JAC Advance Access originally published online on January 24, 2008
Journal of Antimicrobial Chemotherapy 2008 61(3):721-728; doi:10.1093/jac/dkm514
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Original research |
Recent changes in bacterial epidemiology and the emergence of fluoroquinolone-resistant Escherichia coli among patients with haematological malignancies: results of a prospective study on 823 patients at a single institution
1 U. O. Ematologia, Spedali Civili, Brescia, Italy 2 Istituto di Malattie Infettive e Tropicali, Università di Brescia, Brescia, Italy
* Corresponding author. Tel: +39-3996573; Fax: +39-303700852; E-mail: chiara.cattaneo{at}libero.it
Received 20 July 2007; returned 25 November 2007; revised 2 September 2007; accepted 2 December 2007
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Abstract |
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Background: Regular monitoring of bacterial epidemiology allows evaluation of antibacterial strategies adopted. The aim of this study was to disclose evolving trends in the epidemiology of infections and emerging antibiotic resistance in unselected inpatients with haematological cancers.
Methods: Febrile/infectious episodes occurring in 823 patients consecutively admitted to a single institution during a 16 month period were analysed. Levofloxacin prophylaxis was used in patients with >7 days expected neutropenia.
Results: Fever developed in 364 patients (44.2%) and an infection was documented in 187 (22.7%), either clinically (6.1%) or microbiologically (16.6%). Levofloxacin prophylaxis, used in 39.4% of cases, caused a reduction in febrile episodes only among neutropenic patients and no difference in the frequency of documented infections. Among 164 pathogens isolated, Gram-negative (49.4%) outweighed Gram-positive bacteria (40.9%), Escherichia coli being most frequent (23.2%). Fluoroquinolone resistance and methicillin resistance were the most frequent types of antibiotic resistance, occurring in 56.1% of bacterial isolates and in 66.7% of staphylococci, respectively. Fluoroquinolone-resistant E. coli accounted for 20.1% of all isolates and for 86.8% of E. coli. Multivariate analysis of risk factors for fluoroquinolone resistance identified prophylaxis (P < 0.001) and neutropenia >7 days (P = 0.02) as independent. Methicillin resistance was independently associated with prophylaxis (P = 0.041) and central venous catheters (P = 0.036). Infections by fluoroquinolone-resistant strains did not show a worse outcome.
Conclusions: A shift towards Gram-negative bacteria has been occurring in recent years in the bacterial epidemiology of haematological patients. Fluoroquinolone resistance is emerging as a major type of antibacterial resistance, particularly among E. coli strains. Further investigation is needed to explore the consequences of such epidemiological changes.
Keywords: infections , neutropenia , resistance
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Introduction |
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Chemotherapy-induced myelosuppression in haematological cancer patients causes increased susceptibility to infections, which can be severe and life-threatening. For decades, the possibility of reducing the frequency of infections by using primary antibacterial prophylaxis in neutropenic patients has been weighted against the possibility of favouring the selection of antibiotic-resistant bacterial strains. The use of oral non-absorbable antibiotics, trimethoprim/sulfamethoxazole and, more recently, of the more effective fluoroquinolones, was able to significantly reduce the frequency of Gram-negative bacteraemia, the most dangerous infectious complication occurring during neutropenic periods.1,2 However, the use of antibacterial prophylaxis has become a major determinant of the bacterial epidemiology at oncohaematological institutions.3 As observed in a number of large epidemiological studies, its widespread use has led to a marked shift in the bacterial flora at oncohaematological institutions from Gram-negative to Gram-positive bacteria, particularly to methicillin-resistant staphylococci.3–5
Levofloxacin, a recently introduced fluoroquinolone, shows good activity also against Gram-positive organisms and was therefore considered a promising choice for extended-spectrum prophylaxis. Indeed, two recently published large randomized studies proved the effectiveness of levofloxacin prophylaxis among neutropenic cancer patients.6,7 Notably, a reduction in the frequency of febrile episodes was documented also among patients with high-risk neutropenia, as defined by severity (<100/mm3) and duration (>7 days).6 Moreover, a meta-analysis demonstrated a reduction of infection-related and overall mortality among neutropenic cancer patients receiving fluoroquinolone prophylaxis.8 In recent years, a number of studies documented an increase in colonization by fluoroquinolone-resistant Escherichia coli of haematological-oncological patients exposed to fluoroquinolone prophylaxis.9–11 However, the global impact of fluoroquinolone prophylaxis on the bacterial epidemiology of oncohaematological patients as well as the clinical consequences of an increase in fluoroquinolone-resistant E. coli12–14 is still only partially known. To this end, we investigated the epidemiology, predisposing factors and susceptibility to antibiotics of the bacterial pathogens isolated from febrile patients as well as the clinical outcome among 823 inpatients consecutively admitted to our institution during a period of 16 months.
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Patients and methods |
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From June 2004 to September 2005, all patients admitted to our institution were prospectively observed for the occurrence of febrile episodes and/or of infections. Fever was defined as an axillary temperature
38.3 or 38°C for at least 1 h, according to the IDSA guidelines.15 An infection was considered ‘clinically proven’ when pertinent symptoms, objective signs or diagnostic radiological findings were present. It was ‘microbiologically proven’ when microorganisms were isolated from: blood [bacteraemia in one positive culture; two positive cultures were needed for diagnosing coagulase-negative staphylococci (CoNS) infection]; urine (>105 cfu/mL); sputum or bronchoalveolar lavage (>105 cfu/mL); and ulcers, abscesses or other infection sites. Bacteraemia was defined as central venous catheter (CVC)-related when the blood culture specimen obtained from the catheter became positive at least 2 h before the specimen obtained from the peripheral vein.16
Institutional guidelines called for routine antibacterial prophylaxis with levofloxacin 500 mg/day only when the expected duration of neutropenia was 7 days. Empirical antibiotic therapy with the combination of third-generation cephalosporin plus amikacin was used in neutropenic patients with fever of unknown origin.
After every admission patients were classified as having had: (i) no fever/infection; (ii) fever of unknown origin (FUO); (iii) clinically documented infection; and (iv) microbiologically documented infection.
Microbiological studies performed at the onset of fever included at least two separate blood specimens for culture, urine culture, galactomannan antigen detection and all other tests whenever indicated. They were performed with standard methods and susceptibilities of the isolated pathogens to antibiotics were evaluated according to Kirby–Bauer methods.
During every episode of fever/infection, the following clinical parameters were recorded:
- Site of infection.
- Isolated microorganism(s).
- Antibiotic susceptibility of the isolated microorganism(s).
- Type of the underlying haematological disease.
- Autologous stem cell transplantation (aSCT).
- Status of the underlying haematological disease, identified as ‘active’ in patients at diagnosis or with refractory/relapsed disease or as ‘controlled’ in patients responsive to treatment and in partial or complete remission.
- Presence or absence of neutropenia (neutrophils <0.5 x 109/L).
- Neutropenia lasting more than 7 days.
- Previous prophylactic therapy, evaluable in 109 microbiologically documented infections.
- Presence or absence of CVC.
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Results |
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Patient population and characteristics of febrile episodes
During the period of the study (June 2004–September 2005), 823 patients were admitted to the haematological ward of our institution. Acute leukaemia (AL) was the underlying haematological disease in 30.1% of admissions, lymphoma in 28.3% and multiple myeloma in 23.7%. Eighty-one patients underwent aSCT.
Febrile/infectious episodes were observed during 364 of 823 admissions (44.2%). An infection was documented in 187 of them (51.4%). In 50 of 187 (26.7%), a clinical documentation was achieved (30 pneumonia, 8 soft tissue infection, 5 enteritis, 2 pharyngitis, 1 retinitis, 1 cholangitis, 1 cerebral abscess, 1 pyelonephritis and 1 visceral leishmaniasis), whereas a microbiological documentation was obtained in 137 cases, i.e. in 37.6% of febrile episodes and in 16.6% of total admissions. Figure 1 shows the flow chart of all febrile/infectious episodes documented.
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Eighty-four of the patients admitted to our institution during the study period were already on an antibiotic. Of the remaining 739 patients, 291 received prophylaxis with levofloxacin and 292 were actually neutropenic at admission to our institution.
Considering all 739 patients, a febrile/infectious episode was documented in 131/448 (29.2%) patients not receiving prophylaxis and in 159/291 (54.6%) patients receiving levofloxacin (P < 0.01). A microbiologically documented infection was diagnosed in 56/448 (12.5%) patients not receiving prophylaxis and in 70/291 (24%) patients receiving levofloxacin (P < 0.01), respectively.
Among neutropenic patients at admission, febrile/infectious episodes were more frequent among patients not receiving prophylaxis (42/54, 77.8%) in comparison with those on prophylaxis (124/238, 52.1%) (P < 0.01). The frequency of microbiologically documented infection was slightly higher among patients not receiving prophylaxis (16/54, 29.6% versus 56/238, 23.6%, respectively; P = not significant).
Characteristics of microbiologically documented infections
The total number of isolated pathogens was 164, since in 24 of 137 cases (17.5%) a polymicrobial infection was documented (2 pathogens were responsible for 22 infections; and 3 and 4 pathogens were involved in 2 cases each). Among pathogens isolated, 148 were bacteria (90.3%), 14 fungi (8.5%) and 2 miscellaneous (1.2%) (Table 1). Eighty-one of 148 (54.7%) bacteria isolated were Gram-negative and 67 (45.3%) were Gram-positive.
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Overall, E. coli was the most frequent microorganism detected, accounting for 23.2% of all isolates, followed by Staphylococcus aureus and CoNS, which accounted for 14% and 11.6% of all isolates, respectively. Among Gram-negative bacteria, Enterobacteriaceae were the most frequent (54/81; 66.7%), particularly E. coli, (38/81, 46.9%), followed by Pseudomonaceae (13/81; 16%), whereas among Gram-positive bacteria, staphylococci were the most frequent (42/67; 62.7%), with S. aureus (23/67, 34.3%) being more frequent than CoNS (19/67, 28.4%) and enterococci (13/67; 19.4%).
Table 2 shows the correlation between the six most frequent types of microorganism isolated and the clinical parameters analysed. By univariate analysis, a documented infection by E. coli was significantly associated with a diagnosis of AL (Fisher's exact test: P = 0.0232), neutropenia at the onset of fever (Fisher's exact test: neutrophil count <0.5 x 109/L: P = 0.0009; neutrophil count <0.1 x 109/L: P = 0.0002), previous fluoroquinolone prophylaxis (Fisher's exact test: P = 0.0238) and bacteraemia (Fisher's exact test: P = 0.0007). None of the microbiologically documented pneumonia was caused by E. coli. An infectious episode caused by S. aureus was more frequently observed in patients with active underlying haematological disease (Fisher's exact test: P = 0.0006), a neutrophil count >0.5 x 109/L (Fisher's exact test: P < 0.0001) and absence of previous prophylaxis (Fisher's exact test: P = 0.0236). A documented infection by Pseudomonaceae was significantly associated with bacteraemia (Fisher's exact test: P = 0.0234). Of note, a documented infection by CoNS was not significantly associated with the presence of a CVC.
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Antibiotic resistance
Fluoroquinolone resistance and methicillin resistance were the most relevant types of antibiotic resistance observed among Gram-negative and Staphylococcus spp. isolated, as they were observed in 43/81 Gram-negative (53.1%) and in 28/42 staphylococci (66.7%), respectively. Fluoroquinolone resistance was particularly frequent among E. coli, where it occurred in 33 of 38 cases (86.7%). Indeed, fluoroquinolone-resistant E. coli represented overall the most frequent type of bacteria identified (33/164; 20.1%). Fluoroquinolone-resistant E. coli were 96.5% among patients on prophylaxis and 44.4% among those not receiving prophylaxis.
With the aim of clarifying the impact of prophylaxis on fluoroquinolone resistance and methicillin resistance, infectious episodes occurring in patients already on treatment with systemic antibiotics were excluded. One hundred and fourteen potentially fluoroquinolone-susceptible microorganisms (Gram-negative/Gram-positive) and 27 Staphylococcus spp. infections were evaluable for analysis.
Incidence of infections due to fluoroquinolone-resistant pathogens was significantly higher among patients receiving prophylaxis (51/291, 17.5%) in comparison with patients not receiving prophylaxis (13/448, 2.9%) (P < 0.0001). Considering only the 291 actually neutropenic patients, infections due to fluoroquinolone-resistant pathogens were also more frequent in the subgroup on prophylaxis (45/237, 19% versus 5/54, 9%; P = 0.1). Table 3 shows the correlation between antibiotic resistance (fluoroquinolone resistance and methicillin resistance) and antibacterial prophylaxis as well as with the following clinical parameters: underlying haematological disease, aSCT, disease activity, neutropenia, presence of CVC and the type of infection. Fluoroquinolone resistance was detected in 64/114 Gram-negative/Gram-positive organisms (56.1%), while 16/27 staphylococci (59.3%) showed methicillin resistance. Patients receiving prophylaxis showed significantly higher frequencies of fluoroquinolone resistance and methicillin resistance in comparison with those not receiving prophylaxis (51/65, 78.5% versus 13/49, 26.5%; P < 0.0001 and 11/12, 91.7% versus 5/15, 33.3%; P = 0.009, respectively). By univariate analysis, fluoroquinolone resistance was also significantly associated with AL (P = 0.04), neutropenia (P < 0.001), duration of neutropenia >7 days (P < 0.001) and CVC (P = 0.04), and methicillin resistance with the presence of CVC (P = 0.007). Multivariate analysis showed that only fluoroquinolone prophylaxis and duration of neutropenia >7 days were both independent risk factors for fluoroquinolone resistance. Both fluoroquinolone prophylaxis and the presence of CVC remained significantly associated with methicillin resistance.
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Further types of antibiotic resistance detected were resistance to ampicillin in 8 (61.5%) and vancomycin resistance (VRE) in 3 (23.1%) of 13 enterococci, respectively.
Only one of the 50 Gram-negative organisms isolated in neutropenic patients showed resistance to both third-generation cephalosporin and amikacin (A. xylosoxidans); therefore, the rate of resistance of bacterial isolates to the combination therapy for febrile neutropenic patients adopted in our institution was only 2%.
None of the isolated Pseudomonas spp. showed multiresistance to antibiotics.
Outcome of infectious episodes
The crude mortality among all febrile/infectious episodes was 5.8% (21 of 364). It was 10.2% among documented infections (19/187) and 8% among microbiologically documented infections (11/137). Fungi were involved in three cases (one pulmonary aspergillosis and two candidaemia), Gram-positive pathogens in seven cases (one VRE, one VRE + methicillin-resistant Staphylococcus spp., two enterococci + methicillin-resistant Staphylococcus spp. and two methicillin-susceptible and one methicillin-resistant Staphylococcus spp.) and Gram-negative pathogens in only one case (fluoroquinolone-resistant E. cloacae). An active underlying haematological disease was present in 19 of 21 febrile episodes causing patient's death (P = 0.0014). It was the only clinical parameter significantly associated with crude infectious mortality.
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Discussion |
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The population analysed in the present study can be considered representative of unselected hospitalized oncohaematological patients. Indeed, the frequencies of clinically and microbiologically documented infections detected in patients developing fever were similar to those already reported.17–19 While during the last decade most epidemiological studies showed a predominance of Gram-positive infections, which was attributed to the use of intravascular devices as well as to the widespread use of antibacterial prophylaxis, mainly targeted against Gram-negative microorganisms,3–5,17 this study shows that a clear epidemiological shift from Gram-positive infections towards Gram-negative infections has occurred in very recent years. Prophylaxis with levofloxacin, a recently introduced fluoroquinolone effective also against Gram-positive bacteria, was given to patients at high risk of prolonged neutropenia, who accounted for
40% of the entire population. While the overall frequency of FUO and microbiologically documented infection remained higher among this more at-risk subgroup, among actually neutropenic patients, the use of levofloxacin resulted in a reduction of febrile episodes, whereas the frequency of microbiologically documented infection was lower but not significantly different from that of patients not on prophylaxis. The prophylactic use of levofloxacin may have played a major role in the epidemiological shift observed, particularly by favouring fluoroquinolone-resistant Gram-negative isolates. Indeed, Enterobacteriaceae spp. were the predominant type of microorganism, and E. coli was the most frequent pathogen, accounting for 23.2% of all isolates and showing the highest frequency of fluoroquinolone resistance. A similar shift in bacterial epidemiology has been recently noted also in other monocentric studies of smaller series of oncohaematological patients18 developing bloodstream infections,19–21 raising concerns and prompting a thorough analysis of the real dimensions of the phenomenon and of its predisposing factors.
Infection by E. coli occurred characteristically as bacteraemia in acute leukaemic patients during the neutropenic phase of potentially curative treatments and was therefore more clinically relevant than Gram-positive infections, mainly due to S. aureus, which occurred more often in non-neutropenic patients with uncontrolled underlying disease. Of note, among Gram-positive bacteria, CoNS were less frequent than S. aureus and were not significantly associated with the presence of CVC. That represented a change in the bacterial epidemiology at our institution compared with previous years (data not shown), when programmes of CVC insertion as well as of strict CVC care by dedicated teams had not yet been implemented, suggesting that bacterial epidemiology can be successfully modified by timely interventions.
The relevance of the shift from Gram-positive to Gram-negative infections was further underscored by the high frequency of antibiotic-resistant bacterial isolates detected also among Gram-negative microorganisms, with the addition of fluoroquinolone resistance to the already well-known methicillin resistance and ampicillin resistance of Gram-positive isolates. The incidence of methicillin resistance and ampicillin resistance is quite variable among haematological cancer patients, ranging between 66% and 100%18,22 and between 0% and 41%,18,23 respectively. Our study confirmed the high frequency of methicillin resistance, which occurred in 59.3% of staphylococci, and showed ampicillin resistance in 61.5% of enterococci. In 23% of cases, enterococci were resistant to vancomycin. The occurrence of fluoroquinolone resistance in over half of the Gram-negative isolates was less expected, since its previously reported frequency ranged between 20% and 40%,6,18,22 and its clinical impact could be more relevant. The incidence of fluoroquinolone resistance was particularly high in patients receiving levofloxacin (88.1% versus 25%). Similar figures were observed by Bucaneve et al.6 in a nationwide study in Italy, who reported fluoroquinolone resistance in 37.8% of 37 Gram-negatives isolated and specifically in 77% of Gram-negatives isolated from patients on prophylaxis with levofloxacin, in comparison with 16.7% observed in patients not on prophylaxis. Our study further shows that the increase in fluoroquinolone-resistant strains was absolute since prophylaxis did not cause a significant reduction in the frequency of microbiologically documented infection both overall and among the subgroup of neutropenic patients. Fluoroquinolone resistance was most prevalent among E. coli where it occurred in 86.7% of strains, fluoroquinolone-resistant E. coli being the most frequent microorganism isolated from our patients and representing nearly 20% of all isolates. Fluoroquinolone resistance was less frequent among Pseudomonas aeruginosa isolates. This finding was also reported by Kern et al.24 and may be at least in part explained by the loss of fitness of fluoroquinolone-resistant P. aeruginosa, compared with fluoroquinolone-resistant E. coli, which may result in a lower rate of nosocomial fluoroquinolone-resistant Pseudomonas strain transmission.
The analysis of factors predisposing to antibiotic resistance showed that the use of levofloxacin prophylaxis was the most significant risk factor for both methicillin resistance and fluoroquinolone resistance in multivariate analysis. Fluoroquinolone resistance was also associated with prolonged neutropenia (>7 days), maybe due to the fact that this condition predisposes patients to a more frequent exposure to antibiotic therapy, including levofloxacin. As expected, the presence of a CVC was an independent risk factor for methicillin resistance in our study and methicillin resistance and fluoroquinolone resistance were closely associated, as already reported.14,25
Only one of the E. coli strains isolated in patients receiving levofloxacin prophylaxis had maintained susceptibility to fluoroquinolones in vitro, suggesting a very high penetrance of fluoroquinolone resistance particularly among E. coli. Taken together, these data consistently suggest that the widespread use of fluoroquinolones as prophylaxis of neutropenia may contribute to the changes in bacterial epidemiology.
Such observations are challenging and raise questions regarding the appropriateness of maintaining a policy of fluoroquinolone prophylaxis, even in patients with an expected neutropenia of long duration. The clinical management of those high-risk patients who, after developing fluoroquinolone-resistant bacterial infections, are expected to have further periods of prolonged neutropenia, when receiving additional intensive chemotherapy cycles, appears particularly difficult, since they would be candidates for further fluoroquinolone prophylaxis.
The choice of completely discontinuing prophylaxis does not seem advisable based on available data. Indeed, the efficacy of levofloxacin in neutropenic oncohaematological patients has been recently confirmed by two prospective randomized clinical trials6,7 as well as by a meta-analysis,8 which demonstrated a significant reduction in overall mortality among patients receiving fluoroquinolone prophylaxis, as well as the superiority of fluoroquinolone prophylaxis compared with any other type of antibacterial prophylaxis. A significant reduction in febrile episodes among neutropenic patients receiving prophylaxis in comparison with those not on levofloxacin was also observed in our study. Moreover, Reuter et al. recently reported an attempt to discontinue fluoroquinolone prophylaxis. A sudden increase in the mortality rate due to Gram-negative sepsis was recorded, which promptly subsided when prophylaxis was reintroduced.26 Of note, in this, as well as in other studies, fluoroquinolone resistance was transient and did not spread when prophylaxis was withheld.26 In our study, the prognosis of microbiologically documented infections was not severe. The mortality rate was acceptable, the prognostic factor mainly associated with infectious mortality being an active underlying haematological disease. Fluoroquinolone resistance was detected in only one infectious episode (E. cloacae) with a fatal outcome. Death was caused predominantly by nosocomially acquired enterococci in patients with refractory leukaemia or lymphoma, whereas none of the E. coli infections was fatal. The death rate of enterococcal infection was 30.8% (4 of 13 episodes), confirming its relationship with a worse prognosis in uncontrolled haematological cancer disease.27 The empirical use of the association of ceftriaxone and amikacin may have contributed to the overall fair outcome of infectious episodes.
An alternative to the discontinuation of levofloxacin prophylaxis may be a careful epidemiological monitoring of high-risk patients in order to optimize empirical antibiotic therapy, as well as routinely performing surveillance cultures for the presence of fluoroquinolone-resistant microorganisms in rectal swabs. Perianal area colonization by fluoroquinolone-resistant E. coli was an occasional finding in otherwise healthy individuals but rose to 10.6% among patients on fluoroquinolone prophylaxis.28 The use of prophylaxis with oral non-absorbable antibiotics, to which fluoroquinolone-resistant Enterobacteriaceae may be susceptible, either alone or in association with a fluoroquinolone, may be considered in colonized patients in order to decontaminate the gastrointestinal tract, which is the main reservoir of Enterobacteriaceae.
In summary, the recent ecology of bacterial pathogens detected in haematological cancer inpatients with infections and their susceptibility to antibiotics shows a predominance of Gram-negative pathogens and an increasing resistance to antibiotics, particularly to fluoroquinolones. However, fluoroquinolone resistance per se seems not to be responsible for a greater morbidity. Local epidemiological surveillance is warranted, as further mechanisms of resistance (methicillin resistance and resistance to carbapenems) may be favoured by the routine use of fluoroquinolones.
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Funding |
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No specific funding has been received for this study.
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Transparency declarations |
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None to declare.
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References |
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