Journal of Antimicrobial Chemotherapy (2009) 63, Suppl. 1, i3 i13 doi:10.

1093/jac/dkp074

Fever and neutropenia: the early years

Gerald P. Bodey*
Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard (Unit 402), Houston, TX 77030, USA
The importance of neutropenia as a predisposing factor for infection in patients with haematological malignancies was not clearly appreciated until effective therapeutic agents became available. This led to the important advance of administering antibiotics promptly to neutropenic patients when they developed fever, before a diagnosis was established. Although some antibiotics available in the 1960s had activity against many pathogens in vitro, they were ineffective against infections in neutropenic patients. The development of methods to administer white blood cell transfusions along with antibiotics was benecial to some patients. The development of new antibiotics was of critical importance, such as methicillin for treatment of Staphylococcus aureus and carbenicillin for Pseudomonas aeruginosa. Prevention of infection was attempted, using isolation rooms, air ltration and prophylactic antibiotics. All of these early efforts laid the foundations for the many important current investigations. Keywords: antibiotics, infection, acute leukaemia, prophylaxis

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Introduction
Infection has been recognized as a complication of leukaemia in case reports dating back at least to 1845.1 While fever in acute leukaemia was attributed to infection, it was also attributed to the general hypermetabolic condition caused by the disease. Early literature incriminated a variety of bacteria, viruses or parasites as the cause of leukaemia. Although neutropenia was a common consequence of acute leukaemia, its role in infection was often not examined or recognized. Hence, the presence of neutropenia can only be assumed in some of the early studies of infection. Also, it is difcult to compare the early studies because of a lack of standard denitions, including the denition of fever. This review will focus almost exclusively on studies conducted before the 1980s.

Early studies of infection

Until the introduction of aminopterin by Farber2 in 1948, there was no specic therapy for acute leukaemia. Most patients died of haemorrhage or infection. Since there was little to do to favourably affect the course of the disease, there was little impetus to study the infectious complications. For example, Dameshek and Gunz3 published a book on leukaemia in 1958 in which infectious complications were not mentioned. Boggs et al.4 published a 48 page review on acute leukaemias that devoted only 2 pages to infections. They observed that infections were signicantly more likely to occur in patients whose

neutrophil count was ,3000 cells/mm3 on initial examination and that bacterial infection was likely to disseminate rapidly in patients with acute leukaemia. Initial infections usually responded to antibiotic therapy but, unless remission occurred, superinfection rapidly ensued, usually caused by Pseudomonas aeruginosa, Staphylococcus aureus or fungi. For this reason, they concluded that antibiotic therapy should be kept to a minimum. They concluded that fever alone was not an indication for a trial of antibiotic therapy, but they recognized that other signs of infection may be absent in neutropenic patients. Several studies of infectious complications in acute leukaemia published in the 1950s and 1960s are cited here, but data on neutrophil counts were generally not mentioned. Among the prominent early studies were those of Boggs and Frei,5 Raab et al.6 and Silver et al.7 The latter two studies included only patients with acute leukaemia whereas that of Boggs and Frei included all cancer patients, most of whom had haematological malignancies. The authors mentioned that it was often difcult to differentiate fever due to infection from other causes of fever. The degree of fever and the fever pattern were not helpful in discriminating between fever due to infection and fever due to other causes. Both Boggs and Raab concluded that neutrophil counts were not helpful in identifying infectious fever. Silver concluded that fever should be considered to be due to infection until proven otherwise. Boggs concluded that only 44% of the 193 febrile episodes in their study were due to infection, whereas in the other two studies that included only patients with acute leukaemia, 64% to 68% of febrile episodes were diagnosed as presumed or proven infection.

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*Tel: 1-713-792-6830; Fax: 1-713-745-6839; E-mail: gbodey@mdanderson.org

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# The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Bodey
The most common sites of infection in the studies of Boggs and Raab were bacteraemias and pneumonias, whereas in the study of Silver, most proven infections were pharyngitis and urinary tract infections, which is surprising in a study of leukaemic patients. The major pathogen was S. aureus, which in the study of Raab had a mortality rate of 62%. P. aeruginosa infections were uncommon in the two studies of leukaemia patients but all of these infections were fatal. Although these authors recognized an association between neutropenia and infection, its predominant importance did not seem to be fully appreciated. For example, Boggs concluded that prolonged leucopenia was the cause of frequent bacterial infections, whereas Silver concluded that susceptibility to bacterial infection was not entirely ascribable to neutropenia. Raab was of the opinion that it was not possible to demonstrate that neutrophil counts were lower in patients with infection compared with those without infection. Curtin and Marshall8 recognized that neutropenia could impair phagocytic activity but believed that other factors were also important in predisposing to infection. It was also concluded that recovery from infection was not related to absolute neutrophil count. In general, caution was advised in the use of antibiotics and there was considerable concern about the occurrence of superinfections caused by resistant organisms. Raab et al.6 recommended discontinuing antibiotics if no cause for fever could be identied in 5 days, but they also suggested administering antibiotics empirically to profoundly ill patients. During the two decades after Farber demonstrated the activity of aminopterin, prednisolone, 6-mercaptopurine, cyclophosphamide and vincristine became available. The most important advance was the introduction by Freireich of the four-drug regimens, VAMP (ve courses of a regimen of vincristine, aminopterin, 6-mercaptopurine and prednisolone) and POMP (monthly courses of prednisolone, oncovin, methotrexate and purinethol) for children with acute lymphocytic leukaemia. Of the 66 children receiving these regimens, 59 (90%) achieved a complete remission. Some remissions lasted in excess of 2 years and some patients were ultimately cured of their disease.9 With the availability of effective therapy, the successful management of common complications became increasingly critical. An important improvement in supportive care was the introduction of platelet transfusions. Gaydos et al.10 demonstrated that there was a quantitative relationship between platelet counts and haemorrhage in patients with acute leukaemia. Platelet transfusions increased the number of circulating platelets, making it possible to prevent haemorrhagic complications. During this time, S. aureus emerged as the predominant pathogen in neutropenic patients. In a study of 78 acute leukaemia patients extending from 1951 to 1966, S. aureus caused 92% of skin infections, 36% of pneumonias and 30% of bacteraemias.11 Many isolates of S. aureus were penicillin-resistant and failed to respond to the available antibiotics, which were predominantly only bacteriostatic, hence, the fatality rate was generally high until methicillin became available.
Table 1. Changes in cause of death in acute leukaemia 1954 59 Parameter Patients Infection (total) S. aureus Escherichia coli Klebsiella spp. P. aeruginosa fungi Infection alone Haemorrhage (total) Haemorrhage alone Other (total) number 184 124 30 27 9 31 10 45 123 40 24 % 67 24 22 7 25 8 24 67 22 13 196063 number 170 131 6 17 16 45 30 80 69 25 23 % 71 5 13 12 34 23 44 37 14 12 NS ,0.001 NS NS NS ,0.001 ,0.001 ,0.001 ,0.05 NS
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P value

NS, not signicant. Modied with permission from Hersh et al.12

Autopsy studies
In 1964, Hersh et al.12 conducted an autopsy study of 414 patients with acute leukaemia who were treated at the National

Cancer Institute from 1954 to 1963. Causes of death were compared between those who died from 1954 to 1959 and those who died from 1960 to 1963 to determine where progress had been made and where challenges for improvement existed (Table 1). During the two periods, haemorrhage as the cause of death decreased from 67% to 37%, reecting the efcacy of platelet transfusions. However, death from infection remained essentially unchanged (67% versus 71%). S. aureus septicaemia as the cause of death decreased from 24% to 5% during the two time periods (P, 0.01), largely due to the efcacy of methicillin therapy. Unfortunately, P. aeruginosa septicaemia increased from 25% to 34% of fatal infections and invasive fungal infections increased from 8% to 23%. Because pneumonia emerged as a signicant cause of fatal infection in neutropenic leukaemic patients, an autopsy study of 50 consecutive patients who died from 1962 to 1963 was conducted.13 The lungs were expanded and whole lung slices prepared for histological examination. Cultures of bronchi, lung and heart blood were collected. Thirty-one patients had major pathological lesions; the remaining subjects had only minor lesions. Twenty-six patients had major infections, 14 had minor infections and only 10 (20%) had no infection. The most common pathogens isolated from sites of lung infection were P. aeruginosa, Candida spp. and Aspergillus spp. Only 13 of the 31 major infections had been recognized clinically and the pathogen was identied antemortem in only 7. Thirty-seven patients had chest X-ray examinations during the last week of life: 23 had major pulmonary lesions and 14 had minor lesions. The clinical X-ray diagnosis was conrmed at autopsy in only 57%. Also, major pulmonary infection was not diagnosed correctly from the chest roentgenogram in 55%. The X-ray examination in 30% of patients with major infection was interpreted as normal, incorrectly, by the radiologists. Fungal infection had been recognized as a potential complication of leukaemic patients since the 1940s. Stefanini and Allegra14 reported a 3% incidence of fungal infection in patients with acute leukaemia from 1943 to 1947, which increased to

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22% from 1954 to 1956. Others reported increases in candidiasis, aspergillosis and mucormycosis but not in histoplasmosis and cryptococcosis.15 It was also noted that increases in fungal infection were greater in leukaemia and lymphoma than in other diseases.16 A third autopsy study, focusing specically on fungal infections in 454 patients with acute leukaemia, was conducted at the National Cancer Institute between 1954 and 1964.17 A total of 189 fungal infections were identied in 161 (35%) patients; of these, 127 were major infections. Among the major infections were 73 cases of candidiasis, 38 of aspergillosis and 6 of mucormycosis. The frequency of major fungal infections increased from 10% during 1954 through 1958 to 30% during 1959 through 1964. There was a signicant increase in the frequency of fatal fungal infections due to Candida spp. (P, 0.001) and Aspergillus spp. (P,0.02) during the latter period. Only 30% of severe Candida infections and Aspergillus infections were diagnosed antemortem. When compared with a control group without fungal infection at autopsy examination, the fungal group spent a signicantly greater proportion of time prior to death with neutropenia [,1500 neutrophils ( polymorphonuclear leucocytes; PMN)/mm3] and a greater proportion of time receiving adrenal corticosteroids (P,0.02). There were no differences in lymphocyte counts or antibiotic consumption between the two groups.
Table 2. Episodes of severe infection related to leucocyte counts Episodes of severe infectiona Blood leucocyte count (cells/mm3) ,100 101500 ,500 5011000 1001 1500 1501 2000 .2000 neutrophils 43 19 12 5 5 5 lymphocytes 27 12 10 4 6

a Episodes per 1000 days without severe infection. Approximated from graphs with permission from Bodey et al. 18

Quantitative leucocyte studies

It became apparent that if substantial progress were to be made in the treatment of acute leukaemia, prevention and control of infection were of critical importance. The data on the importance of neutropenia as a factor in the susceptibility to, and recovery from, infection were conicting. Furthermore, myelosuppressive regimens were being used increasingly for the treatment of other malignancies. Hence, a study was initiated at the National Cancer Institute to dene the quantitative relationships between circulating leucocytes (not just neutrophils) and infection in patients receiving treatment for acute leukaemia.18 This study was based on the previous study by Gaydos et al.10 that examined the relation between platelet count and haemorrhage. The absolute neutrophil and lymphocyte counts of 52 patients undergoing therapy for acute leukaemia who were followed from initial admission (beginning August 1959) until death or April 1963 were tabulated. There were a total of 17 743 patient-days and during 38% of the time (6768 days), the patients had active leukaemia. The frequency of severe infectious episodes began to increase when the neutrophil level was 501 1000 cells/mm3 ($5 episodes/1000 days) and increased progressively as the neutrophil count decreased, to 43 episodes/1000 days when the neutrophil level was ,100 cells/mm3 (Table 2). The frequency was consistently much higher at every neutrophil level for patients in relapse than those in remission. A similar correlation existed for lymphocyte levels, although the number of episodes was consistently lower. The number of episodes of severe infection/ 1000 days was highest when both neutropenia and lymphopenia were present in the patients, but the incidence was much higher when neutropenia alone was present than when lymphopenia alone was present (Table 3). Fluctuations in neutrophil and lymphocyte counts during the week prior to infection were also examined. The neutrophil

count fell during 331 1 week periods and 12% terminated in severe infection. The greatest risk for developing severe infection was not the magnitude of the decrease but the nal neutrophil count. For example, a decrease from any neutrophil level of .500 cells/mm3 resulted in a 16% incidence of severe infection, while a decrease of .1000 cells/mm3 resulted in an incidence of 17%. However, a decrease from any level to a nal count of 1500 PMN/mm3 resulted in a severe infection rate of 5%, but a decrease of any magnitude to ,100 PMN/mm3 was associated with a rate of 28%. The risk of developing severe infection increased with longer duration of neutropenia. One hundred percent of episodes of severe neutropenia (,100 PMN/mm3) lasting 3 weeks or more were accompanied by identied infection compared with 65% of episodes lasting 1 week. The episodes with ,1000 PMN/mm3 for 3 weeks were associated with a 60% frequency of identied infection. This study also demonstrated that the outcome of severe infections was related to changes in neutrophil count. For example, if the neutrophil count was ,1000 cells/mm3 at the onset of severe infection and remained unchanged or decreased during the rst week of infection, the fatality rate was 59%. However, if the neutrophil count increased to .1000 cells/mm3, the fatality rate was 27%. If the PMN count was ,100 cells/ mm3 and did not increase, the fatality rate was 80%. A study in children with acute leukaemia found that no episodes of pneumonia were associated with septicaemia in children with PMN

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Table 3. Relative importance of neutropenia and lymphopenia in predisposing to severe infection in acute leukaemia Cell counts (cells/mm3) neutrophils .1000 .1000 ,1000 ,1000 lymphocytes .1000 ,1000 .1000 ,1000 Episodes of severe infection* 3 6 14 28

*Episodes/1000 days without severe infection. Modied with permission from Bodey et al. 18

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Table 4. Clinical manifestations of infection related to neutrophil count Percentage of patients with a neutrophil count of Signs and symptoms Fever Bacteraemia Fluctuance Exudate Purulent sputum Pyuria Infection overall overall anorectal skin pneumonia urinary tract infection ,100 cells/mm3 98 43 8 5 8 11 .1000 cells/mm3 76 13 67 92 84 97

Modied with permission from Sickles et al. 20

counts .1000 cells/mm3, whereas septicaemia occurred in 80% of children with PMN counts ,100 cells/mm3.19 Sickles et al.20 conducted a study of the frequency of several manifestations of infection related to the patients neutrophil counts by comparing a group of patients with severe neutropenia (,100 PMN/mm3) with a group with adequate neutrophil counts (.1000 PMN/mm3). Fluctuance was present in skin infections of 6% of the former group compared with 52% of the latter group (Table 4). Among patients with pneumonia, only 8% of severely neutropenic patients produced purulent sputum compared with 84% of those with adequate neutrophils. Among patients with urinary tract infections, pyuria was found in 11% and 97%, respectively. The presence of neutropenia affected the detection of abnormalities on the initial chest X-ray examinations of cancer patients with Gram-negative bacillary pneumonia.21 Among patients with evidence of pneumonia on X-ray examinations, 85% had .1000 PMN/mm3. Among patients without evidence of pneumonia on initial examination, 81% had ,1000 PMN/ mm3 and 70% had ,500 PMN/mm3. Among those patients who developed evidence of pneumonia on subsequent examinations, 67% had an increase in their PMN count. The lack of signs and symptoms of infection obviously diminishes the physicians ability to discriminate between infectious and non-infectious fever. In a study of neutropenic patients given antibiotic therapy based on their temperatures, the prescribing physicians were required to make a diagnosis of infection or no infection [fever of unknown origin (FUO)] before instituting therapy.22 Among patients ultimately diagnosed with an infection, 28% were incorrectly diagnosed as FUO at onset of therapy. Among patients ultimately diagnosed as FUO, 37% were considered to be infected at the initial assessment. Hence, the prescribing physicians initial assessment was incorrect in 33% of the cases.

White blood cell (WBC) transfusions

The frequency of serious infectious complications in neutropenic patients represented a major obstacle in the treatment of acute leukaemia and other malignancies. Most available antibiotics were of limited efcacy in neutropenic patients. Using the technique of plasmapheresis, sufcient platelets could be collected to prevent haemorrhage in thrombocytopenic patients but the number of

neutrophils that could be collected from normal donors was insufcient to be useful for transfusion to infected patients. Freireich et al.23 were the major pioneers in developing methods that provided effective numbers of WBCs for transfusion. Patients with chronic myelogenous leukaemia (CML) with counts exceeding 100000 WBCs/mm3, most of which were neutrophils, proved to be effective donors. They demonstrated that there was a direct relationship between the number of cells transfused and the increment in the recipients neutrophil count. When given to febrile neutropenic patients who were not responding to antibiotic therapy, 54% had fever defervesence.24 The proportion responding correlated with the dose of neutrophils transfused and total doses of 11010 or fewer were virtually ineffective. Using the Rebuck skin-window technique, it was possible to demonstrate that transfused neutrophils migrated into inammatory lesions.23 A larger study of the efcacy of WBC transfusions collected from CML donors was conducted in 128 neutropenic patients (111 with acute leukaemia) who had fever that failed to respond to two to three doses of antibiotic therapy.25 The patients received a median of two transfusions containing a mean of 1.31011 WBCs. The overall response rate was 49% and was similar among patients with pneumonia, septicaemia and infections caused by Gram-negative bacteria. Improvements in the collection of WBCs made it possible to use normal donors. Hydroxyethyl starch was used to improve the sedimentation of red blood cells and administration of etiocholanolone to donors increased the number of circulating neutrophils. The combination improved the collection of neutrophils. A major advance developed by Freireich et al. was the continuous cell-separating machine, as reported in the early study by Hester et al.26 As WBC transfusions were used more extensively, several potential adverse effects were reported. Wright et al.27 reported acute dyspnoea, respiratory deterioration and new chest inltrates in 64% of 22 patients who received amphotericin B while receiving WBC transfusions compared with 6% and 3% among 35 patients without amphotericin B. In the former group, 41% had acute dyspnoea and 32% required ventilatory assistance. However, in other studies, the frequency of pulmonary complications following WBC transfusion was similar with or without amphotericin B.28 A possible explanation for this complication in some patients was the rapid accumulation of transfused neutrophils in a site of pulmonary infection that had been undetected because of a lack of an inammatory response due to neutropenia.

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Another potential adverse effect was reported in a randomized trial of prophylactic WBC transfusions to bone marrow transplant recipients.29 Among transfusion recipients, 61% developed cytomegalovirus infections compared with 21% of controls (P 0.045). Reports of graft versus host disease occurring in recipients of transfused WBCs have led to routine irradiation of neutrophils collected for transfusion. There is controversy over the potential adverse effects of radiation on the function of transfused cells. Bishton and Chopra30 reviewed seven prospective, randomized trials of WBC transfusions in neutropenic patients with clinical evidence of infection. They concluded that WBC transfusions showed clear benet in three of these studies, benet in certain patients in two studies and no benet in two studies; however, all of these studies included only small numbers of patients. It should also be noted that most of these studies ignored the dose of neutrophils that was transfused, hence, many patients may have received an inadequate dose. WBC transfusions were used extensively at some institutions in the 1970s, but their use diminished thereafter because many physicians were unconvinced of their efcacy. A resurgence of interest in these transfusions has occurred in recent years because of the availability of granulocyte-colony stimulating factor (G-CSF) and improvements in collection procedures.31 The administration of G-CSF to donors considerably improves the quantity of neutrophils collected, increases the activity of neutrophils against infection and prolongs neutrophil survival. Generally, the transfusions have been well tolerated, although leucocyte alloimmunization is a potential problem.
Table 5. Persistent organisms in leukaemic patients on PEPA programme Percentage of patients with: Site Stool Throat Nose Skin sterile cultures 24 3 32 2 non-pathogens 14 80 64 96 pathogens 16 25 9 33 fungi 66 60 7 40

Modied with permission from Bodey and Rosenbaum.35

Protected environment (PE) prophylactic antibiotic programmes

Increasingly effective chemotherapeutic regimens for acute leukaemia and some other malignancies were developed but they caused substantial neutropenia. Hence, prevention of infection became of increasing importance. The availability of PEs for patients, in the form of isolation units, plus the development of prophylactic topical and oral non-absorbable antimicrobial regimens (PA) led to studies of the efcacy of such PEPA programmes. These programmes were generally designed to make the patient and his/her environment as free of microorganisms as possible. The rst PE was essentially a bed surrounded by a plastic canopy with gauntlets attached to the canopy to access the patient.32 All items entering the unit were sterilized, food was prepared aseptically and the air was high efciency particulate air (HEPA)-ltered. Subsequently, permanently installed and semi-portable laminar air ow (LAF) units were utilized.33 These were rooms with one entire wall consisting of HEPA lters, providing high rates of minimally turbulent air exchange. Special water and toilet facilities were provided. Personnel dressed in sterile attire when they entered the units and all items placed in the rooms were sterilized. Institutions utilizing LAF units developed individualized programmes for microbiological monitoring of patients and their environment. Usually, environmental monitoring included air sampling, oor and surface sampling and settling plates. In a study comparing results obtained from LAF rooms with those from regular hospital rooms, none of the air samples from hospital rooms was sterile whereas 53% of samples from LAF rooms were

sterile. Only 1% of air samples from LAF rooms contained potential pathogens compared with 59% from regular hospital rooms.34 Patient culture specimens were collected once or twice weekly from ears, nose, throat, stool, urine and skin (and other body sites at some institutions). Special techniques were developed to obtain semi-quantitative throat and total body skin culture specimens. Some of these procedures were timeconsuming and eventually had to be discontinued. A study of the effects of the oral antimicrobial regimen in 91 patients demonstrated that a majority of aerobic bacteria were no longer cultured during prophylaxis (Table 5).35 A substantial number of persistent organisms were non-pathogenic. Despite the administration of large doses of antifungal agents, most isolates of Candida spp. persisted or increased in concentration during prophylaxis and a substantial number of new isolates were cultured. Weekly cultures of stool specimens demonstrated that although some bacteria could not be isolated during antibiotic prophylaxis, they rapidly reappeared when prophylaxis was discontinued, indicating that they had only been suppressed. Only a few of these persistent organisms had developed resistance to the PA regimen. In a study conducted by Klastersky et al.36 of PEPA versus PA only, they concluded that isolation did not reduce the frequency of persistent bacteria from patient cultures, which suggested that these persistent bacteria originated from the faecal ora rather than the environment. Unlike the earlier-mentioned study, they found that persistent bacteria were more resistant to PA. Persistent organisms were likely to be the cause of the infections occurring in patients on the PEPA programme.37 In a study of 102 patients, there were 68 single organism bacterial infections. Fifty were caused by organisms cultured prior to entry to the programme, including 13 of 18 Pseudomonas infections. Klastersky et al.36 noted that Gram-negative bacilli that were cultured repeatedly from patients on PA were often responsible for subsequent infections. Schimpff et al.38 reported that patients receiving PA who discontinued the regimen while still on antileukaemic therapy were at substantial risk of morbidity and mortality from infection. The rst study comparing outcomes of patients receiving antileukaemic chemotherapy on the PEPA programme with controls was a case-controlled but not randomized study.39 The complete remission rate was not signicantly higher (61% versus 48%) for the PEPA group, but the duration of remission and survival were signicantly longer in the PEPA group, which was most likely because the PEPA patients received more intensive chemotherapy. Three prospective, randomized comparative studies of PEPA programmes were conducted in patients with

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Table 6. Randomized trials of PEPA programmea Yates and Holland PEPA 25 5 33 9 control 80 19 31 12 Schimpff et al. PEPA control 17 17 54 62 52 24

Levine et al. Measure Patients with major infection Patients with fatal infection Patients with colonization resistance Time with major infection (days) ,100 PMN/mm3 101 1000 PMN/mm3 .1000 PMN/mm3 PEPA 14 0 45 12 8 3 control 50 24 43 40 10 12

a Numbers represent percentages of patients or percentages of days. Data compiled with permission from Levine et al.,40 Yates and Holland41 and Schimpff et al.38

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acute leukaemia in the USA (Table 6). All of the studies included a third group who received only PA.38,40,41 The remission rates between PEPA and control patients were not statistically signicant in two of the studies. However, in the study of Schimpff et al., the complete remission rates were signicantly higher in the PEPA and PA alone groups than those in the controls (54%, 63% and 24%, P, 0.05). The median survival was also nearly twice as long in the PEPA and PA groups. All of the studies demonstrated some benecial effect from the PEPA programme on infection. Bodey et al.39 found that the proportion of days on study with severe infection was higher among the controls and the difference was statistically signicant for those infections when the neutrophil count was ,1000 cells/mm3 but not when it was ,100 cells/mm3. Levine et al.40 found that the number of episodes of severe infection per 100 days on study was 0.67 for PEPA patients, 1.73 for PA patients and 1.88 for controls, differences that were statistically signicant (P, 0.025). Deaths due to infection occurred in 0%, 24% and 25%, respectively (P, 0.05). In the study of Schimpff et al., PEPA, PA only and control patient groups spent equivalent times with severe neutropenia.38 The patients assigned to PEPA and PA contracted half as many severe infections as control patients. Only 17% of PEPA patients died of infection compared with 32% of PA and 52% of controls (P, 0.05). The complete remission rates were 54%, 63% and 24% (P, 0.05). The median duration of survival was half as long for control patients compared with the other two groups. During the early 1970s, seven European hospitals conducted a prospective, randomized trial of PEPA in 137 evaluable patients undergoing antileukaemic chemotherapy.42 There was a great diversity in age, chemotherapy regimens, number of prior regimens, isolation units and prophylactic antimicrobial regimens. Group A consisted of 42 patients assigned to PEPA, Group B consisted of 44 patients assigned to PE only and the 51 patients in Group C received routine hospital care. Patients in Groups B and C received oral amphotericin B or nystatin, but no antibacterial agents. The proportions of days spent with ,100 PMN/mm3 were 25%, 29% and 19%, respectively. The numbers of episodes of severe infection and frequency of fever were essentially the same in the three groups. Only

14% of patients in Group A were free of potential pathogens in their gastrointestinal ora during the entire induction period and none was free of potential pathogens in the other two groups. Patients in Group A had a greater proportion of infections caused by Gram-positive cocci, which responded better to therapy. Lower respiratory tract infections were signicantly more frequent in Group C (6%, 7%, 24%, respectively), suggesting some benet from isolation. The complete remission rates of 69%, 61% and 49% were not signicantly different and the differences were more likely due to the chemotherapy than the prophylactic measures. Survivals at 30 days after the end of therapy were 79%, 79% and 75%. The authors concluded that the programme was not effective in preventing infection. Subsequently, studies were initiated in other malignancies such as small cell carcinoma of the lung and breast carcinoma. Randomized trials were designed for patients with lymphoma and soft tissue sarcoma (tumours that were susceptible to chemotherapy regimens) to determine whether the reduction in risk of infections during periods of neutropenia accomplished by the PEPA programme would permit dosage escalation of chemotherapeutic agents,43,44 also, whether dosage escalation would improve remission rates and duration of remission and survival. Unfortunately, the results were not sufciently encouraging to justify continuing such investigations. For example, in the lymphoma study, patients on the PEPA programme had more prolonged severe neutropenia (255 versus 147 days) and a lower proportion of days with major infection (2% versus 10%).43 Full dosage escalation was achieved in 96% of PEPA patients compared with 77% of controls (P, 0.09). Unfortunately, despite these benets, the complete remission rate among patients who received full dosage escalation was only modestly higher than for those with no dosage escalation. The PEPA programme was very labour-intensive and expensive, hence, programmes at most institutions were discontinued or extensively modied. LAF rooms were replaced by HEPA-ltered units, and sterile food by cooked food. Trimethoprim/sulfamethoxazole and, later, uoroquinolones were used for antibacterial prophylaxis with and without patient isolation.45 Unfortunately, the benets of such prophylaxis have been offset by the emergence of resistant organisms at some institutions.

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Colonization resistance (CR) and selective decontamination of the digestive tract (SDD)
During this time, van der Waaij46 introduced the concept of CR, which was dened as the resistance which a potentially pathogenic microorganism encounters when it attempts to colonize the mucosa of the three tracts that have open communication with the outside world. In the digestive tract, the resident anaerobic ora plays a major role in CR along with host factors. Anaerobes were believed to prevent long-term intestinal colonization by aerobes. Since many infections originate in the gastrointestinal tract, much attention was focused on this site. The administration of some antibiotics can have a profound effect on the anaerobic ora, thus permitting colonization by potential pathogens. Antibiotics were classied into three categories: (i) those that suppressed organisms providing CR at any clinical dose, (ii) those that have an effect only at high doses, and (iii) those that are non-toxic to CR-providing organisms at doses that eliminate potential pathogens. Since anaerobic organisms are an infrequent cause of infection in neutropenic patients, antibiotics in Group 3 could be used to selectively remove potential aerobic pathogens, yet retain CR for the acquisition of new pathogens. This SDD would provide an alternative to gut sterilization regimens. A prospective, randomized trial of SDD was conducted in hospitalized neutropenic patients with acute leukaemia or aplastic anaemia.47,48 There were 53 evaluable patients in the SDD group and 52 controls. Antibiotics used for SDD were nalidixic acid, trimethoprim/sulfamethoxazole or polymyxin B (for resistant Gram-negative bacilli) and amphotericin B or nystatin. There was no patient isolation, but salads and raw meat were excluded from their diet. There were 18 Gram-negative bacilli or yeast infections in the controls compared with only 2 in SDD patients. Additionally, there were 15 clinically documented infections in 12 controls compared with 4 infections in 3 SDD patients (both differences were statistically signicant). Nine patients in the control group died of infection compared with none in the SDD group. All of the faecal samples after the rst negative sample remained free of Gram-negative bacilli in 15 of the SDD patients and in 14 patients only one sample was positive. Gram-negative bacilli were cultured from 26% of 406 faecal samples from the SDD patients compared with 95% of 325 from the control patients (P, 0.0005). Although this study and the animal studies of van der Waaij et al. were provocative, over time this concept diminished in importance with the availability of trimethoprim/sulfamethoxazole and, subsequently, uoroquinolones for prophylaxis.45

who were Pseudomonas carriers for !50% of the time developed Pseudomonas infections. A more intensive study was conducted by Schimpff et al.50 in 48 leukaemic patients. Cultures were collected from 12 body sites once or twice weekly. Cultures from the rectum, gingiva, urine, nose and axilla detected all of the organisms that subsequently led to infection. Colonization by P. aeruginosa was most often detected from rectal cultures. Fifteen of the 22 Pseudomonas carriers developed Pseudomonas infection. The pathogen was previously isolated from surveillance cultures in 39 of the 43 patients who developed bacteraemias. In 22 of these patients, the organism had been acquired from the hospital. The pathogen causing 36 of the 44 non-bacteraemic infections had been isolated earlier from surveillance cultures and 13 of them were acquired from the hospital. In another study, it was concluded that patients hospitalized with acute leukaemia experience changes in the oropharyngeal and faecal ora, independent of antibiotic administration.51 However, administration of antibiotics causes further alterations that result in a predominance of Gram-negative bacteria. In general, surveillance cultures were not helpful in predicting organisms causing infection. The general consensus is that surveillance cultures have been useful for epidemiological and other research studies, but are time-consuming, expensive and inefcient as indicators of pathogens causing specic infections.52

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Early antibiotic therapy for neutropenic patients

Several new antimicrobial agents became available during the 1950s, but no systematic studies of any of them were conducted to determine their efcacy in neutropenic patients. Prior to the availability of methicillin, penicillin-resistant S. aureus was the major threat to neutropenic patients. Only bacteriostatic agents, such as novobiocin and chloramphenicol, were available and they were often ineffective. The mortality rate from S. aureus infections in these patients usually exceeded 50%. For example, Raab et al.6 reported that this organism caused 50% of bacteraemias in patients with acute leukaemia and the recovery rate was only 38%. Methicillin became available in the early 1960s and had a dramatic impact, curing most S. aureus infections even in severely neutropenic patients and ultimately reducing the frequency of these infections. As cited earlier, the proportion of fatal infections due to S. aureus at the National Cancer Institute decreased from 39% in 1954 to 0% in 1963, presumably due largely to the use of methicillin.12 Cephalothin represented a potentially important addition to the antibiotic armamentarium for neutropenic patients. It was the rst b-lactam antibiotic available that was active against penicillin-resistant S. aureus and most of the common pathogenic Gram-negative bacilli except P. aeruginosa. Consequently, it replaced methicillin in therapeutic regimens for febrile neutropenic patients. Therapeutic trials of cephalothin alone were not conducted in neutropenic patients but most early therapeutic trials in these patients included a regimen with cephalothin in combination with another antibiotic. Colistimethate was introduced during the 1950s and it was anticipated to be benecial due to its antipseudomonal activity in vitro. Unfortunately, it had minimal effect in neutropenic

Surveillance cultures
During this period, several institutions began programmes to collect surveillance cultures from patients with acute leukaemia to identify potential pathogens and body sites of potential infection. In one study, throat and stool cultures were collected from 87 patients and tested for the presence of P. aeruginosa.49 Within the rst 7 days of hospitalization 25% were already colonized and this carrier rate increased to 47% by 2 4 weeks. Among those patients studied for at least 1 month, 50% of those

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patients and as a consequence, P. aeruginosa emerged as the major pathogen causing death in leukaemic patients.12 The devastating effects of Pseudomonas infections were reported in several studies of cancer patients, many of whom had acute leukaemia and were neutropenic. One of the earliest studies of Pseudomonas bacteraemia involved 23 patients whose illness was treated at the National Institutes of Health from 1954 to 1957.53 Twenty-one patients had cancer and 13 of these 21 had acute leukaemia. Skin lesions, including ecthyma gangrenosum, vesicular lesions or haemorrhagic cellulitis, were observed in 39% of patients. Seventy-seven percent of the patients were already receiving antibiotics when they developed Pseudomonas bacteraemia. The median period of survival from the time when the rst positive blood specimen was collected was only 4 days, and only one patient recovered. Whitecar et al.54 reported a study of 67 cancer patients with Pseudomonas bacteraemia from 1965 to 1968, 34 of whom had acute leukaemia. The lung was the site of origin in 36 patients and 19 (28%) had ecthyma gangrenosa. Seventy percent of the patients had a neutrophil count of ,500 cells/mm3 and 37% had a neutrophil count of ,100 cells/mm3. Although all isolates were susceptible to polymyxins in vitro, these drugs were not very effective as therapy. Forty-six patients received polymyxin B or colistimethate as therapy and only 24% recovered. Twenty-two patients were already receiving a polymyxin when P. aeruginosa was rst cultured from their blood and only three (14%) survived. The survival rate was 58% with a polymyxin as therapy for those neutropenic patients whose neutrophil count increased, compared with only 8% for those whose neutrophil count remained unchanged or decreased. Between 1970 and 1972, P. aeruginosa caused 28% of all cases of bacteraemia at the Baltimore Cancer Research Center and 36% of cases in patients with acute leukaemia.55 The major factors predisposing to septicaemia were prior colonization by P. aeruginosa and a neutrophil count ,1000 cells/mm3. Investigators at Memorial Sloan-Kettering Cancer Center (New York) reported on their experience with 50 episodes of Pseudomonas septicaemia in patients with malignant diseases from 1967 to 1968 and with 52 episodes from 1971 to 1972.56 Thirty-ve patients had acute leukaemia and 30 had lymphoma. Of the 102 infections, 92 were acquired in the hospital. Mortality was 78% during the rst period and 69% during the latter period. In both series, survival was dependent on the patients WBC count. Only 15% of the 39 patients with ,1000 WBCs/mm3 survived. In contrast, 22% of the 37 patients with 1000 10000 WBCs/mm3 and 50% of the 26 patients with .10 000 WBCs/mm3 survived. developed documented infections while on the study. The authors concluded that fevers were not favourably affected by tetracycline, infections were more severe and the bacterial ora was altered unfavourably. Hence, a trial of antibiotic therapy was not warranted for FUO in cancer patients. A study of gamma globulin (GG) as adjunctive therapy of fever in patients with acute leukaemia was conducted from 1963 to 1964.58 Patients were randomly assigned to antibiotics alone (methicillin colistimethate) or antibiotics GG. The cure rates were 64% and 77%, respectively. Subsequently, the study was continued with a third arm consisting of antibiotics GG prednisolone.59 Although the cure and death rates were lowest in the third group, the number of patients was too small to identify any statistically signicant differences. It is interesting that by this time, S. aureus infections were uncommon and all of them responded to this therapeutic regimen.

The beginning of major antibiotic trials

Gentamicin sulphate, an aminoglycoside antibiotic introduced in the early 1960s, was an important advance because of its broader spectrum of activity against Gram-negative bacilli, including P. aeruginosa. Since aminoglycosides given intravenously could cause neuromuscular blockade, a potentially fatal adverse reaction, initially, its use was limited to intramuscular administration. Most cancer patients who developed serious Pseudomonas infections had myelosuppression with thrombocytopenia, which prevented intramuscular injections. Eventually, it was demonstrated that neuromuscular blockade could be avoided by giving the drug slowly, intravenously (over 2 h every 6 h).60 Unfortunately, despite its excellent in vitro activity against Gram-negative bacteria (including P. aeruginosa), gentamicin was only minimally effective in treating neutropenic patients. In one early study of cancer patients, gentamicin cured 51% of all 122 infections, 56% of 76 single organism Gram-negative bacillary infections and 45% of infections caused by P. aeruginosa.61 The remaining patients had Gram-positive coccal, multiple organism and anaerobic infections or the organism could not be identied. During 55 episodes, the patients had received other antibiotics initially that were proved to be ineffective. Response was related to the patients PMN counts. Considering only patients with Gram-negative infections, 23% of those patients with initial counts ,100 PMN/mm3 responded, compared with 79% of those with initial counts .1000 PMN/mm3. The response rate among those patients whose PMN counts increased during therapy was 74% compared with 31% among those whose PMN counts decreased. Carbenicillin was a major advance in antibiotic therapy because it was the rst b-lactam with activity against P. aeruginosa.62 Its activity in vitro was marginal and doses of 5 g every 4 h were utilized for treating infections in cancer patients. In vitro susceptibility testing was not always reliable, in that some infections caused by isolates only marginally susceptible or resistant to carbenicillin could be treated successfully. Of special importance to leukaemic patients was its efcacy in severely neutropenic patients. In an early study of 59 evaluable cancer patients with Pseudomonas infections (38 with bacteraemia), treatment with carbenicillin alone resulted in a cure rate of 75%.63 The cure rate was 75% among patients with ,100 PMN/

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Early prospective, randomized trials for febrile neutropenic patients

Very few prospective, randomized trials of therapy for infections in cancer patients were conducted prior to the availability of gentamicin and carbenicillin. Probably the rst study, conducted in 1958 59, evaluated the effect of tetracycline versus placebo on FUO in 44 cancer patients. Twenty-six patients had acute leukaemia and 11 had other haematological malignancies.57 Several fever patterns were included for eligibility. Five patients receiving tetracycline (one died) and three receiving placebo

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mm3 compared with 56% among those with .1000 PMN/mm3. There was little difference in outcome among patients whose neutrophil counts increased or decreased during therapy (82% versus 76%). The availability of carbenicillin had a dramatic impact on the ability to treat patients with acute leukaemia with myelosuppressive chemotherapy. The rst prospective, randomized trial of empirical antibiotic regimens for febrile neutropenic patients (,1000 PMN/mm3) was initiated in 1969, comparing carbenicillin plus cephalothin (C C) with carbenicillin plus kanamycin (C K). Kanamycin was selected in preference to gentamicin to demonstrate the efcacy of carbenicillin alone for treating Pseudomonas infections.64 The 151 patients experienced 98 identied infections. The response rates were 60% for C C and 58% for C K. Fourteen of 16 (88%) Pseudomonas infections responded. Response on day 4 for patients with severe neutropenia (,500 PMN/mm3) was 43% for C C and 42% for C K. The authors concluded that neither regimen was routinely efcacious and both were essentially equivalent. Major advances were beginning to be made against many infections in neutropenic patients, making it possible to use more intensive chemotherapeutic regimens. Schimpff et al.65 published a study of the combination of carbenicillin and gentamicin in 1969. Of 48 patients with documented bacterial infections, 52% improved on therapy as did 8 of 12 patients with probable infections. Fourteen (67%) of 21 documented Pseudomonas infections improved during therapy. Only four patients died of their Pseudomonas infections. Although some investigators had already begun the practice of initiating antibiotic therapy empirically to febrile neutropenic patients, it became a generally accepted practice following their reports. An important contribution introduced during this period was Klasterskys organization of the multi-institutional infection study group of the EORTC. Their rst study comparing carbenicillin/cephalothin, carbenicillin/gentamicin and cephalothin/ gentamicin began an ongoing series of investigations providing answers to important questions for optimizing the therapy of infections in neutropenic patients.66 Among these were his many studies evaluating the impact of serum bactericidal activity on outcomes of infections in neutropenic patients.67 Extensive clinical experience demonstrated that although the discoveries of new aminoglycosides and b-lactam antibiotics were both important, the broad-spectrum b-lactams were especially benecial for neutropenic patients.68 An example is the experience with Pseudomonas bacteraemia from 1972 to 1981 at the M. D. Anderson Cancer Center. Aminoglycosides alone (almost entirely gentamicin and tobramycin) were the only active antibiotics used to treat 128 patients and the cure rate was 29%. Among patients with .1000 PMN/mm3 initially, the cure rate was 54% whereas it was only 17% among patients with ,100 PMN/mm3 initially. Among the latter group, the cure rate was only 6% if the PMN count remained unchanged during therapy. The cure rate was 72% among the 90 patients treated with an antipseudomonal penicillin alone (mostly carbenicillin, ticarcillin and moxalactam). It was 76% among those patients with .1000 PMN/mm3 and 70% among those with ,100 PMN/ mm3. Since those early years, many physicians have conducted studies of the infectious complications of neutropenic patients and have made useful contributions that have improved the management of their patients. Many of these studies compared different antimicrobial regimens.69,70 These signicant advances in the diagnosis and therapy of infectious diseases have played a critical role in the successful outcomes of many cancer patients. Effective therapy of infections occurring in these patients has permitted the use of more aggressive therapeutic approaches for malignant diseases. Unfortunately, the battle against infection continues. Fungi have emerged as increasingly frequent pathogens and often pose difcult diagnostic and therapeutic challenges. Viruses are being increasingly recognized as a cause of acute and chronic diseases in these patients. Despite the plethora of antimicrobial agents the early nemeses, S. aureus and P. aeruginosa have re-emerged as life-threatening pathogens due to the appearance of strains resistant to most currently available antibiotics. Formerly uncommon pathogens have become common and are often resistant to most antibiotics. Unfortunately, as long as patients are neutropenic, it is likely that some of them will develop infectious complications.
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References
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