Correspondence

Gentamicin Contaminated with Endotoxin

N Engl J Med 1999; 340:1122April 8, 1999

Article

To the Editor:

A succession of at least 57 moderate-to-severe endotoxin-like reactions has occurred in the western United States over an approximately six-month period. These reactions were associated with the administration of endotoxin-contaminated gentamicin for injection manufactured by Fujisawa USA.1

Endotoxin (a lipopolysaccharide) is a component of the cell wall of gram-negative bacteria and mediates many of the clinical features observed in gram-negative bacterial sepsis. These include fever, shaking chills, and cardiovascular symptoms, and in more severe cases include muscle proteolysis, uncontrolled intravascular coagulation, shock, and death. Endotoxin stimulates mononuclear cells to produce interleukin-1, tumor necrosis factor α, and possibly interleukin-6. These cytokines, when administered experimentally to humans, produce symptoms analogous to those elicited by endotoxin.2

The Food and Drug Administration (FDA) acknowledged the presence of endotoxin in Fujisawa's gentamicin early on. However, the concentration of endotoxin was within United States Pharmacopeia (USP) limits as long as the drug was administered as labeled (every 8 to 12 hours). Over the past decade, once-daily dosing of aminoglycoside antibiotics (such as gentamicin) has come into vogue. Considering the cost savings, potentially increased efficacy, and reduced toxicity associated with once-daily dosing,3 it logically follows that this dosing schedule would become a preferred approach, though not approved by the FDA. Even though the endotoxin contamination of the gentamicin was below USP limits and thus below the FDA-enforceable limit of 1.7 endotoxin units per milligram, peak systemic endotoxin concentrations in these patients often surpassed the pyrogenic threshold of 5 endotoxin units per kilogram of body weight when gentamicin (5 to 7 mg per kilogram per day) was infused as a single dose,1 and hence the deluge of reported adverse reactions.

Gentamicin has been a nonproprietary product for nearly 20 years. Therefore, pharmaceutical firms have no monetary impetus to petition for approval of once-daily dosing of gentamicin. If approval were granted, the USP would set a new upper limit for endotoxin in parenteral gentamicin preparations.

As an “off-label” use, once-daily dosing of aminoglycosides containing deleterious contaminants, such as endotoxin, presents formidable challenges for the FDA and for practitioners, as well as for patients. An interesting turn in an already twisted story relates to the FDA Modernization Act of 1997, according to which off-label uses of drugs may be promoted. This contrasts with the FDA's previously conservative position, forbidding pharmaceutical manufacturers from announcing nonapproved uses. This leaves us with the inevitable question: who is financially, ethically, and morally responsible for damage caused by endotoxin from gentamicin (or gentamicin misuse)? The FDA says that Fujisawa was acting within the law. Is the FDA acting within the law? Are we? Potential uses certainly outnumber the thousands of drugs that constitute the pharmaceutical armamentarium in the United States. Undoubtedly, these issues will arise again.

On November 30, 1998, Fujisawa voluntarily withdrew all unexpired 40-mg-per-milliliter preparations of parenteral gentamicin, as a gesture of good faith. This was not an FDA-forced recall, since no current laws or regulations had been violated. It is noteworthy that Fujisawa recently sold the injectable-drug division that manufactured gentamicin.

Jim A. Krieger, R.Ph., Ph.D.
Lamar Duncan, M.S., R.Ph.
University of New Mexico Health Sciences Center, Albuquerque, NM 87131

3 References

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   Isselbacher KJ, Martin JB, Braunwald E, Fauci AS, Wilson JD, Kasper DL, eds. Harrison's principles of internal medicine. 13th ed. New York: McGraw-Hill, 1994.
   

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   Ali MZ, Goetz MB. A meta-analysis of the relative efficacy and toxicity of single daily dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997;24:796-809
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Citing Articles (3)

Citing Articles

1. 1

   Manfred Hauben, Lester Reich. (2005) Endotoxin‐Like Reactions With Intravenous Gentamicin: Results From Pharmacovigilance Tools Under Investigation • . Infection Control and Hospital Epidemiology 26:4, 391-394
   CrossRef

2. 2

   Udo Buchholz, Chesley Richards, Rekha Murthy, Matthew Arduino, Doreen Pon, Wayne Schwartz, Elsie Fontanilla, Clare Pegues, Noemy Boghossian, Carol Peterson, Jacob Kool, Laurene Mascola, William R. Jarvis. (2000) Pyrogenic Reactions Associated With Single Daily Dosing of Intravenous Gentamicin • . Infection Control and Hospital Epidemiology 21:12, 771-774
   CrossRef

3. 3

   &NA;. (1999) Endotoxin-like reactions reported with gentamicin. Reactions Weekly &NA;:747, 2
   CrossRef