Gentamicin sulfate
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS number |
| 1.4.2 Other numbers |
| 1.5 Brand names, Trade names |
| 1.6 Manufacturers, Importers |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First aid measures and management principles |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical properties |
| 3.3.1 Properties of the substance |
| 3.3.2 Properties of the locally available formulation |
| 3.4 Other characteristics |
| 3.4.1 Shelf-life of the substance |
| 3.4.2 Shelf-life of the locally available formulation |
| 3.4.3 Storage conditions |
| 3.4.4 Bioavailability |
| 3.4.5 Specific properties and composition |
| 4. USES |
| 4.1 Indications |
| 4.2 Therapeutic dosage |
| 4.2.1 Adults |
| 4.2.2 Children |
| 4.3 Contraindications |
| 5. ROUTES OF ENTRY |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Other |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination by route of exposure |
| 7. PHARMACOLOGY AND TOXICOLOGY |
| 7.1 Mode of action |
| 7.1.1 Toxicodynamics |
| 7.1.2 Pharmacodynamics |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 7.7 Main adverse effects |
| 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Material sampling plan |
| 8.1.1 Sampling and specimen collection |
| 8.1.1.1 Toxicological analyses |
| 8.1.1.2 Biomedical analyses |
| 8.1.1.3 Arterial blood gas analysis |
| 8.1.1.4 Haematological analyses |
| 8.1.1.5 Other (unspecified) analyses |
| 8.1.2 Storage of laboratory samples and specimens |
| 8.1.2.1 Toxicological analyses |
| 8.1.2.2 Biomedical analyses |
| 8.1.2.3 Arterial blood gas analysis |
| 8.1.2.4 Haematological analyses |
| 8.1.2.5 Other (unspecified) analyses |
| 8.1.3 Transport of laboratory samples and specimens |
| 8.1.3.1 Toxicological analyses |
| 8.1.3.2 Biomedical analyses |
| 8.1.3.3 Arterial blood gas analysis |
| 8.1.3.4 Haematological analyses |
| 8.1.3.5 Other (unspecified) analyses |
| 8.2 Toxicological Analyses and Their Interpretation |
| 8.2.1 Tests on toxic ingredient(s) of material |
| 8.2.1.1 Simple Qualitative Test(s) |
| 8.2.1.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.1.3 Simple Quantitative Method(s) |
| 8.2.1.4 Advanced Quantitative Method(s) |
| 8.2.2 Tests for biological specimens |
| 8.2.2.1 Simple Qualitative Test(s) |
| 8.2.2.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.2.3 Simple Quantitative Method(s) |
| 8.2.2.4 Advanced Quantitative Method(s) |
| 8.2.2.5 Other Dedicated Method(s) |
| 8.2.3 Interpretation of toxicological analyses |
| 8.3 Biomedical investigations and their interpretation |
| 8.3.1 Biochemical analysis |
| 8.3.1.1 Blood, plasma or serum |
| 8.3.1.2 Urine |
| 8.3.1.3 Other fluids |
| 8.3.2 Arterial blood gas analyses |
| 8.3.3 Haematological analyses |
| 8.3.4 Interpretation of biomedical investigations |
| 8.4 Other biomedical (diagnostic) investigations and their interpretation |
| 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations |
| 8.6 References |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 CNS |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Other |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ear, nose, throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-base disturbances |
| 9.4.12.2 Fluid and electrolyte disturbances |
| 9.4.12.3 Others |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Other |
| 9.6 Summary |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Relevant laboratory analyses |
| 10.2.1 Sample collection |
| 10.2.2 Biomedical analysis |
| 10.2.3 Toxicological analysis |
| 10.2.4 Other investigations |
| 10.3 Life supportive procedures and symptomatic/specific treatment |
| 10.4 Decontamination |
| 10.5 Elimination |
| 10.6 Antidote treatment |
| 10.6.1 Adults |
| 10.6.2 Children |
| 10.7 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 11.2 Internally extracted data on cases |
| 11.3 Internal cases |
| 12. Additional information |
| 12.1 Availability of antidotes |
| 12.2 Specific preventive measures |
| 12.3 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) |
PHARMACEUTICALS
1. NAME
1.1 Substance
Gentamicin sulfate
1.2 Group
Aminoglycoside antibiotic
1.3 Synonyms
Gentamicin
Gentamycin
1.4 Identification numbers
1.4.1 CAS number
1405-41-0 (Gentamicin sulfate)
1.4.2 Other numbers
89 - c (Martindale Online monograph link number)
LY2450000 (Gentamycin) RTECS
1.5 Brand names, Trade names
Gentamicin injection B.P.
Gentamicin sulphate injection (U.S.P.)
Cidomycin (Roussel)
Genticin (Nicholas), Lugacin (Lagap)
Sintepul, Gentamina, Glevomicina, Rovixida (Argentina)
Refobacin (Australia)
Geomycin (Belgium)
Gentalline, Gentalyn (France)
Refobacin, Sulmycin (Germany),
Gentacin (Japan)
Genalfa, Gentalyn, Gentibioptal, Genticol, Ribomicin (Italy)
Biogen, Espectrocina, Genta-Gobens, Gentadavur, Gentallenas,
Gentamin,
Gentamival, Gento, Gentoma, Nuclogen, Sulgemicin (Spain)
Garamicina (Sweden)
Genoptic (USA)
Garamycin (Kirby - Warrick, UK)
Gentamicin BDH (E. Merck, UK)
Gentigan (E. Merck, UK)
Cidomycin Intrathecal Injectable (Roussel, UK)
Gentamicin L - BDH (E. Merck, UK) (Nicholas, UK)
Cidomycin Injectable Paediatric (Roussel, UK)
Garamycin Paediatric Injection (Kirby - Wanick, UK)
Genticin Paediatric Injection (Nicholas, UK)
Cidomycin Sterile Powder (Roussel, UK)
Genticine Pure Powder (Nicholas, UK)
Gentamicin Powder
Gentamicin eye drops (B.P.) (0.3% sulphate) (for both eye and
ear)
Minims Gentamicin (S & N Pharma UK),
Gentamicin sulphate ophthalmic solution (U.S.P.)
Alcomicin (Alcon, UK:Farillon, UK)
Gentamicin eye ointment (0.3% sulphate)
Gentamicin ear drops (0.3% sulphate)
Gentisone HC (Nicholas)
Gentamicin cream
Genticin HC (Nicholas)
Gentamicin skin ointment
Cidomycin Topical (Roussel)
Gentamicin Ointment,
Pangram
Septotal
Sulmycin
U-gencin
Bristagen
Duragentam
Garasol
Gentak
Gentibioptal
Gentocin
Gentogram
Gent-Ophtal
Lugacin
Nichogencin
Ophtagram
(Merck, 1989)
1.6 Manufacturers, Importers
Chinoin (Hungary), Roussel (UK), Kirby-Warrick (UK), Nicholas
(UK), E. Merck (UK)
Local importers: Hoechst (Ceylon) Ltd., and Chemical
Industries (Colombo) Ltd.
2. SUMMARY
2.1 Main risks and target organs
The main toxic effects are vestibular damage, deafness and
renal dysfunction. The damage on the vestibular portion of
the eighth cranial nerve appears to be greater than that on
the cochlear portion. The main target organs are the eighth
cranial nerves and the kidneys.
2.2 Summary of clinical effects
Damage to eighth cranial nerve (both divisions) resulting in
tinnitus, deafness, nausea, vomiting, vertigo, dizziness and
nystagmus, and nephrotoxicity causing acute tubular necrosis
resulting in renal failure.
2.3 Diagnosis
Loss of hearing, dizziness, vertigo, ataxia, nausea, vomiting
and renal impairment developing in a patient on gentamicin
therapy suggests a diagnosis of gentamicin toxicity. Other
toxic features are muscular paralysis and respiratory
depression.
Monitoring serum drug concentration is useful both to detect
toxicity and in the management of acute poisoning.
Assessment of renal function (blood urea, serum creatinine,
creatinine clearance) is helpful to detect renal damage.
Audiometry may help in the detection of ototoxicity.
2.4 First aid measures and management principles
No first-aid measures are available.
Stop further administration of gentamicin.
Gentamicin can be removed from the body by haemodialysis,
peritoneal dialysis and charcoal haemoperfusion.
Approximately 50% of the administered dose can be removed in
12 hours by haemodialysis.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Gentamicin was isolated in 1963 by Weinstein and colleagues
from the soil fungus Micromonospora purpura (of the
Actinomycete group) (Sande and Mandell, 1985). It was
introduced in the USA in 1969. It is a "complex" of
gentamicins C1, C1a and C2 and also gentamycin A which differs
from the other members of the complex but is similar to
Kanamycin C (Merck, 1989). Within the aminoglycoside family
the suffix "- mycin" is used in the name when the antibiotic
is produced by Streptomyces species and "micin", when produced
by Micromonospora species.
3.2 Chemical structure
Gentamicin C
In Gentamicin C1, R1 = R2 = CH3
Gentamicin C2, R1 = CH3; R2 = H
Gentamicin C1a, R1 = R2 = H
Gentamicin C1, C21H43N5O7
Gentamicin C2, C20H41N5O7
Gentamicin C1a, C19H39N5O7
Gentamicin has two amino sugars joined in a glycosidic linkage
to a hexose nucleus. The hexose in this case is 2-
deoxystreptamine. Hence the compound is an aminoglycosidic
aminocyclitol.
Gentamicin C1a, C19H39N2O7,
0-3-deoxy-4-C-methyl-3-(methylamino)-ß-L-arabinopyranosyl-(1
6)-0-[2,6-
diamino-2,3,4,6-tetradeoxy- -D-erythro-hexopyranosyl-(1 4)-2-
deoxy-D-streptamine.
Also known as gentamicin D.
Gentamicin A, C18H36N4O10, 0-2-amino-2-deoxy- -D-
glucopyranosyl-(1 4)-0-[3-deoxy-
3-(methylamino)- -D-xylopyranosyl-(1 6)]-2-deoxy-D-
streptamine.
3.3 Physical properties
3.3.1 Properties of the substance
Highly water soluble polar cation with an
optimum pH of 6 to 8. Antibiotic activity is
inhibited by acid pH and divalent cations.
Gentamicin sulphate is a white to buff coloured,
odourless, hygroscopic powder containing not
more than 15% water. Melts with decomposition
between 200 and 250°C. Moderately soluble in
ethanol, methanol and acetone. Practically
insoluble in benzene and halogenated
hydrocarbons. A solution in water is
dextrorotatory. A 4% solution in water has a pH
of 3.5 to 5.5.
3.3.2 Properties of the locally available formulation
3.4 Other characteristics
3.4.1 Shelf-life of the substance
Refer to the manufacturers instructions.
Stable in light, air and heat
3.4.2 Shelf-life of the locally available formulation
3.4.3 Storage conditions
Store in air-tight containers.
The potency of gentamicin sulphate is lost in plastic
disposable syringes and a brown precipitate is formed.
Storage in glass disposable syringes should not exceed
30 days.
3.4.4 Bioavailability
The bioavailability of gentamicin by intramuscular and
intravenous injection is assumed to be complete.
3.4.5 Specific properties and composition
No data available.
4. USES
4.1 Indications
Gentamicin is widely used in the treatment of severe
infections. It is active against many strains of Gram-
negative bacteria and Streptococus aureus. It is
inactive against anaerobes and poorly active against
Streptococus haemolyticus and pneumococcus. When used as
presumptive treatment prior to microbiological
identification of the pathogen, gentamicin is combined
with penicillin and/or metronidazole.
Examples of use: septicaemia; neonatal sepsis; neonatal
meningitis; biliary tract infection; pyelonephritis,
prostatitis; endocarditis.
4.2 Therapeutic dosage
4.2.1 Adults
In patients with normal renal function: 2 to 5 mg/kg
daily in divided doses eight-hourly.
In patients with impaired renal function: serum
concentrations of gentamicin must be measured during
therapy, and dosage adjusted to give peak concentrations
below 10 mg/l and trough concentrations below 2 mg/l.
The dose interval should be increased to 12 hours when
creatinine clearance (CCr) is 30 to 70 ml/minute; to 24
hours when CCr is 10 to 30 ml/minute; to 48 hours when
CCr is 5 to 10 ml/minute; and three to four days after
dialysis at 5 ml/minute.
In a usual ten-day course, the peak and trough
gentamicin level in serum must be measured at least
once. If no facilities for measurement are available it
is better not to continue treatment beyond 72 hours.
Intrathecal administration: 1 to 5 mg/day in divided
doses every eight hours, with concurrent intramuscular
administration of 2 to 4 mg/kg/day.
4.2.2 Children
Serum concentrations should be monitored daily.
In children with normal renal function:
Up to 2 weeks of age: 3 mg/kg every 12 hours
2 weeks to 12 years: 2mg/kg every 8 hours.
Neonates with severe infections
3 mg/kg 12-hourly
Impaired renal function: Serum concentrations of
gentamicin must be measured during therapy, and dosage
adjusted to give peak concentrations below 10 mg/l and
trough concentrations below 2 mg/l.
4.3 Contraindications
Pregnancy; myasthenia gravis
Cautions in use: pre-existing renal disease; advanced age;
simultaneous use of loop diuretics, cephalosporins, or
neuromuscular blocking agents
5. ROUTES OF ENTRY
5.1 Oral
Gentamicin is not absorbed after oral administration.
5.2 Inhalation
No data available.
5.3 Dermal
In ointment form, gentamicin is absorbed slowly. However
topical creams may give rise to rapid absorption sufficient to
cause adverse effects and substantial systemic absorption may
occur after application to large areas of denuded skin (as in
burns).
5.4 Eye
The pyrogen-free solution (intrathecal preparation) may also
be used for ocular administration (subconjunctival or
intravitreous).
5.5 Parenteral
Ototoxicity and nephrotoxicity are seen principally with this
form of administration.
5.6 Other
Administration by intrathecal and intraperitoneal routes can
also result in poisoning.
6. KINETICS
6.1 Absorption by route of exposure
Parenteral (IM, SC and IV):
Less than 1% of a dose of gentamicin is absorbed following
oral or rectal administration; it is well absorbed after
subcutaneous and intramuscular injection. Serum levels after
intramuscular administration are slightly lower than after
intravenous administration.
After intramuscular administration, peak plasma concentrations
are reached in 30 to 90 minutes. A dose of 1 mg/kg produces
average peak plasma concentration of about 4 µg/ml although
there may be considerable inter-individual variation and
higher concentrations in patients with renal impairment
(Reynolds, 1982). In critically ill patients (especially with
shock) the absorption from intramuscular sites is poor.
6.2 Distribution by route of exposure
Gentamicin is not significantly protein bound. Peak serum
levels are observed 30 to 60 minutes after an intramuscular
dose and immediately after an intravenous dose.
The volume of distribution is approximately 25% of lean body
weight and equal to extracellular fluid volume.
The concentration of gentamicin in secretions and most tissues
is low. High concentrations are found in renal cortical
tissue, endolymph and perilymph of the inner ear. The
concentration in bile approaches close to 30% of serum
concentration. Penetration into respiratory secretions is
poor. Diffusion into pleural and synovial fluid is slow but
considerable concentrations may be achieved with repeated
dosing.
The concentration in cerebrospinal fluid (CSF) is less than
10% of the concomitant plasma concentration, though in the
presence of meningeal inflammation the concentration may reach
20% of plasma levels. In neonates with meningitis, therapeutic
concentrations may be reached in CSF with parenteral dosing
alone; in adults, intrathecal administration is necessary.
Similarly, penetration to ocular tissue is minimal and
periocular injection of gentamicin is necessary in the
treatment of bacterial endophthalmitis.
6.3 Biological half-life by route of exposure
The elimination half-life in patients with normal renal
function is 2 hours. When creatinine clearance is halved the
t1/2 in serum doubles; adjustments are therefore necessary in
patients with renal failure (Cutler, 1972). The elimination
half-life is 20 to 40 times greater in anephric patients than
in patients with normal renal function and it is also
prolonged in neonates.
6.4 Metabolism
Gentamicin is not metabolized. It is excreted by glomerular
filtration in an active, unchanged form.
6.5 Elimination by route of exposure
Extremely high urinary concentrations may be achieved: after
an intravenous dose of 1 mg/kg, the urinary concentration may
reach 100 mg/l and, after 2 mg/kg, 300 mg/l. Gentamicin
accumulates in renal cortical tissue, from which it is
released over two to three weeks after cessation of therapy.
Extremely sensitive assay techniques can detect very small
quantities of gentamicin in renal cortical tissue for several
months after administration (Schentag et al, 1977).
High concentrations of gentamicin are reached in the liver,
but it is not excreted in bile. Drug levels are low in
biliary obstruction.
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
As gentamicin accumulates in the renal cortex, a
critical concentration is reached when the concentrating
ability of the kidney becomes impaired.
Nephrotoxicity appears to be related to the duration for
which the trough serum concentration exceeds 2 µg/ml (De
Broe et al, 1986). The exact mechanism of toxicity is
unknown.
Ototoxicity and vestibular toxicity seem most highly
correlated with elevated peak concentrations (greater
than 10 µg/ml) of gentamicin. Gentamicin accumulates in
endolymph and perilymph (Huy et al, 1983) and
progressive destruction of ventricular and cochlear
cells occurs. Repeated courses of gentamicin may
produce progressive destruction of cells leading to
deafness. Gentamicin appears to damage the vestibular
portion more than the cochlear portion.
Neuromuscular blockade with acute muscular paralysis and
apnoea may occur rarely. Most episodes have occurred in
association with anaesthesia or administration of other
neuromuscular blockers but may also occur after
intrapleural or intraperitoneal instillation of large
doses of gentamicin or other aminoglycosides. This
phenomenon may occur after intravenous or intramuscular
administration (Pittinger et al, 1970).
7.1.2 Pharmacodynamics
The bactericidal effect of gentamicin is due to
inhibition of protein synthesis in susceptible bacteria.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Plasma concentrations above 10 mcg/ml are
associated with high risk of toxicity, although
individual tolerance may vary. Acute renal
failure has developed in patients after
treatment with 1.7 to 2.9 g given over 12 to 18
days (Reynolds, 1982).
7.2.1.2 Children
No data available.
7.2.2 Relevant animal data
No data available.
7.2.3 Relevant in vitro data
No data available.
7.3 Carcinogenicity
No data available.
7.4 Teratogenicity
Foetal auditory and vestibular nerve damage may occur. The
foetus is at greatest risk during the second and third
trimesters.
7.5 Mutagenicity
No data available.
7.6 Interactions
Concomitant use of ethacrynic acid, frusemide, piretanide and
vancomycin have been reported to increase the ototoxicity of
gentamicin. The nephrotoxicity is increased by concurrent use
of some cephalosporins, cisplatin and indomethacin (Reynolds,
1982).
The aminoglycoside molecule (gentamicin) is inactivated
chemically by physical contact with penicillins and to a
lesser extent by cephalosporins (Farchione, 1981). Although
this is a laboratory phenomenon with no great clinical
importance, these antibiotics must not be mixed together.
7.7 Main adverse effects
Ototoxicity, which may be irreversible.
Both vestibular and auditory dysfunction may occur.
Nephrotoxicity may precipitate impairment of renal function or
overt renal failure.
A syndrome of acute neuromuscular paralysis may occur after
administration of gentamicin and general anaesthesia or
neuromuscular blocking agents. Although rare, neuromuscular
blockade may also occur after intracavitory installation or
parenteral injections of gentamicin.
Intrathecal/intraventricular administration may cause local
inflammation leading to radiculitis and other complications.
Fever and pleocytocis of CSF may occur after intrathecal
administration of gentamicin.
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Overall Interpretation of all toxicological analyses and
toxicological investigations
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Not relevant.
9.1.2 Inhalation
Not relevant.
9.1.3 Skin exposure
No data available.
9.1.4 Eye contact
No data available.
9.1.5 Parenteral exposure
Poisoning from this route causes acute renal failure due
to acute tubular necrosis. It also causes tinnitus,
impairment of hearing, nausea, vomiting, dizziness,
vertigo and nystagmus.
9.1.6 Other
No data available.
9.2 Chronic poisoning
9.2.1 Ingestion
Not relevant.
9.2.2 Inhalation
Not relevant.
9.2.3 Skin exposure
Systemic absorption may occur following application to
large denuded areas of the body (especially in cream
form). Serum concentrations of 1 µg/ml may be achieved
and 2 to 5% of the applied dose is excreted in the
urine. Cases of total deafness following inadvertent
systemic absorption of neomycin, another aminoglycoside,
have been reported (Greenberg & Momary, 1965).
9.2.4 Eye contact
No data available.
9.2.5 Parenteral exposure
Prolonged administration can cause both renal and 8th
cranial nerve toxicity.
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
Acute renal failure caused by gentamicin is reversible.
Deafness may be permanent.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
No significant effects.
9.4.2 Respiratory
Respiratory depression may occur as a result of
neuromuscular blockade.
9.4.3 Neurological
9.4.3.1 CNS
There may be convulsions, encephalopathy,
lethargy, confusion, hallucinations, mental
depression and delirium (Pleocytocis can be
observed in the cerebrospinal fluid).
9.4.3.2 Peripheral nervous system
Cochlear damage: Hearing loss, initially, high
pitched.
Vestibular damage: This is more common than
hearing loss. Onset of labyrinthine dysfunction
may be preceded by a headache for one to two
days. This is followed by an acute phase during
which nausea, vomiting and difficulty in
balancing develops and persists for one to two
weeks; other features include dizziness, vertigo,
tinnitus and roaring in the ears. Vertigo is
worse on standing. Inability to perceive
termination of movement ("mental past pointing")
may occur. Drifting of eyes occurs at the
cessation of movement so that focusing and
reading are difficult; positive Romberg's sign
and nystagmus are also observed.
Chronic labyrinthitis: Ataxia, inability to walk
or make sudden movements. Sensory symptoms such
as numbness, tingling may occur.
9.4.3.3 Autonomic nervous system
No information available.
9.4.3.4 Skeletal and smooth muscle
Muscle twitching may occur. Neuromuscular
paralysis is a rare but important toxic effect.
9.4.4 Gastrointestinal
Nausea and vomiting.
9.4.5 Hepatic
Increased serum aminotransferase and serum bilirubin
levels have been reported rarely (Reynolds, 1982).
9.4.6 Urinary
9.4.6.1 Renal
A reversible, mild renal impairment may occur in
8 to 26% of patients who are given gentamicin.
Proximal tubular cells (PCT) may be damaged due
to retention of gentamicin. This may be manifest
as increased excretion of renal PCT tubular
brush border enzymes such as alanine
aminopeptidase, alkaline phosphatase and beta-D-
glucosaminidase. This stage is followed by the
appearance of granular and hyaline casts in
urine, proteinuria and a defect in renal
concentrating ability. The glomerular
filtration rate is reduced. Acute tubular
necrosis and interstitial nephritis may occur.
9.4.6.2 Other
No data available.
9.4.7 Endocrine and reproductive systems
No data available.
9.4.8 Dermatological
Skin rashes have been reported. Loss of hair and
eyebrows has been reported in a patient during treatment
with gentamicin (Yoshioka & Matsuda, 1970).
9.4.9 Eye, ear, nose, throat: local effects
Subconjunctival infection: pain, hyperaemia and
conjunctival oedema (Reynolds, 1993).
9.4.10 Haematological
Rarely, anaemia and purpura have been reported
(Reynolds, 1982).
9.4.11 Immunological
Hypersensitivity to gentamicin can occur rarely (see
9.4.13).
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No information available.
9.4.12.2 Fluid and electrolyte disturbances
Hypomagnesaemia may occur with prolonged
therapy. There may be hypocalcaemia and
hypokalaemia.
9.4.12.3 Others
No data available.
9.4.13 Allergic reactions
Hypersensitivity reactions, and very rarely anaphylaxis
can occur. Collapse with tachycardia, hypotension and
apnoea has occurred within a minute of starting to
inject 80 mg of gentamicin IV (Hall, 1977).
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Pregnancy: gentamicin is contraindicated due to the
risk of auditory and ves-tibular damage. Accumulation
in foetal plasma and amniotic fluid occurs after
administration during late pregnancy.
Breast feeding: no data available.
Enzyme deficiencies: no data available
9.5 Other
No data available.
9.6 Summary
10. MANAGEMENT
10.1 General principles
Make a proper assessment of airway, breathing,circulation
and neurological status of the patient.
Discontinue gentamicin therapy when early signs of vestibulo-
cochlear toxicity, such as tinnitus and impairment of
hearing are observed. Careful observation of renal function
is necessary and when renal failure is established. Toxic
concentrations of gentamicin can be reduced by either
haemoperfusion or dialysis.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
Collect blood for serum gentamicin levels (peak or
trough samples or random sample) and biomedical
analysis.
10.2.2 Biomedical analysis
Biochemical profile with blood urea nitrogen,
creatinine, and electrolytes should be obtained.
Creatinine clearance should be determined.
Elevation of serum creatinine, blood urea nitrogen
and serum potassium is observed in renal failure.
10.2.3 Toxicological analysis
Monitor plasma gentamicin levels. Peak levels over
10 mcg/ml or trough levels over 2 µg/ml are
associated with adverse effects.
10.2.4 Other investigations
Not relevant
10.3 Life supportive procedures and symptomatic/specific
treatment
Make a proper assessment of airway, breathing,circulation
and neurological status of the patient.
If respiration is impaired maintain clear airway, aspirate
secretions, and administer oxygen. Support ventilation
using appropriate mechanical device. Assess renal function
regularly. Monitor and correct fluid and electrolyte
balance. Control convulsions by appropriate drugs such as
diazepam. Regular audiometric examinations may help in
follow up.
10.4 Decontamination
Not relevant.
10.5 Elimination
Forced diuresis - Chronic diuretic therapy and loop
diuretics increase the toxicity of gentamicin. Therefore,
the use of these are contraindicated.
Dialysis: peritoneal dialysis and haemodialysis are useful
for removing gentamicin from the body. Approximately 50% of
the administered dose is removed in 12 hours by
haemodialysis. Frequent monitoring of the plasma gentamicin
concentration is advised. Peritoneal dialysis is less
effective than haemodialysis. Clearance rates are
approximately 5 to 10 ml/minute, but is highly variable. In
one case, haemoperfusion through acrylic resin coated
charcoal combined with haemodialysis removed about 70% of
the gentamicin given in excess to an anuric patient.
10.6 Antidote treatment
10.6.1 Adults
No specific antidote is available.
10.6.2 Children
No specific antidote is available.
10.7 Management discussion
Gentamicin is not absorbed from the gastrointestinal tract
and no serious adverse effects would be seen with deliberate
oral ingestion. Toxic doses may be administered
inadvertently to normal subjects or toxicity may occur due
to undetected renal disease.
Dialysis or haemoperfusion is indicated in cases of massive
overdose or when serum concentrations of gentamicin are
extremely high.
Calcium salts given intravenously have been used to counter
the neuromuscular blockade caused by gentamicin. The
effectiveness of neostigmine has been variable (Reynolds,
1993).
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Acute nephrotoxicity has resulted after inadvertent
administration of 25mg to 152mg intramuscularly or
intravenously (Fuquay et al, 1981; Bolam et al, 1982; Smith
1982; Koren et al, 1986).
11.2 Internally extracted data on cases
To be completed by the centre.
11.3 Internal cases
To be completed by the centre.
12. Additional information
12.1 Availability of antidotes
Not relevant.
12.2 Specific preventive measures
Gentamicin should not be used in patients with a known
history of allergy to aminoglycosides. Gentamicin should be
given with care and in reduced dosage to patients with
impaired renal function and plasma concentrations of
gentamicin should be checked frequently. Gentamicin should
be withdrawn immediately if symptoms of ototoxicity occur.
12.3 Other
No data available.
13. REFERENCES
Bolam DL, Jenkins SA, Nelson RM (1982). Aminoglycoside overdose
in neonates. J Ped 100: 835.
Cutler RE et al (1972). Correlations of serum creatinine
concentrations and gentamicin half life. J Am Med Assoc 219:
1037.
DeBroe M et al (1986). Choice of drug and dosage regimen: Two
important risk factors for aminoglycoside nephrotoxicity. Am J
Med 80(6B): 115.
Farchione LA (1981). Inactivation of aminoglycosides by
penicillins. J Antimicr Chemotherapy 8: 27.
Fuquay D, Koup J, Smith AL (1981). Management of neonatal
gentamicin overdosage. J Pediatr 99: 473 - 476.
Greenberg JH, Momary H (1965). Audiotoxicity and nephrotoxicity
due to orally administered neomycin. J Am Med Assoc 194: 827.
Hall FJ (letter) (1977). Lancet 2: 455.
Huy PTB, Meulemans A, Wassef M, Manuel C, Sterkess O, Amiel C
(1983). Gentamicin persistence in rat endolymph and perilymph
after a two day constant infusion. Antimicrob Agents Chemother
23: 344 - 346.
Koren G, Barzilay Z, Greenwald M (1986). Tenfold errors in
administration of drug doses: a neglected iatrogenic disease in
paediatrics. Paediatrics 77: 848 - 849.
Pittinger CB, Eryasa Y, Adamson R (1970). Antibiotic-induced
paralysis. Anesth Analg 49: 482 - 501.
Reynolds JEF (1982). Martindale, The Extrapharmacopoeia. 28th
Edition. London. The Pharmaceutical Press. 1166 - 1173.
Reynolds JEF (1993). Martindale, The Extrapharmacopoeia. 30th
Edition. London. The Pharmaceutical Press. 170 - 172.
Sande MA, Mandell GL (1985). In: Rall TW, Murad F, eds.
Antimicrobial Agents. The Pharmacological Basis of Therapeutics.
7th Edition, New York. Macmillan Publishing Company. 1151-1169.
Schentag JJ et al (1977). Tissue persistence of gentamicin in
humans. J Am Med Assoc 238: 327.
Smith AL (1982). Aminoglycoside overdose in neonates (letter). J
Pediatr 100: 835
Yoshioka H, Matsuda I (letter) (1970). J Am Med Assoc 211: 123.
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Authors: Dr Ravindra Fernando and Dr R.L. Jayakody
National Poisons Information Centre,
General Hospital
Colombo
Sri Lanka
Date: August 1990
Update: Dr R. Fernando
Date: June 1993
Review: IPCS, May 1994