acute leukemia: a review of twenty years'...

1022

Changing Patterns of Blood Culture Isolates from Patients with

Acute Leukemia: A Review of Twenty Years' Experience

Hisashi FUNADA, Toshihiko MACHI and Tamotsu MATSUDA

The Protected Environment Unit and Third Department of Medicine,Kanazawa University School of Medicine, Kanazawa 920, Japan

(Received: March 5, 1992)(Accepted: March 16, 1992)

Key words: acute leukemia, blood cultures, bacteremia, Pseudomonas aeru-

ginosa, cross-infection

Abstract

During the 20-year period, 1972-1991, 286 episodes of bacteremia occurred in 200 (45%) of 445 patientswith acute leukemia in a hematology ward, giving an incidence of 482 episodes per 1,000 hospitaladmissions. The frequency of bacteremia was almost unchanged throughout the study period. Thefrequency of gram-negative bacilli decreased significantly, however, from 81% of all the isolates for the firsthalf of the study period to 50% for the latter half. Despite the common use of ceftazidime and imipenemduring the last 5-year period, Pseudomonas aeruginosa increased in frequency to be the most frequentorganism. This was opposite to the decreased frequencies of Escherichia coli, Klebsiella pneumoniae andEnterobacter cloacae. The isolates of P. aeruginosa obtained during this period, all of which proved sensitiveto ceftazidime and/or imipenem, were almost equally distributed among five serogroups, although atemporal preponderance of a limited number of serogroups was observed during the preceding 15-year

period. On the other hand, the frequency of gram-positive cocci increased from 9% in the first decade to 35%in the latter decade. Staphylococcus epidermidis, Enterococcus species and, to a lesser extent, Staphylococcusaureus were ranked as major pathogens. Among the recent isolates of S. aureus, methicillin-resistantstrains virtually replaced methicillin-sensitive ones. Therefore, until more effective ective means for control of P.aeruginosa bacteremia in particular become available, the occurrence of this infection will continue to limitthe successful treatment of acute leukemia.

Introduction

Advances in the fields of chemotherapy and bone marrow transplantation have remarkably improvedthe prognosis of patients with acute leukemial). Despite the therapeutic or prophylactic use ofantimicrobial agents, however, bacteremia remains a frequent complication with serious morbidity andmortality during remission induction2-4). We have already pointed out that gram-positive cocci showed atendency to predominate among our recent blood culture isolates, with a consequent decreasing frequencyof gram-negative bacilli4>. This report summarizes our experience with bacteremia complicating acuteleukemia at the Third Department of Medicine, Kanazawa University Hospital over the 20-year period,1972-1991, focusing not only on the incidence of bacteremia but also the spectrum of causative organisms

particularly during the last 5-year period.

別刷請求先:(〒920)金沢市宝町13番1号

金沢大学医学部附属病院高密度無菌治療

部舟田久

感染症学雑誌第66巻第8号

BacteremiaComplicatingAcuteLeukemia 1023

Materials and Methods

PatientsThere were 593 periods spent in hospital for 445 patients with acute leukemia (346 with acute

nonlymphocytic leukemia and 99 with acute lymphocytic leukemia) for remission induction during the twodecades, 1972-1991. Patient ages ranged from eight to 86 years (median, 45 years), and 245 (55%) were male.All patients were treated on one 40-bed hospital floor.

Schedules for antileukemic induction therapy were essentially unchanged during this period5,6).Patients receiving intensive chemotherapy were neutropenic below 5004i1 for at least three weeks. Since1982, three courses of consolidation therapy have been carried out on patients achieving completeremission of their leukemia6). Bone marrow transplantation was conducted in 48 patients with acuteleukemia, who were placed in laminar flow isolation and received sterilized food7). During the last 4-year

period, only a small series of patients with acute lymphocytic leukemia received recombinant humangranulocyte colony-stimulating factor (G-C SF) at a daily dose of 75 ,ug/body in order to shorten the period ofchemotherapy-induced neutropenia8). In this preliminary study, the first course of intensive chemotherapywithout G-CSF was followed by subsequent ones with G-CSF.

All patients who were anticipated to have neutropenia of below 500/,ul received antifungal prophylaxiswith oral nystatin or amphotericin B for the length of their stay in hospital.

Since 1980, long-term central venous access has often been used in patients requiring chemotherapeu-tic agents, antibiotics, blood products, and parenteral nutrition9).

Suspected as well as documented infections were usually treated with a /3-lactam antibiotic and anaminoglycoside in combination. First-generation cephems, such as cephalothin and cefazolin, andcarboxypenicillins, such as carbenicillin and sulbenicillin, which were commonly used from 1972 to 1981,were in most cases switched thereafter to second- and third-generation cephems, such as cefmetazole andlatamoxef, and ureidopenicillins, such as piperacillin. Since 1987, ceftazidime (a third-generation cephem)and imipenem (a carbapenem), both of which have more potent antipseudomonal activity, have also beencommonly used on the ward. Gentamicin, and less frequently, amikacin were used throughout the study

period. Moreover, neutropenic patients with fever persisting after four to seven days of such antibacterialtherapy were treated with additional intravenous amphotericin B or fluconazole.Bacteremia

The diagnosis of bacteremia was based on at least one positive blood culture from a patient with aconsistent clinical setting. Polymicrobial bacteremia was defined as the recovery of more than oneorganism from the blood during any one-week periodo.Blood cultures

Blood cultures were carried out as described elsewhere. The organisms isolated were identified by thecriteria of Cowan and Steel10) and also according to the description in the Bailey & Scott's DiagnosticMicrobiology11>. In order to investigate the probable occurrence of nosocomial infections by a limitednumber of strains, Pseudomonas aeruginosa isolates were serogrouped using commercially available sera

(Pseudomonas aeruginosa antisera, Denka Seiken)12).Antimicrobial sensitivities were determined by a triple disk method using Tridisks (Eiken). The

results were expressed in a four-graded rating of sensitivity from -to +I+. The isolates showing -I+ and 4I-were classified as sensitive, and those showing -and + as resistant. Methicillin-resistant Staphylococcusaureus (MRSA) strains were defined according to the criteria described by Yokota13> as those showingresistance at 37C and sensitivity at 43C to latamoxef and/or ceftizoxime after overnight incubation onMueller-Hinton agar (BBL).Statistics

平成4年8月20日

1024 Hisashi FUNADA et al

Differences in proportions were evaluated using Yates' x2 analysis, and means were compared usingStudent's t-test.

Results

Incidence of bacteremiaDuring a 20-year period, 286 episodes of bacteremia were documented in 200 (45%) of a total of 445

patients with acute leukemia admitted to our department [ 159 (46%) of 346 with acute nonlymphocyticleukemia and 41 (41%) of 99 with acute lymphocytic leukemia), which gives an average of 1.4 episodes per

patient (Table 1). The distribution of these patients with bacteremia by age, sex and leukemic type did notdiffer materially from that of the total patient population with acute leukemia. The overall incidence ofbacteremia during this study period was 482 episodes per 1,000 hospital admissions (286 episodes occurringduring 593 periods in hospital). Moreover, polymicrobial bacteremia occurred in 42 episodes (15%).

Considering the change in the type of 13-lactam antibiotics commonly used at our department, thestudy period was divided into three parts: the first 10-year period, 1972-1981, for first-generation cephemsand carboxypenicillins, the second 5-year period, 1982-1986, for second- and third-generation cephems andureidopenicillins, and the last 5-year period, 1987-1991, represented by both ceftazidime and imipenembecause of their more specific activity against P. aeruginosa (Table 1). The three patient groups weresimilar with respect to age, sex and leukemic type.

There was no statistically significant difference in the percentage of patients with bacteremia, in thedistribution of patients with bacteremia by age and sex, or in the incidence of polymicrobial bacteremiaamong the three periods. Furthermore, the frequency of bacteremia per patient remained almost the samethroughout the study period. Thus, the changes in the frequency of bacteremia per 1,000 hospitaladmissions were less marked than initially apparent (435 episodes for the first period compared with 523and 492, respectively, for the second and last periods).Blood culture isolates

A total of 336 blood culture isolates were obtained from all the episodes of bacteremia over the 20-year

period (Table 2). The isolates as well as the episodes were almost equally distributed among the threeperiods mentioned above. Aerobic gram-negative bacilli were the most frequent organisms, accounting for60% of all the isolates, followed in frequency by aerobic gram-positive cocci (27%), anaerobes (9%), Candidaspecies (3%) and aerobic gram-positive bacilli (2%). This order of frequency was essentially unchanged

Table 1 Frequency of bacteremia in patients with acute leukemia

1) Patients with multiple episodes are included only once .


Bacteremia Complicating Acute Leukemia 1025

Table 2 Changing patterns of blood culture isolates from patients with acute leukemia

throughout the study period.

As described in our previous reporto, there was a great change in the spectrum of blood culture isolates

between the first and second periods, which coincided with the common use of second- and third-generation

cephems and central venous catheters. Briefly, the frequency of gram-negative bacilli decreased

significantly from 81% of all the isolates for the first period to 50% for the second period, whereas the

frequency of gram-positive cocci increased from 9% to 36%. Escherichia coli and Klebsiella pneumoniae were

isolated in markedly decreasing frequency, but P. aeruginosa and Enterobacter cloacae in relatively constant

frequency, while Staphylococcus epidermidis, Enterococcus species and S. aureus emerged as important

pathogens.The relative frequency of individual species or groups of blood culture isolates did not change

平成4年8月20日


Table 3 Distribution of serogroups of P.

aeruginosa isolates, by 5-year periods

1) Serogroups recommended by the Japan Pseudomonas

aeruginosa Society12)

markedly when the second and last 5-year periods were compared. During the last period, however, P.aeruginosa increased in frequency and became the most frequent organism (23 isolates, 21%), althoughother gram-negative bacilli, especially E. coli (nine isolates, 8%), E. cloacae (four isolates, 4%) and K.

pneumoniae (three isolates, 3%) decreased further in frequency. With regard to the isolates of gram-positivecocci, the frequency of S. aureus increased only slightly throughout the study period in contrast to S.epidermidis and Enterococcus species which showed a marked increase in frequency. Four of the fiveisolates of S. aureus found during the last period were classified as methicillin-resistant, as compared withonly one of the seven in the second period. Among the 14 isolates of Enterococcus species found during thelast period, seven belonged to Enterococcus faecium, six to Enterococcus faecalis and one to Enterococcusavium. This pattern was similar to that seen during the second period (seven isolates of E. faecalis and sixof E. faecium). Anaerobic, non-spore-forming gram-negative bacilli, including Bacteroides species andFusobacterium nucleatum, accounted for the majority of anaerobic isolates throughout the study period.Among Candida species, Candida albicans comprised only one-third.

The frequency of individual species or groups of organisms found in polymicrobial bacteremia was

similar to their frequency of occurrence in monomicrobial bacteremia.Serogrouping of P. aeruginosa isolates

A total of 58 isolates of P. aeruginosa were obtained from 57 episodes of bacteremia in our hospital wardduring the 20-year period. All but two isolates belonged to nine serogroups (Table 3). Serogroups E, B, Gand I were most prevalent, accounting for 76% (44 isolates). Serogroup I was most frequently isolatedduring the first quarter of the study period, 1972-1976, followed by serogroups B and E in successionduring the second and third quarters, 1977-1981 and 1982-1986, respectively, while all but one isolateobtained during the last quarter, 1987-1991, were almost equally distributed among serogroups A, B, E, Gand I. Incidentally, all of the 23 isolates obtained during the last quarter were sensitive to ceftazidimeand/or imipenem.

Discussion

The frequency of bacteremia, whether monomicrobial or polymicrobial, in our patients with acute



leukemia was almost unchanged during the 20-year period, 1972-1991. Overall, 45% of the patient

population with acute leukemia had an average of 1.4 episodes of bacteremia per patient, giving anincidence of 482 episodes per 1,000 hospital admissions, which corresponds to an about 40-fold higherincidence than that for internal illnesses other than severe hematologic disorders4>. The major changes in

patient care, including central venous access, consolidation therapy and antibiotics used, did not have anyapparent influence on the incidence of bacteremia in our hospital ward. Likewise, Armstrong and hiscolleagues2,3) reported that the incidence of bacteremia in patients with hematologic neoplasms orneutropenia at Memorial Sloan-Kettering Cancer Center was about the same between the study in 1972and that in 1982. Their patients also had an average of 1.4 episodes of bacteremia per patient. Such a highincidence of bacteremia in patients with acute leukemia is considered, therefore, to reflect an unremittingleukemic process and/or profound prolonged neutropenia. In this sense, as Ohno et al.14> reported, theadministration of G-CSF is expected to materially reduce the incidence of infectious complications byaccelerating recovery from chemotherapy-induced neutropenia. There is, however, some concern thattreatment with G-CSF may result in an increase in leukemic blast cells in the bone marrow of patientswith acute myelogenous leukemia15>, although no unequivocal evidence for this has yet been reported14,16).

We have already reported a great change in the spectrum of blood culture isolates between the first10-year and second 5-year periods4). The relative frequency of individual species or groups of organisms didnot change substantially, however, when the second and last 5-year periods were compared. Nevertheless,the spectrum of organisms during the last period changed in that P. aeruginosa increased in frequency to bethe most frequent organism in marked contrast with the decreased frequencies of E. coli, K pneumoniaeand E. cloacae. Such a consequence was opposite to what had been expected from the common use ofceftazidime and imipenem on our ward, both of which have the most potent activity against P. aeruginosaamong the currently available f3-lactam antibiotics. Indeed all of the P. aeruginosa isolates obtained duringthe last period proved sensitive to either of the drugs. This may indicate either the necessity of more activeantibiotics for control of P. aeruginosa bacteremia or the difficulty in eradicating the infection by means ofeffective drugs alone. Incidentally, the clinical settings in which this organism can be anticipated havebeen well described in patients with hematologic malignancy17,18.

The isolates of P. aeruginosa obtained during the last 5-year period were almost equally distributedamong five serogroups, although a temporal preponderance of a limited number of serogroups was observedduring the preceding 15-year period. Colonization with P. aeruginosa in patients with acute leukemia isoften related to the subsequent development of bacteremia18-20). Reducing the acquisition of the organismfrom the hospital environment is, therefore, most urgent for preventing infection. Attention should bedrawn, however, to the recent of Brun-Buisson et al.21> that patients in intensive care units receivingintestinal decontamination with oral nonabsorbable antibiotics were more likely to have rectal overgrowthof resistant strains than the control patients not receiving antibiotics. Moreover, rectal concentrations ofPseudomonas species did not differ between the two patient groups. The routine use of such antibiotics is,therefore, potentially hazardous, although intestinal decontamination proved helpful in preventingendemic nosocomial infections21).

Referecnes

1) Champlin, R. & Gale, R.P.: Acute myelogenous leukemia; recent advances in therapy. Blood 69: 1551-1562, 1987.2) Singer, C., Kaplan, M.H. & Armstrong, D.: Bacteremia and fungemia complicating neoplastic disease. A study of 364

cases. Am. J. Med. 62: 731-742, 1977.3) Whimbey, E., Kiehn, T.E., Brannon, P., Blevins, A. & Armstrong, D.: Bacteremia and fungemia in patients with

neoplastic disease. Am. J. Med. 82: 723-730, 1987.4) Funada, H., Machi, T. & Matsuda, T.: Bacteremia complicating acute leukemia with special reference to its

平成4年8月20日


incidence and changing etiological patterns. Jpn. J. Clin. Oncol. 18: 239-248, 1988.5) Yoshida, T., Hattori, K., Nakamura, S., Mitamura, E., Kobayashi, S., Ohtake, S. & Tanimoto, K.: A simple rapid

autoradiography for 3H-thymidine labeling index and its application to therapy of adult acute leukemia. Cancer 46:2298-2307, 1980.

6) Nakamura, S., Yoshida, T., Ohtake, S., Itoh, K., Kobayashi, K., Egami, K., Tanaka, K. Nakamura, E., Natori, K. &Nakagoshi, D.: New combination chemotherapy for adult acute nonlymphocytic leukemia. J. Jpn. Soc. Cancer Ther.20: 2314-2321, 1985.

7) Funada, H., Machi, T. & Matsuda, T.: Early infectious complications of bone marrow transplantation in totalprotective environment. Bifidobacteria Microflora 8: 75-86, 1989.

8) Yoshida, T., Nakamura, S., Ohtake, S., Okafuji, K., Kobayashi, K., Kondo, K., Kanno, M., Matano, S., Matsuda, T.,Kanai, M., Sugimoto, R., Ogawa, M. & Takaku, F.: Effect of granulocyte colony-stimulating factor on neutropeniadue to chemotherapy for non-Hodgkin's lymphoma. Cancer 66: 1904-1909, 1990.

9) Ohtake, s., Yamamura, M., Odaka, K., Teshima, H., Shiobara, S., Kobayashi, S., Matsue, K., Ishino, C., Yoshida, T.,Funada, H., Nakamura, S., Hattori, K. & Harada, M.: Application of central venous access and intravenoushyperalimentation to the management of patients with hematologic malignancy. Jpn. J. Clin. Hematol. 22: 1720-1728, 1981.

10) Cowan, S. T. & Steel, K J.: Manual for the Identification of Medical Bacteria. Cambridge University Press, London,1973.

11) Baron, E J. & Finegold, S. M.: Bailey & Scott's Diagnostic Microbiology, 8th ed. Mosby, St. Louis, 1990.12) Homma, J. Y.: Designation of thirteen O-group antigens of Pseudomonas aeruginosa: an amendment for the tentative

proposal in 1976. Jpn. J. Exp. Med. 52: 317-320, 1982.13) Yokota, T.: Infection due to MRSA. J. Med. Technol. 32: 770-775, 1988.14) Ohno, R., Tomonaga, M., Kobayashi, T., Kanamaru, A., Shirakawa, S., Masaoka, T., Omine, M., Oh, H., Nomura,

T., Sakai, Y., Hirano, M., Yokomaku, S., Nakayama, S., Yoshida, Y., Miura, A. B., Morishima, Y., Dohy, H., Niho, Y.,Hamajima, N. & Takaku, F.: Effect of granulocyte colony-stimulating factor after intensive induction therapy inrelapsed or refractory acute leukemia. N. Engl. J. Med. 323: 871-877, 1990.

15) Souza, L. M., Boone, T. C., Gabrilove, J. L., Lai, P. H., Zsebo, K. M., Murdock, D. C., Chazin, V. R., Bruszewski, J., Lu,H., Chen, K., Barendt, J., Platzer, E., Moore, M. A. S., Mertelsmann, R. & Welte, K.: Recombinant human granulocytecolony-stimulating factor: effects on normal and leukemic myeloid cells. Science 232: 61-65, 1986.

16) Kobayashi, Y., Okabe, T., Ozawa, K., Chiba, S., Hino, M., Miyazono, K., Urabe, A. & Takaku, F.: Treatment ofmyelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor: a preliminary report.Am. J. Med. 86: 178-182, 1989.

17) Funada, H., Machi, T. & Matsuda, T.: Pseudomonas aeruginosa bacteremia associated with hematologic disorders.

[I] Predisposing factors and clinical manifestations. J. Jpn. Assoc. Infect. Dis. 63: 867-873, 1989.18) Funada, H., Machi, T. & Matsuda, T.: Pseudomonas aeruginosa bacteremia associated with hematologic disorders.

[II] Blood culture isolates and surveillance cultures. J. Jpn. Assoc. Infect. Dis. 63: 874-879, 1989.19) Bodey, G. P.: Epidemiological studies of Pseudomonas species in patients with leukemia. Am. J. Med. Sci. 260: 82-89,

1970.20) Schimpff, S. C., Greene, W. H., Young, V. M. & Wiernik, P. H.: Significance of Pseudomonas aeruginosa in the patient

with leukemia or lymphoma. J. Infect. Dis. 130 (Suppl.): S24-S31, 1974.21) Brun-Buisson, C., Legrand, P., Rauss, A., Richard, C., Montravers, F., Besbes, M., Meakins, J. L., Soussy, C. J. &

Lemaire, F.: Intestinal decontamination for control of nosocomial multiresistant gram-negative bacilli: study of anoutbreak in an intensive care unit. Ann. Intern. Med. 110: 873-881, 1989.



過去20年間における急性白血病患者からの血液分離菌の推移

金沢大学医学部附属病院高密度無菌治療部・第3内科

舟田久真智俊彦松田保

(平成4年3月5日受付)

(平成4年3月16日受理)

要旨

過去20年間(1972～1991年)に,血液内科病棟

に入院した急性白血病445例のうちの200例(45%)

に286回の菌血症が発症した.菌血症の頻度は入院

1,000回あたり482回であったが,調査期間中ほぼ

変化なかった.しかし,血液分離菌のなかで,前

半の10年間に81%を占めた好気性グラム陰性桿菌

が後半の10年間には50%と有意の減少を示した.

最後の5年間は,セフタジジムとイミペネムの常

用と裏腹に,緑膿菌が血液分離菌の首位を占める

までに分離頻度が上昇した.この期間中に分離さ

れた緑膿菌菌株は5つの血清群にほぼ均等に分布

し,それまでの15年間は少数の血清群が相次いで

優勢を占めたのと対照的であった。大腸菌,クレ

ブシエラとエソテロバクターの分離頻度は緑膿菌

の場合と逆に著明に減少した.一方,好気性グラ

ム陽性球菌の頻度は前半の10年間の9%から後半

の10年間の35%へ上昇した.これとともに,表皮

ブドウ球菌,腸球菌群,さらに黄色ブドウ球菌,

とくにメチシリン耐性菌株が主要な原因菌として

位置づけられた.こうした血液分離菌の推移を考

慮すれば,とりわけ緑膿菌菌血症の制御にもっと

効果的な手段が実用化されないかぎり,本菌菌血

症が急性白血病の治療を今後も制約していくこと

になりかねない.

平成4年8月20日

acute leukemia: a review of twenty years'...

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