Ceftriaxone-Associated Biliary Complications of Treatment of Suspected Disseminated Lyme Disease -- New Jersey, 1990-1992

Lyme disease (LD) is endemic in Monmouth and Ocean counties, New Jersey (1). In June 1992, CDC and the New Jersey Department of Health (NJDOH) conducted a telephone survey in both counties of 65 schoolchildren who required home instruction because of suspected LD to determine the public health impact of the disease. Most children had received prolonged and repeated courses of oral antimicrobials and/or home intravenous infusion of antimicrobials; 79% had been hospitalized for treatment of suspected LD or management of treatment complications, most notably drug- induced symptoms of gallbladder disease occurring in patients receiving ceftriaxone (Rocephin *), and bloodstream infections associated with intravenous catheters. To determine the characteristics of and treatment complications for patients hospitalized for treatment of LD, a computerized search of hospital discharge data in New Jersey was performed; nearly 30% of all hospitalizations for LD during 1990- 1991 were at a regional hospital serving Monmouth and Ocean counties. This report presents findings of an analysis of patients admitted to that hospital for treatment of LD.

A total of 1352 patients was identified as having been discharged from the hospital during January 1, 1990-November 11, 1992, with a primary or secondary diagnosis of LD (International Classification of Diseases, Ninth Revision {ICD-9}, code 088.81). To determine risk factors for biliary complications of treatment of suspected LD, a case-control study was conducted. A case was defined as the occurrence of cholecystitis, cholelithiasis, or a cholecystectomy within 90 days of receiving antimicrobial treatment for LD. Cases were identified through cross-referencing the 1352 patients with codes for biliary disease (ICD-9 codes 574.0-576.9) or cholecystectomy (ICD-9 codes 51.22-51.23). Controls were selected randomly from hospitalized patients who had received antimicrobial treatment for LD but who did not develop evidence of gallbladder disease.

Twenty-five (2% of the cohort) case-patients were identified, with a median age of 12.0 years (range: 3-40 years); 84% were female. All had received intravenous ceftriaxone within 90 days preceding the onset of biliary symptoms. Daily dosage of ceftriaxone at the time of onset of biliary symptoms averaged 57 mg/kg (range: 27-96 mg/kg) in 17 case-patients for whom information was available in inpatient medical records. The median duration of treatment with ceftriaxone in the treatment course immediately preceding the onset of biliary symptoms was 28 days (range: 4-170 days) in 21 case-patients for whom information was available in medical records. Of the 25 patients, 14 (56%) underwent laparoscopic cholecystectomy; 12 of these 14 patients were less than or equal to 18 years of age. In 11 of these 14 surgical cases, pathology reports described gallbladder calculi (often multiple) of 2-10 mm in diameter and in some cases soft and greenish in color. In two surgical cases, the gallbladder was acalculous; in one, it contained fine gravel.

Fifteen (58%) of 26 controls were documented to have received at least one course of intravenous ceftriaxone for treatment of LD. When case-patients were compared with controls, risk factors for biliary disease included being aged less than or equal to 18 years (odds ratio {OR}=8.4; 95% confidence interval {CI}=1.4- 64.5), being female (OR=4.5; 95% CI=1.0-21.0), or having a history of treatment with intravenous ceftriaxone (OR undefined; pless than 0.001, Fisher's exact test).

Of those for whom data were available in their inpatient records, one of 24 case- patients and one of 21 controls had a documented history of physician-observed erythema migrans (EM), and four of 24 case-patients and two of 21 controls had documented objective evidence of disseminated LD (i.e., secondary EM, arthritis, carditis, meningitis, neuritis, encephalomyelitis, or encephalopathy) (2,3). Laboratory reports of results of serologic tests for antibody to Borrelia burgdorferi were contained in the medical records of 22 (88%) case-patients and 18 (69%) controls. Of the 51 patients, six (12%) had only positive test results documented; 26 (51%) had only negative test results documented; eight (16%) had both positive and negative tests results documented; and 11 (22%) had no results documented. Case-patients and controls had each received a median of three courses of antimicrobials (range: 1-7) for suspected LD.

A review of records of the original cohort also revealed 22 patients with intravenous catheter-associated bloodstream infections; 29 separate episodes of bloodstream infection occurred in these patients. The median duration of catheterization in these patients (measured from insertion to diagnosis of bloodstream infection) was 152.5 days (range: 16-764 days). The blood isolates from these patients included a variety of gram-positive and gram-negative bacteria. Studies are in progress to identify risk factors for such infections.

Reported by: Jersey Shore Medical Center, Neptune; C Genese, L Finelli, DrPH, W Parkin, DrPH, KC Spitalny, MD, State Epidemiologist, New Jersey Dept of Health. Investigation and Prevention Br, Hospital Infections Program; Bacterial Zoonoses Br, Div of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: During 1982-1991, more than 40,000 cases of LD were reported by state health departments to CDC, 92% of which were reported by states in northeastern, north central, and Pacific coast areas in which LD is known to be endemic (4). Early localized LD is characterized by an EM lesion and a variety of nonspecific symptoms and signs (2). Disseminated LD usually is preceded by untreated or inadequately treated EM by weeks to years and characterized by major manifestations such as arthritis, neuritis, meningitis, encephalomyelitis, encephalopathy, or carditis (2). Most patients infected with B. burgdorferi develop detectable antibody within a few weeks after infection (although early treatment may delay or prevent further development of antibody) and most patients with late LD are seropositive (2,3,5). However, not all LD patients develop a recognized EM, signs and symptoms of disseminated LD are protean and can lead to diagnostic confusion, and problems exist with the reliability and accuracy of serologic tests (2,5,6). Most patients treated for local or disseminated LD respond to standard courses of oral or parenteral antimicrobials, including ceftriaxone (5).

This report highlights several important issues related to the diagnosis and management of suspected LD. Most patients hospitalized for suspected LD in this study lacked documented objective manifestations of disseminated LD or seropositivity to B. burgdorferi. The demographic profile of these patients, mostly preadolescent and adolescent females, differs from that of LD patients reported nationally during the study period (4). The repeated and often prolonged courses of antimicrobials prescribed in these cases suggest that antimicrobial therapy did not achieve satisfactory remission of symptoms and was associated with biliary complications resulting in cholecystectomy in some patients.

Ceftriaxone is recommended in the literature for treatment of disseminated LD (7), although it has not been approved for this use by the Food and Drug Administration. Ceftriaxone is a semisynthetic third-generation cephalosporin that is excreted primarily in urine but also in bile (7). Biliary precipitation of ceftriaxone as a calcium salt is a known cause of sporadic cases of pseudocholelithiasis (sludging), frank cholelithiasis, biliary colic, and cholecystitis (8,9). Upper abdominal ultrasonography should be considered for patients who develop biliary colic while receiving ceftriaxone. Biliary precipitates of ceftriaxone may be evident sonographically after as few as 4 days of treatment, are possibly dose-related, and are often asymptomatic (7-9). Spontaneous disappearance of these precipitates within 2-63 days following the last dose of ceftriaxone has been documented; discontinuation of ceftriaxone and nonsurgical management of this complication has been recommended (8,9). Although bloodstream infection is a well recognized complication of indwelling central catheters (10), it has not been previously reported in relation to LD treatment.

Physicians should be familiar with the diagnosis and management of LD and its treatment complications (2,5,6). Hospitals and clinics, particularly in areas with endemic LD, should follow recommendations that address these issues, as well as the use and interpretation of laboratory diagnostic tests (6). In-home intravenous therapy programs as well as health-care facilities should be alert to potential complications associated with LD treatment. Because new information on LD is rapidly developing, ongoing medical-education programs on this disease are needed. CDC is working with professional societies and others to develop guidelines on diagnosis and management and to provide training materials. LD information can be obtained from CDC's Voice Information System, telephone (404) 332-4555; from CDC's Bacterial Zoonoses Branch, Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, telephone (303) 221-6453; or from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Office of Communications, telephone (301) 496-5717.

References

1. Schulze TL, Taylor RC, Taylor GC, Bosler EM. Lyme disease: a proposed ecological index to assess areas of risk in the northeastern United States. Am J Public Health 1991;81:714-8.

2. Steere AC. Lyme disease. N Engl J Med 1989;321:586-96.

3. Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med 1990;323:1438-44.

4. Dennis DT. Epidemiology. In: Coyle PK, ed. Lyme disease. St. Louis: Mosby- Year Book, 1993:27-37.

5. Rahn DW, Malawista SE. Lyme disease: recommendations for diagnosis and treatment. Ann Intern Med 1991;144:472-81.

6. National Institutes of Health. Diagnosis and treatment of Lyme disease. Clinical Courier 1991;9:1-8.

7. Shiffman ML, Keith FB, Moore EW. Pathogenesis of ceftriaxone-associated biliary sludge. Gastroenterology 1990;99:1772-8.

8. Heim-Duthoy KL, Caperton EM, Pollock R, Matzke GR, Enthoven D, Peterson PK. Apparent biliary pseudolithiasis during ceftriaxone therapy. Antimicrob Agents and Chemother 1990;34:1146-9.

9. Schaad UB, Wedgwood-Krucko J, Tschaeppeler H. Reversible ceftriaxone-associated biliary pseudolithiasis in children. Lancet 1988;1: 1411-3.

10. Maki DG. Infections due to infusion therapy. In: Bennett JV, Brachman PS, eds. Hospital infections. 3rd ed. Boston: Little, Brown, and Company, 1992:849-

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