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* From the Anti-Infective Research Laboratory, Wayne State University, Detroit, MI (Drs. Rybak and McKinnon); the Department of Pharmacy, Barnes Jewish Hospital, St. Louis, MO (Dr. McKinnon); the Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT (Dr. DeRyke); and Albany College of Pharmacy, Albany, NY (Dr. Lodise).
Correspondence to: Peggy S. McKinnon, PharmD, Barnes-Jewish Hospital, Mailstop 90–52-411, 216 South Kings Hwy, St. Louis, MO 63110; e-mail: psm9154{at}bjc.org
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Abstract |
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Design: Retrospective cohort analysis.
Setting: This study was conducted at Detroit Receiving Hospital and University Health Center, which is a 279-bed, level 1 trauma center in Detroit, MI.
Patients: All episodes of NBSAP identified from January 1, 1999, to April 30, 2004.
Results: Of 206 patients identified over a 5-year period with positive blood and respiratory cultures for S aureus, 60 patients met strict clinical, radiographic, and microbiological criteria for NBSAP. The overall mean (± SD) characteristics include the following: age, 55.5 ± 15.0 years; acute physiology and chronic health evaluation II score, 20 (range, 3 to 41); ICU at onset, 93.3%; mechanical ventilation, 83.3%; length of stay (LOS) prior to NBSAP, 9 days (range, 2 to 81 days); methicillin-resistant S aureus (MRSA) rate, 70%; and all-cause hospital and infection-related mortality (IRM), 55.5% and 40.0%, respectively. Overall, S aureus pneumonia developed late in the patient’s hospital stay in ICU patients previously receiving mechanical ventilation and was associated with high crude mortality and IRM rates. No significant difference existed with respect to mortality or infection-related LOS between patients who had received early appropriate antibiotic therapy vs those who had received delayed appropriate antibiotic therapy at the onset of pneumonia or in patients with methicillin-sensitive S aureus pneumonia vs those with MRSA pneumonia.
Conclusion: IRM from NBSAP is high, and standard therapies evaluated at the time of this study resulted in poor clinical outcomes. Delayed therapy was not found to be a predictor of adverse outcomes; however, this lack of ability to detect a difference may be a product of small sample size. These findings suggest that newer agents with enhanced clinical activity in NBSAP are needed and that these should be evaluated in a real-world setting, where outcomes of the most ill patients can be assessed.
Key Words: bacteremia • clinical outcomes • critical care • cross-infection • hospital mortality • ICU • infection • staphylococcal infections • staphylococcal pneumonia • ventilator-associated pneumonia
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although there is increased recognition of S aureus as a major pathogen causing nosocomial pneumonia, there are few studies4567 with descriptive data specifically evaluating patient outcomes of S aureus pneumonia. In addition, in the last decade, evidence has accumulated demonstrating that initial inappropriate antibiotic treatment is an important independent predictor of excess mortality in patients with nosocomial pneumonia.891011 To our knowledge, no data exist examining the impact of delayed appropriate antibiotic treatment specifically for bacteremic S aureus pneumonia. In a retrospective study12 evaluating S aureus bacteremia, a delay in treatment with antibiotics for > 44.75 h was found to be an independent predictor of infection-related mortality (IRM) [adjusted odds ratio, 3.8; 95% confidence interval, 1.3 to 11.0; p = 0.01]. It is unknown if this 44.75-h breakpoint is applicable to patients with bacteremic S aureus pneumonia. Although the impact of methicillin resistance on the outcomes of patients with S aureus bacteremia has been extensively evaluated, little information exists on the impact of the methicillin resistance of patients with nosocomial bacteremic S aureus pneumonia (NBSAP). Furthermore, less information exists on the impact of empirical antibiotic selection on NBSAP. Over the past few years, studies13141516 have suggested that vancomycin may not be optimal for the treatment of S aureus pneumonia, especially in the subset of patients who have been infected with methicillin-resistant S aureus (MRSA). To evaluate the epidemiology, treatment, and outcomes of NBSAP, a retrospective cohort analysis was performed. Specifically, we examined the impact of methicillin resistance, empirical therapy, and delayed treatment on the outcomes of patients with NBSAP.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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48 h after hospital admission and excluding any infection that was incubating at the time of hospital admission.17
For the purposes of this investigation, the diagnosis of NBSAP was defined based on clinical, radiographic, and microbiological criteria.18192021 Within 72 h of the first positive culture, a chest radiograph must also have been abnormal, and the patient must have had signs and symptoms consistent with nosocomial pneumonia. In order to fulfill the requirement for bacteremic pneumonia, at least one S aureus-positive blood culture not related to another source of infection and one S aureus-positive respiratory culture must have been obtained within 72 h of each other as well. Possible respiratory cultures included positive growth in the culture of pleural fluid, positive sputum culture/tracheal aspirate (defined as secretions from the lungs, bronchi, or trachea that contain numerous or a moderate number of neutrophils and rare or few squamous epithelial cells) findings, and a positive quantitative culture result from minimally contaminated lower respiratory tract specimens (eg, BAL fluid with 10,000 cfu/mL). Radiographic criteria for pneumonia were met if the chest radiograph yielded a new or progressive and persistent infiltrate, consolidation, or cavitation. Persistence of an infiltrate was defined as having the infiltrate present radiographically for at least 72 h. Patients were defined as symptomatic if one of the following were present: fever (ie, temperature > 38°C or 100.4°F) or hypothermia (ie, temperature < 35°C or 95°F) with no other recognized cause; leukopenia (ie, WBC count, < 4,000 cells/µL) or leukocytosis (ie, WBC count, 10,000 cells/µL); or, for adults > 70 years old, altered mental status with no other recognized cause. Patients also had to exhibit one of the following signs: new onset of purulent sputum, change in the character of the sputum, increased respiratory secretions, or increased suctioning requirements; new onset or worsening of cough, dyspnea, or tachypnea (respiratory rate, > 25 breaths/min); or worsening gas exchange (eg, O2 desaturation [PaO2/fraction of inspired oxygen ratio of 
240], increased oxygen requirements, or increased ventilation demand).
Medical charts were screened to exclude the following possible alternative causes for fever and radiographic chest densities. The presence of atelectasis was defined by the complete disappearance of radiographic densities within 48 h of evaluation. Congestive heart failure with pulmonary edema was defined as a resolution of pulmonary infiltrates following diuresis. A pulmonary embolism was defined by the presence of at least two segmental or larger mismatched perfusion abnormalities on a ventilation-perfusion scan or suggestive radiographic findings on pulmonary angiography and spiral CT scan.
Patients with endovascular infections, including endocarditis, were excluded because of the potential for hematogenous spread of S aureus to the lungs, thus complicating our retrospective diagnosis of S aureus pneumonia. Patients with endocarditis were identified by transthoracic or transesophageal echocardiography and/or documentation of the diagnosis in the medical record.
Study Design
To evaluate the epidemiology, treatment, and outcomes of NBSAP, a retrospective cohort analysis was performed. Specifically, we examined the impact of methicillin resistance, empirical therapy, and delayed treatment on the outcomes of patients with NBSAP.
Data Collection
Clinical Data:
Data extracted from the patient medical records and pharmacy database included the following: age; sex; comorbidities present; prior antibiotic use (within 30 days prior to NBSAP); length of hospitalization before the onset of nosocomial pneumonia (total hospitalization and hospitalization in the ICU); mechanical ventilation at the onset of nosocomial pneumonia; Charlson comorbidity index score22; and severity of illness based on APACHE (acute physiology and chronic health evaluation) II scores at the time of admission to the ICU.23 If the patients were not admitted to the ICU, the APACHE II score was determined at hospital admission.
The following comorbid conditions were documented: diabetes mellitus; heart failure; COPD; asthma; hepatic dysfunction; renal failure (as indicated by the necessity for dialysis); malignancy; HIV infection; alcoholism; presence of decubitus ulcers (stage II to IV); administration of immunosuppressive drugs (ie, receipt of > 20 mg prednisone or an equivalent corticosteroid per day for 14 days before the onset of nosocomial pneumonia or the receipt of any neoplastic chemotherapy in the 3 months before the onset of nosocomial pneumonia); surgery requiring > 48 h of hospitalization in the 30 days before the onset of nosocomial pneumonia; and the presence of burns on > 30% of the body surface area.
Microbiological Data: Collected microbiological data included all of the positive blood or respiratory culture findings, irrespective of the pathogen identified. Susceptibility testing was performed using the microtiter-well method, and the results were interpreted according to National Committee for Clinical Laboratory Standards guidelines24 by the clinical microbiological laboratory.
Treatment Data: All of the antimicrobial agents administered to provide activity against S aureus isolates were noted. Empiric treatment was the first antibiotic regimen provided following the onset of infection. Treatment was considered to be appropriate on the basis of the following two factors: the timing of treatment relative to the first positive blood or respiratory culture finding; and the in vitro susceptibility of the blood or respiratory isolate. Timing was evaluated based on a previously described breakpoint of 44.75 h, which was determined by classification and regression tree analysis (CART) as an independent predictor of mortality in S aureus bactermia.12 If a patient had received at least one IV antibiotic to which the S aureus blood or respiratory isolate was susceptible and the antibiotic had been administered within 44.75 h, it was considered to be appropriate early treatment. For example, an individual with MRSA bacteremia receiving vancomycin within 44.75 h would be classified as having received early appropriate treatment. A patient with MRSA initially treated with a ß-lactam but not receiving vancomycin within 44.75 h would be considered as having received delayed treatment. In addition, we utilized CART analysis to determine whether there was a different breakpoint to better describe the critical time to appropriate antibiotic treatment for this cohort of NBSAP patients.
Outcome Assessment
The following primary end points were assessed: (1) IRM; (2) hospital (crude) mortality; and (3) infection-related length of stay length (IR-LOS) after the onset of NBSAP. Secondary outcomes included the following: (1) clinical response; (2) microbiological response; and (3) cost of hospitalization after the onset of NBSAP.
For the early treatment vs delayed treatment analyses, patients who died within 72 h of the onset of infection were excluded. Clinical and microbiological outcomes were assessed at the following four time points: day 3; day 7; day 10; and at the end of antimicrobial therapy. To prevent bias, investigators involved in the outcome assessments were blinded to both susceptibility data and treatment data, including the time to receipt of treatment.
Definitions
Clinical outcomes were evaluated as successes or failures. Clinical success included clinical resolution, which was defined as the complete resolution of all signs and symptoms of pneumonia (return to preinfection baseline) along with improvement, or lack of progression, of all abnormalities on the chest radiograph, and clinical improvement, which was defined in patients if a partial resolution of clinical signs and symptoms occurred such that no additional antimicrobial therapy was required, along with the improvement or stabilization of chest radiographic findings. Patients who died or whose conditions did not improve were deemed as having clinical failure. Clinical failure was defined as the persistence of clinical signs and symptoms, the persistence of positive culture findings, and/or a lack of resolution of infiltrates on the chest radiograph.
Microbiological outcomes were categorized as eradication or persistence. Microbiological eradication included documented eradication, defined as the elimination of baseline pathogens based on subsequent negative blood and respiratory culture findings, and presumed eradication, which was denoted in patients in whom presumed eradication occurred based on clinical resolution, but no subsequent cultures were obtained. Microbiological persistence included documented persistence, which was defined as the persistence of bacteria despite the appropriate use of antibiotic therapy based on in vitro susceptibility results, and presumed persistence, which was denoted in patients in whom presumed microbiological failure occurred based on clinical failure, but no subsequent cultures were obtained.
Death was considered to be related to NBSAP (ie, IRM) if one or more of the following criteria were present: (1) blood and/or respiratory cultures were positive for S aureus at the time of death; (2) death occurred before the resolution of signs and symptoms of the nosocomial pneumonia; (3) death occurred 14 days after the onset of nosocomial pneumonia without another explanation; (4) autopsy findings indicated pneumonia as a cause of death; and (5) pneumonia was indicated as a cause of death on the death certificate.
The calculation of IR-LOS was measured from the time when the first positive blood or respiratory culture finding was collected until the end of antimicrobial treatment, death, or hospital discharge. The calculation of IR-LOS excluded patients who died secondary to nosocomial pneumonia.
An infection-related cost of hospitalization was determined for each patient. The Detroit Receiving Hospital accounting department supplied the cost figures. For patients who lived or did not die secondary to NBSAP, the cost was calculated from the onset of infection until the last day that antimicrobial therapy active against S aureus was administered (ie, the IR-LOS). For those patients who died because of NBSAP, the cost was calculated from the onset of infection until the day of the patient’s death.
Statistical Analysis
Categoric variables were compared by the Pearson 
2 test or Fisher exact test, and continuous variables were compared by the Student t test or Mann-Whitney U test. Multivariate analyses were performed to determine the independent association of antibiotic resistance and delayed treatment with the clinical outcome of interest while adjusting for confounding variables. Clinical features significantly associated with the outcome by univariate analysis were included in the explanatory multivariate model. The univariate predictors had to represent > 10% of the cohort to prevent overfitting of the multivariate model. Dichotomous outcomes (eg, IRM and clinical status) were analyzed with standard logistic regression. A p value of < 0.05 was considered to be significant for two-tailed tests. A statistical software package (SPSS, version 10.0; SPSS; Chicago, IL) was used for all of the calculations.
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Results |
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The origin of the respiratory cultures used for the microbiological determination of pneumonia came from aspirated sputum in 90% of the cases, and from BAL fluid in 10% of cases. Of the 60 patients, 42 patients (70%) were infected with MRSA. Forty-four patients (73.3%) had concomitant organisms (6 in blood only, 7 in blood and respiratory cultures, and 31 in respiratory cultures only). The most common concomitant organisms in the blood were as follows: Enterococcus spp (five cases); Acinetobacter baumannii (three cases); Streptococcus viridans (two cases); Klebsiella pneumoniae (one case); Streptococcus pneumoniae (one case); and one cogulase-negative Staphylococcus sp. The most common concomitant respiratory organisms were P aeruginosa (nine cases); A baumannii (eight cases); Klebsiella spp (seven cases); Escherichia coli (six cases); Candida albicans (four cases); Enterobacter spp (three cases); and nine others.
The clinical and microbiological success rates at the end of treatment were 56.7% and 53.3%, respectively. Thirty-three patients (55.5%) died during hospitalization, and 24 (40.0%) died secondary to NBSAP (ie, IRM). Nine patients died for reasons not attributable to the pneumonia. In seven cases, treatment for NBSAP had stopped at least 2 weeks before the patient died. Withdrawal from support occurred in two patients irrespective of the concomitant pneumonia.
The relationship between APACHE II score and death is shown in Figure 1 . A linear relationship existed demonstrating that patients who were more acutely ill at the time of admission to the ICU had a greater mortality rate (R2 = 0.74).
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The comparison values of hospital mortality, IRM, and IR-LOS between MSSA and MRSA patients are displayed in Figure 3 . No significant differences in these primary end points were observed between the groups. Similarly, no significant differences in hospital mortality, IRM, and IR-LOS were noted for the different empiric antibiotic regimens, stratified by methicillin susceptibility. Multivariate analyses were performed, and the associations between methicillin susceptibility and outcomes were identical to those from the univariate analyses.
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Overall clinical success was achieved in 59.5% of MRSA patients compared with 50.0% of MSSA patients. No differences in clinical or microbiological success were determined at days 3, 7, or 10, or at the end of antimicrobial therapy for any treatment regimen, stratified by methicillin susceptibility. Similarly, because 83.3% of patients were receiving mechanical ventilation at the time of onset, no difference in clinical response was observed in this VAP subset of patients compared with the whole cohort. Of note, the overall clinical cure rate in patients receiving vancomycin was 56.3%; 58.3% in the subset of MRSA patients.
Outcomes in Delayed vs Early Appropriate Therapy
Five patients were excluded in the appropriate therapy analyses secondary to death within 72 h of the onset of infection. Of the remaining 55 patients, 24 patients (43.6%) did not receive appropriate antibiotic treatment within 44.75 h of the onset of infection, and 31 patients (56.4%) received appropriate antibiotic treatment within 44.75 h of the onset of infection. There were no significant differences between the two groups (delayed vs early) with respect to the APACHE II score at time of admission to the ICU (20.5 [range, 5 to 41] vs 18 [range, 4 to 40], respectively; p = 0.6) and Charlson comorbidity index score (2 [range, 0 to 6] vs 2 [range, 0 to 6], respectively; p = 0.9). The median time to the start of appropriate treatment was 68.5 h (range, 45 to 149 h) in the delayed-treatment group and 25 h (range, 4 to 44 h) in the early-treatment group. Only 16 patients received appropriate antibiotic treatment within 24 h of the onset of infection
No differences existed with respect to the primary outcomes based on the receipt of delayed vs early appropriate antibiotic therapy (Fig 4 ). In addition, no significant difference in the rate of response was seen at days 3, 7, and 10, and at the end of antimicrobial therapy or the first day to clinical improvement (5 days [range, 2 to 14 days] vs 5 days [range, 2 to 11 days], respectively). In the CART analysis that was performed to identify a specific "time to therapy" for the bacteremic S aureus pneumonia cohort, no additional time breakpoint in appropriate antibiotic treatment was found that produced an increased probability of IRM.
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Complete, infection-related cost data were available for 22 of the 60 patients. The greatest reason for increased cost was length of hospitalization. In the patients who lived, the median total cost was $35,072 (range, $19,764 to $312,511) compared with $22,098 (range, $1,218 to $66,351) in the patients who died. No differences in cost were evident in patients based on methicillin susceptibility or early empiric treatment.
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Discussion |
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Clinical success has been reported in S aureus nosocomial pneumonia in a number of trials, mostly comparing vancomycin with the newer agents quinupristin/dalfopristin and linezolid. Fagon et al27 compared the efficacy of therapy with quinupristin/dalfopristin and vancomycin in Gram-positive pneumonia patients. In the 55 patients with bacteriologically evaluable S aureus pneumonia, the overall clinical success rate in vancomycin-treated patients was 50.9% compared with 44.4% in the 18 patients infected with MRSA. Stevens et al14 specifically evaluated therapy with linezolid vs therapy with vancomycin for the treatment of MRSA infections. Data from 29 patients with MRSA pneumonia revealed that a clinical cure was achieved in 75.0% of patients treated with either agent. In a study analyzing data from two previous double-blind studies of patients with S aureus nosocomial pneumonia, Wunderink et al15 found that there was no difference in clinical cure between the use of linezolid and vancomycin among all of the S aureus nosocomial pneumonia patients (51.5% vs 43.4%, respectively; p = 0.182). However, in the subset of 133 MRSA nosocomial pneumonia patients, a significant difference was found (59% vs 35.5%, respectively; p = 0.009). Kollef et al16 examined clinical cures in patients who specifically had VAP and found significant differences in favor of the empiric use of linezolid over vancomycin in both the S aureus VAP group (48.9% vs 35.2%, respectively; p = 0.06) and the MRSA VAP group (62.2% vs 21.2%, respectively; p = 0.001). Our findings were similar to these reported values. Overall clinical success was achieved in 56.7% of all patients and in 59.5% of the subset of MRSA patients compared with 50.0% of the subset of MSSA patients. Highlighting the empiric use of vancomycin, the overall clinical success rate was 56.3%, with 58.3% cure rates in the MRSA patient population. Among patients with MRSA, the IRM rate was higher in patients receiving empiric vancomycin (45.8%) compared with that in patients receiving empiric ß-lactam agents (25.0%). These findings were not statistically significant, and an additional evaluation of this subset of patients revealed that patients empirically treated with ß-lactam agents tended to be younger and to have lower APACHE II scores, partially explaining this finding. Because > 80% of patients were already receiving mechanical ventilation at the onset of NBSAP, these percentages did not change after analyzing this subset of patients.
Patients included in this analysis were critically ill and had numerous underlying chronic comorbidities, as evidenced by a median APACHE II score of 20 (range, 3 to 41). Consequently, the mortality rate was high in our study, with an associated crude mortality rate of 55.5% and an IRM rate of 40.0%. These values also correlate well with those from previous literature67282930 in which the mortality rate attributable to S aureus has ranged between 28% and 50%. The mortality rate among nosocomial acquired bacteremic pneumonia patients was found to be 52.5% in a previous study.5
The most surprising outcomes from our results were a lack of difference with respect to overall hospital mortality rate, IRM rate, and IR-LOS based on the receipt of early vs delayed antibiotic therapy. Numerous reports891011 have been published stating that mortality significantly increases in patients who develop pneumonia if empiric antibiotic therapies are not started at the time of clinical suspicion, before cultures have been collected and sensitivity has been reported. Our lack of ability to detect a difference may be a product of a small sample size leading to a potential type II error. In a previous study12 examining S aureus bacteremia, a delay in therapy of > 44.75 h was found to be associated with a 3.8 times higher rate of IRM. The 44.75-h breakpoint for appropriate therapy, however, was not predictive in this series of pneumonia patients. In addition, an additional breakpoint of time to appropriate therapy was not identified using CART. Some potential reasons for no differences being detected are the low number of patients (n = 60) and the high mortality rate (55%) associated with this series. In addition, only 16 patients received appropriate antibiotic therapy within 24 h of the onset of infection. It may be difficult to ascertain the impact of delayed therapy given the high rate of delayed treatment.
Of interest, as demonstrated in Figure 1, a linear relationship existed with respect to IRM and increasing APACHE II score. Because of the requirement of concomitant bacteremia, this subset of pneumonia patients likely represents those patients who are most severely ill with rapid disease progression. The severe illness exhibited in these patients may be the main factor determining mortality and may serve as the reason why appropriate antibiotic treatment did not predict clinical success or decreased mortality. Another reason may be in part attributable to the slow activity or lack of efficacy of vancomycin, such that even the early administration of this agent is associated with poor clinical outcomes.3132
The greatest limitation of our study was the small number of patients (n = 60) who met our strict inclusion criteria. The main reason that so few patients were available for inclusion over the 5 years was the requirement for patients to have concomitant S aureus bacteremia, as well as pneumonia. This requirement was essential because of the retrospective design of our investigation and the high rate of tracheal aspirates used as the respiratory source of this pathogen. We wanted to be confident that the patients who were involved in this analysis developed bacteremia secondary to nosocomial pneumonia and not by hematogenous spread of S aureus, as can occur in other conditions, such as endocarditis, which was one of the exclusion criteria.
Additional limitations were inherent to the retrospective design of the study. Characterizing NBSAP was difficult, although stringent inclusion criteria were used. Many patients who likely had nosocomial S aureus pneumonia were excluded from the analysis because of the lack of a concomitant positive blood culture finding. Also, numerous comorbidities confounded the accurate assessment of IRM. To account for this, an independent reviewer with no knowledge of the culture and sensitivity data or of the choice and timing of antibiotic therapy was designated to determine the primary outcome based on clinical data recorded throughout the course of the patient’s hospital stay.
In conclusion, this investigation includes one of the largest collections of patients to have bacteremic nosocomial pneumonia that was specifically attributable to S aureus. S aureus pneumonia developed late in the patient’s hospital stay and in ICU patients who had previously received mechanical ventilation, and was associated with a high crude mortality and IRM rates. No significant differences were detected with respect to crude mortality, IRM, or IR-LOS between patients who developed MSSA vs those who developed MRSA pneumonia or depending on whether the patient had received early vs delayed appropriate antibiotic therapy. The small sample size may have precluded our ability to detect a difference in these groups. Patients who were empirically treated with vancomycin for MSSA and MRSA pneumonia experienced a high mortality rate. These findings suggest that newer agents with enhanced clinical activity in NBSAP are needed and that these should be evaluated in a real-world setting, where outcomes of the sickest patients can be assessed. The group of patients who will experience the greatest benefit from these newer agents remains to be determined.
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Footnotes |
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Received for publication December 23, 2004. Accepted for publication January 26, 2005.
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This article has been cited by other articles:
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M. H. Kollef and S. T. Micek Staphylococcus Aureus Pneumonia: A "Superbug" Infection in Community and Hospital Settings Chest, September 1, 2005; 128(3): 1093 - 1097. [Full Text] [PDF]
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