Article edited by Assoc. Prof. R Philpot. Special acknowledgement to Shivani Manini and Michael Soriano for performing the survey.

New Guidelines

With the release of the 14th edition of the Antibiotic Guidelines (‘the pink book’) published by Therapeutic Guidelines Limited in Melbourne, the South Australian expert Advisory Group on Antimicrobial Resistance (SAAGAR) developed a state-wide recommendation on aminoglycoside use, dosing and monitoring.

This useful document was circulated by SA Health throughout the public hospitals of South Australia to improve the interpretation of the guidelines. HPS Pharmacies implemented the recommendations for the group of private hospitals represented on SAAGAR.

Our Survey

As a precursor to this article, HPS Pharmacies performed a three-month survey of the use, dosing, and monitoring of gentamicin in selected hospitals. The salient findings include:

  1. The majority of patients who received gentamicin throughout the group of hospitals, received empirical gentamicin therapy, i.e. 24 to 48 hours only.
  2. The majority of gentamicin doses given were conservative, and in over 70% of patients were under-dosed according to the 14th edition of the Antibiotic Guidelines. This was thought to be related to the prescribers’ perceived toxicity risk associated with gentamicin use.
  3. Of those patients who were on gentamicin greater than 48 hours, only a very small number had serum levels done to allow dosage optimisation.

Current practical guidelines

The results were not surprising for a number of reasons: gentamicin is a rapidly bactericidal antibiotic with low resistance rates shown in both community and hospital acquired gram-negative pathogens. It is well suited to empirical therapy for rapid control of serious infection.

Gentamicin is both ototoxic and nephrotoxic. This may cause prescribers’ to under-dose or avoid use by choosing a broader spectrum antibiotic (e.g. cephalosporin or quinolone). This practice has been linked to increasing patterns of antibiotic resistance (MRSA, VRE, multi-resistant gram-negative pathogens).

With this in mind, the working group of the 14th edition of the Antibiotic Guidelines aimed to simplify the dosing/monitoring of aminoglycosides, including gentamicin, by recommending that empirical therapy be limited to a duration of 48 hours with the dosage being dependent on the patient’s renal function, ideal body weight and age.

Monitoring of plasma concentrations is not required if not using gentamicin beyond 48 hours.

Dosage tables from the Therapeutic Guidelines

The 14th edition of the Antibiotic Guidelines provides dosage tables advising that gentamicin for empirical and directed therapies should be initiated between 4-7mg/kg up to 640mg daily depending on age and the severity of the infection. Streptococcal and enterococcal endocarditis infections at any age should be treated with the lower dose of 3mg/kg/day in divided doses as synergistic treatment.

Subsequent dosing for directed therapy is based on plasma concentration monitoring as discussed below. Empiric therapy should have the dosing interval adjusted according to renal function, using a recent creatinine measurement, although this might still overestimate renal function in acute renal failure.

Greater than 48 hours of gentamicin dosing

Subsequent antibiotic use should be guided by susceptibility results. Even if initial cultures have been uninformative in defining directed therapy the beta-lactamase inhibitor combinations, e.g. piperacillin and tazobactam, are better substitutes than broad spectrum antibiotics like third generation cephalosporins, since they generate less selective pressure for multi-resistant organisms.

The only indications for continuing gentamicin as a part of directed therapy are:

  • Infections involving organisms resistant to safer antimicrobials;
  • Combination therapy for serious Pseudomonas aeruginosa infections; and
  • Low doses as synergistic treatment for streptococcal and enterococcal endocarditis (frequent trough serum levels required in this population).

When deciding on directed therapy including aminoglycosides, appropriate patient selection should involve avoiding known risk factors such as poor renal function, advanced age, poor baseline hearing, pre-existing ear conditions (tinnitus), and previous exposure to aminoglycosides.

Monitoring of serum gentamicin levels should begin with the first dose of directed therapy, i.e. after 72 hours in patients on daily doses of gentamicin. The graphical nomogram for dosage calculation that was available in previous editions of the Antibiotic Guidelines has been deleted in the 14th edition, since it had significant limitations such as pharmacokinetics data being only validated in an adult population with normal renal function. This simple nomogram, or trough concentration monitoring, is no longer recommended.

A computerised aminoglycoside dose prediction method based on area under the concentration curve (AUC) should be used. A number of computer programs exist, such as TCI Works®, Aladdin® and SeBagen®, and are available online at no charge. HPS’ pharmacists use TCI Works® and can provide accurate dosing recommendations where a peak level (one hour post infusion) is provided along with other patient details (age, height, weight, serum creatinine) and, if available, a subsequent serum level of 6 to 14 hours post infusion. It is imperative that the timing of the dose and any subsequent serum level collection times are recorded in the patient’s medication chart, medical notes and pathology request form.

Toxicity detection and monitoring

Renal effects can be monitored by serial readings of eGFR (population estimate of glomerular filtration rate in an individual), as well as serum urea and creatinine.

The recommendation of monitoring for ototoxicity by auditory and vestibular testing in patients on therapy greater than five days has raised great debate and concern amongst practitioners. SAAGAR noted that the efficacy of such monitoring is not established, and that services to the public sector, let alone the private sector, are significantly limited. SAAGAR therefore recommended appropriate patient selection and adoption of accurate monitoring and dosing guidelines to reduce the risk of toxicity.

A simple and practical way of determining vestibular function is to ask the patient to walk as accurately as they can and to walk heel-to-toe (if safe). Record the result on each occasion. Audiometry is cumbersome and costly, so ask the patient if they can hear a watch ticking.

Conclusions

  • The new guidelines make gentamicin therapy easier and safer.
  • Most patients need less than 48 hours of gentamicin dosing so blood assays are not required.
  • All patients who are given gentamicin for greater than 48 hours are potentially at risk of toxicity, especially if:
    • they remain unwell, e.g. increasing renal dysfunction and/or poor general health; and
    • they receive gentamicin for more than seven days.
  • All patients receiving gentamicin therapy for greater than 48 hours require serum level and toxicity monitoring to achieve safe antibiotic stewardship.

References:

  1. Antibiotic Expert Group. Therapeutic Guidelines: Antibiotic. Version 14. Melbourne: Therapeutic Guidelines Limited; 2010.
  2. SAAGAR (South Australian expert Advisory Group on Antimicrobial Resistance). Aminoglycosides: recommendations for use, dosing and monitoring. Feb 2011.
  3. Moulds R, Jeyasingham MS. Gentamicin: a great way to start. Austr Prescr 2010; 33: 134–5.

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