Nosocomial Outbreak of Burkholderia pickettii Infection Due to a Manufactured Intravenous Product Used in Three Hospitals

Clinical Infectious Diseases, Jun 1996

Forty-six cases of nosocomial infection caused by Burkholderia pickettii were reported between June and November 1993 in three metropolitan hospitals in Madrid. A case-control study of the outbreak was conducted to identify its cause. Seventy-four percent of the patients were males; the mean age ± SD of the patients was 54 ± 20 years. Sixty-five percent of the patients presented with some gastrointestinal disorder, and 80% had a peripheral catheter; 98% were treated with intravenous fluids, and 96% were treated with intravenous ranitidine. On the basis of results of a descriptive study and knowledge of the epidemiologic features of B. pickettii, a provisional causal hypothesis was formulated: intravenous ranitidine was the source of the outbreak. As a control measure, it was advised to stop treatment with this drug. On the basis of results of logistic regression and the microbiological isolation of B. pickettii in an ampule of the drug, we concluded that intravenous ranitidine was the cause of the outbreak.

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Nosocomial Outbreak of Burkholderia pickettii Infection Due to a Manufactured Intravenous Product Used in Three Hospitals

Cristina Fernandez 0 1 Isabel Wilhelmi 0 1 Elena Andradas 0 1 Carmen Gaspar 0 1 Javier Gomez 0 1 Jose Romero 0 1 Jose Alberto Mariano 0 1 Octavio Corral 0 1 Margarita Rubio 0 1 Javier Elviro 0 1 Jose Fereres 0 1 0 Received 23 May 1995; revised 25 January 1996. This work was presented in part at the 3rd International Conference of the Hospital Infection Society held on 4-8 September 1994 in London and at the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy held on 4-7 October 1994 in Orlando, Florida . Service , San Carlos University Hospital , Profesor Martin Lagos sin, Madrid 28040 , Spain . Clinical Infectious Diseases 1996 ; 22:1092-5 1996 by The University of Chicago. All rights reserved. 1058--4838/96/2206-0031$02.00 1 From the Preventive Medicine and Clinical Microbiology Services, Hospital Universitario San Carlos; the Microbiology and Infectious Diseases Services, Hospital Severo Ochoa; and the Epidemiology Service , Comunidad de Madrid, Madrid, Spain Forty-six cases of nosocomial infection caused by Burkholderia pickettii were reported between June and November 1993 in three metropolitan hospitals in Madrid. A case-control study of the outbreak was conducted to identify its cause. Seventy-four percent of the patients were males; the mean age SD of the patients was 54 20 years. Sixty-five percent of the patients presented with some gastrointestinal disorder, and 80% had a peripheral catheter; 98% were treated with intravenous fluids, and 96% were treated with intravenous ranitidine. On the basis of results of a descriptive study and knowledge of the epidemiologic features of B. pickettii, a provisional causal hypothesis was formulated: intravenous ranitidine was the source of the outbreak. As a control measure, it was advised to stop treatment with this drug. On the basis of results of logistic regression and the microbiological isolation of B. pickettii in an ampule of the drug, we concluded that intravenous ranitidine was the cause of the outbreak. - Materials and Methods Case descriptions. An outbreak of 46 cases of nosocomial infection by B. pickettii occurred between June and November 1993 in three hospitals in Madrid: Hospital Universitario San Carlos (HUSC; 1,500 beds), Hospital Severo Ochoa (HSO; 425 beds), and Hospital General de M6stoles (HGM; 401 beds). Microbiological method. The clinical samples were pro cessed by means of standard procedures. The drug samples were inoculated in hyperconcentrated nutrient broth, brain heart infusion broth, or commercial hemoculture bottles. Iso lates of B. pickettii from clinical or environmental samples were identified on the basis of colony morphology and results of gram staining, the oxidase test, and the API 20 NE identifi cation system (bioMerieux, Marcy l'Etoile, France). Identification of the causes. We conducted a case-control study of this epidemic. Every patient for whom microbiological culture was positive for B. pickettii was defined as a case. The controls were randomly selected from patients who were admitted to the same department where a case was detected on the same day ( 2 days) that the sample from which B. pickettii had been isolated was obtained. Two controls were selected for each case from a group of possible controls. The information on all cases was gathered 48 hours before the sample positive for B. pickettii was taken. Statistical methods. The crude magnitude of the risk (odds ratio) for the possible evaluated factors was estimated. Stra tified analysis was performed to determine if there were any biases or interactions. The logistic regression model was ad justed by the forward strategy. The 95% confidence intervals for the odds ratios were calculated. Outbreak description. A total of 46 cases of B. pickettii infection were reported. The infections first developed in HUSC (20 cases). Twenty-one (46%) of the cases occurred in HSO, and five cases (11 %) occurred in HGM. There was no history of epidemiologic outbreaks due to B. pickettii in any of the three hospitals. The epidemic curve (figure 1) suggested that the cases were produced by a common source in HUSC and HSO. The clinical characteristics of the cases are summa rized in tables 1 and 2. ~~~~~~~;;;;;;~~~~~~; ~'):~'S",'}4 :~~~~::t:~:~q~~~~~~,. "I~ 't/"fI, l 't/tO'I'JV fI," fI,(i,sJ~,;)(1' ...... '11 o'jV),"~ ,.}> 0,/'"v'" ..~."-_y~v"~-.4' .. "~.',~\-i!\: Clinical/microbiological description. The 46 cases had 48 infections. The most frequent infection was bacteremia (fre quency, 96% [44 cases]). Two (4%) of the cases had catheter infections without associated bacteremia. Thirty-five percent of the cases presented with an infection by another organism. No death was attributed to the infection. Afterward, B. pickettii was isolated from six parenteral nutrition samples that con tained ranitidine (BBL, Alonga, Madrid). Ranitidine vials were collected again for culture, and B. pickettii was isolated from an intravenous ranitidine vial (lot R30; BBL, Alonga) at RUSe. B. pickettii was isolated in 47 blood cultures, from three intra venous catheter tips, and from an exudate of surgical drainage of a pancreatic pseudocyst. Thirty-three isolates were analyzed for the biotype. Identification ofthe causes. The 92 controls were homoge neous with the cases on all studied variables. The crude odds ratios for the risk factors studied are shown in figure 2. When Characteristic Mean age (SO) in y Previous average hospital stay (SO) in d Total average hospital stay (SO) in d Percentage of cases with indicated characteristic Male sex Digestive pathology Nonfatal basic disease Department of Medicine Recovery in ICU Parenteral nutrition P value NOTE. HGM = Hospital General de M6stoles; HSO = Hospital Severo Ochoa; HUSC = Hospital Universitario San Carlos; ICU = intensive care unit. stratified analysis was applied to all variables that were signifi cant in the univariate analysis, intravenous ranitidine remained significant. We also observed that nasogastric tubes behaved as a modifying variable with regard to the effect of intravenous ranitidine (table 3). Discussion There was epidemiologic evidence that B. pickettii was the causal agent in our outbreak. Our findings were consistent with those of all other reported outbreaks of B. pickettii infection [2 -1 0]. Our outbreak involved a greater number of cases than did any previously documented outbreak. B. pickettii variant 2, which was isolated in our outbreak, has been described as the least virulent variant. In our study, this low virulence was confirmed by the absence of death attributed to this microor ganism. The greatest difficulty in the search for the cause of the outbreak was the distribution of the drug in the hospitals. RUSe used three different manufacturer's products for intravenous ranitidine treatment, and the commercial brand of ranitidine Coefficient OR 95% CI P value 1.28-58.85 0.83-8.47 Risk factor Immunodeficiency (OR,1.36) Surgery (OR,1.54) Peripheral catheter (OR, 1.93) Mechanical ventilation (OR,2.09) Bladder catheter (OR, 3.02) Central venous catheter (OR,6.07) Nasogastric tube (OR, 12.75) 0.73 1 0.82 1 0.49 1 1.41 1 Odds ratio 21.40 I Odds ratio 2.66 1 5.26 ..... -......130.87 1 35.37 Figure 2. Results of a univariate analysis of the risk factors (top) and administered treatments (bottom) of Burkholderia pickettii infection. Crude odds ratios and 95% confi dence intervals are shown. that was administered was not recorded in the nurse's notebook. HSO used only ranitidine from BBL, Alonga; this product was suspected when B. pickettii was isolated from the parenteral nutrition containing intravenous ranitidine. All the patients from HSO with B. pickettii- induced bacteremia had been treated with intravenous ranitidine within the previous 48 hours. The two patients with nasogastric tubes did not receive intravenous ranitidine during the 48 hours before the specimen for hemoculture was obtained. Therefore, the presence of a nasogastric tube interacts with ranitidine administration. HSO supplied intravenous ranitidine ampules to HGM, where a small outbreak occurred; ranitidine was administered intravenously in all five cases of the outbreak. As a control measure, the boards of medical directors of the three hospitals were informed when intravenous ranitidine became suspected as the likely source of the outbreak (18 November 1993). The fact that no new cases were detected or reported once the product stopped being dispensed (13 Decem ber 1993) supports our hypothesis. The intravenous ranitidine ampules may have been contami nated during the sterilization process of its production. The usual process consists of filtration through 0.45 or 0.22 micro pore filters. Reports have shown that B. pickettii may be able to pass through these filters [11]. After the collection of the drug vials, B. pickettii was isolated from two lots of the product (H30 and H33). Epidemiologic analysis and microbiological evidence (the same biotype identified in all the strains studied and isolation of B. pickettii from an ampule of the drug [lot H30]) confirmed that intravenous ranitidine was the cause of nosocomial infec tions by B. pickettii. This outbreak highlights the importance of considering manufactured products as a possible cause of nosocomial infections and offers a sobering reminder of the need to maintain high standards for sterilization techniques and quality control procedures. Acknowledgments The authors are grateful to A. Vicente, M.D., and M. Vinuesa, M.D. (Preventive Medicine Service, Hospital General de Mos toles); J. L. Gomez, M.D. (Microbiology Service, Hospital General de Mostoles); R. Coello, M.D., M. Tafalla, M.D., P. Arroyo, R.N., D. Minguez, R.N., P. Uribe, R.N., and P. Sanchez, R.N. (Preven tive Medicine Service, Hospital Universitario San Carlos); and P. Fragoso, R.N., and M. J. Vega, R.N. (Preventive Medicine Service, Hospital Severo Ochoa) for their cooperation and assistance during this investigation.


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Cristina Fernández, Isabel Wilhelmi, Elena Andradas, Carmen Gaspar, Javier Gomez, Jose Romero, Jose Alberto Mariano, Octavio Corral, Margarita Rubio, Javier Elviro, José Fereres. Nosocomial Outbreak of Burkholderia pickettii Infection Due to a Manufactured Intravenous Product Used in Three Hospitals, Clinical Infectious Diseases, 1996, 1092-1095, DOI: 10.1093/clinids/22.6.1092