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Septicaemia in febrile neutropenic children with cancer in Saudi Arabia
Journal
of Hospital
Infection
(1991)
18, 307-312
SHORT
Septicaemia
REPORT
in febrile neutropenic children cancer in Saudi Arabia
I. M. Al-Fawaz, A. M. Kambal*, S. A. Al-Rasheed, Y. A. Al-Eissa
with
A. A. Al-Rabeeah**, and J. B. Familusi
Department of Pediatrics, *Microbiology and **Surgery, King University Hospital, College of Medicine, King Saud University, Saudi Arabia Accepted for publication
21 May
Khalid Riyadh,
1991
Summary: The pattern of sepsis among 56 children admitted for various forms of cancer to the King Khalid Universitv Hosnital. Rivadh. Kingdom of Saudi Arabia during a 6-year period, was retrospedtiveiy reviewed. Atotal of 148 febrile neutropenic episodes occurred and 55 of these, in 40 patients, were associated with positive blood cultures. The isolates were Grampositive bacteria in 54% of instances, Gram-negative bacteria in 39.4% and Candida in 6.6% and polvmicrobial sepsis occurred in five patients. Profound neutropenia (neutrophil-counts <0.1*X lo9 1-l) significantly predisposed to Gram-negative sepsis (I’< 0.02), which was responsible for about one-third of deaths in this series. Central venous catheters were present prior to 49% of the septicaemic episodes, but were not significantly associated with either increased Gram-negative or Gram-positive bacterial sepsis. However, all four cases of candidaemia occurred in patients with a central venous catheter in situ, and it is recommended that early empirical treatment for candida be considered in all febrile neutropenic cancer patients with central venous catheters. Keywords:
Septicaemia;
neutropenia;
central
venous
catheters.
Introduction
Septicaemia is a major consideration whenever oncology patients present with fever and neutropenia. t Studies during the early 1970s mainly identified aerobic Gram-negative bacilli, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa as the major causative agents of infection in such patients.‘z2 However, in recent years, Gram-positive organisms, especially Staphylococcus aweus and Staphylococcus epidermidis Correspondence King Khalid
to: Dr University
01954i01/91/080307+06
Ibrahim Hospital,
M.
Al-Fawaz, P.O. Box
Department 2925, Riyadh
$03.00/O
of Pediatrics 11461, Saudi
(39). College Arabia.
of Medicine
0 1991 The Hospital
307
Infectmn
and
Society
308
I. M. Al-Fawaz
et al.
have emerged as the commonest isolates. 1,3m5 The majority of infections with these organisms are hospital-acquired, and the causative organisms vary from one institution to another and change from one period to another in the same hospital. ‘~2~ Continuous monitoring of the spectrum of pathogens responsible for infections in these patients is therefore highly desirable. The present paper reports the current pattern of infections in febrile neutropenic children with cancer admitted to the King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia.
Materials
and methods
The case records of all the paediatric oncology patients admitted to the KKUH from October 1983 to September 1989 were retrospectively reviewed. Those who developed febrile neutropenic episodes were identified, and constitute the subjects for the present study. All oncology patients in our unit routinely had their temperatures and white blood counts (WBC) monitored at 4-hourly and 72-hourly intervals respectively, or more often if clinically indicated. Fever, for the purpose of the present study, was defined as a temperature of more than 38.5”C on one occasion or two readings of more than 38°C within a 24-hour period. Neutropenia was defined as an absolute neutrophil count < 0.5 x lo9 1-i; counts < O-1 X lo9 1-l were considered as ‘profound neutropenia’. A routine septic screen was performed in those patients who developed fever and/or neutropenia; it included cultures of blood, urine, stool and throat as well as other relevant investigations such as chest radiographs. Blood cultures were obtained from peripheral veins in all patients, but patients who had central venous catheters (CVC) in situ had concomitant cultures taken from these. Blood samples were inoculated into two bottles, one containing tryptic soy broth and the other thiol broth (Difco Laboratories, Michigan, USA). The cultures were incubated at 37°C for 7 days and examined daily for signs of growth. Gram’s stain was performed and subcultures were made onto blood, MacConkey and ‘chocolate’ agar plates. Isolates were identified by antibiotic therapy, following standard microbiological tests. Empirical initial investigation, consisted of either a combination of carbenicillin and gentamicin (before December 1986) or a combination of piperacillin, amikacin and cloxacillin (since December 1986). Changes were made to the antimicrobial therapy as dictated by culture results. Empirical amphotericin B therapy was added if unexplained fever persisted for more than one week, or if fungal infection was otherwise suspected. Also empirical treatment with cotrimoxazole for Pneumocystis carinii was added if the clinical situation of the patient suggested this diagnosis; lung biopsy for confirmation of the diagnosis of pneumocystis infection was not performed in any of the patients.
Septicaemia
in children
with
cancer
309
Results
A total of 79 children with various malignant tumours were admitted to our oncology unit during the period under review. Fifty-six of these (38 males and 18 females) developed episodes of fever with neutropenia during their admission and therefore satisfied the criteria for inclusion in the present study. The underlying diagnoses in the 56 study subjects were: leukaemia in 38 patients (68%), lymphoma in ten (18%) and solid tumours in eight (14%). The 56 patients had 148 episodes of fever with neutropenia. The recorded initial fever was more than 38.5”C in all the episodes, while the absolute neutrophil count (ANC) at onset of fever was < 0.1 x lo9 1-l in 50 episodes (34%) and between O*l-0.5 x lo9 1-i in 98 (66%) episodes. Fifty-five (37%) of the total 148 febrile neutropenic episodes were associated with positive blood cultures; repeated blood cultures in the remaining 93 (63 O/o)episodes were, however, consistently negative and fever in these cases was unexplained. Fifty-five documented episodes of septicaemia occurred in 40 patients, 30 of whom had one episode; seven patients had two episodes, two patients had three episodes and one patient had five episodes. In 27 (49%) of the septicaemic episodes, central venous catheters (Hickman or Broviac catheters) were in situ at the onset of sepsis. A total of 61 organisms comprising 14 species were isolated during the 55 episodes of septicaemia. Single pathogen sepsis occurred in 50 (91”/) of the episodes and polymicrobial sepsis in five (9”/). Fifty-four percent of the total isolates were Gram-positive bacteria, 39.4% were Gram-negative bacteria, while 6.6% were due to Candida albicans. The most common organisms isolated were P. aeruginosa and S. epidermidis (19.7% each), followed by Streptococcus spp. (18%). Escherichia coli was isolated in 8.2% and S. aweus and C. albicans were each responsible for four (6.6%) of the total isolates. The pattern of blood culture isolates in children with CVC in situ and those without CVC are compared in the Table, which also shows the distribution of isolates in febrile episodes during profound neutropenia and non-profound neutropenia. Statistical analysis using the X2-test shows that there were no significant differences between episodes with CVC compared with those without CVC, either in respect of the overall incidence of sepsis or the isolation of Gram-positive and Gram-negative organisms h2=0.5123; P>O.4). Eight of 12 patients with S. epidermidis sepsis had CVC in situ at the onset of sepsis compared with 19 of 43 patients with other organisms but this difference was not significant (P>O*O5). Profound neutropenia was present in five out of 12 episodes (42%) of S. epidermidis sepsis compared with 20 out of 43 septic episodes (46.5%) caused by other pathogens, but this was not significantly different (P> 0.1). However, all the candida isolates were associated with a CVC, and febrile episodes associated with profound neutropenia had a significantly higher proportion
310
I. M. Al-Fawaz et
al.
Septicaemia
in children
with cancer
311
of Gram-negative organisms than episodes associated with non-profound neutropenia (PC 0.02). Management was successful in 71% of the episodes of sepsis (39 of 55) in that the fever resolved, the ANC increased to > 0.5 x lo9 l-i, and follow-up blood cultures were sterile within 7 days of starting appropriate antibiotics. Four patients who had CVC in situ remained febrile despite appropriate antibiotic therapy, until their central venous catheters were removed. The isolates from the CVC in these patients were C. albicans (two cases), S. epidermidis (one case) and E. coli (one case). Twelve patients died. Six of the deaths occurred in patients whose neoplasms were in relapse; these were leukaemia (three cases), lymphoma (two cases) and stage IV solid tumour (one case). The other six deaths occurred in children who were in remission at the time of death. Three of these had pseudomonas septicaemia; one had sepsis with Serratia marcescens and viridans streptococci, another had klebsiella septicaemia and pneumonia, and the last had systemic candidiasis. Discussion
This retrospective review clearly indicates that septicaemia is of paramount importance in oncology children who present with fever and neutropenia in our unit. Our findings are, in general, in agreement with previous reports differences are from other parts of the world, 2-5,7 but some significant apparent when our findings are compared with other studies. For example, Gram-positive organisms were generally less common in our patients than in some of the recent reports from Western countries,3-5’7 and S. epidermidis, which is now the predominant isolate from febrile neutropenic cancer patients in these countries,3m5 was isolated from only 30% of our septicaemic patients. On the other hand, Gram-negative organisms, particularly P. aeruginosa, which has declined considerably in incidence during the 1980s in Western countries,‘p3-’ was a major cause of septicaemia and death among our patients. We were unable to find any reasonable explanations for these important differences, and the subject is worthy of further studies. Some previous studies have associated S. epidermidis sepsis with long-term usage of CVC,8,9 while others3-’ dispute such an association. In the present series, S. epidermidis was more commonly isolated from patients in whom CVCs were present than in patients without CVCs, but the difference was not significant. Future studies with larger series are required for the clarification of this point. Also, in contrast to findings in other studies,3 profound neutropenia did not significantly predispose to S. epidermidis sepsis in our patients. However, our patients with profound neutropenia revealed a significant predisposition to Gram-negative sepsis, which was a major cause of death in the present series. The probability of CVC predisposing to candidaemia is currently gaining attention and was
312
I. M. Al-Fawaz
et
al.
recently reviewed by Walsh & Pizzo. lo The fact that all four candida isolates in the present series were from patients with CVC in situ is therefore noteworthy. Previous authors have recommended empirical therapy with amphotericin B in patients with persistent fever on clinical suspicion of fungal sepsis after a period of 5-7 days or in the presence of rapid clinical deterioration.‘B7,” We recommend that a special search for fungal infection should be undertaken routinely in all febrile neutropenic patients with CVC in situ and, as has been suggested for adult patients in a recent report from our hospital, l1 that empiric amphotericin B should be commenced if fever persists for more than 72 hours despite broad spectrum antibiotic therapy. We wish to thank Dr Hassan M. Bahakim for permission to review Miss Gloria Palacay for her secretarial assistance in the preparation
some of his patients of this manuscript.
and
References 1. Pizza PA. After empiric therapy: what to do until the granulocyte comes back. Rev Infect Dis 1987; 9: 214-219. 2. Pizzo PA,, Robichaud KJ, Wesley R, Commers JR. Fever in the pediatric and young adult patients with cancer: a prospective study of 1001 episodes. Medicine (Baltimore) 1982; 61: 153-156. 3. Wade JC, Schimpff SC, Newman KA, Wiernick PH. Staphylococcus epidermidis. An increasing cause of infection in patients with granulocytopenia. Ann Intern Med 1982; 97: 503-508. 4. Friedman LE, Brown AE, Miller DR, Armstrong D. Staphylococcus epidermidis septicemia in children with leukemia and lymphoma. Am J Dis Child 1984; 138: 715-719. 5. Langley J, Gold R. Sepsis in febrile neutropenic children with cancer. Pediatr Infect Dis J 1988; 7: 34-37. 6. Schimpff SC, Young VM, Greene WH, Vermeulen GD, Moody MR, Wiernik PH. Origin of infection in acute non-lymphocytic leukemia. Significance of hospital acquisition of potential pathogens. Ann Intern Med 1972; 77: 707-714. J. Concept of empiric therapy with antibiotic combinations. Indications and 7. Klastersky limits. AmY Med 1986; 80 (Suppl. SC): 2-12. and fungemias in oncology patients 8. Lowder JN. Lazarus HM, Herzig RH. Bacteremias with central venous catheters. Arch Intern Med 1982; 142: 1456-1459. ED, Wald ER, Nelson KA, Spiegelman KN. Broviac catheter-related 9. Shapiro bacteremia in oncology patients. Am J Dis Child 1982; 136: 679-681. fungal infections: A classification for hospital acquired 10. Walsh TJ, Pizzo PA. Nosocomial fungal infections and mycoses arising from endogenous flora or reactivation. Ann Rev Microbial 1988; 42: 517-545. CR, Zeoitany RG. Infectious complications 11. El Saghir NS, Hall AD, Santhosh-Kumar during therapy of acute leukemia in Saudi Arabia. J Hasp Infect 1989; 14: 2099215.
of Hospital
Infection
(1991)
18, 307-312
SHORT
Septicaemia
REPORT
in febrile neutropenic children cancer in Saudi Arabia
I. M. Al-Fawaz, A. M. Kambal*, S. A. Al-Rasheed, Y. A. Al-Eissa
with
A. A. Al-Rabeeah**, and J. B. Familusi
Department of Pediatrics, *Microbiology and **Surgery, King University Hospital, College of Medicine, King Saud University, Saudi Arabia Accepted for publication
21 May
Khalid Riyadh,
1991
Summary: The pattern of sepsis among 56 children admitted for various forms of cancer to the King Khalid Universitv Hosnital. Rivadh. Kingdom of Saudi Arabia during a 6-year period, was retrospedtiveiy reviewed. Atotal of 148 febrile neutropenic episodes occurred and 55 of these, in 40 patients, were associated with positive blood cultures. The isolates were Grampositive bacteria in 54% of instances, Gram-negative bacteria in 39.4% and Candida in 6.6% and polvmicrobial sepsis occurred in five patients. Profound neutropenia (neutrophil-counts <0.1*X lo9 1-l) significantly predisposed to Gram-negative sepsis (I’< 0.02), which was responsible for about one-third of deaths in this series. Central venous catheters were present prior to 49% of the septicaemic episodes, but were not significantly associated with either increased Gram-negative or Gram-positive bacterial sepsis. However, all four cases of candidaemia occurred in patients with a central venous catheter in situ, and it is recommended that early empirical treatment for candida be considered in all febrile neutropenic cancer patients with central venous catheters. Keywords:
Septicaemia;
neutropenia;
central
venous
catheters.
Introduction
Septicaemia is a major consideration whenever oncology patients present with fever and neutropenia. t Studies during the early 1970s mainly identified aerobic Gram-negative bacilli, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa as the major causative agents of infection in such patients.‘z2 However, in recent years, Gram-positive organisms, especially Staphylococcus aweus and Staphylococcus epidermidis Correspondence King Khalid
to: Dr University
01954i01/91/080307+06
Ibrahim Hospital,
M.
Al-Fawaz, P.O. Box
Department 2925, Riyadh
$03.00/O
of Pediatrics 11461, Saudi
(39). College Arabia.
of Medicine
0 1991 The Hospital
307
Infectmn
and
Society
308
I. M. Al-Fawaz
et al.
have emerged as the commonest isolates. 1,3m5 The majority of infections with these organisms are hospital-acquired, and the causative organisms vary from one institution to another and change from one period to another in the same hospital. ‘~2~ Continuous monitoring of the spectrum of pathogens responsible for infections in these patients is therefore highly desirable. The present paper reports the current pattern of infections in febrile neutropenic children with cancer admitted to the King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia.
Materials
and methods
The case records of all the paediatric oncology patients admitted to the KKUH from October 1983 to September 1989 were retrospectively reviewed. Those who developed febrile neutropenic episodes were identified, and constitute the subjects for the present study. All oncology patients in our unit routinely had their temperatures and white blood counts (WBC) monitored at 4-hourly and 72-hourly intervals respectively, or more often if clinically indicated. Fever, for the purpose of the present study, was defined as a temperature of more than 38.5”C on one occasion or two readings of more than 38°C within a 24-hour period. Neutropenia was defined as an absolute neutrophil count < 0.5 x lo9 1-i; counts < O-1 X lo9 1-l were considered as ‘profound neutropenia’. A routine septic screen was performed in those patients who developed fever and/or neutropenia; it included cultures of blood, urine, stool and throat as well as other relevant investigations such as chest radiographs. Blood cultures were obtained from peripheral veins in all patients, but patients who had central venous catheters (CVC) in situ had concomitant cultures taken from these. Blood samples were inoculated into two bottles, one containing tryptic soy broth and the other thiol broth (Difco Laboratories, Michigan, USA). The cultures were incubated at 37°C for 7 days and examined daily for signs of growth. Gram’s stain was performed and subcultures were made onto blood, MacConkey and ‘chocolate’ agar plates. Isolates were identified by antibiotic therapy, following standard microbiological tests. Empirical initial investigation, consisted of either a combination of carbenicillin and gentamicin (before December 1986) or a combination of piperacillin, amikacin and cloxacillin (since December 1986). Changes were made to the antimicrobial therapy as dictated by culture results. Empirical amphotericin B therapy was added if unexplained fever persisted for more than one week, or if fungal infection was otherwise suspected. Also empirical treatment with cotrimoxazole for Pneumocystis carinii was added if the clinical situation of the patient suggested this diagnosis; lung biopsy for confirmation of the diagnosis of pneumocystis infection was not performed in any of the patients.
Septicaemia
in children
with
cancer
309
Results
A total of 79 children with various malignant tumours were admitted to our oncology unit during the period under review. Fifty-six of these (38 males and 18 females) developed episodes of fever with neutropenia during their admission and therefore satisfied the criteria for inclusion in the present study. The underlying diagnoses in the 56 study subjects were: leukaemia in 38 patients (68%), lymphoma in ten (18%) and solid tumours in eight (14%). The 56 patients had 148 episodes of fever with neutropenia. The recorded initial fever was more than 38.5”C in all the episodes, while the absolute neutrophil count (ANC) at onset of fever was < 0.1 x lo9 1-l in 50 episodes (34%) and between O*l-0.5 x lo9 1-i in 98 (66%) episodes. Fifty-five (37%) of the total 148 febrile neutropenic episodes were associated with positive blood cultures; repeated blood cultures in the remaining 93 (63 O/o)episodes were, however, consistently negative and fever in these cases was unexplained. Fifty-five documented episodes of septicaemia occurred in 40 patients, 30 of whom had one episode; seven patients had two episodes, two patients had three episodes and one patient had five episodes. In 27 (49%) of the septicaemic episodes, central venous catheters (Hickman or Broviac catheters) were in situ at the onset of sepsis. A total of 61 organisms comprising 14 species were isolated during the 55 episodes of septicaemia. Single pathogen sepsis occurred in 50 (91”/) of the episodes and polymicrobial sepsis in five (9”/). Fifty-four percent of the total isolates were Gram-positive bacteria, 39.4% were Gram-negative bacteria, while 6.6% were due to Candida albicans. The most common organisms isolated were P. aeruginosa and S. epidermidis (19.7% each), followed by Streptococcus spp. (18%). Escherichia coli was isolated in 8.2% and S. aweus and C. albicans were each responsible for four (6.6%) of the total isolates. The pattern of blood culture isolates in children with CVC in situ and those without CVC are compared in the Table, which also shows the distribution of isolates in febrile episodes during profound neutropenia and non-profound neutropenia. Statistical analysis using the X2-test shows that there were no significant differences between episodes with CVC compared with those without CVC, either in respect of the overall incidence of sepsis or the isolation of Gram-positive and Gram-negative organisms h2=0.5123; P>O.4). Eight of 12 patients with S. epidermidis sepsis had CVC in situ at the onset of sepsis compared with 19 of 43 patients with other organisms but this difference was not significant (P>O*O5). Profound neutropenia was present in five out of 12 episodes (42%) of S. epidermidis sepsis compared with 20 out of 43 septic episodes (46.5%) caused by other pathogens, but this was not significantly different (P> 0.1). However, all the candida isolates were associated with a CVC, and febrile episodes associated with profound neutropenia had a significantly higher proportion
310
I. M. Al-Fawaz et
al.
Septicaemia
in children
with cancer
311
of Gram-negative organisms than episodes associated with non-profound neutropenia (PC 0.02). Management was successful in 71% of the episodes of sepsis (39 of 55) in that the fever resolved, the ANC increased to > 0.5 x lo9 l-i, and follow-up blood cultures were sterile within 7 days of starting appropriate antibiotics. Four patients who had CVC in situ remained febrile despite appropriate antibiotic therapy, until their central venous catheters were removed. The isolates from the CVC in these patients were C. albicans (two cases), S. epidermidis (one case) and E. coli (one case). Twelve patients died. Six of the deaths occurred in patients whose neoplasms were in relapse; these were leukaemia (three cases), lymphoma (two cases) and stage IV solid tumour (one case). The other six deaths occurred in children who were in remission at the time of death. Three of these had pseudomonas septicaemia; one had sepsis with Serratia marcescens and viridans streptococci, another had klebsiella septicaemia and pneumonia, and the last had systemic candidiasis. Discussion
This retrospective review clearly indicates that septicaemia is of paramount importance in oncology children who present with fever and neutropenia in our unit. Our findings are, in general, in agreement with previous reports differences are from other parts of the world, 2-5,7 but some significant apparent when our findings are compared with other studies. For example, Gram-positive organisms were generally less common in our patients than in some of the recent reports from Western countries,3-5’7 and S. epidermidis, which is now the predominant isolate from febrile neutropenic cancer patients in these countries,3m5 was isolated from only 30% of our septicaemic patients. On the other hand, Gram-negative organisms, particularly P. aeruginosa, which has declined considerably in incidence during the 1980s in Western countries,‘p3-’ was a major cause of septicaemia and death among our patients. We were unable to find any reasonable explanations for these important differences, and the subject is worthy of further studies. Some previous studies have associated S. epidermidis sepsis with long-term usage of CVC,8,9 while others3-’ dispute such an association. In the present series, S. epidermidis was more commonly isolated from patients in whom CVCs were present than in patients without CVCs, but the difference was not significant. Future studies with larger series are required for the clarification of this point. Also, in contrast to findings in other studies,3 profound neutropenia did not significantly predispose to S. epidermidis sepsis in our patients. However, our patients with profound neutropenia revealed a significant predisposition to Gram-negative sepsis, which was a major cause of death in the present series. The probability of CVC predisposing to candidaemia is currently gaining attention and was
312
I. M. Al-Fawaz
et
al.
recently reviewed by Walsh & Pizzo. lo The fact that all four candida isolates in the present series were from patients with CVC in situ is therefore noteworthy. Previous authors have recommended empirical therapy with amphotericin B in patients with persistent fever on clinical suspicion of fungal sepsis after a period of 5-7 days or in the presence of rapid clinical deterioration.‘B7,” We recommend that a special search for fungal infection should be undertaken routinely in all febrile neutropenic patients with CVC in situ and, as has been suggested for adult patients in a recent report from our hospital, l1 that empiric amphotericin B should be commenced if fever persists for more than 72 hours despite broad spectrum antibiotic therapy. We wish to thank Dr Hassan M. Bahakim for permission to review Miss Gloria Palacay for her secretarial assistance in the preparation
some of his patients of this manuscript.
and
References 1. Pizza PA. After empiric therapy: what to do until the granulocyte comes back. Rev Infect Dis 1987; 9: 214-219. 2. Pizzo PA,, Robichaud KJ, Wesley R, Commers JR. Fever in the pediatric and young adult patients with cancer: a prospective study of 1001 episodes. Medicine (Baltimore) 1982; 61: 153-156. 3. Wade JC, Schimpff SC, Newman KA, Wiernick PH. Staphylococcus epidermidis. An increasing cause of infection in patients with granulocytopenia. Ann Intern Med 1982; 97: 503-508. 4. Friedman LE, Brown AE, Miller DR, Armstrong D. Staphylococcus epidermidis septicemia in children with leukemia and lymphoma. Am J Dis Child 1984; 138: 715-719. 5. Langley J, Gold R. Sepsis in febrile neutropenic children with cancer. Pediatr Infect Dis J 1988; 7: 34-37. 6. Schimpff SC, Young VM, Greene WH, Vermeulen GD, Moody MR, Wiernik PH. Origin of infection in acute non-lymphocytic leukemia. Significance of hospital acquisition of potential pathogens. Ann Intern Med 1972; 77: 707-714. J. Concept of empiric therapy with antibiotic combinations. Indications and 7. Klastersky limits. AmY Med 1986; 80 (Suppl. SC): 2-12. and fungemias in oncology patients 8. Lowder JN. Lazarus HM, Herzig RH. Bacteremias with central venous catheters. Arch Intern Med 1982; 142: 1456-1459. ED, Wald ER, Nelson KA, Spiegelman KN. Broviac catheter-related 9. Shapiro bacteremia in oncology patients. Am J Dis Child 1982; 136: 679-681. fungal infections: A classification for hospital acquired 10. Walsh TJ, Pizzo PA. Nosocomial fungal infections and mycoses arising from endogenous flora or reactivation. Ann Rev Microbial 1988; 42: 517-545. CR, Zeoitany RG. Infectious complications 11. El Saghir NS, Hall AD, Santhosh-Kumar during therapy of acute leukemia in Saudi Arabia. J Hasp Infect 1989; 14: 2099215.