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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)--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 250C.  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 g/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 g/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 g/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 g/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 g/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



    See Also:
       Toxicological Abbreviations