netilmicin and Body-Weight

Once-daily administration of aminoglycoside antibiotics has become the most acceptable dosing schedule for the majority of patients. There are few published data on the impact of post-natal age on aminoglycoside concentrations in preterm infants receiving once-daily dosage regimens. Netilmicin was administered as a once-daily dose of 4 mg/kg. In 141 episodes of suspected sepsis in 123 babies, trough netilmicin concentrations ranged from undetectable to 4.0 mg/l. Netilmicin concentrations were above a level of 2 mg/l in 10.6% of episodes. Netilmicin concentrations decreased with increasing post-natal age and weight. Levels were higher in males compared to females. Increased creatinine concentrations were associated with higher netilmicin concentrations. This study emphasises the importance of post-natal age as a determinant of aminoglycoside concentrations with a once-daily dosing regimen in a neonatal intensive care population. Trough levels should be carefully monitored and consideration given to extending dosage intervals particularly when netilmicin is administered once daily to preterm infants in the first week of life.

Topics: Aging; Anti-Bacterial Agents; Audiology; Body Weight; Creatinine; Enterobacteriaceae Infections; Enterococcus; Escherichia coli Infections; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Intensive Care, Neonatal; Linear Models; Male; Netilmicin; Retrospective Studies; Sepsis; Staphylococcal Infections; Streptococcal Infections

Netilmicin pharmacokinetics were studied in neonates of 27 to 42 weeks' gestational age and 0.8 to 5.0 kg body weight in their first 2 weeks of life by the population pharmacokinetic approach. The data were best described by a two-compartment model. Clearance depends on body weight, gestational age, and postnatal age. Volume of distribution of the central and peripheral compartments was also related to body weight. Including these patient characteristics in the population pharmacokinetic regression model resulted in a marked reduction of the unexplained interindividual variability. This enabled us to derive dosage recommendations that result in peak and average concentrations within the desired range for 95% of the neonates with gestational age above 31 weeks, thus avoiding the need for individual drug-level monitoring in a well-defined large group of patients. Only for infants with gestational age less than 31 weeks who are less than 6 days old is individual dose adjustment based on serum concentration measurements required.

Topics: Body Weight; Computer Simulation; Female; Gestational Age; Humans; Immunoenzyme Techniques; Infant, Newborn; Male; Netilmicin; Prospective Studies; Radioimmunoassay; Regression Analysis

The nephrotoxicity of hydroxygentamicin and amikacin was examined in young adult Fischer 344 rats. Serum creatinine (SCr) and urea nitrogen (BUN) levels were not significantly affected following sc injection of 80 or 160 mg/kg/day of hydroxygentamicin for 15 days. However, 250 mg/kg of amikacin produced significant increases in both parameters and in kidney/body weight ratios. The ratios were also significantly increased after 80 or 160 mg/kg of hydroxygentamicin, but kidneys of rats receiving amikacin were considerably heavier than those of rats treated with hydroxygentamicin. The antibacterial potency of 250 mg/kg of amikacin is comparable to that of 100 mg/kg of hydroxygentamicin. Additional studies, directly comparing hydroxygentamicin, a mutational biosynthetic, with gentamicin or netilmicin, all at 40, 80, and 160 mg base/kg, and incorporating renal function parameters as well as SCr, BUN, organ weight, tissue concentration, and kidney histopathology, revealed a characteristic pattern typical of aminoglycoside nephrotoxicity in mature adult male rats. In most parameters, values in rats given hydroxygentamicin or netilmicin were normal and comparable to those in controls, but kidney/body weight ratios were significantly increased at high doses. However, kidneys of rats medicated with gentamicin at comparable doses were considerably heavier than those of hydroxygentamicin-treated rats. Significant nephrotoxicity also was seen in rats given low doses of gentamicin or netilmicin. Eosinophilic granulation and vacuolization of renal proximal tubular epithelium, interstitial inflammation, and tubular dilation were observed microscopically with all three drugs in the following descending order of severity: gentamicin greater than netilmicin greater than hydroxygentamicin. The effects on proximal tubular epithelial cells following treatment with amikacin, netilmicin, or hydroxygentamicin correlated reasonably well with renal drug concentrations, but drug concentrations of gentamicin, which produced the most extensive kidney injury, were lower than those of the other three aminoglycosides. Elevated SCr or BUN were indicative of the presence of nephrosis, but early stages of tubular epithelial degeneration were not predicted by increases in BUN or SCr. Although minimal or mild nephrosis was seldom predicted by polyuria, proteinuria, or changes in osmolality, effects observed in renal function parameters usually correlated well with renal histopathology. Howeve

Topics: Amikacin; Aminoglycosides; Animals; Anti-Bacterial Agents; Blood Urea Nitrogen; Body Weight; Creatinine; Gentamicins; Kidney Diseases; Kidney Function Tests; Male; Netilmicin; Organ Size; Rats; Rats, Inbred F344

The plasma peak, trough, and peak-trough concentrations of netilmicin given to preterm and term infants were measured after different regimens to determine which dosage would provide satisfactory peak and trough concentrations. In infants aged less than 7 days, dosage regimens of 3.0 or 2.5 mg/kg every 12 hours gave satisfactory peak levels (range 5.2-12.0 micrograms/ml) but troughs were above the desirable maximum level of 3 micrograms/ml in more than half the preterm infants. Subsequently a dosage regimen of 3.0 mg/kg immediately followed by 2.0 mg/kg every 12 hours resulted in trough levels that exceeded 3 micrograms/ml in only 2 of 25 preterm determinations and never in term infants, yet gave satisfactory peak levels (range 4.5-7.4 micrograms/ml). In preterm infants aged 4 to 7 weeks a dosage of 3 mg/kg every 8 hours gave satisfactory peak and trough levels.

Topics: Body Weight; Drug Administration Schedule; Gentamicins; Humans; Infant, Newborn; Infant, Premature; Injections, Intravenous; Netilmicin

Topics: Animals; Blood Chemical Analysis; Body Weight; Female; Gentamicins; Hearing Tests; Hematologic Tests; Kidney; Lethal Dose 50; Liver; Male; Mice; Mice, Inbred ICR; Netilmicin; Rats; Rats, Inbred Strains; Urine

Topics: Animals; Blood Chemical Analysis; Body Weight; Drinking; Eating; Female; Gentamicins; Hematologic Tests; Injections, Intramuscular; Kidney; Male; Netilmicin; Organ Size; Rats; Rats, Inbred Strains; Spleen; Urine

Topics: Animals; Blood Chemical Analysis; Body Weight; Dogs; Drinking; Eating; Female; Gentamicins; Hematologic Tests; Injections, Intramuscular; Kidney; Male; Netilmicin; Organ Size; Urine

Teratological study on netilmicin (NTL), a new aminoglycoside antibiotic, was carried out in Sprague-Dawley rats (Slc : SD). NTL was administered intramuscularly to female rats from day 7 to day 17 of gestation at the dosages of 12.5, 25, 50 and 100 mg/kg. The decrease of food intake at the dosage of 50 mg/kg and more, and the resultant depression of maternal body weight gain at the dosage of 100 mg/kg were observed in dams receiving NTL. The depression of fetal growth, such as body weight and ossification of the sternebrae and caudal vertebrae, were detected in animals treated with 50 and 100 mg/kg of NTL. However, NTL failed to induce the external, visceral and skeletal anomalies in fetuses. Also, NTL did not cause any significant changes in birth rate, suckling rate, weaning rate, body weight, postnatal development, behavior and reproductive performance in F1. These results suggest that NTL has no adverse effect on rat fetuses and F1 generation at the dosage of 25 mg/kg or less.

Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Behavior, Animal; Body Weight; Drinking; Eating; Embryo Implantation; Female; Fertility; Fetus; Gentamicins; Injections, Intramuscular; Male; Maternal-Fetal Exchange; Netilmicin; Organ Size; Pregnancy; Rats; Rats, Inbred Strains

Perinatal and postnatal study on netilmicin (NTL), a new aminoglycoside antibiotic, was carried out in Sprague-Dawley rats (Slc : SD). NTL was administered intramuscularly from day 17 of gestation throughout day 20 after delivery at the daily dose of 12.5, 25, 50 and 100 mg/kg. Water intake of pregnant and nursing dams was increased in the animals treated with 50 mg/kg or more of NTL. The increase of cecum weight was observed in F1 animals in all treated groups at 3 weeks of age. However, birth rate, suckling rate, weanling rate, body weight, postnatal development, behavior and reproductive function remained within normal ranges in all treated groups.

Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Body Weight; Female; Fertility; Fetus; Gentamicins; Injections, Intramuscular; Kidney; Lactation; Male; Maternal-Fetal Exchange; Netilmicin; Organ Size; Pregnancy; Rats; Rats, Inbred Strains; Sexual Behavior, Animal

The pharmacokinetics of netilmicin were analyzed in 30 children, including 13 premature and seven gestationally mature newborns. Ten were children ranging in age from 3.5 months to 13 years. The newborns exhibited more variation in serum levels than the older children, and the premature babies more than those born at term. The serum half-life (t1/2), tended to show higher values in premature than in mature newborns, although this was not statistically significant. The newborns had a t1/2 of 5.9 hours, compared to 2.5 hours in the older children. There was no statistically significant difference in distribution volumes or coefficients between the two groups of newborns who had an insignificantly higher relative apparent beta-phase distribution volume coefficient of 0.420 l/kg, compared to 0.377 l/kg in the older children. All had distribution coefficient values within the same range. The total body clearance in absolute terms, and when referred to body surface of 1.73 m2, was significantly lower in the newborns than in the older children, but the clearance, when referred to body weight, was of the same order in the babies and older children. The age differences affect dosage. Dosage schedules based on pharmacokinetics are proposed for gestationally premature babies, mature newborns, and older children. Premature infants can receive 2.5 mg/kg body weight and gestationally mature newborns 3.0 mgkg, both every 12 hours; the monitoring of serum concentrations is mandatory. Children aged three months and older can receive 3.0 mg/kg every eight hours.

Topics: Adolescent; Age Factors; Bacterial Infections; Body Surface Area; Body Weight; Child; Child, Preschool; Gentamicins; Gestational Age; Half-Life; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature, Diseases; Kinetics; Netilmicin

The ototoxicity of netilmicin (NTL) in pregnant guinea pigs (Hartley strain) and the newborn was examined and compared to that of gentamicin (GM). NTL was administered intramuscularly at dose of 90 mg/kg to pregnant guinea pigs from day 0 to day 35 of pregnancy (the early period of pregnancy) or from day 42 of pregnancy to 1 day prior to delivery (the late period of pregnancy). GM at dose of 45 mg/kg or physiological saline were administered intramuscularly to pregnant guinea pigs during the late period of pregnancy. Four of 5 dams given NTL during the early period of pregnancy, 4 of 7 dams given TNL during the late period of pregnancy, and 2 of 4 dams given GM during the late period of pregnancy died. No pinna reflex loss in frequency range from 2 to 20 KHz were detected in mother guinea pigs treated with NTL either during the early period of pregnancy or during the late period of pregnancy. GM caused a loss of pinna reflex at 20 KHz in mother guinea pigs treated during the late period of pregnancy. Histopathologically, no damages were detected in the cochlea of mother guinea pigs treated with NTL during the early or late period of pregnancy, whereas slight scattered loss of hair cells was seen in the vestibulum. However, GM at dose of 45 mg/kg, caused an incomplete scattered loss of outer hair cells in the spiral organ, moderate atrophy of the spiral ganglion cells and a partial loss of hair cells in the vestibular organs in mother guinea pigs treated during the late period of pregnancy. In newborn guinea pig from the pregnant one treated with NTL during the early period of pregnancy, there was no loss of pinna reflex. The same results were obtained in newborn guinea pigs from the pregnant ones treated with either NTL or GM during the late period of pregnancy. No histopathological damages were detected. The present study suggests that NTL has a minimal effect on the auditory and vestibular organs in pregnant guinea pigs and the newborn and is considered to be 1 of the aminoglycosides with low ototoxic potential.

Topics: Animals; Animals, Newborn; Body Weight; Ear, External; Ear, Inner; Female; Fetal Death; Fetus; Gentamicins; Guinea Pigs; Male; Maternal-Fetal Exchange; Netilmicin; Pregnancy; Pregnancy, Animal; Reflex, Acoustic

Topics: Amikacin; Aminoglycosides; Animals; Anti-Bacterial Agents; Body Weight; Cochlea; Ear Diseases; Electrophysiology; Female; Gentamicins; Guinea Pigs; Hearing Disorders; Male; Netilmicin; Tobramycin

Metabolic balance and morphologic studies were performed on rats receiving gentamicin 100 mg/kg/day for a period of 8--10 days and during the recovery period. Daily urine flow rate increased with the administration of gentamiccin and remained elevated up to 20 days following the discontinuation of gentamicin, although BUN and plasma creatinine were virtually normal 10 days after the discontinuation of gentamicin. During the development of renal failure means daily electrolyte excretion remained normal. During the recovery period, however, sodium and potassium excretion exceeded control values while chloride and net acid excretion remained normal. Proteinuria developed during the administration of gentamicin and returned to normal 6--10 days after the discontinuation of gentamicin. Ten days of netilmicin administration (150 mg/kg/day) resulted in only mild tubular degeneration and no azotemia.

Topics: Animals; Blood Urea Nitrogen; Body Weight; Creatinine; Electrolytes; Gentamicins; Hematocrit; Kidney; Male; Netilmicin; Polyuria; Rats; Time Factors; Uremia

Topics: Animals; Anti-Bacterial Agents; Blood Urea Nitrogen; Body Weight; Creatinine; Gentamicins; Kidney; Kidney Diseases; Kidney Tubules; Netilmicin; Rats; Tobramycin; Water-Electrolyte Balance