Introduction
For a patient to succeed with a medical malpractice action against a health-care professional, the patient must prove the following four elements: (1) standard of practice for the particular health-care practitioner, (2) breach of the standard of practice, (3) causation and (4) damages. Any case involving gentamicin-induced toxicity will require a detailed analysis of the case circumstance in order to determine if the above elements can be demonstrated and substantiated with expert testimony.
Gentamicin is a member of a class of antibiotics referred to as aminoglycosides (AGs).
Pharmacology
Gentamicin is a member of a class of antibiotics referred to as aminoglycosides (AGs). These agents were introduced in the late 1940s for use against tuberculosis infections and remain in use today for use against more generalized infections. Gentamicin is the most widely prescribed AG and will serve as the prototype for this discussion. Gentamicin- type agents are well known for their inherent ability to cause nephrotoxicity and ototoxicity. While the true incidence is difficult to determine, reported incidences of 8% for nephrotoxicty and 2-5% for ototoxicity are reported. Gentamicin-induced nephrotoxicity is usually reversible while ototoxicity is irreversible, although some patients can experience partial recovery if diagnosed at early onset of symptoms. Gentamicin-induced ototoxicity can occur as hearing loss (cochlear) or loss of balance/equilibrium/spatial orientation (vestibular). Either form of ototoxicity may occur with any of the aminoglycosides but certain aminoglycosides (amikacin) are more prone to cause hearing loss while others (gentamicin, tobramycin) more often induce vestibular dysfunction. Some patients experience both forms of ototoxicity.
Risk factors proposed for gentamicin-induced nephrotoxicity and ototoxicity are controversial and include: total drug exposure, excessive dosages, elevated trough concentrations and pre-existing renal impairment among others. However, there does appear to be a consensus for prolonged duration of therapy (e.g., >5-7-10-14 days). To complicate matters, gentamicin-induced toxicity can occur even when the drug is properly dosed, when nephrotoxicity does not develop and when blood levels are therapeutic. This can occur during, at the end of and up to a week or so after therapy is completed. For these reasons, gentamicin use is restricted to serious or life-threatening infections for which no equally effective but less toxic antibiotic is available.
Indications for Clinical Use
Because of their well known propensity for toxicity, aminoglycosides are not considered first line agents except in limited instances (discussed below). Their use is generally restricted to the following circumstances: (1) in combination therapy against resistant gram-negative organisms, (2) synergistic use (reduced dose and duration of therapy) in combination with a beta-lactam (penicillin-related) antibiotics or vancomycin in the treatment of gram-positive bacterial endocarditis or (3) as a single agent in the treatment of pyelonephritis or other urinary tract gram-negative infections. For the record, AGs are used as one-time prophylactic agents prior to invasive urinary tract procedures.
However, it should be pointed out that studies comparing the effectiveness and outcomes between beta-lactam monotherapy and beta-lactam/aminoglycoside combination therapies of patients with bacterial endocarditis and gram-negative infections failed to demonstration that monotherapy was inferior to combination therapy with an aminoglycoside.
It is clinically appropriate to use gentamicin as a component of broad spectrum combination therapy to empirically treat a specific clinical syndrome until such time as the culture and sensitivity results become available. Once the infecting organism(s) is identified and antibiotic sensitivities determined, therapy can be changed to agents with a narrower spectrum and less toxicity, in the case of gentamicin.
[Guide To Testing and Evaluating Medical Legal Cases involving Hearing Loss Claims]
Gentamicin Dosing
Prior to the mid-1990s, gentamicin was dosed at approximately 1.7mg/kg every eight hours, with peak and trough levels expected to range from 6-10mcg/ml and <2mcg/ml, respectively. Toxicity was believed to be associated with elevated peak levels. In attempts to decrease gentamicin-induced nephrotoxicity, animal and human research confirmed gentamicin could be dosed once-daily with less nephrotoxicity. However, no meta-analysis to date has demonstrated that once-daily gentamicin dosing is less ototoxic.
As a result, nomograms appeared in the literature supporting once-daily gentamicin administration at dosages ranging from 5-7mg/kg/24 hours. One significant difference in once-daily dosing methodology recognized ototoxicity as resulting from elevated gentamicin trough rather than peak concentrations. These nomograms were pharmacokinetically designed to produce peak levels of at least 10 times the gentamicin minimum inhibitory concentration or 20 mcg/ml as well as a sufficient drug-free period of (concentration, < 0.5mcg/ml) of at least 4 hours before the next dose. The once-daily administration frequency is determined based on a single aminoglycoside concentration obtained 6-14 hours after administration of the first dose.
Use of the nomogram is simple: the (concentration, time) point is plotted on the nomogram. If the point falls in the area designated every 24 hours, the dosage interval is every 24 hours (the same holds for the other areas). If the point is on the line or above the line, the longer dosing interval is chosen. If the point falls off the nomogram, aminoglycoside treatment is stopped and the drug concentration is monitored to determine the time for administration of the next dose. [Clin Pharmacokinet 2001;40(1):803-14]
Monitoring Renal Function
Renal function is monitored by means of a serum creatinine level which can range from 0.6 – 1.3 mg/dL depending upon the laboratory. Creatinine is a by-product of muscle metabolism that is eliminated by the kidneys. However, the rate of formation is constant such that the plasma level is used as a marker for renal function, (i.e., creatinine levels will increase in the face of renal decline). Creatinine levels can be incorporated into a formula along with patient age and ideal body weight to determine a creatinine clearance or glomerular filtrate rate which is defined as the amount of blood filtered per minute by the kidneys. The so-called Hartford nomogram [Antimicrob Agents Chemother 1995;39:650-5] doses gentamicin patients with a drug administration interval based on estimated creatinine clearance: ≥60ml/min every 24h, 59-40ml/min every 36h, and 39-20ml/min every 48h.
Patients prescribed gentamicin-type drugs should have a baseline creatinine level determined prior to initiation of therapy, at least weakly thereafter and no less than every 2-3 days in the event of increasing creatinine levels. Nephrotoxicity is defined as a rise in the serum creatinine of ≥0.5mg/dL above the baseline value during aminoglycoside therapy.
Monitoring Gentamicin Concentrations
Clinicians can choose to monitor gentamicin levels by a number of different means. If a nomogram is utilized, then a 6-14 hour post-dose level should be determined after the first or second dose and the concentration-time point plotted on the nomogram for a decision on continuation of the selected dose. In younger healthy patients, gentamicin levels should be monitored no less than every 5-7 days and more often in the face of renal decline (i.e. gradually rising creatinine levels) or elevated gentamicin concentrations.
An alternative method would be to monitor the trough concentration after the first or second dose and then no less than every 5-7 days thereafter with appropriate levels and stable renal function. While there is controversy as to what an appropriate gentamicin trough level should be, (i.e., <2mcg/ml, <1mcg/ml, <0.5mcg/ml), the primary consideration for once-daily gentamicin dosing was to create a drug-free interval of 4-6 hours prior to the next dose in order to reduce the incidence of renal toxicity.
In should be noted that some clinicians prefer to monitor gentamicin dosing with pharmacokinetic programs which offer a more sophisticated means of predicting appropriate gentamicin dosages and peak/trough concentrations.
While the adoption of gentamicin nomograms have improved patient care, they do have drawbacks. A number of clinicians mistakenly assume that because gentamicin levels are therapeutic, the risk of nephrotoxicity and ototoxicity is eliminated or greatly reduced. When faced with increasing creatinine levels and/or gentamicin concentrations, the naïve practitioner simply reduces the dose and rechecks lab in a week only to have to reduce the dose even more the next week and so on. Gentamicin-induced renal toxicity is non-oliguric (the patient will continue to diurese). It is incorrect to assume that as long as the patient is urinating as per usual, renal function is unaffected, especially with increasing creatinine levels. Renal damage will lag behind creatinine levels by 2-3 days, so those labs must be monitored daily in the face of declining renal function. Naïve practitioners tend to fixate on dosage reductions while failing to understand the clinical significance of rising creatinine and gentamicin levels and the relationships to gentamicin-induced renal and ototoxicity. Serious consideration should be given to discontinuing gentamicin therapy.
[EMTALA and Bad Faith as Additional Causes of Actions in Medical Malpractice Suits]
Informed Consent
Any patient treated with gentamicin should be thoroughly and meticulously informed of the inherent potential for renal and ototoxicity associated with use of the drug and these instructions should be recorded in the patient’s chart. It is substandard to simply advise the patient that the drug might adversely affect hearing or balance and then put the burden on the patient to drink plenty of fluids and call if dizziness occurs. Gentamicin-induced ototoxicity is a phenomenon that results from gradual loss of sensory hair cells in the cochlea (hearing loss) and the semicircular canals (vestibular dysfunction) of the inner ears. By the time the patient can discern symptoms, toxicity is in evolution to the point that excess capacity is being been destroyed. Once the patient is aware of adverse symptoms, the drug should be stopped immediately in an attempt to limit further toxicity.
In is not considered standard of practice for patients receiving long-term gentamicin treatment to receive routine hearing tests, although there is certainly no reason why these could not be performed at baseline and periodically during therapy. This decision should be made by the patient. Patients should be counseled to be aware of feelings of fullness in the ears, tinnitus, or decreased hearing acuity.
There are, however, bedside tests that can be easily performed on patients that are not critically ill. These include head thrust, Romberg and dynamic visual acuity testing. Early manifestations of possible gentamicin-induced vestibulotoxicity at its earliest stages can include headache, flu-like symptoms, a vague sensation of feeling poorly, malaise, nausea, vomiting, dizziness, a sense of imbalance, and gait disturbances. The important clinical consideration here is that unless gentamicin patients are appropriately counseled, they may fail to identify early warning signs and symptoms associated with vestibular toxicity, regarding them instead as simply nebulous.
Culpability
During the last 30-40 years, professional/legal practice patterns have evolved from physicians prescribing, pharmacists dispensing and nurses administering prescription drugs to one of multiple overlapping responsibilities, depending upon state practice acts. It is not unusual to see aminoglycosides prescribed by physicians on a per protocol basis, with clinically trained pharmacists in hospitals and home-infusion pharmacies then assuming clinical responsibility for drug dosing and monitoring renal function and drug levels. Nurses in home health agencies participate by teaching patients to properly administer the medication; draw blood for labs; and monitor patients for compliance, site care, and possible development of side effects. As a result, multiple health care professionals have responsibilities in caring for patients undergoing gentamicin therapies.
Pharmacists participating in collaborative practices requiring specialized knowledge are held to standards higher than those usually required for traditional dispensing practices, (i.e. technical accuracy and basic duty to warn). Pharmacists acting in such capacities are directly responsible for the patients’ therapy. Along with increasing professional responsibility comes increased professional liability. State pharmacy regulations regarding patient counseling and prospective drug review as well as practice guidelines from the American Society of Health-Care Pharmacists on the pharmacists role in home care and clinical pharmacokinetic monitoring, Joint Commission on Accreditation of Health-Care Organization standards on home pharmacy infusion accreditation and Infectious Disease Society of America practice guidelines for outpatient parenteral antimicrobial therapy all recognize that pharmacists are trained to understand the appropriateness of drug therapies, dosing strategies and clinical monitoring.
[Unrecognized Soft Tissue Injuries In A Medical Practice]
Conclusion
Both defense and plaintiff attorneys should look at a gentamicin toxicity case and analyze the case circumstance based on the following questions:
(l) Was the use of gentamicin necessary because an equally effective antibiotic was not clinically appropriate?
(2) Was the drug used for longer than clinically necessary?
(3) Was the drug appropriately dosed and monitored?
(4) Did the patient receive informed consent to the extent that he/she fully understood risks known to be associated with gentamicin treatment and how to monitor for prodromal symptoms?
(5) In the event that nephrotoxicity or ototoxicity was experienced, was the drug discontinued and the patient referred to an appropriate specialist (nephrologist, neurologist, otolaryngologist) for diagnosis and treatment?
As stated by others, gentamicin is not necessarily a bad drug, just one that can be used badly.
Written by: Pharmacology Expert Witness No. 1925
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