PEDIATRICS Vol. 118 No. 1 July 2006, pp. e212-e215 (doi:10.1542/peds.2005-2617)
EXPERIENCE AND REASON |
Life-Threatening Sepsis Caused by Burkholderia cepacia From Contaminated Intravenous Flush Solutions Prepared by a Compounding Pharmacy in Another State
a Department of Pediatrics, Division of Infectious Diseases
d Department of Pediatrics, Division of Hematology/Oncology
g Internal Medicine
h Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut
b Infectious Disease Division, Connecticut Department of Public Health, Hartford, Connecticut
c Epidemic Intelligence Service Program
i Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia
e Department of Laboratory Medicine, Yale-New Haven Hospital, New Haven, Connecticut
f Department of Internal Medicine and the Clinical Epidemiological Research Center, VA Connecticut Healthcare System, West Haven, Connecticut
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ABSTRACT |
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 TOP ABSTRACT CASE REPORTSMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We report 2 life-threatening cases of Burkholderia cepacia sepsis caused by infusate contamination during compounding. Bacterial isolates from the patients' blood cultures and the infusate were indistinguishable by pulsed-field gel electrophoresis. Proper quality controls at a local and national level are important for ensuring safe delivery of compounded medications to patients in all settings, including those outside health care facilities.
Key Words: Burkholderia cepacia • compounding • contamination • antibiotic-lock solution • sepsis
Abbreviations: CDC, Centers for Disease Control and Prevention • FDA, Food and Drug Administration • PFGE, pulsed-field gel electrophoresis USP, US Pharmacopeia
Compounding pharmacies are a valuable resource for health care providers who prescribe noncommercial medication preparations. Many clinicians remain unaware of the risks that are associated with such compounded medications, and even the pharmacists who procure them may not know their manufacturing conditions. 1,2 Infection with certain organisms should alert the health care provider to the possibility of contamination of intravenous products. We describe the presentation and investigation of 2 patients who developed bloodstream infections with Burkholderia cepacia from contaminated antibiotic-lock solution.
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CASE REPORTS |
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TOPABSTRACTCASE REPORTSMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Case1.
A 5-year-old Asian boy with known factor VIII deficiency (hemophilia A) presented to the Yale-New Haven Children's Hospital emergency department on June 27, 2004, with a history of intermittent fevers and chills. The parents noted that symptoms developed shortly after home treatment with recombinant factor VIII and resolved spontaneously. The patient had an indwelling Broviac catheter that had been placed 1 year previously and had not been a source of any problem. Blood cultures were obtained from both lumens of the central venous catheter and a peripheral venipuncture. The child became afebrile and seemed well otherwise when examined in the emergency department and was discharged to home.
The next day, in the hematology infusion clinic, the central catheter was flushed with a heparin-vancomycin solution after an infusion of factor VIII, which was brought by the patient's family from home to be administered in the outpatient clinic. Within 1 hour, the patient became hypotensive, hypoxic, and unresponsive with seizure activity. Resuscitation included endotracheal intubation and mechanical ventilation. Blood cultures that were obtained from the Broviac catheter on June 27, 2004, before antimicrobial treatment with intravenous ceftazidime, grew B cepacia. Broviac blood cultures also grew B cepacia on June 28, 2004, although a peripheral blood culture that was obtained by venipuncture before flushing the Broviac catheter was sterile. The catheter was removed, and subsequent blood cultures on the next 3 days were sterile. The patient stabilized and recovered completely after 14 days of ceftazidime treatment.
Case2.
A 6-year-old white boy with factor VIII deficiency was seen at another medical facility on July 2, 2004, with a chief complaint of fever and chills 
1 hour after prophylactic factor VIII infusion via a central venous catheter (Port-a-Cath; Deltec, St Paul, MN). Before administration of the factor VIII, the patient's catheter was flushed with a heparin-vancomycin flush solution. Blood cultures were obtained, and he was given 1 intravenous dose of ceftriaxone and discharged from the emergency department. The next day, Gram-negative rods were growing in the blood culture that was obtained from the central venous catheter. Central venous catheter blood cultures that were obtained on July 2, 2004, grew B cepacia. The child was admitted, treated with cefepime, and transferred to Yale-New Haven Children's Hospital on July 6, 2004, to be closer to his home. Subsequent blood cultures that were collected through the catheter from July 3 through July 8 all grew B cepacia. On July 8, 2004, the antimicrobial regimen was changed to Bactrim and gentamicin on the basis of the susceptibility of the isolate. Additional blood cultures that were obtained after July 8, 2004, were sterile. The patient was discharged from the hospital and recovered fully after 3 weeks of antibiotics. On the basis of the findings of these 2 cases, the Connecticut Department of Public Health was notified and an investigation, in conjunction with the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), and the Connecticut Consumer Drug Safety Department and its Florida counterpart, was initiated.
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METHODS |
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TOPABSTRACTCASE REPORTSMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients and parents were interviewed, and medical charts were reviewed. Remaining intravenous infusion supplies were obtained from both patients, and bacterial cultures were performed on both patients' unopened heparin-vancomycin, saline, and sterile water solutions. Each syringe lot was tested. When 1 sample became positive, the entire lot then was tested. Bacterial isolates from patients' blood cultures and intravenous supplies were compared using pulsed-field gel electrophoresis (PFGE). PFGE patterns were compared using standard published criteria.3
The Florida compounding pharmacy staff was interviewed, and the pharmacy was inspected. Additional cases were sought by notifying all Connecticut infectious diseases physicians via an e-mail and posting a report on Epi-X, the CDC's national secure epidemic information exchange for local, state, and federal public health officials. Isolates were forwarded to the CDC's Division of Healthcare Quality Promotion laboratory for PFGE comparison with other B cepacia isolates that were identified from recent national product recalls.
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RESULTS |
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TOPABSTRACTCASE REPORTSMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Laboratory Investigation
Of 21 heparin-vancomycin flush solutions for patient 1, 1 flush grew B cepacia. Of 14 heparin-vancomycin flush solutions for patient 2, 1 flush grew B cepacia. Cultures of unopened intravenous supplies were sterile. The B cepacia isolates that were recovered from both children's heparin-vancomycin flush solutions and both children's blood cultures were indistinguishable as determined by PFGE. No PFGE matches were identified with other B cepacia isolates from other recent CDC investigations (Figure 1). 4,5
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DNA (48.5 kb) as molecular mass markers; lane 2, isolate from vancomycin-heparin flush from patient 1; lane 3, blood culture isolate from patient 1 obtained from the Broviac catheter before antibiotic treatment; lane 4, blood culture isolate from patient 1 obtained from the Broviac catheter; lane 5, isolate from vancomycin-heparin flush from patient 2; lane 6, blood culture isolate from patient 2 obtained from a central venous catheter before ceftriaxone dose; lane 7, blood culture isolate from patient 2 obtained from a central venous catheter after treatment with cefepime; lane 8, nasal spray isolateEpidemiologic Investigation
The intravenous heparin-vancomycin solution that was used by both patients was supplied by a national home care company that obtained it from a compounding pharmacy in Florida. The infusion solutions were from a single lot that was prepared specifically for the 2 patients at the request of their common physician. The only other parenteral medications that were compounded at the pharmacy on the same day as these were for intrathecal injection. A formal trace forward was not conducted because these products were not from the same lot and spinal injection-site infections likely would have been reported if they had occurred (no reports were received). No additional cases were reported by Connecticut infectious diseases physicians or other sources that are alerted via Epi-X. The FDA inspected the compounding pharmacy and identified no specific deficiencies. However, pharmacy personnel had already conducted extensive internal investigation and remediation. The source of B cepacia contamination within the pharmacy was not identified.
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DISCUSSION |
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TOPABSTRACTCASE REPORTSMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We report 2 life-threatening cases of B cepacia sepsis caused by contamination of antibiotic-lock solution during compounding. During the investigation, isolates from blood cultures and the infusate were indistinguishable by PFGE, further suggesting a common source of infection. No additional cases were found after active case finding nationally, and PFGE patterns of B cepacia contaminating other nationally distributed products did not match these isolates, providing additional evidence of pharmacy-level contamination. To our knowledge, this is the first report of contamination of a compounded medication infusate that resulted in serious morbidity.
B cepacia (formally Pseudomonas cepacia) is a Gram-negative bacillus that can be found in soil, water, and other environmental sources.6 B cepacia is known to cause serious disease in patients with cystic fibrosis as well as immunodeficiencies such as chronic granulomatous disease.7 The clinical spectrum of bacteremia ranges from nearly asymptomatic to fulminant septic shock. Although there is evidence that immunocompetent hosts may develop necrotizing pneumonia as a result of B cepacia, isolation of this organism should alert the clinician to either an underlying immunodeficiency or health care–associated infection.8
B cepacia complex species often are resistant to disinfectants and antiseptic solutions,9–11 have a unique ability to survive in standing water, and occasionally are a cause of health care–associated infection as a result of contamination.12–14 Nosocomial infection with this organism also has been described. In 1 large outbreak, 74 patients at 2 hospitals in Arizona had B cepacia bacteremia during a 2-year period.11 None of the patients had medical conditions associated with infection with B cepacia. In these cases, B cepacia infection was associated with contaminated mouthwash.
Legislation in the 1990s granted the FDA the power to identify certain drug products that were difficult to compound and for which compounding could adversely affect patient safety or drug effectiveness, but the Supreme Court ruled this legislation unconstitutional in 2001.15 The resulting termination of the FDA's Pharmacy Compounding Advisory Committee has contributed to uncertainty surrounding the enforcement of quality control for compounding companies.16 Some health care providers choose to have compounding pharmacies formulate antibiotic-lock solutions, such as the heparin-vancomycin flush that was used by the patients reported here, when medications are unavailable commercially or require special formulations. However, systemic antibiotic prophylaxis or antibiotic-lock solution prophylaxis is not recommended routinely by the CDC for preventing catheter-related bloodstream infections.17 The use of vancomycin for prophylaxis also may contribute to the development or acquisition of resistant organisms.18
The publication of guidelines on preparing sterile products by the American Society of Health-System Pharmacists and the United States Pharmacopeia (USP) in 2000 was a response to many of the previously mentioned concerns.2,19–21 Compliance with USP chapter 797, which outlines the requirements and procedures with which compounding pharmacies must comply,16,21 will need rigorous enforcement by the FDA to prevent such potentially serious sequelae. We have demonstrated by these cases that there can be serious consequences to contaminated intravenous products. Exophiala dermatitidis was the cause of 4 cases of meningitis after epidural injection of a compounded steroid.22 In March 2005, there was a nationwide recall of a heparin-saline flush solution, which was contaminated with Pseudomonas fluorescens during commercial preparation.23 This flush solution was administered to patients in at least 4 states, most of whom had serious underlying medical conditions. Isolation of organisms such as certain Pseudomonas species and unusual bacteria or fungi should alert clinicians to possible extrinsic contamination. These cases should be reported to local health authorities for additional investigation.
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CONCLUSIONS |
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TOPABSTRACTCASE REPORTSMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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B cepacia sepsis in people who receive infusion therapy and do not have additional risk factors for infection with this organism should raise the possibility of exposure to products that are contaminated during manufacturing or pharmacy compounding. Clinicians should be aware of the potential risks that are associated with compounded medications and should weigh the risks and benefits of using such intravenous products as antibiotic-lock solutions that are made by outside pharmacies. Enforcement of American Society of Health-System Pharmacists and USP guidelines on a state and national level may help to prevent the kind of life-threatening infections described here.
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ACKNOWLEDGMENTS |
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We thank John Gadea (Connecticut Department of Consumer Protection); Mark Frank and J. Ernest Clausnitzer (FDA); and Arjun Srinivasan, Matthew Arduino, and Dan Jernigan (CDC) for assistance with this investigation.
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FOOTNOTES |
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Accepted Jan 12, 2006.
Address correspondence to Melissa R. Held, MD, Connecticut Children's Medical Center, Department of Pediatrics, 282 Washington St, Hartford, CT 06106. E-mail: mheld{at}ccmckids.org
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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