Inappropriate initial antimicrobial therapy (IIAT), defined as an antimicrobial regimen that lacks in vitro activity against the isolated organism or organisms responsible for the infection, has been associated with excess mortality in patients with serious infections including health care-associated pneumonia (HCAP).7,10,11,14,18 This is largely related to increasing bacterial resistance to antibiotics as a result of their greater use and limited availability of new agents.3,4 Escalating rates of antimicrobial resistance lead many clinicians to empirically treat critically ill patients with presumed infection with a combination of broad-spectrum antibiotics, which can perpetuate the cycle of increasing resistance.4 IIAT can lead to treatment failures and adverse patient outcomes.12 Individuals with HCAP appear to be at particularly high risk of excess mortality when IIAT is administered.18,27
The 2005 update of the American Thoracic Society and Infectious Diseases Society of America (ATS/IDSA) nosocomial pneumonia guidelines incorporated for the first time the concept of HCAP.2 On the basis of the published data, patients with recent or chronic contact with the health care system appear to be at increased risk of infection with multi-drug resistant pathogens.13,15 These pathogens are frequently not covered by the initial antimicrobial treatment recommended in guidelines for community-acquired pneumonia (CAP).17 However, many physicians are unaware of the risk factors for HCAP and the clinical relevance of distinguishing it from CAP.22 Since patients classified as having HCAP are often heterogeneous, and reports on HCAP sometimes differ in setting and methodology, some authors have criticized the concept of HCAP.9 Therefore, we performed a clinical study to determine whether empiric antibiotic regimens targeting methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa are associated with greater appropriate therapy in patients with HCAP.
PATIENTS AND METHODS
A retrospective cohort analysis was performed of all culture-positive patients admitted to Barnes-Jewish Hospital (1200-bed urban teaching hospital) with a diagnosis of HCAP between January 1, 2003, and December 31, 2008.
One of the investigators (RMR) identified all study patients by the presence of a primary or secondary International Classification of Diseases (ICD)-9-CM code indicative of pneumonia and a concomitant positive respiratory bacterial culture, blood culture, or urine antigen test specific for Legionella pneumophila serogroup 1. The study database was constructed by merging patient-specific data from the automated hospital records, microbiology database, and pharmacy database of Barnes-Jewish Hospital.
Health care-associated pneumonia (HCAP) was defined in patients admitted to the hospital with a diagnosis of pneumonia who met 1 of the following criteria: 1) admitted from a nursing home, rehabilitation hospital, or other long-term nursing care facility; 2) previously hospitalized within the immediately preceding 12 months; 3) receiving outpatient hemodialysis, peritoneal dialysis, or infusion therapy necessitating regular visits to a hospital-based clinic; or 4) having an immunocompromised state. (Immunosuppression was defined as positive for human immunodeficiency virus, having received a solid organ or bone marrow transplant, having chemotherapy within 60 days for an underlying malignancy, or receiving corticosteroids at an equivalent dose of at least 20 mg of prednisone per day.)
Prior antimicrobial exposure was any exposure to an antibiotic within the preceding 90 days.
The diagnosis of HCAP was verified by 1 of the investigators (MHK) from the medical records and required the presence of a new radiographic infiltrate plus at least 2 of the following: 1) white blood cell count of >10,000 × 103/mL; 2) temperature ≥38.3°C; 3) purulent secretions from the lower respiratory tract; and 4) a ratio of the partial pressure of arterial oxygen to the inspired fraction of oxygen (PaO2/FiO2) <300. Acceptable positive culture specimens included sputum, tracheal aspirate, bronchoscopic or blind bronchoalveolar lavage (BAL), or blood. Blood cultures were accepted if the same microorganism was identified in a respiratory specimen and no other source for the positive blood culture could be identified. Additionally, a positive urine antigen for Legionella species qualified as a culture-positive specimen.
Antimicrobial treatment was classified as appropriate if the initially prescribed antibiotic regimen was active against the identified pathogen based on in vitro susceptibility testing and administered within 24 hours of hospital admission. For patients with polymicrobial infection, the initial antimicrobial regimen had to be active against all identified pathogens in order to be classified as appropriate. We defined CAP antibiotics as those used at Barnes-Jewish Hospital during the study period, including ceftriaxone, ampicillin, amoxicillin, amoxicillin/clavulanate, moxifloxacin, azithromycin, clarithromycin, and doxycycline. Similarly, standard antibiotics for the treatment of MRSA pneumonia, including HCAP attributed to MRSA, included vancomycin and linezolid. The anti-pseudomonal antibiotics used during the study were piperacillin-tazobactam, cefepime, imipenem, meropenem, gentamicin, and amikacin.
Antimicrobial Cultures and Susceptibility Testing
All respiratory culture specimens were cultured quantitatively. The tubes containing the respiratory specimens were first vortexed for 15 seconds. A 0.01-mL calibrated loop was placed into the respective specimens and then onto the center of 3 media plates (blood agar, chocolate agar, and MacConkey agar). The media plates were then streaked using the pin-wheel streak method and incubated in C02 at 35°C.23 Bacterial culture growth was quantified according to the number of colonies observed per plate: <10 colonies per plate represented <103 colony-forming units (CFU)/mL; 10-100 colonies per plate represented 103 to 104 CFU/mL; 100-1000 colonies per plate represented 104 to 105 CFU/mL; and >1000 colonies per plate represented >105 CFU/mL. Sputum and endotracheal aspirate specimens were considered positive if ≥105 CFU/mL were identified. BAL samples were considered positive at ≥104 CFU/mL. The microbiology laboratory tested antimicrobial susceptibility of bacterial isolates using the disk diffusion method according to guidelines and breakpoints established by the Clinical Laboratory and Standards Institute (CLSI) and published during the inclusive years of the study.6,19
Continuous variables were reported as mean ± the standard deviation. The Student t test was used to compare normally distributed data, and the Mann-Whitney U test was used to analyze non-normally distributed data. Categorical data were expressed as frequency distributions, and the chi-square test was used to determine if differences existed between groups. We performed multiple logistic regression analysis to identify clinical risk factors that were associated with appropriate antibiotic therapy and hospital mortality using SPSS, v. 11.0 for Windows (SPSS, Inc., Chicago, IL). Multivariate analyses were performed using models that were judged a priori to be clinically sound. This was prospectively determined to be necessary to avoid producing spuriously significant results with multiple comparisons. All tests were 2-tailed, and a p value < 0.05 was determined to represent statistical significance.
During the study period, 757 consecutive patients with culture-positive HCAP were admitted to Barnes-Jewish Hospital. The mean age of the population was 61.1 ± 17.0 years (range, 18-102 yr); 418 (55.2%) patients were male and 339 (44.8%) were female (Table 1). Prior hospitalization was the most common risk factor for HCAP. Antibiotic treatment within the preceding 90 days occurred in 430 (56.8%) patients. One hundred eighteen (15.6%) patients had BAL specimens, while 639 (84.4%) patients had sputum or endotracheal aspirate cultures obtained.
MRSA (n = 198, 26.2%) was the most common bacterial pathogen associated with HCAP, followed by P. aeruginosa (n = 174, 23.0%), Enterobacteriaceae (n = 140, 18.5%), methicillin-susceptible S. aureus (n = 110, 14.5%), Streptococcus pneumoniae (n = 100, 13.2%), Haemophilus influenzae (n = 45, 5.9%), and Acinetobacter species (n = 43, 5.7%). We found 119 (15.7%) patients with polymicrobial infection, and 253 (33.4%) patients with secondary bacteremia. Patients receiving appropriate initial antibiotic therapy were significantly more likely to be infected with Str. pneumoniae, Haemophilus influenzae, and methicillin-susceptible S. aureus (see Table 1). In contrast, patients receiving appropriate initial antibiotic therapy were significantly less likely to be infected with other streptococcal species, P. aeruginosa, Acinetobacter species, and Stenotrophomonas maltophilia.
Appropriate Antimicrobial Treatment
Appropriate initial antimicrobial therapy was administered to 544 (71.8%) patients within 24 hours of hospital admission, and 213 (28.1%) patients received IIAT. Figure 1 provides the rates of appropriate initial antimicrobial treatment according to the type of empiric antimicrobial regimen prescribed. Most patients received an initial antimicrobial regimen that included empiric coverage for P. aeruginosa (n = 557, 73.6%), MRSA (n = 543, 71.7%), or for both P. aeruginosa and MRSA (n = 486, 64.2%). However, 131 (17.3%) patients were empirically treated with an antimicrobial regimen targeted at CAP pathogens. Patients receiving CAP antibiotics were less likely than other patients to have had prior hospitalization in the preceding 90 days (39.7% vs. 60.2%; p < 0.001), admission from an extended care facility (9.2% vs. 25.9%; p < 0.001), chronic hemodialysis (5.3% vs. 10.4%; p = 0.074), immunosuppression (34.4% vs. 43.0%; p = 0.069), prior antibiotic exposure (49.6% vs. 58.3%; p = 0.068), intensive care unit admission (30.5% vs. 61.2%; p < 0.001), and mechanical ventilation (24.4% vs. 51.0; p < 0.001), and had numerically fewer HCAP risk factors (1.8 ± 0.8 vs. 2.2 ± 0.9; p < 0.001).
Initial antimicrobial regimens targeting P. aeruginosa and/or MRSA were significantly more likely to provide appropriate initial therapy (see Figure 1), while initial therapy targeted at CAP was more likely to provide IIAT. Patients treated with a CAP regimen were less likely than other patients to be infected with MRSA (17.6% vs. 28.0%; p = 0.014), P. aeruginosa (8.4% vs. 26.0%; p < 0.001), Acinetobacter species (2.3% vs. 6.4%; p = 0.093), and Stenotrophomonas maltophilia (0.0% vs. 2.1%; p = 0.140). Logistic-regression analysis demonstrated that empiric treatment with anti-pseudomonal antibiotics, empiric treatment with anti-MRSA antibiotics, infection with Str. pneumoniae, absence of Acinetobacter species infection, absence of P. aeruginosa infection, and absence of Stenotrophomonas maltophilia infection were independent predictors for the administration of appropriate antibiotic therapy (Table 2).
The overall hospital mortality rate was 23.7% (180 of 757 patients died during hospitalization). Patients receiving appropriate initial antimicrobial treatment were significantly less likely to die during hospitalization compared to those receiving IIAT (20.8% vs. 31.5%; p = 0.002). Logistic-regression analysis demonstrated that IIAT, absence of anti-MRSA antibiotics, increasing age, immunosuppression, and mechanical ventilation were independent predictors of hospital mortality (Table 3). When IIAT was removed from the multivariate analysis a similar model resulted, except that it retained treatment with a CAP antibiotic regimen as a predictor of hospital mortality (adjusted odds ratio, 2.73; 95% confidence interval [CI], 1.63-4.60; p = 0.053).
In the current study we found that appropriate initial antimicrobial therapy of HCAP was more likely to occur in patients whose empiric antibiotic regimen included anti-MRSA and anti-pseudomonal drugs. Initial empiric treatment with a CAP antibiotic regimen was more often associated with IIAT. This was likely due to the common etiologic causes of HCAP being antibiotic-resistant bacteria, including MRSA, P. aeruginosa, and Acinetobacter species. Interestingly, we also observed that patients with HCAP initially treated with a CAP antibiotic regimen, lacking MRSA and anti-pseudomonal activity, had fewer risk factors for health care-associated infection and less severe illness compared to patients prescribed empiric therapy with broader spectrum antibiotics. Finally, we confirmed the importance of IIAT as a predictor of hospital mortality in HCAP.
A number of investigators have compared the outcomes of patients with CAP and HCAP.5,15,18,20,23,25,26 Despite some differences in the inclusion criteria, all studies observed statistically greater mortality in patients with HCAP compared to CAP. Some authors attributed the increased mortality in HCAP to differences existing in terms of median age or presence of comorbidities.9 This is supported by the study from Rello and coworkers,20 who found greater mortality in patients with HCAP compared to CAP even though Str. pneumoniae was the causative agent of infection in all patients. However, other investigators have shown that patients with HCAP had a worse prognosis compared to patients with CAP independent of differences in age, comorbidities, or immunosuppression.25 A critical disparity appears to be the more common administration of IIAT in patients with HCAP compared to those with CAP, as a result of a greater incidence of infection with antibiotic-resistant pathogens among patients with HCAP.5,18,23,24,27 The current study supports the overall importance of IIAT for antibiotic-resistant pathogens as a determinant of outcome in patients with HCAP.
The pathogens most commonly associated with IIAT in HCAP are MRSA, P. aeruginosa or other nonfermenting gram-negative rods, and antibiotic-resistant Enterobacteriaceae species.18,25 In a Japanese study,23 HCAP patients with potentially drug-resistant pathogens (including MRSA, P. aeruginosa, and extended-spectrum β-lactamase-producing Enterobacteriaceae organisms) had a risk ratio of 14.0 (95% CI, 4.5-43.6; p < 0.001) with respect to IIAT. Unfortunately, no simple clinical approach for the identification of resistant bacteria as the etiologic agent of HCAP currently exists. Several attempts have been made to identify predictors of resistant bacteria in HCAP.21,24 The limitation of these approaches is that the prospective identification of these risk factors (for example, prior antibiotic exposure) can be problematic, and none of these prediction instruments has been validated for widespread use. Therefore, to optimize treatment, clinicians must rely on their awareness of the predominant pathogens causing health care-associated infections, and the antimicrobial susceptibilities of those pathogens, in the hospitals where they practice.
It appears that physicians in the current study may have used severity of illness as a key decision factor regarding the spectrum of empiric antibiotics they prescribed to patients with HCAP. This is supported by the significantly greater use of a CAP antibiotic regimen in patients not requiring intensive care unit admission or mechanical ventilation. Unfortunately, several studies have shown that patients prescribed IIAT with less severe illness have a greater attributable mortality compared to more severely ill patients receiving IIAT.1,8 A potential explanation for this finding is that the early use of appropriate antibiotic therapy, before the development of organ dysfunction, may help to minimize progression of illness related to the underlying infection.10 Therefore, clinicians should be cautious in using severity of illness as a determinant of antibiotic selection in patients with health care-associated infections.
There are several important limitations of the current study. First, the study was performed at a single center, and the results may not be generalizable to other institutions. However, the findings from other investigators corroborate the importance of appropriate initial antibiotic therapy as a determinant of outcome for patients with HCAP.18,25 Second, the retrospective and observational nature of the study limits our ability to establish causality between specific antibiotic regimens and clinical outcomes like hospital mortality. In spite of this, the potential negative impact to the individual patient from IIAT can be profound, and clinicians should at least consider this issue when prescribing empiric antibiotics to patients with HCAP. Another important limitation of our investigation is that we could not determine the rationale behind physicians' decisions regarding the types of antibiotic regimens they prescribed. Better understanding of this issue could provide institution-specific strategies for improving antibiotic use and avoiding IIAT. Finally, our study focused on patients with culture-positive HCAP. It is important to recognize that patients with culture-negative HCAP appear to be different, having less severe illness and being more likely to respond to CAP antibiotic regimens.16
In conclusion, the current study supports the use of an antibiotic regimen targeting MRSA and P. aeruginosa in patients with HCAP. However, local antibiotic treatment guidelines should be established based on the prevalence of HCAP and the pathogens, as well as their antibiotic susceptibility profiles, associated with this infection. It is unlikely that a clinical prediction rule will ever be available that can accurately designate the type of antibiotic regimen that should be empirically prescribed to patients presenting with pneumonia that minimizes both IIAT and the unnecessary use of broad-spectrum drugs. What would help clinical decision making is the availability of a rapid and accurate method for establishing the etiologic diagnosis of pneumonia, including antibiotic susceptibility. Such an approach could increase the appropriateness of initial therapy while also avoiding unnecessary antimicrobial use.
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