In the 1960s, almost all patients who developed gram-negative bacterem
ia during granulocytopenia died; death occurred before blood culture r
esults were available in about 50% of cases; many patients received an
tibiotics that were, at best, suboptimal and frequently inactive again
st the invading pathogen. In the early 1970s epidemiological studies d
emonstrated that more than 50% of gram-negative bacteremias were cause
d by hospital-acquired strains which colonized along the alimentary ca
nal and caused infection in a limited number of locations, especially
the pharynx, lungs, colon, and perianum. Surveillance culture studies
have demonstrated that among acquired gram-negative bacilli, Pseudomon
as aeruginosa will almost invariably proceed to bacteremia if the pati
ent becomes profoundly neutropenic, with Estherichia coli and Klebsiel
la pneumoniae leading to bacteremia in only a moderate number of patie
nts and other gram-negative bacilli rarely progressing to bacteremia d
espite colonization. Hence, the leading causes of bacteremia in the gr
anulocytopenic patient are E. coli, K. pneumoniae and P. aeruginosa. F
urther investigations demonstrated that gram-negative bacilli were acq
uired from hands, food, and water, thus leading to approaches to infec
tion prevention which included careful handwashing, low-microbial-cont
ent diet, and attention to water sources, including ice machines. Anot
her basic approach to infection prevention has been to suppress gram-n
egative bacilli colonizing the alimentary canal with oral nonabsorbabl
e antibiotics or, more recently and more effectively, with agents such
as the fluoroquinolones which, unlike previous regimens, do not concu
rrently suppress the anaerobic flora, hence maintaining colonization r
esistance. The third basic approach to infection prevention is to impr
ove the host defense factors, principally by a more rapid-return of ci
rculating granulocytes with the use of colony-stimulating factors such
as granulocyte/macrophage colony-stimulating factor or granulocyte co
lony-stimulating factor. As to therapy, the fundamental approach with
presumed gram-negative bacteremia is the prompt institution of empiric
antibiotic therapy when fever first develops in the setting of granul
ocytopenia. There is a short ''window of opportunity'' after which no
therapy will be effective. Combinations of antibiotics such as a beta-
lactam and an aminoglycoside are used for multiple reasons: to afford
coverage in the event the pathogen proves resistant to one of the agen
ts, to afford a synergistic activity thus improving and prolonging the
serum bactericidal activity, and to reduce the development of resista
nce. However, patients can be divided into two risk groups: those with
granulocytopenia and a regenerating bone marrow and those with an apl
astic marrow who will have persistent, profound (< 100 mul) granulocyt
openia. Those in the former group can often be treated with a single b
road-spectrum beta-lactam antibiotic. Those in the latter group have a
poor prognosis but appear to respond better to a combination of agent
s, preferably a synergistic combination that achieves a high serum bac
tericidal activity. It is with this latter group of patients that the
therapeutic addition of colony-stimulating factors may prove to be mos
t valuable and, likewise, although there are no definitive data among
granulocytopenic patients as yet, monoclonal antibodies, such as HA-1A
or E5, may prove to be of added value.