Scottish
The Journal of the Royal Medico-Chlrnllll.cal Society of Gla.gow. the Medlco-Chlrnrglcal Society of Edlnhurgh. and the Scottloh Society for Experimental Medicine Volume 20 MAY 1975 Number 3
GENTAMICIN IN CLINICAL PRACTICE The first clinical use of gentamicin in the United Kingdom occurred in Glasgow and it seems appropriate that the tenth anniversary of this event should be celebrated by holding a Scottish Symposium (reported on page 141) in the same city. In the first patient bacteriological cure was obtained at the cost of some deafness (McAllister, 1974). Over the years no-one has seriously challenged the potency of the drug but the 'toxamicin' image has been slow to dispel. Even a neologism deserves to be spelt '-MICIN' to reflect the derivation of the parent drug from MICromonospora purpurea rather than a StreptoMYCes species. The almost constant misspelling of gentamicin is an etymological curiosity but reflects to some degree the innate conservatism and lack of knowledge of many users. It has been of interest to witness the evolution of gentamicin from the situation where it was held 'in the wings' until the patient was almost moribund to its present pre-eminence as the drug of choice in most cases of septicaemia (McAllister, 1975). The recurrent theme of the symposium was the need to avoid failure by consolidating the knowledge gained over 10 years. The commonest causes offailure are: (1) underdosagea relic of earlier caution; (2) use of bizarre antibiotic combinations; and (3) failure to cover innately resistant bacteria such as Bacteroides species and some streptococci. The 1975 gentamicin image is, rightly, that of a highly-potent modestly-toxic drug of immense value in life-threatening sepsis. There is a need for early and vigorous therapy of suspected septicaemia by use of nomograms at the bedside and assay results from the laboratory. The necessary clinical and laboratory liaison is achieved in most major teaching centres but, sadly, there is widespread reluctance to shed the older image and adopt the aggressive approach essential for good therapeutic results.
Medical Journal
Gentamicin is a broad-spectrum bactericidal antibiotic which acts by producing irreversible inhibition of protein synthesis at the bacterial ribosome. Its spectrum includes most common Gram-negative and Grampositive pathogens including E. coli, Kl. aerogenes, Pro mirabilis, Salmonellae, Shigellae, Neisseriae, H. influenzae, Staph. aureus and Staph. albus. Most strains of Ps. aeruginosa are sensitive. It is, indeed, an extreme rarity to detect resistance in any of the common pathogens, although there is an obvious need to monitor the situation. The drug, however, is not perfect. It is inactive against the anaerobes Bacteroides and Clostridium welchii and many strains of streptococci such as Strep. faecalis are also resistant. In clinical practice lincomycin (or clindamycin) or metronidazole is added for Bacteroides, and the former suffices for many strains of streptococci. Carbenicillin may antagonize gentamicin in vitro and in vivo and its addition seems unnecessary and potentially wasteful. The minimum inhibitory concentrations (MIC) of sensitive strains are in the range 0.25 to 4 iLg. per m!. and it is important to exceed this level for clinical efficacy. The range 4 to 10 iLg. per m!. is desirable. The plate-diffusion method of assay is in common use. This is reliable and reasonably accurate but requires 18 hours although this may be shortened to 6 hours. There is an increasing demand for accurate rapid methods, especially in intensive care areas. At present these comprise (1) urease method, (2) enzymatic transfer of radio-labelled adenyl groups and (3) radioimmunoassay using tritiated gentamicin, but are not generally available. The drug must be administered parenterally and is excreted almost exclusively by the kidneys, high urinary levels being attained (up to 200 iLg./m!.). In renal impairment excretion is delayed, leading to more prolonged serum levels. The levels attained in the bile, bronchial secretions and cerebrospinal 97
Leading Articles
fluid are low and the treatment of meningitis requires intrathecal therapy. Children, particularly neonates, require higher doses per kg. body weight than adults. Some patients show a damped response with lower peak levels and a prolonged excretory phase. Peak serum levels are measured 45 minutes after 1M injection and 15 minutes after bolus IV injection. Trough levels are measured just prior to the next injection. Gentamicin is in widespread use in hospitals and is now primary choice for the 'best guess' treatment of life-threatening situations such as proven or strongly-suspected septicaemia. The modem tendency is to administer the drug as early as possible in high doses, but it is also strongly favoured by 'shock teams' when severe sepsis is complicated by a shock phase. This is particularly common when the host is compromised by the presence of immune or phagocytic defects, malignancy or cytotoxic drugs. As outlined above, combination therapy may be used but a policy of blind polypharmacy is deprecated. Gentamicin has also been used for the treatment and prophylaxis of urinary tract infection. It can be prescribed with confidence in posttransplant patients and in the presence of renal failure, providing the dosage is carefully controlled. Other common uses are: neonatal septicaemia and meningitis (intrathecal therapy required); the treatment of colonized Spitz-Holter valves in hydrocephalic children (usually Staph. albus); infected bums; panophthalmitis (subconjunctival injection); cystic fibrosis by parenteral and aerosol administration; proven Ps. aeruginosa infection in many sites; Gram-negative pneumonia; gonorrhoeae; orally (it is not absorbed) in the treatment of gastroenteritis and as part of a gut-sterilization regime in the treatment of leukaemia and, finally, local use in the treatment of skin, ear and eye infections, although this route should not be encouraged as it tends to select resistant mutants. The dosage of gentamicin must be individualized for each patient and this demands a knowledge of pharmacokinetics and access to reliable assay. The prime function of monitoring is to ensure that therapeutic levels are attained. Premature neonates age 0 to 7 days 98
should receive 3 mg. per kg. as a loading dose followed by 2 mg. per kg. 12-hourly. Fullterm neonates and prematures more than 7 days old should receive the same loading dose followed by 2 mg. per kg. 8-hourly. Other children should receive 2 mg. per kg. 8-hourly. In all cases monitoring should commence at 24 hours and the dosage modified accordingly. In adults the dose should be at least 5 mg. per kg. per day in divided doses and the Mawer nomogram (Mawer et al., 1974) is of great value at the bedside. In adults with renal failure the scheme proposed by Gingell and Waterworth (1968) is now outmoded and should be replaced by the Chan nomogram (Chan et al., 1972). The evidence for gentamicin nephrotoxicity is extremely sparse and it has usually been associated with the administration of a cephalosporin, frusemide, or other agents which themselves may cause renal failure. Ototoxicity is associated with renal impairment. Although peak levels > 12 p.g. per ml. should be avoided in this context, ototoxicity seems to correlate best with the pharmacokinetic baseline area, i.e. the product of the length and height of the trough (Reeves, 1974). T. A. McALLISTER REFERENCES
Chan, R. A., Benner, E. J., Hoepricb, M.D. (1972). Gentamicin therapy in renal failure: a nomogram for dosage. Annals of Internal Medicine, 76, 773 Gingell, J. c., Waterwortb, P. M. (1968). Dose of gentamicin in patients with normal renal function and renal impairment. British Medical Journal, 2,19 Mawer, G. E., Ahmad, R., Dobbs, S. M" McGough, J. G., Lucas, S. 8., Tooth, J. A. (1974). Prescribing aids for gentamicin. British Journal of Clinical Pharmacology, 1,45 McAllister, T. A. (1974). Gentamicin in paediatrics. Postgraduate Medical Journal, 50 (Suppl. 7), 45 McAllister, T. A. (1975). Medical Journal, 20, 85
Septicaemia. Scottish
Reeves, D. S. (1974). Gentamicin therapy. British Journal of Hospital Medicine, 12, 837 RECENT REVIEWS Second international symposium on gentamicin (1971). Journal of Infectious Diseases, 124 (Dec. Suppl.), SI-300 Gentamicin (1974). Postgraduate Medical Journal, 50 (Suppl. 7), 1-64
The Journal of the Royal Medico-Chlrnllll.cal Society of Gla.gow. the Medlco-Chlrnrglcal Society of Edlnhurgh. and the Scottloh Society for Experimental Medicine Volume 20 MAY 1975 Number 3
GENTAMICIN IN CLINICAL PRACTICE The first clinical use of gentamicin in the United Kingdom occurred in Glasgow and it seems appropriate that the tenth anniversary of this event should be celebrated by holding a Scottish Symposium (reported on page 141) in the same city. In the first patient bacteriological cure was obtained at the cost of some deafness (McAllister, 1974). Over the years no-one has seriously challenged the potency of the drug but the 'toxamicin' image has been slow to dispel. Even a neologism deserves to be spelt '-MICIN' to reflect the derivation of the parent drug from MICromonospora purpurea rather than a StreptoMYCes species. The almost constant misspelling of gentamicin is an etymological curiosity but reflects to some degree the innate conservatism and lack of knowledge of many users. It has been of interest to witness the evolution of gentamicin from the situation where it was held 'in the wings' until the patient was almost moribund to its present pre-eminence as the drug of choice in most cases of septicaemia (McAllister, 1975). The recurrent theme of the symposium was the need to avoid failure by consolidating the knowledge gained over 10 years. The commonest causes offailure are: (1) underdosagea relic of earlier caution; (2) use of bizarre antibiotic combinations; and (3) failure to cover innately resistant bacteria such as Bacteroides species and some streptococci. The 1975 gentamicin image is, rightly, that of a highly-potent modestly-toxic drug of immense value in life-threatening sepsis. There is a need for early and vigorous therapy of suspected septicaemia by use of nomograms at the bedside and assay results from the laboratory. The necessary clinical and laboratory liaison is achieved in most major teaching centres but, sadly, there is widespread reluctance to shed the older image and adopt the aggressive approach essential for good therapeutic results.
Medical Journal
Gentamicin is a broad-spectrum bactericidal antibiotic which acts by producing irreversible inhibition of protein synthesis at the bacterial ribosome. Its spectrum includes most common Gram-negative and Grampositive pathogens including E. coli, Kl. aerogenes, Pro mirabilis, Salmonellae, Shigellae, Neisseriae, H. influenzae, Staph. aureus and Staph. albus. Most strains of Ps. aeruginosa are sensitive. It is, indeed, an extreme rarity to detect resistance in any of the common pathogens, although there is an obvious need to monitor the situation. The drug, however, is not perfect. It is inactive against the anaerobes Bacteroides and Clostridium welchii and many strains of streptococci such as Strep. faecalis are also resistant. In clinical practice lincomycin (or clindamycin) or metronidazole is added for Bacteroides, and the former suffices for many strains of streptococci. Carbenicillin may antagonize gentamicin in vitro and in vivo and its addition seems unnecessary and potentially wasteful. The minimum inhibitory concentrations (MIC) of sensitive strains are in the range 0.25 to 4 iLg. per m!. and it is important to exceed this level for clinical efficacy. The range 4 to 10 iLg. per m!. is desirable. The plate-diffusion method of assay is in common use. This is reliable and reasonably accurate but requires 18 hours although this may be shortened to 6 hours. There is an increasing demand for accurate rapid methods, especially in intensive care areas. At present these comprise (1) urease method, (2) enzymatic transfer of radio-labelled adenyl groups and (3) radioimmunoassay using tritiated gentamicin, but are not generally available. The drug must be administered parenterally and is excreted almost exclusively by the kidneys, high urinary levels being attained (up to 200 iLg./m!.). In renal impairment excretion is delayed, leading to more prolonged serum levels. The levels attained in the bile, bronchial secretions and cerebrospinal 97
Leading Articles
fluid are low and the treatment of meningitis requires intrathecal therapy. Children, particularly neonates, require higher doses per kg. body weight than adults. Some patients show a damped response with lower peak levels and a prolonged excretory phase. Peak serum levels are measured 45 minutes after 1M injection and 15 minutes after bolus IV injection. Trough levels are measured just prior to the next injection. Gentamicin is in widespread use in hospitals and is now primary choice for the 'best guess' treatment of life-threatening situations such as proven or strongly-suspected septicaemia. The modem tendency is to administer the drug as early as possible in high doses, but it is also strongly favoured by 'shock teams' when severe sepsis is complicated by a shock phase. This is particularly common when the host is compromised by the presence of immune or phagocytic defects, malignancy or cytotoxic drugs. As outlined above, combination therapy may be used but a policy of blind polypharmacy is deprecated. Gentamicin has also been used for the treatment and prophylaxis of urinary tract infection. It can be prescribed with confidence in posttransplant patients and in the presence of renal failure, providing the dosage is carefully controlled. Other common uses are: neonatal septicaemia and meningitis (intrathecal therapy required); the treatment of colonized Spitz-Holter valves in hydrocephalic children (usually Staph. albus); infected bums; panophthalmitis (subconjunctival injection); cystic fibrosis by parenteral and aerosol administration; proven Ps. aeruginosa infection in many sites; Gram-negative pneumonia; gonorrhoeae; orally (it is not absorbed) in the treatment of gastroenteritis and as part of a gut-sterilization regime in the treatment of leukaemia and, finally, local use in the treatment of skin, ear and eye infections, although this route should not be encouraged as it tends to select resistant mutants. The dosage of gentamicin must be individualized for each patient and this demands a knowledge of pharmacokinetics and access to reliable assay. The prime function of monitoring is to ensure that therapeutic levels are attained. Premature neonates age 0 to 7 days 98
should receive 3 mg. per kg. as a loading dose followed by 2 mg. per kg. 12-hourly. Fullterm neonates and prematures more than 7 days old should receive the same loading dose followed by 2 mg. per kg. 8-hourly. Other children should receive 2 mg. per kg. 8-hourly. In all cases monitoring should commence at 24 hours and the dosage modified accordingly. In adults the dose should be at least 5 mg. per kg. per day in divided doses and the Mawer nomogram (Mawer et al., 1974) is of great value at the bedside. In adults with renal failure the scheme proposed by Gingell and Waterworth (1968) is now outmoded and should be replaced by the Chan nomogram (Chan et al., 1972). The evidence for gentamicin nephrotoxicity is extremely sparse and it has usually been associated with the administration of a cephalosporin, frusemide, or other agents which themselves may cause renal failure. Ototoxicity is associated with renal impairment. Although peak levels > 12 p.g. per ml. should be avoided in this context, ototoxicity seems to correlate best with the pharmacokinetic baseline area, i.e. the product of the length and height of the trough (Reeves, 1974). T. A. McALLISTER REFERENCES
Chan, R. A., Benner, E. J., Hoepricb, M.D. (1972). Gentamicin therapy in renal failure: a nomogram for dosage. Annals of Internal Medicine, 76, 773 Gingell, J. c., Waterwortb, P. M. (1968). Dose of gentamicin in patients with normal renal function and renal impairment. British Medical Journal, 2,19 Mawer, G. E., Ahmad, R., Dobbs, S. M" McGough, J. G., Lucas, S. 8., Tooth, J. A. (1974). Prescribing aids for gentamicin. British Journal of Clinical Pharmacology, 1,45 McAllister, T. A. (1974). Gentamicin in paediatrics. Postgraduate Medical Journal, 50 (Suppl. 7), 45 McAllister, T. A. (1975). Medical Journal, 20, 85
Septicaemia. Scottish
Reeves, D. S. (1974). Gentamicin therapy. British Journal of Hospital Medicine, 12, 837 RECENT REVIEWS Second international symposium on gentamicin (1971). Journal of Infectious Diseases, 124 (Dec. Suppl.), SI-300 Gentamicin (1974). Postgraduate Medical Journal, 50 (Suppl. 7), 1-64
