrations ranging from 5 to 150 micrograms/ml bound to plasma proteins to the extent of 6.32% +/- 0.42%. A satisfactory intravenous dosage regimen of amikacin in bovine calves would be 13 mg/kg followed by 12 mg/kg at 12 h intervals.

[Determination of amikacin by single oscillopolarography in the presence of formaldehyde].

The singlescan oscillopolarographic behavior of formaldehyde derivative of amikacin (AMK) in the medium of Britton-Robinson buffer solution (pH 8.0) has been studied and the mechanism of its electrode process has been discussed. Under optimum conditions, the peak current increases linearly with the increase of AMK concentration in the range of 6.0 x 10(-7)-5.0 x 10(-5) mol.L-1 and its correlation coefficient is 0.9988. The detection limit is 2.4 x 10(-7) mol.L-1. This method has been applied to the determination of trace AMK in samples of its injection, urine and blood serum without pretreatment. Its recovery was 90%-100% and the relative standard deviation was less than 4.1%.

Lack of pharmacokinetic interaction between cefepime and amikacin in humans.

The interaction potential between cefepime and amikacin was investigated in a steady-state pharmacokinetic study in 16 healthy male subjects. Eight subjects (group A) received a first course of 2,000 mg of cefepime; this was followed by a second course of 2,000 mg of cefepime with 300 mg of amikacin and a third course of 2,000 mg of cefepime. Eight other subjects (group B) received a first course of 300 mg of amikacin, a second course of 300 mg of amikacin with 2,000 mg of cefepime, and a third course of 300 mg of amikacin. Each course consisted of four consecutive doses administered every 8 h as 30-min intravenous infusions. Serial plasma and urine samples, which were collected after administration of the fourth dose of each course, were assayed for cefepime and/or amikacin by validated high-performance liquid chromatographic assays. Trough levels of cefepime and amikacin indicated that these antibiotics attained a steady state prior to administration of the fourth dose of each course. Key pharmacokinetic parameters for each antibiotic were determined by noncompartmental methods. The peak concentrations of cefepime and amikacin in plasma when the drugs were given alone were about 160 and 27 micrograms/ml, respectively. Levels of each antibiotic in plasma declined, with an apparent half-life of approximately 2.2 h. Urinary recovery of cefepime and amikacin accounted for more than 85% of the administered dose of each antibiotic. Mean renal clearances for cefepime and amikacin ranged from 79 to 95 ml/min and suggested that glomerular filtration is the primary excretion mechanism. The results of the statistical analyses indicated that the pharmacokinetic parameters of cefepime following the concurrent administration of amikacin and following the discontinuation of the amikacin following the concurrent administration of cefepime and following the discontinuation of the cefepime therapy were not significantly altered. Cefepime and amikacin can be coadministered to patients with normal renal function by using the standard recommended dosing regimens.

High-performance liquid chromatographic assays for the quantification of amikacin in human plasma and urine.

Amikacin, an aminoglycoside antibiotic, is frequently coadministered with penicillins and broad-spectrum cephalosporins to synergize the activity of these agents. Sensitive, selective and reproducible high-performance liquid chromatographic assays have been developed for the quantification of amikacin in plasma and urine collected from human subjects. The plasma method involves the ultrafiltration of plasma prior to derivatization. An aliquot of plasma ultrafiltrate or urine is mixed with dimethyl sulfoxide and tris(hydroxymethyl)aminoethane followed by derivatization of amikacin with 1-fluoro-2,4-dinitrobenzene at 58 degrees C for 30 min. The reaction mixture is then injected directly onto a reversed-phase C18 column preceded by a guard column. The column is eluted with a mobile phase containing acetonitrile and 2-methoxyethanol in 1% Tris buffer. Amikacin derivative is detected at 340 nm. The methods were applied for the analysis of amikacin in plasma and urine samples from volunteers receiving amikacin and cefepime, a fourth-generation cephalosporin, in a clinical pharmacokinetic drug interaction study.

Treatment of disseminated Mycobacterium avium complex infection of beige mice with liposome-encapsulated aminoglycosides.

Free and liposome-encapsulated amikacin are active in vitro against intracellular Mycobacterium avium complex (MAC). To examine whether liposome-encapsulated aminoglycosides might kill intracellular MAC more effectively in vivo, beige mice were infected with MAC strain 101 (serotype 1) and after 1 week were treated intravenously every other day (5 doses total) with amikacin liposomes (0.2, 1, or 4 mg/dose), amikacin solution (0.2, 1, or 2 mg), gentamicin liposomes or gentamicin solution (0.2 or 1 mg), placebo liposomes (without aminoglycosides), or buffer. Amikacin and gentamicin liposomes significantly reduced bacterial counts in blood, liver, and spleen (98.5%, 92.7%, and 92.8%, respectively, for the 1-mg dose of amikacin and 92.8%, 99.7%, and 99.4% for gentamicin; 95.7%, 69.7%, and 89.1%, respectively, for the 0.2-mg dose of amikacin and 49.9%, 76.7%, and 89.1% for gentamicin) compared with placebo liposomes and buffer. Equivalent doses of free drug were not associated with significant decreases in viable bacteria. Thus, aminoglycoside liposomes improved bactericidal effects over conventional treatment in disseminated MAC infection, offering potential application in treating MAC infection in humans.

Serum bactericidal activity and postantibiotic effect in serum of patients with urinary tract infection receiving high-dose amikacin.

Ten patients received a 30-min infusion of amikacin (30 mg/kg) on day 1 and 15 mg/kg on day 2. Mean serum creatinine was 1.1 +/- 0.3 (standard deviation) mg/dl before and 1.0 +/- 0.3 mg/dl 3 days after the second infusion. Mean serum amikacin concentrations before, at the end of infusion, and 1, 6, 12, and 24 h after 30 and 15 mg/kg were 0, 157, 79, 31, 16, 5, 5, 85, 51, 19, 12, and 5 mg/liter, respectively. Five strains each of Staphylococcus aureus, Staphylococcus epidermidis susceptible and resistant to oxacillin, Streptococcus (Enterococcus) faecalis, corynebacterium sp. strain JK, Listeria monocytogenes, Mycobacterium fortuitum (three strains), Klebsiella pneumoniae, Serratia marcescens, Acinetobacter calcoaceticus, and Pseudomonas aeruginosa were tested. Serum bactericidal activities (SBAs) were greater than or equal to 1:8 in greater than or equal to 80% of the sera 1 and 6 h after 30 mg/kg and in greater than or equal to 60% of the sera 1 and 6 h after 15 mg/kg against Staphylococcus aureus and Staphylococcus epidermidis susceptible to oxacillin, A. calcoaceticus, and K. pneumoniae. L. monocytogenes, Serratia marcescens, and P. aeruginosa had lower SBAs. Very low or no activity was observed against oxacillin-resistant staphylococci and Streptococcus faecalis. The study of the killing rate in serum confirmed these results. Postantibiotic effect was studied by incubating a strain from each species in serum samples obtained 1 and 6 h after both regimens for 0.5, 1, or 2 h. The duration of postantibiotic effect depended on the duration of contact and the concentration of amikacin for the following organisms: oxacillin-susceptible staphylococci, L. monocytogenes, P. aeruginosa, A. calcoaceticus, K. pneumoniae, and Serratia marcescens. M. fortuitum was killed after 30 min of contact. No postantibiotic effect was observed with Streptococcus faecalis, Corynebacterium sp. strain JK, or oxacillin-resistant staphylococci. Amikacin at 30 mg/kg provided high levels and SBAs against susceptible pathogens. Prolonged postantibiotic effects were observed. No signs of nephrotoxicity occurred.

[Toxicological studies on isepamicin (HAPA-B). VII. Chronic intramuscular test in the rat].

Chronic toxicity in the rat of isepamicin (HAPA-B), a new aminoglycoside antibiotic, was examined in comparison with amikacin (AMK). Daily doses of 3.125, 6.25, 25 and 100 mg/kg of HAPA-B or 25 and 100 mg/kg of AMK were injected intramuscularly for 6 months, and recovery test was carried out for 2 months after discontinuing the drug. No animal died and there were no changes in general symptoms except for hemorrhage of injection sites of both drugs. Decreases in body weight gain and food consumption were observed in 100 mg/kg dose group of either drug. Water consumption was markedly increased in males of the AMK 100 mg/kg dose group during administration and recovery periods. Decreases in erythrocytes, hematocrit and hemoglobin were observed in 100 mg/kg dose group of either drug. These decreases seemed to be due to renal injury. An increase in the number of platelets was also observed. This was likely caused by the hemorrhage at injection sites. These changes persisted into the recovery period. Elevation of BUN was observed in the 100 mg/kg dose group of either drug. Its value in the AMK 100 mg/kg dose group was markedly higher than that in the HAPA-B 100 mg/kg dose group and did not decrease back to the normal values even during the recovery period. An increase of urine volume and a decrease of urine specific gravity were observed in males in the 100 mg/kg group of either drug. Furthermore, NAG was elevated in a dose-dependent manner from 25 mg/kg with both drugs. The weight of kidney increased dose-relatedly and significantly in groups administered with 25 mg/kg or more of either drug and weight of caecum increased dose-relatedly and significantly in groups administered with 6.25 mg/kg or more of HAPA-B or 25 mg/kg or more of AMK. Discoloration and enlargement of the kidney occurred in a dose-dependent manner as observed by necropsy. Eosinophilic granular degeneration, swelling, fatty degeneration, necrosis, calcification in the epithelial cells of the proximal convoluted tubuli, and thickenings of Bowman'S capsule and tubular basement membrane were observed at 25 and 100 mg/kg dose groups of either drug. In recovery periods, after the necrosis disappeared, calcification and regeneration were observed in epithelial cells. Electron microscopic findings showed an increase in the number of large lysosomes containing myeloid bodies in the epithelial cells of the proximal convolute tubuli with either drug.(ABSTRACT TRUNCATED AT 400 WORDS)