INTRODUCTION
Bloodstream infections (BI) are a well recognized problem after solid organ transplantation and they have been associated with loss of graft and increased mortality. However, most existing information is found in papers that review the whole spectrum of infection in transplant patients and do not specifically emphasize BSI.
BSI affects 22.4–49% of liver transplant patients, 3.5–76.7% of kidney recipients, and 25% of lung transplant patients, but information is particularly scarce in heart transplant (HT) patients.
The objective of this study is to describe the incidence and clinical characteristics of BSI in HT recipients and to analyze the risk factors for this complication.
PATIENTS AND METHODS
Institution and Patient Population
Our institution is a 1,750-bed tertiary teaching hospital serving a population of approximately 650,000 inhabitants. In our hospital, 324 patients underwent heart transplantation between August 1988 and December 2003. In all, 309 patients who survived more than 7 days after transplantation were included in the study [256 men (82.8%); mean age: 53 years (range: 18–69)]. None of the patients who died perioperatively developed BSI. Underlying heart diseases included ischemic heart disease (154, 49.8%), dilated myocardiopathy (107, 34.6%), valvular diseases (31, 10%), and others (17, 5.5%: congenital 4, myocarditis 1, re-transplantation 12).
Immunosuppression and Antimicrobial Prophylaxis
General methodology of the transplant procedure was standard and has been described elsewhere. In brief, the immunosuppressive regimen consisted of induction with OKT3 (first 18 patients) or 3–5 doses of antithymocyte globulin (ATG) until October 2002 when daclizumab induction was started. Maintenance consisted of cyclosporine A, azathioprine and corticosteroids until 1998 when mycophenolate mofetil and tacrolimus were introduced. Rejection episodes were diagnosed by endomyocardial biopsy and treated with IV boluses of methylprednisolone for three days. Antithymocyte globulin was administered when a steroid-refractory acute rejection episode was observed and in patients with severe allograft dysfunction. The number of treated rejection episodes was quantified in each patient before developing a BSI episode.
The prophylaxis protocol includes pneumococcal vaccine before transplantation, surgical prophylaxis with cefazolin and a short course (7–21 days) of postsurgical intestinal decontamination with norfloxacin. All patients received cotrimoxazole prophylaxis (a double-strength dose, three days a week during the first year), as well as prophylaxis against tuberculosis when indicated. Prophylaxis against cytomegalovirus (CMV) was administered to all patients at risk of primary infection (seronegative recipient and seropositive donor) with hyperimmune gammaglobulin (CMVIG) plus IV ganciclovir (5 mg/kg every 12 hr for the first 15 days after transplantation). From June 1999, universal prophylaxis with IV ganciclovir was also administered to seropositive recipients in the early postoperative period (5 mg/kg bid for 14 days). No significant structural or environmental changes were performed in the heart transplantation ward during the study period. From October 1994 to December 2000, we administered oral itraconazole prophylaxis to all patients who received heart transplantation at our center from day 5 after transplantation at a loading dose of 600 mg/d for the first three days and subsequently at 400 mg qd PO for a period of 3 to 6 months. Before this period, no antifungal prophylaxis was administered to the remaining patients and, after December 2000, it was only administered to those patients with risk factors for invasive fungal infection.
Blood Cultures
Blood samples for culture where obtained by standard procedures. Until November 1995, blood cultures were processed by a semiautomatic procedure (BACTEC-NR 640, Becton Dickinson Diagnostic Instrument Systems). From that date to the end of the study, the BACTEC 9240 (Becton-Dickinson Diagnostic Instrument System) was introduced, which is more automatic and includes a procedure for continuous shaking. We kept blood incubation samples for 5 days before classing them as negative.
Isolates were identified by means of standard microbiological tests and automated methods (Microscan, Baxter Laboratories, West Sacramento, CA). The antimicrobial susceptibility tests were carried out with broth microdilution, using the criteria of the NCCLS (National Committee on Clinical Laboratory Standards) as breakpoints.
Definitions
All patients were prospectively followed up by one ID physician who collaborated in the diagnosis and treatment of all infectious episodes and prospectively completed a preestablished data entry sheet recording the baseline data and characteristics of every BSI episode.
We considered bacteremia as significant when one or more microorganisms were isolated in one or several blood cultures. In cases involving microorganisms of doubtful significance (e.g., Bacillus species, nonhemolytic Streptococcus species, coagulase-negative Staphylococcus species), clinically relevant episodes were defined as those in which there was evidence of clinical manifestation of infection with no other explanation and in which the microorganisms were isolated from ≥2 different blood cultures. Specimens for culture were obtained when clinically indicated, and no surveillance was routinely performed. BSI was considered community-acquired if the first positive blood culture specimen was taken in outpatients or within the first 48 hours after admission. After this period (or before, if it was clearly related to an invasive procedure carried out in the hospital), the infection was considered nosocomial. The source of BSI was considered documented if there were focal signs or symptoms of infection and/or the same microorganism was isolated from blood and the infected site. In the absence of a recognized source, BSI was classified as primary. Risk factors for BSI identified in the literature for other types of transplantation recipients were recorded and compared for our patients with and without BSI to establish their influence on HT. Hemodialysis included patients requiring renal replacement therapy (hemodialysis or continuous venovenous hemodialysis).
Invasive aspergillosis episodes were defined according to Mycoses Study Group criteria. CMV infection and CMV disease definitions were standard. CMV infection was based on the isolation or detection of the virus from any body fluid by shell vial assay or antigenemia. CMV disease consisted of the detection of signs or symptoms attributable to this microorganism and included viral syndrome and CMV focal disease. Pretransplantation active infections were those that were still being treated when the patient underwent the transplant.
Clinical condition previous to transplant was defined according to United Network for Organ Sharing (UNOS) criteria. Death was attributed to the infectious process if the patient died within 10 days of the bacteremic episode with a clinical course suggesting persistent infection, and if death could not be clearly attributed to other causes.
Statistical Analysis
Preoperative, operative, and postoperative potential risk factors were analyzed for their association with bloodstream infection . For univariate statistics, the chi-square test was used for categorical variables, Mann-Whitney’s U test for continuous variables that were not normally distributed and analysis of variance or t test to compare means of approximately normal continuous variables. Cox regression analysis was used in the multivariate analysis to control for potential confounders of risk factors for BSI and to asses the influence of BSI on patient survival.
Variables with a P value <0.1 in the univariate analysis were included in the multivariate model. Statistical significance was defined by a P value <0.05. Statistical analysis was performed with the SPSSWIN 11.5 package.
RESULTS
We diagnosed 60 episodes of BSI in 49 out of 309 patients (15.8%) during the 15-year study period. Overall, BSI episodes occurred a median of 51 days (range 1–2385) after transplantation, and 63% occurred during the first 100 days posttransplantation. When we analyzed the incidence of BSI during the study period, the proportion of BSI/transplanted patient decreased significantly: 21.2% from 1988 to 1993, 14.3% from 1994 to 1998 and 7.5% from 1999 to 2003 (P =0.03) (Table 1 ).
TABLE 1: bloodstream infection (BSI) episodes in heart transplant patients during the study period
BSI episodes were distributed among the three standard posttransplantation periods as follows: 22 (37%) occurred in the first month, 20 (33%) during months 2–6, and 18 (30%) more than 6 months after transplantation. The main characteristics of the BSI during these three periods are shown in Table 2 .
TABLE 2: bloodstream infection episodes according to posttransplantation periods
Most episodes were nosocomially-acquired (66%), especially those occurring earlier after transplantation: median posttransplant days of nosocomial BSI was 28 (range 1–2385) vs. 318 (range 33–2091) for community-acquired BSI (P <0.001).
Regarding portal of entry, lower respiratory tract infection (23%), urinary tract infection (20%) and catheterrelated-BSI (16%) were the most frequent sources of bacteremia (Table 3 ). We found a clear relationship between time of onset and some characteristics of the BSI. During the first month after transplantation, 95% of the BSI were nosocomially-acquired and the main origins were: IV catheter (32%), surgical site and lower respiratory tract (LRT; 18% each). From month 2 to month 6, 70% of the BSIs were nosocomially acquired and the main origins were UTI and LRT (25% each). After the sixth month, only 22% of the BSI episodes were nosocomial and the most common portals of entry were: LRT (33%), primary bacteremia (22%), and UTI (17%) (P =0.1; Table 2 ).
TABLE 3: bloodstream infection in 49 heart transplant patients
As far as etiology was concerned, Gram-negative microorganisms predominated (55.3%), followed by Gram-positive microorganisms (44.6%), 6 (10%) episodes were polymicrobial and there was one case of fungemia (Table 3 ). Gram-negatives accounted for 54% of infections in the first month, 50% during months 2–6 and 72% of infections occurring afterwards (P =0.3; Table 2 ). We found a shift towards an increasing importance of Gram-negative microorganisms during the study period. The proportion of BSI caused by Gram-negative microorganisms during each five-year period was: 55.6% during 1988–1993, 57.9% during 1994-1998 and 80% during 1999–2003 (P =0.5). This evolution may be related to the decrease in catheter-related and SSI-related bacteremias (from 27.8% and 35.6% of BSI in the first and second period, respectively, to none in the third period; Table 1 ).
No significant changes in resistance patterns were found among any microorganisms, despite prophylaxis. In our series, only two out of nine P. aeruginosa isolates and 2 out of 24 Enterobacteriaceae isolates were ciprofloxacin-resistant.
Among patients with BSI, only four had a previous rejection. BSI did not increase the rate of acute or late rejection. Nine patients (18.4%) had a previous CMV infection. Half of the episodes (50%) were considered potentially lethal or severe. The maximum status in the sepsis scale reached by patients with BSI was: sepsis 50%, septic shock 30%, and multiorganic failure 20%. Therapy was administered intravenously in 85% of the episodes and orally in the remaining 15% (seven patients). The latter group was in good clinical condition and received oral quinolones for the treatment of urinary tract infections (four patients), cholecystitis (one patient), and Salmonella bacteremia (two episodes).
Patients with and without BSI were compared to identify risk factors for BSI. During the pretransplantation period, older recipient age (P =0.04), grade IV heart failure according to the NYHA classification (P =0.03) and critical clinical condition (P =0.01) were found to be risk factors for BSI. After transplantation, identified risk factors were: an ICU stay longer than 5 days (P =0.002), renal failure (P =0.002), hemodialysis (P <0.001), viral (P =0.04) or systemic fungal infection (P =0.007), and use of azathioprine (P =0.021). No other immunosuppressive drug showed an influence on developing BSI. Interestingly, patients who received viral or parasitic prophylaxis had fewer BSI episodes (8.2% vs. 21.9%, P =0.02 and 38.8% vs. 56.2%, P =0.02; Table 4 ).
TABLE 4: bloodstream infection (BSI) in heart transplant patients
Multivariate analysis showed that the independent risk factors for having BSI after HT were: hemodialysis (P <0.001, OR 6.5; 95%CI 3.2–13), prolonged ICU stay (P =0.002, OR 3.6; 95%CI 1.6–8.1) and viral infection (P =0.01, OR 2.1; 95%CI 1.1–4; Table 5 ).
TABLE 5: bloodstream infection (BSI) among heart transplant patients
Overall mortality among patients with BSI was 59.2%, but only in 12.2% of bacteremic patients death was directly attributable to the infection. Risk factors for mortality in patients with BSI were lung origin (67%, P =0.01) and polymicrobial etiology (33%, P =0.04). BSI was an independent risk factor for death (P =0.003, OR 1.8; 95% CI 1.2–2.8; Fig. 1 ).
FIGURE 1.:
Cox regression probability graph showing survival in heart transplant patients with (black) and without (grey) BSI (P <0.003, OR 1.8; 95% CI 1.2–2.8).
DISCUSSION
To the best of our knowledge, we report the largest series of bloodstream infections in heart transplant recipients and the first to focus exclusively on this problem. We studied our entire HT recipient population in order to describe BSI episodes and to establish risk factors for this complication. We found an incidence of BSI of 15.8%, with a 12.2% related-mortality rate. In the late 1980s, other authors found an incidence as high as 27%. We observed a significant decline in the incidence of BSI during the study period (from 21% in 1988–93 to 7.5% in 1999–2003). Data published by our group on incidence of BSI after cardiovascular surgery was found to be 5.4%, which is quite similar to the incidence of BSI in our HT population in the third period (7.5%). This is in accordance with the literature in bone marrow transplant recipients, although in liver transplant recipients an increase has been found (10% in 1989–93 and 48% during 1998–2003). There may be several explanations for these trends. Our group kept along this period a sustained policy of good catheter care, rapid diagnosis of catheter-related infections, reduction of VAP, etc. This has resulted in generalized lower infection rates of nosocomial infections. Probably the use of ganciclovir prophylaxis, daclizumab induction therapy and accumulated experience of the transplantation team also had an impact in the incidence of complications, including infection.
BSI in this population are an early, nosocomial problem (65% of patients) because they occur mostly within the first 2 months posttransplantation. In our study, only four of the BSI occurring after the first 6 months posttransplantation were nosocomial (three LRTI and one osteomyelitis). This agrees with reports on other types of organ transplant recipient.
Origin of infection varies according to the type of transplant; urinary tract infection has been identified as the most important source of BSI in kidney recipients and catheter-related bacteremia in liver patients. Pneumonia is a well-known problem after heart transplantation and continues to be one of the leading causes of death. Previous episodes of pulmonary edema, fluid stasis due to heart failure, and surgical factors could predispose to this condition. In our series, the lung was the most frequent origin of BSI and only in the first month after transplant was catheter-related BSI more frequent. Wagener et al. also found in their study of BSI in heart, kidney and liver transplant recipients, that pneumonia was the first source of bacteremia in heart transplant recipients (25% of cases). In liver recipients, it accounted for 10% of BSI episodes and for 4% in kidney recipients. Catheter was the origin of BSI in 17% of our episodes, although the reports of other authors indicate that its origin should not be underestimated as it was the main origin of BSI in HT patients. As expected, there were no catheter-related BSIs or surgical site infection after the sixth month posttransplantation.
Gram-negative microorganisms have been described as the most frequent etiologic agents of BSI after liver and kidney transplantation. In heart transplantation, Gram-positive bacteria have been reported more frequently, although we found a higher proportion of Gram-negative microorganisms (58% vs. 48%), except during the first 5-year period (1988–1993) when Gram-positives predominated (45% vs. 59%, P =0.1). This trend towards a predominance of Gram-negative bacteria has recently been reported by Singh et al. and Moreno in liver transplantation, and is similar to what has been reported in other groups of immunocompromised hosts, such as neutropenic patients. Prophylaxis with trimethoprim/sulfamethoxazole may influence this trend, since patients that received it had few episodes of BSI due to Gram-positive microorganisms. However, in our series, we did not find high resistance rates among the most frequent etiologic agents.
As already described for other types of infection, we found hemodialysis to be an independent risk factor for bacteremia. Here, immune alterations produced by renal failure and by hemodialysis itself have been proposed as reasons for the increased risk. However, it is possible that the frequent manipulation of vascular access might contribute to a higher incidence of bacteremia.
Our study showed that a longer stay in the ICU increased the risk of developing BSI. This probably reflects a more severe clinical condition and the need for more invasive procedures.
We also found that viral infection, mainly CMV, was an independent risk factor for BSI. The immunomodulating effect of this virus predisposing to other kinds of infection is well known, especially in fungal infections, and recently Munoz-Price et al. found that CMV prophylaxis with >14 days of ganciclovir after liver transplantation was significantly associated with a decreased risk of bloodstream infection . Further research on this aspect is necessary. These findings suggest that the best way of preventing BSI after HT is optimizing the posttransplant care of the patients, reducing ICU stay, avoiding nephrotoxicity and providing effective anti CMV prophylaxis.
We found BSI to be a risk factor for infection-related death. Other authors have described similar findings. In liver transplant patients, Singh et al. found a higher mortality at 14 days after transplantation in patients with bacteremia (28% vs. 4%, P =0.03). In kidney recipients, the death rate after two months of follow-up was 14% in bacteremic patients and 1% in nonbacteremic patients. These data seem to confirm that BSI should be considered a signal of poorer outcome.
Our patients with BSI were more likely to die if the source of infection was the lung, and high mortality in heart transplant patients with pneumonia has already been described. Cisneros et al. reported 31% mortality among 65 patients with RTI from a series of 307 heart transplant recipients. Another risk factor for mortality in our study was the polymicrobial etiology of BSI. In four of these patients, the episodes occurred within the first three months after transplantation, when immunosuppression is at its highest levels. Regarding etiology as a risk factor for mortality, S. aureus has been described as a risk factor for mortality in liver transplantation, although we could not confirm this finding. Both lung origin and polymicrobial etiology as risk factors for mortality among transplant patients with BSI had been reported previously in a large series of 125 episodes in 472 patients. BSI has a high mortality, the first 48 hr being crucial for the survival of the patient. We have recently demonstrated that only 58.5% of patients with BSI received appropriate empirical antimicrobial therapy. Inadequate treatment was related to a longer hospital stay, a higher mean risk of Clostridium difficile –associated diarrhea, a higher mean overall mortality rate, and a higher risk of infection-related mortality. So once blood cultures are obtained, empirical broad-spectrum antimicrobials guided by the clinical condition of the patient and the presumed origin, should be promptly started. When results of blood cultures are available, antibiotics should be adjusted according to susceptibility patterns of the isolates. This antibacterial de-escalation strategy attempts to balance the need to provide appropriate, initial antibacterial treatment while limiting the emergence of antibacterial resistance.
In our experience, there is no need of modifying immunosuppressive therapy. Appropriate antibiotics are usually effective enough to avoid this situation, considering its risk-benefit consequences. In critical, nonresponding patients, decreasing immunosuppression levels seems logical and is common practice in some institutions. However, we were unable to find evidence based information in the literature to support this measure.
BSI is a significant problem in heart transplantation. Further investigation in this field is necessary because these findings may influence early diagnosis, treatment, and prophylaxis in this population.
ACKNOWLEDGMENTS
We would like to thank Mr. Thomas O’Boyle for help with English usage.
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