aDepartment of Pharmacy, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZB bThe Infection Unit, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZB cDepartment of Medical Microbiology, University of Aberdeen, UK
Abstract
Fifty-five patients who received od gentamicin were studied. The protocol for od gentamicin was followed in 23/55 (48%). Cure rates were 22/23 (96%) when the protocol was followed and 24/32 (75%) when not followed (P = 0.06). Toxicity was more common in those in whom the protocol was not followed (9/32; 28%) than in those in whom it was followed (1/23; 4%) (P< 0.05). The number needed to treat with the protocol to produce one additional cure was 4.84 (95% CI 2.64 to 28.66) and the number needed to treat to prevent one case of toxicity was 3.61 (95% CI 2.16 to 10.99).
Introduction
Gentamicin has proven efficacy against many aerobic Gram-negative organisms and staphylococci.1,2 It is associated with low levels of resistance in common nosocomial pathogens1,3,4 and demonstrates rapid concentration-dependent bactericidal activity and post-antibiotic effect.3 Peak serum concentration to MIC ratios of over 10:1 have been found to improve clinical outcome and reduce the incidence of bacterial resistance.2,3,4 Drawbacks to the widespread use of gentamicin have included the perceived need for frequent administration, its adverse effect profile and the requirement for therapeutic drug monitoring. However, it continues to have a role in the management of life-threatening and multidrug-resistant infections, particularly when used in combination therapy.2,3,5
Clinical guidelines and a nomogram (Hartford nomogram) have been developed for od therapy with gentamicin.2,4 The guidelines suggests the use of 57 mg/kg bodyweight of gentamicin in od administration with adjustment of the dosage interval according to the nomogram, following monitoring of the drug concentration on a serum sample taken between 6 and 14 h post dose.2,4 This has been adopted as the protocol for gentamicin use in our hospital.
The use of gentamicin therapy was audited in this study in order to assess compliance with the antimicrobial policy and the influence of the policy on disease outcome and drug toxicity.
Materials and methods
The study took place over 3 months at the Aberdeen Royal Infirmary. All adult hospitalized patients treated with gentamicin were included, unless it was given as a single dose for surgical prophylaxis. Data were collected prospectively on gender, age, any relevant medical condition, site of infection, sensitivity or resistance to gentamicin of any pathogen isolated, gentamicin dose, dose interval, dose adjustments, duration of treatment, timing and frequency of serum gentamicin concentrations, antibiotic combinations, gentamicin toxicity and patient outcomes. Assessment was also made of adherence to the Hartford nomogram in patients given od gentamicin.
Clinical cure was defined as resolution of the signs and symptoms of the infection. Bacteriological cure was defined as negative cultures at the end of treatment. Treatment failure was defined as death or deterioration owing to infection. Nephrotoxicity was defined as a rise in serum creatinine concentrations by 30 µmol/L from the baseline. Ototoxicity was estimated subjectively, based on the reports of dizziness, vertigo or hearing impairment after gentamicin therapy.
Categorical data were analysed by Fisher's exact test (two-tail), using SPSS for windows. The number needed to treat was calculated using the method described by Cook & Sackett.6
Results
The number of patients included in the study was 60; 29 males (48%) and 31 females (52%). The minimum age was 16 years, the maximum age 80 years, with the median of 55 years.
Fifty of the patients (83.3%) were cured on gentamicin therapy, mostly in combination with ß-lactam antibiotics. Nine of the 60 patients (15%) died and in one patient the gentamicin was discontinued after the isolation of a gentamicin-resistant Escherichia coli strain. Of the nine who died, five (56%) received sub-optimal doses of od gentamicin (i.e. <5 mg/kg bodyweight), compared with only one of the 50 who were cured (2%; P< 0.001).
The clinical indications for gentamicin therapy and the antimicrobials used in combination with gentamicin are shown in Table I. Antibiotic therapy was based on culture and sensitivity in 33 out of the 60 patients (55%) and empirical in 27 of the 60 patients (45%). Forty of 41 pathogens isolated were sensitive to gentamicin; an isolate of E. coli was resistant from the onset of therapy. There was no evidence of resistance being acquired during treatment.
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Discussion
Conventionally, gentamicin has been administered in multiple daily doses. Recent clinical trials have, however, demonstrated equal or better therapeutic response and reduced toxicity by utilizing a larger single daily dosage regimen.2,3,4 Notwithstanding the numerous publications and meta-analyses of the advantages of the single daily dosage regimen, concerns have been expressed on the efficacy and safety of the use of the Hartford nomogram for gentamicin therapy in serious infections and particularly in immunocompromised patients.1,4,5,7 We therefore investigated the safety, efficacy and the quality of gentamicin use with regard to the hospital's protocol (based on the Hartford nomogram) for gentamicin therapy.
Despite a diverse range of conditions being included in this study a better outcome was observed where gentamicin was used according to the protocol. Treatment failure was associated with the use of sub-optimal doses (<5 mg/kg bodyweight). These observations are in keeping with the evidence from other studies which show that sub-optimal dosing of aminoglycosides can compromise the pharmacodynamic killing properties of these agents.3,4
Of all pathogens isolated, only one strain of E. coli showed resistance to gentamicin, reflecting its restricted use in a large (1500 beds) acute hospital. The need for its continued appropriate use to avoid the emergence of resistant mutants has been emphasized previously.1,4,8
Gentamicin toxicity was observed in 17% of the sample and was significantly more common in cases where the serum concentrations were not monitored appropriately. The importance of following a standardized protocol for the monitoring of gentamicin serum concentrations was thus evident from this study.
Our data indicate that od gentamicin therapy in a dose of 57 mg/kg bodyweight, with dosage adjustments based on the Hartford nomogram, is effective as part of the antimicrobial treatment of patients with serious infections. Adherence to the protocol for administration and monitoring of gentamicin therapy (Hartford nomogram) improves the clinical efficacy of gentamicin and significantly reduces the incidence of drug toxicity.
Acknowledgments
The authors wish to thank Susan Heally, Clinical Pharmacy Manager, and staff of the Clinical Audit Unit at Aberdeen Royal Hospital. This paper was presented at the Fifth Conference of the Federation of Infection Societies, Manchester, 1998.
Notes
* Corresponding author. Tel: +44-1224-681818; Fax:
+44-1224-849154; E-mail: rbs.laing{at}arh.grampian.scot.nhs.uk
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Received 3 March 1999; returned 1 July 1999; revised 2 September 1999; accepted 8 September 1999