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Pseudomonas Bloodstream Infections Associated with a Heparin/Saline Flush --- Missouri, New York, Texas, and Michigan, 2004--2005
On January 26, 2005, CDC was notified of four cases of Pseudomonas fluorescens bloodstream infection among patients at an oncology clinic in Missouri. All patients had received a heparin/saline flush to prevent clotting of indwelling, central venous catheters. The flushes were preloaded in syringes by IV Flush and distributed by Pinnacle Medical Supply (Rowlett, Texas). On January 31, a nationwide alert against use of all heparin or saline flushes preloaded in syringes by IV Flush was issued by the Food and Drug Administration; the company recalled these products. As of February 15, state and local health departments and CDC had identified a total of 36 Psuedomonas species infections in patients in four states who were administered the heparin/saline flushes from multiple lots. This report describes the ongoing investigation and provides recommendations for investigation and management of potential cases.
During December 29, 2004--February 1, 2005, a hospital physician diagnosed nine cases of P. fluorescens infection; eight were in patients at an oncology clinic, and one was in a patient hospitalized with sickle cell disease. Median age of the nine patients was 57 years (range: 32--72 years). Of the eight patients with cancer, three (38%) had received stem-cell transplants within 6 months of infection. All nine patients had long-term, indwelling, central venous catheters and had received heparin/saline flush prepared by IV Flush, usually in 10 mL syringes. Patients had either fever or fever and chills within 2--26 days after their catheters were flushed. Blood cultures drawn through the catheters grew P. fluorescens; simultaneous, peripheral blood cultures did not grow the organism. In one patient, a tissue sample from the area surrounding the catheter grew P. fluorescens. In addition, cultures of unopened heparin/saline syringes from IV Flush grew P. fluorescens in the laboratory of the hospital. Catheters were removed, and the patients were treated with intravenous and/or oral antibiotics; all patients recovered from their infections.
On February 4, 2005, a hospital notified the New York City Department of Health and Mental Hygiene (NYCDOHMH) and the New York State Department of Health (NYSDOH) of six cases of P. fluorescens infections in children with central venous catheters. All six patients had received heparin/saline flush, preloaded in syringes by IV Flush. NYSDOH and NYCDOHMH immediately alerted providers and laboratories and asked them to perform surveillance for cases of bacteremia or sepsis with P. fluorescens and to submit isolates to their public health laboratories for confirmation and molecular typing. Surveillance of cases during December 13, 2004--February 8, 2005, resulted in identification of 12 cases of P. fluorescens infections. All 12 patients were children; median age was 9 years (range: 8 months--18 years). All 12 had long-term, indwelling, central venous catheters and had been administered heparin/saline flush, preloaded in syringes by IV Flush. Blood cultures were obtained through the catheters in 10 patients (83%) and from peripheral sites in three patients (25%). Of the 12 patients, 10 (83%) had cancer, one had cystic fibrosis, and one had an X-linked immunodysregulatory disease. All the patients had fever, and three (25%) had hypotension. Nine (75%) were admitted to the hospital for treatment with intravenous antibiotics, and one required admission to the intensive care unit for management of hypotension; seven (58%) had recurring febrile episodes. All 12 patients were treated with antibiotics; six (50%) patients also required catheter removal. All 12 patients recovered. Cultures of unopened heparin/saline syringes from IV Flush grew P. fluorescens in the New York State Public Health Laboratory.
During December 12, 2004--February 5, 2005, physicians diagnosed 14 Pseudomonas species bloodstream infections (11 P. fluorescens and three unknown Pseudomonas species) among patients in one hospital. The 14 patients had been admitted for various conditions, including seizure, colon cancer, pneumonia, urinary-tract infection, and sepsis. Median age of the patients was 50 years (range: 16 days--86 years). All patients had either short- or long-term, indwelling, central venous catheters and had received heparin/saline flush prepared by IV Flush. In all cases, the Pseudomonas species were recovered from peripheral blood cultures. All patients had fever during their hospital stays; all were treated with intravenous antibiotics, and peripherally inserted central catheters and central venous lines were removed. Thirteen (93%) of the patients recovered; one infant remained hospitalized as of March 22, but the continued hospitalization was not related to the infection. Cultures of unopened heparin/saline syringes from IV Flush grew P. fluorescens in the hospital laboratory. Pulsed-field gel electrophoresis (PFGE) testing at the Texas State Public Health Laboratory revealed that isolates from eight patients and an unopened heparin/saline syringe from IV Flush were indistinguishable by one enzyme.
In January 2005, a patient with a chronic, indwelling, central venous catheter had onset of chills and fever several hours after the catheter had been used during a surgical procedure. The patient had received a heparin/saline flush, prepared by IV Flush, at a local clinic during the preceding week. Blood cultures were obtained through the catheter and grew P. fluorescens. The patient was treated with antibiotics and recovered.
Investigation of IV Flush
A trace-back investigation by state and local health departments and CDC determined that IV Flush was the source of the heparin/saline flush administered in preloaded syringes to all patients with P. fluorescens infections. To produce its heparin/saline flush, IV Flush ordered heparin powder and sent it to a compounding pharmacy, where a concentrated heparin solution was made. This concentrated solution was then returned to IV Flush, where it was added to bags of saline solution, from which the syringes were filled. Sterility testing of the concentrated heparin solution by IV Flush was reportedly not performed. After discovering that the heparin/saline flush was contaminated, the physician in Missouri informed IV Flush and the Missouri State Department of Health and Senior Services. The state health department notified CDC, which notified FDA, and IV Flush subsequently initiated a nationwide recall. On January 31, 2005, FDA issued an alert against use of the flush and subsequently issued an updated alert on February 4 (1).
Samples of unopened heparin/saline flush syringes were sent to CDC, where bacterial cultures of seven of nine lots grew P. fluorescens. CDC also plans to conduct PFGE tests on isolates from all four states; as of March 22, the only molecular typing results were from the Texas State Public Health Laboratory. Information obtained by FDA indicated that the heparin/saline flush might have been distributed to locations in as many as 17 states during the preceding year. CDC continues to work with state and local health departments and FDA to ensure that heparin/saline syringes from IV Flush are no longer in use in these locations and to search for additional cases.
Reported by: DJ Kennedy, MD, P Masidonski, EM Swierkosz, PhD, Saint Louis Univ; K Davidson, MPH, City of St. Louis Dept of Health; D Dodson, MS, Missouri State Dept of Health and Senior Svcs. BT Edwards, MD, EM Vellozzi, Albert Einstein College of Medicine; PD Latta, PhD, P Graham, MD, O Mitano, PhD, M O'Keefe, MPH, J Marcus, MD, A Lee, MD, L Saiman, MD, Columbia Univ, New York-Presbyterian Hospital, New York City; D Olson, MPH, LV Lee, MS, D Weiss, MD, New York City Dept of Health and Mental Hygiene; A Genovese-Cendela, MBA, A Greenberg, MD, M Sherman, Nassau County Dept of Health, Mineola; B Harper, MD, D Graham, MD, P Dillon, MD, L Barlow, MS, J Bolta, J Esser, MPH, J Schweitzer, Suffolk County Dept of Health Svcs, North Babylon; W Terry, MPH, A Huang, MD, J Lipsman, MD, Westchester County Dept of Health, New Rochelle; D Kohlerschmidt, A Carpenter, S Jose, N Dumas, Wadsworth Center Laboratory; J Greenko, MPH, P Kurpiel, MPH, R Gallo, M Kacica, MD, G Johnson, P Smith, New York State Dept of Health. PJ White, C Weindorf, Medical Center of Lewisville, Lewisville; J Gullion, PhD, Denton County Health Dept, Denton; N Pascoe, M Richardson, Texas Dept of State Health Svcs Laboratory. EV Wells, MD, MJ Wilkins, DVM, Michigan Dept of Community Health. Food and Drug Admin. A Srinivasan, MD, D Jernigan, MD, E Meites, MPH, B Jensen, MMSc, J Noble-Wang, PhD, M Arduino, PhD, Div of Healthcare Quality Promotion, National Center for Infectious Diseases; S Stonecipher, DVM, Div of Public Health Partnerships, National Center for Health Marketing; S Benoit, MD, EIS Officer, CDC.
The findings from this ongoing investigation indicate that heparin/saline flush, preloaded in syringes by IV Flush, was contaminated with P. fluorescens during commercial preparation and administered to multiple patients in at least four states. Exposure to the contaminated flush has been associated with infections in 36 patients; additional potential cases are under investigation. Most of the patients had serious underlying medical conditions and subsequently had bloodstream infections; many required hospitalization and surgical removal of long-term, indwelling, catheters. CDC, FDA, and state and local health departments continue their efforts to ensure that the recalled syringes are no longer being used.
P. fluorescens is a member of the fluorescent pseudomonad bacteria group and is an infrequent cause of blood stream infections. Optimal temperature range for growing the organism is 77ºF--86ºF (25ºC--30ºC); P. fluorescens can be difficult to grow when samples are incubated at 98.6ºF (37ºC), the temperature at which most bacterial cultures are incubated in hospital microbiology laboratories (2). Depending on laboratory capabilities, identification of P. fluorescens can be difficult; therefore, patients who received the heparin/saline flush and were infected with unidentified Pseudomonas species were included in the case count in this report.
FDA is investigating the source of contamination in this outbreak, which might have occurred either at IV Flush or at the compounding pharmacy that prepared the heparin solution. Preparation of drug products to fill prescriptions for specifically designated patients is considered pharmaceutical compounding, not manufacturing. However, companies that prepare products not requested by a prescription are considered manufacturers and should follow requirements set forth by FDA regulations on good manufacturing practices (3). These regulations help ensure the sterility of products intended for injection and include requirements for measures such as validation of sterilization techniques and sterility testing of finished products. In this case, sterility testing of the finished product was reportedly not performed. Had it been done, the contamination that led to this outbreak might have been detected before the product was distributed.
Contaminated products prepared in compounding pharmacies have also been implicated in previous clusters of infections, including Exophiala dermatiditis joint infections caused by injectable steroids (4); Chryseomonas and Serratia species infections, resulting in meningitis from epidural injections (CDC, unpublished data, 2002; Contra Costa Health Services, unpublished data, 2002); and Burkholderia cepacia blood stream infections from intravenous flush (CDC, unpublished data, 2004). Regulatory oversight of compounding pharmacies varies among states. However, compounding pharmacies are subject to inspection by pharmacy boards, FDA, and accreditation organizations. The American Society of Health-System Pharmacists and the U.S. Pharmacopeia have developed guidance and standards that address quality assurance and sterile preparation of compounded products (5,6). In addition, in May 2004, the Pharmacy Compounding Accreditation Board (PCAB) established a task force to set standards for a voluntary accreditation board for compounding pharmacies (7).
Companies that manufacture products intended for injection should follow FDA regulations for ensuring the sterility of these products (3). Health-care providers who detect cases of Pseudomonas species infection in patients with central venous catheters are urged to determine whether their patients received the heparin/saline flush recalled by IV Flush. Although the product has been recalled, cases have occurred up to 1 month after receipt of the product. Indwelling, intravenous catheters that are used infrequently can become colonized with organisms in a biofilm, and symptoms might not develop until the catheter is used. Susceptibility patterns of organisms isolated from the 36 identified patients have varied, with multiple isolates resistant to third-generation cephalosporins and carbapenem antibiotics. Treatment for potential patients should include targeted antimicrobial therapy and consideration of removing their catheters (8). In addition, cases that might be related to use of this product should be reported to state and local health departments, CDC, and the FDA MedWatch program (http://www.fda.gov/medwatch/report.htm or 1-800-FDA-1088, press 0).
The findings in this report are based, in part, on contributions by BP Zhu, MD, Missouri State Dept of Health and Senior Svcs.
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