SPECTINOMYCIN
First draft prepared by
Dr K. Woodward
Veterinary Medicines Directorate
Ministry of Agriculture, Fisheries and Food
Addlestone, Surrey, United Kingdom
1. EXPLANATION
Spectinomycin is an aminocyclitol antibiotic produced by
Streptomyces spectabilis. It is used in human medicine for the
treatment of uncomplicated gonorrhoea. In veterinary medicine
spectinomycin is used therapeutically for bacterial respiratory and
enteric infections. Spectinomycin is administered singly or in
combination with other antibiotics to cattle, pigs and poultry by
injectable solutions and orally as aqueous solutions or in feed.
Spectinomycin has not been reviewed previously by the Committee.
The structure of spectinomycin is shown in Figure 1.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Absorption, distribution and excretion
2.1.1.1 Rats
When spectinomycin hydrochloride labelled with tritium in the
4-position of the pyran ring was given to groups of 4
Sprague-Dawley rats (2 males, 2 females) by oral intubation at a
dose of 5 mg/kg bw/day for 2, 4, or 5 days, 60-80% of the
administered dose was recovered in the faeces, with only 2-3% in
the urine. Most of the radioactivity found in the animals was
detected in liver, kidney and muscle, but it was found to be
present as tritiated water. In faeces, only 1% of the radioactivity
was tritiated water, but 1-43% of radioactivity in urine was
recovered as tritiated water. This exploratory study demonstrated
that the label was not stable (Hamlow & Jaglan, 1988).
A group of 4 Sprague-Dawley rats (2 males, 2 females) was
given 3 oral doses of 5 mg/kg bw/day spectinomycin labelled with
tritium at the 6'-methyl of the pyran ring. Absorption appeared to
be poor, with around 10-84% of the administered dose being found in
faeces and 4-7% in urine. Low levels of radioactivity were detected
in kidney, liver, muscle, and fat (Jaglan et al., 1991a).
As part of the study that was summarized in the previous
paragraph, 5 groups of Sprague-Dawley rats (1 male, 1 female per
group) were given i.m. injections of 5 mg/kg bw/day radiolabelled
spectinomycin for 1-5 days. The majority of the dose was excreted
in the urine (54-73%), with the remainder (1-24%) in the faeces
(Jaglan et al., 1991a).
A group of 4 Sprague-Dawley rats was given approximately 5
mg/kg bw/day spectinomycin sulfate as the 3H-6-methyl derivative,
orally or i.m. for 3 days. After oral administration, the majority
of the dose (10-84%) was recovered in faeces, with approximately 5%
in urine. After i.m. administration, approximately 66% of the dose
was recovered from urine, with 10-21% in faeces. Very low levels
were found in tissues (Roof & Jaglan, 1993).
2.1.1.2 Dogs
Spectinomycin hydrochloride was administered orally (single
dose) by gavage to 3 dogs at 100 and 500 mg/kg bw. Antimicrobial
activity was assayed in serum over the following 24 hours using
Rhodopseudomonas sphaeroides. Mean peak serum concentrations of
22 µg/ml and 80 µg/ml with 100 and 500 mg/kg bw doses,
respectively, were noted approximately 4 hours after
administration. The plasma half-life after the 100 mg/kg bw dose
was approximately 3 hours (Stern et al., 1984a).
A group of 3 dogs were given single i.m. injections (40 mg/kg
bw) of 6'-n-propylspectinomycin, a drug closely related
structurally to spectinomycin. The drug was rapidly absorbed with
a mean peak serum concentration of 136 µg/ml 15 minutes after
injection and a plasma half-life of approximately 0.7 hours (Stern
et al., 1984b).
2.1.1.3 Sheep
A single dose (2 mg/kg bw/day) of spectinomycin hydrochloride
was administered i.v. or i.m. to groups of 3 Awassi ewes. The drug
was assayed in milk and serum using Escherichia coli.
Antimicrobial activity in serum and milk declined rapidly after
i.v. administration and was undetectable after 6 hours. The
elimination half-life was approximately 1 hour. After i.m.
administration, the elimination half-life was around 3 hours, and
serum levels were undetectable after 8 hours (Ziv & Sulman, 1973).
2.1.1.4 Pigs
A pig (mixed breed) was given a single oral dose of
3H-6-methyl spectinomycin (44 mg/kg bw), and then maintained in
a metabolism cage for 24 hours. Most of the dose (79%) was
recovered from the gastrointestinal tract, with approximately 3% in
the urine. Less than 1.5% of these recoveries were tritiated water.
Only low levels of radioactivity, equivalent to 0.2% of the dose or
less, were detected in other tissues, but around 3% of the dose was
found in muscle. However, 30-100% of tissue radioactivity was
tritiated water (Jaglan et al., 1991b; Roof & Jaglan, 1993).
When pigs consumed feed containing lincomycin/spectinomycin
(44 ppm of each, equivalent to 1.6 mg/kg bw/day) or spectinomycin
alone (1.6 mg/kg bw/day) for 8 days, lincomycin concentrations
averaged around 40 ng/ml 3 and 6 hours after cessation of
treatment, with none detectable at 12 hours, whereas spectinomycin
was not detected in pigs given either lincomycin and spectinomycin
together or spectinomycin alone (limit of detection of 100 ng
spectinomycin/ml) (Hovius et al., 1989).
When pigs were given single i.v. injections of 20 or 40 mg/kg
bw, or single i.m. injections of 40 mg/kg bw spectinomycin, the
majority of the dose was excreted in urine in 12 hours. Similarly,
when pigs were given single i.v. injections of 40 mg/kg bw
spectinomycin, the majority of the dose was excreted in the urine
in 12-15 hours. In these studies around 70-80% of the dose was
recovered in the urine samples and total recovery was over 90%
(Seymour, 1964, 1965).
Rapid declines in plasma spectinomycin concentrations to below
the limit of detection (within 14 hours) occurred in pigs given
single i.m. injections of the drug (Barbiers et al., 1968).
2.1.1.5 Cattle
A group of 4 Friesan dairy cows was given single i.v. or i.m.
injections of 20 mg/kg bw spectinomycin and antimicrobial activity
was assayed in milk and serum. Activity declined rapidly after i.v.
administration and was undetectable after 6 hours. The elimination
half-life was approximately 1 hour. After i.m. administration, the
elimination half-life was 3 hours and serum levels were
undetectable after 8 hours (Ziv & Sulman, 1973).
In a preliminary study where cattle (2) were given single i.m.
injections of 0.15 mg/kg bw 3H-6-methyl spectinomycin, most of
the administered dose (55%) was found in urine before one animal
was killed after 24 hours. From 2 to 5% of the radioactivity in
urine and faeces was tritiated water. Only low levels (less than 1%
of the dose) were found in liver, lung, kidney and muscle. The
other animal was killed 72 hours after administration and most of
the radioactivity was found in the urine (45%) and faeces (38%)
during the first 24 hours after injection. Again, very low levels
were found in liver, lung, kidney, and muscle (Roof & Jaglan,
1993).
In a further study, cattle (2, 150 kg) were given single i.m.
injections of 0.15 mg/kg bw 3H-6-methyl spectinomycin sulfate. One
animal was killed 24 hours after dosing and the other at 72 hours.
The majority of the dose was detected in the first 24 hours in
urine (56%) and faeces (20%) in the animal killed at 24 hours.
Similar values were found for the animal killed at 72 hours (47%
and 43% in the first 24 hours in urine and faeces, respectively).
Approximately 3-4% of the radioactivity in these urine and faecal
samples was tritiated water. Very low levels of radioactivity (less
than 1%) were found in liver, lung, kidney, and muscle (Roof et
al., 1993).
A group of 6 Friesan calves was given single i.v. injections
of 20 mg/kg bw spectinomycin and a group of 12 Friesan calves was
given the same dose as single i.m. injections. After i.v.
injection, blood levels rose rapidly and declined rapidly; the
plasma elimination half-life was of the order of 1-2.5 hours.
Following i.m. injection, the blood levels also rose rapidly
(tmax = 0.1-0.8 hours). The plasma elimination half-life was of
the order of 1-2 hours (Bligny, 1988).
A group of 3 steers was treated daily for 4 consecutive days
with 20 mg/kg bw/day spectinomycin i.m.; a fourth animal served as
a control (animals were Angus/Hereford cross, Hereford or
Limousin). The animals were slaughtered 6 hours or 3 or 7 days
after the final dose. The majority of the dose was excreted in the
urine within 24 hours; 78% of the dose had been collected by 7
days. At the 6-hour slaughter time, liver, kidney, muscle, and fat
had the highest levels of drug (around 1-1.5% of the administered
dose); at day 3 levels in these tissues had declined significantly
(0.3-0.6% of the dose). A further decline had occurred by day 7
(0.1-0.3% of the dose) (Wilkes, 1990).
2.1.1.6 Humans
In humans, absorption after oral administration of
spectinomycin is poor, but it is rapidly absorbed after i.m.
injection. Peak serum concentrations occur approximately 1 hour
after injection of 2 g spectinomycin (approximately 30 mg/kg bw)
and 2 hours after injection of 4 g spectinomycin (approximately 60
mg/kg bw). The mean plasma elimination half-life was approximately
2 hours. In humans, the volume of distribution was 10-13 kg and
there was no significant binding to plasma. Around 75% of the i.m.
dose was excreted in the urine. Patients with renal impairment
excreted the drug more slowly than otherwise normal subjects; the
half-life ranged from 4.7 to 29 hours after a 2 g (approximately 30
mg/kg bw) i.v. dose. Spectinomycin penetrated genital tract tissues
but it did not appear to reach cerebrospinal fluid (Delgado et
al., 1980; Elder et al., 1976; Ksiezyk & Danek, 1973; Kusumi
et al., 1981; Wagner et al., 1967; Holloway, 1982).
2.1.2 Biotransformation
2.1.2.1 Animals
No information available.
2.1.2.2 Humans
Spectinomycin appears not to be metabolized; 70-100% of the
administered dose (route not specified but probably i.m.) was
excreted unchanged in urine within 48 hours (Dollery, 1991).
2.1.3 Effects on enzymes and other biochemicals parameters
No information available.
2.2 Toxicological studies
2.2.1 Acute toxicity studies
The results of acute toxicity studies with spectinomycin are
shown in Table 1.
Spectinomycin sulfate and hydrochloride salts were of low
toxicity in the mouse and rat with i.p. LD50 values often in
excess of 3000 mg/kg bw. The substance was of low oral toxicity in
the rat. Where death did occur, it was preceded by depression and
mild convulsions.
Spectinomycin sulfate was of low toxicity to newborn rats when
given; the LD50 value was in excess of 5000 mg/kg bw although
2/10 animals given this dose died (Gray & Purmalis, 1961a). No
toxic effects were seen in dogs given 200 - 270 mg/kg bw rally
(Gray & Purmalis, 1962a,b). Low acute toxicity has also been
observed in poultry given spectinomycin orally, either alone or in
combination with lincomycin (Glenn et al., 1969a-c; Glenn et
al., 1970b).
2.2.2 Short-term toxicity studies
2.2.2.1 Rats
Groups of 10 male and 10 female rats were given oral doses of
0, 200, 500, 1000, 2000, or 3000 mg/kg bw/day spectinomycin in
water by gavage for 28 days. There were no effects on body weights,
behaviour, food consumption or mortality during the study and, at
necropsy, there were no drug-related gross or histopathological
findings. Organ weights and clinical chemistry parameters were
unaffected by drug administration (Wedig, 1990).
A 1:1 solution of spectinomycin and lincomycin in aqueous
methylcellulose was given by oral intubation to groups of 20
TUC-SPD rats (10 male, 10 female) at doses of 0, 100, 300, or 1000
mg/kg bw/day for 90 days. Food consumption and body-weight gain
were similar in treated and control groups and the only observation
made was that faeces from treated groups appeared darker than those
from controls. Haematological parameters were similar in treated
and untreated animals.
Changes were seen in clinical chemistry parameters, notably
elevations in serum glucose, uric acid and protein. However, there
was no clear dose-response. Moreover, glucose levels in control
animals were slightly higher than in historical controls. Changes
occurred in serum aspartate aminotransferase levels, but these
could not be related to administration of the drugs and occurred
Table 1. Acute toxicity of spectinomycin
Species Sex Route LD50 References
(mg/kg bw)
Mouse - oral > 20 000 Hwang et al., 1961
Mouse F oral 10 000 Hwang et al., 1961
Mouse - ip > 3800 Raab, 1975
Mouse - ip* 3577 Highstrete, 1964
Mouse - ip* 3867 Jones, 1959
Mouse - ip 5724 Gray & Weaver, 1966a
Mouse - ip 4472 Gray & Weaver, 1967a
Mouse - ip 4472 Gray & Weaver, 1967b
Mouse - iv 1022 Highstrete, 1964
Mouse - iv > 2000 Anonymous, 1992
Mouse F iv 2500 Hwang et al., 1961
Mouse M iv 2850 Hwang et al., 1961
Rat - oral* > 5000 Jones, 1959
Rat - sc* > 5000 Gray & Purmalis, 1961b
Rat - ip > 5000 Gray & Weaver, 1966b
Rabbit - ic** 5 Hwang et al., 1961
Cat - iv 400 Hwang et al., 1961
Dog - oral 1000 Hwang et al., 1961
Dog - iv 800 Hwang et al., 1961
Monkey - oral > 500 Hwang et al., 1961
* Sulfate; others are hydrochloride salt.
** Intracisternal in anaesthetized rabbits.
only in males given 1000 mg/kg bw/day and in females given 300
mg/kg bw/day spectinomycin. LDH was decreased at 300 mg/kg bw/day
but not at 1000 mg/kg bw/day in males. Histopathological
examination revealed no compound-related lesions. The NOEL in this
study was 100 mg/kg bw/day spectinomycin: lincomycin, equivalent to
50 mg/kg bw/day spectinomycin (Glenn & Burr, 1970a).
Groups of 10 (5 male, 5 female) Sprague-Dawley rats were given
daily s.c. injections of spectinomycin (salt not specified) in
isotonic saline at 0, 30, 100, or 300 mg/kg bw/day, for 28 days. No
clinical signs were observed although males in the highest dose
group gained less weight than controls. There were no
haematological effects and organ weights were comparable to
controls. Slight inflammatory reactions were seen at the injection
sites. The NOEL in this study was 100 mg/kg bw/day based on the
body-weight reductions in males (Gray et al., 1960a).
Spectinomycin was given s.c. to groups of 10 male and 10
female TUC rats at doses of 0, 300, or 1000 mg/kg bw/day for 3
months. The major change noted in this study was a lowering of
haemoglobin in males (19%) and females (24%) given the highest
dose, with lower packed cell volumes in both sexes. There were no
gross or histopathological findings that could be related to drug
administration. The NOEL was 300 mg/kg bw/day (Ray & Ceru, 1969a).
2.2.2.2 Dogs
Two male dogs (unspecified breed) were given single oral doses
of 50 mg/kg/bw/day spectomycin for 5 weeks, followed by 500 mg/kg
bw/day for a further 4 weeks. No signs of toxicity occurred and
there were no gross or microscopic abnormalities seen at necrosy
(Hwang et al., 1961).
In a one-week oral range-finding study groups of 2 male and 2
female beagle dogs were given 0, 1000, or 3000 mg/kg bw/day
spectinomycin in gelatine capsules. No signs of toxicity were seen
during the study except for a dose-related increase in the
incidences of emesis and soft stools. At necropsy, the large
intestines of all spectinomycin-treated dogs contained a
green-yellow material. Dogs given the lowest dose had minimal
chronic colitis while those given the highest dose had minimal
catarrhal enteritis in the ileum with slight colitis in the colon
(Krohmer, 1990a).
Based on the results of the range-finding study summarized in
the previous paragraph, groups of 4 male and 4 female beagle dogs
were given daily oral doses of 0, 100, 250, 500, 750, or 1000 mg/kg
bw spectinomycin in gelatine capsules for 28 days. The only effect
seen during the study was an increase in soft faeces at the highest
dose. There were no effects on clinical biochemistry parameters
and, at necropsy, there were no gross or microscopic abnormalities.
The NOEL in this study was 750 mg/kg bw/day (Krohmer, 1990b).
A 1:1 mixture of spectinomycin and lincomycin as a powder in
gelatine capsules was administered to groups of 4 male and 4 female
beagle dogs at doses of 0, 100, 300, or 1000 mg/kg bw/day for 90
days. Intermittent diarrhoea occurred at 1000 mg/kg bw/day while
soft faeces were the only clinical signs seen. All other
observations, including food consumption, body weights, gross
pathology, histopathology, urinalysis and clinical chemistries were
comparable with control values. The NOEL was 100 mg/kg bw/day,
equivalent to 50 mg/kg bw/day spectinomycin (Glenn & Burr, 1970b).
Pairs of 2 beagle dogs were given spectinomycin hydrochloride
i.v. in aqueous solution for 5 or 8 days at doses of 30, 100, or
300 mg/kg bw/day, in half doses administered twice daily. No
adverse effects were noted on body weight, clinical chemistry,
haematology or urinalyses, but no controls were used in this study
therefore no firm conclusions could be drawn (Gray & Purmalis,
1960, 1966).
Three groups of beagle dogs (2 male, 2 female) were treated
with 0, 300, or 1000 mg/kg bw/day spectinomycin hydrochloride by
infusion at 4 ml/minute into the cephalic or saphenous veins, 6
days per week, for one month. Vomiting, salivation and thirst were
observed in the high-dose animals but not in controls or low-dose
dogs. This was thought to be due to the volume of infusate and its
hypertonic nature. No drug-related effects were observed in this
study (Sawa & Frielink, 1969).
Spectinomycin hydrochloride injected i.m. at doses of 3.2
g/day for 4 days or 6.4 g/day for 3 days had no effect on beagle
dogs, except for a slight inflammatory reaction at the injection
site (Gray & Weaver, 1966c).
Four groups of 6 beagle dogs (3 animals of each sex) were
given daily i.m. injections of 0, 50, 100 or 150 mg/kg bw/day for
14 days. Signs of transient pain at the injection site were noted
2-8 hours after administration, and inflammation occurred at the
injection site in the 100 and 150 mg/kg bw/day groups. Clinical
biochemistry, urinalyses and haematology parameters remained normal
while organ weights were comparable with controls (Gray & Purmalis,
1961a).
Similar findings were made in a study where dogs, presumably
beagles although this was not specified, were given daily i.m.
injections of 0, 300, or 800 mg/kg bw/day spectinomycin for 3
months. Blood biochemistry parameters were normal throughout the
study and the only clinical signs were limping and local
irritation, possibly due to the large volumes injected. No gross or
histopathological changes at necropsy were observed (Ray & Ceru,
1969b).
2.2.2.3 Pigs
Groups of 8 neonatal pigs (breed unspecified) were given daily
oral doses of 0, 8, 25, or 50 mg/kg bw spectinomycin for 9 days.
There was no evidence of toxicity and leucocyte counts and
haemoglobin determinations at 8, 11, 15, and 29 days after
treatment were normal (Welter & Johnson, 1963).
A group of 12 pigs was fed a diet containing 20 g/ton of 1:1
lincomycin/spectinomycin for 28-50 days. No information was
provided on dietary intake, nor on age of the pigs, and so it was
not possible to estimate intake. Two pigs were given control diets
only. No adverse effects other than soft faeces were noted, and
there were no gross or histopathological findings (Glenn & Burr,
1970c).
In a similar study, 11 pigs were fed diets containing 1:1
lincomycin/spectinomycin 1000 g/ton for 35 (6 pigs) or 85 (5 pigs)
days. Two further groups of pigs were fed the control diet only.
Soft faeces were noted in treated animals. There were no adverse
effects on behaviour, haematology, clinical chemistry, organ
weights, or gross pathology, and there were no histopathological
findings (Glenn et al., 1970a).
No adverse effects were noted when pigs were fed diets
containing 0, 40, or 400 g/ton 1:1 lincomycin/spectinomycin for 56
days (Glen et al., 1976).
In a further experiment, groups of 6-9 neonatal pigs were
given daily i.m. injections of 0, 5, 15, or 30 mg/kg bw
spectinomycin for 9 days. There were no signs of toxicity in
treated pigs, which showed better rates of weight gain than
untreated controls. There were no gross or microscopic
abnormalities seen at necropsy (Welter & Woods, 1963).
2.2.3 Long-term toxicity/carcinogenicity studies
The only available study was a 2-year oral toxicity study in
the rat (Abbott Laboratories, 1970). However, this study was
conducted by Industrial Bio-Test Laboratories, a testing
laboratory, which around the time the study was conducted, was
involved with the production of a number of toxicology studies that
have been found to be invalid. The manufacturer was unable to
obtain the individual animal data or slides from this study and
hence was unable to validate it (Maxey, 1990). Hence, the study
cannot be used to assess the carcinogenicity or long-term toxicity
of spectinomycin.
2.2.4 Reproduction studies
2.2.4.1 Rats
Groups of 10 male and 20 female Sprague-Dawley rats were
treated with 100 or 300 mg/kg bw/day spectinomycin hydrochloride,
s.c. from 40 days of age through breeding for males and 14 days
before breeding through gestation and lactation for females. A
group of 10 untreated males and 10 untreated females served as
controls. No treatment-related effects were seen on reproductive
performance in either sex. Litters from treated females were
slightly larger than controls, and pup weights were higher (Graham
et al., 1969).
In a 3-generation study, spectinomycin was given orally to
groups of 10 male and 20 female Sprague-Dawley rats at doses of 0,
100, 200, or 400 mg/kg bw/day by incorporation into the diet. The
parental animals of all generations were fed the diets for 10
weeks. The parents of the first two generations were then subjected
to two subsequent matings, and the parents of the third generation
to three subsequent matings. Body weight, food consumption,
parental survival, pregnancy rates, numbers of implantations,
offspring survival, sex ratios, necropsy, and histopathological
findings were all evaluated as part of the study.
Survival rates, body-weight gain, and food consumption were
comparable to controls in all generations. Reproductive performance
was unaffected by treatment at 100 and 200 mg/kg bw/day, but at the
high dose the pregnancy rate was significantly reduced. The sex
ratio of live pups at birth was also reduced (0.4-0.5) in the
second and third generations at the high dose when compared with
controls (1.0).
There were no abnormalities on gross necropsy of litters in
the F1, F2, or F3 generations, but histopathological
examination revealed hepatocellular swelling and clumped basophilic
material in the cytoplasm of hepatocytes in some of the F1b
animals. The NOEL in this study was 100 mg/kg bw/day based upon
altered hepatic histology. No drug-related histopathological
alterations were observed in any of the F3b pups at 400 mg/kg
bw/day (Reno et al., 1976).
2.2.4.2 Pigs
Pairs of sows (numbers unspecified) were fed diets containing
0 or 100 g/ton spectinomycin equivalent to 4 mg/kg bw/day, for 2
weeks before breeding until 2 weeks after breeding, and for one
week before farrowing until the piglets were weaned when 2 weeks
old. The experiment was carried out for 4 farrowings. Conception
rates, average number of piglets per litter, and average number of
live piglets per litter were slightly higher in treated animals,
while the number of deaths at birth per litter was slightly lower.
Similarly, the average number of surviving piglets at weaning were
higher in treated pigs. No adverse effects were noted (Boston,
1966).
2.2.5 Special studies on embryotoxicity/teratogenicity
2.2.5.1 Mice
Spectinomycin dihydrochloride in 0.9% benzyl alcohol was
administered i.p. to groups of 20 or 21 pregnant SCL-ICR mice on
days 7-12 of gestation at 0, 400, or 1600 mg/kg bw/day. No
treatment-related effects were observed in dams with respect to
body weights, implants per litter, fetal mortality, sex ratio,
average body weights of pups at term, external or visceral
abnormalities, or skeletal development (Inoue, 1974a).
Pregnant ICR mice were given spectinomycin i.p at 0, 400, or
1600 mg/kg bw/day from days 7 to 12 of gestation. On day 21 of
gestation the animals were killed and the uterine contents
examined. There were no effects on body weights in the dams and no
increases in fetal mortality occurred. The sex ratios in treated
and untreated mice were similar. The number of external and
internal abnormalities was similar in fetuses from treated and
untreated mice (Katsuya et al., 1974).
2.2.5.2 Rats
Spectinomycin dihydrochloride in 0.25% methylcellulose was
administered by gastric intubation at doses of 0, 100, or 300 mg/kg
bw/day to groups of 10 pregnant TUC/SPD rats from days 6-15 of
gestation. No major effects were noted in dams in this study and
the incidence of visceral or skeletal anomalies in fetuses was
unremarkable (Carlson et al., 1969a).
Groups of 6 pregnant Sprague-Dawley rats were given 0, 100,
300, 1000, or 3000 mg/kg bw/day spectinomycin in water by gavage on
days 6 to 15 of gestation. Animals were killed on day 20 of
gestation and the uterine contents examined. Maternal body weights
were normal during the study. There were no adverse effects on
litter sizes, the numbers of corpora lutea, live fetuses,
resorptions, dead fetuses, or non-implantations. There were no
increases in the incidences of skeletal or visceral abnormalities
attributable to spectinomycin (Krohmer, 1990c).
Spectinomycin dihydrochloride in 0.9% benzyl alcohol was
administered i.p. to groups of 16-18 JCL-SD rats on days 9-14 of
gestation at doses of 0, 400, or 1600 mg/kg bw/day. There were no
treatment-related effects on body weights of dams, average numbers
of implants per litter, fetal mortality, sex ratio, average body
weight of live pups at term, or on external or internal anomalies.
The average incidence of ossified coccygeal vertebra centrum was
significantly reduced in pups from dams given 400 mg/kg bw/day
spectinomycin, but this was not seen in the high-dose group.
Postnatal development of pups was normal (Inoue, 1974b).
Groups of 10 pregnant TUC/SPD rats were given daily s.c.
injections of 0, 100, or 300 mg/kg bw spectinomycin in 0.9% benzyl
alcohol. There was no evidence of teratogenicity in this study, but
one litter in the 300 mg/kg bw/day group was undersized and two
pups in this litter had no centres of ossification in the hind and
forepaws, no supraoccipital bones and no pubic bones. The NOEL in
this study was 100 mg/kg bw/day (Bollert & Highstrete, 1969).
In a similar study, groups of 20 pregnant SPF CD rats were
given daily s.c. injections of 0, 150, or 300 mg/kg bw
spectinomycin or 0.9% saline on days 6-15 of gestation. There were
no effects on the dams nor on litter parameters or embryonic or
fetal development (Feenstra, 1973a).
Spectinomycin dihydrochloride was administered as single s.c.
injections at doses of 0, 300, 900, or 2500 mg/kg bw to groups of
5 pregnant SPF Sprague Dawley rats on one of the days 6-15 of
gestation. No treatment-related effects were seen in dams, the
numbers of resorption sites, litter size, or pup weights. There
were no effects on the incidences of skeletal or visceral anomalies
(Bollert et al., 1971).
2.2.5.3 Rabbits
In a preliminary study, groups of 6 New Zealand white rabbits
were given 400 or 600 mg/kg bw/day spectinomycin for 6 days by s.c.
injection. High toxicity occurred in both groups with anorexia,
weight loss and one death in the high-dose group, probably due to
the effects of the drug on the gastrointestinal flora following
biliary excretion (Feenstra 1973b).
Groups of 13 pregnant New Zealand white rabbits were given
daily s.c. doses of 0, 150, or 300 mg/kg bw spectinomycin or 0.9%
saline on days 8-18 of gestation. Pregnancy rates and
pre-implantation losses were similar to controls. Litter sizes and
weights were reduced in both treated groups but embryonic and fetal
development were unaffected. The effects seen were most probably
due to the effects of spectinomycin on the maternal
gastrointestinal tract (Feenstra, 1973b).
Aqueous spectinomycin dihydrochloride was administered by i.m.
injection at doses of 0, 100, or 300 mg/kg bw/day on days 6-18 of
gestation to groups of 17-18 inseminated Dutch belt rabbits. Only
12/17 controls, 8/18 low dose, and 7/18 high-dose rabbits were
pregnant. Maternal body weights were reduced in a dose-dependent
manner in treated animals. One low-dose dam and 2 high-dose dams
died, but the cause of death was unclear.
Several animals were recorded as being pregnant, but no pups
(dead or alive) and no resorption sites were recorded. Dorsiflexion
of the digits of the foot was noted in 3/9 pups from 2 litters in
the high dose group; the significance of this was unclear. No other
compound-related effects, including visceral or skeletal anomalies,
were reported. The NOEL in this study was probably 100 mg/kg bw/day
but the study was inadequate because of the low number of pregnant
animals and poor reporting (Carlson et al., 1969b).
To investigate the teratogenic potential of spectinomycin
further, a second study was undertaken. Groups of 20 inseminated
Dutch belt rabbits were given daily i.m. injections of 0 or 100
mg/kg bw spectinomycin dihydrochloride on days 6-18 of gestation.
There were no effects on treated dams, nor on pregnancy rates, pups
per litter, average pup weight, resorption sites, or total implants
per dam. Several anomalies (e.g., absence of left kidney and
ureter, exencephaly, submandibular edema, rib defects, and
incomplete skull ossification) were noted but they were considered
by the authors to be spontaneous or were present at a similar rate
in controls. However, no data were provided for the incidence of
abnormalities in historical controls in this strain of rabbit, and
no data were provided on clinical observations, maternal body
weights or food intake. Therefore, even though the apparent NOEL
was 100 mg/kg bw/day it was not possible to draw any conclusions on
the teratogenicity of spectinomycin in the rabbit from this study
(Bollert et al., 1970).
2.2.5.4 Pigs
Groups of 8 domestic white pregnant sows were treated daily
with spectinomycin in 0.9% aqueous benzyl alcohol by i.m. injection
at doses of 0, 75, or 150 mg/kg bw/day on days 12 to 42 of
gestation. Animals were slaughtered on day 100 of pregnancy. One
low-dose and 2 high-dose animals had localized reactions at the
injection sites and all groups experienced a transient reduction in
mean body-weight for the first 7 days of the study. The effect was
slightly more marked in treated pigs. During the second week group
mean body weights recovered to initial values in all groups. There
were no effects on pregnancy rates, litter parameters, or embryonic
and fetal development (Feenstra, 1974).
2.2.6 Special studies on genotoxicity
The results of genotoxicity studies with spectinomycin are
shown in Table 2. Spectinomycin gave negative results in several
in vitro and in vivo studies covering a range of endpoints.
2.2.7 Special studies on irritation
I.M. injections of spectinomycin in benzyl alcohol and
carboxymethyl cellulose in the rabbit have been shown to result in
moderate local irritant effects characterized by haemorrhage and
necrosis at the injection site (Gray 1966; Gray et al., 1960b;
Johnston & Schwikert, 1961a,b; Weaver & Gray, 1975). Spectinomycin
hydrochloride produced only mild conjunctivitis when applied
directly to the rabbit eye without a vehicle (Coombs & Leong,
1982a) and was not irritating when applied to intact and abraded
rabbit skin using an occlusive dressing for 24 hours or for 5
consecutive days (Coombs & Leong, 1982b).
2.2.8 Special studies on ototoxicity
Spectinomycin was administered i.m. to groups of 3 cats at
doses of 0, 30, 60, or 120 mg/kg bw/day for 75-90 days.
Twice-weekly investigations of cochlear function revealed no
abnormalities and there was no evidence of diminished eighth nerve
function (Gray et al., 1960c,d).
2.2.9 Special studies on microbiological effects
One article cites MIC values for a range of bacterial species,
most of which were said to be of animal origin. These are shown in
Table 3.
Table 2. Results of genotoxicity assays on spectinomycin
Test system Test object Concentration Results Reference
Ames test1 S.typhimurium 250-2000 µg/plate Negative Mazurek &
TA98, 100, 1535, Swenson, 1981
1537, 1538
Ames test1 S.typhimurium 250-2000 Negative Mayo & Aaron,
TA97a, 98, 100, µg/plate 1990
102, 1535
Ames test1 S.typhimurium 100-5000 µg/plate Negative Lawlor, 1991
TA98, 100, 1535,
1537, 1538
Forward1 Chinese hamster 100-1000 µg/ml Negative Bichet, 1990
mutation assay V-79 fibrolasts
(HPRT assay)
Forward1 Mouse lymphoma 0.5-5.0 mg/ml Negative Cifone, 1991
mutation assay (L5178Y TK +/-)
Unscheduled Rat lymphocytes 100-3000 µg/ml Negative McKeon, 1991
DNA synthesis
In vitro Chinese hamster 1270-5060 µg/ml Negative Murli, 1991
cytogenetics ovary cells
In vitro 1 Human 9.8-5000 µg/ml Negative Brooker et al.,
cytogenetics lymphocytes 1990
In vitro 1 Chinese hamster 40-5000 µg/ml Negative Aaron, 1991a
cytogenetics
Unscheduled Rat hepatocytes 10-3000 µg/ml Negative Harbach &
DNA synthesis Filipunas, 1990
Micronucleus CD-1 mouse bone 0, 625, 1250, Negative Aaron, 1991b
test marrow 2500 mg/kg bw
Micronucleus Sprague-Dawley 0, 750, 1500, Negative Trzos et al.,
test rat bone marrow 3000 mg/kg bw 1981
1 With and without metabolic activation.
Table 3. Minimum inhibitory concentrations of spectinomycin
(Burrows, 1980)
Organism MIC (µg/ml)
Staphylococcus aureus 50
Streptococcus pyrogenes 100
Corynebacterium pyogenes 100
Escherichia coli 20
Klebsiella and Enterobacter 25
Proteus spp. 25+
Salmonella typhimurium 30
Pasteurella multicoda and 25
P. haemolytica
Pseudomonas aeruginosa 200+
Actinobacillus equuli 15
Brucella canis 0.5
Bordetella bronchisepticus 100
Bacteroides melaninogenicus 60
Bact. nodosus 60
Clostridium perfringens 100+
Mycoplasma hyosynoviae 3
M. bovigenitalium 5
In another study, the MIC values for a range of human
isolates were determined for several antibiotics, including
spectinomycin. These results are shown in Table 4.
Full details of the origins of the isolates for incubation
conditions, media, etc., were provided in the paper by Zurenko et
al., 1988. However, neither of the two papers summarized in
Tables 3 and 4 cover all the species usually considered most
relevant and representative of human gut flora. In particular,
there is a need for data on the effects of spectinomycin on Gram
positive strict anaerobes such as Bifidobacterium spp.,
Eubacterium spp., and Peptostreptococcus spp. Information on
another Gram positive facultative anaerobe such as Lactobacillus
spp., would be useful. However, there was sufficient information on
Gram negative strict anaerobes (e.g., bacteroides) and Gram
negative facultative anaerobes (e.g., E. coli and Proteus
spp.). From the information available, the lowest relevant MIC50
was 16 µg/ml in E. coli.
Table 4. MIC values for spectinomycin against a range of human
isolates (Zurenko et al., 1988).
Organism1 Range MIC(µg/ml)2
50% 90%
Staphylococcus aureus (23) 64->256 64 >256
Staphylococcus epidermidis (12) 32-64 64 64
Streptococcus faecalis (10) 64 64 64
Streptococcus pneumoniae (13) 16-32 16 32
Streptococcus spp. (10) 16-32 16 16
Acinetobacter spp. (10) 16->512 32 256
Citrobacter diversus (10) 16->512 16 16
Citrobacter freundii (10) 16->512 32 >512
Enterobacter spp. (20) 16-512 16 16
* Escherichia coli (11) 16->512 16 >512
Haemophilus influenza:
(ß-lactamase negative) (10) 8-32 16 16
(ß-lactamase positive) (10) 8-32 8 16
Klebsiella pneumoniae (10) 16-512 16 32
Morganella morgani (9) 16->512 32 -
* Proteus mirabilis (10) 16-512 32 256
* Proteus rettgari (10) 16->512 64 >512
* Proteus vulgaris (10) 16-512 32 256
Providencia stuartii (10) 512->1024 >1024 >1024
Pseudomonas aeruginosa (11) 8-1024 128 >1024
Pseudomonas spp. (9) 8->1024 128 -
Salmonella spp. (10) 32-128 64 64
Table 4. (cont'd) MIC values for spectinomycin against a range of human
isolates (Zurenko et al., 1988).
Organism1 Range MIC(µg/ml)2
50% 90%
Serratia marcescens (10) 32-128 32 128
Shigella spp. (10) 64->512 64 64
* Bacterioides fragilis (11) 16-128 128 128
* Bacterioides spp. (8) 8>-128 32 -
1 Numbers in parentheses are numbers of isolates.
2 MICs for 50% and 90% of isolates tested.
In a study specifically designed to determine the effects of
spectinomycin on the human gut flora, bacterial strains were
obtained from the faeces of healthy human volunteers at Toulouse
hospital, France. The following bacteria were isolated:
Escherichia coli, Bifidobacterium spp. and Bacteroides
fragilis. MIC values were determined using serial dilutions of
spectinomycin and an 18-hour incubation period.
The following concentrations were without effect:
E. coli - 4 µg/ml
Bifidobacterium - 32 µg/ml
Bacteroides fragilis - 16 µg/ml
The MIC50 for E. coli was determined to be 7 µg/ml, while
the MIC90 was 19 µg/ml. The MICs for the other two bacteria were
in excess of 32 µg/ml (Richez, 1992).
Several studies have investigated the antibacterial effects of
spectinomycin and have reported MIC values. One such study examined
the activity of the drug against a number of anaerobes in different
agar media. The following ranges of MIC values were obtained:
Bacteroides fragilis - 25-138 µg/ml
B. melanogenicus - 8-13 µg/ml
Clostridium perfringens 64 ->128 µg/ml
C. ramosum - 16-64 µg/ml
All the bacteria were human clinical isolates (Rosenblatt &
Gerdts, 1977).
In a study of bacteriological susceptibility to spectinomycin,
MICs were in the range of 8-38 µg/ml with Bacteroides fragilis
(Phillips & Warren, 1975).
In vitro studies of spectinomycin against a range of
bacteria in different media produced a range of MIC values (Mason
et al. ; date unspecified):
Staphyloccoccus aureus - 16.5-83 µg/ml
Diplococcus pneumoniae - 4.1-21 µg/ml
Streptococcus faecalis - 6-165 µg/ml
Clostridium perfringens - 66-165 µg/ml
Proteus vulgaris - 8.3-83 µg/ml
Salmonella spp. - 4.1-83 µg/ml
Shigella dysentariae - 8.3-83 µg/ml
S. flexneri - 8.3-41 µg/ml
Klebsiella pneumoniae - 4.1-21 µg/ml
In a study to investigate the in vitro activity of
spectinomycin against a number of aerobic and anerobic organisms,
MIC50 and MIC90 values were determined. The results are shown
below (Montiel et al., 1990):
Organism MIC50 MIC90
µg/ml µg/ml
Bacteroides fragilis 320 >320
B. distasonis 320 >320
B. vulgatus 160 >320
B. melaninogenicus 80 >320
Peptococcus spp. 80 >320
Peptostreptococcus spp. 80 >320
Clostridium perfringens 320 >320
Clostridium spp. 160 160
Fusobacterium spp. 160 320
A study was specifically designed to examine the effects on
anerobic organisms commonly found in the human gut. MIC values
against Bifidobacterium and Eubacterium strains were
determined. The MICs against Eubacterium ranged from 4-256 µg/ml
and for Bifidobacterium from 2-64 µg/ml. Within experiments
several strains showed 2- to 8-fold increases in MIC values when
the inoculum densities were higher, but these were within the
variations expected (Thurn et al., 1993).
An extensive in vitro study investigated the effects of
spectinomycin on representative organisms of the human gut flora.
These included several species of Bifidobacterium, Eubacterium,
Bacteroides, Peptococcus, and Fusobacterium. The effects of
pH, inoculum density and serial passage were also investigated.
Many had MIC50 values of greater than 50 µg/ml but Bifidobacteria
were more sensitive with MIC values in the range 2-32 µg/ml. The
modal MIC for Bifidobacteria was 16 µg/ml with an inoculum density
of 106 and 8 µg/ml with an inoculum density of 104 (Kotarski, 1993).
2.3 Observations in humans
Urticaria, dizziness, nausea, chills and fever have been
reported after single doses of spectinomycin in clinical trials.
Anaphylactic reactions have been rarely reported (Dollery, 1991;
Reynolds, 1993).
Spectinomycin produced no signs of ototoxicity in 15 healthy
male volunteers given 8 g/day (130 mg/kg bw/day) i.m. for 21 days
as evidenced by tests of cochlear and vestibular function. The only
untoward effect noted was pain at the injection site (Novak et
al., 1974).
3. COMMENTS
A range of studies on spectinomycin was submitted for
assessment including data on pharmacokinetics and metabolism, as
well as information from acute, short-term, reproductive,
developmental and genotoxicity studies.
Toxicokinetic studies suggested poor absorption after oral
dosing in rats, dogs, pigs and cattle, with most of the orally
administered dose found in the faeces. Absorption was also poor in
humans following oral administration. There were no data available
on biotransformation in animals, but limited information in humans
suggested that the drug is not extensively metabolized.
Single oral doses of spectinomycin were of low toxicity to
mice and rats (LD50 = 3000 - 20 000 mg/kg bw) although the drug
appeared to be more toxic to dogs (LD50 = 1000 mg/kg bw) and
monkeys (LD50 = 500 mg/kg bw).
No major toxicological effects were noted following repeated
oral or parenteral administration to rats or dogs. The most common
findings were changes in the consistency of the faeces in treated
animals, and the NOELs for these findings varied from 50 to 750 mg/
kg bw/day.
Adequate carcinogenicity studies were not available. However,
both in vitro and in vivo genotoxicity studies covering a
variety of end-points were negative and spectinomycin does not
share structural similarities with known carcinogens. Therefore,
the Committee was of the opinion that the drug did not present a
carcinogenic risk and carcinogenicity studies were not deemed
necessary.
A multi-generation reproduction study in rats in which
spectinomycin was administered orally showed no adverse effects on
reproductive parameters up to the highest dose tested, 400 mg/kg
bw/day. Hepatocellular swelling and clumped basophilic material in
the cytoplasm of hepatocytes were noted. This occurred only in some
animals of the F1b generation. The NOEL was 100 mg/kg bw/day.
Developmental toxicity was examined in mice, rats and rabbits.
Spectinomycin was not teratogenic in rats after oral doses of up to
3000 mg/kg bw/day. There was no evidence of teratogenic effects
after i.p. or s.c. administration in this species. It was not
teratogenic in mice after i.p. doses of up to 1600 mg/kg bw/day.
The study in rabbits revealed no teratogenic effects after s.c. or
i.m. doses of up to 300 mg/kg bw/day.
There was no evidence of ototoxicity in cats after i.m. doses
of up to 120 mg/kg bw/day for periods of 75 to 90 days, nor in
humans (males) after an i.m. dose of 130 mg/kg bw/day for 21 days.
The Committee concluded that there were no major toxicological
effects associated with spectinomycin in humans or animals.
The potential for adverse effects on the human GI tract flora
was considered. In vitro MIC data covering a wide range of animal
and human pathogens and commensals was submitted for assessment.
The Committee examined MIC data for a number of bacterial
species representative of the anaerobic microbial flora in the
human gastrointestinal tract including Bacteroides,
Peptostreptococcus, Fusobacterium, Eubacterium and Clostridium
spp. Many had MIC50 values greater than 50 µg/ml.
Bifidobacterium spp. were more sensitive, with MIC values for
spectinomycin in the range of 2-32 µg/ml. The modal MIC for
Bifidobacterium spp.was 16 µg/ml with an inoculum density of
106 cells and 8 µg/ml with an inoculum density of 104 cells.
The Committee used the value of 16µg/ml in its calculations.
In calculating the ADI, the formula developed at the
thirty-eighth meeting of the Committee (Annex 1, reference 97) was
used:
Concentration without
effect on human gut x Daily faecal bolus (g)
Upper limit of flora (µg/ml)
temporary ADI = ____________________________________________
(µg per kg of Fraction of
body weight oral dose x Safety factor x Weight of human (60
kg) bioavailable
= 16 x 150
__________
1 x 1 x 60
= 40 µg/kg bw
1. The Committee concluded that sufficient experimental data had
been provided and that no specific factors to account for the
range of MICs to cover sensitive bacteria, the anaerobic
environment, bacterial density, or pH were required to adjust
the modal MIC of 16 to a "microbiological no effect level".
2. The Committee noted that absorption of spectinomycin from the
gastrointestinal tract was poor. It therefore adopted a
conservative factor which assumed 100% availability of
ingested spectinomycin to organisms in the gastrointestinal
tract.
3. A substantial amount of MIC data covering a variety of
organisms were available. In addition, recently published data
suggested that variability among populations was low. A safety
factor of 1 was therefore adopted by the Committee.
4. EVALUATION
Taking into account all of these factors, an ADI of 0-40 µg/kg
bw was established. In view of the extensive range of organisms
examined, and as data were provided on the effects of pH, inoculum
density and resistance to spectinomycin, and taking into account
the discussions on the microbiological safety of residues held
during the meeting (Annex 1, reference 110), the Committee
considered that in this instance, a full ADI was appropriate.
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See Also:
Toxicological Abbreviations
SPECTINOMYCIN (JECFA Evaluation)