Journal of Antimicrobial Chemotherapy (1998) 41, Suppl. D, 13–24
Control of Gram-negative bacillary infections
Fever and infection as a consequence of neutropenia,
mainly in acute leukaemia or agranulocytosis, were first
described about 100 years ago.1,2Because of its rarity, little
attention was devoted to the syndrome until neutropenic
fever and infection became a significant clinical problem
with the common use of cytostatic therapy for cancer.
It was Bodey et al.3who clearly demonstrated the close
relationship between the level and the duration of
neutropenia and the frequency of infection in patients
treated with chemotherapy for acute leukaemia. A t that
time, bacteraemia complicating severe neutropenia was
mainly caused by Gram-negative bacilli, namely Pseudo -
monas aeruginosa, and was associated with a disastrous
90% mortality rate,4in spite of the availability of anti-
biotics active in vitro.
Two major events played a basic role in the change of
the mortality of Gram-negative bacillary infections in
neutropenic patients: (i) the wide acceptance of empirical
therapy and (ii) the optimal use of antibiotic combina-
It has been recognized that infection with Gram-
negative organisms, especially when P. aeruginosa was
involved, was often fulminant in neutropenia and killed
more than half of the patients within 48 h of onset.5In
addition, it became clear that neutropenia minimized
many signs and symptoms of infection and that fever was
often the only early manifestation of sepsis.6Based on
these observations, the concept of empirical therapy for
fever in neutropenic patients was proposed by Schimpff
et al.7In the study that launched the concept, a com-
bination (carbenicillin gentamicin) active against P.
aeruginosa and other Gram-negative bacilli was used
empirically as soon as neutropenic patients became
febrile, without waiting for clinical and/or microbiological
evidence of infection. There was a dramatic reduction in
the mortality associated with retrospectively documented
infection due to P. aeruginosa. A lthough it was unclear
whether the empirical approach or the effective com-
bination played the major role, the concept of empirical
therapy was very widely accepted without any further
controlled investigation. Of course, the early (empirical)
use of antibiotics for fever in neutropenic patients makes
the microbiological documentation of infection more
difficult. A s shown in Table I, summarizing data from trials
V III and IX of the International A ntimicrobial Therapy
Cooperative Group–European Organization for Research
and Treatment of Cancer (IA TCG-EORTC) in 1290 cases
of febrile neutropenia, microbiological documentation
was obtained in about 25% of the febrile patients, usually
through positive blood cultures. However, as many as 40%
of patients remained without any microbiological and/or
clinical documentation of infection. The respective res-
ponse rates to empirical therapy in these two groups of
neutropenic patients were 38% and 57%.8,9
The value of synergic antibiotic combinations for the
treatment of Gram-negative bacillary bacteraemia in
neutropenic patients has been demonstrated by Klastersky
et al.10in a series of studies, culminating in the IA TCG-
EORTC clinical comparative trial IV , which showed that a
full course of ceftazidime
regimen in which amikacin was discontinued early.11In
that study, the overall mortality rate in patients with acute
leukaemia and Gram-negative bacillary bacteraemia who
received the optimal therapy was 17% (definite infectious
amikacin was superior to a
Science and pragmatism in the treatment and prevention of
J . Klastersky
Service de Médecine Interne et L aboratoire d’Investigation Clinique H. Tagnon, Institut Jules Bordet,
Centre des Tumeurs de l’Université L ibre de Bruxelles, 1 rue Héger-Bordet, 1000 Brussels, Belgium
The following aspects of the management of patients with granulocytopenia and fever are
reviewed in this article: adaptation of initial antibiotic regimens to the recent changes in the
most common causative pathogens (namely a change from Gram-negative bacteria to Gram-
positive bacteria and fungi); subsequent modifications of the empirically administered treat-
ments; improvement of the host’s defence by reducing the duration of neutropenia; and
indications for out patient therapy of febrile episodes.
© 1998 The British Society for A ntimicrobial Chemotherapy
J . Klastersky
mortality was 8%), a dramatic difference from the 91%
figure reported 25 years earlier.4
Besides providing the benefit of synergy, amino-
glycoside-containing combinations have the advantage of
not leaving untreated a patient whose pathogen would be
resistant to -lactams. In IA TCG-EORTC trial I, the
combination of carbenicillin
carbenicillin cephalothin because infections caused by
microorganisms resistant to both
poorly;12in fact, most patients infected with doubly
resistant strains died. In IA TCG-EORTC trial III, in-
fections caused by -lactam-resistant and aminoglycoside-
sensitive organisms did not have an increased mortality
compared with those due to fully sensitive pathogens,
although their response rate to empirical therapy was
significantly lower.13These observations suggest that the
gentamicin was superior to
inclusion of the aminoglycoside into the empirical com-
bination might ‘buy time’ and allow for antibiotic
adjustment according to microbiological documentation.
Of course, the more frequent use of an aminoglycoside
can lead to greater toxicity and requires the monitoring
of blood concentrations. However, the value of synergic
aminoglycoside-containing combinations has only been
demonstrated in patients with prolonged and severe
granulocytopenia and concomitant Gram-negative bacter-
aemia. These conditions were found in only 75 (3.2%) of
2356 patients included in the last three IA TCG-EORTC
trials, so empirical aminoglycosides can be discontinued
early in all other patients.11
Changing microbiological pattern
During the last decade, Gram-negative bacilli have gradu-
ally been replaced by Gram-positive cocci as the cause of
microbiologically documented infections complicating
A s indicated in Table II, summarizing the blood culture
data from seven consecutive IA TCG-EORTC trials,
Gram-positive microorganisms (mainly Staphylococcus
epidermidis and various strains of streptococci) now
represent 70% of the bacteraemic isolates. That trend has
been observed universally. In addition, new pathogens
have emerged in neutropenic patients, but at a slower pace
than in A IDS patients, and resistant pathogens have
become more common. The resistance is either intrinsic,
such as the resistance of Candida krusei to imidazoles, or
acquired, as exemplified by recent outbreaks of vanco-
mycin-resistant enterococci in patients treated previously
with cephalosporins or vancomycin. Constant epidemio-
Table I. Infection documentation in IA TCG-EORTC
trials V III nd IX
Fever not related to infection
Table II. Single-organism bacteraemia in IA TCG-EORTC trials
I II III IVVV IIIIX
(1973–8) (1978–80)(1980–83) (1983–6)(1986–8)(1989–91)(1992–4)
febrile episodes (%)
Gram-negative bacteraemia (%)
Gram-positive bacteraemia (%)
other Gram-positive organisms
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