Community-Acquired Pneumonia: March 2006

John G. Bartlett, MD


March 08, 2006

In This Article

Treatment Clinical Trials

Welte T, Petermann W, Schurmann D, Bauer TT, Reimnitz P; MOXIRAPID Study Group. Treatment with sequential intravenous or oral moxifloxacin was associated with faster clinical improvement than was standard therapy for hospitalized patients with community-acquired pneumonia who received initial parenteral. Clin Infect Dis. 2005;41:1697-1705. The study was a prospective, multicenter, randomized, open-label, comparative study conducted between 2002 and 2003 in 54 centers in Germany, France, Greece, Lithuania, and Poland. The purpose was to determine the relative merits of 2 regimens for hospitalized patients with CAP. The regimens tested were moxifloxacin (400 mg/day) IV with the option of switch to oral therapy or ceftriaxone (2 g IV/day) with the option of adding erythromycin, 1 g IV every 6-8 hours. The duration of therapy in both groups was 7-14 days. The results were evaluated by rates of cure defined as resolution or improvement in the clinical signs and symptoms related to infection that did not require any antibiotic therapy at the test of cure visit 5-20 days after the last dose of antibiotics. In addition, the investigators measured the time to defervescence and the time to resolution of symptoms.

Results: Of the 397 patients who were randomized, 317 were considered evaluable. Cure rates were similar, but defervescence occurred 1 day earlier in the moxifloxacin group (median, 3 days vs 4 days)as well as earlier subjective improvement (median, 3 days vs 4 days) and shorter length of stays (mean, 9 days vs 11 days). These data are summarized in Table 4 .

Conclusion: Adult patients hospitalized with CAP had better outcomes with moxifloxacin in terms of the more rapid response to therapy as indicated by shorter hospital stay, more rapid defervescence, and shorter time to subjective improvement.

Comment: There are a number of reasons why conclusions from this study are limited:

  • The study was not blinded;

  • Only 38% of the participants in the ceftriaxone arm received erythromycin, thus indicating noncompliance at least with the US guidelines from IDSA and ATS; and

  • There was no oral treatment option in the beta-lactam arm, and the choice of erythromycin at 3-4 g/day would be generally unacceptable in North America.

Although these conclusions may be quite appropriate in areas where these regimens represent standard practice, they are limited when applied to North America. Despite the shortcomings, there is one feature of the study that is worth much praise. As shown by a multitude of other studies that compare fluoroquinolones with alternative agents, cure rates were the same in the 2 regimens; however, this study fine-tuned the outcome by measuring time to defervescence and subjective improvement with patient diaries. Thus, the results of this study, like many others, show equivalence in the overall outcome, but a faster response among those who receive fluoroquinolones. John H. Powers, MD,[9] Lead Medical Officer, Antimicrobial Drug Development and Resistance Initiative, Office of Drug Evaluation IV Center for Drug Evaluation and Research, US Food and Drug Administration (FDA), has been advocating for the use of such a method for registration trials to achieve results with a substantial reduction in the sample size and therefore cost. This would mean fewer total patients studied for cure vs failure at some arbitrary downstream time to establish "noninferiority." Instead, studies would be augmented by demonstrating time to defervescence, time to subjective improvement, or an objective clinical measurement other than complete resolution. In the accompanying editorial, Tom File, MD, Professor of Medicine, Infectious Diseases, Summa Health System, Akron, Ohio, and James S. Tan, Section of Infectious Disease, Department of Internal Medicine, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio,[10] suggest "time to clinical stability" as defined by Halm and colleagues[11] as such an alternative measurement.

van der Eerden MM, Vlaspolder F, de Graaff CS, et al. Comparison between pathogen directed antibiotic treatment and empirical broad spectrum antibiotic treatment in patients with community acquired pneumonia: a prospective randomised study. Thorax. 2005;60:672-678. This prospective, randomized, open-label study from Amsterdam, The Netherlands, was conducted between 1998 and 2000, with the intent of evaluating outcome in patients given pathogen-directed treatment vs empiric broad-spectrum antibiotic treatment. Empiric treatment was based on the 1993 ATS guidelines with a beta-lactam-beta-lactamase inhibitor plus erythromycin. Patients admitted to the ICU were given ceftazidime and erythromycin IV. Physicians with patients in the empiric arm were blind to the outcome of microbial studies. Lab studies done in the pathogen-directed treatment group consisted of a sputum that had cytologic screening prior to culture and urinary antigen test for Legionella pneumophila. Serology on days 1 and 14 of treatment were done for the detection of M pneumoniae, Chlamydia pneumoniae, L pneumophila, influenza, parainfluenza, respiratory syncytial virus, and adenovirus.

The results are based on observations in 262 patients, including 128 randomized to the empiric treatment arm and 134 given pathogen-directed treatment. There were 196 potential pathogens identified. The most common pathogens were S pneumoniae (92), M pneumoniae (23), and Haemophilus influenzae (19). All strains of S pneumoniae were sensitive to penicillin and macrolides. The results by intent-to-treat analysis for outcome showed no significant differences in length of stay, treatment failure, or mortality. In the "as-treated analysis," there was a significantly larger number of deaths attributed to CAP in the group given empiric antibiotics. The rate of adverse reactions was much greater in the group given empiric antibiotics (60% vs 17%). These results are summarized in Table 5 .

Conclusion: Empiric treatment was as effective as pathogen-directed treatment.

Comment: The major significant difference between the 2 treatment arms was the rate of adverse reactions with a 60% incidence in the group given empiric antibiotics compared with 17% of the pathogen-directed treatment group. Perhaps this is not surprising considering that IV erythromycin was standard treatment in the empirically treated group. It should also be noted that the application of these data to other institutions must be done with care because The Netherlands is blessed with a very low rate of antibiotic resistance by almost all bacteria, including S pneumoniae. The outcome that cannot be assessed is the effect of empiric treatment vs pathogen-directed treatment on resistance, especially resistance over time. Another concern is that the antibiotics recommended for routine use in hospitalized patients with CAP in North America require cephalosporins or fluoroquinolones, the two classes of antibiotics that are now implicated as the most common agents of antibiotic-associated colitis due to Clostridium difficile. Thus, efficacy alone may not be enough when assessing these treatment strategies.


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