Outbreak of Acinetobacter baumannii Bacteremia Related to Contaminated Morphine Used for Patient‐Controlled Analgesia
We investigated a cluster of postoperative febrile episodes and episodes of Acinetobacter baumannii bacteremia in obstetrics and gynecology wards after an electrical blackout and loss of the water supply. The use of patient‐controlled analgesia was the only independent risk factor associated with postoperative fever, and A. baumannii isolates recovered from the blood of patients who had received patient‐controlled analgesia were genetically related to an isolate recovered from the diluted morphine solution used for this procedure. After inappropriate preparation of the morphine solution was identified and stopped, the outbreak ended.
Received January 5, 2007; accepted May 8, 2007; electronically published August 3, 2007.
Acinetobacter baumannii, an aerobic gram‐negative coccobacillus, is commensal in nature, and has emerged as a significant nosocomial pathogen primarily affecting patients in the intensive care unit. In the literature, outbreaks of A. baumannii infection involving various body sites, including the respiratory tract, bloodstream, urinary tract, and wounds, have been reported.1 A variety of contaminated hospital environments are considered to contribute to the transmission of the organisms, as are various medical items, such as intravascular catheters, pulsatile lavage equipment, the surfaces of medical devices, and infusates, as well as the hands of healthcare workers.1
From June 10 to June 17, 1999, a cluster of 6 patients with postoperative fever was noticed in the obstetrics and gynecology (OB/GYN) wards of a tertiary care hospital. A. baumannii was recovered from the bloodstreams of 2 of 6 patients. We report here the results of a case‐cohort study that investigated risk factors for postoperative fever following OB/GYN surgery and an extensive epidemiologic investigation to determine the source of A. baumannii bacteremia in the hospital.
Methods
Between 1995 and 1997, A. baumannii accounted for 6.9% of nosocomial bloodstream infections in National Cheng Kung University Hospital, a 900‐bed tertiary care hospital in southern Taiwan that had 50 intensive care unit beds for adults. Nosocomial A. baumannii bacteremia had never occurred in the OB/GYN wards before 1999. An accidental fire led to the shutdown of main and back‐up power systems for 3 hours on June 2, 1999, as well as to disconnection of the water supply for 2 days and of the air‐conditioning system for 1 week. Elective surgeries ceased immediately after the fire and resumed on June 10 (Figure).
Figure. Epidemic curves for the outbreak of Acinetobacter baumannii bacteremia. A, Number of patients with nosocomial A. baumannii bacteremia in each month of 1999. B, Time line of the A. baumannii bacteremia outbreak. Black arrow, day that the fire occurred; white arrow, day that elective surgeries resumed; gray arrow, day infection control measures were initiated.
On June 17, an OB/GYN staff member reported that 6 patients had had a febrile episode within 48 hours after surgeries that were performed between June 10 and June 16. Blood cultures were performed for 3 of 6 patients, and 2 of these cultures grew A. baumannii isolates that shared the same susceptibility pattern. An outbreak of A. baumannii bacteremia was suspected, and an appropriate epidemiological investigation was initiated.
Because blood cultures were not done for all patients with postoperative fever, a case‐cohort study was performed to investigate the risk factors for postoperative fever. Adults admitted to the OB/GYN wards for surgeries from June 10 to June 21—the 12‐day period before the initiation of infection control measures—were included in the analysis. Case patients were defined as individuals who experienced a febrile episode (ie, body temperature greater than 38°C) within 48 hours after an operation, and control patients were defined as those without fever. Medical records were reviewed for demographic information, underlying diseases, operation date, length of hospital stay before operation, duration and location of operation, methods of surgery and anesthesia used, surgeons and assistants, receipt of parenteral medications, receipt of antibiotic prophylaxis or blood component transfusion, use of central venous or urinary catheters, methods used for postoperative pain control, and clinical outcome.
Before the epidemiological investigation, microbiological surveys were performed for febrile patients at the discretion of attending physicians. Blood cultures performed in the hospital were processed with the Bactec 9240 system (Becton Dickinson). Specimens other than blood were obtained for culture and processed in accordance with standard procedures.2 After June 17, it was suggested that a diagnostic workup for sepsis be done for patients in the OB/GYN wards with a new onset of postoperative fever, and the related specimens (ie, those from sites suspected of infection on the basis of epidemiologic analysis) were collected for surveillance cultures. A. baumannii was identified on the basis of gram‐negative morphology and biochemical information derived from traditional techniques and from use of the Vitek system (bioMériuex). Antimicrobial susceptibility was determined by the disk‐diffusion method.3 To assess the genetic relatedness of A. baumannii isolates, molecular typing was performed with pulsed‐field gel electrophoresis on the basis of chromosomal DNA digested by ApaI, as described elsewhere.4
SPSS software for Windows, version 11.5 (SPSS), was used for data analysis. Continuous variables were compared by the unpaired (ie, 2‐sample) Student t test, and categorical variables were compared by the Fisher exact test or the χ2 test. A multivariate stepwise logistic regression was performed, and variables with a P value of .1 or less were included in the univariate analysis. A P value of less than .05 was considered statistically significant.
Results
Risk Factors for Postoperative Febrile Events
A total of 31 patients underwent OB/GYN operations during the study period (June 10‐21). Eleven (35.5%) experienced a febrile episode within 48 hours after the operation. Blood cultures were done for 6 febrile patients, and A. baumannii bacteremia was found in 3 patients. Therefore, 11 febrile patients and 20 afebrile patients were included in the case‐cohort study. Older age, longer duration of operation, undergoing operation for pelvic tumors, receipt of general anesthesia during the operation, and the use of patient‐controlled analgesia for postoperative pain were significantly associated with postoperative fever in the univariate analysis (Table 1). A multivariate logistic regression analysis revealed that the use of patient‐controlled analgesia (odds ratio [OR], 32.8 [95% confidence interval {CI}, 2.1‐504.1]; 
) was the only independent factor associated with the febrile episodes. Therefore, we further reviewed the preparation process for the morphine solution used in the hospital for patient‐controlled analgesia.
Preparation of Morphine Solution Used for Patient‐Controlled Analgesia
The preparation procedures were routinely performed in the Department of Pharmacy and the Department of Anesthesiology. Each ampule of morphine sulfate (20 mg per 1‐mL ampule) was immersed in 70% alcohol before use. Morphine was drawn from 75 ampules using a 30‐mL sterile syringe, and then was purged through a 0.22‐μm pore filter into a 1‐L, preservative‐free, sterile plastic bag, which had been filled with 925 mL of 0.9% saline by an automix device. The final concentration of the diluted morphine solution was 1.5 mg/mL. This procedure was performed in a laminar air flow hood in the Department of Pharmacy. Usually, the diluted morphine solution was prepared every Tuesday, according to the expected needs of the following week.
Via multiple punctures of the hub of the plastic bag, diluted morphine solution was withdrawn and then dispersed into containers for patient‐controlled analgesia on the prescribed day. Puncturing and dispersing were performed by nurses on an ordinary work bench in the Department of Anesthesiology. The plastic bags containing residual solution were refrigerated at 4°C until they were used up. There were 2 plastic bags containing diluted morphine solution, designated bag A and bag B, that were prepared on May 27 (1 week before the accidental fire). The contents were dispersed into patient‐controlled analgesia containers; bag A was given to patients from June 2 to June 17, and bag B was given to patients from June 17 to June 21.
Identification of the Extent and Source of Outbreak
The case‐cohort study indicated that the use of patient‐controlled analgesia was the independent risk factor associated with postoperative fever, and thereafter the list of patients using patient‐controlled analgesia in this hospital was reviewed. During the study period (June 10‐21), 25 (83.3%) of 30 patients who used patient‐controlled analgesia developed postoperative fever. Of 13 patients for whom blood cultures were performed, 9 were found to have A. baumannii bacteremia (Figure). When compared with June in the preceding 3 years (ie, 1996‐1998), June 1999 had a greatly increased number of cases of A. baumannii bacteremia (
). Moreover, A. baumannii isolates with the same antimicrobial susceptibility pattern as that of the isolates from blood was recovered from the tips of central venous catheters in 3 patients, from the residual infusate of the line connecting with the patient‐controlled analgesia device belonging to a patient, and from the residual morphine solution in bag B. Bag A was emptied and discarded before the initiation of the outbreak investigation. Surveillance culture samples were collected from each component used for preparing the morphine solution, including 3 randomly selected morphine ampules, the 70% alcohol solution, and the normal saline, all of which yielded no growth on culture.
Overall, there were 12 patients with postoperative A. baumannii infections related to this outbreak. Their demographic and clinical characteristics are summarized in Table 2. Of 9 patients with A. baumannii bacteremia, 1 had concurrent Acinetobacter lwoffii bacteremia. Fever subsided soon after the discontinuation of morphine infusion in all patients. None of them died and all recovered fully from the infection.
Drug Susceptibility Pattern and Genetic Relatedness of Isolates
All isolates exhibited the same susceptibility pattern, being susceptible to gentamicin, amikacin, ampicillin‐sulbactam, piperacillin‐tazobactam, ceftazidime, imipenem, and ciprofloxacin, and being resistant to piperacillin, aztreonam, and moxalactam. Pulsed‐field gel electrophoresis patterns showed genetic relationships among 9 isolates recovered from bacteremic patients, 1 isolate recovered from residual morphine in a patient‐controlled analgesia device, and 1 isolate from residual morphine in bag B.
Infection Control Measures and Follow‐Up
Because the diluted morphine solution was identified as the potential source of the patient‐controlled analgesia–related outbreak of A. baumannii bacteremia, staff members were advised to prepare the diluted morphine solution individually for each patient‐controlled analgesia device, instead of following the past practice of preparing pooled morphine solutions. After the intervention on June 22 (Figure), no further episode of A. baumannii bacteremia occurred among patients in the OB/GYN wards, nor among those using patient‐controlled analgesia. Although the timing and detailed mechanism of contamination could not be traced, it was suspected that the prolonged use of preservative‐free, diluted morphine; inappropriate drug storage conditions; and inadequate environmental decontamination during the period of the electrical outage were contributing factors to bacterial overgrowth in the contaminated morphine solution.
Discussion
The cluster of cases of A. baumannii bacteremia in patients who underwent elective OB/GYN surgery—and who were at a low risk for this infection—satisfied the criteria for outbreak events, as described elsewhere.5 In the literature, an abrupt increase in bloodstream infection episodes among hospitalized patients is usually caused by contamination of infusate, shared parenteral medicine, or devices.5‐8 Indeed, after an epidemiological investigation that did not include environmental or personnel surveillance in the present study, the contaminated morphine solution used for patient‐controlled analgesia was regarded as the source of A. baumannii bacteremia. The fact that the outbreak ended after an intervention to stop inappropriate preparation of the morphine solution further supports this speculation.
Because it is common for patients to have low‐grade fever after major operations, we rarely use such fevers as a reason to obtain a diagnostic workup for sepsis. Therefore, we defined the case patients as patients who developed fever within 48 hours after their operations during the study period, instead of those with A. baumannii bacteremia. Once the patient‐controlled analgesia solution was suspected as the source of this outbreak, a hospital‐based epidemiological survey and microbiological studies demonstrated its real extent.
Although the outbreak ended soon after the intervention, there were several limitations to this study. First, the details of bacterial contamination in bag B were not be defined because of the paucity of microbiological evidence. Second, in the literature, contaminated parenteral narcotics have been reported as the source of bacteremia and traced to illicit narcotic use by healthcare workers.8 Not only medical responsibilities, but also legal and ethical concerns, would be addressed in such a situation. There was a lack of personnel surveillance in this study, and therefore, our experience provided little information on this issue. Policy makers in hospitals should take these issues into consideration if an outbreak is not halted by infection control measures. Third, the strategy of defining febrile patients as the case patients, rather than those with A. baumannii bacteremia, in the case‐cohort study is not uncommon in outbreak investigation regarding postoperative fever.9 However, this strategy increases the likelihood that misclassification bias will lead to the identification of risk factors that are not truly associated with the bacteremic episodes.
In summary, 2 lessons have been learned from the outbreak. First, standard protocols for preparation and storage of medication should be followed to prevent microbiological contamination.10 Second, it is important to launch applicable infection control measures in healthcare facilities confronting an internal disaster.
Acknowledgments
We are grateful to the staff at the National Cheng Kung University Hospital for their assistance in various aspects of this investigation and efforts to halt this outbreak even in the difficult situation following the blackout.
Financial support. This study was supported by grants from the National Cheng Kung University Hospital, Tainan, Taiwan (NCKUH90‐035).
Potential conflicts of interest. All authors report no conflicts of interest relevant to this article.
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