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Prospective Analysis of Staphylococcus aureus Bacteremia in Nonneutropenic Adults With Malignancy

From the Division of Infectious Diseases and Departments of Medicine and Pediatrics, Duke University Medical Center, Durham, NC.

Address reprint requests to Ajay K. Gopal, MD, Division of Medical Oncology, University of Washington Medical Center, Box 356043, Seattle, WA 98195-6043; email agopal{at}u.washington.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the primary sources and secondary complications of Staphylococcus aureus bacteremia (SAB) in cancer patients, as well as predictors of outcome in cancer patients with SAB.

PATIENTS AND METHODS: Fifty-two patients at Duke University Medical Center met entry criteria between September 1994 and December 1996 for this prospective cohort study involving hospitalized nonneutropenic adult cancer patients with SAB. All subjects were observed throughout initial hospitalization and were evaluated again at 6 and 12 weeks or until death.

RESULTS: SAB was intravascular device–related in 42%, tissue infection–related (TIR) in 44%, and unidentifiable focus–related (UFR) in 13%. Seventeen patients (33%) were found to have metastatic infections or conditions, with eight (15%) developing infectious endocarditis (IE). Patients with TIR bacteremia were less likely than other patients to develop IE (4% v 24%, P = .06). The overall mortality rate was 38%, the SAB-related mortality rate was 15%, and the rate of SAB relapse was 12%. Methicillin resistance was not associated with adverse outcome. Inability to identify a point of entry (UFR bacteremia), however, was associated with a higher overall mortality rate (100% v 24%, P = .0006). Furthermore, a 72-hour surveillance blood culture positive for organisms was associated with an increased incidence of IE (P = .0006), metastatic infections or conditions (P = .0002), SAB relapse (P = .038), and SAB-related death (P = .038).

CONCLUSION: SAB in cancer patients is associated with significant morbidity from frequent metastatic infections or conditions including IE, as well as considerable mortality. Unknown initial infection site and 72-hour surveillance cultures positive for organisms were predictive of a complicated course and poor final outcome.

	INTRODUCTION

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STAPHYLOCOCCUS AUREUS is a common cause of bacteremia in cancer patients.^1,2 Studies not limited to cancer patients have shown that these infections arise primarily from wounds and intravascular devices^3-10 and have steadily increased over the last decade, closely paralleling the increasingly frequent use of indwelling catheters.^11-13 These series demonstrated considerable morbidity and mortality from secondary complications such as infective endocarditis (IE) and metastatic abscesses.^3-10,14-16 Unfortunately, these studies did not specifically focus on cancer patients with SAB.

Cancer patients are a unique cohort, frequently having semipermanent central venous access and relative immunocompromise even without overt neutropenia. Although some studies suggest the existence of higher rates of SAB in nonneutropenic patients, to date most studies attempting to evaluate SAB in patients with malignancy have involved small retrospective series frequently limited to patients with neutropenia.^17-19 These studies have demonstrated a broad range of complication and mortality rates and have been commonly confounded by high numbers of non–SAB-related deaths. Overall, there remain few prospectively collected data on this large unique group of patients. In this study, we prospectively evaluated nonneutropenic adult cancer patients with SAB in an attempt to identify the primary sources of bacteremia, evaluate the secondary complications of infection, and define the predictive factors for outcome.

	PATIENTS AND METHODS

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Subjects and Setting
The Staphylococcus aureus Bacteremia Group (SABG) prospectively evaluated consecutive episodes of bacteremia in adult inpatients at the Duke University Medical Center (DUMC), Durham, NC. Entrance into the SAB registry was initiated on determination by the DUMC microbiology laboratory that a blood culture was positive for S aureus and subsequent notification of a member of SABG. All patients were evaluated within 36 hours of determination that blood cultures were positive. Patients meeting the eligibility criteria and in whom the diagnosis of cancer had been made were evaluated. The characteristics of these episodes of SAB in cancer patients are reported. This protocol was approved by the institutional human subjects review board.

Eligibility Criteria
A patient was considered to have SAB if one of the following two criteria were met: (1) two separate blood cultures positive for S aureus obtained within 24 hours or (2) one set of blood cultures positive for S aureus and clinical evidence of systemic infection. Blood cultures were obtained using standard technique by inoculating 5 to 10 mL of blood into at least one aerobic and one anaerobic Bactec bottle (Becton Dickinson, Franklin Lakes, NJ). The DUMC microbiology laboratory used disc diffusion methods to test for antimicrobial sensitivities. Patients were considered to have cancer if they had received antineoplastic therapy within 6 months of enrollment or if a new diagnosis of cancer had been made within that time.

Patients were excluded from the study if they were younger than 18 years, had polymicrobial bacteremia, had previously been enrolled onto this study within 6 months, had not been hospitalized at any time after blood cultures positive for S aureus were obtained, died before evaluation, or had absolute neutrophil counts less than 1,000/mm³ at the time blood cultures positive for S aureus were obtained. We excluded neutropenic patients because we hypothesized that the neutropenia could override other predictors of outcome as well as hinder the localization of a primary focus because of a blunted inflammatory response.

Definitions
SAB was categorized as tissue infection–related (TIR) or intravascular device–related (IVDR). Each patient with TIR bacteremia had a wound culture positive for S aureus and/or clinical evidence of wound infection without another identified source of infection; S aureus cultured from sputum or endotracheal aspirate and a compatible clinical syndrome such as an infiltrate on a chest radiograph; and no other identified portal of infection.²⁰ Patients with IVDR bacteremia had an exit-site culture positive for S aureus and pus or erythema; or an intravascular device quantitative culture positive for S aureus.²¹ SAB was deemed unidentifiable focus–related (UFR) if physical examination, radiologic studies, cultures, or surgical exploration did not, according to the primary physician, reveal a point of entry.

IE was defined using the Duke criteria.²² A nosocomial infection was considered present when there was initial medical recognition after at least a 72-hour stay or within 7 days of discharge from a hospital or nursing home. A metastatic infection was defined as IE or an infection at a distant site in a patient with another known portal. S aureus pneumonia was considered metastatic if an initial portal was identified before development of clinical pneumonia.

Treatment Evaluation
Patients were classified as having received vancomycin or beta-lactam (usually nafcillin or cefazolin) therapy if one of these agents was prescribed for the entire treatment period or if therapy was converted to one of these treatment types within 2 days of initiating treatment with another antibiotic type. Vancomycin was dosed on the basis of measured serum drug levels; nafcillin was dosed at 2 g intravenously (IV) every 4 to 6 hours, and cefazolin was dosed at 1 to 2 g IV every 8 hours. Some patients receiving vancomycin for methicillin-resistant S aureus (MRSA) bacteremia also received rifampin 600 mg daily. The duration of antibiotic therapy was defined as the length of time in days that the patient received effective (as determined by antibiotic sensitivities) IV antibiotic.

Outcome
Patients were observed prospectively and outcomes were assessed by a member of SABG at 6 and 12 weeks after the first blood culture positive for S aureus. Patients or their treating physicians were contacted either in person or by telephone. Patient outcome was initially classified as resolution or failure. All patients with treatment failure died. Patients with resolved infection were further observed up to 12 weeks and classified as having being cured or relapsed. This approach resulted in four patient groups, distinguished by the following outcomes: cure (resolution of clinical signs of infection during therapy and no evidence of recurrent SAB within 12 weeks of follow-up), relapse (clinical resolution of signs and symptoms of infection during therapy but recurrent SAB within 12 weeks of follow-up), death due to SAB (clinical and microbiologic evidence of infection at the time of death, without an alternate explanation of death), and non–SAB-related death (death due to underlying malignancy or another process, with no evidence of infection at the time of death).

Statistics
Data were entered into Microsoft Access (Microsoft Corporation, Redmond, WA) and analyzed using the two-sided Fisher’s exact test for categoric variables. Statistical significance was defined as P .05.

	RESULTS

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Four-hundred thirty episodes of SAB were identified at DUMC between September 1994 and December 1996, with 122 (28%) occurring in patients with cancer. Of these patients, 33 (27%) had neutropenia, 17 patients (14%) had polymicrobial bacteremia, 10 patients (8%) were younger than 18 years, seven patients (5.7%) died before initial evaluation, and three (2.5%) remained outpatients after blood cultures positive for S aureus were obtained; all of these patients were excluded. The remaining 52 patient episodes were assessable, and all surviving patients underwent 6- and 12-week follow-up. Baseline characteristics of these patients are presented in Table 1. The overall mortality rate was 38%, the SAB-specific mortality rate was 15%, and the rate of SAB relapse was 12%.

Surveillance cultures were obtained from 32 of 52 eligible patients 72 hours after pathogen-directed antibiotic therapy was begun, in an effort to predict complicated bacteremia. Fifteen (47%) of these cultures were positive (Table 3). Having a surveillance culture positive for S aureus was associated with metastatic infections or conditions (P = .0002) and, specifically, IE (P = .0006). Such a culture was also predictive of SAB relapse (P = .038) and SAB-related mortality (P = .038).

Twenty patients (38%) presented with MRSA bacteremia, whereas 32 (62%) had methicillin-susceptible S aureus (MSSA) bacteremia. Seventeen (65%) of 26 patients with a nosocomial source developed MRSA bacteremia, whereas only three (12%) of 26 patients with community-acquired isolates had MRSA bacteremia (P = .0001). Methicillin resistance was not associated with overall mortality, SAB-specific mortality, relapse of SAB, primary source of infection, frequency of 72-hour surveillance cultures positive for S aureus, or development of IE. Of the 32 patients with MSSA bacteremia, 10 were treated with vancomycin and 22 were treated with a cephalosporin or penicillin. Antibiotic choice in this group was not associated with adverse outcome. Of the 20 patients with MRSA bacteremia, all received vancomycin and five patients also received rifampin. Of the patients with MRSA bacteremia who did not die from their malignancy, all four of those treated with rifampin and vancomycin were alive and free from SAB relapse at 3 months, compared with three (25%) of 12 of those treated with vancomycin alone (P = .02).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This first prospective evaluation of a large group of cancer patients with SAB resulted in several provocative findings. First, we demonstrated a high rate of complicated infections, with one third of SAB patients developing metastatic infections or conditions and 15% developing endocarditis. Second, SAB was associated with a high mortality even in nonneutropenic hosts. Third, SAB patients with 72-hour surveillance cultures positive for S aureus had increased rates of SAB-specific complications, relapse, and mortality.

Previous studies evaluating SAB in cancer patients demonstrated metastatic infections in 0% to 16% of patients.^17,23 In contrast, 33% of our patients developed metastatic infections or conditions, more closely paralleling findings by Raad et al,²⁴ whose study was limited to cancer patients with intravascular devices. However, our patients did not achieve the 23% rate of septic thrombosis of the study by Raad et al. This lower rate of septic thrombosis may be due to our varied primary foci of bacteremia, prospective identification of infections, and frequent removal of catheters suspected to be involved. The overall higher rate of metastatic infections or conditions in our study may be due to the fact that we prospectively evaluated patients and aggressively looked for IE. In contrast to previous studies, we focused on a nonneutropenic population that not only may have a longer survival time in which to develop complications, but also may have a more vigorous inflammatory response, manifesting more metastatic infections. However, we may have overestimated the rate of IE; other groups have demonstrated high rates of noninfectious cardiac vegetations in solid-tumor cancer patients.²⁵

In addition to a high complication rate, our patients with SAB had significant overall mortality (38%) and SAB-specific mortality (15%) rates. These figures are in contrast to the 4.3% to 19% overall mortality rate found in the few previous studies of SAB in cancer patients.^17,23 In our study, overall mortality was significantly higher in patients with UFR bacteremia. These patients seemed to die rapidly from their cancer and may have had a blunted inflammatory response, hindering localization of the primary focus.

Patients whose surveillance cultures obtained 72 hours after starting antibiotic therapy were positive for S aureus had an increased rate of SAB relapse. These same patients had higher rates of metastatic infections or conditions and IE. Our findings agree with those of a previous study evaluating retrospectively identified IVDR SAB in cancer patients.²⁶ Despite recognition of ongoing bacteremia and initiation of pathogen-directed therapy, our patients with 72-hour cultures positive for S aureus also had higher rates of SAB relapse and SAB-related mortality. These observations, likely representing either an inability to clear ongoing bacteremia or a sequestered nidus, can serve as guides for the clinician to locate and remove possible foci of infection as well as for more aggressive investigation of potential metastatic infections such as IE. Furthermore, these same patients may require a longer course of antibiotic therapy to prevent relapse and possibly reduce SAB-related mortality.

The primary source of SAB also seemed to influence outcome. In addition to the finding of increased mortality in UFR SAB, we demonstrated that patients with TIR SAB had lower rates of IE compared with those with other types of SAB that trended toward significance. One could hypothesize that this low rate of IE in patients with tissue infections may be related to a lower level or duration of bacteremia in this group than in patients with intravascular infections. Patients with TIR SAB and surveillance cultures negative for S aureus may be considered at very low risk of developing IE or metastatic complications.

Identification of MRSA as primarily a nosocomial pathogen is consistent with findings of previous studies.^27,28 We confirmed that there is no increase in mortality with MRSA compared with MSSA infection.^17,29 We did find, however, that patients with MRSA infection who were receiving rifampin with vancomycin had a statistically significantly improved outcome compared with those receiving vancomycin alone. This is not unexpected given rifampin’s excellent in vitro activity against S aureus, although only a few studies have evaluated its clinical efficacy.^30-32 Unfortunately, as with previous studies, the limited number of assessable patients and the possibility of unmeasured confounding variables (eg, functional status and ability to receive oral rifampin) make it impossible to draw definitive conclusions.

This study has several limitations. First, the observational design of this study limited treatment comparisons. Second, we were limited in statistical power by our overall sample size. Finally, using mutually exclusive end points such as competing causes of death can also influence results (ie, patients who died from cancer could not also die from SAB or have relapse of SAB). Despite these limitations, this project represents the first prospective assessment of SAB in nonneutropenic patients with malignancy and may serve as the basis for future investigations.

In summary, our study demonstrates that SAB in nonneutropenic cancer patients carries with it high complication and mortality rates that are associated with both infection source and persistence of bacteremia. Future confirmatory trials can focus on an algorithmic approach to the treatment of SAB in nonneutropenic cancer patients.^33-35 We anticipate that such an approach will eventually improve the outcome of the increasing number of cancer patients with SAB.

	ACKNOWLEDGMENTS

 
Supported by a Health Services Research and Development fellowship from the Veterans Administration Medical Center, Durham, NC.

	REFERENCES

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Submitted June 29, 1999; accepted September 30, 1999.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gopal, A. K. Articles by Corey, G. R. Search for Related Content PubMed PubMed Citation Articles by Gopal, A. K. Articles by Corey, G. R. Social Bookmarking                            What's this?