Single vs Multiple Antibiotics in Community-Acquired Pneumonia

By Richard G. Wunderink, MD, FCCP; and Grant W. Waterer, MBBS, FCCP

Objectives

Explain that limitations of diagnosis prohibit defining optimal antibiotic therapy.
Recognize the frequency of polymicrobial etiology for community-acquired pneumonia (CAP).
Realize that empiric therapy that includes coverage of atypical microorganisms is associated with lower mortality.
Understand that combination therapy of severe CAP due to Streptococcus pneumoniae may be associated with lower mortality.
Realize that the spectrum of severe CAP includes Gram-negative microorganisms and that combination therapy with aminoglycosides may be warranted.

Key words

guidelines; monotherapy; mortality; pneumonia; Streptococcus pneumoniae; treatment

Abbreviations

APACHE = Acute Physiology and Chronic Health Evaluation; CAP = community-acquired pneumonia; FDA = Food and Drug Administration; MIC = minimum inhibitory concentration

The optimal antibiotic management of community-acquired pneumonia (CAP) has always been controversial. Wide variations in antimicrobial prescribing patterns have been the focus of outcomes interventions. The controversial nature of CAP treatment is illustrated by the fact that several professional societies and government agencies have recently published similar but not identical antibiotic guidelines.^1-3 Outside the United States, there is also a considerable diversity of opinion regarding optimal therapy, as reflected by the recent British Thoracic Society guidelines⁴ that differ markedly from North American guidelines.

The controversies regarding optimal antibiotic management of CAP have been driven by several factors (Table 1). Behind the controversy is the fact that multiple classes of antibiotics have good activity against Streptococcus pneumoniae, the most frequent cause of CAP in almost all settings. Antibiotics also will not affect the outcome in the 10 to 15% of patients with CAP caused by viral infections. As the mortality rate in nonsevere CAP is low (ie, < 1% for Pneumonia Severity Index grade I to III),⁵ if patients with severe CAP are excluded, as in most pharmaceutical industry studies, mortality differences between regimens will be very difficult to detect. As a result of these two factors, demonstration of equivalency in Food and Drug Administration (FDA) licensing studies is not difficult to achieve. Almost all recently released antibiotics, therefore, include CAP as an indication and are marketed as such to a variable degree by the pharmaceutical industry.

Emergence of resistance to many of the standard classes of CAP antibiotics in S pneumoniae in the last few years has complicated standard management. By far the most important is the development of penicillin and cephalosporin resistance. However, increasing macrolide, quinolone, sulfa, clindamycin, and tetracycline resistance also occurs. Unfortunately, neither the incidence nor the pattern of resistance is consistent from one area to the next. For example, macrolide monotherapy may be adequate in many areas but may lead to serious complications in an area of high macrolide resistance. An important aspect of application of guideline recommendations for CAP treatment is knowledge of the local antibiotic resistance patterns. The development of antibiotic resistance has prompted much of the surge in CAP antibiotic development.

By far, the main reason for controversy concerning the most appropriate therapy of CAP is the inability to accurately diagnose the etiology of CAP in the vast majority of patients. This issue affects almost all of the other problems related to defining optimal management. The limitations of expectorated sputum and blood cultures have been well described. Most atypical microorganisms can only be diagnosed by serologic conversion, making prospective comparison studies of the various agents active against Legionella, Chlamydia, or Mycoplasma impossible to perform.

Because of this, randomized clinical trials in CAP have combined all patients within a range of severity of illness rather than directly comparing treatment for a specific etiology. Retrospective analysis of patients with a defined etiology is occasionally used to suggest the comparative merits of the two drugs for certain microorganisms. However, other than pneumococcus, no prospective randomized comparison of two drugs for a specific etiology of CAP has been performed.

Further complicating the problems with diagnosis is the finding in several studies that polymicrobial CAP can occur in a significant percentage of hospitalized patients. The incidence has varied from < 10% up to > 40%.⁶ While occasionally two "typical" bacteria can be found on culture, the usual finding is a "typical" microorganism on culture and one or more microorganisms that are "atypical" detected on convalescent serum samples.

In patients with severe CAP, difficult-to-treat pathogens usually associated with nosocomial pneumonia—such as Pseudomonas, Acinetobacter, other Gram-negative bacilli, and even methicillin-resistant Staphylococcus aureus—have been found. As already mentioned, patients with severe CAP are often excluded from FDA-sponsored clinical trials, and no randomized controlled antibiotic trials have specifically addressed the severe-CAP population.

Clinical trials (at least for licensing purposes) are flawed in several critical aspects. In addition to combining all etiologies, the primary outcome parameter has always been clinical response rates (rather than microbiologic cure).^7-10 Unfortunately, the inability to accurately diagnose the cause and occurrence of antibiotic failure is very limiting. Only recently have researchers begun to address this important issue. One critical finding is that failure of antibiotic treatment in CAP results from nosocomial superinfection as often as from failure of the initial therapy.¹¹

An ongoing issue for CAP is the persistent, if not increasing, mortality. Pneumonia (combined with influenza) is the seventh leading cause of death in the United States. Whether correct antibiotic choices affect that mortality in the first 48 h is unclear. Early studies with penicillin treatment of bacteremic pneumococcal pneumonia did not show a difference in mortality compared with placebo for the first 48 h or more. However, recent data have suggested that initial antibiotic management, specifically the time to first dose, is associated with mortality differences.¹² Intuitively, the time to first adequate antibiotic dose in a patient with a drug-resistant isolate (and therefore the choice of appropriate therapy) would also affect mortality.¹³

All these factors are involved in the debate regarding single vs combination therapy of CAP.

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