INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
TOXICOLOGICAL EVALUATION OF CERTAIN
VETERINARY DRUG RESIDUES IN FOOD
WHO FOOD ADDITIVES SERIES 45
Prepared by the
Fifty-fourth meeting of the Joint FAO/WHO
Expert Committee on Food Additives (JECFA)
World Health Organization, Geneva, 2000
LINCOMYCIN
First draft prepared by
Kevin J. Greenlees
Center for Veterinary Medicine, Food and Drug Administration,
Rockville, Maryland, USA
Arturo Anadon
Department of Toxicology, Faculty of Veterinary Medicine, Universidad
Complutense de Madrid, Madrid, Spain
and
Carl Cerniglia
National Center for Toxicological Research, Food and Drug
Administration, Little Rock, Arkansas, USA
Explanation
Biological data
Biochemical aspects
Absorption, distribution, and excretion
Biotransformation
Toxicological studies
Acute toxicity
Short-term studies of toxicity
Long-term studies of toxicity and carcinogenicity
Genotoxicity
Reproductive toxicity
Multigeneration studies
Developmental toxicity
Special studies
Immune responses
Ototoxicity
Microbiological effects
Observations in humans
Comments
Evaluation
References
1. EXPLANATION
Lincomycin, like pirlimycin and clindamycin, belongs to a class
of antibiotics known as lincosaminides. Lincomycin is active mainly
against Gram-positive bacteria. It exerts its antibiotic action by
inhibiting RNA-dependent protein synthesis through action on the 50S
subunit of the ribosome. Lincomycin is used alone or in combination
with other antimicrobial agents such as spectinomycin, neomycin,
sulfadiazine, and sulfadimidine. It can be given orally in feed or
drinking-water, by intramuscular injection, or as an intramammary
infusion.
The recommended doses are: 0.5 mg/kg bw in feed and 3-50 mg/kg bw
in drinking-water for poultry; 0.2-13 mg/kg bw in feed, 5-10 mg/kg in
drinking-water, and 5-10 mg/kg bw intramuscularly in pigs; 5 mg/kg bw
intramuscularly in calves and sheep; and 200-330 mg/quarter of the
udder as an intramammary infusion, three times after each milking, in
dairy cows.
The Committee has not previously evaluated lincomycin.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Absorption, distribution, and excretion
Dogs
A preliminary study, which did not comply with good laboratory
practice (GLP), conducted in a male and a female dog showed that
lincomycin is rapidly absorbed after intramuscular injection at 20
mg/kg bw (Sokolski, 1962). Peak serum concentrations were reached 30
min after injection of 9 mg of the base per ml. In two beagle dogs
given a single dose of 300 mg/kg bw by capsule, peak absorption
occurred within 1-2 h of dosing (Grady & Treick, 1961; Gray &
Purmalis, 1961a).
In a 90-day study, lincomycin was determined in lung, liver,
kidney, muscle, bile, spinal fluid, and serum of beagles dosed orally
at 0, 400, or 800 mg/kg bw per day. The highest concentrations were
observed in kidney and bile (66 and 680 mg/g, respectively) and the
lowest concentrations in spinal fluid (below the limit of detection)
from animals at the high dose. One control had a concentration of 39
mg/g in the lung and trace levels in the liver; it was speculated that
the animal had been inadvertently dosed just before sacrifice (Gray &
Purmalis, 1964a).
Humans
The pharmacokinetics of lincomycin in humans has been determined
after administration by several routes (Table 1). About 72% is bound
to proteins in human serum. Lincomycin is widely distributed, with a
volume of distribution approximating total body water, and it is
excreted in the faeces. Biliary excretion has also been reported to be
an important route of elimination. Significant concentrations of
lincomycin are achieved in a number of tissues and fluids regardless
of the route of administration. These include bile, peritoneal fluid,
pleural fluid, the eye, brain, bone, bone marrow, joint capsules,
synovial fluid, and cerebrospinal fluid. It is generally poorly
distributed into cerebrospinal fluid except in the presence of
inflammation. Therapeutic concentrations have been achieved in the
presence of meningitis (Fass, 1981).
Table 1. Pharmacokinetics of lincomycin in humans
Route Parameter Dose (mg) Reference
Intramuscular 600 1000 1500 Smith et al.
Peak serum concentration (µg/ml) 12 17 22 (1981)
AUCto 24 (mg/mlÊh) 82 120 150
AUCto infinity (mg/mlÊh) 92 130 160
Time of peak (h) 1.2 1.5 0.92
Elimination t1/2 (h) 4.5 5.3 5.3
Peak saliva concentration (mg/ml) 0.86 1.6 2.7
Time of peak (h) 3.7 4.7 3.9
AUCto 24 (mg/mlÊh) 5.3 10 18
Intravenous, 300 600 Fass (1981)
2 h Mean concentration (mg/ml) 7.7-12 16-21
Oral Adults 500 1000 Fass (1981)
Peak serum concentration (mg/ml)a 1.8-5.3 2.5-6.7
Elimination t1/2 (h) 4.2-5.5
Time of peak (h) 2-6, usually 4
Children 22-33 mg/kg bw
Peak serum concentration (mg/ml) 4-9 (maintained above
1.0 mg/ml for 15 h)
a Presence of food in the stomach markedly impairs absorption (Kucers & Bennett, 1979;
Fass, 1981). The oral bioavailability is estimated to be 25-50% after fasting but only 5%
with a meal (Hornish et al.,1987).
Lincomycin has been shown to cross the placenta, and peak
concentrations in amniotic fluid of 0.2-3.8 mg/ml are sustained for
52 h after a single intramuscular injection of 600 mg to pregnant
women. Lincomycin has been found to be present in milk post partum
(Fass, 1981).
In a report written to support the safety of the lincosaminide
pirlimycin, which also addressed the safety of lincosaminides in
general and of lincomycin in particular, it was noted that only a
fraction of an oral dose of lincosaminides reaches the lower intestine
(Kotarski, 1995). While orally administered clindamycin is nearly
completely absorbed after oral administration (Kapusnik-Uner et al.,
1996), lincomycin is poorly although rapidly absorbed from the
gastrointestinal tract (Goodman & Gilman, 1975). The human
bioavailability of orally administered lincomycin is estimated to be
25-50% for fasting individuals but only 5% after a meal (Hornish et
al., 1987). About 10% of orally administered clindamycin is excreted
unaltered in the urine, and a small fraction is found in the faeces
(Kapusnik-Uner et al., 1996).
2.1.2 Biotransformation
The comparative metabolism of lincomycin was reported in rats,
cows, pigs, and chickens. Lincomycin was extensively metabolized in
all tissues but not in cow's milk (after intramammary infusion only).
Some 16 metabolites were identified, although there were as many as 26
in pig liver. The principal residues were parent lincomycin,
N-desmethyl lincomycin, and lincomycin sulfoxide (Hornish et al.,
1987; Nappier, 1998).
Approximately 5% of an oral dose administered to rats was
excreted in urine, where lincomycin and lincomycin sulfone comprised
97% of the excreted drug; 95% of the drug was found in the
gastrointestinal tract (Hornish et al., 1987).
The principal urinary and faecal metabolite in dogs and humans
after oral and intramuscular administration was unchanged lincomycin,
representing 40% of the excreted dose; most of the remainder was
unidentified. There was no evidence of glucuronide or sulfate
conjugation (Hornish et al., 1987).
Pig excreta contained markedly less unchanged lincomycin than
that of other species studied. The urine contained 11-21% of an oral
dose, and half of this was unchanged parent. Only trace amounts of
N-desmethyllincomycin were identified. The contents of the
gastrointestinal tract accounted for 79-86 % of the excreted drug. In
faecal samples, only 17% of the excreted dose was unchanged parent,
and the remainder was uncharacterized metabolites (Hornish et al.,
1987)
2.2 Toxicological studies
2.2.1 Acute toxicity
Lincomycin was toxic in mice and rats when administered
parenterally and was practically nontoxic after oral administration.
Lincomycin was toxic to rabbits by all routes of administration.
Mice
The acute LD50 in male mice treated orally was determined for
USP grade and Premix grade lincomycin (Buller, 1979). No significant
difference between the LD50 values of 20 000 and 17 000 mg/kg bw was
determined in this non-GLP study. An LD50 value of 210 mg/kg bw was
measured in mice treated intravenously, and the signs of toxicity in
the survivors included severe sedation lasting 1-2 min (Gray &
Highstrete, 1963a).
Rats
The acute toxicity of lincomycin was determined in a preliminary
non-GLP study in newborn and adult rats treated by subcutaneous
injection (Gray & Purmalis, 1962a). The LD50 in newborn rats was 780
mg/kg bw, while that in adults was 10 000 mg/kg bw. An intravenous
injection was reported to be more toxic, with an LD50 of 340 mg/kg bw
(Gray & Highstrete, 1963a).
The acute toxicity of agricultural-grade lincomycin (Glenn &
Garza, 1971) and of USP-grade lincomycin (Brown, 1977a,b) was
determined in a series of non-GLP studies in Sprague-Dawley rats.
Lincomycin was administered orally to groups of five animals of each
sex at doses of 5000-16 000 mg/kg bw, and clinical signs and body
weights were monitored for 2 weeks after treatment. All doses resulted
in clinical signs of toxicity including diarrhoea and ataxia.
Depression was observed at doses > 8000 mg/kg bw, and death,
preceded by coma, was observed at doses of 12 500 and 16 000 mg/kg bw.
While there was no significant effect on body-weight gain, the
survivors continued to have diarrhoea for up to 36 h after treatment.
The LD50 was determined by probit analysis to be about 15 000 mg/kg
bw for USP lincomycin and 11 000 mg/kg bw for the agricultural-grade
product. In a separate study, an LD50 of 16 000 mg/kg bw was
determined for a premix grade preparation of lincomycin (Nielsen,
1975).
Rabbits
Rabbits have been shown to be quite sensitive to orally
administered lincomycin (Gray et al., 1965a). After a single
intravenous injection of 0.5 mg/kg bw, 5 out of 10 rabbits either died
or were killed for humane reasons within 2 weeks of dosing, and 7 out
of 10 rabbits had died by 1.5 months. In two studies that did not
comply with GLP, in which groups of three rabbits were given
lincomycin, only the lowest dose of 0.5 mg/kg bw was not lethal. All
the other doses (5, 50, 100, and 150 mg/kg bw) caused death, such that
by 4 weeks 9 out of 15 and 12 out of 15 rabbits had died. Histological
examination revealed gastrointestinal stasis and, in those animals
that died, haemorrhagic suffusion of the serosal surface of the
caecum. Attempts to modify the toxicity by supplementation with
Lactobacillus culture or intubation with fresh (rabbit) caecal
contents were not successful. The observed toxicity was considered to
result from gastrointestinal Gram-positive floral imbalance.
The irritability of lincomycin to tissues was investigated in
rabbits in a series of studies that did not comply with GLP. Doses of
up to 300 mg/kg bw were injected into the lumbar muscle at pH 4 (Gray
& Purmalis, 1962b) or pH 7.4 (Gray & Purmalis, 1962c). No difference
was seen in the minimal to mild muscular irritation after slaughter up
to 7 days after treatment. Injection of up to 150 mg of lincomycin
into the stifle joint of New Zealand white rabbits caused no
treatment-related effects, such as intra-articular irritation (Gray &
Highstrete, 1965).
Dogs
A series of studies that did not comply with GLP were conducted
in dogs. In one study of single intrathecal injections of lincomycin,
two dogs received 15 mg in 1 ml of solution, eight dogs received 50 mg
in 1 ml of solution, and 10 dogs received the vehicle (isotonic saline
and benzyl alcohol at 9 mg/ml). No treatment-related clinical effects
were reported. Cerebrospinal fluid samples taken up to 48 h after
injection were cloudy and had increased cell counts consisting
predominantly of lymphocytes. Gross and microscopic examination 24-72
h after injection did not reveal treatment-related effects, such as
meningeal irritation (Gray et al., 1965b).
When intravenous or intramuscular injections of 150 mg/kg bw per
day were given for 5 and 3 days, respectively (Gray & Purmalis,
1962d), no treatment-related effects were reported.
Lincomycin was injected subcutaneously for 14 days into four pups
from each of three litters within 24 h of birth at a dose of 0, 30,
60, or 90 mg/kg bw per day. No significant treatment-related effects
were reported (Gray et al., 1962).
In a preliminary study, lincomycin was administered at a dose of
4000 mg/kg bw orally by gavage for 5 days to two female beagles. While
both animals vomited for 1-2 h after gavage, no treatment-related
effects (such as diarrhoea) were reported. In the same study, a third
dog received an intravenous dose of 940 mg/kg bw in a volume of 230 ml
as two injections. Transient prostration and slightly increased
activities of alanine and aspartate aminotransaminases were seen,
suggesting some hepatic toxicity. The heart rate and respiration
remained normal, and no histopathological alterations were found in a
liver biopsy sample 5 days later. The dog appeared clinically normal
during the subsequent 2 weeks of observation, and no other
treatment-related effects were reported (Gray & Purmalis, 1963a).
2.2.2 Short-term studies of toxicity
Mice
Lincomycin of premix grade was administered for 90 days to groups
of 15 B6C3F1 mice of each sex at concentrations of 0, 70, 200, 700,
2000, or 20 000 mg/kg in the feed, equivalent to daily doses of 0, 10,
30, 100, 300, and 3000 mg/kg bw per day. While the study was completed
in 1979, before initiation of GLP requirements, a quality assurance
statement was provided which addressed deviations from GLP. The
highest dose resulted in a significant suppression of body weight,
increased food consumption and intestinal weight (with pancreas), a
decreased serum glucose concentration, and, in females, increased
serum corticosterone concentration, decreased serum globulin
concentration, and decreased mean thymus weight. While the mean organ
weights of animals at the highest dose were the lowest for heart,
liver, spleen, and kidney (males only), the differences were not
statistically significantly different from controls. Histologically,
the lumina of the large and small intestine were found to be distended
and dilated. The next highest dose of 300 mg/kg bw per day also
increased intestinal weight (with pancreas) and increased the
incidence of luminal distention and dilatation of the small and large
intestines. The serum glucose values were also depressed. The NOEL was
100 mg/kg bw per day (Platte & Seaman, 1981).
Rats
In a study that did not conform to GLP, groups of five Wistar
rats of each sex were given lincomycin at a dose of 0, 30, 100, or 300
mg/kg bw per day by oral gavage for 30 days. Effects on body weight,
food consumption, organ weights, haematological values, and
pathological findings were reported, but no significant
treatment-effects were found at any dose. The NOEL was 300 mg/kg bw
per day, the highest dose tested (Gray & Purmalis, 1961b).
In an extension of this study to 3.5 months, lincomycin was
administered orally by gavage at a dose of 0, 30, 100, or 300 mg/kg bw
per day to groups of 10 Upjohn Wistar rats of each sex. No
drug-related effects were observed on body-weight gain, food
consumption, or pathological findings. The NOEL was 300 mg/kg bw per
day, the highest dose tested (Gray & Purmalis, 1962e).
When the study was repeated in groups of 20 rats of each sex at a
dose of 600 or 1000 mg/kg bw per day for 3 months, the average weight
of the intestinal tracts of all treated animals was greater than that
of controls, but it was not clear whether this was due to the tissue
or the content, as no changes were observed in the intestinal wall or
mucosa on gross or microscopic examination. The NOEL was 1000 mg/kg bw
per day, the highest dose tested (Gray & Purmalis, 1964b).
Dogs
In a study that did not conform to GLP, groups of three beagles
received lincomycin by intramuscular injection at a dose of 0, 15, 30,
or 60 mg/kg bw per day administered twice daily for 4 weeks. Two of
the dogs -- one control and one at 60 mg/kg bw per day -- showed mild
lymphocytic infiltration of the thyroid. Since this effect occurred in
only two animals and equally in treated and control groups, it was not
ascribed to lincomycin. Aside from mild inflammatory reactions at the
injection site observed at necropsy in all groups, including controls,
no treatment-related effects were reported. The NOEL was 60 mg/kg bw
per day, the highest dose tested (Gray & Purmalis, 1962f).
In a further study that did not comply with GLP, lincomycin was
given to groups of three beagles by capsule three times a day for 30
days at a dose of 0, 30, 100, or 300 mg/kg bw per day. Daily
examinations for body weight, haematological and urinary analyses, and
gross and histopathological examination revealed no treatment-related
effects (Gray & Purmalis, 1962g).
In another study that did not comply with GLP, groups of four
beagles of each sex were given lincomycin at a dose of 0, 400, or 800
mg/kg bw per day in gelatin capsules administered three times a day
for 90 days. Transient increases in serum alanine aminotransferase
activity were observed during the first month of treatment at 800
mg/kg bw per day and in one animal at the low dose, but the level had
returned to normal by the end of the study. Bilateral lymphocytic
thyroiditis was observed in three controls, two animals at 400 mg/kg
bw per day and two at 800 mg/kg bw per day. This condition had also
been observed in other beagle colonies. Mild lymphocytic infiltration
was reported in other organs as well. These lesions did not appear to
be treatment-related. The NOEL was 800 mg/kg bw per day, the highest
dose tested (Gray & Purmalis, 1964a).
In a study that did not comply with GLP, lincomycin was
administered in capsules to groups of two beagles of each sex at a
dose of 0, 30, 100, or 300 mg/kg bw per day for 6 months. No
treatment-related effects were reported on body weight, organ weights,
or haematological, clinical chemical, or urinary end-points. The
summary and conclusions of the report state that further
histopathological analysis revealed lymphocytic thyroiditis in the
male and female at the high dose and similar infiltration of the
kidney in one of the animals (Gray et al., 1963b). Lesions of this
type were observed at all doses in a later, 90-day study (Gray &
Purmalis, 1964a). The European Medicines Evaluation Agency (1998)
identified a NOEL of 100 mg/kg bw per day in the study of Gray et al.
(1963b) on the basis of an increase in adrenal weight at the high
dose. However, while a paired t test showed a significant difference
in adrenal weights, the relative weights were not significantly
altered and no significant difference was found in an unpaired t
test. The NOEL was 300 mg/kg bw per day, the highest dose tested.
Lincomycin was administered orally as the premix grade at a dose
of 0, 0.38, 0.75, or 1.5 mg/kg bw per day or as the USP grade at 1.5
mg/kg bw per day in gelatin capsules for 1 year to groups of five
beagles of each sex in a study that did not conform to GLP. The doses
were chosen to support a proposed tolerance of lincomycin of 1 mg/kg
in the edible tissues of poultry, pork, beef, lamb, and dairy
products, and were based on multiples of 25, 50, and 100 times the
maximum theoretical human dietary intake. The measured end-points
included clinical and ophthalmic parameters, food consumption, body
weights, clinical pathological, chemical, and urinary parameters,
organ weights, and gross and histological appearance. No differences
were observed between animals receiving the premix and USP grades, and
no treatment-related effects were reported. The NOEL was 1.5 mg/kg bw
per day of each grade of lincomycin, the highest doses tested (Goyings
et al., 1979a).
2.2.3 Long-term studies of toxicity and carcinogenicity
Rats
Groups of 10 rats of each sex received lincomycin at a dose of 0,
30, 100, or 300 mg/kg bw per day by oral gavage for 1 year. The study
did not comply with GLP. All rats were necropsied, four of each sex
per group were examined histologically, and haematological parameters,
body-weight gain, organ weights, and pathological findings were
reported. No treatment-related effects were found. While there was a
significant difference ( p = 0.019, two-tailed t test) in the
weight of the liver between controls (19 ± 2.3 g) and rats at the high
dose (24 ± 4.9 g), the weights relative to body weight were not
significantly different. The NOEL was 300 mg/kg bw per day, the
highest dose tested (Gray et al., 1963a).
In a study that did comply with GLP, groups of pregnant
Sprague-Dawley rats and groups of 60 of the resulting offspring of
each sex received field-grade premix lincomycin orally at a dose of 0,
0.38, 0.75, or 1.5 mg/kg bw per day or USP-grade lincomycin at a dose
of 1.5 or 100 mg/kg bw per day. Treatment of the offspring was
continued for 26 months. Food consumption per cage (two rats per cage)
was monitored weekly; body weights were monitored weekly through week
56 and during alternate weeks thereafter. Serum chemistry was
evaluated at 6 and 12 months and at termination, and haematological
parameters were assessed before treatment, at 3, 6, and 12 months, and
at termination. Organ weights and urinary parameters were measured at
the interim kills and at termination. All rats that died or were
killed were examined grossly and histologically; a full
histopathological examination was performed on animals in the control
and the two high-dose groups.
The percentage survival, clinical and ophthalmological
end-points, food consumption, organ weights, and haematological, serum
chemical, and urinary parameters were unaffected by treatment. A
statistically significant effect on growth promotion was observed up
to day 574 of the study in animals given 0.75 mg/kg bw per day of
premix, but not thereafter. An increased incidence of non-neoplastic
microscopic lesions of the prostate and seminal vesicles (acute
prostatitis and seminal vesiculitis) was reported in males at 1.5
mg/kg bw per day of premix and at 100 mg/kg bw per day of USP grade.
The frequency of prostatis was 21/59 in controls, 1/35 in rats at 0.38
mg/kg bw per day, 5/45 in rats at 0.75 mg/kg bw per day, 40/60 in
those at 1.5 mg/kg bw per day of premix, 3/40 in rats at 1.5 mg/kg bw
per day of USP grade, and 31/59 in those at 100 mg/kg bw per day of
USP grade. At the 1-year interim slaughter, the frequency of prostatis
was 4/10 in controls, 2/10 in rats at 0.75 mg/kg bw per day of premix,
and 2/10 for those at 100 mg/kg bw per day of USP grade. A review of
the data for individual animals showed no dose-response relationship,
and there was no increase in the relative severity of the lesions. The
prostatis was therefore considered to be unrelated to treatment with
lincomycin.
The numbers of benign, malignant, and total tumours in each
treated group were not statistically significantly different from
those in the concurrent vehicle control group (Table 2). A
statistically significant increase in the number of males with
subcutaneous fibromas was observed at the high dose of USP-grade
material when compared with concurrent controls, but the total number
of fibromas was not significantly different. A statistically
significant increase in the incidence of lymphosarcoma was observed in
females at 1.5 (6/52) and 100 mg/kg bw per day (7/60) of USP grade
when compared with control females (1/59). A trend analysis of these
incidences did not, however, show a significant linear component, and
it was concluded that the lymphosarcomas were not related to
treatment. No increase in the incidence of lymphosarcomas was seen in
males. The incidence of mammary adenomas and cystadenomas in females
at 1.5 mg/kg bw per day of USP material (10/52) was greater than that
in concurrent control females (4/59, p = 0.083) but there was no
difference in the total number of benign mammary neoplasms. Similarly,
the incidence of mammary adenocarcinomas and carcinomas in females at
1.5 mg/kg bw per day of USP material (9/52) exceeded that in
concurrent female controls (3/59, p = 0.063). However, the 5.1%
incidence rate of mammary carcinomas in the concurrent control females
was well below the 12% incidence rate (23/196) reported for historical
female controls. While a large number of pituitary adenomas and
mammary fibroadenomas were observed, these lesions are common in
Upj:TUC(SD) rats and were not related to treatment.
Table 2. Numbers of benign, malignant, and total tumours in rats fed diets containing
lincomycin of two grades
Sex Tumour Vehicle Premix (mg/kg bw per day) USP (mg/kg bw per day)
0.38 0.75 1.5 1.5 100
Males Malignant 9 11 13 9 15 10
Benign 39 25 33 35 22 37
Total 43 29 38 38 33 40
Females Malignant 12 12 15 11 18 15
Benign 43 39 43 44 40 47
Total 47 44 47 49 49 51
Neither premix nor USP-grade lincomycin was carcinogenic under
the conditions of the assay, but the low maximum dose used and the
poor survival preclude a definitive conclusion. The NOEL for
non-neoplastic effects was 100 mg/kg bw per day, the highest dose
tested.
2.2.4 Genotoxicity
A battery of tests that complied with GLP were conducted to
address the genetic toxicity of lincomycin (Table 3). The only
positive result was obtained in an assay for unscheduled DNA synthesis
in rat primary hepatocytes (Harbarch & Aaron, 1987). While only an
abstract of this study was available, the positive result was
duplicated in another assay at the relatively low dose of 0.17 µg/ml.
In these assays, scoring could not be done at doses > 0.17 µg/ml
because of the cytotoxicity of lincomycin. In addition, while the full
report with raw data is available, it was not made available to the
Committee. The positive results were addressed in a subsequent report
to the US Food and Drug Administration (Aaron, 1988b), which refers to
a similar assay in which negative or equivocal results were obtained
(Seaman, 1982) after use of an improved procedure for microscope slide
preparation. The report also noted that negative results were obtained
in a study that did not conform to GLP in which the same lot of
lincomycin was used as that in the assay with positive results. In the
second assay, the toxicity of lincomycin was much lower (> 300
µg/ml), allowing scoring at doses as high as 1000 µg/ml. The lower
toxicity is consistent with that in other assays with negative results
(Seaman, 1982; Aaron, 1988a). The weight of the evidence suggests that
lincomycin is not genotoxic.
2.2.5 Reproductive toxicity
(a) Multigeneration studies
In a three-generation study of reproductive toxicity that did not
comply with GLP, 30 male and 60 female F0 and 10 male and 20 female
F2 and F3 Sprague-Dawley rats were treated with lincomycin premix
grade at 0, 0.38, 0.75, or 1.5 mg/kg bw per day or USP grade at 1.5 or
100 mg/kg bw per day in the diet, beginning with F0 weanling rats,
through successive breeding of the F0, F1, and F2 progeny, to
weaning of the F3a litters. The doses of premix grade were based on
multiples of 0, 25, 50, 100, and 7000 times the maximum anticipated
human dietary intake, given a tolerance in edible tissues of 1 mg/kg.
No treatment-related effects were reported on clinical status,
fertility, or maintenance of pregnancy in the adults. All other
variables were only summarized, but the report indicated that litter
parameters such as pup viability, growth rate, sex ratio, survival
rates, clinical status, and gross and histological appearance were
also unaffected. The NOEL was 1.5 mg/kg bw per day of premix-grade
lincomycin and 100 mg/kg bw per day of USP-grade lincomycin, the
highest doses tested (Goyings et al., 1979b).
Table 3. Results of tests for the genotoxicity of lincomycin
End-point Test object Concentration Result Reference
In vitro
Reverse S. typhimurium 120-1000 µg/plate Negativea,b Mazurek &
mutation TA98, TA100, Swenson (1981)
TA1535, TA1537,
TA1538
Reverse S. typhimurium 620-5000 µg/plate Negativea,c Aaron & Mazurek
mutation TA98, TA100, (1987)
TA102, TA1535,
TA1537
Forward Chinese hamster 30-3000 µg/ml Negatived Harbach et al.
mutation V79 lung fibroblasts, (1982a)
hprt locus
Forward Chinese hamster 100-3000 µg/ml Negativee,f Harbach et al.
mutation V79 lung fibroblasts, (1982b)
hprt locus
DNA damage Chinese hamster 13-1300 µg/ml Negativea,g Petzold (1981)
(alkaline V79 lung fibroblasts
elution)
Unscheduled Primary rat 10-2500 µg/mlh Negativei Seaman (1982)
DNA synthesis hepatocytes
Unscheduled Primary rat 0.17-17 µg/mlj Positive Harbarch &
DNA synthesis hepatocytes Aaron (1987)k
DNA repair Human peripheral 2800-5000 µg/ml Negativea,l Aaron (1991a)
lymphocytes
In vivo
Cytogenicity Rat bone marrow 1500-3000 mg/kg Negativen Trzos &
bwm Swenson (1981)
Cytogenicity Mouse bone marrow 150-600 mg/kg bw Negativeo Aaron (1991b)
Sex-linked Drosophila 25 000 and 50 000 Negative Aaron (1988a)k
recessive lethal melanogaster µg/ml
mutation
Table 3. (Continued)
a With and without rat liver microsomal fraction (S9)
b 2-Acetylaminofluorene (TA98, TA100, TA1538), cyclophosphamide (TA1535), and
9-aminoacridine (TA1537) used as positive controls
c 2-Aminoanthracene (all strains with S9), 2-nitrofluorene (TA98, TA100 without S9), sodium
azide (TA1535 without S9), 9-aminoacridine (TA1437 without S9), and cumene hydroperoxide
(TA102 without S9) used as positive controls
d Without S9
e With S9
f 7,12-Dimethylbenz[a]anthracene used as positive control
g N-Methyl- N'-nitro- N-nitrosoguanidine and epichlorohydrin used as complete carcinogen
positive controls and benzo[a]pyrene, 4-nitroguinoline-1-oxide, and 2-acetylaminofluorene
as procarcinogen positive controls
h Concentrations of 5000 and 10 000 µg/ml were also tested but were lethal to the cell
cultures. Toxicity was observed at doses as low as 50 µg/ml.
i 2-Aminoathracene used as positive control
j Concentrations > 16.7 µg/ml were lethal to the cell cultures.
k Only abstract provided; full report available from the sponsor upon request
l Cyclophosphamide (with S9) and 4-nitroquinoline-1-oxide (without S9) used as positive
controls
m One-half the dose was administered at 0 and 24 h. Administration of a single dose of
3000 mg/kg (one-half of a 6000 mg/kg dose) was lethal.
n Cyclophosphamide used as positive control
o Triethylenemelamine used as positive control
In another study that did not conform to GLP, groups of 24
pregnant rats were given premix-grade lincomycin by gastric gavage at
a dose of 0, 10, 30, or 100 mg/kg bw per day on days 6-15 of
gestation. The dams were killed and their fetuses removed on day 20.
The fetuses were weighed, sexed, and evaluated for gross, visceral,
and skeletal anomalies. There was no evidence of maternal toxicity at
any dose. A statistically significant increase in embryolethality was
reported at the high dose, as indicated by a fetal resorption rate of
8%, while that of the controls was 2.9% and that of historical
controls was 5.3%. There was a corresponding decrease in the number of
live fetuses. No evidence of teratogenicity was seen. The NOEL for
fetal toxicity was 30 mg/kg bw per day on the basis of increased fetal
resorptions at the high dose. The NOEL for maternal toxicity was 100
mg/kg bw per day, the highest dose tested (Morris et al., 1980).
In a two-generation study of reproductive toxicity that complied
with GLP, groups of 30 SPF rats of each sex received lincomycin by
oral gavage at a dose of 0, 100, 300, or 1000 mg/kg bw per day.
Lincomycin was administered to the F0 generation for 60 days before
mating until delivery of the F1 generation for males or for 14 days
before mating until 21 days post partum for females. All females
were allowed to deliver and nurse their offspring until weaning. One
F1 male and one F1 female pup were randomly selected from each
litter for breeding. Dosing of the F1 pups began on the day that the
last litter was weaned and followed a similar schedule to that for the
F0 rats. Gross observations were made on all groups, but only the
control and high-dose groups were examined microscopically. The only
treatment-related effect reported was a transient increase in body
weight and weight gain in all treated females during the first 14 days
of treatment, but body weight was not affected beyond 21 days of
treatment. No treatment-related effects were reported on indices of
reproductive or developmental toxicity, consistent with a maternal and
fetal NOEL of 1000 mg/kg bw per day (Black et al. 1988).
(b) Developmental toxicity
Rats
A series of studies was conducted before the requirement for GLP.
In a preliminary study, lincomycin was administered to 10 pregnant
Upjohn Sprague-Dawley breeder rats by subcutaneous injection at a dose
of 50 mg/kg bw per day during gestation. Treatment was well tolerated,
with no apparent effect on the number of young born per dam, birth
weights, or sex ratios. No effects were observed on body-weight gain
or at necropsy 3 weeks post partum. In a related preliminary study,
the same dose of lincomycin was injected subcutaneously to dams during
lactation. Antibiotic activity was detectable, although not
quantifiable, in the tissues of two of three groups of suckling rats.
The only treatment-related effect was superficial lesions at the
injection site in 4 of the 11 dams. No treatment-related abnormalities
were found on physical examination and necropsy (Gray & Purmalis,
1962a).
Lincomycin was administered subcutaneously at a dose of 30 mg/kg
bw to 65 newborn rats from six litters for 5 weeks beginning 24 h
after birth. No treatment-related effects on body weight, body-weight
gain, or pathological end-points were reported (Gray & Purmalis,
1962h).
A subcutaneous dose of 75 mg/kg bw per day was administered to 10
male and 20 female rats for 60 days and throughout two mating cycles
(84 days). A concurrent control group received saline injections.
Litter size, sex ratio, appearance, weight gain, and behaviour of the
offspring were not affected. No treatment-related effects were
reported in the parents or either of the two successive litters (Gray
et al., 1963c).
Fifty rat dams were injected subcutaneously once between days 7
and 16 of gestation with 300 mg/kg bw lincomycin, while 10 received a
single injection of cyclophosphamide at 10 mg/kg bw as positive
controls and 15 were untreated. Summarized data were provided for 407
fetuses from 42 dams. The only effect reported was an injection-site
lesion (Mulvihill & Gray, 1965).
Dogs
Six pregnant beagles were given an intramuscular injection of
lincomycin at 50 mg/kg bw, in a study that did not comply with GLP;
five controls were available. Individual data were not provided, but
the memorandum described no significant effects of treatment on the
bitches or pups. Under the conditions of this study, no NOEL could be
identified (Gray & Purmalis, 1963b).
2.2.6 Special studies
(a) Immune response
The ability of lincomycin to initiate hypersensitivity responses
in humans and animals was assessed in a summary of unpublished reports
of adverse effects after human use of lincomycin, 61 unpublished
proprietary reports submitted to the US Food and Drug Administration
in support of new animal drug applications, and published literature
(DeGeeter, 1974). During the period 1965-74, 62 incidents of
sensitization reactions were reported after administration of some 10
thousand million oral doses. None of the incidents involved persons
handling lincomycin or lincomycin-medicated feed intended for
agricultural use. In addition, the published literature emphasized the
hypoallergenicity of lincomycin. The unpublished proprietary reports
of testing of lincomycin in 13 species gave no evidence of
sensitization.
(b) Ototoxicity
A study that did not conform to GLP was conducted to investigate
the potential ototoxicity of lincomycin administered by intramuscular
inejction at 30 or 60 mg/kg bw per day to groups of three cats for 2.5
months. Two cats were kept as controls and given saline injections.
Hearing and vestibular function were evaluated from standardized
hearing responses and post-rotational nystagmus times. No histological
examinations were performed. Lincomycin had no ototoxic effects (Gray
& Highstrete, 1963b).
(c) Microbiological effects
Despite the small fraction of lincomycin excreted into the
intestine (see section 2.1.1), its antimicrobial activity may last
more than 5 days after parenteral administration (Kapusnik-Uner et
al., 1996).
While no information was available on the formation of
metabolites of lincosaminides in the gastrointestinal tract of humans,
parent lincomycin is present in the faeces of persons receiving
therapeutic doses (Kotarski, 1995). In the absence of other data,
therefore, faecal recoveries of lincosaminides may be presumed to
reflect exposure of the gut flora to ingested lincosaminide residues,
and the doses received therapeutically and from residues are assumed
to be proportional. The microbiological activity of metabolites of
lincomycin, evaluated in Micrococcus luteus, in pig plasma, liver,
and kidney, and in cows' milk has been reported. Parent lincomycin
accounted for nearly all of the microbiological activity,
N-desmethyl lincomycin and lincomycin sulfoxide having 15- and
100-fold less activity than the parent, respectively (Hornish et al.,
1987; Nappier, 1998).
The effect of pirlimycin, a related lincosaminide, on the
viability of anaerobic bacteria in dense cell suspensions was tested
by adding the compound at a concentration of 0, 3, or 6 mg/ml to
suspensions of pure cultures of 39 strains of Bacteriodes,
Bifidoacteria, Clostridium, Fusobacterium, Peptococcus or
Peptostreptococcus, Lactobacillus, and Eubacterium. The population
densities of the cell suspensions were decreased by less than one log
(average, 0.4 log10) at the highest dose . The cell suspension
concentrations were considerably lower (107-109 colony-forming
units [CFU]/ml) than those typically found in the gastrointestinal
tract (1011 CFU/g) (Greening et al., 1995). Similar data for
lincomycin are not available. Kotarski (1995) suggested that 6 mg/ml
is the NOEL for microbiological activity on gut flora. Clindamycin was
also tested in semi-continuous cultures of composite human faecal
samples. The drug was added at 0, 0.26, 2.6, 25, or 260 mg/ml culture
for 7 days. During these treatments and for 7-8 days thereafter,
Clostridium difficile ATTCC 43255 was added daily at 103 cells/ml.
The NOEL was 2.6 mg/ml was on the basis of overgrowth of
C. difficile, changes in pH, and changes in the profile of volatile
fatty acids (Cerniglia & Kotarski, 1999).
Therapeutic daily oral doses of 600 mg of clindamycin (Cerniglia
& Kotarski, 1999) and > 1500 mg of lincomycin (Kotarski, 1995) to
an adult (equivalent to 10 mg/kg bw for clindamycin and 25 mg/kg bw
for lincomycin) can cause marked changes in the gastrointestinal
flora. One side-effect of the therapeutic use of lincosaminides is
disruption of the intestinal microflora (Fass, 1981; Kotarski, 1995),
and therapeutic regimens of lincomycin and clindamycin have been
associated with marked decreases in anaerobic flora, concurrently with
increases in aerobic and facultatively anaerobic Gram-negative
bacilli, enterococci, and yeasts (Fass, 1981). Colitis has been
reported in 0-2.5% of patients and diarrhoea in 2.6-31% (Fass, 1981;
Kotarski, 1995). Clindamycin-induced pseudomembranous colitis was
recognized after the drug had been approved for use in humans, as was
the role of C. difficile toxin in the disease process (Tedesco et
al., 1974; Kucers & Bennett, 1979; Fass, 1981; Jaimes, 1991; Gilbert,
1994). This condition has been reported at a frequency as high as 10%
after administration of lincomycin (Kotarski, 1995). Adverse drug
reactions to clindamycin are essentially limited to rash and
diarrhoea. Diarrhoea was reported at a frequency of 20-31% in
susceptible AIDS patients, while diarrhoea associated with
C. difficile toxin was reported in 0.01-18% of treated patients
(Gilbert, 1994). A review of the literature indicated that clindamycin
at a daily oral dose of 150 mg had no adverse effects in 99 adults
treated for up to 12 months (Kotarski, 1995). The results of studies
of antibiotic-associated colitis in hamster models, based on a review
of the published literature and unpublished technical reports, are
summarized in Table 4.
The ability of lincomycin to affect the faecal excretion of
pathogens in food animals was investigated in a study of 32 pigs, 4-5
weeks of age, which received lincomycin at 0 or 100 g/t, equal to 5.6
mg/kg bw per day, in the feed for 7 days before bacterial challenge
and throughout the study. Ten pigs given lincomycin and nine controls
were challenged by gavage with 1 × 1011 CFU of nalidixic-resistant
S. typhimurium in 50 ml trypticase soya broth, while one group
receiving lincomycin and three further control groups were
mock-challenged with trypticase soya broth. Faecal samples were
obtained on days -7, -4, -1, 2, 4, 5, 6, 8, 10, 12, 14, 17, 24, 31,
39, 46, and 53. When two consecutive negative faecal cultures were
found after day 31, the animal was slaughtered. All remaining pigs
were slaughtered on day 53. Colon, liver, spleen, and mesenteric lymph
node from each animal were cultured for S. tymphimurium at
termination. Effective colonization was verified by the presence of an
average of 1 × 104 CFU of nalidixic acid-resistant bacteria 2-5 days
after challenge. Lincomycin had no effect on the quantity, duration,
or prevalence of excreted Salmonella spp., and medication for up to
39 days had no effect on the sensitivity of S. typhimurium to 10
antibiotics (DeGeeter & Stahl, 1974).
The sensitivity of staphylococci isolated from farm animals to a
number of antibacterial agents was determined over 10 years (DeVriese,
1980). No consistent trend was observed in the susceptibility to
lincomycin of S. aureus strains isolated from pigs (1973-80) or
poultry (1970-80).
Human clinical data have been used to determine patterns of
susceptibility to lincosaminides. The susceptibility of nearly 6
million bacterial strains from an average of 242 hospitals across the
United States and of 200 000 strains from the Massachusetts General
Hospital, Boston, Massachusetts, and the Bronx Lebanon Hospital
Center, New York, between 1971 and 1984 are shown in Table 5
(Atkinson, 1986; Atkinson & Lorian, 1984). Yancey (1988) suggested
that these data indicate that lincomycin has little effect on the
susceptibility of Gram-positive and anaerobic bacteria isolated from
humans. The sensitivity of selected human isolates in vitro to
lincomycin was similar in 1968 (Kucers & Bennett, 1979). On the basis
of the data collected in the US hospital survey (Atkinson, 1986;
Atkinson & Lorian, 1984), the European Medicines Evaluation Agency
(1998) has proposed use of the reported median inhibitory
concentration (MIC50) for Fusobacterium of 0.2 mg/ml (range,
0.2-0.4 mg/ml) as the NOEC for the antimicrobial effect of lincomycin
on human gut flora. Additional data on the MIC50 of lincomycin and
the related lincosaminide, clindamycin, for selected human intestinal
bacteria are shown in Table 6 (Kotarski, 1995).
Table 4. Results of studies of antibiotic-associated colitis in the hamster model
Drug Route of Weight of Challenge with No./dose LD100 LD50 No effect Reference
administration animals (g) C. difficile (mg/60 kg) (mg/60 kg) (mg/60 kg)
Lincomycin Single subcutaneous 80-100 Yes 10 or 6 NR 174-282 NR Staepert et al.
injection (1983, 1991)
Single intersca pular, 60-100 No 10 or 15 > 600 6-66 6 Lusk et al.
subcutaneous, or (1978)
intraperitoneal injection
Clindamycin Single subcutaneous 80-100 Yes NR > 750a 240b NR Staepert et al.
injection (1983, 1991)
Topical, daily for 14 80-100 No 4 or 7 or . 600a .6-60 6 Feingold et al.
days NR (1979)
Single intraperitoneal 60-90 No 6 > 60 6-60 6 Rifkin et al.
injection (1978)
Single intersca pular, 60-100 No 15 or 10 . 300 32-43 30 Lusk et al.
subcutaneous, or (1978)
intraperitoneal injection
Pirlimycin Single subcutaneous 80-100 Yes NR NR 156 mg/kg NR Staepert et al.
injection (1983, 1991)
Doses reported by authors in mg/kg are presented as mg/60 kg equivalent body weight. For doses reported by the authors as daily dose per
hamster, it was assumed that each hamster weighed 100 g.
a Mortality at 300 mg/60 kg equivalent body weight was not tested.
b Mean values of four experiments; range, 302-420 mg/60 kg equivalent body weight
Table 5. Inhibition of selected bacteria by lincomycin
Organism No. of Cumulative percentage of strains inhibited by various Reference
strains concentrations of lincomycin (µg/ml)
Dose(s) µg/ml % µg/ml % µg/ml %
Acinetobacter calcoaceticus
var. anitratis 11 > 400 Finland et al. (1976a)
Actinomyces spp. 20 0.12-4.0 0.12 65 0.25 90 2.0 95 Lerner (1968)
Bacillus anthracis 0.25-8.0 Barker & Prescott (1973)
Bacteroides fragilis 195 0.1-12.5 0.8 31 1.6 71 12.5 71 Martin et al. (1972)
Bacteroides melaninogenicus 29 0.1-0.2 0.1 89 0.2 96 Martin et al. (1972)
Bifidobacterium eriksonii 5 0.1-1.6 0.1 40 0.2 80 1.6 100 Martin et al. (1972)
Bordetalla pertussis 36 3.1-50 6.25 1 12.5 25 25 93 Bass et al. (1969)
Brucella abortus, melitensis
and suis 1.25-> 100 1.25 10 50 65 100 100 Hall & Manion (1970)
Campylobacter fetus (Vibrio
fetus) 95 0.78-100 6.3 38 12.5 76 50 91 Vanhoof et al. (1978)
Clostridium perfringens 34 0.1-6.2 0.2 29 1.6 76 3.1 97 Martin et al. (1972)
Clostridium spp. 17 0.1-12.5 0.1 23 1.6 53 3.1 76 Martin et al. (1972)
Corynebacterium diphtheriae 14 0.4-0.8 0.4 93 Gordon et al. (1971)
Edwardsiella tarda 37 > 5 5 0 Nasu et al. (1981)
Eikenella corrodens 20 > 100 Robinson & James (1974)
Enterobacter spp. 33 > 400 Finland et al. (1976a)
Eubacterium alactolyticum 2 0.1 0.1 1000 Martin et al. (1972)
Eubacterium lentum 14 0.1-3.1 0.1 21 0.8 71 1.6 93 Martin et al. (1972)
Flavobacterium meningosepticum 11 > 100 > 100 100 Altman & Bogokovsky (1971)
Fusobacterium spp. 18 0.1-6.2 0.1 39 0.8 67 3.1 94 Martin et al. (1972)
Haemophilus spp. 68 0.8-12.5 1.6 25 3.1 53 6.3 87 Williams & Andrews (1974)
Haemophilus influenzae 70 > 20 > 20 100 McLinn et al. (1970)
Klebsiella Pneumoniae 35 > 400 Finland et al. (1976a)
Mycoplasma pneumoniae 5 1.6-4.8 1.6a Atkinson & Moore (1977a);
Barker & Prescott (1971)
Neisseria gonorrhoeae 82 0.5-> 32 4 7 16 44 32 77 Phillips et al. (1970)
Table 5. (Cont'd)
Organism No. of Cumulative percentage of strains inhibited by various Reference
strains concentrations of lincomycin (µg/ml)
Dose(s) µg/ml % µg/ml % µg/ml %
Neisseria meningitidits 40 16-> 100 46 5 > 100 100 Devine & Hagerman (1970)
Nocardia spp. 25 100-> 400 100 5a 299a 25 Bach et al. (1973)
Peptococcus 145 0.1-> 25 0.1 29 0.4 69 0.8 92 Martin et al. (1972)
Peptostreptococcus 72 0.1-3.1 0.1 39 0.4 72 1.6 100 Martin et al. (1972)
Propionibacterium acnes 16 0.1-1.6 0.1 81 0.4 94 1.6 100 Martin et al. (1972)
Proteus spp. 34 > 200 Finland et al. (1976a)
Providencia stuartii 34 > 400 Finland et al. (1976a)
Pseudomonas aeruginosa 35 > 400 Finland et al. (1976a)
Pseudomonas pseudomonallei 10 > 100 Eikhoff et al. (1970)
Staphylococcus aureus 106 0.12-2.0 0.25 25 0.5 63 1.0 96 Phillips et al. (1970)
Staphyloccus epidermidis 35 0.2-> 100 0.2 5 0.4 93 Sabath et al. (1976)
Streptococcus pyogenes
(Group A) 35 < 0.01-0.4 0.04 10 0.1 33 0.2 80 Finland et al. (1976b);
Karchmer et al. (1975)
Streptococus agalaciae
(Group B) 25 0.04-0.19 Karchmer et al. (1975)
Streptococcus faecalis
(enterococcus) 382 1.6-> 100 25 18 50 55 100 88 Toala et al. (196925.
Streptococcus (Group D,
not enterococcus) 22 0.04-0.39 Karchmer et al. (1975)
Streptococcus pneumoniae 25 0.12-1.0 0.12 12 0.25 56 0.5 84 Upjohn Co. (undated)
Streptococcus viridans 27 0.12-1.0 0.12 37 0.25 85 Upjohn Co. (undated)
Viellonella 13 0.1-6.2 0.1 46 0.2 77 1.6 92 Martin et al. (1972)
Vibrio alginolyticus 24 8-32 Hollis et al. (1976)
Vibrio parahemolticus 24 8-32 Hollis et al. (1976)
Yeserinia enterocolitica 190 4 4 (3) Raevvori et al. (1978)
a Results taken from a graph
Table 6. MIC50 values of lincomycin and clindamycin for selected human intestinal bacteria
Bacterial genus Clindamycin Lincomycin
No. MIC50 (µg/ml) No.a MIC50 (µg/ml)
Median Range
Bacteroides 15 1 1158 3.1 0.1-12.5
Bifidobacterium 13 0.03 42 0.4 0.2-1.6
Eubacterium 13 0.06 21 0.8 0.1-0.8
Fusobacterium 6 0.03 91 0.2 < 0.1-12.5
Peptococcus / 19 0.03 446 0.4 0.2-0.4
Peptostreptococcus
Clostridium 8 0.5 506 1 1-25
Lactobacillus 2 0.06 124 1 1
Enterococcus 10 16 27 16 4-32
Escherichia coli 12 > 128 21 > 128 > 128
Modified from Kotarski (1995)
a Number of strains surveyed in several studies
2.3 Observations in humans
Gastrointestinal effects are the most commonly reported adverse
reactions to lincomycin in humans (Fass, 1981; Gilbert, 1994). The
effects can include nausea, vomiting, abdominal cramps, and diarrhoea.
Pseudomembranous colitis, when associated with lincomycin or
clindamycin therapy, usually appears 2-25 days after the start of
treatment and may occur in up to 20% of patients (Goodman & Gilman,
1975; Kucers & Bennett, 1979). Rarely, hypersensitivity reactions have
been reported, most commonly resulting in a rash, although anaphylaxis
has been reported (Kucers & Bennett, 1979). Patients undergoing
anaesthesia while receiving lincomycin and clindamycin have been
reported to show inhibition of neuromuscular transmission, with
possible potentiation by concurrently administered neuromuscular
blocking agents (Fass, 1981; Kapusnik-Uner et al., 1996).
There were no reported effects on fetal development after
administration of lincomycin to 300 pregnant women (Fass, 1981).
3. COMMENTS
The Committee considered data on the pharmacokinetics,
metabolism, acute toxicity, short-term and long-term studies of
toxicity, carcinogenicity, genotoxicity, reproductive toxicity,
developmental toxicity, immunotoxicity, ototoxicity, and
microbiological safety of lincomycin. The results of studies on the
functionally and structurally related drug clindamycin were considered
in the assessment of the microbiological safety of lincomycin. In all
of the studies considered, the concentrations of the compound were
reported as the activity of lincomycin base. While many of the studies
were conducted prior to the development of GLP, all of the pivotal
studies were carried out according to appropriate standards for study
protocol and conduct.
Dogs given lincomycin intramuscularly or orally showed rapid
absorption, peak serum concentrations being achieved within 0.5 and
1.5 h, respectively. In pigs given an oral dose, 53% (with a standard
deviation of 19%) was bioavailable, and 5-15% was bound to plasma
proteins. The peak concentrations in serum were reached within 3.6 h
(standard deviation, 1.2 h), with a half-time of 3.4 h (standard
deviation, 1.3 h). Pig excreta contained little unchanged lincomycin:
urine contained 11-21% of the oral dose, half of which was unchanged
parent compound. Only trace amounts of N-desmethyllinco-mycin were
identified. The contents of the gastrointestinal tract accounted for
79-86% of the excreted drug. In faecal samples, only 17% of the
excreted dose was unchanged parent compound, and the remainder was
uncharacterized metabolites.
Lincomyin is well distributed in the human body. The tissues and
fluids that contain significant concentrations include bile, pleural
fluid, brain, bone marrow, synovial fluid, bone, joint capsule, eye,
and peritoneal fluid. The distribution of the compound in
cerebrospinal fluid is generally poor except in the presence of
inflammation. Lincomycin has been shown to cross the placenta, and
peak concentrations of 0.2-3.8 µg/ml were found in amniotic fluid,
which were sustained for 52 h after a single intramuscular injection
of 600 mg to pregnant women. Lincomycin was present in the milk of
these women. The systemic oral bioavailability of lincomycin in
persons who had fasted was 25-50%, but this value can be as low as 5%
in the presence of food; 72% of the amount found in serum was bound.
Peak serum concentrations are usually reached within 4 h, with a
half-time of 4.2-5.5 h.
Lincomycin is extensively metabolized, as less than 10% of
unchanged parent drug is found in animal tissues. The numerous
metabolites include N-desmethyllincomycin and lincomycin sulfoxide,
which are reported to have 15-100 times less microbiological activity
than the parent compound.
Toxicological data
Lincomycin has high acute toxicity only in rabbits. The LD50
after oral administration was 17 000-19 000 mg/kg bw in mice and
11 000-16 000 mg/kg bw in rats, while the lethal dose in 9 of 15
rabbits was reported to be 50 mg/kg bw.
Lincomycin was administered to mice for 90 days in the feed to
provide a dose of 0, 10, 30, 100, 300, or 3000 mg/kg bw per day.
Animals given the two higher doses showed increased weight of the
intestine (with pancreas) and an increased incidence of luminal
distension and dilatation of the small and large intestines. The NOEL
was 100 mg/kg bw per day.
In a 90-day study of toxicity, groups of four male and four
female dogs were given an oral dose of lincomycin at 0, 400, or 800
mg/kg bw per day. Transient increases in serum alanine
aminotransferase activity were observed during the first month of
treatment in dogs at the high dose and in one dog at the low dose, but
the activity had returned to normal by the end of the study. No other
treatment-related effects were reported. The NOEL was 800 mg/kg bw per
day, the highest dose tested.
Lincomycin was administered to groups of two male and two female
dogs in capsules for 6 months at a dose of 0, 30, 100, or 300 mg/kg bw
per day. The NOEL was 300 mg/kg bw per day, the highest dose tested.
In a 1-year study, lincomycin was administered orally by gelatin
capsule to groups of five male and five female dogs, as the premix
grade at a dose of 0, 0.38, 0.75, or 1.5 mg/kg bw per day, or as the
USP grade at a dose of 1.5 mg/kg bw per day. The NOEL was 1.5 mg/kg bw
per day, the highest dose tested.
Groups of 10 rats of each sex were treated for 1 year with
lincomycin at a dose of 0, 30, 100, or 300 mg/kg bw per day by oral
gavage. No treatment-related effects were reported at any dose. The
NOEL was 300 mg/kg bw per day, the highest dose tested.
In a long-term study of toxicity and carcinogenicity, pregnant
female rats and groups of 60 offspring of each sex were given feed
containing premix-grade lincomycin to provide a dose of 0, 0.38, 0.75,
or 1.5 mg/kg bw per day or USP-grade lincomycin to provide a dose of
1.5 or 100 mg/kg bw per day. Treatment of the offspring was continued
for 26 months. While lincomycin was not carcinogenic under the
conditions of the assay, the Committee considered the administered
dose to be insufficient for assessing the carcinogenicity of
lincomycin. The NOEL for non-neoplastic lesions was 100 mg/kg bw per
day, the highest dose tested.
Lincomycin was tested for its capacity to induce reverse mutation
in bacteria, gene mutation in Chinese hamster lung fibroblasts,
unscheduled DNA synthesis in primary rat hepatocytes, chromosomal
aberrations in peripheral human lymphocytes in vitro, DNA damage in
V79 cells, micronuclei in rat and mouse bone marrow, and sex-linked
recessive lethal mutations in Drosophila melanogaster in vivo. The
only positive finding was the induction of unscheduled DNA synthesis
in primary rat hepatocytes, but this result could not be replicated.
Adequate studies of carcinogenicity were not available. However,
the weight of the evidence indicates that lincomycin is not genotoxic.
Furthermore, lincomycin is not structurally similar to known
carcinogens. The Committee therefore concluded that the drug does not
present a carcinogenic risk, and further carcinogenic studies were
deemed unnecessary.
The reproductive and developmental toxicity of lincomycin was
evaluated in a three-generation study conducted prior to the
formulation of GLP. Groups of 30 male and 60 female F0 rats and 10
male and 20 female F1, F2, and F3 animals were given diets
containing lincomycin of premix grade to provide a dose of 0, 0.38,
0.75, or 1.5 mg/kg bw per day or the USP grade to provide a dose of
1.5 or 100 mg/kg bw per day, beginning with F0 weanling rats and
continuing through successive breeding of the F0, F1, and F2
progeny to weaning of the F3 litters. No treatment-related effects
were seen at any dose. The NOEL was 100 mg/kg bw per day for the USP
grade, the highest dose tested.
In a two-generation study of reproductive toxicity, lincomycin
was administered to groups of 30 male and 30 female rats by oral
gavage at a dose of 0, 100, 300, or 1000 mg/kg bw per day. No
treatment-related effects were observed at any dose. The NOEL was 1000
mg/kg bw per day, the highest dose tested.
In a study of developmental toxicity, pregnant rats were given
lincomycin by gastric gavage at a dose of 0, 10, 30, or 100 mg/kg bw
per day on days 6-15 of gestation. An increased incidence of fetal
resorptions was observed at the highest dose. The NOEL for
embryotoxicity was 30 mg/kg bw per day.
The potential ototoxicity of lincomycin was tested in groups of
three cats that received intramuscular injections of 30 or 60 mg/kg bw
per day for 2.5 months. Hearing and vestibular function were evaluated
on the basis of standardized hearing tests and post-rotational
nystagmus times, respectively. No treatment-related effects were
reported.
Microbiological data
The Syrian hamster is used as an experimental model to evaluate
antibiotic-associated colitis. In studies in which lincomycin was
administered by various parenteral routes to hamsters, the NOEL for
antibotic-associated colitis was 0.1 mg/kg bw per day.
Administration of lincomycin at an oral therapeutic dose of 25-66
mg/kg bw daily to 12 patients for periods varying from 6 to 150 days
caused antibiotic-associated colitis. The condition was also found
after administration of the structurally and functionally similar
compound clindamycin to 10 patients for 7 days at a dose of 10 mg/kg
bw per day. When clindamycin was administered to 99 patients at doses
up to 2.5 mg/kg bw per day for up to 12 months, the NOEL for adverse
effects on the gastrointestinal microflora was 2.5 mg/kg bw per day.
The ability of lincomycin to affect faecal excretion of pathogens
was investigated in a study of 32 pigs aged 4-5 weeks that were given
the drug for periods up to 45 days at a concentration of 100 g/t of
feed, equivalent to 5.6 mg/kg bw per day. Treatment had no effect on
the faecal excretion of S. typhimurium when these animals were
compared with pigs that received the vehicle alone, nor did it alter
the susceptibility of the bacteria to lincomycin.
The sensitivity of staphylococci isolated from farm animals to
lincomycin was investigated in a 10-year study that ended in 1980. No
change in the susceptibility of S. aureus strains isolated from pigs
or poultry was observed.
A study was conducted between 1971 and 1982 to examine the
patterns of susceptibility to antibiotics of more than 5 million
bacterial strains from hospitals across the USA. The susceptibility of
Gram-positive aerobic and anaerobic bacteria to lincomycin changed
little during the survey period. In a separate study, the MIC50 for
representative bacteria from the human gut was reported for
lincomycin. The NOEC for the effect of lincomycin on Fusobacterium,
the most sensitive representative species, was 0.2 mg/ml.
Clindamycin was tested at a concentration of 0, 0.26, 2.6, 25, or
260 mg/ml of culture for 7 days in semi-continuous cultures of
composite faecal samples from humans. During these treatments and for
7-8 days thereafter, Clostridium difficile was added daily at a
concentration of 103 cells/ml. The NOEL for clindamycin was 2.6
mg/ml on the basis of overgrowth of C. difficile, changes in pH, and
changes in the profile of volatile fatty acids in the culture medium.
A 'decision tree' for evaluating the potential of veterinary drug
residues to affect human intestinal microflora was developed by the
Committee at its fifty-second meeting (Annex 1, reference 140;
Figure 1). At its present meeting, the Committee used the decision
tree to answer the following questions in its assessment of
lincomycin:
1. "Does the ingested residue have antimicrobial properties?"
Yes. While the spectrum of activity of lincomycin is essentially
the same as that of clindamycin, the MIC50 of lincomycin is higher
(less potent) than that of clindamycin for the relevant species of
bacteria in the human gastrointestinal tract.
FIGURE 1a;V45JE01.BMP
FIGURE 1b;V45JE01B.BMP
2. "Does the drug residue enter the lower bowel by any route?"
Yes. In humans, 40-50% of an oral dose of lincomycin is excreted
in faeces. The systemic absorption of lincomycin in humans is
significantly reduced in the presence of food: while the systemic
bioavailability of an oral dose of lincomycin is estimated to be
25-50% in fasting individuals, it may be only 5% with a meal. The
intestinal bioavailability of lincomycin may therefore be as high as
95-100%. Measurements of lincomycin activity in the faeces of patients
receiving therapeutic doses are shown in Table 7. The concentrations
on day 1 were not included in the calculation below because the full
concentrations had not been attained. Thus,
(2.2 + 1.7 + 6.6 + 2.3 + 2.4 + 2.6 + 3.0 + 2.9) mg/g = 23.7 mg/g
(23.7 mg/g) / 8 observations = 3.0 mg/g
Faecal lincomycin therefore accounts for (3.0 mg lincomycin per g
faeces) × (220 g faeces)/(2000 mg oral dose) or approximately 33% of
an oral dose. As the drug is extensively metabolized and many of the
metabolites have little to no antimicrobial activity, a conservative
estimate of the bioavailability of lincomycin in the gastrointestinal
tract would be 5%.
3. "Is the ingested residue transformed irreversibly to inactive
metabolites by chemical transformation, metabolism mediated by
the host or intestinal microflora in the bowel and/or by
binding to intestinal contents?"
Yes, but microbiologically active residues remain. Lincomycin is
extensively metabolized to about 16 metabolites, three of which have
been identified as lincomycin sulfoxide, N-desmethyl lincomyin, and
N-desmethyllincomycin sulfoxide. None of the metabolites was found
to have significant microbiological activity. N-Desmethyl and
lincomcyin sulfoxide have 15 and 100 times less microbiological
activity, respectively, than lincomycin. There was no evidence that
the remaining metabolites have any microbiological activity.
4. "Do data on the effects of the drug on the colonic microflora
provide a basis to conclude that the ADI derived from
toxicological data is sufficiently low to protect the
intestinal microflora?"
No. A review of studies of the toxicity of orally administered
lincomycin indicates that the pivotal study is the 26-month study of
toxicity and carcinogenicity in rats.
Table 7. Concentrations of lincomycin in faeces of patients receiving therapeutic
doses of 2000 mg/person per day orally
Dose regimen No. of Treatment Mean concentration of Reference
patients day lincomycin (mg/g)a
500 mg 4 times 5 1 1.0 Upjohn Co.
daily for 3 days 2 2.2 (undated)
3 1.7
4 6.6
5 2.3
500 mg 4 times 6 1 0.6 (0-3.5) Rotblatt et al.
daily 2 2.4 (0-4.8) (1982)
3 2.6 (0-4.4)
4 3.0 (1.6-4.4)
5 2.9 (2.3-3.5)
6 1.9 (0.1-3.5)
a The average faecal concentrations in humans given daily doses of 2000 mg may be calculated
(Kotarski, personal communication).
NOEL
ADI =
Safety factor
100 mg/kg bw per day
ADI =
100
ADI = 1 mg/kg bw
The adverse effects of lincomycin on the intestinal microflora
have been indicated in a number of studies.
An evaluation of the MIC50 values for relevant gastrointestinal
microflora provides a NOEL of 0.2 mg/ml. This value may be used to
calculate a microbiological ADI as follows:
MIC50 × MCC
Upper limit of ADI (mg/kg bw) =
FA × SF × BW
(0.2 mg/g) × (220 g)
Upper limit of ADI (mg/kg bw) =
0.5 × 1 × 60 kg
Upper limit of ADI = 1.4 µg /kg bw per day
Fusobacterium was among the most sensitive of the relevant
gastrointestinal microflora tested. An MIC50 of 0.2 mg/ml was
established. A conservative factor of 0.5 was determined for
gastrointestinal bioavailability on the basis of its systemic
bioavailability in the presence of food (as low as 5%) and the
measured percentage of an orally administered dose in faeces (as high
as 15%). A safety factor of 1 was used because sufficient and relevant
microbiological data were available.
Clindamycin has also been tested in semi-continuous cultures of
composite faecal samples from humans. The NOEL was 2.6 mg/ml on the
basis of overgrowth of C. difficile, changes in pH, and changes in
the profile of volatile fatty acids.
MIC50 (mg/g) × MCC(g)
Upper limit of ADI (mg/kg bw) =
FA × SF × BW (kg)
(0.26 mg/g) × (220 g)
Upper limit of ADI (mg/kg bw) =
0.05 × 1 × 60 kg
Upper limit of ADI = 19 µg/kg bw per day
Faecal excretion of clindamycin represents 5-10% of an oral dose. A
safety factor of 1 was used because sufficient and relevant
microbiological data were available.
The model of antibiotic-associated colitis in hamsters given
lincomycin intraperitoneally may be used to determine a microbiolgical
ADI, as follows:
NOEL
ADI =
Safety factor
0.1 mg/kg bw per day
ADI =
10
ADI = 10 µg/kg bw
The NOEL was 0.1 mg/kg bw per day. A safety factor of 10 was used to
address inter-animal variation. No correction was applied for
extrapolation from animals to humans because of the sensitivity of the
hamster model.
The results of studies with a model of faecal excretion of
Salmonella by pigs could also be used to evaluate the effects of
lincomycin on the intestinal microflora. No effects of a single dose
were seen on the quantity, duration, or prevalence of excreted
Salmonella spp. or on the sensitivity of the faecally excreted
Salmonella to 10 antibiotics, including lincomycin. The ADI may be
calculated as:
NOEL
ADI =
Safety factor
5.6 mg/kg bw per day
ADI =
100
ADI = 56 µg/kg bw
The observed NOEL was 5.6 mg/kg bw per day, the only dose tested. A
safety factor of 10 was used to address variation between animals, and
a second safety factor was applied to address the uncertainty in
extrapolating from data on pig gastrointestinal microflora to that of
humans.
Information was available from a clinical study of 99 patients on
the effects of clindamycin on human gastrointestinal microflora over
2-4 months. The microbiological ADI may be calculated as follows:
NOEL
ADI =
Safety factor
2.5 mg/kg bw per day
ADI =
100
ADI = 30 µg/kg bw
The observed NOEL was 2.5 mg/kg bw per day. While this was the highest
dose administered, other studies showed an effect on the
gastrointestinal microflora of clindamycin at 10 mg/kg bw per day and
of lincomycin 25 mg/kg bw per day. A safety factor of 10 was used to
address variation between human subjects, and an additional correction
factor of 10 was used to address the 10-fold higher bioavailability of
lincomycin than clindamycin to the colon.
5. "Do clinical data from the therapeutic use of the class of
drugs in humans or data from in vitro or in vivo model
systems indicate that effects could occur in the
gastrointestinal flora?"
Yes. Gastrointestinal effects are the most commonly reported
adverse reactions to therapeutic use of lincomycin in humans. The
effects can include nausea, vomiting, abdominal cramps, and diarrhoea.
Pseudomembranous colitis associated with lincomycin or clindamycin
therapy usually appears 2-25 days after the start of treatment and may
occur in up to 20% of patients. The results of model systems that
indicate that effects could occur in the gastrointestinal flora are
discussed above.
6. "Determine which is the most sensitive adverse effect of the
drug on the human intestinal microflora."
The available data indicate that disruption of the colonization
barrier for human gastrointestinal microflora is the major concern,
rather than the emergence of resistance. Lincosaminides are used
widely in human medicine and have been shown to cause disruption of
intestinal microflora. In a study of the magnitude of and trends in
the development of bacterial resistance to lincosaminides, the pattern
of susceptibility of human isolates of Gram-positive aerobic and
anaerobic bacteria changed little over a 12-year period (1971-83).
Resistance does develop in staphylococci, as seen in humans or
animals, but most isolates remain susceptible to lincomycin. While no
data were available on the effects of lincomycin on the metabolic
activity of the intestinal microflora, disruption of the
gastrointestinal colonization barrier is the most appropriate
microbiological end-point for determination of an ADI for lincomycin.
7. "If disruption of the colonization barrier is the issue,
determine the MIC of the drug against 100 strains of
predominant intestinal flora and take the geometric mean MIC
of the most sensitive genus or genera to derive an ADI using
the formula for estimating an ADI. Other model systems may be
used to establish a NOEC to derive an ADI."
Disruption of the colonization barrier of the gastrointestinal
microflora is the microbiological end-point of concern for lincomycin.
No studies were available to establish a NOEL for effects of
lincomycin on the human gastrointestinal microflora, but clindamycin,
a structurally and functionally related lincosaminide, has the same
spectrum of activity as lincomycin, has the same reported spectrum of
adverse clinical effects as lincomycin, and is generally considered to
be a more potent antibacterial agent than lincomycin. The availability
to the colon of orally administered clindamycin is one-tenth that of
lincomycin. The study of clinical use of clindamycin is the most
appropriate one for determining the microbiological safety of
lincomycin
4. EVALUATION
The Committee could have established a toxicological ADI of 300
µg/kg bw on the basis of the NOEL of 30 mg/kg bw per day for
embryotoxicity in rats and a safety factor of 100. The Committee
noted, however, that lincomycin belongs to a group of lincosaminides
that is active against Gram-positive bacteria and that the human
gastrointestinal flora are sensitive to therapeutic doses of this
group of compounds. Because this is the most sensitive end-point, the
Committee established an ADI of 0-30 µg/kg bw on the basis of the NOEL
of 2.5 mg/kg bw per day for the effects of clindaymcin on the
gastrointestinal microflora and a safety factor of 100. As is its
usual practice, the Committee rounded the value of the ADI to one
significant figure.
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See Also:
Toxicological Abbreviations
LINCOMYCIN (JECFA Evaluation)