ORIGINAL ARTICLE

A multi-centre prospective study of febrile neutropenia in Norway:Microbiological findings and antimicrobial susceptibility

KATRIN SIGURDARDOTTIR1, ASBJØRN DIGRANES2, STIG HARTHUG1,

INGERID NESTHUS1, JON-MAGNUS TANGEN3, BRITT DYBDAHL4, PETER MEYER5,

GUNNAR HOPEN6, TURID LØKELAND7, KJELL GRØTTUM8, WENCHE VIE2 &

NINA LANGELAND1

From the 1Institute of Medicine, Haukeland University Hospital, Bergen, 2Department of Microbiology and Immunology,

Haukeland University Hospital, Bergen, 3Department of Haematology, Ulleval University Hospital, Oslo, 4Department of

Clinical Chemistry, Ulleval University Hospital, Oslo, 5Department of Haematology and Oncology, Stavanger University

Hospital, Stavanger, 6Institute of Medicine, Telemark Hospital, Skien, 7Department of Oncology, Haukeland University

Hospital, Bergen, and 8Institute of Medicine, Sørlandet Hospital Kristiansand, Kristiansand, Norway

AbstractThe urgent need to treat presumptive bacterial or fungal infections in neutropenic patients has meant that initial therapy isempiric and based on the pathogens most likely to be responsible, and drug resistance. The traditional empirical treatmentin Norway has been penicillin G and an aminoglycoside, and this combination has been criticized over recent y. We wishedto analyse the microbiological spectrum and susceptibility patterns of pathogens causing bacteraemia in febrile neutropenicpatients. This was a prospective multicentre study. During the study period of 2 y, a total of 282 episodes of fever involving243 neutropenic patients was observed. In 34% of episodes bacteraemia was documented. Overall, 40% of the episodeswere caused by Gram-positive organisms, 41% by Gram-negative organisms and 19% were polymicrobial. The mostfrequently isolated bacteria were Escherichia coli (25.6%), a- and non-haemolytic streptococci (15.6%), coagulase-negativestaphylococci (12.4%) and Klebsiella spp. (7.4%). None of the Gram-negative isolates was resistant to gentamicin,meropenem, ceftazidime or ciprofloxacin. Only 5 coagulase-negative staphylococci isolates were resistant to both penicillinG and aminoglycoside. The overall mortality rate was 7%, and 1.2% due to confirmed bacteraemic infection.

Introduction

In the 1960s, Bodey et al. first reported the relation-

ship between the depth and duration of neutropenia

and the risk of infection in cancer patients receiving

chemotherapy [1]. Since then infections in immu-

nocompromized patients are increasing in number,

aetiologies and complexity [2].

The bacterial aetiology is often unknown at the

onset of infection. Knowledge of the prevalence of

causative bacteria in neutropenic patients with fever

is important since prompt adequate antimicrobial

therapy is of vital importance. The epidemiology of

bacteraemia in neutropenic cancer patients has

changed [3�/5]. Published studies by the Interna-

tional Antimicrobial Therapy Cooperative Group of

the European Organisation for Research and Treat-

ment of Cancer (IATCG-EORTC) have demon-

strated the changing epidemiology over the past 3

decades. Gram-negative bacteria caused approxi-

mately 70% of monomicrobial bacteraemia in the

1970s, but the situation was completely reversed by

the late 1980s and 1990s, with Gram-positive

organisms causing approximately 70% of the epi-

sodes [6�/12]. The emergence of coagulase-negative

staphylococci (CoNS), viridans streptococci

and enterococci are mainly responsible for this

change [4].

In Norway, only 2 studies concerning infection in

febrile neutropenic patients have been published

[13,14].

Correspondence: K. Sigurdardottir, Institute of Medicine, Haukeland University Hospital, NO-5021 Bergen, Norway. (Fax: �/47 55 59 02 71. E-mail:

katrin.sigurdardottir@helse-bergen.no)

Scandinavian Journal of Infectious Diseases, 2005; 37: 455�/464

(Received 9 March 2004; accepted 11 April 2005)

ISSN 0036-5548 print/ISSN 1651-1980 online # 2005 Taylor & Francis

DOI: 10.1080/00365540510038497

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The clinician must also have knowledge of the

antibiotic susceptibilities among pathogenic bacteria

in the local area. Antimicrobial resistance is an

increasing problem worldwide. It affects the treat-

ment of infectious diseases resulting in increased

morbidity and mortality, as well as increased costs. It

is well established that there is an association

between the usage of antimicrobial agents and the

occurrence of resistant bacteria. There are probably

several reasons for the low level of antimicrobial

resistance in Norway [15�/20]. The level and profile

of antimicrobial consumption both in hospitals and

general practice is undoubtedly an important factor

[19,21]. Conventional empirical treatment of febrile

neutropenia in Norway has been penicillin G and an

aminoglycoside. Due to reports from other countries

of alternative broad-spectrum regimens being more

effective, we wished to analyse the microbiological

spectrum and susceptibility patterns of pathogens

causing bacteraemia in febrile neutropenic patients.

Materials and methods

Setting

Between June 1998 and June 2000, a total of 285

episodes of fever involving 243 neutropenic patients

were observed within 7 major Norwegian hospitals at

the haematology and oncology divisions (Ulleval

University Hospital, St. Olav’s Hospital, Haukeland

University Hospital, Stavanger University Hospital,

Telemark Hospital, Sørlandet Hospital Kristiansand

and Sørlandet Hospital Arendal). All clinical and

microbiological data were collected prospectively.

Patient eligibility

The patient population consisted of adults with

acute and chronic leukaemias, lymphomas, other

haematological malignancies or solid tumours.

Patients were eligible if they had fever (]/38.58Con 1 occasion or ]/38.08C on 2 occasions) and

absolute neutrophil count (ANC)5/0.5�/109/l.

This report represents a subgroup of patients who

had bacteraemia/fungaemia.

The trial was conducted in accordance with the

Declaration of Helsinki and all applicable national

and local ethical requirements (The Regional Com-

mittee for Ethics in Medical Research, Health

Region III).

Clinical and laboratory evaluation

All patients were examined for clinical signs and

possible sources of infections and had 2 sets of blood

cultures taken for aerobic and anaerobic culture.

Blood cultures were taken from the central lines as

well as peripheral veins.

Patients were given empirical antibiotic therapy

while awaiting the culture results.

Bacterial isolates

In the study period each laboratory collected blood

culture isolates from neutropenic patients with fever.

Only 1 isolate of any species from the same episode

was included. The isolates were forwarded to the

Department of Microbiology and Immunology,

Haukeland University Hospital, for confirmation of

identification and susceptibility testing. Isolates were

identified by standard methods [22�/24]

Blood stream infections were defined as the

isolation of any bacterial or fungal strain from 1 or

more blood cultures. When more than 1 organism

was isolated from a patient’s blood cultures drawn

within 48 h from inclusion, the episode was defined

as polymicrobial.

Further infections (i.e. secondary infections) were

defined as those caused by a new organism not

recognized as the initial pathogen and which

occurred during an empirical therapy for more

than 48 h.

Death was considered to be attributed to infection

when it occurred as a direct consequence of either

the presenting infection or a further infection.

Susceptibility testing

The minimum inhibitory concentrations (MICs) of

different antibacterial agents were determined, using

the E-test from AB Biodisk, (Solna, Sweden)

according to the recommendations from the manu-

facturer. PDM Antibiotic Sensitivity Medium II (AB

Biodisk) was employed as the test medium for the

great majority of the isolates. For the streptococcal

isolates the medium was supplemented with 5%

horse blood. Anaerobic bacteria were tested on

Fastidious Anaerobe Agar (IDG, UK).

The susceptibility of the staphylococcal isolates to

oxacillin was determined on Mueller-Hinton agar II

(Difco Laboratories, Detroit, USA) containing 4%

NaCl.

The isolates were categorized as resistant to

various agents according to breakpoints recom-

mended by the NCCLS [25].

Statistical analysis

In the comparison between distribution of species in

this study and previous studies the data were

evaluated by 2�/2 contingency tables with the use

456 K. Sigurdardottir et al.

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of the x2 test. Results of p B/0.05 were considered

statistically significant.

Results

Study population

During the study period a total of 285 episodes of

fever involving 243 neutropenic patients was

recorded. Three of the episodes did not fulfil the

inclusion criteria and were excluded. Thus, 282

episodes were eligible for microbiological evaluation.

There were 106 (38%) episodes with microbiologi-

cally documented infection, 95 (34%) with bacter-

aemia and 11 (4%) without bacteraemia. There were

missing clinical data in 8 episodes.

56% of the bactereamic episodes occurred in

males and 44% in females, and the mean age was

47 y (range 15�/79 y). 76% of patients were

profoundly neutropenic (ANC5/0.1�/109/l). 99%

of episodes occurred in patients with haematological

malignancy.

As their initial empirical treatment regimen 51

patients (58.6%) received penicillin and aminoglyco-

side, and in another 8 (9.2%) episodes it was

combined with an antifungal drug, and in a further

3 (3.4%) episodes with other antibacterial agents.

Ten (11.5%) patients received third-generation

cephalosporins, and in combination with an anti-

fungal drug in 2 (2.3%) episodes, and combined

with another antibacterial agent in 3 (3.4%) epi-

sodes. Two (2.3%) patients received carbapenem

and 1 (1.1%) in combination with vancomycin. The

rest of the patients (8%) received other combina-

tions, most commonly combined with an aminogly-

coside.

Microorganisms and susceptibility to antimicrobial agents

A total of 122 microorganisms was isolated in the 95

bacteraemic/fungaemic episodes (Table I).

Overall, 40% of episodes were caused by Gram-

positive organisms, 41% by Gram-negative organ-

isms and 19% were polymicrobial. The distribution

of the microorganisms identified is shown in Table I.

The most frequently isolated bacteria were Escher-

ichia coli (25.4%), a- and non-haemolytic strepto-

cocci (15.6%), coagulase-negative staphylococci

(CoNS) (12.3%) and Klebsiella spp. (7.4%). Pseu-

domonas aeruginosa accounted for 4.1% of all

Table I. Microorganisms isolated from 95 patients with blood stream infection (bacteraemia/fungaemia).

Primary infection Secondary infection Total

Microorganism No. (%) of isolates No. (%) of isolates No. (%) of isolates

Facultatively aerobic bacteria

Gram-positive bacteria 48 (48) 8 (36.4) 56 (45.9)

a-and non-haemolytic streptococci 19 (19) 19 (15.6)

Abiotrophia adiance 3 (3) 1 (4.5) 4 (3.3)

Beta-haemolytic streptococci 4 (4) 4 (3.3)

Coagulase-negative staphylococci 12 (12) 3 (13.6) 15 (12.3)

Staphylococcus aureus 6 (6) 6 (4.9)

Enterococcus spp. 2 (2) 3 (13.6) 5 (4.1)

Bacillus spp. 1 (1) 1 (4.5) 2 (1.6)

Corynebacterium spp. 1 (1) 1 (0.8)

Gram-negative bacteria 49 (49) 11 (50) 60 (49.2)

Escherichia coli 25 (25) 6 (27.3) 31 (25.4)

Klebsiella spp. 9 (9) 9 (7.4)

Enterobacter spp 5 (5) 1 (4.5) 6 (4.9)

Pseudomonas spp 4 (4) 1 (4.5) 5 (4.1)

Moraxella spp. 3 (3) 3 (2.5)

Serratia spp. 2 (9.1) 2 (1.6)

Citrobacter spp 2 (2) 2 (1.6)

Haemophilus influenzae 1 (1) 1 (0.8)

Neisseria spp. 1 (4.5) 1 (0.8)

Anaerobic bacteria 2 (2) 2 (9.1) 4 (3.3)

Fusobacterium spp. 2 (2) 2 (1.6)

Bacteroides spp. 1 (4.5) 1 (0.8)

Clostridium spp. 1 (4.5) 1 (0.8)

Fungi 1 (1) 1 (4.5) 2 (1.6)

Candida albicans 1 (4.5) 1 (0.8)

Candida krusei 1 (1) 1 (0.8)

Febrile neutropenia in Norway 457

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isolates. Two different bacterial strains were isolated

in 15 episodes (16%), and in 3 episodes (3%) more

than 2 strains were isolated. Two cases of fungaemia

were documented with Candida albicans and Can-

dida krusei isolates.

In 15 of the 95 bacteraemic episodes the bacter-

aemia occurred after empirical therapy for more than

48 h. Four episodes were caused by a Gram-positive

organism, 8 were due to a Gram-negative organism

and 3 were polymicrobial. 50% of the isolated

bacteria were aerobic Gram-negative aerobes and

36.4% were aerobic Gram-positive. E. coli, CoNS,

Enterococcus spp. and Serratia spp. were the most

common isolates. Anaerobic bacteria accounted for

9.1% of all isolates.

A total of 106 bacterial isolates was available for

antimicrobial susceptibility testing and the suscept-

ibility patterns of the isolates are shown in Tables II

and III. The majority of Staphylococcus aureus

(67%) and CoNS (93%) isolates produced b-lacta-

mase. Resistance to oxacillin was detected in 57% of

CoNS isolates and in none of the S. aureus isolates.

Five CoNS isolates were both penicillin and genta-

micin resistant

Table II. Antibiotic susceptibility of 46 Gram-positive blood culture isolates.

Microorganism

(no. of isolates) Agent

MIC (mg/l)

range

Resistant isolates

(no. of isolates)

a- and non-haemolytic streptococci cefuroxime 5/0.016�/2

(16) ceftazidime 0.023�/]/4

gentamicin 1�/24 a

vancomycin 0.38�/1

penicillin 0.0012�/0.38

clindamycin 0.032�/]/256 1

Beta-haemolytic streptococci cefuroxime 5/0.016

(4) ceftazidime 0.065�/4

gentamicin 4�/12 a

vancomycin 0.25�/0.38

penicillin 0.003�/0.012

clindamycin 0.032�/]/256 1

Abiotropha adiance cefuroxime 1.5�/2

(2) ceftazidime 6

gentamicin 4 a

vancomycin 1�/1.5

penicillin 0.047�/0.094

clindamycin 0.094�/0.38

Enterococcus spp. ampicillin 0.38�/0.75

(4) gentamicin 3�/1024 ab

vancomycin 2�/8

penicillin 0.5�/2

Coagulase-negative staphylococci cephalothin 0.064�/16 8c

(14) cefuroxime 0.094�/16 8c

ceftazidime 2�/32 8c

gentamicin 0.064�/]/256 5

vancomycin 0.75�/2

penicillin 13d

oxacillin 0.125�/]/256 8

clindamycin 0.032�/]/256 3

Staphylococcus aureus cephalothin 0.094�/0.38

(6) cefuroxime 0.38�/0.75

ceftazidime 3�/6

gentamicin 0.125�/0.38

vancomycin 1

penicillin 4d

oxacillin 0.094�/1.5

clindamycin 0.064�/0.64

aBreakpoints not established by the NCCLS.b1 isolate exhibited high level gentamicin resistance.cOxacillin resistant isolates.dPositive b-lactamase test.

458 K. Sigurdardottir et al.

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During the study period 19 episodes of a- and

non-haemolytic streptococci bacteraemia were regis-

tered. No streptococcal isolates were penicillin

resistant. The MICs of gentamicin for most of the

streptococcal isolates were within the range 1�/24

mg/l. Eight of the 20 streptococcal isolates had

Table III. Antibiotic susceptibility of the 58 Gram-negative blood culture isolates.

Microorganism

(no. of isolates) Agent

MIC (mg/l)

range

Resistant isolates

(no. of isolates)

Escherichia coli ampicillin 2�/]/256 15

(31) cefuroxime 1.5�/12

cefotaxime 0.023�/0.32

ceftazidime 0.047�/2

meropenem 0.0012�/0.032

ciprofloxacin 0.006�/0.25

gentamicin 0.094�/3

Klebsiella spp. ampicillin 16�/64 4

(8) cefuroxime 0.75�/2

cefotaxime 0.016�/0.064

ceftazidime 0.032�/0.5

meropenem 0.016�/0.023

ciprofloxacin 0.012�/0.047

gentamicin 0.125�/0.75

Enterobacter spp. ampicillin 8�/24

(5) cefuroxime 2�/6

cefotaxime 0.094�/0.19

ceftazidime 0.125�/0.75

meropenem 0.016�/0.16

ciprofloxacin 0.008�/0.016

gentamicin 0.25�/0.5

Serratia spp. ampicillin 4�/96 1

(2) cefuroxime 16�/48 1

cefotaxime 0.19

ceftazidime 0.094�/0.125

meropenem 0.016�/0.032

ciprofloxacin 0.016�/0.032

gentamicin 0.38

Citrobacter spp. ampicillin 2

(1) cefuroxime 2

cefotaxime 0.125

ceftazidime 0.38

meropenem 0.016

ciprofloxacin 0.012

gentamicin 0.125

Pseudomonas aeruginosa cefotaxime 8�/�/256 3

(5) ceftazidime 1�/8

meropenem 0.125�/6

ciprofloxacin 0.064�/0.25

gentamicin 0.75�/3

tobramycin 0.75�/3

Moraxella spp. ampicillin 0.032�/1

(3)/ cefuroxime 0.023�/4

Haemophilus influenzae cefotaxime B/0.016�/0.094

(1)/ ceftazidime 0.023�/0.064

Neisseria spp. meropenem 0.002�/0.25

(1) ciprofloxacin 0.012�/0.032

gentamicin B/0.064�/0.5

penicillin 0.25

Bacteroides spp meropenem 0.032

(1) penicillin 6

clindamycin 0.094

metronidazole 0.094

cefoxitin 2

Febrile neutropenia in Norway 459

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MICs�/8 mg/l but none exhibited high-level genta-

micin resistance. No glycopeptide-resistant Gram-

positive isolates were isolated in blood cultures.

None of the Gram-negative isolates was resistant

to gentamicin, meropenem, ceftazidime or cipro-

floxacin.

Mortality

The overall mortality rate was 7%. Mortality due to

the presenting (0.8%) or further bacteraemic infec-

tion (0.4%) was relatively uncommon. Table IV

shows underlying disease and characteristics of the

3 patients who died with microbiologically con-

firmed bacteraemia. Death occurred at a median of

10 d (range 1�/90 d) after entry. There was no death

related to Gram-negative septicaemia. Two patients

died from their presenting infections (bacteraemia)

with Gram-positive microbes. One of them had a

multiple-organism septicaemia with S. aureus and

a-haemolytic streptococci. This patient received

empirical treatment with penicillin and gentamicin,

and the S. aureus was penicillin-resistant and sus-

ceptible to gentamicin. The other had septicaemia

(Streptococcus pneumoniae) and pneumonia and

was treated with cefotaxime to which the isolate

showed full susceptibility. One patient died from

further infection with C. albicans and CoNS,

resistant to the empirical treatment with penicillin

and gentamicin.

Discussion

Over the past 25 y there has been a dramatic shift in

the microbiological pattern of infection in neutro-

penic patients. In studies conducted by the Eur-

opean Organisation for Research and Treatment of

Cancer (EORTC), Gram-positive cocci, mainly

CoNS and viridans streptococci increased in

frequency as causative agents of bacteraemia from

29% in the period 1974�/1976 [6,8,11] to over 65%

in the period 1988�/1990 [7].

This prospective multicentre observational study

on cancer patients with febrile neutropenia is the

first of its kind performed in Norway. The only

available data on febrile neutropenia in Norway are

from two retrospective studies [13,14]. In contrast to

many other studies no significant changes were

observed in the proportion of aerobic Gram-positive

cases in the 2 previous reports in the period 1990�/

1995 (44%) [13,14] compared to the present report

1998�/2000 (46%). Within the groups of organisms

there have been changes. In 1990�/1995 CoNS

(24%) [13,14] were the most commonly isolated

Gram-positive bacteria, with the a- and non-haemo-

lytic streptococci (10%) forming the second largest

group. In the present study the CoNS (12%) have

slipped back to second place (significant reduction

with p B/0.01) behind the a- and non-haemolytic

streptococci (15.6%) (significant increase with

p B/0.04). In recent y CoNS have been recognized

as 1 of the leading causes of bacteraemia in

neutropenic patients [4,26,27]. The criteria used to

assign clinical significance of CoNS in blood culture

will influence the proportion of bacteraemia assigned

to these organisms. The criterion used in the present

study, isolation of bacteria from 1 blood culture, may

result in an overestimation of the incidence of CoNS

as the cause of bacteraemia. The incidence of

streptococcal infections in cancer patients has been

rising for the past decade and the viridans strepto-

cocci have now become prominent as 1 of the

leading organisms causing bacteraemia in neutrope-

nic patients [4]. The proportion of bacteraemia due

to streptococci has increased in Norway from 11% in

the 1990�/1995 period [13,14] to 22% (p B/0.01)

(including the 4 Abiotrophia isolates) in the present

study. Gram-negative aerobic bacteria were isolated

in approximately 50% of bacteraemias in both

periods, with E.coli (1990�/1995 (23%)) [13,14],

and 1998�/2000 (25%)) as the leading cause.

In a report by Maschmeyer et al. the incidence of

infection due to P. aeruginosa was 1�/2.5% among all

patients presenting with first fever during neutrope-

nia, and 5�/12% among patients with microbiologi-

cally documented infections [28]. In our material

P. aeruginosa accounted for 4% of all isolates and no

deaths were related to this infection. The low

incidence of fungaemia is consistent with a previous

report from Norway where the fungaemia rates per

Table IV. Underlying disease and characteristics of the 3 patients who died with documented bacteraemia.

Underlying disease Age Cause of death Microorganisms Empirical therapy

1. Acute lymphoblastic leukaemia 43 Septic shock S. aureus a-hemolytic

streptococci

penicillin and aminoglycoside

2. Acute lymphoblastic leukaemia 59 Septic shock S. epidermidis C. albicans penicillin, aminoglycoside and

amphotericin B

3. Non-Hodkgins lymphoma 69 Pneumonia and

septic shock

S. pneumoniae cefotaxime

460 K. Sigurdardottir et al.

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10,000 patient d were 0.29 in 1991 and 0.27 in 1996

[29]. Compared to reports from other countries, it is

remarkable that Norway has such a low incidence of

fungaemia. Possible reasons for this might be

restricted antibiotic use and that the agent used is

different from that in many other countries. Treat-

ment for septicaemia of unknown aetiology in Nor-

way is a combination of an aminoglycoside and

penicillin G. The use of an aminoglycoside might be

important since this group of antibiotics has no

impact on the anaerobic gut flora, and yeast over-

growth is less likely to occur [30,31]. Secondary

(further) nosocomial blood stream infections are

associated with higher mortality rates [32] and the

occurrence of superinfection is a major problem in

the management of neutropenic patients [33,34].

The frequency of such further infections in different

clinical trials for neutropenic patients varies between

1 and 23% [34�/39]. In this series 15 (16%) of the

blood stream infections occurred after an empirical

therapy for more than 48 h. In previous studies these

infections have been caused by fungi and antibiotic

resistant Gram-negative bacteria [34] and in the

present study 53.3% were caused by Gram-negative

bacteria, 26.7% by Gram-positive bacteria and 20%

of the episodes were polymicrobial. When choosing

antibiotic treatment for such episodes, the results of

the present studies show that E. coli, CoNS,

enterococci and anaerobic bacteria must be taken

into consideration.

Susceptibility to antimicrobial agents

There are probably several reasons for the low level

of antimicrobial resistance in Norway. The overall

consumption of antibiotics for systemic use (ATC

group J01) in humans was 16.8 defined daily doses

(DDD)/1000 inhabitants/d in the y 2001 [19,21]

which is lower than in many other European

countries [40]. In European collaborative studies,

the incidence of antibiotic resistant bacteria was

higher in southern Europe than in northern and

central Europe [41,42]. Resistance to penicillin

among viridans streptococci is common in many

hospitals, with rates exceeding 50% in some reports

[43]. In the present study all the streptococcal

isolates were penicillin-susceptible. None of the

Gram-positive bacterial isolates in our material was

vancomycin resistant, probably reflecting the low

consumption of glycopetides (0.001 DDD/1000

inhabitants/d in the y 2001) in Norway [19,21].

The prevalence of methicillin resistant S. aureus

differs markedly among European countries (B/1%�/

80%), with the lowest rate in the Scandinavian

countries with less than 1% prevalence [44�/46].

This is consistent with our findings; none of the

S.aureus isolates was methicillin-resistant.

Over recent y, reports have been emerging con-

cerning fluoroquinolone-resistant E.coli causing

bacteraemia in neutropenic cancer patients [47].

Widespread use of fluoroquinolones to prevent

infection in patients with cancer and neutropenia is

associated with increased occurrence of resistance in

E.coli and CoNS [47,48]. Antibiotic prophylaxis in

neutropenic patients is not routinely performed in

Norway and none of the E.coli isolates in the present

study was ciprofloxacin resistant. None of the Gram-

negative isolates was resistant to gentamicin and this

is consistent with the findings of Hammerstrøm et al.

[14] and Tangen et al. [13]. A national surveillance

programme for the y 2003 found more than 99%

susceptibility to aminoglycosides in blood culture

isolates of E.coli and Klebsiella [49] Gram-negative

enteric bacilli are almost always resistant to penicillin

and aminoglycoside alone, and this is considered

suboptimal therapy for neutropenic patients [9].

Today we know that aminoglycoside shows a con-

centration-dependent bacterial killing. For optimal

antibacterial efficiency the peak/MIC ratio should be

�/10 to prevent the selection of a resistant subpo-

pulation of bacteria [50]. Most trials on empirical

treatment of febrile neutropenia in the 1970s and

1980s did not reach this peak/MIC ratio [9,51].

The combination of penicillin and aminoglycoside

as empirical treatment of febrile neutropenia is a

Norwegian treatment tradition and there are no

international studies to our knowledge. Two retro-

spective Norwegian studies have evaluated antimi-

crobial therapy in febrile neutropenic patients

[13,14]. Both studies conclude that the combination

of penicillin G and an aminoglycoside seems to be a

safe empirical treatment for febrile neutropenia,

provided that the treatment is modified in patients

with unsatisfactory clinical response. In our clinical

practice survival of the patient is the main clinical

criterion of success, even if the response rate by strict

definition is lower than 60%. The response rate in

the penicillin and aminoglycoside group was 24% in

the present study, which is low, and it is due to the

stringent definition of failure of empirical treatment

using the guidelines published by the Immunocom-

promized Host Society [52]. However, this high

failure rate was not associated with high mortality.

In recent y, an increasing proportion of infections

in neutropenic cancer patients is caused by organ-

isms which have multi-drug resistance, including

Acinetobacter spp., Stenotrophomonas maltophilia,

Klebsiella spp., Enterobacter spp., and Enterococcus

spp. [53]. Such resistant strains were not found in

our study.

Febrile neutropenia in Norway 461

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Mortality

The overall mortality in neutropenic patients is

largely related to factors other than infection, such

as extensive neoplasia. The infectious mortality rate

itself, including deaths from initial and subsequent

infections, is low. Although the percentage of deaths

attributable to infection has fallen considerably from

70�/80% recorded in the 1960s and 1970s, a study of

trials published by the EORTC-IATCG from 1978

to 1994 revealed that among nearly 800 documented

bacteraemias observed in 8 therapeutic trials (I�/V,

VIII, IX and XI), the overall mortality rate decreased

from 21% to 7% [3,54]. Recent IATCG-EORTC

trials show that the overall mortality ranges between

5% and 12% with an infectious mortality rate

between 1% and 3% [5,7,11]. Our data were

compatible with these reports with an overall mor-

tality rate of 7% and an infectious related mortality

of 2.1%.

Gram-negative bacteraemia is an important cause

of mortality and surprisingly no death was related to

Gram-negative bacteraemia in the present study.

S. aureus, viridans streptococci and pneumococci

may cause fulminant infections resulting in serious

complication or death, if not treated promptly

[55,56], and we report 2 deaths caused by those

microorganisms. The potential fatal complications

associated with streptococcal bacteraemia highlights

the need to attack the streptococci effectively with

first line therapy. The only death among patients

with bacteraemic further infection was due to mixed

infection with C. albicans and CoNS, the latter

being resistant to the empirical treatment with

penicillin and gentamicin.

Conclusions

The present study shows a distribution of pathogens

and antibiotic susceptibility pattern of the isolated

bacteria that is favourable compared to what has

been found in other countries. None of the Gram-

negative isolates was resistant to gentamicin and only

5 coagulase-negative staphylococci isolates were

resistant to both penicillin G and aminoglycoside.

Studies reporting local microbiological findings are

necessary because they support an antibiotic choice

for empirical therapy more accurately than

reports from other areas. We consider the combina-

tion of penicillin G and an aminoglycoside as initial

empirical treatment for patients with neutro-

penic fever safe for the time being, provided

that the treatment is modified in patients not

responding.

Acknowledgements

The Norwegian Research Council funded the study.

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