Relevant BNF section: 5.1.4
Six aminoglycosides (amikacin, gentamicin, kanamycin, netilmicin, streptomycin and tobramycin) are licensed for parenteral use in the UK. As a group, they remain effective against infections caused by aerobic gram-negative organisms and Staphylococcus aureus, including species commonly resistant to beta-lactam antibiotics. However, their use is limited by the severity of their unwanted effects and by their route and frequency of administration; traditionally, they have been given intravenously two to four times daily. Increasingly, they are being given once daily in an attempt to simplify treatment without reducing efficacy or increasing toxicity.1,2 Here we evaluate the advantages and disadvantages of this once-daily approach.
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Relevant BNF section: 5.1.4
Influences on dosing frequency
In a patient with a susceptible infection, the effects of any aminoglycoside will be influenced by the concentration of the drug in the plasma, the bactericidal effect once the antibiotic has been cleared (post-antibiotic effect) and the drug's accumulation at particular sites such as the kidney.
A key factor determining the rate at which bacteria are killed by an aminoglycoside is the concentration of the drug at the site of infection.3 In the treatment of serious sepsis, the aminoglycoside peak serum concentration should be about eight times the minimum inhibitory concentration of the likely pathogen.4 Multiple-dosage regimens often fail to produce such levels until several doses have been given,5 and to achieve them in seriously ill patients, a loading dose is usually given at the start of treatment.
In vitro, bacterial growth may remain inhibited long after the antibiotic has been removed from the culture medium. For some aminoglycosides, this post-antibiotic effect occurs with gram-negative organisms.6 It is argued that a long post-antibiotic effect increases the duration of a drug's therapeutic effect, allowing it to be given less frequently, e.g. once daily.6 Several factors could influence the post-antibiotic effect. These include the concentration of the drug in the plasma and the length of time the bacteria are exposed to the drug. A combination of two or more antimicrobials may influence the relationship.7–10
Accumulation in the kidneys
Aminoglycosides, which are filtered by the glomerulus and partially reabsorbed in the proximal tubule, are excreted unchanged in the urine. The concentration in renal cortical tissue is 10-50 times that in the plasma and such accumulation can damage cortical structures.11 Once-daily doses of, for example, gentamicin and netilmicin could reduce renal tissue accumulation and so renal toxicity.12
Clinical efficacy and safety
Once-daily administration of aminoglycosides has been studied for over 20 years. In 1974, it was reported that 160mg of gentamicin given once daily was as effective as 60-80mg given 8 hourly in the management of urinary tract infection.13 Since then, at least 20 studies have been published using once-daily aminoglycosides. In most of these, once-daily and multiple-daily dosing have been compared using netilmicin (10 studies) or amikacin (8 studies). In general, these have involved small numbers of patients with uncomplicated infections (e.g. urinary tract, pelvic or lower respiratory tract infections); only four have involved immunocompromised patients.14 Few of the studies have evaluated aminoglycosides given alone, so the effectiveness of the different dosing schedules is difficult to discern.
Five meta-analyses15–19 and one review20 of once-daily administration of aminoglycosides have been published in the last 2 years. Between 13 and 24 individual trials were included in each analysis. Although endpoints differed, overall the results of these meta-analyses suggest that once-daily dosing is as effective as, and no more toxic than, multiple-daily dosing in the patients studied. However, data on once-daily dosing in relation to the incidence of inner ear damage are still limited because of the small numbers of patients studied and because there is no standardised way of ascertaining cochlear or vestibular impairment. About 80% of the trials have excluded patients with impaired renal function.14
What serum levels?
There is no agreed way of monitoring aminoglycoside concentrations to ensure optimum efficacy and safety with once-daily dosing. In most studies of once-daily dosing, the dose of aminoglycoside has not been adjusted in response to serum trough concentrations.21 In some, the dose has been reduced or stopped if trough concentrations for netilmicin or gentamicin exceed 1mg/L or 2mg/L and for amikacin 5mg/L.21 However, adjusting the dose on the basis of trough concentrations alone might lead to inner ear damage or kidney damage in patients with impaired renal function.
One strategy for targeting concentrations has been to give a fixed dose of the aminoglycoside and then use a nomogram to determine the appropriate dosing interval according to creatinine clearance following the first dose and using post-dose serum levels for the remainder of the course. Such a nomogram has been developed using data from over 2000 patients:22 it is useful but not definitive. The clearance rate of an aminoglycoside varies between patients even in the absence of renal impairment. Another approach has been to aim for a target total amount of drug over 24 hours, thus avoiding the need to determine the trough concentration.23
Which dose regimen?
Data sheets for aminoglycosides recommend the following once-daily dosage regimens: gentamicin in the treatment of urinary tract infections 160mg/day; netilmicin in urinary tract infections 150mg/day and for gonorrhoea a single dose of 300mg; tobramycin for urinary tract infections 2-3mg/kg/day. Once-daily dosage regimens for other indications are not stipulated. Patients with renal impairment (i.e. likely to have an aminoglycoside plasma half-life of more than 4 hours) will probably have raised aminoglycoside concentrations throughout the course of treatment if a dosing interval of 24 hours is used.24 They may experience a higher incidence of aminoglycoside toxicity, as occurs when continuous infusions of the drug are used. In patients with a high cardiac output (e.g. with anaemia or Paget's disease), the aminoglycoside plasma half-life is likely to be short (i.e. less than 2 hours) and dosing intervals of 12 hours probably remain more appropriate.
As discussed above, the only conclusive data for the effectiveness and safety of once-daily doses of aminoglycosides is in patients with uncomplicated infections of the urinary tract, abdomen, pelvis and respiratory tract. In most such cases another antibiotic, such as a beta-lactam, would also be needed. There are few data on patients with neutropenia and other immunodeficiencies, although many centres use once-daily dosing for such patients. It is important to be cautious in patients with endocarditis, impaired renal function or liver failure, as well as in children, and pregnant or breast-feeding women.
Once-daily aminoglycoside therapy is as effective as, and no more toxic than, multiple daily dosing in patients with uncomplicated infections of the urinary tract, abdomen, pelvis and respiratory tract. It is likely to be similarly effective and safe in susceptible infections at other sites. However, caution should be used in children, women who are pregnant or breast-feeding and patients with endocarditis. There are not enough data to give clear guidelines for once-daily regimens apart from the licensed once-daily doses for gentamicin, netilmicin and tobramycin for certain named infections. Target serum concentrations for once-daily therapy need to be agreed.
[M=meta-analysis; R=randomised controlled trial]
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