Eur. J. Epidemiol. 0392-2990
Vol. 8, No. 5
EUROPEAN JOURNAL
September 1992, p. 687-692
OF
EPIDEMIOLOGY
OCCURRENCE OF BACTEREMIAIN HEMATOLOGICPATIENTS D. D'ANTONIO *l, E. PIZZIGALLO**, A. IACONE*, M. DELL'ISOLA*, G. FIORITONI*, S. BETTI*, A. PIERGALLINI*, R. DI GIANFILIPPO*, P. OLIOSO* and G. TORLONTANO* *Cattedra di E m a t o l o g i a - Universith G. D ' A n n u n z i o 66100 Chieti - Italy. **Cattedra di M a l a t t i e l n f e t t i v e - UniversiM "G. D ' A n n u n z i o " - Chieti - Itatv.
Key words: Bacteremia - Hematologic patients - Risk factors In the present study we reviewed eighty-six episodes of bacteremia occurred in 60 neutropenic patients and thirty-one episodes occurred in 30 non-neutropenic patients. Twenty-four out of 60 neutropenic patients suffered from multiple episodes of bacteremia, while only one out of 30 nonneutropenic patients presented multiple episodes. In neutropenic patients, 29 episodes of bacteremia were polymicrobial, whereas only one non-neutropenic patient had polymicrobial bacteremia. Intravascular catheters were the most common source of bacteremia (23.2%) in neutropenic patients, as compared with infections of the genito-urinary tract (45.10/0) among nonneutropenic patients. In both groups, aerobic gram-positive cocci were the microorganisms most frequently isolated (71.6%). Anaerobic microorganisms showed an higher incidence in polymicrobial episodes than in monomicrobial episodes x 2 = 5.39 p = 0.02 OR = 2.97 950/0 CI (1.2-7.7).
INTRODUCTION
MATERIALS AND METHODS
Twenty to 30% of febrile patients undergoing treatment for hematologic malignancies are diagnosed as suffering with a microbiologically documented infection with bacteremia (7, 18). Because of the rapid onset of life-threatening complications, and of the frequent uncertainty and delay of microbiological testing, the prompt empiric administration of broadsprectrum antibiotics has become current practice in the treatment of such patients (5, 16). However, revealing the microbial etiology is of great importance in the evaluation of the empirical treatments undertaken or in the choice of a different therapy. In order to classify recurrent types of bacteremia, we reviewed the outcome of 117 episodes of bacteremia which occurred in 90 neutropenic and non neutropenic patients who had received cytotoxic chemotherapy.
In this study we reviewed, blood cultures positive for bacteria in patients with hematologic malignancies, performed between May 1989 and April 1991. All patients were prophylactically treated with floroquinolones: Ciprofloxacin (500 mg twice daily) or Ofloxacin (400 twice daily) were administered 1-4 days prior to cytotoxic chemotherapy. Prophylactic drugs were well tollerated and continued until peripheral blood granulocytes reached 1000 cells/mm3. The floroquinolones were also continued when fever developed and empirical antibiotic therapy was administered. The patients, all with central venous catheter (CVC), were divided into neutropenic patients (PMN < 500 x 10e9/L, n = 60 Group A) and non-neutropenic patients (PMN > 500 x 10e9/L, n = 60 Group B). In febrile patients (fever was defined as an axillary temperature of 38°C or more in two occasions in the same day, unrelated to blood products or pyrogenic drug administration) peripheral
i Corresponding author.
687
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Eur. J. Epidemiol.
venous and CVC blood sample cultures were collected for every 8 hours, until the infective episode resolved. All patients received at least one, but frequently more, antibiotics during this period. Blood samples were taken when the antimicrobial concentrations were expected to be at their lowest level, generally prior to the administration of the next dose. Routine blood culture vials, consisting of Bactec blottes with resins, one containing aerobic medium NR-16A and one with anaerobic medium NR-17A (3), were entered into the Bactec NR-660 system data base, and incubated at 37°C. The Bactec NR-660 system (Becton Dickinson Italia, Milan Italy) was used as previously described (4, 10). A semiquantitative culture method was used for identifing intravenouscatheter-related infections (13). Aerobic and facultative anaerobic blood culture isolates were identified according to the Manual of Clinical Microbiology (11). Anaerobic microorganisms were identified by using the criteria described in the Anaerobe Laboratory Manual (9). Drug-susceptibility tests of the microorganism isolated were performed on an AUTOSCAN slide (1). Bacteremic episodes were defined as a clinical illness associated with at least one positive blood culture. This was applied to all pathogens except for Staphylococcus epidermidis, Propionibacterium species, or Diphtheroids (excluding Corynebacterium fieikeium) in which at least two positive results of blood cultures were required. The episodes of bacteremia according to previously described criteria (21) were classified as follows: a) MONOMICROBIAL BACTEREMIA: episodes characterized by the presence of a single microorganism in the blood culture sample; b) POLYMICROBIAL BACTEREMIA: episodes characterized by the presence of more than one microorganism in the same blood sample; c) MULTIPLE EPISODES OF BACTEREMIA: repeated episodes of bacteremia of different microorganisms within the same febrile episode. The sources of bacteremia were determined as follows: 1) Infections associated with an intravascular catheter: a) Exit site infection: characterized by erythema/ warmth/tenderness and induration with or without purulent material, within 2 cm of the exit site, b) Tunnel infection: characterized by erythema, tenderness and induration along the subcutaneous tract of the catheter, c) Septic thrombophlebitis: characterized by infected venous occlusions along the catheter. Bacteremia was ascribed to the catheter when associated with an exit site infection, a tunnel infection and/or septic thrombophlebitis with persistent positive blood cultures from both the catheter and the peripheral vein. The presence of colonization of the intravascular catheter alone was characterized by persistent positive blood cultures obtained through the catheter and by negative peripheral blood cultures, taken simultaneously. In all of these circumstances catheters were removed. The colonization of the catheter alone was not considered. 2) Pneumonia: it was diagnosed when an x-ray scan
showed an otherwise unexplained pulmonary infiltrate and the same organisms could be isolated from both blood samples and sputum. Spontaneously expectorated sputum was not acceptable for the assessment of infection when the microscopic screening showed more than ten squamous epithelial cells per low-power field (x 100) (8). 3) Upper respriratory tract, skin or soft tissue, gastrointestinal tract and urinary tract: culture of the same organisms from the primary site was required together with clinical evidence of infection. 4) Unknown origin: none of the aforementioned criteria fulfilled.
Statistical analysis Tests for the statistical significance of differences among proportions were based on Chi-square Values, comparing the number of observed and expected events. The probability for neutropenic patients to develop multiple and polymicrobial bacteremia as compared to non-neutropenic patients was determined by using odds ratios (OR), as estimates of the relative risks, and their 95% confidence intervals (C.I.). RESULTS
In this study, 117 episodes of bacteremia were reviewed in 90 febrile patients (50 males and 40 females), 39 occurred in patients with acute leukemia, 21 in patients with non-Hodgkin's lymphoma, 10 in patients with Hodkgin's lymphoma, 9 in patients who had undergone autologous bone marrow transplantation (7 for non-Hodgkin's lymphoma, 2 for Hodgkin's lymphoma) and 11 in patients who had undergone allogenic bone marrow transplantation (8 for acute leukemia, 2 for thalassaemia, 1 for aplastic anaemia). Their mean age was 40 years (range: 16 to 70). a) Group A - Neutropenic patients: Eighty-six of bacteremia occurred in 60 neutropenic patients. Out of these, 36 presented a single episode and 24 had more than one episode ofbacteremia (22 patients with two and 2 patients with three episodes). The duration of neutropenia was less than 21 days in patients with a single episode of bacteremia, between 21 and 35 days in those with two episodes and 42 and 48 days in the two patients with three episodes. In the 36 patients with single episodes, the most frequent cause of monomicrobial bacteremia (29 episodes) was Staphylococcus epidermidis (18 isolates); the other microorganisms isolated are shown in Table 1. The remaining seven episodes showed a polymicrobial etiology, with two microorganisms in the same sample (Table 1). In the 24 patients with multiple episodes, the most frequent cause of monomicrobial bacteremia (29 episodes) was Staphylococcus epidermidis (15 isolates), the other microorganisms are shown in Table 1. The remaining 21 episodes showed a polymicrobial etiology, due to the presence, in 19 episodes, of two microorganisms in the same sample
688
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Bacteremia in hematologic patients
TABLE 1. - Microorganisms causing bacteremia in neutropenic patients. Single episodes
Multiple episodes
Monomicrobial
Polymicrobial
Monomicrobial
Polymicrobial
Staphylococcus epidermidis
18
6
15
12
Staphylococcus aureus
3
2
3
5
Streptococcus viridans
3
1
2
6
Streptococcus faecalis
-
-
2
4
1
Streptococcus pneumoniae
1
-
2
1
1
Serratia marcescens
-
-
1
Clostridium difficile
-
-
Escherichia co#
2
2
7
-
2
1
6
-
-
1
2
-
1
1
Peptostreptococcus anaerobius Bacteroides fragilis Corynebacterium
1
" -
1
CDC-JK Propionibacterium
1
species
and, in 3 episodes, of 3 microorganisms. The bacterial agents are shown in Table 1. The sources of bacteremia are listed in Table 3. Infections originating from the intravascular catheter were the most common (20 cases, 12 with exit site infection and 8 with tunnel infection), followed by those with an upper respiratory tract source (14 cases) and skin-soft tissue (9 cases). In 23 episodes the source of bacteremia could not be determined. b) Group B - Non-neutropenic patients (Table 2): Thrifty-one episodes of bacteremia occurred in 30 patients: 29 of them presented a single episode and one had two episodes. In patients with a single episode the most frequent cause of monomicrobial bacteremia was Staphylococcus epidermidids (14 isolates); the other microorganisms are shown in Table 2. In the patient with two episodes ofbacteremia, Staphylococcus aureus was isolated in one episode and E. coli and Bacteroides fragilis were isolated in the other. The sources of bacteremia are listed in Table 3. Infections
originating from the genito-urinary tract were the most common (14 cases), followed by those from the upper respiratory tract (5 cases). One intravascular catheter source was due to septic thrombophlebitis. In 6 episodes of bacteremia, the source could not be determined. Statistical analysis The groups ofneutropenic patients showed a high incidence of multiple (x 2 = 13.4; p < 0.0001) and plymicrobial (x 2 = 10.7; p = 0.001) bacteremias. Conversely, in non-neutropenic patients, the risk of developing multiple episodes of bacteremia was 19.3 (95% C.I. 2.46-151.2), while the risk of developing a polymicrobial bacteremia was 14.7 (95% C.I. 1.87115.3). A positive association also emerged between polymicrobial bacteremia and multiple episodes (x 2 = 4.85; p = 0.028) and between polymicrobial bacteremia and isolation of anaerobic microorganisms (x 2 = 5.39; p = 0.02).
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TABLE 2. - Microorganisms causing bacteremia in non-neutropenic patients. Single episodes Monomicrobial
Staphylococcus epidermidis Staphylococcus aureus Streptococcus faecalis Escherichia coil Proteus mirabilis Bacteroides fragilis
Multiple episodes Monomicrobial
Polymicrobial
Polymicrobial
14
4 5
2 3
TABLE 3. - Sources of Bacteremia. Group A
Group B
neutropenic patients
non-neutropenic patients
Source
Genitourinary tract
4
4.60%
Upper respiratory tract Gastrointestinal tract Pneumonia Intravascular catheter
14 5 6 20
16.20% 5.80o/0 6.90% 23.20o/0
Skin-soft tissue Multiple Unknown origin
9 5 23
10.40% 5.80O/o 26.74%
DISCUSSION
Despite the use of antimicrobial prophylaxis and antibacterial combination therapy, patients receiving cytotoxic therapy or bone marrow transplants are subject to high risk of bacterial infection and breakthrough bacteremia. The isolation of microorganisms from bacteremic patients is necessary and must be performed very early to test susceptibility to antimicrobial agents in order to design the best treatment. A microbiological diagnosis is often difficult in these patients, due to the presence of antimicrobial agents in their blood. Such agents are transferred into the culture bottle with the blood sample and can thus suppress or slower bacterial growth. In fact, blood cultures from patients undergoing antibacterial therapy show a lower
14 5
45.10% 16.10%
1 3 1 1
3.20°/0 9.60% 3.20O/o 3.20%
6
19.35%
x2 = 28.7 P < 0.0001
x2 = 6.2 p = 0.013
recovery rate of bacteria than positive blood cultures from patients that are not (15). Therefore, bacterial suppression is related to the level of antibacterial activity in blood samples and to the susceptibility or resistance of the microorganisms to antimicrobial agents. To improve the recovery of bacteria from blood cultures, blood samples must be taken when the antimicrobial concentrations are expected to be at their lowest level, just before the administration of the antimicrobial therapy. We used the NR 660 system, because in several studies (12, 2) it has been proven to provide a quicker means of detection of positive blood cultures and a more acceptable level of reliability than conventional system as well. Moreover, we used Bactec resin-containing blood culture media because they are superior to non-resin broth media for the isolation of bacteria from the blood of patients
690
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Bacteremia in hematologic patients
receiving a high-antibiotic-concentration regimen. That is due to the ability of such resin to remove or neutralize various antibiotics in the blood samples (17, 20). Our data provide evidence of a higher incidence of multiple (x 2 = 13.4 p = 0.0001 OR = 19.3 95% C.I. 2.46-151.2) and polymicrobial bacteremia (x 2 = 10.7 p = 0.001 OR= 14.7 95% CI 1.87-115.3) in the group of neutropenic patients, indicating that these subjects are at higher risk. In 24/60 neutropenic patients, multiple episodes o f bacteremia were observed, while only one out of 30 non-neutropenic patients present multiple episodes. In 24 neutropenic patients with multiple episodes, 22 had two episodes of bacteremia, while 2 patients presented three episodes. This difference in the course of bacteremia was related to the grade and duration of neutropenia. The higher incidence of episodes o f polymicrobial bacteremia in neutropenic (29/86) than in non-neutropenic patients (1/30) is likely to be due to the frequent occurrence of cutaneous and mucosal lesion in neutropenic patients. These lesions can allow the passage of more than one microorganism into the bloodstream. Polymicrobial bacteremia was more frequent in neutropenic patients with multiple episodes than in those with single episodes ( x 2 = 4.85 p = 0.028 O R = 3 950/0 C.I. 1.1-8.1). Moreover, it is of interest that anaerobic microorganisms were isolated more frequently in polymicrobial episodes than in monomicrobial episodes (x 2 = 5.39 p = 0.02 OR = 2.97 95% C.I. 1.27.7). Both in the two groups and in the different types of bacteremia, the aerobic gram-positive cocci were the microorganisms most frequently isolated (71.6%). An increased incidence of gram-positive microorganisms in patients with hematological neoplasms has been already reported (14, 19, 22). According to others (6, 23), the lack o f Pseudomonas bacteremia could be due to the difficulty in recovering these bacteria from the blood o f patients treated with Ciprofloxacin or Ofloxacin. A high number of episodes of bacteremia by Staphylococcus epidermidis was seen in both groups of patients, even though the sources of infection were different. Concerning the sources of bacteremia, a different behaviour was observed in the two groups. The intravascular catheter was the most c o m m o n source (23.20/0) in neutropenic patients, followed by the upper respiratory tract (16.20/0) and skin or soft tissues (10.4°/0). A multiple source was seen in 5 episodes (5.8%). In non-neutropenic patients the most c o m m o n source was the genito-urinary tract (45.1%) followed by the upper respiratory tract (16.1%) while a multiple source of bacteremia was never seen. These results suggest that blood culture samples should be taken immediately when bacteremia is suspected because of the occurrence of fever, and an empirical therapy is then started without delay. The best choice o f antimicrobial agents should be based on the knowledge of the current local ecology and of the antibiotic resistance patterns of endemic strains of bacteria.
Acknowledgement
Supported by AIDS Project, 1991,N. 6203.043 and M.P.I. 40-60o/0. REFERENCES
1. Baker C., Stocker S., Rhoden D. and Thornsberry C (1986): Evaluation of the antimicrobial-susceptibility system with the autoSCAN-4 automated reader - J. Clin. Microbiol. 23: 143-148. 2.
Caslow M., Ellner P. and Kiehn T. (1974): Comparison of the BACTEC system with blind subculture for the detection of bacteremia - Appl. Microbiol. 28: 435-438.
3.
Courcol R., Durocher A., Roussel-Del Vallez 114., Fruchart A. and Martin G. (1988): Routine evaluation of BACTEC NR-16A and NR-17A media - J. Clin. Microbiol. 26: 1619-1622.
4.
Courcol R., Fruchart A., Roussel-Del Vallez M. and Martin G. (1986): Routine evaluation of the non radiometric BACTEC NR 660 system - J. Clin. Microbiol. 24: 26-29.
5. D'Antonio D., lacone A., Fioritoni G., Angelini A., Dragani A., Betti S., Di Bartolomeo P., Di Bartolomeo G., Accorsi P., Quaglietta A., D'Arcangelo L., Piccolomini R. and Torlontano G. (1990): Infection after autologous blood-derived stem cell transplantation - Haematologica 75 Suppl. 1: 83-86. 6. Dekker A., Rozenberg-Arska M. and Verhoef J. (1987): Infection prophylaxis in acute leukemia: a comparison of ciprofloxacin with trimethoprim-sulfamethoxazole and colistin - Ann. Intern. Med. 106: 7-12. 7. De Pauw B., Donnely J., Elves A., Verhagen C, Novakova L and Van der Meer J. (1990): Towards individually tailored empiric antibiotic therapy in febrile granulocytopenic patients - Neth. J. Med. 37: 111-119.
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8: Geckler R., Ellenbogen C comparison aspirates - J.
Gremillon D., Mc Allister C. and (1977): Microscopic and bacteriological of paired sputa and transtracheal Clin. Microbiol. 6: 396-399.
9. Holdeman L., Cato E. and Moore W. (1977): Anaerobe laboratory manual. In: Virginia Polytechnic Institute, 4th ed. Blaksburg. 10. Jungkind D., Millan J., Allen S., Dyke J. and Hill E. (1986): Clinical comparison of a new automated infrared blood culture system with BACTEC 460 system - J. Clin. Microbiol. 23: 262-266. 11. Lennette E., Spaulding E. and Truant J. (1974): Manual of clinical microbiology - 2nd edition American Society for Microbiology, Washington. 12. Levi M., Gialanella P., Motyl M. and Mc Kitrick J. (1988): Rapid detection of blood cultures with the BACTEC NR 660 does not require first-day subculturing - J. Clin. Microbiol. 21: 2262-2265.
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Eur. J. Epidemiol.
13. Maki D., Wise C. and Sarafin H. (1977): A semiquantitative culture method for identifying intravenous-catheter-related infection - N. Engl. J. Med. 296: 1305-1309.
19. Wade J., Schimpff S., Newman K. and Wiernik P. (1982): Staphylococcus epidermidis: an increasing cause of infection in patients with granulocytopenia Ann. Intern. Med. 97: 503-508.
14. Martin M., Pfaller M. and Wenzel R. (1989): Coagulase-negative Staphylococcal bacteremia Ann. Intern. Med. 110: 9-16.
20. Washington II and Ilstrup D. (1980): Blood cultures: issues and controversies - Rev. Inf. Dis. 8: 792-802.
15. Rodriguez F. and Lorin V. (1985): Antibacterial activity in blood cultures - J. Clin. Microbiol. 21: 262263. 16. Schimpff S. (1977): Therapy of infection in patients with granulocytopenia -Med. Clin. N. Am. 61: 11011118. 17. Smith S. and Eng R. (1983): In vitro evaluation of the BACTEC resin-containing blood culture bottle - J. Clin. Microbiol. 17: 1120-1126. 18. Wade J., Johnson D. and Bustamante C. (1986): Monotherapy for empiric treatment of fever in granulocytopenic cancer patients - Am. J. Med. 80 (SuppL 5C): 85-95.
692
21. Whimbey E., Kiehn T., Brannon P., Blevins A. and Armstrong D. (1987): Bacteremia and fungemia in patients with neoplastic disease - Am. J. Med. 82: 723-730. 22. Winston D., Dudnick D., Chapin M. et aL (1983): Coagulase-negative staphylococcal bacteremia in patients receiving immunosuppressive therapy Arch. Intern. Med. 143: 32-36. 23. Winston D., Ho W., Bruckner D., Gale R. and Champlin R. (1990): Ofloxacin versus vancomycin/ polymyxin for prevention of infections in granulocytopenic patients - Am. J. Med. 88: 36-42.
Vol. 8, No. 5
EUROPEAN JOURNAL
September 1992, p. 687-692
OF
EPIDEMIOLOGY
OCCURRENCE OF BACTEREMIAIN HEMATOLOGICPATIENTS D. D'ANTONIO *l, E. PIZZIGALLO**, A. IACONE*, M. DELL'ISOLA*, G. FIORITONI*, S. BETTI*, A. PIERGALLINI*, R. DI GIANFILIPPO*, P. OLIOSO* and G. TORLONTANO* *Cattedra di E m a t o l o g i a - Universith G. D ' A n n u n z i o 66100 Chieti - Italy. **Cattedra di M a l a t t i e l n f e t t i v e - UniversiM "G. D ' A n n u n z i o " - Chieti - Itatv.
Key words: Bacteremia - Hematologic patients - Risk factors In the present study we reviewed eighty-six episodes of bacteremia occurred in 60 neutropenic patients and thirty-one episodes occurred in 30 non-neutropenic patients. Twenty-four out of 60 neutropenic patients suffered from multiple episodes of bacteremia, while only one out of 30 nonneutropenic patients presented multiple episodes. In neutropenic patients, 29 episodes of bacteremia were polymicrobial, whereas only one non-neutropenic patient had polymicrobial bacteremia. Intravascular catheters were the most common source of bacteremia (23.2%) in neutropenic patients, as compared with infections of the genito-urinary tract (45.10/0) among nonneutropenic patients. In both groups, aerobic gram-positive cocci were the microorganisms most frequently isolated (71.6%). Anaerobic microorganisms showed an higher incidence in polymicrobial episodes than in monomicrobial episodes x 2 = 5.39 p = 0.02 OR = 2.97 950/0 CI (1.2-7.7).
INTRODUCTION
MATERIALS AND METHODS
Twenty to 30% of febrile patients undergoing treatment for hematologic malignancies are diagnosed as suffering with a microbiologically documented infection with bacteremia (7, 18). Because of the rapid onset of life-threatening complications, and of the frequent uncertainty and delay of microbiological testing, the prompt empiric administration of broadsprectrum antibiotics has become current practice in the treatment of such patients (5, 16). However, revealing the microbial etiology is of great importance in the evaluation of the empirical treatments undertaken or in the choice of a different therapy. In order to classify recurrent types of bacteremia, we reviewed the outcome of 117 episodes of bacteremia which occurred in 90 neutropenic and non neutropenic patients who had received cytotoxic chemotherapy.
In this study we reviewed, blood cultures positive for bacteria in patients with hematologic malignancies, performed between May 1989 and April 1991. All patients were prophylactically treated with floroquinolones: Ciprofloxacin (500 mg twice daily) or Ofloxacin (400 twice daily) were administered 1-4 days prior to cytotoxic chemotherapy. Prophylactic drugs were well tollerated and continued until peripheral blood granulocytes reached 1000 cells/mm3. The floroquinolones were also continued when fever developed and empirical antibiotic therapy was administered. The patients, all with central venous catheter (CVC), were divided into neutropenic patients (PMN < 500 x 10e9/L, n = 60 Group A) and non-neutropenic patients (PMN > 500 x 10e9/L, n = 60 Group B). In febrile patients (fever was defined as an axillary temperature of 38°C or more in two occasions in the same day, unrelated to blood products or pyrogenic drug administration) peripheral
i Corresponding author.
687
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Eur. J. Epidemiol.
venous and CVC blood sample cultures were collected for every 8 hours, until the infective episode resolved. All patients received at least one, but frequently more, antibiotics during this period. Blood samples were taken when the antimicrobial concentrations were expected to be at their lowest level, generally prior to the administration of the next dose. Routine blood culture vials, consisting of Bactec blottes with resins, one containing aerobic medium NR-16A and one with anaerobic medium NR-17A (3), were entered into the Bactec NR-660 system data base, and incubated at 37°C. The Bactec NR-660 system (Becton Dickinson Italia, Milan Italy) was used as previously described (4, 10). A semiquantitative culture method was used for identifing intravenouscatheter-related infections (13). Aerobic and facultative anaerobic blood culture isolates were identified according to the Manual of Clinical Microbiology (11). Anaerobic microorganisms were identified by using the criteria described in the Anaerobe Laboratory Manual (9). Drug-susceptibility tests of the microorganism isolated were performed on an AUTOSCAN slide (1). Bacteremic episodes were defined as a clinical illness associated with at least one positive blood culture. This was applied to all pathogens except for Staphylococcus epidermidis, Propionibacterium species, or Diphtheroids (excluding Corynebacterium fieikeium) in which at least two positive results of blood cultures were required. The episodes of bacteremia according to previously described criteria (21) were classified as follows: a) MONOMICROBIAL BACTEREMIA: episodes characterized by the presence of a single microorganism in the blood culture sample; b) POLYMICROBIAL BACTEREMIA: episodes characterized by the presence of more than one microorganism in the same blood sample; c) MULTIPLE EPISODES OF BACTEREMIA: repeated episodes of bacteremia of different microorganisms within the same febrile episode. The sources of bacteremia were determined as follows: 1) Infections associated with an intravascular catheter: a) Exit site infection: characterized by erythema/ warmth/tenderness and induration with or without purulent material, within 2 cm of the exit site, b) Tunnel infection: characterized by erythema, tenderness and induration along the subcutaneous tract of the catheter, c) Septic thrombophlebitis: characterized by infected venous occlusions along the catheter. Bacteremia was ascribed to the catheter when associated with an exit site infection, a tunnel infection and/or septic thrombophlebitis with persistent positive blood cultures from both the catheter and the peripheral vein. The presence of colonization of the intravascular catheter alone was characterized by persistent positive blood cultures obtained through the catheter and by negative peripheral blood cultures, taken simultaneously. In all of these circumstances catheters were removed. The colonization of the catheter alone was not considered. 2) Pneumonia: it was diagnosed when an x-ray scan
showed an otherwise unexplained pulmonary infiltrate and the same organisms could be isolated from both blood samples and sputum. Spontaneously expectorated sputum was not acceptable for the assessment of infection when the microscopic screening showed more than ten squamous epithelial cells per low-power field (x 100) (8). 3) Upper respriratory tract, skin or soft tissue, gastrointestinal tract and urinary tract: culture of the same organisms from the primary site was required together with clinical evidence of infection. 4) Unknown origin: none of the aforementioned criteria fulfilled.
Statistical analysis Tests for the statistical significance of differences among proportions were based on Chi-square Values, comparing the number of observed and expected events. The probability for neutropenic patients to develop multiple and polymicrobial bacteremia as compared to non-neutropenic patients was determined by using odds ratios (OR), as estimates of the relative risks, and their 95% confidence intervals (C.I.). RESULTS
In this study, 117 episodes of bacteremia were reviewed in 90 febrile patients (50 males and 40 females), 39 occurred in patients with acute leukemia, 21 in patients with non-Hodgkin's lymphoma, 10 in patients with Hodkgin's lymphoma, 9 in patients who had undergone autologous bone marrow transplantation (7 for non-Hodgkin's lymphoma, 2 for Hodgkin's lymphoma) and 11 in patients who had undergone allogenic bone marrow transplantation (8 for acute leukemia, 2 for thalassaemia, 1 for aplastic anaemia). Their mean age was 40 years (range: 16 to 70). a) Group A - Neutropenic patients: Eighty-six of bacteremia occurred in 60 neutropenic patients. Out of these, 36 presented a single episode and 24 had more than one episode ofbacteremia (22 patients with two and 2 patients with three episodes). The duration of neutropenia was less than 21 days in patients with a single episode of bacteremia, between 21 and 35 days in those with two episodes and 42 and 48 days in the two patients with three episodes. In the 36 patients with single episodes, the most frequent cause of monomicrobial bacteremia (29 episodes) was Staphylococcus epidermidis (18 isolates); the other microorganisms isolated are shown in Table 1. The remaining seven episodes showed a polymicrobial etiology, with two microorganisms in the same sample (Table 1). In the 24 patients with multiple episodes, the most frequent cause of monomicrobial bacteremia (29 episodes) was Staphylococcus epidermidis (15 isolates), the other microorganisms are shown in Table 1. The remaining 21 episodes showed a polymicrobial etiology, due to the presence, in 19 episodes, of two microorganisms in the same sample
688
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Bacteremia in hematologic patients
TABLE 1. - Microorganisms causing bacteremia in neutropenic patients. Single episodes
Multiple episodes
Monomicrobial
Polymicrobial
Monomicrobial
Polymicrobial
Staphylococcus epidermidis
18
6
15
12
Staphylococcus aureus
3
2
3
5
Streptococcus viridans
3
1
2
6
Streptococcus faecalis
-
-
2
4
1
Streptococcus pneumoniae
1
-
2
1
1
Serratia marcescens
-
-
1
Clostridium difficile
-
-
Escherichia co#
2
2
7
-
2
1
6
-
-
1
2
-
1
1
Peptostreptococcus anaerobius Bacteroides fragilis Corynebacterium
1
" -
1
CDC-JK Propionibacterium
1
species
and, in 3 episodes, of 3 microorganisms. The bacterial agents are shown in Table 1. The sources of bacteremia are listed in Table 3. Infections originating from the intravascular catheter were the most common (20 cases, 12 with exit site infection and 8 with tunnel infection), followed by those with an upper respiratory tract source (14 cases) and skin-soft tissue (9 cases). In 23 episodes the source of bacteremia could not be determined. b) Group B - Non-neutropenic patients (Table 2): Thrifty-one episodes of bacteremia occurred in 30 patients: 29 of them presented a single episode and one had two episodes. In patients with a single episode the most frequent cause of monomicrobial bacteremia was Staphylococcus epidermidids (14 isolates); the other microorganisms are shown in Table 2. In the patient with two episodes ofbacteremia, Staphylococcus aureus was isolated in one episode and E. coli and Bacteroides fragilis were isolated in the other. The sources of bacteremia are listed in Table 3. Infections
originating from the genito-urinary tract were the most common (14 cases), followed by those from the upper respiratory tract (5 cases). One intravascular catheter source was due to septic thrombophlebitis. In 6 episodes of bacteremia, the source could not be determined. Statistical analysis The groups ofneutropenic patients showed a high incidence of multiple (x 2 = 13.4; p < 0.0001) and plymicrobial (x 2 = 10.7; p = 0.001) bacteremias. Conversely, in non-neutropenic patients, the risk of developing multiple episodes of bacteremia was 19.3 (95% C.I. 2.46-151.2), while the risk of developing a polymicrobial bacteremia was 14.7 (95% C.I. 1.87115.3). A positive association also emerged between polymicrobial bacteremia and multiple episodes (x 2 = 4.85; p = 0.028) and between polymicrobial bacteremia and isolation of anaerobic microorganisms (x 2 = 5.39; p = 0.02).
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TABLE 2. - Microorganisms causing bacteremia in non-neutropenic patients. Single episodes Monomicrobial
Staphylococcus epidermidis Staphylococcus aureus Streptococcus faecalis Escherichia coil Proteus mirabilis Bacteroides fragilis
Multiple episodes Monomicrobial
Polymicrobial
Polymicrobial
14
4 5
2 3
TABLE 3. - Sources of Bacteremia. Group A
Group B
neutropenic patients
non-neutropenic patients
Source
Genitourinary tract
4
4.60%
Upper respiratory tract Gastrointestinal tract Pneumonia Intravascular catheter
14 5 6 20
16.20% 5.80o/0 6.90% 23.20o/0
Skin-soft tissue Multiple Unknown origin
9 5 23
10.40% 5.80O/o 26.74%
DISCUSSION
Despite the use of antimicrobial prophylaxis and antibacterial combination therapy, patients receiving cytotoxic therapy or bone marrow transplants are subject to high risk of bacterial infection and breakthrough bacteremia. The isolation of microorganisms from bacteremic patients is necessary and must be performed very early to test susceptibility to antimicrobial agents in order to design the best treatment. A microbiological diagnosis is often difficult in these patients, due to the presence of antimicrobial agents in their blood. Such agents are transferred into the culture bottle with the blood sample and can thus suppress or slower bacterial growth. In fact, blood cultures from patients undergoing antibacterial therapy show a lower
14 5
45.10% 16.10%
1 3 1 1
3.20°/0 9.60% 3.20O/o 3.20%
6
19.35%
x2 = 28.7 P < 0.0001
x2 = 6.2 p = 0.013
recovery rate of bacteria than positive blood cultures from patients that are not (15). Therefore, bacterial suppression is related to the level of antibacterial activity in blood samples and to the susceptibility or resistance of the microorganisms to antimicrobial agents. To improve the recovery of bacteria from blood cultures, blood samples must be taken when the antimicrobial concentrations are expected to be at their lowest level, just before the administration of the antimicrobial therapy. We used the NR 660 system, because in several studies (12, 2) it has been proven to provide a quicker means of detection of positive blood cultures and a more acceptable level of reliability than conventional system as well. Moreover, we used Bactec resin-containing blood culture media because they are superior to non-resin broth media for the isolation of bacteria from the blood of patients
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receiving a high-antibiotic-concentration regimen. That is due to the ability of such resin to remove or neutralize various antibiotics in the blood samples (17, 20). Our data provide evidence of a higher incidence of multiple (x 2 = 13.4 p = 0.0001 OR = 19.3 95% C.I. 2.46-151.2) and polymicrobial bacteremia (x 2 = 10.7 p = 0.001 OR= 14.7 95% CI 1.87-115.3) in the group of neutropenic patients, indicating that these subjects are at higher risk. In 24/60 neutropenic patients, multiple episodes o f bacteremia were observed, while only one out of 30 non-neutropenic patients present multiple episodes. In 24 neutropenic patients with multiple episodes, 22 had two episodes of bacteremia, while 2 patients presented three episodes. This difference in the course of bacteremia was related to the grade and duration of neutropenia. The higher incidence of episodes o f polymicrobial bacteremia in neutropenic (29/86) than in non-neutropenic patients (1/30) is likely to be due to the frequent occurrence of cutaneous and mucosal lesion in neutropenic patients. These lesions can allow the passage of more than one microorganism into the bloodstream. Polymicrobial bacteremia was more frequent in neutropenic patients with multiple episodes than in those with single episodes ( x 2 = 4.85 p = 0.028 O R = 3 950/0 C.I. 1.1-8.1). Moreover, it is of interest that anaerobic microorganisms were isolated more frequently in polymicrobial episodes than in monomicrobial episodes (x 2 = 5.39 p = 0.02 OR = 2.97 95% C.I. 1.27.7). Both in the two groups and in the different types of bacteremia, the aerobic gram-positive cocci were the microorganisms most frequently isolated (71.6%). An increased incidence of gram-positive microorganisms in patients with hematological neoplasms has been already reported (14, 19, 22). According to others (6, 23), the lack o f Pseudomonas bacteremia could be due to the difficulty in recovering these bacteria from the blood o f patients treated with Ciprofloxacin or Ofloxacin. A high number of episodes of bacteremia by Staphylococcus epidermidis was seen in both groups of patients, even though the sources of infection were different. Concerning the sources of bacteremia, a different behaviour was observed in the two groups. The intravascular catheter was the most c o m m o n source (23.20/0) in neutropenic patients, followed by the upper respiratory tract (16.20/0) and skin or soft tissues (10.4°/0). A multiple source was seen in 5 episodes (5.8%). In non-neutropenic patients the most c o m m o n source was the genito-urinary tract (45.1%) followed by the upper respiratory tract (16.1%) while a multiple source of bacteremia was never seen. These results suggest that blood culture samples should be taken immediately when bacteremia is suspected because of the occurrence of fever, and an empirical therapy is then started without delay. The best choice o f antimicrobial agents should be based on the knowledge of the current local ecology and of the antibiotic resistance patterns of endemic strains of bacteria.
Acknowledgement
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