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Changing Patterns of Infections and Antimicrobial Susceptibilities

Changing Patterns of Infections and Antimicrobial Susceptibilities

ABSTRACT: Nosocomial bloodstream infections across the United States and in Europe are increasingly attributable to gram-positive species— a trend that represents a reversal of the gram-negative predominance of the previous decades. Data from Memorial Sloan-Kettering Cancer Center and elsewhere show that patients with hematologic malignancies or patients who are immunocompromised because of anticancer treatments are experiencing this shift in microbial spectrum. Most common among gram-positive species are coagulase-negative Staphylococci. Antimicrobial resistance continues to increase, which makes treatment more difficult for infections caused by some species, especially vancomycin-resistant enterococcal species. The underlying causes of changes in microbial spectrum and drug-resistance patterns are incompletely understood, but it is clear that antibiotic exposure exerts a significant selective pressure on pathogens, resulting in partial or complete resistance. New drugs or drug combinations will be necessary to treat drug-resistant infections in cancer patients. [ONCOLOGY 14(Suppl 6):9-16, 2000]

Introduction

Patients with hematologic malignancies and other patients with cancer
who are receiving aggressive treatment with chemotherapeutic regimens
are highly susceptible to infections because of lowered leukocyte
counts and breakdown in their mucosal and immunologic barriers.[1]
These patients often experience episodes of fever and neutropenia,
and are hospitalized to receive intravenous antimicrobial therapy
until their acute illness resolves. The appropriate choice and prompt
delivery of antibacterial drugs is crucial to decrease morbidity and
mortality in these patients.

Selection of empiric treatment for any bacterial infection must
account for antibiotic resistance patterns. The kinds of organisms
that predominate vary geographically, temporally, between patients,
and within the same patient over time.

The predominant infectious organisms in patients with neutropenia and
fever have shifted over the past few decades: gram-negative bacilli
were more prevalent in the past, but gram-positive cocci now
predominate. This shift in pathogens is one of several factors that
must be taken into account in the design of an effective empiric drug
regimen.

This article will review changes in the prevalence of bacterial
species causing bloodstream infections in the United States and
Europe. The article will also review microbial resistance patterns
and present evidence regarding newer drugs that are active against
resistant bacterial strains. Data from microbiologic surveys in
institutions that treat cancer patients are considered, along with
surveillance data of bloodstream infections among the general
hospitalized population.

Emergence of Gram-Positive Bacterial Predominance

The pattern of isolates causing bloodstream infections in
hospitalized patients, both in the United States and in Europe, has
changed, and gram-positive organisms are now predominant. The
investigators conducting the Surveillance and Control of Pathogens of
Epidemiologic Importance (SCOPE), a national surveillance program,
recently reported findings from 10,617 cases of nosocomial
bloodstream infections at 49 hospitals in the United States.[2] For
all patients and hospital departments combined, well over half (64%)
of the isolates were gram-positive cocci (Table
1
).

The most common isolates were coagulase-negative staphylococci,
followed by Staphylococcus aureus, and then enterococcus
species. Streptococcal species accounted for about 6% of all
bloodstream isolates, of which half were due to the viridans group
(especially Streptococcus mitis, Streptococcus sanguis, and Streptococcus
salivarius
).[3] Gram-negative bacilli were isolated in 27% of
these samples. This is a reversal of the pattern of the organisms
recovered in the 1970s, when gram-negative species were isolated in
more than 75% of nosocomial bloodstream infections.

The pathogens reported in the SCOPE study were from clinically ill
patients with bloodstream infections. An analysis of patient
subgroups revealed that, among neutropenic patients, S aureus
was isolated less often, and streptococci of the viridans group were
identified more often, than in patients with a normal neutrophil
count.[2] There was also a clear difference in the frequency of
specific pathogens when data were subdivided into cases from
intensive care units (ICUs) and other inpatient wards (Figure
1
).

For example, Enterobacter species (gram-negative) were nearly twice
as common in ICUs than in regular wards, but the reverse was true for Escherichia
coli
and viridans group streptococci. These observations are a
reminder that patterns of pathogens vary among patient subpopulations
and hospital departments.

Similar trends have been seen at Memorial Sloan-Kettering Cancer
Center (MSKCC), a hospital (approximately 18,000 admissions/year) in
New York City that specializes in cancer. Data have recently been
compiled that describe the prevalence and resistance patterns of
bacteria among all cancer patients, most of whom had leukemia or
lymphoma or were recipients of a hematopoietic stem-cell transplant.
Some of the findings in this pool of patients parallel those of the
SCOPE study, while others reflect local variation.

A basic finding at MSKCC was that the rate of bloodstream infection
cases had increased over the past decade, despite increased
prophylactic use of fluoroquinolones and other antibiotics. When the
number of specific organisms was analyzed, gram-positive species were
detected in blood samples from patients with bloodstream infections
more frequently than were gram-negative bacteria (Figure
2
). While gram-negative infections have decreased, they still
pose a significant potential threat of morbidity and mortality for
immunocompromised patients.

The bacterial species most likely to cause infections at MSKCC were
coagulase-negative staphylococci, S aureus, and enterococci.
Coagulase-negative staphylococci outnumbered S aureus by about
400%. Among gram-negative species, E coli, Klebsiella species,
Pseudomonas aeruginosa,
and Enterobacter species were
still the most common pathogens, accounting for about 44%, 28%, 16%,
and 12% of gram-negative infections, respectively.

Shifting Pathogen Prevalence in Europe

As in the United States, many European centers are experiencing a
rise in the prevalence of gram-positive bacteria and a relative
decline of gram-negative species. The International Antimicrobial
Therapy Cooperative Group of the European Organization for Research
and Treatment of Cancer (EORTC) has for decades recorded patterns of
infectious microbes among cancer patients entered into their
treatment trials.[4] In the 1970s, gram-negative species accounted
for about 70% of single-organism bloodstream infections, but by the
late 1980s, gram-positive bacteria had become predominate. Currently,
gram-positive bacteria account for about 70% of bloodstream
infections in these patients (Figure
3
).

It should be noted, however, that gram-negative organisms (eg, P aeruginosa)
are still common enough to require an empiric regimen that includes
antibacteria activity against such species. As is the case in the
United States, coagulase-negative staphylococci were the most common
pathogens, but the prevalence of viridans group streptococci varies
between individual centers, and also has varied over the years
recorded by the EORTC (Figure 4).
For example, in a survey conducted in France with the support of the
Maurice Rapin Institute, a low incidence of viridans infection (4% of
total cases of febrile neutropenia) was noted, contrary to some other
institutions.[Ribaud P. December 1999. Unpublished data.]

Pediatric Cancer Populations

Pediatric cancer patients who are neutropenic typically experience
fever of unknown origin. The populations of suspected causative
organisms display several features similar to those of adult
populations. In children, as in adults, a predominance of
gram-positive infections has been reported in several recent series,
both in the United States[5] and Europe.[1,6,7] Coagulase-negative
streptococcal species are a common cause of infection.

The Rainbow Babies and Children’s Hospital in Cleveland, Ohio,
recently reported infection rates among their leukemia/lymphoma and
solid tumor patients.[5] Eighty-three percent of patients developed
infections. Bloodstream infections and otitis media were the most
prevalent infections, each accounting for 23% of all cases.
Gram-positive organisms dominated the blood culture isolates (49%)
compared to gram-negative species (34%). Coagulase-negative
staphylococci were the predominate gram-positive species.

Mortality due to all causes was 36% in these pediatric patients,
one-fifth of which was attributed to infection, particularly gram-negative
bloodstream infections.[5] A recent analysis of pediatric blood
isolates from an Italian transplant center reported a suspected
infection (fever during the granulocytopenic period) in 87% of
patients, with bloodstream infections being the most common type of
infection. Gram-positive species were isolated more than twice as
often as gram-negative species.[1] Almost all gram-positive species
were either coagulase-negative staphylococci or viridans group
streptococci.

The frequency of isolates of viridans group streptococci varies
widely among reports for pediatric cancer patients at different
centers. A pediatric oncology department in Germany found viridans
streptococci to be more common than coagulase-negative isolates among
leukemia/lymphoma patients.[6] Patients with solid tumors, however,
experienced more coagulase-negative infections.[7]

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