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. 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.
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. 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). 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. 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. 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 and Europe.[1,6,7] Coagulase-negative streptococcal species are a common cause of infection.
The Rainbow Babies and Childrens Hospital in Cleveland, Ohio, recently reported infection rates among their leukemia/lymphoma and solid tumor patients. 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. 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. 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. Patients with solid tumors, however, experienced more coagulase-negative infections.