STREPTOMYCIN
1. EXPLANATION
Streptomycin is a natural aminoglycoside antibiotic produced by
the soil Actinomycete Streptomyces griseus. Streptomycin is used
in combination with penicillins for the treatment of bacterial
infections in cattle, sheep and pigs. It is also used in agriculture
to control bacterial and fungal diseases of selected fruit,
vegetables, seed, specialized field crops, ornamental crops, and in
ornamental ponds and aquaria to control algae.
Both dihydrostreptomycin and streptomycin were evaluated at the
twelfth meeting of the Committee (Annex 1, Reference 17). An ADI was
not established for either compound at that time.
The two compounds are aminoglycoside antibiotics, and are closely
related in structure as shown in Figures 1 and 2 below.
Both dihydrostreptomycin and streptomycin are used for treatment
of bacterial infections in food-producing animals.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Absorption, distribution and excretion
2.1.1.1 Mice
After subcutaneous injection of 5000 to 50 000 units
streptomycin/kg bw in mice peak blood concentrations of 6.5 units/ml
were reached in approximately 15 minutes. After oral administration of
high doses (200 000 units/kg bw) peak blood levels of 2 units/ml were
reached at 45 to 60 minutes (Stebbins et al., 1945).
2.1.1.2 Rats
See section 2.1.1.1 of the monograph on dihydrostreptomycin for
the results of studies on streptomycin.
2.1.1.3 Rabbits
After administration of a single i.v. dose of 5000 units
streptomycin/kg bw to rabbits, 5-10% of the dose was recovered in bile
over 8 hours after injection. Following intraduodenal administration
of 8000 units/kg bw, no drug was detected in bile after the same time
period (Stebbins et al., 1945).
2.1.1.4 Dogs
After oral administration of 420 000 units streptomycin to dogs,
no drug was detected in plasma, but up to 3.9% of the dose was
recovered from urine (Graham et al., 1946).
After oral administration to dogs of 100 000 to 200 000 units/kg
bw streptomycin, no drug was detected in bile and 5-10% was recovered
in urine. In dogs killed 24 hours after drug administration, 60-80% of
the drug was recovered unabsorbed from the gastrointestinal tract
(Stebbins et al., 1945).
After repeated i.m. administration of 3685-3740 units
streptomycin/kg bw to dogs every 3 hours, therapeutic blood
concentrations of 3-18 units/ml were maintained (Stebbins et al.,
1945).
The volume of distribution in dogs after injection of 20 mg/kg bw
streptomycin was 23% to 36% of body weight, corresponding to
extracellular fluid volume. Renal clearance appeared to be by
glomerular filtration alone, and was 34-59 ml plasma/minute (Marshall,
1948).
2.1.1.5 Monkeys
After i.m. administration of 10 000 or 50 000 units
streptomycin/kg bw to groups of 2 monkeys, 61-69% and 38-42% of the
dose was excreted in urine, respectively, after 1 day. After repeated
daily injections for 5 days, the amount recovered in urine per day did
not differ significantly over the course of treatment (Stebbins
et al., 1945).
2.1.1.6 Cattle
Streptomycin was eliminated in the milk of cattle from 6 to 18
hours after a single i.m. dose of 5 mg/lb bw (11 mg/kg bw). Absorption
of streptomycin after intramammary infusion was poor; it was
undetectable in blood, but significant amounts were detected in urine
up to 27 hours after intramammary infusion (Huber, 1966).
2.1.1.7 Humans
Aminoglycoside antibiotics cross membranes very poorly and Pratt
& Fekaty (1986) have reported that only about 1% of an oral dose is
absorbed, even when there is intestinal inflammation or ulceration.
Anderson and Jewell (1945) reported that after oral
administration of 600 000 units of streptomycin to a fasted patient,
no drug was detected in serum for the following 12 hours when assayed
micro-biologically using Staph. aureus. Failure to detect serum
levels of the drug could not be attributed to inactivation of the drug
by gastric juices, since incubation in gastric juice in vitro at 37
°C for 3 hours did not produce any loss of activity.
Elias and Durso (1945) also reported no demonstrable streptomycin
in blood after oral administration of 4 000 000 units streptomycin.
Only 1% of the dose was recovered in urine and >64% was eliminated in
faeces.
Dollery (1991) reported that after oral administration of
streptomycin, 60%-100% of the drug was recovered unchanged from the
faeces.
Streptomycin is poorly absorbed by inhalation, therefore high
levels may be produced in respiratory secretions, causing a marked
decrease in bacterial flora in the upper respiratory tract (Huber,
1966).
Pharmacokinetic parameters in humans following i.m.
administration are summarized in Table 1.
The volume of distribution of streptomycin ranged from 30-35%
body weight, corresponding to the extracellular fluid volume.
(Marshall, 1948).
Approximately 0.5% of the maternal dose of streptomycin was
excreted in breast milk in 24 hours; thus, a nursing infant could
ingest approximately 5 mg in 24 hours. The recommended therapeutic
dose for infants is 10-20 mg/kg bw/day (Dollery, 1991).
After parenteral administration of streptomycin, approximately
50% to 60% of the dose was excreted unchanged in the urine within 24
hours (Anderson & Jewell, 1945).
Table 1. Pharmacokinetic parameters for streptomycin in humans
Adult daily therapeutic dose 15-25 mg/kg bw/day
Route of administration Intramuscular
Normal dosage interval 12 hours
Peak serum level 25-30 ug/ml
Half-Life:
Normal 2.5 hours
Anuric 50-110 hours
elderly* 9 hours
premature/newborn infants* 7 hours
Volume of distribution
well-nourished patients* 95.9 ± 19.5 litres
malnourished patients* 66.3 ± 7.4 litres
Plasma protein binding 35%
(Pratt & Fekaty, 1986 / * = Dollery, 1991)
Renal clearance values for streptomycin ranged from 30-80 ml
plasma/minute in humans after i.v. infusion of 10-20 mg/kg bw in 100
ml saline over 10 minutes (Marshall 1948). A small amount of
reabsorption occurs at the proximal tubules (Pratt & Fekaty, 1986).
Approximately 20% of a parenteral dose of streptomycin could not
be accounted for in urine, but no metabolites have yet been
identified. Approximately 1% was excreted in bile (Dollery, 1991).
The excretion rate for aminoglycosides after parenteral
administration is dependent on renal function and is linearly related
to the creatinine clearance rate. The elimination half-life in adults
is 2 hours, but 5-6 hours in neonates due to their lower glomerular
filtration rate (Pratt & Fekaty, 1986).
2.1.2 Biotransformation
The aminoglycosides are reported not to be metabolized in humans
and are excreted in their active forms by glomerular filtration (Pratt
& Fekaty, 1986).
2.1.3 Effects on enzymes and other biochemical parameters
No information available
2.2 Toxicological studies
2.2.1 Acute toxicity studies
2.2.1.1 Mice
The acute toxicity of various batches of streptomycin of
different purities, was studied in groups of 5 or 10 mice per dose, by
various routes of administration. The oral LD50 ranged from 15
000-30 000 mg/kg bw, the s.c. LD50 was 500-550 mg/kg bw, the i.v.
LD50 was 85-111 mg/kg bw, and the i.p. LD50 was 610-575 mg/kg bw (see
Table 2). Clinical signs of toxicity prior to death included
restlessness, respiratory depression, loss of balance,
unconsciousness, motor paralysis and coma following all routes of
administration. Coma was more often associated with s.c. dosing. After
oral dosing, restlessness and excessive thirst were observed, possibly
due to an osmotic effect. At autopsy, the only gross anatomical or
histological lesions observed were haemorrhagic lesions in the
gastrointestinal tract of animals dosed orally. Oral administration of
sodium chloride of the same tonicity as the streptomycin produced
similar lesions (Bacharach et al., 1959).
In another study, the oral LD50 of various streptomycin salts was
compared in male Carworth CF1 mice. Streptomycin calcium chloride
complex gave an LD50 of 8750 mg/kg bw, whereas streptomycin sulfate
gave an LD50 of 25 000 mg/kg bw (Edison et al., 1951).
Table 2. Acute toxicity of streptomycin in mice
Route of administration LD50 (mg/kg bw) Reference
Intravenous 85 - 111 Bacharach et al., 1959
Intraperitoneal 610 - 575 Bacharach et al., 1959
Subcutaneous 500 - 550 Bacharach et al., 1959
600 Molitor et al., 1946
Oral
Base 15 500 - 30 000 Bacharach et al., 1959
Calcium chloride 8750 Edison et al., 1951
Sulfate 25 000 Edison et al., 1951
2.2.1.2 Rats
Rats were anaesthesized with 30 mg/kg bw nembutal and given
intravenous infusions of streptomycin at rates of 40, 180, or 600 mg/
kg/bw/hour. At the high and intermediate infusion rates respiration
ceased within 6 and 20 minutes, respectively. The heart continued
beating for 4 to 6 minutes after cessation of respiration. The
low-dose rats showed no adverse effects when infusion was stopped
after 1.5 hours, when approximately 60 mg streptomycin had been
infused. However, doses of 40 to 50 mg had proved fatal when injected
more rapidly (Molitor et al., 1946).
2.2.1.3 Hamsters
The oral LD50 of streptomycin sulfate in groups of 10 golden
hamsters was 400 mg/kg bw. The LD50 after s.c. administration was
>500 mg/kg bw. Some animals died up to 2 weeks after dosing. Clinical
signs of toxicity included listlessness, ruffled fur, decreased food
intake, and diarrhoea (DeSalva et al., 1967).
2.2.1.4 Guinea-pigs
The s.c. LD50 for streptomycin was 400 mg/kg bw. The same batch
of streptomycin produced an s.c. LD50 of 600 mg/kg bw in mice (Molitor
et al., 1946).
2.2.1.5 Frogs
Groups of 5 frogs (Rana pipiens) were injected with 25 to
100 mg of streptomycin in the abdominal lymph sac. Within 15 to 20
minutes complete motor paralysis had occurred and no respiratory
movements were observable. The authors reported that, unlike
warm-blooded animals which would have died of respiratory failure at
this stage, the frogs completely recovered within 2 to 3 days when
kept partially submerged in water (Molitor et al., 1946).
2.2.1.6 Cats
Intravenous administration of 10 mg/kg bw "pure" streptomycin to
cats had no effect on blood pressure; 20 mg/kg bw gradually depressed
blood pressure, which subsequently returned to normal; very high
doses, 120 to 375 mg/kg bw, caused vasomotor and respiratory paralysis
for several hours if artificial respiration was maintained. During
this period the heart continued to beat regularly. Injection of less
pure streptomycin concentrates caused a pronounced drop in blood
pressure with peripheral vasodilation, which the authors concluded was
due to the presence of a histamine-like impurity (Molitor et al.,
1946).
The clinical signs of acute toxicity were similar in all species
after i.v. or s.c. injection of streptomycin (see above), but cats and
dogs additionally showed signs of nausea, vomiting and ataxia (Huber,
1966).
Four out of 12 cats receiving a parenteral dose of 250-350 mg/kg
bw streptomycin developed respiratory failure. One animal was
resuscitated and 3 died (Clark, 1977).
2.2.1.7 Dogs
Intravenous injection of streptomycin at doses of 100 to 200
mg/lb bw (220-440 mg/kg bw) in dogs caused an irreversible depression
of blood pressure. Respiration was stimulated by low but paralyzed by
high (165 mg/kg bw) intravenous doses (Huber, 1966).
2.2.1.8 Monkeys
Intravenous and s.c. administration of 30 to 70 mg/kg bw
streptomycin to monkeys caused marked respiratory depression which
sometimes necessitated artificial respiration (Molitor et al.,
1946).
Two monkeys each weighing approximately 4 kg, were lightly
anaesthesized with nembutal. Streptomycin was administered by i.v.
infusion. The first monkey suffered respiratory depression and died
after a total dose of 440 mg. The second monkey tolerated a total
dose of 1920 mg over 42 hours without any significant change in heart
rate, respiratory rate or body temperature (Molitor et al., 1946).
2.2.2 Short-term toxicity studies
2.2.2.1 Mice
Forty mice were injected s.c. with streptomycin at 150 mg/kg
bw/day in three equally divided doses for 6 days. Another group of 20
mice received 1000 mg/kg bw/day in five divided doses subcutaneously
for 6 days. In a third experiment, groups of mice received 150, 300,
600 or 1500 mg/kg bw/day orally in the diet. All the mice remained
clinically normal during treatment and for the following 10-day
observation period. No gross pathological findings were observed in
any of the three experiments (Molitor et al., 1946).
2.2.2.2 Rats
Two groups of 60 weanling rats received streptomycin in the diet
at 300 or 900 mg/kg bw/day. Both groups experienced slightly reduced
body-weight gain compared to controls. In the 900 mg/kg bw/day group
nervous hyperexcitability was observed within 24 hours of treatment.
In the 300 mg/kg bw/day group this developed after about 6 weeks.
Animals were otherwise normal and no abnormalities were found at
necropsy. The duration of the treatment period was not stated in this
study (Molitor et al., 1946).
A group of 30 rats with an average weight of 215 g were injected
s.c. with 100 mg/kg bw/day streptomycin in 3 divided doses for 72
days. No clinical signs of toxicity were observed and no
treatment-related effects were noted on gross anatomical or
histological examination (Molitor et al., 1946).
Two groups of 20 rats received 400 mg streptomycin/kg bw/day for
8 days by s.c. and i.v. injections, respectively. No adverse effects
were observed in either group (Molitor et al., 1946).
2.2.2.3 Hamsters
Forty hamsters (20 of each sex) were divided into 3 groups and
fed 2, 10, or 40 mg/kg bw/day streptomycin in the diet. After 6 days,
all animals in the high-dose group and 90% in the mid-dose group were
dead. All animals in the low-dose group survived.
An escalating dose study was then conducted in which animals were
initally fed 2 mg/kg bw/day streptomycin in the diet. The dose was
then doubled every 2 weeks until the dose reached 64 mg/kg bw/day at
3 months. The streptomycin concentration in the diet was adjusted
weekly to compensate for body-weight gain. All the animals survived
the study. Histological examination revealed damage of the intestine,
caecum and liver in some but not all survivors (DeSalva et al.,
(1969).
2.2.2.4 Guinea-pigs
Groups of 15 guinea-pigs weighing on average 375 g were treated
with 20, 30, 40, or 60 mg/kg bw/day streptomycin s.c. in 3 divided
doses for 6 to 8 weeks. Five animals served as controls. Two animals
in the 40 mg/kg bw/day group died of unknown causes on day 15 of
treatment. All other animals remained clinically normal and no
abnormal findings were noted on gross post-mortem examination (Molitor
et al., 1946).
2.2.2.5 Cats
A daily dose of streptomycin of 25-75 mg/lb bw/day (55-165 mg/kg
bw/day) to cats (route not stated) caused progressive changes in
posture and gait over about 20 days, including ataxia (of the hind
legs first then fore-legs), and a progressive rotational nystagmus.
Withdrawal of the drug resulted in a slow but complete recovery of
vestibular function (Huber, 1966).
Eight cats were administered streptomycin calcium chloride
complex. Four cats received 1 g base/kg bw/day orally, two received
2 g base/kg bw/day orally, and two received 0.1 g base/kg bw/day, s.c.
The oral doses produced vomiting within 30-45 minutes after dosing.
Two cats receiving 1 g base/kg bw/day developed ataxia on days 9 and
12 of dosing; the other 2 cats receiving this dose died on days 8 and
11 with no signs of neurotoxicity. The 2 cats receiving 2 g base/kg
bw/day had more persistent vomiting and developed ataxia later (days
12 and 19). The cats treated s.c. developed ataxia on days 11 and 14
(Edison et al., 1951).
Vestibular function was assessed in 10 cats (5/sex) treated daily
with oral doses of 40 mg dihydrostreptomycin/kg bw/day for 90 days.
Streptomycin sulfate was used in this study as a positive control (200
mg/kg bw/day, s.c.), and water as negative (vehicle) control, by
gavage.
Three cats died, one from each of the negative control, positive
control, and dihydrostreptomycin groups, due to urinary obstruction,
which was considered unrelated to treatment. The results with
dihydrostroptomycin are described in section 2.2.2.2 of the monograph
on dihydrostreptomycin.
All the streptomycin-treated cats showed clinical signs of
toxicity after 2 weeks of treatment (disturbed vestibular function
manifested by ataxia, loss of righting reflex and head oscillations,
salivation, decreased food and water intake, and decreased body
weight); therefore, the streptomycin dose was then decreased to the
maximum tolerated dose based on food and water intake (between 25 and
100 mg/kg bw/day). The vestibular dysfunction persisted throughout
the study even at this lower dose. There were no treatment-related
effects on ophthalmoscopic examination. Lesions of the respiratory
system noted during necropsy were considered by the authors as
secondary to inhalation of fluid from excessive salivation in these
animals, and not directly resulting from treatment (Tisdel et al.,
1976).
2.2.2.6 Dogs
Five dogs were injected s.c. or i.m. with streptomycin at 50 or
100 mg/kg bw/day in three divided doses for 20 days. All animals
developed proteinuria at 1 to 2 weeks. Two animals also had decreased
serum protein. Casts, epithelial cells and leucocytes were observed in
urine. At necropsy, 1 dog in the high-dose group had liver changes
suggestive of necrosis, and pale streaks were observed in the kidney
cortex. Considerable fatty deposits were observed on staining with
Sudan IV in the central portion of the nephron, and a small amount in
the liver. Slight tubular necrosis was observed in another dog with
severe proteinuria. Three dogs developed a change in gait and posture
suggesting a labyrinthine or cerebellar disturbance. Auditory
impairment was noted based on failure of these dogs to respond
normally to sudden noises (Molitor et al., 1946).
Dogs treated for cystitis with a daily i.m. injection of 20 mg/lb
bw/day (44 mg/kg bw/day) streptomycin for 14 days developed vestibular
dysfunction. Dogs treated with 85 mg/lb bw/day (187 mg/kg bw/day) for
28 days developed bilateral liquefaction necrosis of the ventral
cochlear nuclei and a clumping of Nissl-like particles in most of the
neurons of these nuclei (Huber, 1966).
2.2.2.7 Monkeys
A group of 4 monkeys were given daily s.c. injections of
streptomycin at 25 mg/kg bw/day for 66 days. The material used was
from 7 different lots, containing between 50 and 170 µg streptomycin
base per mg. All monkeys remained clinically normal, apart from a
slight anaemia and skin irritation at the injection site. No effects
were observed on the kidneys as assessed by blood urea, chemical and
microscopic examination of urine, and histological examination of the
kidneys (Molitor et al., 1946).
A total of 15 monkeys were given 25, 50, or 200 mg/kg bw/day
streptomycin i.v. for 5 days. The two lower doses were given as 3
separate injections, and the 200 mg/kg bw/day dose was given as 6
separate injections daily, in order to minimize respiratory
depression. Two batches of material were used, pure streptomycin (800
µg streptomycin base per mg) and streptomycin concentrate (400 µg
streptomycin base per mg). The only adverse effect observed in the 2
lower dose groups during treatment or the following 10-day observation
period was an occasional transient impairment of hepatic function as
judged by the bromosulfophthalein retention test. In the 200 mg/kg
bw/day group, 1 monkey died on the second day from respiratory
paralysis following injection. The others survived the 15-day period
but had transient proteinuria (Molitor et al., 1946).
Sixteen monkeys were administered streptomycin by the s.c. or
i.m. routes at doses of 10, 50, 100 or 200 mg/kg bw/day for 5 days
followed by a 10-day observation period. In those receiving 10 or 50
mg/kg bw/day only injection site reactions were observed. In the 2
higher dose groups during the 10-day observation period, 3/12 animals
had transient proteinuria and 2/12 animals had bromosulfophthalein
retention (Molitor et al., 1946).
All monkeys from the above studies were necropsied 12-20 days
after the last dose. Injection site damage was observed, especially in
the monkeys dosed i.m. Fatty metamorphosis was observed in the liver
and less often in the kidney in monkeys dosed at 25 mg/kg bw/day or
greater. There was no decrease in liver glycogen. (Molitor et al.,
1946).
The reversibility of the fatty change observed in the liver and
kidneys in the above studies was examined in 8 monkeys administered 25
mg streptomycin/kg bw/day, i.v. for 5 days. Pairs of animals were
sacrificed on the day after the treatment period, and 10 days, 1 month
and 2 months later. All animals remained clinically normal. At
necropsy on the day after the last injection, a moderate amount of fat
was observed in the liver and none was found in the kidney. At 10
days, a large amount of fat was present in liver and a slight amount
in kidney. At 30 days, there was no fat in the kidney and a slight
amount in liver. At 66 days no pathological changes were observed
(Molitor et al., 1946).
2.2.3 Long-term toxicity/carcinogenicity studies
No information available
2.2.4 Reproductive toxicity studies
No information available
2.2.5 Special studies on embryotoxicity/teratogenicity
2.2.5.1 Mice
Groups of 6-7 pregnant Swiss mice were given single s.c.
injections of streptomycin at doses of 0.025 or 0.25 µg/kg bw on day
14 of gestation. There was no effect on litter size and no
malformations were observed in any of the fetuses. In the low-dose
group, F1 females had reduced body-weight gain compared to controls
up to day 24, followed by accelerated body-weight gain, such that at
35 days, weight was comparable to controls. The same effect was seen
in males but to a lesser degree. In the high-dose group, the females
had reduced body-weight gain up to 35 days. Again the same effect was
observed in males, but only up to day 17. Organ weights were reduced
for seminal vesicles and adrenal glands (in both sexes) at the low
dose. At the high dose, all organ weights were reduced except the
liver. Kidney weight (in both sexes) and adrenal and spleen weight in
females were most notably reduced (Boucher & Delost, 1964).
Pregnant C57BL mice were given twice-daily i.m. injections of
streptomycin at 250 mg/kg bw/injection. The timing of treatment in
relation to gestation was not stated. There was no effect on litter
size, no external malformations, and no gross malformations of the
brain or cranial segments of the cervical medulla. Microscopic
findings were observed in head sections of 9/52 embryos, which
included pycnosis, perivascular cell infiltrations, haemorrhages,
ependymal polypus, and eye anomalies. However, these findings occurred
with similar frequency in controls and therefore could not be
attributed to treatment. Streptomycin crossed the placental barrier,
and was identified by microbiological evaluation of tissue fluids of
embryos from treated dams (Ericson-Strandvik & Gyllensten, 1963).
Streptomycin was administered subcutaneously to 14 pregnant mice
at 400 µg/kg bw/day on days 9, 10, and 11 of pregnancy. Twenty-eight
mice used as controls were injected with water. The number of implants
was reduced in treated mice (179 vs 351 in controls). Early deaths
were higher in controls (3.9% in the streptomycin group vs 5.1% in
controls). The percentage of fetal deaths and live fetuses were
similar in treated and control animals. Body weights of treated males
and females were significantly reduced compared to the controls (p
<0.001). No malformations were observed in fetuses in the treatment
group (Nomura et al., 1984).
ICR mice were treated i.p. during days 12 to 16 of gestation with
streptomycin at 250 mg/kg bw/day. Twenty treated and twenty control
F1 offspring were examined by behavioural tests. The morphology of
the inner ear was examined by scanning electron microscopy.
Body-weight increase, activity, and functional development such as
grooming were unaffected by treatment. Vestibular function (assessed
with narrow path and rotor rod tests) was reduced compared to
controls. Morphological changes included degeneration and polyp-like
cytoplasmic extrusions of the inner hair cells (Nakamoto et al.,
1985).
2.2.5.2 Guinea-pigs
See section 2.2.5.1 of the monograph on dihydrostreptomycin for
the results of studies on streptomycin.
2.2.5.3 Humans
The incidence of congenital malformations in newborns was
examined in 1619 mothers who had received treatment for tuberculosis
with streptomycin, hydrasid and p-amino salicylic acid. These results
were compared to a control group of (2711) healthy pregnant women. The
incidence of congenital malformations was 2.34% in tuberculosis
infected subjects and 2.56 in controls. No difference was observed in
the pattern of malformations in the 2 groups; however, the nature of
these malformations was not specified. The dose and time of treatment
were not stated. (Marynowski & Sianozecka, 1972).
See section 2.2.5.3 of the monograph on dihydrostreptomycin for
the results of other studies on streptomycin.
2.2.6 Special studies on genotoxicity
Streptomycin and dihydrostreptomycin bind to and alter the
configuration of the 30S sub-unit of ribosomes, thus inhibiting
protein synthesis and causing misreading of the genetic code. RNA and
DNA synthesis are unaffected (Goldberg, 1965; Davies et al., 1964).
The results of genotoxicity assays with streptomycin are
summarized in Table 3.
2.2.7 Special studies on ototoxicity
2.2.7.1 General
A review of the literature presented by Berg (1951) on
ototoxicity produced by streptomycin states that histological
examination of the auditory system of numerous affected species by
several authors gave either negative findings, or indications that the
lesion was localized to the central nervous system, or indications
that the peripheral sensory epithelium of the labyrinths was affected.
Consequently, it is difficult to draw definitive conclusions on the
site of streptomycin-induced lesions. Berg postulates that the primary
lesion is in fact the vestibular sensory epithelium, rather than the
Organ of Corti, and that changes in vestibular nerves and central
vestibular nuclei are secondary to this effect, resulting from an
ascending atrophy (Berg, 1951).
Table 3. Results of genotoxicity assays on streptomycin
Test System Test Object Concentration Results Reference
In vitro
Cytogenetics Human lymphocytes 4.7-13.7 mg/ml Equivocal1 Obe, 1970
Cytogenetics Human lymphocytes 50-2000 ug/ml Negative Neu 1965
Cytogenetics Human lymphocytes 50-300 ug/ml Inconclusive2 Das & Sharma, 1983
Cytogenetics Mammalian cells 10-20 mM Positive Kodama et al., 1980
In vivo
Cytogenetics Human lymphocytes3 0.75-1.0 g/day Negative Jaju et al., 1983
Cytogenetics Human lymphocytes4 Therapeutic Negative Beek, 1976
does (not stated)
1 Achromatic lesions were induced. The significance of these with respect to mutagenic/carcinogenic
potential was not established.
2 Streptomycin was tested in combination with penicillin in this study.
3 Human lymphocytes were isolated from tuberculosis patients on one of three different treatment
regimes for a minimum of 3 months: streptomycin and isoniazid; streptomycin, isoniazid and p-amino
salicylic acid; or streptomycin, isonazid and thiacetazone. These were compared to lymphocytes
from healthy humans and newly diagnosed tuberculosis patients prior to initiation of therapy.
4 Human lymphocytes were obtained from 21 tuberculosis patients on one of the following 6-month
treatment regimes: streptomycin and p-amino salicylic acid for 3 months followed by 3 months treatment
with streptomycin, isoniazid and ethambutal; or streptomycin, isoniazid, and rifampicin. These were
compared to lymphocytes taken from these same patients prior to initiation of treatment.
Streptomycin damages the hair cells of the Organ of Corti in the
cochlea and the hair cells of the vestibular apparatus which are found
in the macula of the saccule, the macula of the utricule, and the
ampullae of the three semicircular canals. It does not damage the
eighth cranial nerve (Davies, 1991).
2.2.7.2 Guinea-pigs
Groups of 3 to 9 guinea-pigs were treated with streptomycin at
doses of 100-400 mg/kg bw/day for 3 to 6 weeks (the route of
administration was not specified). On histological examination of the
inner ear, degeneration of the nerve cells of the central nuclei
(primarily vestibular and cochlear nuclei), was observed in
association with clinical signs of hearing loss and vestibular
dysfunction in each treatment group. Myelin staining of the eighth
cranial nerve was normal in all animals, as were the sensory cells of
the labyrinth (Christensen et al., 1951).
Tsang and Chin (1963) reported changes in both the peripheral and
central sides of the vestibular and cochlear systems occurring at the
same time in guinea-pigs treated for 21-60 days with 200-400 mg/kg
bw/day streptomycin parenterally. The authors noted that the
vestibular system was more severely affected than the cochlear system.
2.2.7.3 Cats
See section 2.2.8.1 of the monograph on dihydrostreptomycin for
the results of studies on streptomycin.
2.2.7.4 Dogs/humans
Stevenson et al. (1947) performed neuropathological
examinations on 5 patients who had died of tuberculosis, and who
became partially or completely deaf while receiving large doses of
streptomycin. The doses used were typically 3 g/day i.m. in adults.
Doses administered to children were proportionally less. In 4/5
patients, additional doses of streptomycin were administered by the
intrathecal route (dose not stated).
A similar examination was made in 3 dogs treated i.m. with 170
mg/kg bw/day streptomycin for 9 to 28 days. Clinical signs of
toxicity included ataxia, head movements, tail-chasing, and weakness.
One dog died on the 9th day with advanced bilateral necrotising renal
arteriolitis and glomerulitis. The other two dogs were killed at 28
days (Stevenson et al., 1947).
The findings were similar in dogs and humans. Degeneration of
the nuclei of the VIIIth cranial nerve was observed, particularly the
ventral cochlear nuclei and possibly the inferior vestibular nuclei.
The VIIIth cranial nerve was found to be normal in two cases, although
it was unclear whether this was in humans or dogs (Stevenson
et al., 1947).
2.2.8 Special studies on renal toxicity
Renal function was assessed in mice, rats, guinea-pigs, and dogs,
by either a 5-hour observation of water diuresis after a single dose
of streptomycin or observation of the overnight urine volume (18
hours) during and after a prolonged course of streptomycin treatment
in the following experiments:
1. Mice were administered either 400 or 800 mg/kg bw streptomycin
s.c. in 8 divided doses over 24 hours or 150 or 300 mg/kg bw/day
in 3 divided doses over seven days.
2. Groups of rats were administered streptomycin s.c. as a single
injection of 100 or 200 mg/kg bw, 100 mg/kg bw/day in divided
subcutaneous doses for 5 days, or 100 mg/kg bw/day for 8 weeks.
3. Guinea-pigs were administered 30 mg streptomycin/kg bw s.c. in 3
divided doses over 24 hours.
No adverse effects were observed on renal function in the above
experiments (Molitor et al., 1946).
In rats treated with 250 or 500 mg/kg bw of "pure" streptomycin
orally together with a water load, urine output was reduced at 2 hours
but total output at 5 hours was similar to controls. The rate of
output was decreased with treatment. With streptomycin concentrate,
diuresis was decreased even further and the 5-hour urine output was
less than half of controls. This effect on diuresis had disappeared by
the third day after treatment (Molitor et al., 1946).
Monkeys were treated with streptomycin at 25, 50, 100 or 200
mg/kg bw/day s.c. in 3 divided doses for 5 days, 100 or 200 mg/kg
bw/day s.c. for 10 days, or 25, 50 or 200 mg/kg bw/day i.v. in 3 or 6
divided doses for 5 days. At the higher doses, proteinuria was
observed and blood urea increased in most animals but remained within
the normal range of values for this parameter. Overnight urine volumes
were occasionally decreased. After intravenous administration of 25
mg/kg bw/day, overnight urine volumes were reduced on the first day of
dosing by 18, 67, 75 and 80% in 4 monkeys, but had returned to normal
by the tenth day of the observation period. Two monkeys dosed with a
low-potency material had a decreased serum protein level, inflammation
at the injection site and edema of the abdominal skin and genital
region extending to the upper leg. This reaction was attributed by the
authors to a histamine-like impurity present in low-purity batches of
streptomycin (Molitor et al., 1946).
2.2.9 Special studies on local toxicity
2.2.9.1 Eye
An aqueous solution of streptomycin (8 mg base/ml) and an
ophthalmic ointment containing 1 mg/g streptomycin were applied to the
conjunctival sac of lightly anaesthesized rabbits for 30 minutes.
Occasional redness of the conjunctiva was observed which persisted up
to 12 hours after application (Molitor et al., 1946).
2.2.9.2 Intrabuccal
Application of streptomycin as either an aqueous solution (8
mg/ml) or as an ointment (1 mg/g) to the buccal membrane of dogs for
15 minutes had no adverse effects (Molitor et al., 1946).
2.2.9.3 Intradermal
Intradermal injection of 0.1 to 0.4 mg streptomycin in the
abdominal skin of guinea-pigs produced slight reddening followed
occasionally by blister formation (Molitor et al., 1946).
2.2.9.4 Intrapleural
Groups of two rabbits were given an intrapleural injection of
streptomycin at 1, 10, or 100 mg/kg bw. All animals were necropsied on
the fourth day after injection. Dose-related increases in pleural
fluid and congestion of the diaphragm were observed; at the high dose,
small areas of haemorrhage and fibrous adhesions were observed between
the lung, diaphragm and pleural wall (Molitor et al., 1946).
2.3 Observations In humans
2.3.1 Ototoxicity
Patients presenting with ototoxic side effects after treatment
with streptomycin, dihydrostreptomycin or kanamycin, for various
clinical conditions, were studied in a retrospective study. The route
of administration was not stated, although it was probably
intramuscular injection.
Vertigo was reported by the end of the first week of treatment in
25/26 patients treated with streptomycin alone at doses between 0.25
and 2 g/person/day (equivalent to 3 to 36 mg/kg bw/day). Total doses
of 4 g to 71 g were administered. In approximately 70% of cases the
duration of treatment was short (5 to 14 days) and the total dose was
low (4 to 10 g). In most cases (13/19 patients) treatment lasted from
one week to four months. In 6/19 cases the symptoms were still present
at the last examination performed at 1.5 to 6 years after their first
appearance. In 13/18 patients functional impairment of renal clearance
was reported. These tended to be patients treated for longer periods
(9 to 19 days). At lower streptomycin doses (15 mg/kg bw/day) for
about 7 days, only one case of vestibular damage was reported when
over 1000 patients were treated (Erlanson & Lundgren, 1964).
See section 2.3.1 of the monograph on dihydrostreptomycin for the
results of other studies on the aminoglycosides.
2.3.2 Renal toxicity
Evidence of minor renal tubular dysfunction, such as urinary
casts and a minor degree of albuminuria, are not uncommon in humans
treated with streptomycin. However, severe renal damaage (proximal
tubular necrosus) is rare (Dollery, 1991).
Renal damage is usually reversible on cessation of therapy.
Streptomycin is the least nephrotoxic of the aminoglycosides (Pratt &
Fekaty, 1986).
See section 2.3.2 of the monograph on dihydrostreptomycin for the
results of other studies on the aminoglycosides.
2.3.3 Neuromuscular blockade
See section 2.3.3 of the monograph on dihydrostreptomycin for the
results of other studies on the aminoglycosides.
2.3.4 Allergic reactions
Cutaneous and generalized hypersensitivity reactions are common
with streptomycin and can be severe, the most common features being
rash and fever (Dollery, 1991).
Hypersensitivity reactions may occur in response to streptomycin
treatment. Skin reactions are reported to occur in 5% of patients.
Severe exfoliative dermatitis and anaphylaxis have occurred.
Sensitization is common among those handling streptomycin
occupationally (Martindale, 1993; British Pharmaceutical Codex, 1968).
Streptomycin has been reported to cause asthma, but such
reactions are rare compared to those due to penicillin (Davies, 1991).
2.3.5 Other Effects
Other toxicities occur rarely and include neutropenia,
agranulocytosis, and aplastic anaemia. Transient elevation of hepatic
enzymes occur occasionally (Pratt & Fekaty, 1986).
Streptomycin has been reported to cause a toxic neuritis of the
branches of the trigeminal nerve resulting in numbness, tingling or
burning sensations in the face or mouth. In addition, the following
adverse reactions have been reported in connection with streptomycin:
exfoliative dermatitis, systemic lupus erythematosus, purpura, skin
sensitization via a cross reaction with neomycin, contact urticaria,
post-operative respiratory depression, xanthopsia (disturbance of
colour vision), anosmia (lack of olfactory perception), delirium,
paranoid hallucinatory psychoses, agranulocytosis, serum sickness and
anaphylaxis (Davies, 1991).
3. COMMENTS
The Committee considered data on pharmacokinetics, acute and
short-term toxicity, teratogenicity, as well as special studies on
ototoxicity and clinical studies, which were available on both
compounds. In addition, chronic toxicity data and in vitro
microbiological data were available for dihydrostreptomycin. Two
evaluation reports, as prescribed in the report of the fortieth
meeting of the Committee (Annex 1, reference 104), on
dihydrostreptomycin and streptomycin were also reviewed.
Orally administered streptomycin and dihydrostreptomycin are
poorly absorbed and most of the dose is recovered unchanged in the
faeces in humans and domestic animals.
After parenteral administration of either drug to laboratory or
target animals, peak plasma levels are reached within about one hour.
After parenteral administration of aminoglycosides to humans,
including dihydrostreptomycin and streptomycin, antimicrobial activity
is recovered in the urine, which accounts for approximately 80% of the
administered dose. However, no metabolites have been identified. The
elimination half-life after therapeutic doses is 2 hours in adults,
and 5-6 hours in neonates due to their lower glomerular filtration
rate. Dihydrostreptomycin and streptomycin, in common with other
amino-glycoside antibiotics, can be detected in the kidney after
depletion from plasma. Detectable concentrations occur in urine for
several weeks, suggesting accumulation of the drug in the kidney.
Accumulation also occurs in the perilymph of the inner ear and both
streptomycin and dihydrostreptomycin are known to be ototoxic at
therapeutic doses. The risk of ototoxicity is increased when renal
function is compromised.
Placental transfer occurs and fetal serum concentrations range
from 20-40% of maternal serum levels.
Single oral doses of dihydrostreptomycin and streptomycin salts
were slightly toxic to experimental animals. LD50 values for
dihydrostreptomycin in mice range from 12 500 mg/kg bw for the
hydrochloride to > 30 000 mg/kg bw for the sulfate. For streptomycin,
the oral LD50 in mice range from 8750 mg/kg bw for the calcium
chloride complex to 25 000 mg/kg bw for the sulfate.
Parenteral administration of streptomycin at doses of 50-100
mg/kg bw/day to dogs for 20 days resulted in renal damage within 1 to
2 weeks, and 3 of 5 animals developed ataxia.
Ototoxicity was examined in a 90-day study in guinea-pigs treated
orally with 40 mg dihydrostreptomycin/kg bw/day. Interpretation of the
histopathological data was hampered by inadequate fixation of the
cochlea; however, no hearing loss was reported in this study. In a
subsequent 90-day study in cats treated orally with 40 mg
dihydrostreptomycin/kg bw/day, no treatment-related effects were
observed and vestibular function was normal. The NOEL was 40 mg/kg
bw/day in this study.
In a series of studies with streptomycin in monkeys, s.c.
injection of 25 mg/kg bw/day for 66 days caused anaemia. After i.v.
administration of 25-50 mg/kg bw/day in 3 divided doses for 5 days,
transient impairment of hepatic function was observed. After
parenteral administration (i.m., s.c., or i.v. injection) of 100-200
mg/kg bw/day for 5 days, proteinuria was observed in addition to
hepatic impairment. Parenteral doses of 25 mg/kg bw/day or more for 5
days caused fatty changes in the liver and to a lesser extent in the
kidney. There was no decrease in liver glycogen. These changes were
reversible and had disappeared by 66 days after the last injection.
No adverse effects were observed in target animal safety studies
where cattle, sheep and pigs were treated i.m. with 30 mg/kg bw/day
each of dihydrostreptomycin and penicillin G for 5 days (3 times the
therapeutic dose) or 10 mg/kg bw/day of each drug for 15 days (3 times
the recommended duration of treatment).
Limited information was available on the genotoxicity of
dihydrostreptomycin or streptomycin. Streptomycin gave conflicting
results in chromosomal aberration tests in vitro.
In a 2-year toxicity study in rats, dihydrostreptomycin was
administered in the diet to groups of 35 animals/sex/dose. Drug
concentrations were adjusted weekly to give dose levels of 1, 5, or 10
mg/kg bw/day. Interim sacrifices of 5 animals/sex/dose were made at 6
and 12 months; the remaining 25 animals were administered
dihydrostreptomycin for 2 years. After 6 months a slight, but not
dose-related decrease in body-weight gain was observed in all treated
males. At 18 months and 2 years body weights were slightly decreased
in males of the group dosed with 10 mg/kg bw/day. At 2 years the
incidence of tumours in treated groups was no higher than in control
animals. Twelve to 17 out of 25 animals in the treatment groups
survived up to 2 years. Although this study did not meet current
standards regarding the number of animals used, the Committee
concluded that it represented an adequate test of the carcinogenic
potential of the compound. The NOEL was 5 mg/kg bw/day based on
decreased body weight in males at the high dose.
The Committee concluded that the question of carcinogenic
potential of streptomycin had been satisfactorily assessed in the
2-year oral study with dihydrostreptomycin in rats, since the chemical
structure, pharmacokinetic properties, and toxicity profile of the two
compounds are almost identical.
A number of studies were available in which pregnant mice were
treated parenterally with streptomycin at doses up to 250 mg/kg bw/day
on various days covering gestation days 9 to 16. In the F1 animals,
body weights were reduced in both sexes at the lowest dose, and
vestibular function was impaired at the highest dose. Streptomycin
crossed the placental barrier and was identified in tissue fluids of
embryos from treated dams. There was no effect on litter size, and no
fetal malformations were observed at any dose.
Daily i.m. injection of either dihydrostreptomycin or
streptomycin to pregnant guinea-pigs at doses of 25-200 mg/kg bw/day
caused abortions or death. No abortions were produced with either drug
at a dose of 10 mg/kg bw/day. There was evidence of placental damage
at this dose level with both compounds, but no teratogenic effects
were produced. Vestibular and auditory function were normal in F1
animals.
No teratogenic effects were observed in pregnant rabbits treated
orally with 5 or 10 mg dihydrostreptomycin/kg bw/day on days 6-18 of
gestation. However, no maternal toxicity was observed at these doses,
indicating that the dose levels may not have been high enough to fully
exclude teratogenic potential.
A literature review was available on pregnancy outcomes in women
receiving streptomycin or dihydrostreptomycin parenterally for
tuberculosis. The dose administered, where stated, was between 1-2 g
daily or twice weekly, with total doses ranging from 2-202 g. Other
drugs were administered concomitantly for tuberculosis in 162 cases.
The only abnormalities observed were of the inner ear in 35/207
infants (a rate of approximately 1 in 6). These consisted of
vestibular dysfunction and varying degrees of hearing loss. Hearing
loss occurred in the high-frequency range first, i.e. before the
frequencies associated with normal speech were affected.
The Committee considered that the data in animals and humans
indicated that the effects of dihydrostreptomycin and streptomycin on
the middle ear of fetuses were a manifestation of fetotoxicity. The
Committee concluded that these compounds were not teratogens.
No studies were available on either compound on fertility or
peri-/postnatal effects. Dihydrostreptomycin has been used in
veterinary medicine to preserve semen, for intra-uterine treatment of
infections, and for the treatment of orchitis. In these situations, no
adverse effects on reproduction have been reported. However, these
data did not adequately address the potential for effects on fertility
and reproduction.
Minor renal tubular dysfunction, such as urinary casts and minor
degrees of albuminuria occurs occasionally in humans treated with
streptomycin. However, severe renal damage (proximal tubular necrosis)
is rare and renal damage is usually reversible on cessation of
therapy.
In a study in dogs, a dose equivalent to 50 µg
dihydrostreptomycin/kg bw/day caused a change in the intestinal flora
after 15 days of treatment from susceptible lactose fermenting
coliforms to a resistant population. The Committee considered that
this study was not appropriate for extrapolation to effects in human.
The dog was considered to be a more sensitive species than humans for
these effects because of its shorter intestinal length compared to
body mass, and reduced potential for dilution of intestinal contents
with other food, intestinal secretions and intestinal epithelial
cells.
The spectrum of antimicrobial and biological activity is similar
for dihydrostreptomycin and streptomycin. Therefore results of
in vitro antimicrobial activity studies on dihydrostreptomycin were
also applied to streptomycin to calculate the upper limit of a
potential ADI for combined residues of both compounds as follows:
Concentration without x Daily faecal Bolus (g)
effect on human gut
Upper limit flora (µg/ml)a
of ADI =
Fraction of oral x Safety factorc x Weight
dose available of human
to gut florab (60 kg)
32 µg/ml x 150 g
=
1 x 1 x 60 kg
= 80 µg/kg bw.
a The MIC values measured at high cell density (1 x 107 cells/spot) and under
anaerobic conditions were considered to be more representative of conditions
occurring in the human gut than those measured at lower cell density
(1 x 105 cells/spot). Data were available on 17 species, including the 10 most
common genera of human intestinal microbes, with 5-11 strains tested per species.
The most sensitive species was Bifidobacterium spp. An MIC50 value of 32 µg/ml
(equivalent to 32 µg/g) was selected as the concentration without effect on the
human gut flora.
b A conservative estimate of 100% was selected as the fraction of orally ingested
residues of dihydrostreptomycin and streptomycin available to the colonic microflora,
since no information was available on binding of drug residues to gut contents.
c Because the colonic flora are relatively stable and variability within a particular
individual may be as great as variability between individuals, and because it was
recognised that other values selected for this calculation were conservative and
already incorporated an adequate margin of safety, a safety factor of 1 was selected
to cover fully the variability between humans.
4. EVALUATION
Dihydrostreptomycin and streptomycin are closely related in
structure. Their pharmacokinetic properties, toxicological profiles,
and spectrum of antimicrobial and biological activity are similar and
therefore data on the two compounds have been considered together for
the purpose of establishing a single ADI.
The most sensitive effects in all of the available studies on
dihydrostreptomycin and streptomycin were those observed with
dihydrostreptomycin in the two-year oral toxicity study in rats, where
the NOEL was 5 mg/kg bw/day. Based on this NOEL and using a safety
factor of 200, the Committee established a temporary ADI of 30 µg/kg
bw for the combined residues of both dihydrostreptomycin and
streptomycin.
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See Also:
Toxicological Abbreviations
STREPTOMYCIN (JECFA Evaluation)