For Physicians and Pharmacists

A Letter to Physicians and Healthcare Providers Using Gentamicin from Attorney Keith S. Douglass

I am not a physician, although my undergraduate and graduate training was in the biological sciences. I am an attorney who has represented or reviewed the cases of over seventy victims of severe gentamicin-induced ototoxicity. The majority of these cases involved the negligent use or administration of gentamicin. GENTAMICIN OTOTOXICITY CAN USUALLY BE PREVENTED OR MINIMIZED. BEING FOUND NEGLIGENT IN A LAWSUIT INVOLVING GENTAMICIN CAN ALMOST ALWAYS BE PREVENTED IF YOU TREAT GENTAMICIN AS A POTENTIALLY DANGEROUS DRUG, AND GIVE IT THE RESPECT IT DESERVES.

What follows is a series of observations and suggestions that could save your patients the tragedy of becoming victims of gentamicin poisoning, and could save you from being named a defendant in a lawsuit.

It is a myth that once a day dosing (ODA) of gentamicin lessens the risk of ototoxicity. Nephrotoxicity, probably. Ototoxicity, no. Although there are some studies suggesting a decreased incidence of ototoxicity with ODA, there is more evidence to the contrary.

ODA became a popular alternative to three times a day dosing after publication of the Hartford Study. (Nicolau, D. P, Freeman, C. D., Belliveau, P. P., Nightingale, C. H., Ross, J. W. & Quintiliani, R. (1995). Experience with a once-daily aminoglycoside program administered to 2,184 patients. Antimicrobial Agents and Chemotherapy 39, 650–5)

Abstract here

Full Text Here

 

The median length of therapy for the 2,184 patients in this study was 3 days, and the mean 4.5 days. The longest course of therapy was 29 days, and that person suffered irreversible bilateral vestibulopathy. The Hartford study never advocated using high doses of gentamicin for extended periods of time. There is nothing in the Hartford study or subsequent studies of ODA to obviate or supplant the warning in the gentamicin product insert:

WARNING:

Patients treated with aminoglycosides should be under close clinical observation because of the potential toxicity associated with their use.

As with other aminoglycosides, gentamicin sulfate pediatric injectable is potentially nephrotoxic. The risk of nephrotoxicity is greater in patients with impaired renal function and in those who receive high dosage or prolonged therapy.

Neurotoxicity manifested by etotoxicity, both vestibular and auditory, can occur in patients treated with gentamicin sulfate pediatric injectable, primarily in those with pre-existing renal damage and in patients with normal renal function treated with higher doses and/or for longer periods than recommended. Aminoglycoside-induced etotoxicity is usually irreversible. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching, and convulsions.

Renal and eighth cranial nerve functions should be closely monitored, especially in patients with known or suspected reduced renal function at onset of therapy, and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Urine should be examined for decreased specific gravity, increased excretion of protein, and the presence of cells or casts. Blood urea nitrogen, serum creatinine, or creatinine clearance should be determined periodically. When feasible, it is recommended that serial audiograms be obtained in patients old enough to be tested, particularly high-risk patients. Evidence of etotoxicity (dizziness, vertigo, ataxia, tinnitus, roaring in the ears, or hearing loss) or nephrotoxicity requires dosage adjustment or discontinuance of the drug. As with the other aminoglycosides, on rare occasions changes in renal and eighth cranial nerve function may not become manifest until soon after completion of therapy.

Serum concentrations of aminoglycosides should be monitored when feasible to assure adequate levels and to avoid potentially toxic levels. When monitoring gentamicin peak concentrations, dosage should be adjusted so that prolonged levels above 12 g/ml are avoided. When monitoring gentamicin trough concentrations, dosage should be adjusted so that levels above 2 g/ml are avoided. Excessive peak and/or trough serum concentrations of aminoglycosides may increase the risk of renal and eighth cranial nerve toxicity. In the event of overdose or toxic reactions, hemodialysis may aid in the removal of gentamicin from the blood, especially if renal function is, or becomes, compromised. The rate of removal of gentamicin is considerably less by peritoneal dialysis than by hemodialysis. In the newborn infant, exchange transfusions may also be considered.

Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as cisplatin, cephaloridine, kanamycin, amikacin, neomycin, polymyxin B, colistin, paromomycin, streptomycin, tobramycin, vancomycin, and viomycin, should be avoided. Another factor which may increase patient risk of toxicity is dehydration.

The concurrent use of gentamicin with potent diuretics, such as ethacrynic acid or furosemide, should be avoided, since certain diuretics by themselves may cause ototoxicity. In addition, when administered intravenously, diuretics may enhance aminoglycoside toxicity by altering the antibiotic concentration in serum and tissue.

 

Gentamicin is inexpensive. The cost-containment folks love it. Why use gentamicin, with its well-known, permanent side effects, when a different, albeit more expensive antibiotic would suffice? Is the risk of gentamicin therapy outweighed by the benefit? A few hundred dollars savings to the patient’s healthcare insurer could cost your malpractice carrier millions.

Gentamicin is no longer the "big gun" for Pseudomonal infections: In recent years, newer, less toxic anti-pseudomonal drugs have emerged that in most instances are equally or more efficacious than gentamicin. Ceftazidime (Fortaz, Tazicef, Tazidime), piperacillin-tazobactam (Zosyn) and Imipenum (Primaxin) are examples. The following is excerpted from Mandell, Bennett, & Dolin: Principles and Practice of Infectious Diseases, 6th ed at p. 2601: "Thus, none of the dogmas concerning the appropriate therapy for P. aeruginosa bacteremia can be considered to be established by blinded, controlled clinical studies. One firm conclusion appears to be that monotherapy with an aminoglycoside dosed in the approved way should not be the primary choice for antibiotic treatment. [emphasis supplied] Unquestionably, the majority of infectious disease experts still favor the use of combination therapy for P. aeruginosa bacteremia. However, it is difficult to indict the use of a single modern antipseudomonal -lactam antibiotic as being inadequate therapy. Even in the patients most at risk for dying rapidly from P. aeruginosa bacteremia (i.e., high-risk patients with fever and neutropenia), empirical monotherapy [referring to the antipseudomonal -lactam antibiotics such as ceftazidime, piperacillin-tazobactam, or imipenum] designed to treat P. aeruginosa is considered to be as efficacious as empirical combination therapy in the Practice Guidelines of the Infectious Diseases Society of America (IDSA)."

 

If using gentamicin for synergy with a beta lactame, use synergistic doses of gentamicin.

Synergistic dosing of gentamicin is different than monotherapy dosing. The beta lactame acts by breaking town the cell wall of the target organism, allowing gentamicin to diffuse inward to the ribosomal system, which is its site of action. If the beta lactame and gentamicin have a synergistic effect on the particular organism, 2-3 mg/kg/day of gentamicin for the first few days of therapy is typically sufficient.

Why not obtain an infectious disease consult every time you prescribe gentamicin for over 3 days? There may well be an equally efficacious drug outside of your personal pharmacopoeia that could be used. Maybe, when the culture and sensitivity results become available, gentamicin isn’t the drug of choice, even if it seemed the best choice for empiric therapy. In any event, it is far easier to justify a decision to use gentamicin in a court of law when that decision was made on the informed advice of an infectious disease consultant, who was fully appraised of all aspects of your patient’s condition. Again, a few hundred dollars savings to the patient’s health care insurer could cost your malpractice carrier millions.

Emperic, Short Term vs. Long Term Use. The emperic use of gentamicin for 2 to 3 days until positive culture results are obtained is relatively safe. The longer gentamicin is administered, the higher the dose, and the presence of other risk factors all significantly increase the risk of PERMANENT, IRREVERSIBLE, SEVERE LOSS OF VESTIBULAR FUNCTION. Gentamicin accumulates in the endolymph of the inner ear, and can remain in the endolymph for weeks after the cessation of therapy. Gentamicin is toxic to the hair cells of the inner ear. In human adults, the hair cells of the vestibular as opposed to the cochlear system are affected the most.

 

Because Gentamicin Is Solely Eliminated in the Urine, and Is Nephrotoxic, Renal Failure and Toxic Gentamicin Levels Can Quickly Develop.

As the proximal tubule cells become exposed to gentamicin, renal cell damage can occur, with loss of renal function. Although it is the theory of Once Daily Dosing that there is an eight hour period where the serum gentamicin level is practically zero that gives the renal cells a time to rest and regenerate, nephrotoxicity can and does occur in patients on Once Daily Dosing. Because gentamicin is not metabolized, but is excreted in the urine, any loss of renal function without a concomitant decrease in the dose administered will inevitably lead to some increase in the average daily serum gentamicin concentration. Increasing serum gentamicin levels promote further nephrotoxicity, and a vicious circle of increasing serum gentamicin levels and increasing nephrotoxicity results. I have reviewed cases where the serum creatinine level rose from normal to over 3.0 within 3 to 4 days. While gentamicin induced nephrotoxicity is usually transient, and resolves with discontinuance of the drug, the vestibular damage that can result from high serum gentamicin levels secondary to acute nephrotoxicity is usually permanent.

 

Severe, permanent, bilateral vestibulopathy can occur in patients receiving gentamicin, even though their serum gentamicin levels are monitored, and even though renal function studies remain in the normal range. While monitoring can demonstrate early nephrotoxicity, long term exposure to "normal" gentamicin levels can cause ototoxicity. In my litigation practice, I have personally reviewed at least 5 cases where long term (>10 days) gentamicin administration resulted in permanent ototoxicity, but renal function remained unchanged and within normal limits. These were typically doses above 5mg/kg/day where the patient had complained of ototoxic symptoms during gentamicin administration that were ignored.

 

Gentamicin is a very toxic drug.

If, after consultation with an infectious disease specialist, gentamicin is determined to be the best-suited antibiotic, why not go beyond the minimum standard and monitor renal function every 3 days? If serum creatinine rises, even by 20%, why not perform daily renal function tests, or draw a gentamicin random level to determine if there is a rising serum gentamicin concentration resulting from nephrotoxicity? Even though careful monitoring doesn’t guarantee an absence of subsequent vestibulopathy, careful monitoring and adjusting the dosage downward, or discontinuing gentamicin altogether, could likely prevent vestibulopathy, and will almost certainly prevent a lawsuit for failure to monitor if there is a resulting vestibulopathy. Once again, a few hundred dollars savings to the patient’s health care insurer could cost your malpractice carrier millions.

Since gentamicin is a very toxic drug, it pays to obtain the patient’s actual informed consent. This means actually explaining to the patient in detail what permanent, irreversible ototoxicity is, what the alternative treatments are, and/or the consequences of receiving no treatment. (This does not mean handing them a sheet of paper with a list of warnings and telling them to read it.) If the patient then consents, with full knowledge of the risks involved, document the informed consent in detail. Additionally, warn the patient to report immediately any symptoms of vertigo, new tinnitus, or oscillopsia, and inform your staff that any communication with this patient is high priority. A few minutes of your time could save your malpractice carrier millions of dollars.

If you prescribe gentamicin to be administered by a home infusion company, make sure that your orders for careful monitoring of renal function and symptoms of vestibulopathy are actually understood and carried out by the staff of the home infusion company. Imagine trying to explain in front of 12 jurors why you ordered monitoring, but did nothing for two weeks when your office never received lab results or reports from the home infusion company, or why the results were promptly sent by the home infusion company, but were never reviewed by you. Again, a few minutes of your time could save your malpractice carrier millions of dollars.

IF A PATIENT COMPLAINS ABOUT ANY DIZZINESS, LOSS OF BALANCE, BOUNCING OR JERKY VISION, TINNITUS, OR OTHER SYMPTOM OF VESTIBULAR DISTURBANCE, STOP THE GENTAMICIN AND IMMEDIATELY INVESTIGATE THE UNDERLYING CAUSE. These are symptoms of gentamicin toxicity, and while they may not disappear if sufficient vestibular hair cells have been killed, further damage may be avoided by immediately stopping the gentamicin. Unless there is absolutely NO viable alternative to treating a life threatening infection, and permanent, total loss of the patients vestibular system is an acceptable alternative to discontinuing or altering therapy, gentamicin should be discontinued immediately and this patient should never receive gentamicin or any other aminoglycoside in his or her lifetime. Other aminoglycosides are: tobramycin, amikacin, streptomycin and neomycin. In addition, some other antibiotic drugs known to cause vestibular damage are: erythromycin, kanamycin, netromycin and vancomycin. Antibiotics are not the only drugs that can cause ototoxicity.

I have had many cases, and have prevailed against pharmacists, where a pharmacist would adjust downward the dose of gentamicin when a person complained of ototoxic symptoms in the apparent hope that lowered blood gentamicin levels would reverse the ototoxic symptoms. THE APPEARANCE OF OTOTOXIC SYMPTOMS MEANS THAT THE PATIENT IS VERY CLOSE TO (OR ALREADY MAY HAVE EXPERIENCED) IRREVERSIBLE VESTIBULAR DAMAGE. GENTAMICIN MUST BE DISCONTINUED IMMEDIATELY TO ALLOW THE GENTAMICIN REMAINING IN THE ENDOLYMPH TO DIFFUSE OUTWARD WITH A MAXIMUM DIFFUSION GRADIENT.

IT IS A MYTH THAT OTOTOXIC SYMPTOMS WILL DISAPPEAR OVER TIME. Although there may be a rare case where hair cells are merely shocked and will regain function once gentamicin is discontinued, the majority of hair cell damage is permanent. While victims of gentamicin poisoning can learn certain adaptation skills, human hair cells never regenerate once killed. This is one of the reasons that gentamicin poisoning is so insidious: it is usually permanent where the side effects of other antibiotics are more likely transitory. I have reviewed many cases where a pharmacist or physician would adjust the dose of gentamicin downward once symptoms appeared, hoping that they would disappear. In most circumstances, this strategy leads to worsening symptoms and the complete destruction of the vestibular system bilaterally. IF VESTIBULAR OR AUDITORY CHANGES APPEAR, STOP THE GENTAMICIN IMMEDIATELY. While gentamicin-induced nephrotoxicity may resolve over time, gentamicin-induced ototoxicity is usually permanent. The reported improvement in function of some cases of gentamicin-induced ototoxicity is usually due to adaptability, not to any improvement in the vestibular system.

In summary, inform yourself about the real risks of using gentamicin. Understand that it is an ototoxic and nephrotoxic drug that can cause permanent, irreversible injury. If long term therapy is called for, choose other less toxic alternatives. If in doubt, obtain an Infectious Disease consult.

 

Additional Resources:

The RxMed monograph on gentamicin sulfate. Note - This reflects the original package insert - ODA is not considered. Note 5 mg/Kg/day maximum dose.

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