Correspondence

Pyrogenic Reactions to Gentamicin Therapy

N Engl J Med 2000; 343:1658-1659November 30, 2000

Article

To the Editor:

In October 1998, the Centers for Disease Control and Prevention reported 20 endotoxin-like reactions to intravenous gentamicin1 administered in a once-daily dosing regimen. We report on a completed investigation of a series of pyrogenic reactions involving two gentamicin products. The reactions were reported to the Food and Drug Administration (FDA) between May 1998 and December 1999. They involved 155 patients; 38 percent were male and 62 percent were female. Their mean age was 41 years (range, 3 to 85). Dosing information was available for 91 percent of the patients (Figure 1Figure 1Number of Patients with Reactions to Gentamicin, According to the Dose.). Eighty-one percent received once-daily dosing (70 percent at a dose of 5 to 7 mg per kilogram of body weight), and 10 percent received conventional dosing (3 mg per kilogram per day in three divided doses). Information on indications for use was available for 86 percent of the patients. Gentamicin was given to treat underlying infection in 50 percent, for fever and neutropenia in 22 percent, and as prophylaxis in 14 percent.

Reactions typically occurred within three hours after infusion of the drug (in 98 percent of the patients) and lasted for less than three hours (in 96 percent). Patients reported chills or shaking or shivering (75 percent), rigors (23 percent), fever (68 percent), tachycardia (17 percent), hypertension or hypotension (17 percent), and respiratory symptoms (47 percent). More serious reactions also occurred, including cyanosis (in 4 percent of the patients), oxygen saturation of less than 80 (in 7 percent), and pulmonary edema (in one patient). Eight percent of the patients had severe reactions leading to hospitalization (with intubation, resuscitation, or admission to the intensive care unit in five cases). None of the cases were fatal.

The use of a once-daily dosing regimen of gentamicin started in the early 1990s as a way to minimize toxicity and simplify administration.2,3 A recent survey indicates that approximately 75 percent of hospitals use once-daily dosing,4 as compared with 19 percent in 1994.5 This dosing regimen is considered “off-label” because it has not been subject to the FDA's scientific review and is therefore not included in the product labeling. United States Pharmacopeia standards for allowable concentrations of inactive ingredients and impurities in gentamicin products are based on conventional dosing. Use of once-daily dosing therefore results in increased exposure per dose to these other constituents. For example, endotoxin levels in drug products are set so that the patient's exposure per hour is below the threshold level of exposure for a febrile response (i.e., 5 endotoxin units per kilogram per hour, or 1.7 endotoxin units per milligram of gentamicin given as a conventional dose).

These reactions were initially thought to be due to the exposure of patients to higher endotoxin levels with once-daily dosing than with conventional dosing. An FDA investigation revealed that 10 percent of gentamicin lots tested had elevated endotoxin levels (>1.7 endotoxin units per milligram), and an additional 4 percent of the lots would have exposed a patient to levels above the acceptable threshold with once-daily dosing. The two products implicated in these clusters involved the same supplier of bulk gentamicin. Inspection of the bulk supplier revealed inadequacies in manufacturing practices that led to an increase in the overall impurities. The FDA ordered a ban on the import of products from this firm in September 1999. Gentamicin made with a new bulk-drug supply has been uneventfully reintroduced to the market.

The reporting of these adverse events by diligent health care professionals led to the identification, investigation, and withdrawal of these products by the FDA. Health care professionals are encouraged to report adverse events to manufacturers and directly to the FDA through the MedWatch program at 1-800-332-1088 (or at http://www.fda.gov/medwatch).

(The views represented in this letter are those of the authors and not necessarily those of the Food and Drug Administration.)

Mary M. Fanning, M.D., Ph.D.
Ron Wassel, Pharm.D.
Toni Piazza-Hepp, Pharm.D.
Food and Drug Administration, Rockville, MD 20855

5 References

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Citing Articles (5)

Citing Articles

1. 1

   Luis A. Brito, Manmohan Singh. (2011) Acceptable levels of endotoxin in vaccine formulations during preclinical research. Journal of Pharmaceutical Sciences 100:1, 34-37
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2. 2

   2006. Gentamicin. , 1500-1505.
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3. 3

   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

4. 4

   Mary Linda Stotter Cuddy. (2004) The Effects of Drugs on Thermoregulation. AACN Clinical Issues: Advanced Practice in Acute and Critical Care 15:2, 238-253
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5. 5

   Robert J. Coffey, Kim Burchiel. (2002) Inflammatory Mass Lesions Associated with Intrathecal Drug Infusion Catheters: Report and Observations on 41 Patients. Neurosurgery 50:1, 78-87
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