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Endotoxin-Like Reactions Associated with Intravenous Gentamicin -- California, 1998

During April 30-July 26, 1998, 20 patients at a major medical center (hospital A) in Los Angeles County, California, developed severe shaking chills often accompanied by fever, tachycardia, and/or a decrease of greater than or equal to 20 mm Hg in systolic blood pressure within 3 hours after receiving intravenous (IV) gentamicin. Receipt of IV gentamicin was the only medication or procedure temporally associated with reactions among all of the patients. No deaths or serious sequelae were associated with the reactions. Similar incidents were reported by hospital personnel from six other states to CDC or the Food and Drug Administration (FDA) during April-August 1998. All reported reactions were associated with once-daily dosing regimens of gentamicin (lot numbers 170704, 180031, 180133, and 180191) produced by Fujisawa USA, Inc. (Deerfield, Illinois). * On August 13, the Los Angeles County Department of Health Services and CDC initiated an investigation with the assistance of hospital A personnel. This report summarizes the results of this investigation at hospital A, which found that gentamicin with endotoxin levels within the U.S. Pharmacopeia (USP) standards may deliver endotoxin amounts above the threshold for pyrogenic reactions with once-daily dosing.

A gentamicin-associated adverse reaction was defined as documented chills, rigors, or shivering within 3 hours after the start of IV gentamicin administration. A case-patient was defined as any hospital A patient aged greater than or equal to 28 days who had one or more gentamicin-associated adverse reactions from December 1, 1997, through August 25, 1998. Two schedules for gentamicin dosing were used: traditionally dosed (TD) gentamicin was defined as gentamicin administered at intervals of 8, 12, or 16 hours, and once-daily-dosed (ODD) gentamicin was defined as gentamicin administered at intervals of greater than or equal to 24 hours. The protocol for gentamicin dosing at hospital A is based on a dose of 7 mg/kg of body weight per day. Computerized pharmacy records were used to identify all patients who received gentamicin during three time periods: 1) the pre-epidemic period (December 1, 1997-January 15, 1998), before the suspected lots of Fujisawa gentamicin were delivered to the hospital; 2) the epidemic period (May 1-July 29, 1998), when the suspected lots of Fujisawa gentamicin were used; and 3) the postepidemic period (July 30-August 25, 1998), when gentamicin from another manufacturer was used. For the pre-epidemic period, the records of all patients who received ODD gentamicin from Fujisawa were reviewed. For the epidemic period, the records of all patients who received either ODD or TD gentamicin from Fujisawa during the first half of the 12-week epidemic period (May 1-June 15, 1998) were reviewed. For the postepidemic period, the records of all patients who received ODD gentamicin from another manufacturer were reviewed. Hospital A began using gentamicin from another manufacturer on July 29 with no other change in gentamicin administration policy or practices. Patients were excluded if they were aged less than 28 days, had incomplete medical records, or received both TD and ODD gentamicin during their hospital stay.

Of the 289 patients whose medical records were reviewed, 67 were excluded; eight because the patient was aged less than 28 days, 23 because medical record information was incomplete, and 36 because they received both TD and ODD gentamicin. Of the remaining 222 patients, 48 received gentamicin during the pre-epidemic period; 154, during the epidemic period (76 received TD gentamicin and 78 received ODD gentamicin); and 20, during the postepidemic period.

Of the 222 patients who received gentamicin, 24 had a gentamicin-associated reaction. Of these, two (8%) received gentamicin during the pre-epidemic period; 22 (92%), during the epidemic period; and none, during the postepidemic period. The mean age of case-patients was 40 years (range: 18-69 years), and 17 (71%) were women. Indications for gentamicin use included obstetric or gynecologic infections (12), fever and neutropenia (eight), gastrointestinal infections (three), or osteomyelitis (one). During the epidemic period, the adverse reaction rate among patients with ODD gentamicin (20 of 78) was significantly higher than that among patients with TD gentamicin (two of 76; relative risk {RR}=9.7; 95% confidence interval {CI}=2.4-40.3). In addition, among persons receiving ODD gentamicin, the adverse reaction rate during the epidemic period was significantly greater than during the pre-epidemic (two of 48; RR=6.15; 95% CI=1.5-25.2) or the postepidemic (none of 20; RR=indefinite; pless than 0.01) period. Among patients who received ODD gentamicin during the epidemic period, the weight of case-patients did not differ significantly from that of noncase-patients (mean weight: 162 lbs {73 kg}). Compared with noncase-patients, case-patients received higher doses (370 mg compared with 427 mg; p=0.01) and higher doses per kilogram of body weight (mean dose/kg body weight: 5.6 mg/kg compared with 6.2 mg/kg; pless than 0.01).

Samples of Fujisawa gentamicin from hospital A were examined for bacterial and/or endotoxin contamination. Bacterial cultures were negative. Endotoxin levels ranged from 25.6 to 32.0 endotoxin units (EU)/mL (median: 32 EU/mL); samples of gentamicin from another manufacturer that was used at hospital A had endotoxin levels less than 2.0 EU/mL. The USP limit for endotoxins in antibiotic formulations is 68 EU/mL or 1.7 EU/mg.

Reported by: C Peterson, MD, N Bendaċa, M Veza, L Mascola, MD, Acute Communicable Disease Control, Los Angeles County Dept of Health Svcs, Los Angeles; R Murthy, MD, C Pegues, E Fontanilla, R Shane, PharmD, M Kwong, PharmD, R Deamer, PharmD, W Schwartz, PharmD, D Pon, PharmD, B Young, PharmD, M Glick, PharmD, K Gibbs, C Plata, Cedars-Sinai Medical Center, Los Angeles; R Harder, M Zellers, N Boghossian, PharmD, T Breschini, PharmD, S Chang, K Heinzmann, Cedars-Sinai Comprehensive Cancer Center, Los Angeles; J Rosenberg, MD, S Waterman, MD, State Epidemiologist, California Dept of Health Svcs. Office of Regulatory Affairs, Food and Drug Administration. State Br, Div of Applied Public Health Training, Epidemiology Program Office; Hospital Infections Program, National Center for Infectious Diseases; and EIS officers, CDC.

Editorial Note

Editorial Note: Gentamicin is an aminoglycoside antibiotic used to treat serious gram-negative bacterial infections (1). First described and characterized during the early 1960s, gentamicin inhibits bacterial protein synthesis, is rapidly bactericidal, and is usually given in divided daily doses every 8-12 hours. The two most important side effects from gentamicin are ototoxicity and nephrotoxicity. To minimize toxicity and simplify administration, once-daily dosing increasingly has been used. Clinical trials have found ODD gentamicin to be safe and effective, with no increase in adverse reactions and possibly a decrease in nephrotoxicity and ototoxicity (2,3). However, this dosing regimen is considered an off-label use (i.e., not included in product label information) by FDA. Typical doses are 5-7 mg/kg body weight. Approximately 28% of all IV gentamicin administered in the United States is given using once-daily dosing (CDC, unpublished data, 1998).

ODD gentamicin probably was associated with these reactions because of the amount of gentamicin received at one time in this regimen. Parenteral antimicrobials such as gentamicin may contain small amounts of endotoxin. Endotoxin, a lipopolysaccharide found in the cell walls of gram-negative bacteria, may cause chills, fever, and systemic cardiovascular effects when infused into humans. The minimum level of endotoxin to cause pyrogenic activity is approximately 5 EU/kg body weight (4-6). Endotoxin levels responsible for clinical reactions have been reported previously for dialysate or medications (7-9). With traditional dosing, endotoxin present in the gentamicin solution is administered in two to three doses over a 24-hour period. In this outbreak, once-daily dosing may have resulted in the delivery of large enough volumes or amounts of gentamicin with sufficient endotoxin over 1 hour to stimulate a pyrogenic reaction even if the endotoxin concentration was below the USP limit of 68 EU/mL or 1.7 EU/mg. For example, a patient who received a once-daily 5-mg/kg body weight dose of IV gentamicin with the level of endotoxin measured in the Fujisawa product (32 EU/mL or 0.8 EU/mg) would receive 4 EU/kg body weight, whereas a patient who received a once-daily 7-mg/kg body weight dose of IV gentamicin would receive 5.6 EU/kg body weight of endotoxin; the latter is above the threshold of 5 EU/kg body weight for pyrogenic reactions.

Pyrogenic reactions have not been reported in studies involving ODD gentamicin. Studies are in progress to determine the extent of these reactions and to identify their etiology. Physicians using ODD gentamicin should be aware that a patient may receive a level of endotoxin two to three times higher than that of TD gentamicin.

FDA and CDC are aware of 37 additional episodes of endotoxin-like reactions associated with IV gentamicin in seven states. FDA's Division of Anti-Infective Drug Products received reports of pyrogenic reactions from Fujisawa only. Clinicians detecting such reactions in patients within 3 hours after gentamicin administration should report these episodes to CDC's Hospital Infections Program, National Center for Infectious Diseases, telephone (404) 639-6442 or fax (404) 639-6459, and to MedWatch, FDA Medical Products Reporting Program, telephone (800) 332-1088; fax (800) 332-0178; mail to Med Watch, 5600 Fishers Lane, Rockville MD 20852-9787; or on the World-Wide Web site http://www.fda.gov/medwatch.

References

  1. Hardman JG, Limbird LE, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York, New York: McGraw-Hill, 1996.

  2. Bailey TC, Little JR, Littenberg B, Reichley RM, Dunagan WC. A meta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997;24:786-95.

  3. 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.

  4. Burrell R. Human responses to bacterial endotoxin. Circulatory Shock 1994;43:137-53.

  5. Suffredini AF, Fromm RE, Parker MM, et al. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989;321:280-7.

  6. Greisman SE, Hornick RB. Comparative pyrogenic reactivity of rabbit and man to bacterial endotoxin. Proc Soc Exp Biol Med 1969;131:1154-8.

  7. Gordon SM, Oettinger CW, Bland LA, et al. Pyrogenic reactions in patients receiving conventional high-efficiency, or high-flux hemodialysis treatments with bicarbonate dialysate containing high concentrations of bacteria and endotoxin. J Am Soc Nephrol 1992;2:1436-44.

  8. Arduino MJ, Bland LA, McAllister SK, et al. Microbial growth and endotoxin production in the intravenous anesthetic propofol. Infection Control and Hospital Epidemiology 1991;12:535-9.

  9. CDC. Clinical sepsis and death in a newborn nursery associated with contaminated parenteral medications -- Brazil, 1996. MMWR 1998;47:610-2.




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