While many clinical trials have compared individual empiric antibiotic regimens, relatively few studies have simultaneously compared multiple different empiric regimens to identify an association between a certain regimen and a clinical outcome. One prospective, observational, multicenter, cohort study74 (N = 2963) characterized empiric antimicrobial regimens, assessed their compliance with the 1993 ATS guidelines,37 and evaluated associations between therapeutic choice and mortality and length of hospital stay (LOS), in patients admitted for presumed CAP. Compliance with ATS guidelines was 81% among patients with non-severe CAP, and 58% of those whose therapy was in compliance with the guidelines received a second- or third-generation cephalosporin or a p-lactam/p-lactamase inhibitor combination. Treatment with a second- or third-generation cephalosporin or a p-lactam/p-lactamase inhibitor combination with a macrolide was found to be independently associated with decreased mortality, according to multivariate logistic regression analysis (for non-severe CAP: OR 0-4; 95% CI 0-4, 0-8); P = 0-009; the same treatment regimen produced a non-significant trend toward reduced mortality among ICU patients (P = 0-26;

OR 0-5; 95% CI 0-2, 1-6). A retrospective study (N = 213) of inpatient medical records at two hospitals assessed outcomes after non-pseudomonal third-generation cephalosporin treatment alone (group 1, N = 97) or in combination with a macrolide (group 2, N = 116) for the initial treatment of CAP.75 There were no significant differences between groups in mortality rates (3-1% and 0-9% for groups 1 and 2, respectively), length of hospital stay (5-2 days for both), or duration of treatment with intravenous antibiotics (4-1 and 4-2 days for groups 1 and 2, respectively) between the two groups.

A secondary analysis of a prospective study (N = 385) investigated patients with "atypical"-pathogen pneumonia to identify associated clinical factors, rates of co-infection with other respiratory pathogens, and the relationship between mortality and macrolide-based treatment. Treatment for "atypical" agents (i.e. at least one dose of a macrolide or tetracycline) was provided for only seven (54%) of 13 patients with Legionella pneumophila, nine (57%) of 15 patients with Chlamydia spp., and two (66-7%) of three patients with M. pneumoniae. Furthermore, only four (9-3%) of 29 patients with "atypical" pathogens received at least 1 week of treatment for "atypical" agents. However, none of the 29 patients with "atypical" pneumonia died, including those who did not receive antibiotics with "atypical" activity.67

The largest evaluations of the relationship between the initial choice of antibiotics and clinical outcomes for patients with CAP have been performed using the USA Medicare (age 65 or older) database of patients. A retrospective study76 (N = 10 069) of Medicare patients hospitalized in 10 Western USA states during 1993, 1995, and 1997 demonstrated an association between lower 30-day mortality and an initial empiric antibiotic regimen containing either a macrolide or fluoroquinolone. Another retrospective study77 (N = 12 945) set as the reference standard a non-pseudomonal third-generation cephalosporin and demonstrated that the following antibiotic regimens were associated with significantly lower 30-day mortality rates compared with the reference standard: second-generation cephalosporin plus macrolide, third-generation cephalosporin (non-pseudomonal) plus macrolide, and quinolone alone; these results were obtained through multivariate and severity-adjusted analyzes. Results from these large retrospective analyzes76,77 suggest that coverage for "atypical" pathogens with either a macrolide or an antipneumococcal quinolone is important in the treatment of inpatients with CAP

In summary, data from RCTs do not conclusively demonstrate which antibiotic or class of antibiotic is most appropriate for the inpatient treatment of CAP patients. However, findings from large observational studies of USA Medicare patients suggest that coverage for "atypical" pathogens is associated with lower 30-day mortality rates for elderly patients hospitalized with CAP. It should also be noted that some RCTs have shown that patients hospitalized with CAP can be safely and effectively treated with oral antibiotic therapy.78-80

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