Determinants of mortality in oncology patients colonized or infected with Staphylococcus aureus

Determinantes de mortalidade em pacientes colonizados ou infectados por internados em um hospital do câncer. Staphylococcus aureus

Abstracts

Oxacillin-resistant Staphylococcus aureus (ORSA) infection is an important cause of hospital morbidity and mortality. The objective of this study was to identify the main factors associated with death in patients colonized or infected with Staphylococcus aureus in a cancer center. A matched-pair case-control study enrolled all patients infected or colonized with ORSA (cases) admitted to the Hospital do Câncer in Rio de Janeiro from 01/01/1992 to 12/31/1994. A control was defined as a patient hospitalized during the same period as the case-patients and colonized or infected with oxacillin-susceptible Staphylococcus aureus (OSSA). The study enrolled 95 cases and 95 controls. Patient distribution was similar for the two groups (p > or = 0.05) with respect to gender, underlying diseases, hospital transfer, prior infection, age, temperature, heart and respiratory rates, neutrophil count, and duration of hospitalization. Univariate analysis of putative risk factors associated with mortality showed the following significant variables: admission to the intensive care unit (ICU), presence of bacteremia, use of central venous catheter (CVC), ORSA colonization or infection, pneumonia, use of urinary catheter, primary lung infection, prior use of antibiotics, mucositis, and absence of cutaneous abscesses. Multivariate analysis showed a strong association between mortality and the following independent variables: admission to ICU (OR [odds ratio]=7.2), presence of Staphylococcus bacteremia (OR=6.8), presence of CVC (OR=5.3), and isolation of ORSA (OR=2.7). The study suggests a higher virulence of ORSA in comparison to OSSA in cancer patients.

Staphylococcus aureus; Oxacillin-resistance; Mortality; Cancer

DETERMINANTS OF MORTALITY IN ONCOLOGY PATIENTS COLONIZED OR INFECTED WITH STAPHYLOCOCCUS AUREUS

Luiz Claudio Santos Thuler, Eduardo Velasco, Carlos Alberto de S. Martins and Marilak Villanova D'Assunção

RHCFAP/2961

THULER, L.C.S et al. - Determinants of mortality in oncology patients colonized or infected with staphylococcus aureus. Rev. Hosp. Clín. Fac. Med. S. Paulo, 54 (2): 47 - 52, 1999.

SUMMARY: Oxacillin-resistant Staphylococcus aureus (ORSA) infection is an important cause of hospital morbidity and mortality. The objective of this study was to identify the main factors associated with death in patients colonized or infected with Staphylococcus aureus in a cancer center.

A matched-pair case-control study enrolled all patients infected or colonized with ORSA (cases) admitted to the Hospital do Câncer in Rio de Janeiro from 01/01/1992 to 12/31/1994. A control was defined as a patient hospitalized during the same period as the case-patients and colonized or infected with oxacillin-susceptible Staphylococcus aureus (OSSA).

The study enrolled 95 cases and 95 controls. Patient distribution was similar for the two groups (p³0.05) with respect to gender, underlying diseases, hospital transfer, prior infection, age, temperature, heart and respiratory rates, neutrophil count, and duration of hospitalization. Univariate analysis of putative risk factors associated with mortality showed the following significant variables: admission to the intensive care unit (ICU), presence of bacteremia, use of central venous catheter (CVC), ORSA colonization or infection, pneumonia, use of urinary catheter, primary lung infection, prior use of antibiotics, mucositis, and absence of cutaneous abscesses. Multivariate analysis showed a strong association between mortality and the following independent variables: admission to ICU (OR [odds ratio]=7.2), presence of Staphylococcus bacteremia (OR=6.8), presence of CVC (OR=5.3), and isolation of ORSA (OR=2.7).

The study suggests a higher virulence of ORSA in comparison to OSSA in cancer patients.

DESCRIPTORS: Staphylococcus aureus. Oxacillin-resistance. Mortality. Cancer.

In recent decades, methicillin- or oxacillin-resistant Staphylococcus aureus (ORSA) has emerged as a frequent cause of nosocomial infections^3,4. Despite major technological advances and the development of broad-spectrum antimicrobial agents, infections due to these organisms have been recognized as important causes of morbidity and mortality. Several authors^3,4 have shown that 30 to 60% of patients colonized by ORSA have developed subsequent infections. Although some studies have demonstrated similar risks for the development of an infection among patients colonized with ORSA and with methicillin- or oxacillin-susceptible Staphylococcus aureus (OSSA)^15,23, others observed that patients infected with resistant strains were more likely to develop severe infectious complications^13,17. The evolution from staphylococcal colonization to infection is uncertain and highly variable, and depends mainly on patients' intrinsic and extrinsic risk factors. The literature on morbidity and mortality in these infections has been somewhat contradictory. Although some studies have observed similar length of hospital stay and survival among patients harboring resistant or susceptible strains^4,16, others have demonstrated a significantly higher mortality and longer duration of hospitalization among patients with ORSA^7,18,20,22.

These studies prompted us to describe the clinical and epidemiological characteristics of patients colonized or infected with ORSA and OSSA and evaluate the determinants of mortality in patients colonized or infected with Staphylococcus aureus at a cancer referral center.

MATERIALS AND METHODS

A matched-pair case-control study was designed to compare patients colonized or infected with ORSA (cases) to those colonized or infected with OSSA (controls). The study was conducted at the Hospital do Câncer in Rio de Janeiro between January 1992 and December 1994 and enrolled all patients with at least one positive culture for ORSA (cases). A control was defined as a patient hospitalized during the same period as the case-patients and colonized or infected with an oxacillin-susceptible Staphylococcus aureus (OSSA). All patients were identified from microbiology laboratory records, and their charts were reviewed by Infection Control Committee members.

The analysis used the standard definitions of the Centers for Disease Control and Prevention⁹. Patients were considered neutropenic if they had fewer than 1000 neutrophils/mm³. Fever was defined according to Hughes et al.¹² and previous infection when there was evidence of an infectious process in the last 30 days. Death was evaluated if it occurred during the period of hospitalization.

In the statistical analysis, the proportions were compared using the chi-square test (x2) or Fisher's exact test as appropriate, while continuous variables were compared using both parametric (Student's t) test and non-parametric methods (Mann-Whitney). The Kaplan-Meier¹⁴ curve was used for the survival analysis, and the log-rank test was used to calculate statistical significance. Variables in the univariate analyses with p values <0.15 and those biologically plausible were analyzed further using logistic regression. The analyses were performed with the EPI-INFO 6.03 (Centers for Disease Control and Prevention, USA) and SPSS for Windows 6.0 (SPSS Inc., 1993) software.

RESULTS

During the study period, 998 Staphylococcus aureus strains were reported by the microbiology laboratory, of which 234 (23.4%) were oxacillin-resistant. Ninety-five cases and 95 controls were further evaluated. Mean patient age (44.2 versus 41.8 years, respectively; p=0.46) and length of hospitalization (35.5 versus 30.3 days, p=0.20) were similar for cases and controls. Mean length of hospital stay until isolation of staphylococci was longer for patients with ORSA than for those with OSSA (16.5 versus 11.9 days, p=0.04). There was no statistical difference between cases and control for diagnosis of the underlying disease: solid tumors (65 versus 62, respectively; p=0.64), leukemia (6 versus 11, p=0.20), lymphoma (14 versus 10, p=1.0), and others (14 versus 12, p=0.67).

Table 1 shows similar distribution of patients in both groups according to gender, inter-hospital transfer, presence of fever, neutropenia, previous infection, bacteremia, and polymicrobial infection (p<0.05). Nevertheless, the mortality rate was significantly higher among patients with ORSA as compared to those with OSSA (30.5% versus 12.6%; p=0.002; OR [odds ratio]=3.2; 95%CI=1.4-7.4).

The main clinical characteristics were statistically similar among cases and controls: mean value of the highest axillary temperature (37.30C versus 37.40C; p=0.82), heart rate (94.9 versus 104.2; p=0.90), respiratory rate (22.9 versus 22.5; p=0.86), and neutrophil count (7.554 versus 7.775/mm3; p=0.80). The difference was only statistically significant for mean hemoglobin values, which were higher among ORSA patients (11.3 versus 10.4g/100 ml; p=0.01).

As shown in table 2, previous use of antimicrobial agents was significantly more common among patients colonized or infected with ORSA (p=0.0001). However, the presence of a central venous catheter (CVC), mechanical ventilation, admission to the intensive care unit (ICU), prior surgery or chemotherapy, use of an orthopedic prosthesis, mucositis, necrotic tumor, and abscess formation were equally distributed between the two groups (p>0.05).

Mean duration of some risk procedures before laboratory isolation of staphylococci was similar for cases and controls: CVC (18.8 versus 7.7 days; p=0.09), mechanical ventilation or endotracheal intubation (4.8 versus 3.4 days; p=0.60) and indwelling urinary catheter (8 versus 5 days; p=0.05). However, there was a trend towards longer ICU stay among patients with ORSA (8.8 versus 5 days; p=0.05).

Table 3 shows a higher proportion of death among patients admitted to the ICU and those with bacteremia, pneumonia, mucositis, ORSA, CVC, indwelling urinary catheter, and prior use of antibiotics (p<0.05). On the other hand, there was no statistical correlation between mortality and the following variables: gender, underlying disease, presence of fever, neutropenia, hemoglobin value below 12g/100 ml, inter-hospital transfer, abscess formation, surgical site infection, necrotic or ulcerated tumor, polymicrobial infection, mechanical ventilation, or chemotherapy.

We compared outcome according to intensity of patients' exposure to potential risk factors for death at the moment of Staphylococcus aureus isolation. The analysis showed a strong association between mortality and duration of CVC (9 versus 5 days; p=0.0007), indwelling urinary catheter (6 versus 2 days; p=0.02), and hospital stay (34 versus 23 days; p=0.02). Nevertheless, mean duration of antibiotic therapy (6 versus 5 days; p=0.07), mechanical ventilation (3 versus 1 day; p=0.10), and ICU stay (4 versus 8.5 days; p=0.15) were not found to be statistically associated with death.

Multivariate logistic analysis identified four independent predictive factors for mortality (Table 4). They were, in decreasing order: admission to ICU (OR=7.2), bacteremia (OR=6.8), presence of CVC (OR=5.3), and positive culture for ORSA (OR=2.7).

Analysis of Kaplan-Meier curves demonstrated a median survival time of 46 days (95%CI=32-60) for cases and 92 days (95%CI=26-158) [p=0,001] for controls (Figure).

DISCUSSION

The present study initially describes the main characteristics of patients colonized or infected with ORSA or OSSA. The two groups appeared to have no differences according to age, duration of hospitalization, underlying disease, presence of fever, neutropenia, or history of previous infection. Like other studies^1,6,11, we found a strong association between resistant strains and extended hospital stay prior to Staphylococcus aureus isolation (p=0.04) and prior use of antimicrobial agents (p=0.0001). It is important to emphasize our finding showing a trend for a longer ICU stay among ORSA-patients (p=0.05). It is likely that these variables were all markers for severity of patient illness.

Although some authors^4,16 did not observe a significant difference in virulence of ORSA and OSSA strains, our results demonstrated a higher mortality rate among patients with resistant strains (30.5% versus 12.6%; p=0.002). This finding is in agreement with other authors^7,20 who found a worse outcome among patients with ORSA bacteremia. In addition, several risk factors reported in the literature^6,19 were present in our ORSA group of patients, cluding prolonged ICU stay, mechanical ventilation, presence of CVC, and exposure to antibiotics. These variables might interact and increase the risk of severe staphylococcal infection and fatal outcome.

The multivariate logistic regression model indicated that bacteremic patients and those colonized or infected with ORSA, harboring a CVC, or admitted to an ICU were at increased risk of death. Our results confirmed the studies of Romero-Vivas²⁰ and Conterno⁷ who demonstrated a risk of death 3 to 4 times higher among OSSA patients. Nevertheless, other authors^8,10 were unable to show a significant difference in the mortality rate among patients with bloodstream infections caused by resistant as compared to susceptible Staphylococcus aureus.

Our study presents some design limitations that should be considered. Like other authors^1,22, we found it difficult to distinguish between Staphylococcus aureus colonization and infection, which prompted us to evaluate the two categories indistinctly. Thus, a misclassification bias may have arisen, resulting in distortion in the magnitude of the association between exposure and outcome. Furthermore, a reduction in the strength of associations may have occurred due to inclusion of false-positive blood cultures in both groups. Although the consequences of these false results involve an immediate increase in duration of hospital stay, antibiotic therapy, and number of laboratory tests requested²¹, we agree with Carlisle et al.⁵ concerning the difficulty in ruling out a pseudo-bacteremia diagnosis in immunocompromised or neutropenic patients with fever and indwelling intravascular catheters. Therefore, most cases are treated as true infections based mainly on clinical data, despite the undesirable consequences of misdiagnoses.

In conclusion, our results demonstrated an increased virulence of ORSA among cancer patients. The final statistical model identified a high-risk sub-group of patients and improved our understanding of factors influencing the outcome. The study might also contribute to the development of effective strategies for the prevention and management of ORSA infections.

RESUMO

RHCFAP/2961

THULER, L.C.S e col. - Determinantes de mortalidade em pacientes colonizados ou infectados por internados em um hospital do câncer. Staphylococcus aureus. Rev. Hosp. Clín. Fac. Med. S. Paulo, 54 (2): 47 - 52, 1999.

As infecções causadas por Staphylococcus aureus resistentes à oxacilina (ORSA) são causas importantes de morbidade e mortalidade. O objetivo do estudo foi identificar os principais fatores associados à mortalidade em pacientes colonizados ou infectados por Staphylococcus aureus em um hospital de câncer.

Foi realizado um estudo do tipo caso-controle emparelhado envolvendo todos os pacientes colonizados ou infectados por ORSA (casos) internados no Hospital do Câncer do Rio de Janeiro durante o período de 01/01/1992 a 31/12/1994. A cada caso correspondeu um controle, selecionado aleatoriamente entre os pacientes hospitalizados no mesmo período e colonizados ou infectados por Staphylococcus aureus sensível à oxacilina (OSSA).

O estudo avaliou 95 casos e 95 controles. A distribuição dos pacientes quanto ao sexo, doença de base, transferência de outro hospital e história de infecção prévia, assim como a idade, temperatura, freqüência cardíaca e respiratória, contagem de neutrófilos e o tempo de hospitalização foram semelhantes nos dois grupos. A análise univariada dos possíveis fatores associados à mortalidade identificou como significativas as seguintes variáveis: internação na unidade de tratamento intensivo (UTI), presença de bacteriemia, uso de cateter venoso central (CVC), isolamento de ORSA, pneumonia, presença de cateter urinário, foco pulmonar primário, uso prévio de antimicrobianos, mucosite e ausência de abscessos cutâneos. A análise multivariada mostrou uma associação entre a mortalidade e a internação na UTI (OR [odds ratio]=7,2), a presença de bacteriemia (OR=6,8) e CVC (OR=5,3) e o isolamento de ORSA (OR=2,7).

O estudo sugere uma maior virulência do ORSA em comparação ao OSSA em pacientes com câncer.

DESCRITORES: Staphylococcus aureus. Oxacilina-resistente. Mortalidade. Câncer.

Received for publication on the 18/09/98

From "Comissão de Controle de Infecção Hospitalar do Hospital do Câncer, Instituto Nacional de Câncer", Rio de Janeiro.

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Publication Dates

• Publication in this collection
  31 Aug 2000
• Date of issue
  Apr 1999

History

• Received
  18 Sept 1998