Aminoglycoside antibiotics. X. chemical conversion of kanamycin B to kanamycin C and 6'-deoxy-kanamycin C.
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Kanamycin↗
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Ototoxic effects of the interaction between kanamycin and ethacrynic acid. Cochlear ultrastructure correlated with cochlear potentials and kanamycin levels.
The effects of the interaction between kanamycin (KAN) and ethacrynic acid (EA) on the ultrastructure of the guinea pig cochlea were studied 3, 4, 6, and 24 hours following administration of EA (40 mg/kg) to animals pretreated 2 h earlier with KAN (400 mg/kg). Appropriate saline (SAL) controls were included giving 4 treatments: KAN/EA, KAN/SAL, SAL/EA and SAL/SAL. The outer hair cells of the organ of Corti showed nuclear and plasma membrane changes at 3 h and were completely destroyed at 24 h. The inner hair cells were unaffected. Severe swelling was seen in the stria vascularis of both KAN/EA and SAL/EA animals at 3 h and was gone by 24 h. KAN/EA had a greater effect on the stria than had SAL/EA. These results were consistent with the time course of the effect of the drugs on the a.c. and d.c. endocochlear potentials. KAN concentrations in perilymph were unaffected by treatment with EA.
Animals↗
[On the mechanism of kanamycin ototoxicity (I): -tissue levels of kanamycin and acidic glycosaminoglycans (author's transl)].
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Animals↗
Reevaluation of kanamycin dosage in infants and children.
It was recently reported that the dosage of kanamycin formerly recommended for neonates of 7.5 mg/kg every 12 h did not produce therapeutic serum concentrations of 15 to 25 mug/ml, but a larger dosage of 10 mg/kg every 12 h was required. Reevaluation of the pharmacokinetics of kanamycin in infants and children was therefore undertaken. Sixteen time-concentration curves after a dose of 5 mg/kg were obtained from patients 2 months to 12 years of age; the mean peak serum kanamycin concentration was 10.9 (range, 3.6 to 17.9) mug/ml at 0.5 h. Ten time-concentration curves were obtained after a dose of 10 mg/kg; the mean peak serum concentration was 17.6 (range, 8.4 to 30) mug/ml. Eight patients were studied on successive days, and there was doubling of the 1-h peak serum concentration when the dose of kanamycin was increased from 5 to 10 mg/kg. Standard serum bactericidal tests were done against Escherichia coli and Enterobacter cloacae strains, each with a minimal bactericidal concentration of 5 mug of kanamycin per ml. All 3 sera containing 21 mug or more of kanamycin per ml demonstrated a bactericidal titer, whereas only 2 of 23 sera containing less than 21 mug of kanamycin per ml did so. The currently recommended dosage of kanamycin for infants and children fails to produce serum concentrations in the therapeutic range, and preliminary data suggest that the dosage should be increased to 10 mg/kg per dose every 8 h.
Child↗
Cross-resistance in M. tuberculosis to kanamycin, capreomycin and viomycin.
Drug resistant mutants to streptomycin, kanamycin, viomycin, capreomycin, and rifampicin were isolated from four strains of Mycobacterium tuberculosis. The mutants isolated from each parent were then tested for evidence of development of cross-resistance to other drugs. There was no cross-resistance between either streptomycin or rifampicin and any of the other drugs. Complete cross-resistance between viomycin and capreomycin was found. Cross-resistance between kanamycin and capreomycin, and kanamycin and viomycin was variable. A review of the medical histories of 27 patients with kanamycin-resistant tubercle bacilli indicated that cross-resistance with capreomycin and viomycin occurs, but is unpredictable. Because of this variability in cross-resistance and the fact that kanamycin is a more toxic drug than capreomycin, it is suggested that capreomycin be used in the first retreatment regimen for tuberculosis when streptomycin resistance has been demonstrated.
Capreomycin↗
Possible effects of kanamycin and incubation in newborn children with low birth weight.
In an acoustico-vestibular follow-up investigation of 91 four- to six-year-old children with birth weight below 2000 g, the same incidence of sensorineural hearing loss (19%) was found in 54 children treated with kanamycin in the neonatal period as in a group of 37 infants not treated with kanamycin. When comparing a group of children treated with both kanamycin and incubator (54 children) with a group treated with incubator only (16 children), no definite signs of synergism between incubator noise and kanamycin were found. However, the 5 cases of moderate or severe hearing loss all belonged to the group treated with both incubator and kanamycin. These 5 children had more severe neonatal complications, especially apnea, cyanotic spells and hyperbilirubinemia, which may increase the severity of the hearing loss. Among 56 incubator treated children with normal hearing (ISO standards) 52% had an audiogram pattern suggesting minor noise-provoked cochlear lesions. Among 18 non-incubator treated children with normal hearing only one child (6%) had a similar pattern. It should be stressed, however, that these children had no clinical symptoms of hearing loss.
Audiometry↗
The quantification of kanamycin ototoxicity in the rat using conditioned tone discrimination.
Twelve male Lister hooded rats were conditioned to discriminate an 8 kHz tone (56.5 +/- 0.5 dB re 0.0002 dyne cm-2) and were subsequently injected subcutaneously with kanamycin (400 mg kg-1 day-1) for 28 days; during this time and for five weeks after dosage was stopped, the nature and extent of the resultant hearing deficits were studied. The animals' Preyer reflex thresholds were determined at intervals during the study. Only one rat was unaffected by the kanamycin dosage. The onset of hearing impairment (reduced discrimination performance), which was gradual in some rats and sudden in others, generally occurred during the fourth week of kanamycin dosage although the earliest onset was towards the end of the second week. In most animals the hearing impairment progressed after kanamycin was stopped and in one rat there was a latency between the end of drug dosage and onset of hearing impairment. Hearing impairment was irreversible in five rats. One rat, whose impairment was slight, recovered normal hearing. Some rats showed a reduced discrimination performance at a time when their Preyer reflex threshold showed no elevation suggesting that kanamycin, at least initially, caused a threshold elevation rather than reduced sensitivity to intense sounds.
Animals↗
[Effect of various kanamycin dosage forms in experimental nonpenetrating infected injuries to the cornea].
Animals with experimental non-penetrating local wound of the cornea of the type of erosion infected with highly virulent strains of Staph. aureus were treated at various periods, i.e. in 15 minutes, 2, 6 and 9 hours with kanamycin solution (10000 gamma/ml) and kanamycin imbibized films. The therapeutic effect of the kanamycin solution on the non-penetrating infected wound of the cornea was higher when the treatment was started at earlier periods after infection with Staph. aureus. At later periods when the inflammatory process was highly developed the effect of the kanamycin solution on the wound was lower. As for the use of the kanamycin films the regularity was the reverse: they had a higher therapeutic effect in pronounced inflammation and highly developed infection of the eye.
Animals↗
[Dependence of the nephrotoxic effect of kanamycin on its concentration in the blood (an experimental study)].
The kinetics of changes in the urea nitrogen level of the serum was studied experimentally on narcotized cats with constant blood levels of kanamycin. A relationship between the intensity of the nephrotoxic effect of kanamycin and its blood level was found. On the basis of this relationship lower nephrotoxicity of kanamycin as compared to that of gentamicin and streptomycin under conditions of their constant blood levels was shown. However, the concentrations of gentamicin and kanamycin provided in the blood by their use in therapeutic doses differeing 3--4 times allow a conclusion that the nephrotoxic effect of kanamycin and gentamicin to be practically the same.
Animals↗
Effect of kanamycin sulfate on the endocochlear dc potential of guinea pigs.
The magnitudes of the endocochlear dc potential (EP) during adequate ventilation and during five minutes of anoxia were recorded in control guinea pigs and guinea pigs administered various dosages of kanamycin sulfate. The magnitudes of the EP after five minutes of anoxia were -44.6 +/- 5.9 mV in the controls and +26.6 +/- 9.9 mV in the guinea pigs that received kanamycin for seven or ten days. This change occurred after five or six days of administration of kanamycin. However, there was no significant change in the magnitude ot the EP with adequate ventilation with kanamycin intoxication. There is a significant correlation between the magnitude of the negative EP and the maximum output of the cochlear microphonics (r = -.770, P less than .001). These results suggest that the EP may not be the mathematical summation of the positive electrogenic potential and the negative diffusion potential. The mechanism for generating the negative EP during anoxia may have some relationship to hair cell integrity.
Animals↗
Results of hearing testing at 7-year follow-up of kanamycin-treated newborn infants.
A follow-up study 7--8 years after kanamycin treatment of 83 newborn infants in the Tampere University Central Hospital is described. The Apgar scores ranged from 1 to 10, about half of the patients being premature. Only in 1 case (1.2%) a slight bilateral high-tone loss was found. This patient's birth had been complicated by ablation of the placenta with subsequent cesarean section and he had neonatal sepsis as well. The cause of this hearing defect is thus not necessarily the use of kanamycin. Because of the extended use of reserve antibiotics, microorganisms resistant to modern antibiotics may necessitate in some vital cases the use of kanamycin. Our results indicate that, if serum concentrations are monitored adequately, the use of kanamycin does not necessarily result in a hearing defect.
Audiometry↗
Potentiation of kanamycin ototoxicity by a history of noise exposure.
Chinchillas were exposed to a noise band (1,414 to 5,656 Hz, 100-dB sound pressure level [SPL] for one hour) and treated with kanamycin (150 mg/kg a day until hearings loss was noted at 6.0 kHz) either separately, simultaneously, or sequentially. Simultaneous noise and kanamycin resulted in interactive potentiation of threshold shift and cochlear pathologic condition. Kanamycin treatment two months after noise exposure produced similar potentiation. No interaction was seen when noise exposure occurred one month after kanamycin treatment.
Animals↗
Audiometric and histologic correlates of the interaction between kanamycin and subtraumatic levels of noise in the chinchilla.
Difficulty in assessment of potentiating interaction between noise-induced and kanamycin-induced injury of hearing is compounded by the great variability of intersubject response to the same drug dosage. However, in a given subject, response of the two cochleas to kanamycin intoxication may resonably be assumed to be symmetric. The present study was designed to utilize this similarity, in determining whether kanamycin intoxication would potentiate a normally subtraumatic noise stimulus. Under the experimental conditions outlined, it was found that after a dosage of 150 mg/kg/day of kanamycin given to a physiologic end point, normally subtraumatic noise caused consistent increas in hearing loss.
Acoustic Stimulation↗
Effects of kanamycin on the auditory evoked responses during postnatal development of the hearing of the rat.
The ototoxic effects of kanamycin were studied in rats during the early postnatal period and at an adult age. Brain stem potentials as well as auditory cortical potentials were used for the estimating of ototoxic damage. The auditory potentials decreased promptly and markedly in the animals which were treated daily with 400 mg/kg body weight of kanamycin starting from the 11th day after birth. In these animals, the auditory potentials were almost completely abolished within 10 days after the beginning of the kanamycin treatment. However, when the same amount of kanamycin was applied earlier or later than that, i.e., avoiding the period of the initial appearance and the greatest development of auditory functions (from the 11th to the 15th day after birth in the rat), the auditory potentials were not apparently damaged. In light and scanning electronmicroscopy, marked ototoxic changes were observed which underlay the functional damage. The meaning of these findings is discussed.
Age Factors↗
Aminoglycoside antibiotics. XII. Effect of N-alkylation in kanamycin antibiotics.
Four N-ethyl derivatives of kanamycin A and five N-ethyl derivatives of kanamycin B were synthesized. The antimicrobial activity of N-ethyl kanamycin derivatives was determined against aminoglycoside-sensitive and resistant organisms. The structure-activity relationship of these compounds is discussed with reference to the activity of N-acyl kanamycin derivatives.
Alkylation↗
[Experimental protective action of kanamycin, ampicillin and their combination with methyluracil and pyrogenal].
Efficacy of kanamycin, ampicillin and their combinations with methyluracyl and pyrogenal in experimental Coli infections was studied. The antibiotics were administered an hour after the infection. Methyluracyl and pyrogenal were used according to 2 schemes. Scheme No. I: the drug is used daily for 7 days in increasing doses, the last dose is administered 24 hours before the infection. Scheme No. 2: the drug is used once at the moment of the infection. The methyluracyl doses were: 0.5, 1.0, 2.5 mg and 5 mg and 5 mg per a mouse during the following 4 days. The pyrrogenal doses were: 5, 10, 15, 25, 30 and 35 minimum pyrogenic doses. 5 mg of methyluracyl and 35 minimum pyrogenic doses of pyrogenal were used according to scheme No. 2. The most pronounced increase in the efficacy of kanamycin, ampicillin and their combination was observed in the animals treated simultaneously with methyluracyl and pyrogenal according to scheme No. 1. The efficacy of kanamycin and ampicillin increased 3 and 2.68 times respectively. ED50 of kanamycin and ampicillin used in combination in the animals treated with methyluracyl and pyrogenal was lowered 4 and 2.9 times respectively as compared to that in the animal groups treated only with the antibiotic combination and 21 and 15.2 times respectively when the antibiotics were used alone. Sanation of the animal organs was also rather successful. A single administration of methyluracyl and pyrogenal simultaneously with the infection (scheme No. 2) had a lower effect on the efficacy.
Ampicillin↗
Computer-calculated kanamycin dosage regimen and monitoring.
The applicability of a computerized dosage regimen determination based on a recently developed method for drugs following the minimum inhibitory concentration pattern (bacteriostatic drugs) has been tested for kanamycin injected intramuscularly in 8 patients with varying degrees of renal impairment. The dosage regimens for maintaining a minimum therapeutic kanamycin concentration of 5.0 micron g/ml was determined with the Wang 700 C Computer. After the 1st, 2nd, 3rd, 6th, 9th, and 12th dosing interval blood samples were taken and the acual kanamycin serum concentrations determined. The expected multiple dose serum level curves for each patient were simulated using the Comdyna Dose Generator Analog Computer and the individual actual serum concentrations were monitored. The actually found serum level data were compared to the expected values based on the dosage regimen equations and to the steady state equations. Additionally, the expected peak maxima were calculated. The proposed method resulted in effective and safe kanamycin serum levels.
Adult↗
[Antimicrobial effectiveness of sisomicin. I: In vitro activity of sisomicin compared with gentamicin, tobramycin, amikacin and kanamycin (author's transl)].
The aminoglycosides sisomicin, gentamicin, tobramycin, amikacin and kanamycin are highly active against staphylococci including the penicillinase-positive strains. Sisomicin is more effective than amikacin and kanamycin. Mixed infections with staphylococci and Enterobacteriaceae or Pseudomonas aeruginosa are thus on indication for treatment with sisomicin or other aminoglycosides. Infections with E. coli, Enterobacter, susceptible Klebsiella, and susceptible Pseudomonas strains can be treated with sisomicin, gentamicin or tobramycin. In such cases sisomicin is the most effective antibiotic because of its high antimicrobial activity. In infections with these organisms amikacin can also be used for treatment especially if there is resistance to other aminoglycosides. In hospital-acquired infections with Serratia marcescens amikacin and sisomicin are the drugs of choice. Both aminoglycosides have to be given in high doses in infections with Serratia because of the high inhibitory concentration for Serratia. Sisomicin demonstrates a high antimicrobial activity particularly against indole-positive Proteus species such as Proteus vulgaris and Proteus morganii, Enterobacter, and gentamicin-sensitive Pseudomonas strains. In infections with Pseudomonas aeruginosa tobramycin is the most effective bactericidal antibiotic. Amikacin is the drug of choice against gentamicin-resistant Pseudomonas strains which are also not infrequently resistant to other aminoglycosides. The low proportion of resistance to sisomicin of 7,6% in 370 organisms is only exceeded by amikacin with a rate of 0,6% (resistance to tobramycin 11,4%, gentamicin, 13,2% and kanamycin 42,4%). The low rate of resistance and the high antimicrobial activity are essential advantages of sisomicin.
Amikacin↗