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    GENTAMICIN

    First draft prepared by
    Dr G. Roberts
    Commonwealth Department of Human Services and Health
    Canberra, Australia

    1.  EXPLANATION

          Gentamicin is an aminoglycoside antibiotic effective against a
    wide variety of microorganisms.  Gentamicin had not been previously
    reviewed by the Committee.  The structure of gentamicin is shown in
    Figure 1.

    FIGURE 1

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution, metabolism and excretion

          Few specific studies on the pharmacokinetics of gentamicin were
    available, however, the aminoglycosides as a class have been
    extensively reviewed. In view of their polar nature and high aqueous
    solubility, aminoglycosides are essentially not absorbed after oral
    administration. Absorption after intramuscular or subcutaneous
    administration is good with peak blood levels occurring within 30 to
    90 minutes of an intramuscular injection (Riviere  et al., 1991;
    Sande & Mandell, 1990).

          The aminoglycosides distribute into the extracellular space with
    minimal penetration into tissues other than the kidneys and the inner
    ear. Plasma protein binding is reported to be less than 20%. Levels in
    amniotic fluid and fetal tissue are very low in most species.
    Aminoglycosides as a class are not metabolized and are eliminated
    unchanged in the urine by glomerular filtration.  Recovery of 80% to
    90% of the administered dose can occur within 24 hours (Fraser
     et al., 1991).

          One beagle dog was given a single intravenous dose of radio-
    labelled gentamicin sulfate. The apparent half-life of elimination
    from serum was approximately 1 hour initially and approximately 2
    hours 8 and 10 hours after dosing. Distribution to organs and tissues
    was extensive but exceptionally high levels were found in the kidney,
    mainly in the cortex. A comparison of the levels of serum gentamicin
    using radioassay, radioimmunoassay and microbiological assay were
    similar, suggesting that there was little metabolism of the drug.
    Excretion was primarily renal with some 70% recovered in the urine but
    very little (1%) in the faeces. Approximately 2% of the dose remained
    in tissues 8 days after dosing; the remainder was unaccounted for
    (Miller  et al., 1976).

    2.2  Toxicological studies

          Unless specified otherwise, toxicological studies were carried
    out using the gentamicin sulfate salt and dose levels are expressed as
    gentamicin base.

    2.2.1  Acute toxicity studies

          The results of acute toxicity studies with gentamicin are
    summarized in Table 1.

          Clinical signs of intoxication in rodents included convulsions,
    prostration, hypoactivity, polydipsia, dyspnoea and ataxia. Dogs

    exhibited muscle tremors, salivation, and anorexia.  Histopathological
    examination of kidneys from dogs that died up to 13 days after dosing
    revealed necrosis of the proximal convoluted tubule.

    2.2.2  Short-term toxicity studies

    2.2.2.1  Rats

          Doses of 0 or 40 mg/kg bw/day gentamicin in saline were
    administered i.p. to groups of 5 male albino rats. Treatment was for
    10 consecutive days and animals were killed 48 hours after the last
    dose. There were no reported overt signs of toxicity. Serum
    chemistries at termination showed an increase in creatinine, BUN, and
    SGPT. Pathology was restricted to kidneys and liver and included
    degeneration and necrosis of renal tubular epithelium and moderate
    vacuolization of hepatocytes. The author also noted that enhancement
    of nephrotoxicity and hepatotoxicity occurs in alloxan-induced
    diabetic rats administered gentamicin (Atef  et al., 1992).

          Groups of Charles River CD1 rats (15/sex/group) received i.m.
    injections of gentamicin daily for 14 days. The drug was administered
    in saline at dose levels of 0, 10, 25, 50, or 100 mg/kg bw/day. Overt
    signs of toxicity were noted only in the highest-dose group, which
    included reduced body-weight gain, polydipsia, hypoactivity, ataxia,
    lethargy, dyspnoea, emaciation and prostration. A total of 7 rats in
    this group died or were killed because of their moribund condition.

          Clinical laboratory investigations showed indications of
    treatment-related effects on renal function. Serum creatinine and BUN
    were increased. Glucose and occult blood were present in the urine at
    doses of 50 and 100 mg/kg bw/day. Decreased urine specific gravity and
    increased urine volume were noted at 25 mg/kg bw/day and above. At
    necropsy, renal cortical pallor was observed in all treated groups
    with dose-related increases in incidence and severity. At 25 mg/kg and
    above, kidney weights were increased as was the severity of renal
    tubular nephrosis (Robbins  et al., 1973d).

          Neonatal Carworth CFE rats (10 litters per group, 10 pups/litter)
    were administered i.m. injections of gentamicin for 14 days.  The
    doses were 0, 10, 25, 50 or 100 mg/kg bw/day in a water vehicle. 
    There were no clinical signs of toxicity, but body-weight gains were
    depressed at all doses.  Laboratory investigations were not
    undertaken.  At the end of the study, kidney weights were increased at
    all doses.  Dilation of renal pelves was observed in treated groups
    but with no clear dose-response relationship.  At 25 mg/kg bw/day and
    above, pale renal cortices and dark red medullas were noted.  Cloudy
    swelling of renal tubules, the presence of proteinaceous material in
    tubules, desquamation of epithelial cells and tubular necrosis
    occurred in all dose groups, which were considered to be treatment-
    related (Eggert  et al., 1975).

    Table 1.  Acute toxicity 

                                                                       

    Species       Sex    Route       LD50        Reference
                                  (mg/kg bw)
                                                                       


    Mouse         M&F    oral         10 000    Hara  et al., 1977a
                  M      i.v.             40    Robbins  et al., 1971
                  M&F    i.v.          51-57    Hara  et al., 1977a
                  M&F    i.v.          37-40    McCormick, 1983
                  M      i.m.            213    Robbins  et al., 1971
                  M&F    i.m.        223-233    Hara  et al., 1977a
                  M      i.p.            232    Robbins  et al., 1971
                  M&F    i.p.        279-305    Hara  et al., 1977a
                  M      s.c.            228    Robbins  et al., 1971
                  M&F    s.c.        292-312    Hara  et al., 1977a

    Rat           M      oral    8000-10 000    Hara  et al., 1977a
                  M      i.v.             67    Robbins  et al., 1971
                  M      i.m.            384    Eggert  et al., 1965
                  M      i.m.            371    Robbins  et al., 1971
                  M&F    i.m.        489-511    Hara  et al., 1977a
                  M      i.p.            674    Robbins  et al., 1971
                  M&F    i.p.        478-559    Hara  et al., 1977a
                  M&F    s.c.        817-893    Hara  et al., 1977a

    Rat           M&F    i.m.            500    Eggert  et al., 1975
    (neonate)            i.p.            508    Eggert  et al., 1975

    Guinea-pig    M&F    i.m.            320    Robbins  et al., 1973c

    Dog           M&F    i.m.        300-400    Eggert  et al., 1975
                                                                       


          Gentamicin B in an aqueous vehicle was administered i.m. to
    groups of Carworth CFE rats (10/sex/group) for 14 days. Doses were 0,
    50, 100, or 250 mg/kg bw/day. Polydipsia and ptosis were observed in
    all treated rats. Body-weight gain was reduced at 250 mg/kg bw/day.
    Haematology and urinalysis parameters and BUN of treated rats were
    comparable to control values.  At necropsy, haemorrhage and necrosis
    at the injection site was noted in all rats in the high-dose group.
    Renal cortical pallor and increased kidney weights were seen in all
    treated groups. At 250 mg/kg bw/day degenerative changes in proximal
    convoluted tubules were noted including swelling, granularity of
    epithelial cells, casts, loss of brush borders and fat droplets in the
    epithelium. Liver weights were decreased at 100 and 250 mg/kg bw/day
    (Robbins  et al., 1972a).

          Carworth CFE rats (22/sex/group) were administered i.m.
    injections of either gentamicin or gentamicin C1 at doses of 0, 10,
    25 or 50 mg/kg bw/day. In each dose group, 2 males and 2 females were
    killed on days 2, 4, 6, 8, 10, and 12, and 10 males and 10 females
    were killed after 14 days. There was no treatment-related mortality in
    any dose group.  The only adverse effects noted in clinical parameters
    were a slight increase in BUN and reduced body-weight gain in the 50
    mg/kg bw/day group. Histopathological examinations revealed
    haemorrhage and lymphocytic infiltration at the injection site, which
    was seen in all treatment groups. Pale renal cortices were observed in
    all dosed groups, which were more pronounced with increasing doses of
    gentamicin. In the gentamicin-treated groups, lymphocytic infiltration
    in the renal cortex was first noted in the 50 mg/kg bw/day dose group
    after 5 doses and at lower doses thereafter.  Proximal convoluted
    tubule degeneration required 7 doses of 50 mg/kg bw/day.  Gentamicin
    C1 induced lymphocytic infiltration at 25 and 50 mg/kg after 14 days
    only, but with no tubular degeneration, suggesting a lower potential
    for renal toxicity than gentamicin (Robbins  et al., 1972b).

          Carworth CFE rats (10/sex/group) were administered i.m.
    injections of gentamicin in saline, 6 days/week for 4 weeks. The doses
    were 0, 25, 50, or 200 mg/kg bw/day.  Overt signs of toxicity occurred
    at 200 mg/kg bw/day, which included hypoactivity, bradypnoea,
    bradycardia, and increased mortality. Body-weight gain was depressed
    at 50 and 200 mg/kg bw/day. Haematological examinations revealed
    slight depressions in haemoglobin and haematocrit at 200 mg/kg bw/day. 
    Serum chemistry and urinalyses were not performed.  A limited necropsy
    revealed pale renal cortices, increased kidney weights, renal tubular
    necrosis, haemorrhage and inflammatory changes at the injection site,
    and increased parenchymatous degeneration of the liver. These lesions
    were found only at 200 mg/kg bw/day.  The NOEL was 25 mg/kg bw/day
    (Eggert  et al., 1963a).

          Charles River CD rats (5 males/group) received daily subcutaneous
    injections of gentamicin in an aqueous vehicle.  Doses of 0, 50, or
    150 mg/kg bw/day were administered for 14, 21 or 28 days.  At 150
    mg/kg bw/day, food and water intake were reduced and rats exhibited
    prostration, dyspnoea, and "staring coat".  All animals at this dose
    died during week 2.  Body-weight gain was reduced in both dose groups,
    and vestibular function was unimpaired.  Serum chemistry analyses and
    urinalysis revealed evidence of altered renal function at 50 mg/kg
    bw/day in animals killed after 14 days of treatment, but not in those
    killed at later times. The findings included increased serum
    creatinine and BUN, decreased specific gravity and pH of urine,
    glucosuria and a reduced clearance rate of endogenous creatinine. 
    Haematology parameters were not evaluated.  At necropsy, pallor of the
    renal cortex was increased in treated groups.  Histological
    examination, which was restricted to the kidneys, showed proximal
    tubular necrosis in all gentamicin-treated rats, the severity being
    related to dose (Robbins  et al., 1976a).

          Wistar rats (20/sex/group) were administered i.m. injections of
    0, 25, 63, or 156 mg/kg bw/day gentamicin for 30 days.  Groups of 5
    rats/sex/dose were allowed a recovery (no treatment) period of 30
    days. In the highest-dose group, decreased motor activity,
    prostration, ptosis, piloerection, congested conjunctiva, lacrymation,
    ataxia, and soft faeces were noted. Approximately half the high-dose
    animals died within 12 days, the remainder were killed on day 12.
    Body-weight gain and food consumption were depressed at all dose
    levels. 

          Decreases in erythrocytes, haemoglobin, and haematocrit were
    observed in the 63 mg/kg bw/day group.  At 25 mg/kg bw/day and above,
    leucocytes, BUN, cholesterol, albumin/globulin ratio and SGOT were
    increased.  At necropsy, swelling and discoloration of the kidney and
    inflation of the caecum were noted at 63 mg/kg bw/day and above.
    Degeneration of renal cortical tubules, tubular dilatation, protein
    casts and infiltration of round cells in the interstitium were found
    in all treated groups. At 156 mg/kg bw/day, necrosis of renal tubules,
    hepatocyte vacuolation, and bone marrow hypoplasia were also observed.
    Inflammatory cell infiltration, haemorrhage and edema at the injection
    site were dose-related. All changes tended to show some reversal
    following the 30-day recovery period (Hara  et al., 1977a).

          Groups of Charles River CD rats (20/sex/group) received daily
    i.m. injections of gentamicin in an aqueous vehicle.  Doses of 0,
    12.5, or 50 mg/kg bw/day were administered for up to 13 weeks.  After
    4 weeks of treatment, 5 males and 5 females were killed and examined.
    There were no clinical signs of toxicity apart from thinness and
    locomotor ataxia in a 50 mg/kg bw/day male which was killed because of
    its moribund condition on day 15.  The same animal had severely
    depressed haematocrit, haemoglobin and leucocyte counts.  It is
    unlikely that the effects seen in this animal were due to treatment
    with the test article.

          Food intake and body-weight gain were decreased in all treated
    groups. Results of vestibular function tests and ophthalmological
    evaluations were unremarkable. In the 50 mg/kg bw/day group,
    haemoglobin and haematocrit were slightly decreased and BUN was
    slightly increased.  Urine specific gravity and pH were slightly
    decreased at both treatment levels.  Increases in kidney weights,
    renal tubular necrosis, basophilia and leucocytic infiltration were
    observed in both dose groups.  Pale kidneys were reported in the 50
    mg/kg bw/day group only. Injection site haemorrhages were also seen in
    both dose groups (Robbins  et al., 1976b).

          Groups of Sprague-Dawley CD rats (10/sex/group) were fed
    gentamicin in the diet for 13 weeks. The concentration in the diet was
    adjusted as needed to maintain doses of 0, 4, 19 or 116 mg/kg bw/day. 
    The high-dose group was increased to 233 mg/kg bw/day from week 10. 
    No overt signs of toxicity were observed in any dose group. 

    Ophthalmologic evaluations, body-weight gain, food intake, and
    mortality in treated groups were comparable to controls. Soft stools
    were observed in the highest-dose group.  Haematological parameters,
    BUN, blood glucose and serum iron were unaffected by treatment. 
    Urinalyses showed an increased number of high-dose males with ketone
    bodies in urine.  At the end of the study, kidneys, liver, heart and
    brain were weighed and gross and histopathological examinations were
    performed on a wide range of tissues.  No treatment-related effects
    were noted. The NOEL was 19 mg/kg bw/day (Woodard  et al., 1970).

          Carworth CFE rats (controls: 20/sex; treated: 30/sex/group) were
    administered i.m. injections of gentamicin in an aqueous vehicle, 5
    days per week for up to 52 weeks.  The doses were 0, 5, 10, or 20
    mg/kg bw/day.  At 26 weeks, 10/sex from the treatment groups and 5/sex
    from the control group were killed and examined.  The remainder were
    killed at termination.

          There were no clinical signs of toxicity or mortality. Body-
    weight gain was depressed in males in the 20 mg/kg bw/day group from
    week 10, although feed intake was comparable to controls.  Haemoglobin
    and haematocrits were slightly decreased in the mid- and high-dose
    groups during the last half of the study. Leucocytes, blood glucose
    and urinalysis parameters remained within normal limits.

          At necropsy, liver, heart and brain weights were unaffected.
    Adverse effects on the kidney included increased organ weight and
    pitted or mottled surfaces at 10 and 20 mg/kg bw/day.  The onset of
    interstitial nephritis (seen commonly in aging rats) occurred earlier
    in treated groups compared to controls.  At 6 months, only one rat in
    the control group was affected, while almost all rats in the high-dose
    group exhibited this effect.  At 12-months, the incidence was
    statistically significant in the high-dose group only, with the
    incidence in other groups not differing significantly from controls. 
    Injection-site reactions were observed in all dose groups with a dose-
    related increase in severity.  Muscle fibrosis was seen at the higher
    treatment levels.  The NOEL was 5 mg/kg bw/day (Robbins  et al.,
    1970a).

    2.2.2.2  Rabbits

          Two dermal studies were conducted in New Zealand white rabbits at
    doses of 0, 0.5, 1, or 2 mg/kg bw/day gentamicin.  Animals were
    treated 6 hours/day, 5 days/week on intact and abraded skin for either
    21 days (3 females per group) or 90 days (2 males and 1 female per
    group).  A different vehicle (unidentified) was used in each study. 
    Clinical signs, body weight, serum chemistry, haematology, urinalysis,
    and gross and microscopic pathology were unaffected.  Erythema and
    edema at the application sites were slight in one study and moderate
    in the other.  These effects were considered to be vehicle-related
    (Eggert  et al., 1963b; 1964).


    2.2.2.3  Dogs 

          Groups of beagle dogs (2/sex/group) were administered i.m.
    injections of gentamicin or gentamicin C1 in an aqueous vehicle
    (sterile water) daily for 14 consecutive days.  The doses were 0, 15,
    30, or 45 mg/kg bw/day.

          There were no deaths or clinical signs of toxicity, nor were body
    weight or ophthalmological parameters affected.  Clinical chemistry
    analyses showed that both drugs caused an increase in BUN at 45 mg/kg
    bw/day.  Other biochemical and haematological parameters remained
    within normal limits.  Urine specific gravity was lower and urine
    volume increased in the 45 mg/kg bw/day gentamicin group. Occult blood
    and albumin in urine were increased in treated groups, particularly in
    the 45 mg gentamicin/kg bw/day group. One dog in this group also
    showed glucosuria.

          Gross examination of organs revealed pale and congested renal
    cortices at 45 mg/kg bw/day.  Kidney weights were increased in a dose-
    related manner in all treated groups.  Renal proximal convoluted
    tubule degeneration or necrosis was increased with 30 and 45 mg/kg
    bw/day gentamicin and 45 mg/kg bw/day gentamicin C1. Haemorrhage,
    inflammatory changes and/or necrosis were observed at all injection
    sites, including vehicle controls (Robbins  et al., 1972c).

          In another 14-day study, groups of beagle dogs (2/sex/group)
    recieved i.m. injections of 0, 10, or 45 mg/kg bw/day gentamicin or
    45, 90, or 120 mg/kg bw/day gentamicin B in an aqueous vehicle.

          There were no clinical signs of toxicity.  Food intake and body
    weights were depressed at 45 mg/kg bw/day gentamicin and 120 mg/kg
    bw/day gentamicin B.  Three dogs given 45 mg gentamicin/kg bw/day were
    killed on day 14 because of their moribund condition.  Gentamicin-
    induced changes in clinical laboratory investigations were recorded in
    the 45 mg/kg bw/day group, which included increases in neutrophils,
    BUN and SGPT; a slight decrease in urine specific gravity; and glucose
    and occult blood in urine.  Increases in SGPT were seen at all dose
    levels of gentamicin B.

          At necropsy, kidney and liver weights were unaffected by either
    drug at any dose level. Pale renal cortices and increased lymphocytic
    infiltration and coalescence of mitochondria in proximal convoluted
    tubule epithelial cells were seen in all drug-treated groups. 
    Proximal tubular necrosis and excessive fat deposition were associated
    with administration of 45 mg/kg bw/day gentamicin (Robbins  et al.,
    1973a).

          One-day-old beagle puppies (4 litters per dose, 6-9 pups/litter)
    were injected i.m. with gentamicin in an aqueous vehicle daily for 14
    consecutive days.  Doses were 0, 2, 6, or 10 mg/kg bw/day.  Two

    litters per dose were killed after 5 days and 2 pups per litter were
    maintained for a drug-free recovery period of 6 weeks following the
    last treatment.  There was no mortality and no clinical signs of
    toxicity.  Body weight, righting reflex, haematology and serum
    biochemistry parameters remained within normal limits.  Post-mortem
    examination of kidneys and liver showed no effects on organ weight or
    histo-pathology.  Histolopathological evaluations of the vestibular
    apparatus of the ear were unremarkable (Vymetal  et al., 1969).

          Daily i.m. injections of gentamicin in a saline vehicle were
    administered to groups of beagle dogs (2/sex/group) for up to 3 weeks. 
    The doses were 0, 15, 30 or 60 mg/kg bw/day.  Vomiting was reported in
    3/4 dogs in the high-dose group between days 9 and 12 of treatment and
    in 3/4 dogs in the mid-dose group between days 16 and 20 of treatment. 
    Vomiting occurred within one or two hours of treatment.  All dogs in
    the 60 mg/kg bw/day group were killed between days 9 and 12 because of
    their extreme moribund condition characterized by weakness, lethargy,
    recumbency and irregular respiration.  Slight body-weight loss was
    noted during the second week in the 30 mg/kg bw/day group. 
    Ophthalmological findings were unremarkable.

          Haematological parameters remained within normal limits.  Serum
    creatinine and BUN were increased at 30 and 60 mg/kg bw/day.  At the
    end of the study, SGPT was elevated and serum sodium and chloride ions
    were decreased at 30 mg/kg bw/day.  At 30 mg/kg bw/day and above,
    urine specific gravity was decreased compared to controls and
    glucosuria and occult blood were detected.  Urine volume was increased
    at 60 mg/kg bw/day.  Kidney weights were increased in all treated
    groups.  Gross and histopathological examination revealed renal
    cortical pallor and renal tubular necrosis in all treated animals. 
    Liver congestion was observed at 30 and 60 mg/kg bw/day.  Muscle
    degeneration and fibrosis of injection sites were seen at 60 mg/kg
    bw/day (Robbins  et al., 1973b).

          In two separate studies, beagle dogs (2/sex/group) were
    administered i.m. injections of gentamicin consisting of two different
    ratios of the components C1 and C2, viz. 58:42 and 70:30.  Groups
    were treated with 0, 6, 10, or 50 mg/kg bw/day for 7 weeks.  The
    findings were essentially the same for each ratio. Clinical signs were
    reported as anorexia, ataxia, prostration, vomiting and convulsions,
    but the group incidences were not provided.  Dogs in the highest-dose
    group died or were killed during weeks 2 and 3. Body weights were
    unaffected.

          Haemoglobin and haematocrits fell sharply just prior to
    intercurrent death or terminal kill in all treated animals.  Increased
    BUN, glucosuria, albuminuria, and urinary casts were observed in the
    10 and 50 mg/kg bw/day groups.  Pale renal corticies were observed in
    all treated groups.  This finding was accompanied by a gelatinous

    transudate in animals dosed at 50 mg/kg bw/day. Toxic nephrosis was
    noted in treated animals, which was characterized as cloudy swelling
    at 6 mg/kg bw/day to severe tubular necrosis at 50 mg/kg bw/day.
    Muscle damage was seen at injection sites in all groups including
    controls. (Eggert  et al., 1963c; 1973).

          Beagle dogs (2/sex/group) received i.m. injections of 0, 63, or
    100 mg gentamicin/kg bw/day.  The duration was intended to be 30 days,
    but all treated animals died within 18 days. Signs of gentamicin
    toxicosis included vomiting, salivation, gait disturbances, difficulty
    in standing, decreases in heart and respiration rates, and reduced
    body weight and food intake. Gross and histopathological examinations
    revealed swelling, discoloration and increased weight of the kidney,
    degeneration and necrosis of renal tubular epithelium, infiltration of
    round cells, protein casts and narrowing and dilatation of tubules. 
    These findings were observed at both treatment levels. Inflammation
    and muscle fibre degeneration at the injection sites were also
    observed in both dose groups with a dose-related increase in severity
    (Hara  et al., 1977b).

          Groups of beagle dogs (4/sex/group) were administered i.m. doses
    of 0, 12.5, or 25 mg/kg bw/day gentamicin in an aqueous vehicle, for
    12 weeks.  There were no treatment-related clinical signs of toxicity. 
    Food consumption was unaffected.  Body-weight loss occurred in all
    groups, which was more severe in the 25 mg/kg bw/day group and the
    12.5 mg/kg bw/day females.

          Ophthalmological and haematological parameters remained within
    normal limits.  There were slight elevations in SGPT, SGOT and
    creatine phosphokinase at both treatment levels.  At 25 mg/kg bw/day,
    urine specific gravity was decreased and urine volume was increased. 
    Glucosuria and occult blood were present in one 12.5 and two 25 mg/kg
    bw/day animals.  Gross and histopathological findings included
    increased kidney and liver weights, pale renal cortices, and proximal
    renal tubular necrosis in all treated groups (Robbins  et al.,
    1976c).

          Groups of beagle dogs (4/sex/group) were administered oral doses
    of 0, 2, 10, or 60 mg/kg bw/day gentamicin in capsules for 14 weeks.
    The highest level was increased to 120 mg/kg bw/day after 2 months. 
    Emesis and diarrhoea were observed occasionally in treated dogs. 
    There were no effects on body weight, ophthalmology, haematology,
    blood chemistry or urinalysis.  The only postmortem change was
    interstitial nephritis observed in 2 animals in the high-dose group. 
    The NOEL was 10 mg/kg bw/day (Vymetal  et al., 1970).

          Beagle dogs (controls: 2/sex; treated: 4/sex/dose) were injected
    i.m. with doses of 0, 3, 5, or 8 mg/kg bw/day gentamicin in an aqueous
    vehicle. Animals were treated 5 days per week for up to 12 months. 
    One dog per sex per group was scheduled for an interim kill after 6

    months.  Localized pain and transient lameness of the injected leg
    were seen in all groups. Ophthalmological and physical examination
    findings were within normal limits.  Vomiting and profuse salivation
    were noted in one animal in the 8 mg/kg bw/day group in weeks 23 and
    24.  This animal lost considerable body weight during the last 8 weeks
    of treatment and had a slightly increased BUN, glucosuria, decreased
    urine specific gravity and increased urine volume.  Body weight,
    haematology, blood chemistry and urinalysis were within normal limits
    in all other dogs.

          Pale renal corticies and interstitial nephritis were seen after
    gross and histopathological examinations in all treatment groups with
    a dose-response relationship.  Organ weights were similar in all
    groups. Inflammatory changes, haemorrhage and fibrosis at the
    injection sites were present in all groups, with an increase in
    severity in treated animals (Robbins  et al., 1970b).

    2.2.2.4  Monkeys 

          Groups of 4 squirrel monkeys (sex not specified) were
    administered daily s.c. injections of 0, 25, 50 or 75 mg/kg bw
    gentamicin in saline, for up to 3 weeks.  All monkeys receiving
    gentamicin (except one animal in the low dose group) had to be killed
    intercurrently because of their moribund condition.  The average
    survival times were 15.3, 10.3 and 7.5 days at 25, 50 and 75 mg/kg
    bw/day, respectively. Clinical signs included ataxia, weakness,
    hypoactivity, irregular respiration and eye scratching at each dose
    level.  Sporadic convulsions occurred at 50 and 75 mg/kg bw/day. 
    Body-weight loss was recorded in all groups, including controls, which
    appeared to be enhanced with gentamicin treatment.  However, there was
    no clear, dose-response relationship.

          Post-injection acoustic reflex measurements could not be obtained
    from the 75 mg/kg bw/day group due to their rapid decline in
    condition. In addition, instrument failure resulted in the loss of 3
    post-injection data points.  Therefore, evaluations were performed on
    a total of 14 monkeys out of 28.  Results indicated that hearing
    deficits occurred in both the low- and mid-dose groups. Apart from the
    single low-dose survivor, all animals had increased serum creatinine
    and BUN.  The author stated that the majority of dosed animals showed
    severe renal tubular necrosis.  Individual animal data were not
    provided (Igarashi  et al., undated).

          Groups of 3 female Rhesus monkeys were injected i.m. with doses
    of 0, 6 or 30 mg/kg bw/day gentamicin in an aqueous vehicle for 3
    weeks.  Adverse clinical signs were limited to the 30 mg/kg bw/day
    group, which included pronounced facial paling and ptosis, markedly
    disturbed equilibrium from day 20, and depressed food intake and body-
    weight gain from week 2 onwards.  Two monkeys in this group were
    killed because of their moribund condition on day 21.

          Haematological examinations showed decreases in haemoglobin,
    haematocrit, and erythrocytes at 30 mg/kg bw/day.  Serum chemistry
    findings included increases in SGPT, SGOT and LDH, and decreases in
    serum potassium, sodium, chloride and calcium ions in the 30 mg/kg
    bw/day dose group. Serum creatinine and BUN were increased in both
    dose groups.  Urinalyses revealed proteinuria, glucosuria and an
    increased presence of casts and epithelial cells at 30 mg/kg bw/day.

          At necropsy, kidney weights were increased and had a yellow-grey
    appearance.  Histologically, cloudy swelling, cortical striation,
    degeneration and necrosis of proximal convoluted tubules were
    reported.  The renal lesions which were seen in both dose groups, were
    considered to be treatment-related.  Vacuolar degeneration of
    hepatocytes was noted at 30 mg/kg bw/day.  Injection sites showed
    dose-related muscle degeneration and necrosis accompanied by
    haemorrhage and cellular infiltration.  Electron microscopy of renal
    tubules from the 30 mg/kg bw/day monkeys revealed myeloid bodies
    present in both tubular cells and lumen, increased phagosomes,
    disappearance of brush borders and sloughing of epithelial cells from
    the basement membrane (Tanaka  et al., 1977).

    2.2.3  Reproductive toxicity studies

    2.2.3.1  Rats 

          Groups of Carworth CFE rats (30/sex/group) were injected 6 days/
    week with i.m. doses of 0, 5, or 20 mg/kg bw/day gentamicin in saline. 
    Males were injected from 70 days prior to mating until 7 days before
    mating.  Females in the 5 mg/kg bw/day group were injected from 14
    days prior to pairing with a male until post partum day 21.  Females
    in the 20 mg/kg bw/day group were treated from the time of
    impregnation (determined by vaginal smear) until post partum day 21. 
    Ten females per group were killed for litter and dam evaluations on
    gestation day 21, the remainder were allowed to deliver normally.  F1
    offspring were not treated.  Groups of 10 males and 10 females from
    randomly selected litters were paired within treatment levels
    (avoiding brother-sister mating) to produce an F2 generation.
    F1 Dams were allowed to deliver normally.

          After 13 doses, penile bleeding was observed in high-dose F0
    males.  Because of this finding, the dose was reduced to 15 mg/kg
    bw/day after which bleeding ceased.  In F0 males of the high dose,
    body-weight gain was slightly lower during the second half of the
    treatment period.  There were no overt effects in females.

          Pregnancy rates were not affected. There was no prenatal
    mortality and litter sizes and weights were similar between groups. 
    Early postnatal mortality was increased at both doses, which was
    attributed to maternal neglect and failure to lactate, neither of
    which were considered treatment-related.  Fetal abnormalities were not

    observed in delivered pups or caesarian-derived fetuses.  Gentamicin
    was present in the amniotic fluid in 5/10 low-dose dams, and 8/10
    high-dose dams but was not detected in homogenized fetuses.  No
    treatment-related changes in pregnancy rate, litter size and weight,
    prenatal mortality or fetal abnormalities were reported in this study
    (Robbins  et al., 1966).

    2.2.4  Special studies on embryotoxicity and teratogenicity

    2.2.4.1  Mice 

          Female JCL-ICR mice (15-33/group) received s.c. injections of
    gentamicin in saline during gestation days 6 to 10.  The doses
    administered were 0, 1, 10 or 100 mg/kg bw/day.  In the high-dose
    group, body-weight gain was depressed during treatment and kidney
    weight was increased.  Gentamicin was measured in amniotic fluid in
    the high-dose group.  It was not clear whether attempts were made to
    measure gentamicin in amniotic fluid in the other two dose groups.  In
    five control and five 100 mg/kg bw/day dams, delivery of fetuses was
    allowed to occur normally.  The development of eye and ear openings
    was unaffected and kidney and liver weights were similar between
    groups at post partum day 35.  The remaining females were killed on
    gestation day 17 for dam and litter evaluations.  Prenatal loss was
    increased at 10 and 100 mg/kg bw/day.  There were no treatment-related
    increases in fetal abnormalities (Nishio  et al., 1987).

    2.2.4.2  Rats 

          Female Carworth CFE rats (40/group) were injected i.m. with
    gentamicin in saline on gestation days 3 to 16.  The doses
    administered were 0, 25, or 50 mg/kg bw/day, 6 days per week.  Females
    were allowed to deliver normally.  At least 10 days after weaning the
    first litter, dams were bred again and the above procedures were
    repeated.  Adult females showed no clinical signs of toxicity.  Body-
    weight gain was lower in the 50 mg/kg bw/day group during the
    treatment period.  At necropsy, pale renal cortices were observed in
    both dose groups.  Resorption rates were comparable to control values. 
     The number of stillborn pups was slightly increased at 50 mg/kg
    bw/day following the second series of matings.  Offspring were killed
    and examined 21 days post partum.  No treatment-related abnormalities
    were reported (Eggert & Haring, 1964).

          Groups of 17 female Sprague-Dawley rats were given intra-muscular
    injections of 0 or 75 mg/kg bw/day gentamicin in saline.  Treatment
    was on gestation days 10 to parturition.  Dams were allowed to deliver
    normally. Parturition was delayed in gentamicin-treated dams by an
    average of 15 hours and birth weights were lower.  In pups showing the
    lowest birth weights, kidney weight and the number of nephrons were
    reduced at birth and at 14 and 21 days post partum.  Pups with higher
    birth weight showed similar kidney weight and numbers of nephrons to

    controls; however, a relative decrease in the number of nephrons was
    reported in these animals at 14 and 21 days post partum.  Necrosis was
    not reported but vacuoles in proximal tubular epithelium were
    increased with loss of brush border microvilli and the presence of
    debris in the tubular lumen.  Gentamicin was detected in the kidneys
    of all pups born to treated mothers, the levels being higher in pups
    showing the lowest birth weights.

          In 7 litters per group, half the pups received subcutaneous doses
    of 0 or 75 mg/kg bw/day of gentamicin on post partum days 1 to 13,
    then killed on post partum day 14.  Drug treatment caused an increase
    in kidney weight but the number of glomeruli were similar in both
    groups (Gilbert  et al., 1987).

          In an abstract, it was reported that rats were given s.c. doses
    of 0 or 110 mg/kg bw/day gentamicin on either gestation days 10 to 15
    or 15 to 20.  Females were allowed to deliver normally.  Measurements
    of arterial blood pressure in offspring, one year after birth,
    revealed significantly elevated blood pressure in females but not in
    males (Chahoud  et al., 1986).

    2.2.4.3  Guinea-pigs 

          Guinea-pigs (6 females per group) were administered i.m.
    injections of 0 or 4 mg/kg bw/day gentamicin in saline on gestation
    days 48 to 54.  Females were allowed to deliver normally.  Litter size
    and weight and body and kidney weights of offspring from the treated
    group were comparable to controls to day 20 post partum. Studies of
    kidney function in offspring showed a higher excretion of phosphate in
    3-day-old pups but not at 10 days of age.  Excretion of sodium,
    potassium, magnesium and calcium, urinary flow rate, glomerular
    filtration rate and the numbers of glomeruli were unaffected. The
    length of proximal tubules and glomerular volume were reduced at 3 and
    10 days post partum but not at 20 days. Gentamicin was present in pup
    renal cortex at higher levels that in the medulla.  Levels were
    highest 3 days after birth and decreased thereafter (Le Lievre 
     et al., 1987).

    2.2.4.4  Rabbits 

          Groups of 13 female New Zealand white rabbits were administered
    i.m. doses of 0, 0.8, or 4 mg/kg bw/day gentamicin in saline.  The
    high dose was given as two divided doses, 7 hours apart.  Treatments
    were administered on gestation days 6 to 16.  Eight females per group
    were killed for dam and litter evaluations on gestation day 30.  The
    remainder were allowed to deliver normally.  Pups were killed and
    examined on post partum day 21. Adult animals were in good health
    throughout the study.  No treatment-related effects were noted on
    prenatal loss, litter size or weight, fetal morphology, or postnatal
    survival or body-weight gain.  (Robbins & Klein, 1966).

    2.2.5  Special studies on genotoxicity 

          The results of genotoxicity studies on gentamicin are summarized
    in Table 2.

    2.2.6  Special studies on kidney function

    2.2.6.1  Rats 

          A group of 6 male Sprague-Dawley rats was injected i.m. with
    doses of 80 to 160 mg/kg bw/day gentamicin for 7 days.  At
    termination, animals were anaesthetized with thiobarbital and kidney
    function was assessed.  The glomerular filtration rate, as measured by
    inulin clearance, was reduced in a dose-related manner in all
    treatment groups.  Aciduria and glucosuria (determined by Labstix)
    were induced at 160 mg/kg bw/day, but not at the lower doses,
    indicating that reabsorption of glucose in the proximal renal tubule
    had been impaired (Chiu   et al., 1977).

          Sprague-Dawley rats (group sizes not given) were injected s.c.
    with 0 or 100 mg/kg bw/day gentamicin for up to 7 days.  After four
    doses, serum creatinine and BUN were increased and urine osmolality
    was decreased, suggesting impairment of urine concentrating capacity. 
    Tubular reabsorption of solute free water was unaffected.  Tubular
    secretion of para-aminohippurate (PAH) was increased, although
    glomerular filtration rate was decreased, after 4 days. Kidney
    cortical slices, isolated from rats treated with gentamicin,
    accumulated PAH  in vitro at a faster rate than slices from control
    animals; this effect was inhibited in the presence of probenecid. This
    provided evidence that an alteration in the organic acid transport
    system was responsible for the increased rate of PAH accumulation
    (Cohen   et al., 1974).

          Female Sprague-Dawley rats (group sizes not given) were injected
    s.c. with 0, 50, 100, or 150 mg/kg bw/day gentamicin for up to 14
    days.  During the treatment period, urine osmolality was decreased
    followed by a rise in urine volume and water intake.  Proteinuria was
    seen from day 3 and serum creatinine and BUN were increased at 100 and
    150 mg/kg bw/day. At termination, microscopic examination of kidneys
    revealed dose-related injury to proximal tubules in all dose groups,
    consisting of increased lysosomal bodies, disruption of brush borders,
    cellular swelling and necrosis.  Kidney cortical slices, from rats
    treated with gentamicin, showed increased uptake of PAH  in vitro 
    (Kaloyanides, 1977).

          Sprague-Dawley rats (group sizes not given) were injected i.p.
    with 0 or 10 mg/kg bw/day gentamicin for up to 14 days. Kidney
    function was unaffected throughout the treatment period. Animals were
    killed after 1, 4, 7 and 14 doses and kidneys removed for examination. 
    Microscopic examinations found proliferation of lysosomes in proximal

    tubular cells on day 4.  This was associated with decreases in
    lysosomal sphingomyelinase and phospholipase activities, suggesting
    lysosomal dysfunction.  At day 9, protrusion of cells and/or nuclei
    into tubular lumens was observed and several cells had lost part of
    their brush borders.  Focal necrosis was evident on day 14 (Carlier
     et al., 1982).

    2.2.6.2  Dogs

          Male beagle dogs (group sizes not given) were injected i.m. with
    0 or 30 mg/kg bw/day gentamicin for up to 11 days.  Serum creatinine,
    BUN, and urine protein were increased, and creatinine clearance and
    urine osmolality were decreased in gentamicin-treated animals.  In
    addition, urinary levels of beta-glucuronidase, N-acetyl-beta-
    glucosaminidase and muramidase were elevated.  Microscopic renal
    lesions ranged from diffuse moderate hyaline droplet degeneration to
    frank tubular necrosis.  The pathological and enzyme changes appeared
    to precede the functional alterations (Adelman  et al., undated).

    2.2.7  Special study on ototoxicity

    2.2.7.1  Monkeys

          Groups of 3 female Cynomolgus monkeys were injected i.m. with
    doses of 0, 25, or 50 mg/kg bw/day gentamicin for 35 days. All monkeys
    dosed at 50 mg/kg bw/day died:  one on day 7 and the other two on day
    22.  Prior to death, the pinna reflex to high frequencies in these
    monkeys was slightly reduced, but there was no observable ataxia
    indicative of vestibular impairment. Histopathological examination of
    the crista ampullaris showed vacuole formation at both doses and, at
    the higher dose, hair cell loss and a reduction in the thickness of
    sensory epithelium. In the organ of Corti, cochlear hair cell loss was
    noted at 50 mg/kg bw/day while the histology of the macula was not
    significantly affected (Yakota  et al., 1984).

    2.2.8  Special study on neurotoxicity

          Gentamicin was administered parenterally to Charles River CD
    rats, cats and beagle dogs, to assess its neurotoxicity potential. 
    The treatment regimes were as follows:

          Rats  -     0, 6.6, 16.6, 41.5 or 104 mg/kg bw/day, s.c., for
                      41 days.

          Cats  -     0, 2.5, 5.0 or 10.0 mg/kg bw/day, s.c., for 42 days.

          Dogs  -     0, 5.0, 8.3 or 41.5 mg/kg bw/day, i.m., for 49 days.

          In rats, righting reflex was impaired at 104 mg/kg bw/day and
    ataxia was observed in dogs given 8.3 and 41.5 mg/kg bw/day.  Ataxia
    was not produced in cats at any dose (Taber  et al., 1963).

    2.2.9  Special studies on microbiological effects

          Results of investigations into the effects of gentamicin on human
    intestinal flora were not available.  However, two published reports
    were available on the inhibitory activity of gentamicin against a wide
    range of bacterial strains  in vitro. 

        Table 2.   Results of genotoxicity studies on gentamicin 

                                                                                            
    Test system             Test object           Results            Reference
                                                                                            

    Reverse mutation1        S. typhimurium       negative2          Houk  et al., 1989

    Reverse mutation1        S. typhimurium       negative3          Koeda & Hirano, 1979
                            TA98, TA100,        
                            TA1535, TA1536,     
                            TA1537, TA1538      

    Reverse mutation1        S. typhimurium       negative2          Mitchell  et al., 1980
                            TA98, TA100,                           
                            E. coli WP2                            

    Reverse mutation1        E. coli  CM891       negative3          Mitchell & Gilbert, 1984

    Forward mutation1        E. coli  CM891       positive3 at a     Mitchell & Gilbert, 1984
                                                  cytotoxic level
                                                  (0.25 g/ml)

    Forward mutation1        E. coli  WP2         positive2 at a     Mitchell  et al., 1980
                                                  cytotoxic level
                                                  (0.49 g/ml)

    Mitotic crossing-        S. cerevisiae  D5    negative3          Koeda & Hirano, 1979
    over1                                                         

    Gene conversion1         S. cerevisiae  D4    negative3          Mitchell  et al., 1980

    Petite inducation1       S. cerevisiae  D4    positive3 (500     Mitchell  et al., 1980
                                                  g/ml) at pH4.4,
                                                  not pH 7.2

    DNA repair1              E. coli  WP2,        negative2          Mitchell  et al., 1980
                            WP100

    Rec-assay1               B. subtilis          negative3          Kada  et al., 1980
                            M45, H17                               

    SOS function1            E. coli  PQ37        negative2          Mamber  et al., 1986

    DNA-cell binding         E. coli  Q13         positive2          Kubinski  et al., 1981
                                                  (20 g/ml) test 
                                                  not validated
                                                                                            

    Table 2 (contd)

                                                                                            
    Test system             Test object         Results            Reference
                                                                                            

    Chromosome              Mouse L-cells       positive3 but      Leonard & Botis, 1975
    aberrations                                 mitosis inhibited
                                                (500 g/ml x 4 d 
                                                plus 100 g/ml x 
                                                20 d)

    SCE                     Human fibroblasts   positive3 but      McDaniel & Schultz, 1993
                            GM00847             less than doubling
                                                (75-250 g/ml)
                                                                                            

    1  Appropriate positive controls were used.
    2  Both with and without rat liver S9 fraction.
    3  Without metabolic activation. 
    
          One article reported the minimum inhibitory concentrations (MICs)
    for gentamicin in 601 clinical isolates of anaerobic bacteria. The
    experiments were conducted using the agar-dilution technique at 37C
    for 48 hours in an anaerobic incubator, an inoculum of 103 to 104
    colony-forming units and serial concentrations of gentamicin in the
    range of 0.1 to 25 g/ml (Martin  et al., 1972). In a second
    publication, results were reported for  Clostridium difficile 
    strains, but there was no information on the culture conditions
    employed (Lorian, undated). All results are presented in Table 3.

          The susceptibility to gentamicin of most anaerobic bacteria was
    low, the most sensitive being  Eubacterium sp., with a modal MIC
    value of 0.8 g/ml for the 20 strains tested.

    2.3  Observations in humans

          In a prospective, randomized, blinded, comparative trial, 54
    patients treated with gentamicin were evaluated for nephrotoxicity and
    ototoxicity.  The dosage regime was usually 1.7 mg/kg bw i.v. every 8
    hours (5.1 mg/kg bw/day) for 7 to 54 days. Desired serum drug levels
    were maintained by reducing the dose in patients with impaired renal
    function.  Nephrotoxicity, defined as a 50% increase in serum
    creatinine, was produced in 8 (15%) patients.  Auditory toxicity,
    defined as a decrease in the sensorineural threshold of at least 15
    decibels in two or more frequencies, was produced in 3 (6%) patients. 
    Vestibular toxicity, defined as at least a 50% decrease in maximum

    average slow-phase eye speed following water stimulation of the ear,
    was induced in 3 of 33 (9%) patients.  Auditory and vestibular effects
    were not noted in the same individuals (Lerner  et al., 1986).

          Kidney biopsies were obtained from 5 patients with renal cancer
    following surgical removal of both kidneys.  Prior to surgery,
    gentamicin was administered at a dosage of 1.5 mg/kg bw three times a
    day (4.5 mg/kg bw/day) for 4 days.  Microscopic evaluation of the
    kidney specimens revealed increases in lysosome numbers with moderate
    to marked decreases in the activity of sphingomyelinase and acid
    phospholipase A1 (Carlier  et al., 1982).

          In a retrospective study involving patients on chronic
    haemodialysis therapy, 23 patients were treated with gentamicin. 
    Dosages were not identified.  Of the drug-treated subjects, 7 (30%)
    developed clinically detectable vestibular toxicity.  The principal
    risk factors for the development of ototoxicity were age, duration of
    treatment and the total dose administered.  There was no positive
    association with peak serum levels of gentamicin or the total absence
    of kidneys (Gailiunas Jr.  et al., 1978).

          A review, focusing mainly on prospective trials, reported on a
    total of more than 10 000 patients treated with aminoglycoside
    antibiotics.  The incidence of cochlear toxicity associated with
    gentamicin administration ranged from 5 to 10% in adults.  The
    incidence was claimed to be lower in infants (Matz, 1993).

          Adverse reactions to gentamicin during the years 1963 to 1973
    were reviewed.  Of the 3500 patients studied, the main non-specific
    reactions were increases in serum transaminases (16), skin rashes (16)
    and granulocytopaenia (8).  Also presented were results from clinical
    trials with gentamicin. Possible or probable nephrotoxicity was found
    in 22 of 285 (7.7%) patients in 1965 to 1966, 70 of 1450 (4.8%)
    patients in 1967 to 1969 and 48 of 1635 (2.9%) patients in 1970 to
    1973. Possible or probable ototoxicity was found in 16 of 565 (2.8%)
    patients in 1963 to 1966, 27 of 1450 (1.8%) patients in 1967 to 1969
    and 15 of 1635 (1%) patients in 1970 to 1973. Critical doses or
    duration of treatment were not given, but ototoxicity usually occurred
    in association with impaired renal function (Hewitt, 1974).

          The  rates of allergic  cutaneous reactions were determined in 15
    438 consecutive in-patients monitored by the Boston Collaborative Drug
    Surveillance Program from June 1975 to June 1982. Of the 670 patients
    receiving gentamicin, there were 3 (0.5%) skin reactions.  


        Table 3.  Minimum inhibitory concentration (MIC) values for gentamicin against anaerobic bacteria 
                                                                                                         
    Organism (No. of isolates)              Cumulative percent inhibition at each concentration (g/ml)

                                              0.1     0.4     0.8     1.6     3.1     6.2    12.5      25
                                                                                                         

     Bacteroides fragilis            (195)                                                   1         6

     B. incommunio                    (10)                                                   10        40

     B. variabilis                     (5)                                                             60

     B. oralis                         (2)                                                   50        100        

     B. terebrans                      (5)            40                                     60        

     B. melaninogenicus               (29)    24      31              34              45     59        76

     Bacteroides  F1,F2,F3            (11)    27      36                                     45        73

     Fusobacterium fusiforme          (18)                                    5              11        56

     Fusobacterium  sp.                (2)                                                             50

     Clostridium perfringens          (34)                                                             6

     C. difficile                     (15)                                                   20        40

     Clostridium sp.                  (17)    6                                                        18

     Peptococcus sp.                 (145)    2       3       5       7       11      30     62        95

     Peptostreptococcus sp.           (72)    1       9       13      18      20      33     58        78

     Veillonella sp.                  (13)                            8               31     46        85

                                                                                                         

    Table 3 (contd)
                                                                                                         
    Organism (No. of isolates)              Cumulative percent inhibition at each concentration (g/ml)

                                              0.1     0.4     0.8     1.6     3.1     6.2    12.5      25
                                                                                                         
     Propionibacterium acnes         (16)                                     25      56     75        81

     Eubacterium lentum              (14)             43      57      71              85     93        100

     E. alactolyticum                 (2)     50                                                        

     Eubacterium sp.                  (5)     20                                      40                

     Bifidobacterium sp.              (5)                     20                      60     80        100

     Catenabacterium                  (3)                                                              66
     filamentosum

     Catenabacterium sp.              (2)             50                                     100        

                                                                                                         
    

    3.  COMMENTS

          A range of studies on gentamicin was submitted for assessment,
    including information on pharmacokinetics and metabolism, acute
    toxicity, short-term toxicity, reproductive toxicity and
    teratogenicity, genotoxicity, antimicrobial activity, a variety of
    special studies and observations in humans.

          Gentamicin, in common with other aminoglycosidic drugs, is poorly
    absorbed from the gastrointestinal tract.  Parenteral doses distribute
    mainly into extracellular space, but there is significant penetration
    into the kidney cortex and the inner ear. There is negligible
    metabolism of the drug and unchanged gentamicin is excreted rapidly,
    mostly in the urine. 

          Single oral doses of gentamicin were slightly toxic in rodents
    (LD50 = 8000 to 10 000 mg/kg bw), which supports the view that the
    drug is largely unabsorbed when administered by this route. Parenteral
    dosing of mice, rats, guinea-pigs and dogs demonstrated high
    intravenous toxicity (LD50 = 37 to 67 mg/kg bw) and moderate toxicity
    by i.m., s.c. and i.p. routes (LD50 = 213 to 893 mg/kg bw).

          Gentamicin was extensively tested by the i.m. and s.c. routes in
    rats administered the compound for periods of up to 12 months (doses
    up to 200 mg/kg bw/day) in dogs for up to 12 months (doses up to 100
    mg/kg bw/day) and in monkeys for 3 weeks (doses up to 75 mg/kg
    bw/day). The kidney was the primary target organ in each species with
    effects observed predominantly in the renal cortex.  The major
    findings were an increase in interstitial nephritis and toxic
    nephrosis in the proximal convoluted tubules.  The latter was
    characterized by a dose- and time-dependent progression from loss of
    brush borders, cloudy swelling, the presence of casts and
    proteinaceous material in the tubules, desquamation of epithelial
    cells and necrosis. These changes were associated with a profound
    impairment of renal function, and in extreme cases, death of severely
    affected animals.  Special studies in rats suggested that the
    nephrotoxicity may be associated with disruption of lysosomal
    function.  Nephrotoxicity has been observed in humans treated with
    gentamicin.

          Toxicity to the inner ear may occur after exposure to
    aminoglycosides, including gentamicin.  There were no clear
    indications of ototoxicity in the general toxicity studies; however,
    a special study in monkeys, at doses up to 50 mg/kg bw/day, showed
    hair cell loss and reduced sensory epithelium in structures of the ear
    as well as a functional loss in hearing. Observations in humans have
    revealed auditory or vestibular toxicity after therapeutic
    administration of gentamicin.

          Oral dosing of rats and dogs for a period of 3 months, at doses
    up to 116 and 60 mg/kg bw/day, respectively, was virtually without
    systemic effects.  Soft stools or diarrhoea were observed in both
    species and dogs showed interstitial nephritis at high doses.  The
    NOELs were 19 mg/kg bw/day in rats and 10 mg/kg bw/day in dogs.

          A multigeneration reproductive toxicity study in the rat showed
    no adverse effects on reproduction parameters after intramuscular
    injections of 5 or 20 mg gentamicin/kg bw/day. Teratogenicity studies
    in mice, rats, guinea-pigs and rabbits did not identify any potential
    for the production of fetal abnormalities.  Fetotoxicity, in the form
    of fetal death in mice (10 mg/kg bw/day) and rats (50 mg/kg bw/day)
    and reduced birth weight in rats (75 mg/kg bw/day), was observed after
    parenteral dosing.

          Positive results were obtained in some  in vitro genotoxicity
    studies, but none of these was adequate to evaluate the genotoxicity
    of gentamicin.  There were no carcinogenicity studies available on
    gentamicin.  In toxicity studies in animals of up to one year
    duration, there were no pre-neoplastic or neoplastic lesions. The
    Committee considered that the data were inadequate to fully assess the
    carcinogenicity of gentamicin.

          Data on the effects of gentamicin on human gut flora were not
    available. However,  in vitro data were presented on MICs for over
    600 clinical isolates of anaerobic bacteria including some species
    representative of the microbial flora in the human gastrointestinal
    tract. Many of the organisms were found to be resistant to gentamicin;
     Eubacterium species were the most sensitive. Using an inoculum
    density of 103 to 104 colony forming units per plate, MIC values for
     Eubacterium species were in the range 0.1 to 25 g/ml with an MIC50
    of 0.8 g/ml.

          In view of the poor oral absorption of gentamicin and the
    reported occurrence of diarrhoea in experimental animals, it was
    considered that effects on the gastrointestinal microflora would be
    the most sensitive effect of residues. In calculating the ADI, the
    formula developed by the thirty-eighth meeting of the Committee (Annex
    1, reference 97) was employed:

    
                                 Concentration without effect       x  Daily faecal bolus (g)
                                 on human gut flsor (g/ml)a
    Upper limit of ADI      =                                                               
                                 Fraction of oral     x  Safety     x  Human body
                                 dose availableb         factorc       weight
                                                                       (60 kg)

                                 (0.8 x 2) x 150
                            =                  
                                 1 x 1 x 60

                            =    4 g/kg bw

    a     This value accounts for the range of MICs in appropriate 
          bacterial species and the use of the most sensitive anaerobic 
          organism.  A two-fold adjustment was deemed to be necessary to 
          account for the relatively low inoculum density.

    b     Absorption of gentamicin after oral dosing is very poor, therefore 
          a factor of 1 was used to represent 100% availability of ingested 
          drug in the gastrointestinal tract.

    c     Data on more than 600 clinical isolates of anaerobic bacteria were 
          available for determination of the MIC.  Because the colonic flora 
          is relatively stable and variability within a particular individual 
          may be as great as variability between individuals, and because it 
          was recognized that other values selected for this calculation were 
          conservative and already incorporated an adequate margin of safety, 
          a safety factor of 1 was selected to cover fully the variability 
          between people of all extrapolated parameters.
    
    4.  EVALUATION

          In view of the absence of information on the effects of
    gentamicin on microorganisms obtained from the human intestine and the
    need for further genotoxicity studies, the Committee established a
    temporary ADI of 0-4 g/kg bw based on the results of micro-biological
    testing of clinical isolates, with a request for further information. 
    An increased safety factor was not used to account for the temporary
    status of the ADI because conservative factors were used in deriving
    the temporary ADI.  The lowest toxicological NOEL was 10 mg/kg bw/day
    in dogs, which is more than 2000-fold higher than the
    microbiologically based ADI.

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    See Also:
       Toxicological Abbreviations
       Gentamicin (WHO Food Additives Series 41)
       GENTAMICIN (JECFA Evaluation)