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* From the Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT.
Correspondence to: Joseph L. Kuti, PharmD, Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour St, Hartford, CT 06102; e-mail: jkuti{at}harthosp.org
Abstract
Objective: To determine if penicillin-nonsusceptible Streptococcus pneumoniae, among other variables, was significantly associated with greater hospital costs among patients with community-acquired pneumonia (CAP).
Design: Retrospective, cohort study.
Setting: Eight hundred ten-bed, urban, private, teaching hospital.
Patients: Adult patients admitted between 1999 and 2003 with CAP caused by S pneumoniae.
Intervention: Clinical criteria and costs (inflated to 2004 dollars) were collected from the medical charts and detailed hospital bills for each individual patient. Costs were compared according to classification by penicillin susceptibility. Multivariate linear regression was utilized to determine variables independently associated with increased hospital costs and length of stay.
Results: Of 168 patients included, 44 patients (26%) had CAP caused by penicillin-nonsusceptible S pneumoniae. Median total hospital costs were $8,654 (25th to 75th percentile, $5,457 to $16,027), with no difference between susceptible and nonsusceptible groups. Bed costs accounted for 55.6% of total costs, followed by laboratory (9.9%) and pharmacy (9.8%) costs. Regression analyses determined that ICU admission (p < 0.001), unexplained delays in discharge (p = 0.001), and neoplasm (p < 0.04) were independently predictive of both total hospital costs (adjusted r2 = 0.46) and increasing length of stay (adjusted r2 = 0.30). Hospital mortality, bacteremia, and congestive heart failure were also associated with at least one of the dependent variables.
Conclusion: In the current era in which more potent antibiotics are empirically utilized to treat CAP, it does not appear that a simple classification of penicillin nonsusceptibility complicates the economic impact of S pneumoniae infection. Focused efforts to reduce length of stay, including minimizing prolonged and unnecessary observation of patients, should have the most profound effect on reducing total costs.
Key Words: costs • pneumococcal • pneumonia • resistance • Streptococcus pneumoniae
Pneumonia is the sixth-leading cause of death in the United States and the number-one cause of death from an infectious disease.12 The subset of patients who acquire pneumonia while not residing in a hospital or long-term care facility for at least 2 weeks before the onset of symptoms are defined as having community-acquired pneumonia (CAP).1 Of the 4 to 5 million cases of CAP treated annually, a minority (approximately 0.5 to 1 million) are treated in a hospital.3 Yet, this minority has accounted for the majority of health-care costs associated with the infection; $8 billion was spent on hospitalization costs in 1994, compared with $0.4 billion spent among outpatients.4
Although most studies12 have been unable to identify the cause of CAP in approximately 50% of patients, the most common bacteria isolated in most reports have been Streptococcus pneumoniae. In a large metaanalysis5 of > 7,000 CAP cases, S pneumoniae accounted for two thirds of those for whom an etiologic diagnosis was made, as well as two thirds of the patients with bacteremic pneumonia. Decreasing susceptibility to penicillin is the most common epidemiologic marker for tracking resistance among S pneumoniae. A recent surveillance study6 conducted during the 2002 to 2003 flu season determined the overall rate of penicillin resistance (ie, nonsusceptibility) was 34.2% at 45 centers throughout the United States; moreover, resistance had not changed significantly since 1998. Similar resistance rates were also apparent for second-generation cephalosporins, macrolides, and trimethoprim-sulfamethoxazole. Many of these therapies remain first-line treatment options for patients with CAP; however, to date studies7891011 have shown mixed results regarding the effect of penicillin resistance on patient outcomes.
Additionally, antimicrobial resistance has become an increasing health economic concern. Infections caused by numerous species of resistant Gram-positive and Gram-negative bacteria have been associated with increased health-care costs.1213141516 While newer therapies for drug-resistant bacteria are routinely more expensive than the older "standard of care" antibiotics, the majority of attributable costs associated with resistance result from a delayed clinical response due to inappropriate therapy, an increased severity of illness among those acquiring a resistant organism, or the perception that patients require extended treatment or observation.17 All can result in increased hospital length of stay, thereby significantly escalating costs. However, few cost-of-illness studies1819 have attempted to evaluate the economic impact of penicillin susceptibility in patients with CAP caused by S pneumoniae. The primary objective of this study was to determine resource utilization and costs associated with the in-hospital treatment of CAP caused by S pneumoniae, as stratified by susceptibility to penicillin. A secondary objective was to determine other patient covariates that were predictive of a more costly hospital stay.
Materials and Methods
Study Design
This was a retrospective cohort study of adult patients admitted to Hartford Hospital between 1999 and 2003 with documented CAP caused by S pneumoniae. Hartford Hospital is an 810-adult-bed, nonprofit, private, teaching hospital located in urban Hartford, CT. The institutional review board approved this study. Informed consent was not required since the study was retrospective in design and all protected health information was destroyed on completing data collection. Each patient received a subject number corresponding to a consecutively reviewed medical record and hospital bill.
Patients
All patients admitted to the hospital from January 1999 to January 2003 with respiratory or blood culture specimens testing positive for S pneumoniae were identified through the microbiology laboratory computer database. Examination of the medical records of these subjects was conducted to identify the cohort of patients who had the diagnosis of CAP caused by S pneumoniae. Patients were included if they were 
18 years old; had at least one sputum culture (with presence of < 10 squamous epithelial cells and > 25 polymorphonuclear cells per x 100 magnification field; or be obtained from semiquantitative culture) or two blood cultures positive for S pneumoniae; and had signs and symptoms consistent with the diagnosis of CAP including the presence of a new infiltrate on chest radiograph and at least two of the following within 1 day of the first positive culture: documentation of fever (> 38.0°C) or hypothermia (< 35.0°C); WBC count > 10,000/µL or > 15% bands or leukopenia (WBC < 4,500/µL); documentation of auscultory findings on pulmonary examination and/or evidence of pulmonary consolidation; documentation of new cough with or without sputum production; documentation of new-onset dyspnea or tachypnea; or hypoxemia with a PO2 < 60 mm Hg on room air. Patients were excluded if their total hospitalization was < 2 days, if they had impaired immune function (ie, AIDS, HIV, leukocyte count < 1,000/µL), known or suspected tuberculosis, known or suspected Pneumocystis jiroveci, or concomitant pneumonia or other infection at baseline caused by viruses, fungi, or other bacteria except intracellular pathogens (Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumoniae), Haemophilus influenzae, or Moraxella catarrhalis.
Data Collection
Medical charts were reviewed for all identified patients, and data were collected using a standardized collection tool. Information documented included patient demographics; comorbid conditions (diabetes, COPD, neoplasm, congestive heart failure [CHF], cirrhosis, or other chronic liver disease); microbiology data including penicillin susceptibility and culture source; admission year; hospital length of stay; presence of ICU stay; pneumonia severity illness (PSI) score20; antibiotic therapy (including route); daily maximum temperature and WBC count; and crude mortality at end of hospitalization. Penicillin susceptibility was defined according to current Clinical and Laboratory Standards Institute guidelines21 as susceptible (penicillin minimum inhibitory concentration [MIC] 
0.06 µg/mL), intermediate resistant (MIC, 0.12 to 1.0 µg/mL), or resistant (MIC 2.0 µg/mL). Comorbid conditions were positive if they were present at baseline except for neoplasm, which was any cancer except basal or squamous cell cancer of the skin that was active at time of presentation or diagnosed within 1 year of presentation.20
All resource utilization and economic data were derived from the patient’s detailed medical bill. Each bill was separated by the following pertinent charge departments: hospital bed charges (further divided by non-ICU bed or ICU bed), pharmacy, antibiotic specific charges, laboratory, radiology, respiratory care, rehabilitation, and other. At Hartford Hospital, the accounting system considers fixed indirect and direct costs (ie, nursing and physician services, housekeeping, electricity, administration) within the hospital bed charge, and the quantity of services utilized will be reflected in the bed charge (eg, ICU bed charge greater than non-ICU bed charge because of greater intensity of services). All charges were converted to costs using department specific cost-to-charge ratios and inflated to 2004 using the medical component of the consumer price index for all consumers in US cities (www.bls.gov/data/home.htm). Total costs equaled the sum of all department costs. Costs associated with specific services known not to be associated with the patient’s admission for CAP (eg, open-heart surgery) were excluded.
Statistics
Economic analyses were conducted from the hospital perspective. The primary analysis separated the cohort into two groups based on penicillin susceptibility (susceptible vs nonsusceptible). For all comparisons, the nonsusceptible group included both intermediate-resistant and resistant S pneumoniae. Continuous data were compared using a Student t test for normally distributed data or Mann-Whitney U test for nonnormally distributed data (eg, costs and length of stay). 
2 or Fisher exact test were used to compare proportions between the two groups. For cost comparison between susceptible, intermediate, and resistant groups, data were analyzed by the Kruskal-Wallis rank-sum test.
Multivariate linear regression was utilized to control for confounding variables and determine covariates that predicted total costs and length of stay for the entire cohort. For all regression analyses, total costs and length of stay were log-transformed so that parametric tests could be utilized. In both regression models, all variables (patient demographics, comorbidities, S pneumoniae susceptibility, ICU stay, admission year, presence of bacteremia, PSI score, mortality, and receipt of oral antibiotic therapy) were inserted into the model at once to control for covariance. An additional variable, termed unexplained delayed discharge, was added into the models to improve predictability. Knowing that at our hospital the ultimate decision regarding patient discharge is made by the attending physician, this variable was designed to capture prolonged observation of the patient. A patient was defined as having a delayed discharge if they remained in the hospital for > 48 h after they clinically met criteria for discharge. Criteria for discharge included stable normalization of temperature and WBC, and the receipt of oral antibiotics or the ability to receive oral antibiotic therapy, which ever came later. All patients who died in the hospital were automatically excluded from being defined as a delayed discharge.
A p value < 0.05 was considered significant during all statistical analysis. All statistical analysis was conducted using statistical software (SPSS/PC+; SPSS; Chicago, IL).
Results
Of the 543 patients identified with S pneumoniae-positive blood and/or respiratory culture findings, 168 patients met inclusion/exclusion criteria. Patients were excluded from the analysis for the following reasons: 203 patients had HIV infection, 72 patients did not meet clinical criteria or did not have a positive chest radiographic finding, 65 patients were discharged from the emergency department or admitted to the hospital for < 2 days, and 35 patients were infected with another bacteria at baseline other than those allowed in the inclusion/exclusion criteria.
Overall, patients were elderly (mean age, 63 years) and were equally divided among male and female gender (Table 1 ). Twenty-seven percent of patients were directly admitted to the ICU, and 42% had bacteremic pneumonia. The high severity of illness of this population was also apparent in the PSI score with 33% of patients in class IV and 23% in class V. Penicillin susceptibility was 74%; 11% were intermediate resistant, and 16% displayed high-level resistance. Crude mortality was 13% but was 21% among subjects within PSI classes IV and V. Ninety-five percent of patients who died were in PSI classes IV and V; one patient in PSI class III also died. There were no significant differences in patient demographics or clinical characteristics when the cohort was divided by penicillin susceptibility except for bacteremic pneumonia, which was more common among patients infected with penicillin susceptible isolates (48% vs 25%, p = 0.012). Lastly, penicillin susceptibility did not affect the median hospital length of stay for patients, which was 6 days in both groups (p = 0.725), nor did it influence admission to an ICU (p = 0.497). However, patients admitted to the ICU did have a significantly longer median length of stay (11.0 days [25th to 75th percentile, 6.8 to 19.8 days] vs 5.0 days [25th to 75th percentile, 4.0 to 8.0 days]; p < 0.001) compared with those treated outside the ICU.
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Discussion
Health-care costs attributed to managing CAP in the United States are now estimated to be > $10 billion annually, with the majority of these costs credited to treatment in the hospital.322 Therefore, studies aimed at identifying key factors associated with increased health-care costs are essential to improving cost-effectiveness and quality of care. In the current study, we assessed the factors predictive of increasing hospital costs and length of stay for patients admitted with pneumococcal pneumonia to a large, urban, private, teaching hospital over a 5-year period. We observed that hospital bed costs accounted for > 50% of the total resources utilized and that admission to the ICU, neoplasm, and an unexplained delayed discharge were independently associated with total hospital costs and extended length of stay. Additionally, end of hospital mortality was a significant predictor of costs, and the presence of CHF and bacteremia were positive predictors of length of stay.
However, the primary objective of this study was to determine if resistance to penicillin among S pneumoniae had an adverse effect on hospital costs or length of stay. Total median hospital cost for patients infected with penicillin susceptible isolates was $8,503, compared with $9,441 for those infected with nonsusceptible isolates (p = 0.617). As a result, penicillin susceptibility was not a significant variable in any of the multivariate regression models predicting hospital costs or length of stay. The conclusions remained similar even when the definition of penicillin nonsusceptibility was changed to fully resistant (MIC 2 µg/mL) vs susceptible/intermediate (data not shown), or when the total costs were compared for susceptible, intermediate, and resistant independently ($8,503 vs $6,347 vs $10,809, respectively; p = 0.477).
These results conflict with other studies12131415161819 that have identified increased costs attributed to infection with numerous resistant organisms, including S pneumoniae. In particular, our results conflict with a retrospective, cohort study of similar size but different time period by Klepser and colleagues19; these investigators evaluated health-care resource utilization for the treatment of penicillin-susceptible and penicillin-nonsusceptible isolates of S pneumoniae and found that total hospitalization costs were significantly greater for patients infected with penicillin nonsusceptible isolates ($10,309.25 vs $7,801.54, p = 0.0006). The primary reason for the higher cost was a greater length of stay among the nonsusceptible group (14 days vs 10 days, p < 0.05). Length of stay in general was much lower for patients in our study (median, 5 days) and not different between susceptible and nonsusceptible groups. It is most likely that the advances in understanding the time frame and clinical characteristics of the stable CAP patient in the current era (2000 to present) have dramatically reduced the duration of hospital stay compared with when the study by Klepser et al19 was conducted (1995 to 1998), therefore making it more difficult to find a difference if one were to exist.
Another potential reason for the discordance between our results and others is due to the fact that we defined groups according to penicillin susceptibility, yet only one patient actually received penicillin in our study. Instead, most were treated with second-generation or third-generation cephalosporins in combination with a macrolide or with fluoroquinolone monotherapy. Later-generation cephalosporins and fluoroquinolones are known to be more effective against S pneumoniae harboring intermediate-level resistance to penicillin, as well as isolates that are fully resistant with an MIC of 2 µg/mL.1223 ß-Lactam efficacy is only questioned when the penicillin MIC is 4 µg/mL.23 In the study by Klepser et al,19 patients also received a variety of different antibiotic cocktails; however, it was not possible to determine which ß-lactams were used, or if any were penicillin. We had susceptibility data reported solely for penicillin, and only in isolated cases did the microbiology laboratory have data for other antibiotics. This made it difficult to associate antibiotic resistance specific to the antibiotic received with that of hospital cost or length of stay. It also made it impossible for us to evaluate the appropriateness of empiric antibiotic therapy based on in vitro susceptibilities and its effect on the dependent variables. Therefore, from these data we cannot make a final conclusion regarding an association between antibiotic resistance among S pneumoniae and increased costs, except that penicillin resistance matters little in light of few patients still receiving this agent empirically. These data do, however, suggest that differentiation among S pneumoniae using solely penicillin susceptibility may not be sufficient.
The present results do confirm findings from other studies1924252627 demonstrating that hospital bed costs are the major contributor to total costs for CAP. In the study by Klepser et al,19 room costs accounted for 34% of total hospital costs and nursing costs accounted for 37%. Although we were not able to separate nursing costs from that of room costs in our study, our hospital bed costs accounted for both direct and indirect fixed costs. When added together, the percentage of resources dedicated to room and nursing was similar with our reported hospital bed cost percentage of 55.6%. Likewise, in a separate study to assess resource utilization in the treatment of CAP, Orrick and colleagues27 found median costs to be $2,430 for their population, with hospital room costs constituting 83.7% of total costs, followed by antibiotic (4.6%), radiology (2.6%), and respiratory care (0.9%) costs. It is not surprising then that admission to an ICU in our study was significantly associated with an increased cost and length of stay, as daily bed cost and total length of stay (11 days vs 5 days, p < 0.001) were both greater for patients in the ICU compared with a normal hospital bed. Importantly, these data taken together confirm that antibiotic costs account for only a small percentage (< 5%) of total costs in the treatment of hospitalized patients with CAP; moreover, any efforts to reduce total or ICU length of stay, such as IV-to-oral transition or clinical pathways, will have the most profound effect on reducing the economic burden of CAP.2829
The only variable that was significantly different between the susceptible and nonsusceptible groups in this study was the presence of bacteremia. In our analysis, 48% of patients infected with penicillin-susceptible S pneumoniae were also bacteremic, compared with 25% of patients with nonsusceptible isolates (p = 0.012). These results are consistent with numerous other reports7891819 in which invasive disease was more common among susceptible pneumococci. This is probably related to organism serotype, with certain serotypes commonly more susceptible than others, but also more virulent.30 We were unable to confirm this because we did not have access to the S pneumoniae isolates in our study to perform serotyping.
One interesting and perhaps still controversial observation in our study was the significance of the variable we defined as unexpected delayed discharge in predicting total costs and increased length of stay. Although difficult, it was our intent to characterize a measure of prolonged and unnecessary observation. We used clinical criteria (normalization of temperature and WBC) as well as transition to oral antibiotic therapy to determine whether the physicians in our hospital might by using unnecessarily longer observation periods and not discharging patients when they were stable. Excluding those patients who died, median length of stay was 2 days longer in patients who met our definition of delayed discharge. If patients were discharged within 1 day of meeting our clinical definition and receiving oral antibiotic therapy, the median length of stay for these 88 patients would have been 3 days (range, 2 to 6.75 days), with an estimated savings of approximately $507,000. These potential savings are likely underestimated given there was often a delay between IV-to-oral transition and the first day of stable clinical criteria; furthermore, we conservatively used the later day to define discharge eligibility. Our study was conducted at a single hospital, and while our patient population is likely similar to other large urban hospitals in the United States, one study31 has documented the distinct differences in clinical criteria used by physicians from institution to institution to determine when patients are stable for discharge, which may have influenced the impact of this variable. Additionally, clinical outcomes have not been adversely affected by decreases in length of stay (ie, discharge once patients are clinically stable without observation), suggesting that patients with CAP admitted to hospitals with historically long lengths of stay might be treated just as effectively with shorter hospital stays.32 It is important to note the limitations in attempting to define this variable retrospectively. Although there was no affect of age, comorbid illness, or PSI score, prolonged lengths of stay in these patients may be a reflection of numerous other factors in addition to defervescence, WBC normalization, and time to oral transition. Specifically, social issues and physician preferences, which cannot be accounted for in any severity of illness score, are important factors and difficult to account for given this study design. Nevertheless, given the significant impact that this defined variable had on our model, it will be sensible for us to further evaluate criteria for discharge within our institution and determine if changes in practice or discharge management can be addressed to reduce length of stay for CAP.
In conclusion, at our large, urban hospital, we observed that hospital bed costs accounted for > 50% of the total cost of care for patients admitted with CAP due to S pneumoniae. Admission to an ICU, neoplasm, and an unexplained delay in discharge were independently associated with both total hospital costs and increased length of stay; therefore, focused efforts to reduce total and ICU length of stay, including minimizing prolonged and unnecessary observation of patients, should have the most profound effect on reducing total costs. Finally, in the current era in which more potent antibiotics are empirically utilized to treat CAP, it does not appear that a simple classification of penicillin nonsusceptibility complicates the clinical or economic impact of S pneumoniae infection.
Acknowledgements
We thank Sheryl Horowitz, PhD, for guidance and suggestions regarding statistical analysis.
Footnotes
Abbreviations: CAP = community-acquired pneumonia; CHF = congestive heart failure; MIC = minimum inhibitory concentration; PSI = pneumonia severity illness
This study was funded through a competitive Hartford Hospital Research Endowment grant.
This paper was presented, in part, at the American College of Clinical Pharmacy 2005 Annual Meeting, San Francisco, CA, October 2005.
There are no proprietary data presented in this article, and the authors have no conflicts of interest to disclose.
References
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