Aminoglycoside therapy: Balancing risk versus benefit
During the five-year period from 2002 – 2006, 423 legal actions involving medication administration were commenced against Canadian physicians. Of these, 116 (27%) involved antibiotic administration. Aminoglycosides were cited in 16 of the 116 antibiotic cases (14%).
The following is a review of CMPA cases relating to aminoglycoside toxicity. The purpose of this review is to encourage their continued safe use by apprising clinicians of the medico-legal risks associated with these agents.
A 69-year-old male was admitted by his family physician to a rural hospital with recurrent epididymorchitis unresponsive to outpatient treatment with an oral antibiotic. Serum creatinine at the time of admission was within normal limits. Treatment with gentamicin 80 mg IV q8h was initiated and continued through the ensuing 10-day hospitalization. Gentamicin levels on day two and eight were within the therapeutic range. On day 10, the patient was transferred to the care of an urologist at a larger regional centre because of slower-than-expected improvement.
At the time of arrival at the regional center a creatinine level was elevated at 244 µmol/L. The gentamicin was continued for a further five days. It was discontinued on day 15 and a different oral antibiotic was prescribed. No gentamicin levels were performed during the admission to the regional centre.
On day 20 the patient was discharged from the regional centre and care was again assumed by his family physician. Five days later (day 25) he developed weakness, vomiting, dizziness and ataxia prompting readmission to the rural hospital where investigations showed a creatinine of 205 µmol/L and a urinalysis suggestive of mild infection. Gentamicin was restarted at a dose of 80 mg IM q8h. Over the ensuing five days two trough gentamicin levels were reported as within the therapeutic range. A neurologist, consulted five days after his readmission, suggested that the gentamicin should be discontinued. This was done, but the patient’s dizziness and ataxia persisted. Electronystagmography (ENG) findings were consistent with severe bilateral vestibular dysfunction. Renal function returned to normal.
The family initiated a legal action alleging negligence in the care provided by the family physician with specific reference to the duration of therapy and the absence of consent. The plaintiff’s experts were critical of:
At trial the judge made the following statements:
As a result of this judgment, an award was paid to the plaintiff by the CMPA on behalf of the defendant physician.
A 62-year-old female with a past history of recurrent right otitis media with tympanic perforations and a previous right tympanoplasty presented to an ENT consultant with complaints of right ear discomfort and hearing loss. Examination of the ear revealed a small perforation of the tympanic membrane but no otorrhea. An audiogram demonstrated 40 per cent loss of hearing bilaterally. Sofracort® drops (framycetin [a derivative of the aminoglycoside neomycin], gramicidin, and dexamethasone) were prescribed. During the ensuing five months the patient was seen six times. At each visit a persistent small perforation was noted with otorrhea being documented on only one visit. Continued treatment with Sofracort® drops was advised. Seven months after the initial visit the patient was seen by another ENT consultant. An audiogram done at that time showed a near total hearing loss in the right ear and persistence of the 40 per cent loss in the left.
A legal action was commenced by the patient alleging hearing loss secondary to the prolonged administration of the medication. Plaintiff experts were critical of:
Expert support was sought for the ENT consultant, but could not be obtained. On this basis the CMPA made a settlement to the patient on behalf of the attending physician.
The following is a summary based on CMPA experience for the time period 1984 – 2006 inclusive for medico-legal problems resulting from alleged aminoglycoside toxicity.
Number of cases (Figures 1 –3)
During the study period 65 cases were identified, generating 73 medico-legal problems (in eight cases one clinical incident generated both a regulatory authority (College) complaint and a legal action), of which 62 (85%) were legal actions (Figure 1). As can be seen in Figure 2 there has been a variation in the frequency of these actions over the past 10 years. Members’ involvement by their type of work category is shown in Figure 3.
Figure 1: Distribution of medico-legal problems (N=73)
Figure 2: Legal actions opened per five-year periods (N=62)
Figure 3: Type of work
Legal and College outcomes (Figures 1, 4)
Of the 62 legal actions, 56 are now closed and six remain open at the time of writing. The outcomes of these actions are shown in Figure 1. The high proportion of settled cases is in contrast with the overall CMPA experience (Figure 4). Consent was identified as an issue in the statement of claim in 92 per cent of the legal actions.
Figure 4: Aminoglycoside vs. overall CMPA cases 1984 – 2006
Clinical characteristics (Figures 5, 6)
Of the 65 clinical incidents, 56 involved the parenteral administration of an aminoglycoside and nine involved a nonparenteral administration (either topical, intratympanic as a treatment for Meniere’s disease, or oral.) These two groups will be considered separately.
Parenteral administration of aminoglycosides
The average patient age was 54. Thirty-two of the patients (57%) were male. A history of diabetes was documented in 17 (30%). A creatinine level obtained prior to the initiation of therapy was above the upper limit of normal used by the reference laboratory in 13 patients (23%).
Conditions being treated and pathogens
Clinical conditions being treated in order of decreasing frequency were (Figure 5):
Figure 5: Clinical conditions being treated
In 33 cases an organism was cultured. These included Pseudomonas, Staphylococcus aureus, Streptococcus, Escherichia coli, Enterococcus, Citrobacter, and Klebsiella. Only four of the microbiological isolates showed sensitivity only to an aminoglycoside, in the remaining 29 the organism was sensitive to at least one other commonly used antibiotic.
Gentamicin was the antibiotic used in 53 cases (95%), tobramycin in two and netilmicin in one. In addition:
Toxicity (Figure 6)
Common toxicities related to aminoglycoside use are either otic (vestibular or cochlear) or renal. The average duration of time between the onset of therapy and the first appearance of symptoms or signs suggestive of toxicity was 24 days (range 3 – 42 days). In 24 cases (43%) the drug was continued for more than 72 hours after the onset of clinical signs or symptoms of toxicity. In 10 patients, symptoms of toxicity occurred more than seven days after the drug was discontinued. Vestibular toxicity was confirmed with electronystagmography in 46 patients and was unconfirmed in two. In the remaining eight patients the toxicity was either cochlear (4) or renal (4). Figure 6 demonstrates that 93 per cent of patients who initiated medico-legal complaints or actions developed ototoxicity.
Figure 6: Type of toxicity
Non-parenteral Administration of aminoglycosides (topical, intratympanic, oral)
During the study period nine legal actions
were identified related to the use of nonparenteral
aminoglycosides. Six involved
topical treatment for otorrhea, two related to intratympanic administration of gentamicin
for Meniere’s disease, and one case involved
a patient with hepatic encephalopathy treated
with a prolonged (240 day) course of oral
neomycin resulting in cochlear toxicity. In all
six otorrhea cases the tympanic membrane
was not intact, either due to a perforation or
myringotomy tube. Notably, all instances of
medico-legal actions involving topical
aminoglycosides were in the presence of a
non-intact tympanic membrane. The average
duration of therapy was 86 days. Framycetin
(Sofracort®) was the drug involved in one
case, in the remaining five, gentamicin drops
were used. Vestibular toxicity was
documented in four of these cases and
cochlear toxicity was present in the
remaining two. Of the topical cases three
were settled and three dismissed. One of the
two intratympanic cases was settled on an
issue of consent and one dismissed. The
neomycin case was settled.
The bottom line
Identifying risks when choosing a parenteral aminoglycoside
Based on the data presented and expert opinion from the files the following questions may need to be answered prior to the initiation of therapy with an aminoglycoside:
Identifying risks with topical aminoglycosides
In the topical cases, review of expert opinion suggested the following questions should be explored:
Aminoglycosides are effective antimicrobial agents with indisputable efficacy in gram negative infections. Increased awareness of the issues raised here may offer patients both improved and safer clinical care.