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Authors: Charles L. Emerman, MD, Associate Professor of Emergency Medicine, Case Western Reserve University; Department of Emergency Medicine, MetroHealth Medical Center, Cleveland OH. Gideon Bosker, MD, FACEP, Assistant Clinical Professor, Section of Emergency Services, Yale University School of Medicine; Associate Clinical Professor, Oregon Health Sciences University Portland, OR. Lisa A. Miller, MD, Department of Emergency Medicine, MetroHealth Medical Center, Cleveland, OH.
Peer Reviewers: Jonathan Edlow, MD, Acting Chief of Service, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA; Instructor in Medicine, Harvard Medical School, Cambridge, MA. Stephen P. Ernst, PharmD, Clinical Pharmacy Coordinator, Columbia Terre Haute Regional Hospital, Terre Haute, IN; Sandra M. Schneider, MD, Professor and Chair, Department of Emergency Medicine, University of Rochester, Rochester, NY; Steven M. Winograd, MD, FACEP, Attending Physician, Department of Emergency Medicine, Lakeland Regional Health System, St. Joseph, MI.
Antibiotic guidelines for treatment of community-acquired pneumonia (CAP) vary from institution to institution, and, depending upon antimicrobial resistance patterns, such protocols may also vary from region to region. The variability among antimicrobial protocols is exemplified by the somewhat different approaches advocated by national associations, infectious disease experts, and published reviews in the medical literature. As a general rule, however, outcome-effective antibiotic selection, which is the subject of this consensus review, means taking into account local antibiotic resistance patterns, epidemiological and infection incidence data, and patient demographic features; and then, against the background of clinical judgment, determining the most appropriate agent for an individual patient.
Evaluating the advantages and disadvantages among recommendations and protocols issued by different authoritative sources can be problematic and confusing, to say the least. And although management guidelines for CAP must be "customized" for the local practice environment and for the individual patient, there appears to be a consensus regarding one aspect of CAP management: the typical medical ward inpatient or outpatient with CAP—that is, the patient without underlying risk factors such as immunosuppression, acquisition of the infection in a nursing home, or chronic alcoholism—generally requires treatment with an antibiotic that provides adequate coverage against S. pneumoniae, H. influenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae, and L. pneumophila. Empiric activity against these organisms may be considered "correct spectrum" coverage. Accordingly, those agents—most important among them, advanced generation macrolides—which provide this range of coverage within the framework of monotherapy, represent appropriate, initial intravenous therapy for the hospitalized patient.
Unfortunately, no single set of guidelines or critical pathways is applicable to every patient or practice environment; therefore, clinical judgment must take in account other factors that suggest the need for "intensifying" therapy with antibiotics whose spectrum extends beyond the six aforementioned organisms and includes other gram-negative species. In this regard, when patients with CAP present with risk factors or historical features that strongly suggest the likelihood of infection with such gram-negative organisms as Klebsiella pneumoniae (chronic alcoholism) or E. coli (infection acquired in a nursing home), it is appropriate to use an agent (an advanced fluoroquinolone) providing this spectrum of coverage. However, a cautionary note is in order. When, in the setting of CAP, the probability of gram-negative infection with E.coli, Pseudomonas sp., or other enterobacteria is relatively low, using an extended spectrum quinolone as initial therapy may represent "over-extended" coverage, in the sense that resistance pressure may be exerted against organisms not typically implicated in such infections, among them E. coli, Pseudomonas, and other enterobacteria.
Identifying treatment trigger points that support amplifying spectrum of coverage from a "correct spectrum" macrolide to an "extended spectrum" fluoroquinolone are essential for outcome-effective antibiotic use. Yet even when these factors are considered, a number of important questions and drug selection issues still remain: 1) When is intravenous monotherapy for pneumonia an outcome-effective management strategy? 2) When is two drug therapy the appropriate course? 3) What are the specific "intensification and treatment trigger" criteria? and 4) Which macrolides are available for intravenous-to-oral, step-down therapy?
In addition, it is now clear that clinical results in CAP can be optimized by using risk-stratification criteria that predict mortality associated with CAP. Associated clinical findings such as hypotension, tachypnea, impaired oxygen saturation, multi-lobar involvement, elevated blood urea nitrogen, and altered level of consciousness are predictive of more serious disease, as is acquisition of CAP in a nursing home environment.
With these antibiotic selection issues in clear focus, the authors of this comprehensive review present a set of consensus guidelines outlining CAP management for the year 2000. The authors focus on epidemiological data and antibiotic coverage features demonstrating the importance of "correct spectrum" coverage and organism-specific selection of initial intravenous antibiotics for in-hospital management of CAP.
— The Editor
A Brief Overview of the Antibiotic Landscape. The first generation cephalosporins have significant coverage against gram-positive organisms. By comparison, third generation cephalosporins have less gram-positive coverage and increased coverage against aerobic gram-negative rods.1 Ceftazidime has coverage against Pseudomonas, while cefoperazone has a somewhat higher MIC. Some of the second generation cephalosporins, such as cefoxitin, cefotetan, and cefmetazole, provide coverage against Bacteroides species. Imipenem has broad coverage against aerobic and anaerobic organisms. Aztreonam provides significant coverage for gram-negative bacilli such as Pseudomonas.
The aminoglycosides are active against gram-negative aerobic organisms. These agents are generally used for patients with severe CAP, particularly involving Pseudomonas. As a rule, they are combined with a third generation cephalosporin or an extended spectrum quinolone antibiotic, monobactam, or an extended spectrum penicillin when used in these circumstances.2
The tetracyclines are active against Streptococcus pneumoniae, H. influenza, Mycoplasma, Chlamydia, and Legionella. There is, however, a growing incidence of S. pneumoniae resistance to tetracyclines.3 These agents are alternatives to the macrolide antibiotics for empiric therapy for CAP in young healthy adults.4 Convenience and coverage advantages of the new macrolides, however, have thrust the tetracyclines into a secondary role for managing CAP. Clindamycin has activity against the anaerobes, such as B. fragilis,5 as well as against S. pneumoniae and S. aureus.6 Its anaerobic coverage makes it a consideration for the treatment of pneumonia in nursing home patients suspected of aspiration. Metronidazole also has activity against anaerobic bacteria such as B. fragilis. It is used in combination with other antibiotics for the treatment of lung abscesses, aspiration pneumonia, or anaerobic infections.
Appropriate and Adequate Intensity Coverage. Because macrolides and extended spectrum quinolones are effective, appropriate agents for treatment of CAP, they frequently get equal billing as "initial choice" agents for management of CAP. Despite their excellent track record and proven efficacy, however, the macrolides and extended spectrum quinolone have clinically significant differences that should be considered in the antibiotic treatment equation for CAP. Accordingly, a careful analysis of the benefits and potential pitfalls of these agents—one that includes a full accounting of the relevant similarities and differences—will help emergency physicians and intensivists develop criteria that suggest the appropriateness and suitability that each of these classes may have in specific patient subgroups.
Features that may suggest the need for intensification and expansion of bacterial and/or atypical pathogen coverage include the following: 1) increasing fragility of the patient; 2) acquisition of the pneumonia in a skilled nursing facility; 3) the presence of an aspiration pneumonia, suggesting involvement with gram-negative or anerobic organisms; 4) chronic alcoholism, increasing the likelihood of infection with Klebsiella pneumoniae; 5) pneumococcal pneumonia in underlying disease-compromised individual who has not been vaccinated with pneumococcal polysaccharide antigen (Pneumovax); 6) history of infection with gram-negative, anaerobic, or resistant species of S. pneumoniae; 7) history of treatment failure; 8) previous hospitalizations for pneumonia; 9) patient requires or has had previous ICU hospitalization for pneumonia; 10) acquisition of pneumonia in a community with high and increasing resistance among S. pneumoniae species; and 11) immunodeficiency and/or severe underlying disease. (See Table 1.) Many of the aforementioned risk groups can also be treated with the combination of a third generation cephalosporin plus a macrolide, in combination with an aminoglycoside when indicated.
|Table 1. Extended Spectrum Quinolones: Indications for Intensification and Expansion of Coverage in Patients with Community-Acquired Pneumonia|
|Possible Risk Factors, Pathogen Profiles, and Patient Subgroups that Should Prompt Consideration of Extended spectrum Quinolones§ as a Component of Initial Therapy|
|• Increasing severity of CAP|
|• Acquisition of pneumonia in a skilled nursing facility or a nosocomial environment (increases the likelihood of infection with gram-negative organisms)|
|• Aspiration pneumonia (increases likelihood of infection with gram-negative or anaerobic organisms)|
|• Chronic alcoholism (increases the likelihood of infection with Klebsiella pneumoniae)|
|• Pneumococcal pneumonia in underlying disease compromised individual who has not been vaccinated with pneumococcal polysaccharide antigen (Pneumovax)|
|• Previous history of infection with gram-negative, anaerobic, or resistant species of S. pneumoniae|
|• History of treatment failure (possibility of S. pneumoniae resistant species should be considered)|
|• History of recurrent hospitalizations for pneumonia|
|• Patient presently requires or has had previous ICU hospitalization for pneumonia|
|• Immunodeficiency and/or severe underlying disease|
|§ Levofloxacin: indicated for CAP caused by S. pneumoniae, H. influenzae, H. parainfluenzae, K. pneumoniae, S. aureus, M. pneumoniae, M. catarrhalis, L. pneumophila, or C. pneumoniae|
| When anaerobic organisms are suspected, clindamycin or a b-lactam/b-lactamase inhibitor (ampicillin/sulbactam, ticarcillin/clavulanate, or piperacillin/tazobactam) is recommended.|
Correct Spectrum Coverage. When antimicrobial monotherapy is desirable, cost-effective, and/or clinically indicated (and usually, it should be stressed, this is the case) extended spectrum quinolones and advanced generation macrolides best satisfy the empiric, aforementioned pathogen coverage requirements for patients with CAP. Accordingly, they currently represent the therapeutic classes of choice for management of CAP in the outpatient setting.
Although third generation cephalosporins, beta-lactam antibiotics, and TMP/SMX are still deemed valuable by many authorities and practitioners (in particular, in combination with other agents for in-hospital management of CAP), these agents have been allocated for the most part to secondary or alternative status for oral therapy. This is because they are not as a rule clinically indicated for treatment of atypical organisms, including Mycoplasma, Legionella, and C. pneumoniae, whose increasing importance now demand initial, out-of-the-gate coverage.
Because advanced generation macrolides and extended spectrum quinolones constitute the principal oral and intravenous treatment options for CAP, and because they are relatively new agents with activity and properties about which the emergency physician must be knowledgeable, the following sections will discuss indications, side effects, and strategies for their use in CAP. The focus of the discussion will be on newer antibiotics that: 1) provide coverage of bacterial and atypical organisms causing CAP; 2) are available for both outpatient (oral) and in-hospital (IV) management; and 3) are able, when indicated, to provide compliance-enhancing and cost-effective treatment within the context of antimicrobial monotherapy. Antibiotics satisfying these criteria include azithromycin and levofloxacin.
The established new generation macrolide antibiotics include the erythromycin analogs azithromycin and clarithromycin.19,20 Compared to erythromycin, the major advantages of these antibiotics are significantly decreased gastrointestinal side effects, which produce enhanced tolerance, improved bioavailability, higher tissue levels, and pharmacokinetic features that permit less frequent dosing and better compliance, as well as enhanced activity against H. influenzae.21,22 In particular, the long tissue half-life of azithromycin allows this antibiotic to be prescribed for a shorter duration (5 days) than comparable antibiotics given for the same indications.
Macrolides in CAP Therapy: An Overview. Given the cost differences between azithromycin and clarithromycin, as well as the improved compliance patterns associated with short-duration therapy, any rational approach to distinguishing between these agents must consider prescription, patient, and drug resistance barriers.
From the outset, it is fair to say that these newer macrolides, to a great degree, have supplanted the use of erythromycin (as well as cephalosporins and tetrayclines) in community-acquired infections of the lower respiratory tract. Although erythromycin, in particular, has been considered by some to be the antibiotic of choice for CAP, its lack of efficacy against H. influenzae, as well as its adverse gastrointestinal side effects, potential for drug-drug interactions, and poor compliance profile are now recognized as clinically important liabilities in emergency practice.23,24 It is, however, effective against pneumococcal pneumonia, Mycoplasma pneumonia, and many atypical infections, including Legionella. Food decreases the absorption of erythromycin, which interferes with drug metabolism, and the drug should be used with caution in patients on theophylline or warfarin. It should not be used concurrently with terfenadine.
From the perspective of providing definitive, cost-effective, and compliance-promoting therapy, the newer macrolide antibiotics, which include both azithromycin and clarithromycin, have recently emerged as some of the drugs of choice—along with the new quinolones—for outpatient management of CAP.25 When used as oral agents, they play a central role in management of pneumonia in otherwise healthy individuals who do not require hospitalization.
From an emergency medicine and in-hospital management perspective, the value of macrolide therapy has been significantly enhanced by availability of the intravenous formulation of azithromycin, which has been approved for hospitalized patients with CAP. Unlike penicillins, cephalosporins, and sulfa-based agents, azithromycin has the advantage of showing in vitro activity against both atypical and bacterial offenders implicated in CAP.
The macrolides also have the advantage of a simplified dosing schedule, especially azithromycin, which is given once daily for only five days (500 mg po on day 1 and 250 mg po qd on days 2-5). Clarithromycin requires a longer course of therapy and is more expensive. In general, the decision to use a macrolide such as azithromycin rather than erythromycin is based on weighing the increased cost of a course of therapy with azithromycin against its real-world advantages, which include a more convenient dosing schedule, its broader spectrum of coverage, its favorable drug interaction profile, and its decreased incidence of gastrointestinal side effects, which occur in 3-5% of patients taking a five-day, multiple-dose regimen.26 The introduction of a tablet formulation permits consumption of the antibiotic without regard to food ingestion.
Azithromycin. From a practical clinical and cost perspective, the newest and, perhaps most important advance in the area of macrolide therapy is the availability of intravenous azithromycin for the management of hospitalized patients with moderate or severe CAP.27,28 Currently, azithromycin is the only advanced generation macrolide indicated for parenteral therapy in hospitalized patients with CAP due to Chlamydia pneumoniae, H. influenzae, Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Streptococcus pneumoniae, or Staphylococcus aureus.29,30 This coverage would be considered "correct spectrum" coverage for empiric therapy of CAP.
The comparative trials demonstrating clinical success (patients who were cured or improved at 10-14 days post-therapy) rates of about 77%—with concomitant bacteriologic response rates of about 96% for frequently isolated pathogens—with azithromycin in CAP were conducted in a wide variety of patients with moderate and severe pneumonia. These included a significant percentage who were 65 years of age or older, had an abnormal respiratory rate (> 30 breaths per minute), a PaO2 less than 60 mmHg and and/or BUN greater than 20 mg/dL. Many of these patients had concurrent diseases or syndromes, including emphysema, chronic airway obstruction, asthma, diabetes, and/or were cigarette smokers.31
As would be expected, the efficacy of this macrolide was compared to clinical outcomes with a cephalosporin (cefuroxime) used with or without erythromycin. In a randomized comparative investigation, therapy with intravenous azithromycin alone followed by oral azithromycin was as effective as intravenous treatment with the designated "second-generation" cephalosporin, cefuroxime followed by oral cefuroxime axetil, with or without the addition of oral or intravenous erythromycin.31
Azithromycin dosing and administration schedules for hospitalized patients are different than for the five-day course used exclusively for outpatient management, and these differences should be noted. When this advanced generation macrolide is used for hospitalized patients with CAP, 2-5 days of therapy with azithromycin IV (500 mg once daily) followed by oral azithromycin (500 mg once daily to complete a total of 7-10 days of therapy) is clinically and bacteriologically effective. For patients requiring hospitalization, the initial 500 mg intravenous dose of azithromycin should be given in the ED.
Interestingly, among all intent-to-treat patients with CAP receiving azithromycin evaluated in two studies, 24 were found to have S. pneumoniae bacteremia at baseline. Of these 24 patients, 19 (79%) achieved clinical cure, which was accompanied by eradication of the pathogen from the blood. Among the five patients considered to be clinical failures, three of the five had documented eradication of S. pneumoniae from the blood, and the remaining two did not have post-baseline cultures reported. All five patients had significant comorbid conditions that were predictive of poor outcomes, but none of the failures resulted in mortality.31
Like the oral formulation, IV azithromycin appears to be well-tolerated, with a low incidence of gastrointestinal adverse events (4.3% diarrhea, 3.9% nausea, 2.7% abdominal pain, 1.4% vomiting), minimal injection-site reactions (less than 12% combined injection-site pain and/or inflammation or infection), and a low incidence of discontinuation (1.2% discontinuation of IV therapy) due to drug-related adverse patient events or laboratory abnormalities.32
As emphasized earlier, prompt administration of intravenous antibiotics in the emergency department can improve clinical outcomes in patients with community-acquired pneumonia (CAP). Consequently, once appropriate diagnostic tests—including cultures and radiographs—have been performed, initial antibiotic therapy for hospitalized patients should be administered in the ED, especially if delays in getting the patient admitted are anticipated.
Although antibiotic recommendations based on risk-stratification criteria, historical features, site where the infection was acquired, and other modifying factors are provided in Table 4, institutional protocols, hospital-based critical pathways, resistance features, and other factors will influence antibiotic selection.
Despite variations in hospital or departmental protocols, certain requirements regarding drug selection for CAP are relatively consistent. For example, from an empiric antibiotic selection perspective, what appears to be non-negotiable for managing the majority of patients with CAP, is providing mandatory antimicrobial coverage against S. pneumoniae, H. influenzae, M. catarrhalis, Legionella, M. pneumoniae, and C. pneumoniae. Consensus reports and national guidelines support this strategy. Within the framework of monotherapy, IV azithromycin (500 mg IV for 2-5 days, followed by PO 500 mg PO to complete a 7-10 day course) is recommended by many institutional protocols for ward (i.e., non-ICU) patients with CAP who do not have modifying factors (i.e., aspiration, immunosuppression, alcoholism, etc.) suggesting the likelihood of gram-negative pneumonia.7,30,32,44
For hospitalized patients, at least two days of intravenous azithromycin therapy is recommended (the first dose of which can be given in the ED), followed by transition to oral therapy at the discretion of the physician based on clinical factors. It should be noted that intravenous azithromycin is currently the only macrolide that carries an indication for in-hospital, intravenous-to-oral step-down, monotherapeutic management of appropriately risk-stratified patients with CAP caused by the following organisms: S. pneumoniae, H. influenzae, M. catarrhalis, Legionella, M. pneumoniae, C. pneumoniae, or S. aureus. Although other macrolides are available as possible co-therapeutic agents with cephalosporins, their potential limitations should be considered: erythromycin requires multiple daily dosing, it is not recommended for empiric monotherapeutic treatment of in-hospital CAP, and it fails to cover H. influenzae; and clarithromycin is not available as an intravenous formulation for treatment of severe in-hospital CAP. (See Tables 2 and 3.)
|Table 2. Macrolides: Approved Spectrum of Coverage in Community-Acquired Pneumonia|
|Antibiotic||Indicated* for Treatment of CAP Caused by These Organisms|
|S. pneumoniae||H. Influenzae||M. Catarrhalis||M. pneumoniae||C. pneumoniae||L. pneumophila||S. aureus|
|*Indicated, i.e., according to FDA approved indications as specified in the package insert for each agent. The agent may, however, show in vitro activity against organisms for which clinical indications have not yet been established.|
|** Intravenous formulation of azithromycin.|
|Table 3. Available Macrolides for Monotherapy or Co-Therapy in Hospitalized Patients with CAP|
|Antibiotic||Spectrum of Coverage*||Daily Dosing Frequency||IV to Oral Stepdown**||Is Agent Available for IV Monotherapy of CAP?|
|Azithromycin IV||S. pneumoniae||Once daily||Available and Indicated||Yes|
|Erythromycin IV||S. pneumoniae||Four times daily||Available||No|
|Clarithromycin Oral (IV not available)||S. pneumoniae||Twice daily||Not available||No|
|M. pneumoniae||C. pneumoniae|
|* Spectrum of coverage refers to approved indications as they pertain to in-hospital treatment of CAP for organisms specified.|
|** Refers to availability of IV to oral step-down using the same agent, i.e., IV azithromycin to oral azithromycin, IV erythromycin to oral erythromycin, etc.|
Accordingly, a number of critical pathways for pneumonia therapy recommend use of two-drug therapy for CAP—typically, the combination of an IV cephalosporin such as ceftriaxone plus a macrolide, which usually is administered, initially, by the intravenous route. Perhaps the important change in CAP treatment since publication of the American Thoracic Guidelines in 1994 is the current general consensus that atypical organisms such as L. pneumophila, C. pneumoniae, and M. pneumoniae must be covered empirically as part of the initial antibiotic regimen. Whereas previous consensus guidelines indicated that macrolides could be added to a cephalosporin on a "plus or minus" basis for initial CAP treatment, it is now felt that coverage of the atypical spectrum, along with coverage of S. pneumoniae, H. influenzae, M. catarrhalis, is mandatory. New guidelines can be expected to reflect this strategy which, in practical terms, likely means that a macrolide such as azithromycin—or a fluoroquinolone with activity against atypical organisms—will be part of almost every empirical antimicrobial regimen used for CAP.
When combination cephalosporin/macrolide therapy is the accepted hospital protocol, among the macrolides available, IV azithromycin is recommended by the authors as the co-therapeutic agent (i.e., in combination with a cephalosporin) of choice for the following reasons: a) it can be administered on a once-daily basis, thereby minimizing human resource costs associated with drug administration; b) it is the only macrolide indicated for in-hospital, intravenous-to-oral stepdown, monotherapeutic management of CAP caused by S. pneumoniae, H. influenzae, M. catarrhalis, Legionella pneumophila, M. pneumoniae, C. pneumoniae, or S. aureus—an important efficacy and spectrum of coverage benchmark; c) at $19-22 per day for the intravenous dose of 500 mg azithromycin, its cost is reasonable; and d) the intravenous-to-oral "step-down" dose of 500 mg has been established as effective in clinical trials evaluating hospitalized patients with CAP.
Although virtually all protcols using combination cephalosporin/macrolide therapy specify intravenous administration of the cephalosporin, guidelines specifying whether initial macrolide therapy should be by the intravenous or oral route are less concrete. Because atypical infections such a L. pneumophila are associated with high mortality rates, especially in the elderly, and because hospitalized patients with CAP, by definition, represent a sicker cohort, it is prudent and, therefore, advised that initial macrolide therapy in the hospital be administered by the intravenous route. Step-down to oral therapy can be accomplished when the patient’s clinical status so dictates, or when culture results suggest this is appropriate.
In summary, from an antibiotic selection perspective, it stands to reason that the availability of a monotherapeutic agent such as azithromycin—which carries an indication for monotherapeutic efficacy in hospitalized patients, is reasonably priced, and has an established, approved IV-to-oral step-down sequence—should, when combination therapy is appropriate, be given priority consideration over other macrolides which do not carry indications for stand-alone therapy and/or provide a less complete spectrum of coverage against organisms implicated in hospitalized patients with CAP. The decision to use azithromycin as a monotherapeutic agent, or in combination with a cephalosporin for initial therapy of CAP, will be determined by intra-institutional pathways and protocols.
The extended spectrum quinolone levofloxacin is indicated for treatment of CAP. Because levofloxacin is used both as an oral agent and intravenously in the hospital setting, the discussion below will focus on levofloxacin.
Levofloxacin. Levofloxacin, the S-enantiomer of ofloxacin, is a fluoroquinolone antibiotic that, compared with older quinolones, also has improved activity against gram-positive organisms including Streptococcus pneumoniae. This has important drug selection implications for management of patients with CAP and exacerbations of COPD. The active stereoisomer of ofloxacin, levofloxacin is available in a parenteral preparation or as a once daily oral preparation that is given for 7-14 days.
Levofloxacin is indicated for the treatment of adults (> 18 years) with mild, moderate, and severe pulmonary infections including acute bacterial exacerbation of chronic bronchitis and CAP.8 It is active against many gram-positive organisms that may infect the lower respiratory tract, including S. pneumoniae and Staphylococcus aureus, and it also covers atypical pathogens, including Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae. It is also active against gram-negative organisms, including E. coli, H. influenzae, H. parainfluenzae, Klebsiella pneumoniae, and Moraxella catarrhalis. Although it is active against Pseudomonas aeruginosa in vitro and carries an indication for treatment of complicated UTI caused by Pseudomonas aeruginosa, levofloxacin does not have an official indication for CAP caused by this gram-negative organism.
When given orally, levofloxacin is dosed once daily, is well absorbed orally, and penetrates well into lung tissue.9 It is active against a wide range of respiratory pathogens including atypical pathogens and many species of S. pneumoniae resistant to penicillin.10,11 In general, levofloxacin has greater activity against gram-positive organisms than ofloxacin and is slightly less active than ciprofloxacin against gram-negative organisms.12,13
Levofloxacin is available as both an oral and parenteral form, and the oral and IV routes are interchangeable (i.e., same dose). Levofloxacin is generally well tolerated (incidence of adverse reactions, < 7%). Levofloxacin is supplied in a parenteral form for IV use and in 250 mg and 500 mg tablets. The recommended dose is 500 mg IV or orally qd for 7-14 days for lower respiratory tract infections. Food does not affect the absorption of the drug, but it should be taken at least two hours before or two hours after antacids containing magnesium or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc.
Dosage adjustment is recommended in patients with impaired renal function (clearance < 50 mL/min).8 The drug is well-tolerated, with the most common side effects, including nausea, diarrhea, headache, and constipation.14 All quinolones have been associated with cartilage damage in animal studies, and, therefore, they are not recommended for use in children, adolescents, and pregnant and nursing women.
Comparative trials (generally available in abstract form) suggest that levofloxacin is as effective as cefuroxime axetil, cefaclor, and amoxicillin/clavulanate in upper or lower respiratory infections.15-17 In patients with CAP, IV levofloxacin with step-down to oral therapy was superior to ceftriaxone with step-down therapy to cefuroxime axetil.18 About 22% of patients in the cephalosporin arm required the addition of erythromycin or doxycycline due to the presence of atypical respiratory pathogens. The clinical response rates (cure plus improvement) were 88-97% for levofloxacin. Microbiological eradication was reported to be 94-98%; however, a large number of patients (32-43%) were not evaluable for this end point.15,17,18
It should be emphasized that, currently, such macrolides as azithromycin also are recommended for pneumonia in ambulatory, otherwise healthy adults. And, for older patients, an oral cephalosporin, such as cefuroxime axetil plus a macrolide to provide coverage of atypical pathogens may be considered and is recommended by certain consensus panel reports.9
A variety of antibiotics are available for outpatient management of pneumonia. (See Table 4.) Although the selection process can be daunting, as mentioned, a sensible approach to antibiotic selection for patients with pneumonia is provided by treatment categories for pneumonia generated by the Medical Section of the American Lung Association and published under the auspices of the American Thoracic Society.42 This classification scheme, which is now almost six years old, not only helps make clinical assessments useful for guiding therapy, but it is also predictive of ultimate prognosis and mortality outcome. New, more recently devised consensus panel recommendations also are available and will be discussed.
The most common pathogens responsible for causing CAP include the typical bacteria: S. pneumoniae, H. influenzae, and M. catarrhalis, as well as the atypical pathogens: Mycoplasma, Legionella, and Chlamydia pneumoniae.34 H. influenzae and M. catarrhalis are both found more commonly in patients with COPD. Clinically and radiologically, it is difficult to differentiate between the typical and atypical pathogens; therefore, coverage against all these organisms may be necessary. In patients producing sputum-containing polymorphonuclear leukocytes, the sputum Gram’s stain may contain a predominant organism to aid in the choice of empiric therapy. For most patients, therapy must be entirely empiric and is based on the expected pathogens.35,44 (See Table 4.)
|Table 4. Empiric Antimicrobial Therapy of Choice for Outpatient and In-Hospital Management of Community-Acquired Pneumonia|
|Patient Profile/Etiologic Agents||First-Line Antibiotic Therapy||Alternative First-Line Antibiotic Therapy|
|Otherwise Healthy < 60 years of age (outpatient or inpatient therapy; oral or IV)*||Azithromycin||Levofloxacin§ OR Clarithromycin OR Erythromycin (in patient with no history of COPD and who has a low probability of H. influenzae infection)|
|Otherwise Healthy > 60 years of age (Patients deemed to be suitable for outpatient/oral therapy, i.e., no systemic toxicity, high likelihood of compliance, and supportive home environment)*||Azithromycin IV OR Levofloxacin||Cefuroxime plus azithromycin OR Amoxicillin-clavulanate plus azithromycin|
|In-Hospital Underlying Risk Factors or Comorbid Conditions: In-Hospital Management (COPD, history of pneumonia, diabetes, etc.)||Azithromycin IV OR Levofloxacin IV||Ceftriaxone plus azithromycin IV OR Imipenem IV plus azithromycin IV|
|CAP acquired in the nursing home environment (increased likelihood of gram-negative, E. coli, Klebsiella pneumoniae)||Levofloxacin IV OR Ceftriaxone IV plus azithromycin IV||Ceftriaxone plus erythromycin IV OR Imipenem IV plus azithromycin IV|
|CAP in the individual with Chronic Alcoholism (Increased likelihood of Klebsiella pneumoniae infection)||Ceftriaxone IV plus azithromycin IV OR Levofloxacin IV||Ceftriaxone plus erythromycin IV OR Cefepime IV plus azithromycin IV|
|Severe CAP acquired in an area or institution with significant prevalence (> 20%) of S. pneumoniae species showing high level or complete resistance to macrolides, cephalosporins, and/or penicillin, but maintaining high sensitivity to extended spectrum quinolones)||Levofloxacin IV OR Vancomycin¶ plus azithromycin||Vancomycin¶ plus erythromycin|
|Severe CAP complicated by structural disease aminoglycoside IV of the lung (bronchiectasis): increased likelihood of Pseudomonas and polymicrobial infection||Cefepime IV plus levofloxacin IV plus aminoglycoside OR Ciprofloxacin IV plus aminoglycoside IV plus azithromycin IV||Ciprofloxacin IV plus aminoglycoside IV plus azithromycin IV OR Carbapenem IV plus azithromycin IV plus aminoglycoside|
|CAP in a patient with suspected aspiration (increases the likelihood of gram-negative and anaerobic infection**)||Levofloxacin IV plus Clindamycin IV OR plus ticarcillin/clavulanate IV||Levofloxacin IV plus ampicillin-sulbactam IV|
|Severe CAP in a compromised host with a previous hospitalization for, or who resides in a community or facility with a high reported incidence of methicillin-resistant S aureus (MRSA)***||Levofloxacin IV plus vancomycin IV OR Ceftriaxone IV plus azithromycin IV plus vancomycin IV||Levofloxacin IV plus vancomycin IV previous hospitalization for, or who resides in a community or facility with a high reported incidence of methicillin-resistant S. aureus (MRSA)***|
|CAP patient with severe pneumonia requiring ICU hospitalization***||Cefepime IV plus levofloxacin IV plus aminoglycoside (Pseudomonas strongly suspected) OR Levofloxacin IV plus/minus ceftriaxone IV plus beta-lactam/beta-lactamase inhibitor||Ciprofloxacin IV plus aminoglycoside IV plus azithromycin IV OR Ceftriaxone IV plus azithromycin IV plus aminoglycoside OR Levofloxacin IV plus carbapenem IV plus aminoglycoside|
|* Oral therapy/outpatient treatment recommendations are appropriate only for those otherwise healthy patients with CAP of mild enough severity that they are judged to be suitable candidates for outpatient management with oral antibiotics.|
|§ Quinolones are restricted for use in patients > 18 years of age.|
|¶ If S. pneumoniae demonstrates complete resistance to extended spectrum quinolones (very rare), third-generation cephalosporins, and macrolides, then vancomycin may be required as part of initial therapy, although this would be necessary only in rare circumstances.|
| First-line therapy recommendations take into consideration cost of the drug (which may vary from one institution to another), convenience of dosing, daily dose frequency, spectrum of coverage, side effects, and risk of drug-drug interactions.|
|** When anaerobic organisms are suspected as one of the possible etiologic pathogens in a patient with CAP, clindamycin or a b-lactam/b-lactamase inhibitor (ampicillin/sulbactam, tricarcillin/clavulanate, or ticarcillin/tazobacatam) is recommended.|
|*** High community prevalence of, previous history of hospitalization for, or increasing local incidence of methicillin-resistant S. aureus (MRSA) in a patient with a clinical presentation consistent with S. aureus pneumonia; vancomycin should be considered as component for initial therapy.|
| Adapted from references 3,8,33-43|
In these cases, one of the newer macrolides, such as azithromycin, should be considered one of the initial agents of choice. The other monotherapeutic agents of choice consist of the extended spectrum quinolones, such as levofloxacin, which provides similar coverage and is also approved as initial therapy in this patient subgroup.
For the older patient with CAP who is considered stable enough to be managed as an outpatient, but in whom the bacterial pathogen list may also include gram-negative aerobic organisms, the combined use of a second- or third-generation cephalosporin or amoxicillin-clavulanate plus a macrolide has been recommended. Another option may consist of an advanced generation quinolone.
Some experts emphasize that in non-smoking adults without COPD (i.e., patients at a low risk for having H. influenzae), therapy with erythromycin should be strongly considered.35 This is a matter of clinical judgment, but in any event, the newer macrolides, azithromycin and clarithromycin, are recommended in cases of erythromycin intolerance. In patients with COPD, either TMP-SMX or doxycycline usually provides adequate coverage against S. pneumoniae and H. influenzae, but TMP-SMX will not cover atypical pathogens.
Except for the newer quinolones such as levofloxacin, initial use of the older quinolones is not recommended for empiric treatment of community-acquired respiratory infections, primarily because of their variable activity against S. pneumoniae and atypical organisms. Although the older quinolones (i.e. ciprofloxacin) should generally not be used for the empiric treatment of CAP, they may provide an important option for treatment of bronchiectasis, particularly when gram-negative organisms such as Pseudomonas are cultured from respiratory secretions.45 In these cases, ciprofloxacin should be used in combination with another anti-pseudomonal agent when indicated.
The most important issue for the emergency physician or pulmonary intensivist is to ensure that the appropriate intensity and spectrum of coverage are provided, according to patient and community/epidemiological risk factors. In many cases—especially when infection with gram-negative organisms is suspected or there is structural lung disease—this will require shifting to and intensifying therapy with an extended spectrum quinolone. However, in most cases of non-ICU patients admitted to the hospital, azithromycin IV as monotherapy or a cephalosporin plus azithromycin is recommended, depending on institutional protocols.
In this regard, determining which of these antibiotics—macrolides vs. extended spectrum quinolones—should be considered "workhorse" drugs in the ED or hospital setting, for initial CAP treatment requires thoughtful analysis that takes into account cost, convenience, spectrum of coverage, host risk factors, and patient risk stratification. Table 1 outlines clinical factors, pathogen profiles, and patient subgroups that should prompt consideration of extended spectrum quinolones for use in management of CAP.
In the case of azithromycin, its five-day duration of therapy, $39-$42 cost per course of treatment, and targeted coverage of S. pneumoniae, H. influenzae, M. catarrhalis, Chlamydia, and M. pneumoniae, must be weighed against the longer duration and slightly greater cost per treatment course for the quinolones and the fact that their spectrum of coverage includes not only the appropriately targeted, aforementioned organisms commonly implicated in CAP, but extensive activity against gram-negative organisms, which may not always be required, especially in otherwise healthy individuals. This "over-extended" spectrum of coverage may exert resistance pressure on gram-negative organisms frequently encountered in a hospital setting; therefore, quinolone use should be risk-stratified to an appropriate subset.
From a cost-effectiveness perspective, it appears that when gram-negative coverage of Klebsiella and other species is not required, the advanced generation macrolide azithromycin represents a sensible choice as initial therapy, especially in individuals without underlying problems. However, in patients in whom gram-negative infection is more of a concern, the extended spectrum quinolone is an important alternative.
Finally, there is an increasing problem in the United States concerning the emergence of S. pneumoniae that is relatively resistant to penicillin and, less commonly, to extended-spectrum cephalosporins. These isolates may also be resistant to sulfonamides and tetracyclines.42,46,47 Except for vancomycin, the most favorable in vitro response rates to S. pneumoniae are seen with extended spectrum quinolones. See Table 4 for a summary of current recommendations for initial management of outpatient and in-hospital management of patients with CAP.
Role of Specific Pathogens in CAP. Prospective studies for evaluating the causes of CAP in adults have failed to identify the cause of 40-60% of cases of CAP, and two or more etiologies have been identified in 2-5% of cases. The most common etiologic agent identified in virtually all studies of CAP is Streptococcus pneumoniae, and this agent accounts for approximately two-thirds of all cases of bacteremic pneumonia.
Other pathogens implicated less frequently include H. influenzae (most isolates of which are other than type B), Mycoplasma pneumoniae, Chlamydia pneumoniae, S. aureus, Streptococcus pyogenes, Neisseria meningitidis, Moraxella catarrhalis, Klebsiella pneumoniae and other gram-negative rods, Legionella species, influenza virus (depending on the time of year), respiratory syncytial virus, adenovirus, parainfluenza virus, and other microbes. The frequency of other etiologies, (e.g., Chlamydia psittaci [psittacosis], Coxiella burnetii [Q fever], Francisella tularensis [tularemia], and endemic fungi [histoplasmosis, blastomycosis, and coccidioidomycosis]), is dependent on specific epidemiological factors.
The selection of antibiotics, in the absence of an etiologic diagnosis (gram stains and culture results are not diagnostic), is based on multiple variables, including severity of the illness, patient age, antimicrobial intolerance or side effects, clinical features, comorbidities, concomitant medications, exposures, and the epidemiological setting.
The Infectious Disease Society of America (IDSA) through its Practice Guidelines Committee provides assistance to clinicians in the diagnosis and treatment of CAP. The targeted providers are internists and family practitioners, and the targeted patient groups are immunocompetent adult patients. Criteria are specified for determining whether the inpatient or outpatient setting is appropriate for treatment. Differences from other guidelines written on this topic include use of laboratory criteria for diagnosis and approach to antimicrobial therapy. Panel members and consultants were experts in adult infectious diseases.
The guidelines are evidence based where possible. A standard ranking system is used for the strength of recommendations and the quality of the evidence cited in the literature reviewed. The document has been subjected to external review by peer reviewers as well as by the Practice Guidelines Committee, and was approved by the IDSA Council in September 1998. (See Table 5.)
|Table 5. Consensus Report Guidelines|
|Outpatient management: Preferred antimicrobials in most patients (in no special order)|
|• Macrolide*, Extended-spectrum fluoroquinolones**, or doxycycline***|
|• Alternative options: Amoxicillin/clavulanate and some second-generation cephalosporins (cefuroxime, cefpodoxime, or cefprozil). Note: These will not be active versus atypical agents.|
|* Macrolide: azithromycin, erythromycin, or clarithromycin; azithromycin or clarithromycin is preferred if H. influenzae infection is suspected|
|** Fluoroquinolone: levofloxacin is preferred.|
|*** Increasing resistance to S. pneumoniae is observed in some geographical regions in-hospital-general medical ward, non-icu management: preferred antimicrobials in most patients (in no Special order)|
|In-hospital-general medical ward, non-icu management: preferred antomicrobials in most patiens (in no special order)|
|• b-lactama with a macrolideb OR|
|• An intravenous fluoroquinolone (levofloxacin) with expanded coverage against S. pneumoniae|
|• Cefuroxime with a macrolideb OR|
|• Azithromycin (alone) in-hospital-intensive care unit management: preferred antimicrobials in most patients (in no special order)|
|In-hospital intensive care unit management: preferred antimicrobials in most patiens (in no special order)|
|• Azithromycin, erythromycin, or a fluoroquinolone plus cefotaxime, ceftriaxone, or a b-lactam-/b-lactamase inhibitord|
|• Structural disease of lung (bronchiectasis): add anti-pseudomonal penicillin, carbapenem, or cefepime plus macrolideb or fluoroquinolonec plus an aminoglycoside|
|• Likelihood of, or previous history of pseudomonal infection: add antipseudomonal penicillin, carbapenem, or cefepime plus macrolideb or fluoroquinolonec plus an aminoglycoside.|
|• High community prevalence or local incidence of methicillin-resistant Staphylococcus aureus (MRSA) in a patient with clinical presentation suggestive of S. aureus pneumonia: consider adding vancomycin.|
|• Penicillin allergy: fluoroquinolonec with or without clindamycin|
|• Suspected aspiration: fluoroquinolonec plus clindamycin or a b-lactam-/b-lactamase inhibitord a b-lactam: cefotaxime or ceftriaxone b Macrolide: azithromycin, clarithromycin, or erythromycin c Fluoroquinolone: vofloxacin or another fluoroquinolone with enhanced activity against S. pneumoniae d b-lactam-/b-lactamase inhibitor: ampicillin/sulbactam, ticarcillin/clavulanate, or piperacillin/tozabactam; for structural disease of the lung; ticarcillin/clavulanate of piperacillin/clavulanate|
|Adaptation and Summary of Preferred Antimicrobial Recommendations from the Infectious Disease Society of America|
Although the guidelines in Figure 2 do not present an option for observation units, in a health care environment that is sensitive to issues of cost containment, a number of institutions have explored possible use of a 24-hour observation unit for management of patients with CAP. Clearly, the majority of young and middle-age adults can be treated safely on an outpatient basis with oral antibiotic therapy and close follow-up. These patients tend to have a good baseline health status, are not systemically toxic on presentation, have stable vital signs (no evidence of tachypnea, tachycardia, or hypoxia), are not dehydrated, and are able to tolerate oral antibiotics. Appropriate antibiotic therapy for these patients has been discussed earlier.
Conversely, there are patients for whom a full hospital admission and IV antibiotics are indicated. In adults, concurrent medical problems increase the risk of complications from pneumonia.43 Consideration should be given to admission when faced with a patient who also has cardiac, renal, respiratory disease, diabetes, history of CVA, other neuromuscular disorders, malignancy, or is immunocompromised. As was emphasized previously, the immunocompromised patient often presents insidiously, and specialized studies may be required to identify the causative organism so that antibiotic therapy can be appropriately targeted.
For patients that are not well enough to be discharged from the ED, yet may have only one or two indications for admission, a brief period of observation may be warranted. Possibilities include dehydration with inability to tolerate oral intake, tachypnea with a slight decrease in oxygen saturation, patients with an unstable home environment, or exacerbations of asthma or COPD in a pneumonia patient. Such patients may benefit from a 24-48 hour period of IV antibiotics and fluid hydration, with reassessment at the end of this time period.
With a longer treatment time than is usually available during an ED visit, such studies as a sputum gram stain and culture would be more likely to yield preliminary results, allowing specific tailoring of antibiotic therapy. A chest x-ray need not be repeated before discharge, given the lag time in infiltrate development. An obvious exception to this would be the patient whose clinical condition worsened during the observation period, or those with evidence of a pleural effusion on a prior x-ray. These patients would be admitted to the hospital. If the patient has improved clinically, is tolerating oral intake, and has adequate oxygenation and stable vital signs, they may be discharged with close outpatient follow-up.
The use of an observation unit allows the emergency physician greater flexibility in decision-making, and provides a benefit to the patient if a full hospital admission can be avoided. The patient has received an optimized start on antibiotic treatment, coexistent factors may have caused a failure of initial home therapy, such as dehydration, have been corrected. There is a larger time span for clinical testing to pinpoint specific antibiotic therapy. Appropriate social work referral can be made for those requiring home-care assistance. Patient exposure to nosocomial pathogens is limited, avoiding a potential extended hospital stay. As with all decisions faced by the emergency physician, prudence is required when choosing a disposition for the patient with CAP.
The increasing incidence of atypical agents in older children and adults supports the importance of using an antimicrobial agent—both in the outpatient and in-hospital setting—with correct spectrum, adequate intensity coverage, in the majority of patients who are being treated empirically for CAP. Because compliance can be an important determinant of treatment outcome, the agent chosen should be conveniently dosed and be well-tolerated. Currently, these criteria for monotherapeutic efficacy in CAP are best satisfied by initial use of an advanced generation macrolide or, when intensification is required, an extended spectrum quinolone. The specific choice in a particular patient may vary depending on cost, anticipated patient compliance, the use of other medications, and/or the presence of other coexistent diseases. This article has provided systematic criteria for choosing between these two therapeutic classes and for selecting outcome-effective antibiotics within each class. Finally, the mandate for comprehensive patient assessment is as important as the initial antibiotic choice. This is necessary so that an appropriate, outcome-sensitive disposition decision can be made with the aim of optimizing patient care within the framework of fiscal prudence.
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A. S. pneumoniae.
B. H. influenzae.
C. M. catarrhalis.
D. atypical organisms: M. pneumoniae, C. pneumoniae, and L. pneumophila.
E. all of the above.
B. Tachypnea and impaired oxygen saturation
C. Multi-lobar involvement
D. Elevated blood urea nitrogen and altered level of consciousness
E. All of the above
A. is a first-line agent.
B. should always be used as part of initial therapy.
C. is an agent that should be considered in patients with aspiration pneumonia because of its activity against anaerobes.
D. all of the above.
E. none of the above.
A. S. pneumoniae, Pseudomonas, and E. coli.
B. S. pneumoniae, H. influenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae, S. aureus, and L. pneumophila.
C. S. pneumoniae, H. influenzae, M. catarrhalis, Bacteroides fragilis, and K. pneumoniae.
D. S. pneumoniae, H. influenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae, K. pneumoniae, and PCP.
E. none of the above.
A. S. pneumoniae.
B. M. pneumoniae.
C. H. influenzae.
D. L. pneumophila.
E. none of the above.
C. Extended spectrum quinolone (levofloxacin)
E. None of the above
A. bronchiectasis, with Pseudomonas cultured from respiratory secretions.
B. S. pneumoniae as the principal infecting organism.
C. Legionella CAP.
D. Mycoplasma CAP.
E. None of the above.
A. Clindamycin, TMP/SMX, or amoxicillin.
B. Macrolide, extended-spectrum fluoroquinolone, or doxycycline.
C. Ceftriaxone, erythyromycin, or amoxicillin-clavulanate.
D. All of the above.
E. None of the above.