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Part II: Evaluation, Risk Stratification, and Current Antimicrobial Treatment Guidelines for Hospital-Based Management of CAP: Outcome-Effective Strategies Based on New National Committee on Clinical Laboratory Standards (NCCLS) Breakpoints and Recent Clinical Studies
—ASCAP (Antibiotic Selection for Community-Acquired Pneumonia) 2002 Consensus Report
Author: Gideon Bosker, MD, FACEP, Assistant Clinical Professor, Section of Emergency Services, Yale University School of Medicine, Associate Clinical Professor, Oregon Health Sciences University, Portland. Peer Reviewers: Steven M. Winograd, MD, FACEP, Attending Physician, Emergency Department, Jeannette District Memorial Hospital, Jeannette, PA, St. Clair Memorial Hospital and University of Pittsburgh Medical Center, Pittsburgh, PA; James A. Wilde, MD, FAAP, Assistant Professor, Emergency Medicine and Pediatrics, Research Director, Department of Emergency Medicine, Medical College of Georgia, Augusta.
ASCAP (Antibiotic Selection for Community-Acquired Pneumonia) 2002 Consensus Panel Members: Gideon Bosker, MD, FACEP, Section of Emergency Medicine, Yale University School of Medicine and Oregon Health Sciences University, ASCAP Panel Moderator and Chairman, Editor-in-Chief, Emergency Medicine Reports; Charles Emerman, MD, FACEP, ASCAP Panel Associate Chairman, Chairman, Department of Emergency Medicine, Cleveland Clinic Hospitals and Metro Health Center, Cleveland, Ohio; Stephen Ernest, PharmD, Clinical Pharmacist, Infectious Diseases; John Gums, PharmD, Professor, Departments of Pharmacology and Medicine, University of Florida, Gainesville; Dave Howes, MD, FACEP, Program Director and Chairman, Residency Program, Department of Emergency Medicine, University of Chicago Hospitals and Clinics, Associate Professor, Pritzker School of Medicine; Kurt Kleinschmidt, MD, FACEP, Associate Professor, Department of Emergency Medicine, University of Texas Southwestern Medical School, Parkland Memorial Medical Center, Dallas, Texas; David Lang, DO, Operations Medical Director, Department of Emergency Medicine, Mt. Sinai Medical Center, Miami, Florida; Sandra Schneider, MD, FACEP, Professor and Chairman, Department of Emergency Medicine, University of Rochester/Strong Memorial Hospital, Rochester, New York; and Gregory A. Volturo, MD, FACEP, Vice Chairman and Associate Professor, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester.
Statement of Financial Disclosure: In order to reveal any potential bias in this publication, and in accordance with Accreditation Council for Continuing Medical Education guidelines, we disclose that Dr. Emerman receives research grants from Merck, Scios, Sepacor, and serves as a consultant for Scios. He receives honoraria from Pfizer, Cor, Merck, Scios, Pharmacia, and Roche, and owns stock in Scios. Dr. Gums receives research grants from Pfizer, Roche, Merck, and Wyeth-Ayerst. He serves as a consultant for Aventis, Roche, and Wyeth-Ayerst, and he receives honoraria from Wyeth-Ayerst, Roche, and Aventis. Dr. Kleinschmidt is a consultant for Aventis. Dr. Schneider is a stockholder in Roche and received grant funds in 1987 from Smith Kline French. Dr. Volturo receives research grants from Roche, is a consultant for Pfizer and Aventis, and receives honoraria from Roche and Pfizer.
Rational antibiotic decision-making derives from a simple formula: "Use those agents that will cure the patient today and protect the community against antimicrobial resistance tomorrow." Easier to articulate than implement, this "cure and protect" approach to antibiotic selection requires clinicians to select agents that predictably will be active against the expected suite of pathogens causing a particular infection, but without over-extending antibacterial activity to include unlikely pathogens, and in the process, exert unnecessary pressure against organisms that could develop resistance in the future.
Because emergency physicians are responsible for selecting the initial antibiotic regimen for most hospitalized patients with community-acquired pneumonia (CAP), their decisions play an important role in determining clinical success as well as institutional drug resistance patterns. Moreover, it has become clear that the outcomes in patients with CAP can be maximized 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, just as age and acquisition of CAP in a nursing home environment are. These factors may assist emergency physicians in the initial selection of intravenous (IV) antibiotic therapy for hospitalized patients.
In light of important advances, changes, and refinements that have occurred in the area of CAP treatment during the past year—in particular, the introduction of 2002 National Committee on Clinical Laboratory Standards (NCCLS) minimum inhibitory concentration (MIC) breakpoint revisions for ceftriaxone and cefotaxime for treatment of non-meningeal infections caused by Streptococcus pneumoniae—the authors of this comprehensive review present an evidence-based and updated set of guidelines outlining CAP management for the year 2002. Treatment recommendations issued by the Infectious Disease Society of America (IDSA), American Thoracic Society (ATS), and the ASCAP (Antibiotic Selection for Community-Acquired Pneumonia) 2002 Consensus Panel are analyzed for their implications on emergency medicine practice and presented in detail; evidence supporting "cure today, protect tomorrow" treatment guidelines for a wide range of patient subgroups with CAP are outlined in tabular format so they can be incorporated into clinical practice and critical pathways.
Special emphasis has been given to both epidemiological data demonstrating the importance of correct spectrum coverage with specific cephalosporins (ceftriaxone) in combination with a macrolide (azithromycin), or as an alternative, monotherapy with an advanced generation fluoroquinolone (moxifloxacin). The potential for development of antimicrobial resistance through overuse of antibiotics belonging to specific drug classes is highlighted. Finally, the potential benefits of two-drug vs. monotherapeutic (single) drug regimens for treatment of elderly patients with severe CAP associated with Streptococcal bactermia is presented.—The Editor
ASCAP Consensus Panel Recommendations for Outpatient Management
Despite a general consensus that empiric, outpatient treatment of CAP requires, at the least, mandatory coverage of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, as well as atypical organisms (e.g., Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila), antibiotic selection strategies for achieving this spectrum of coverage vary widely. New treatment guidelines for CAP have been issued by such national associations as the IDSA (2000), the ATS (2001), and the Centers for Disease Control and Prevention Drug-Resistant Streptococcus pneumoniae Working Group (CDC-DRSPWG) (2000).
Deciphering the strengths, subtleties, and differences among recommendations issued by different authoritative sources can be problematic and confusing. Because patient disposition practices and treatment pathways vary among institutions and from region to region, management guidelines for CAP in the geriatric patient must be "customized" for the local practice environment. Unfortunately, no single set of guidelines is applicable to every patient or practice environment; therefore, clinical judgment must prevail. This means taking into account local antibiotic resistance patterns, epidemiological and infection incidence data, and patient demographic features.
Patient Management Recommendations. The ASCAP 2002 Consensus Panel concurred that appropriate use of antibiotics requires radiographic confirmation of the diagnosis of CAP. In this regard, physicians should use clinical judgment when ordering chest x-rays, with the understanding that the diagnostic yield of this radiographic modality in CAP is increased in patients with fever greater than 38.5°C; presence of a new cough; and abnormal pulmonary findings suggestive of consolidation, localized bronchoconstriction, or pleural effusion.
Accordingly, a chest x-ray is recommended and encouraged by the ASCAP Consensus Panel, as well as by such national associations as the IDSA, ATS, and American College of Emergency Physicians (ACEP), to confirm the diagnosis of outpatient CAP; however, the panel acknowledges that, on occasion, logistical issues may prevent radiographic confirmation at the time of diagnosis and treatment.
The approach to antibiotic therapy usually will be empiric, and must account for a number of clinical, epidemiological, and unpredictable factors related to antibiotic resistance patterns and respiratory tract pathogens. As a general rule, appropriate antibiotic choice for the patient with CAP requires consideration of strategies that will yield clinical cure in the patient today, combined with antibiotic selection strategies that prevent accelerated emergence of drug-resistant organisms that will infect the community tomorrow.
Based on the most current clinical studies, the principal six respiratory tract pathogens that must be covered on an empiric basis in individuals with outpatient CAP include: S. pneumoniae, H. influenzae, M. catarrhalis, C. pneumoniae, M. pneumoniae, and L. pneumophila. In addition, the ASCAP Consensus Panel emphasized that there may be a "disconnect" (i.e., an incompletely understood and not entirely predictable relationship between an antibiotic’s MIC level and its association with positive clinical outcomes in CAP). This "disconnect" may be explained by the unique qualities of an antimicrobial, such as tissue penetration and/or pharmacokinetics, patient medication compliance, and other factors.
Double-blinded, prospective clinical trials comparing new generation macrolides vs. new generation fluoroquinolones demonstrate similar outcomes in terms of clinical cure and bacteriologic eradication rates in outpatients with CAP.1 However, emergence of resistance among S. pneumoniae species to new generation fluoroquinolones has been reported in several geographic regions, including the United States, Hong Kong, and Canada, and this may have implications for treatment.
The frequency of drug-resistant S. pneumoniae (DRSP) causing outpatient CAP, as estimated by the CDC, is very low (i.e., in the range of 0.14-1.9%). The CDC-DRSPWG cautions against overuse of new generation fluoroquinolones in outpatient CAP, and recommends their use as alternative agents when: 1) first-line therapy with advanced generation macrolides such as azithromycin fails; 2) patients are allergic to first-line agents; or 3) the case is a documented infection with DRSP.2
Given concerns about antibiotic overuse, the potential for emerging resistance among DRSP to fluoroquinolones, and the increasing recognition of atypical pathogens as causative agents in patients with outpatient CAP, the panel concurs with the CDCDRSPWG recommendation advocating macrolides as initial agents of choice in outpatient CAP. The ASCAP Consensus Panel also noted that the Canadian Consensus Guidelines for CAP Management and the 2001 ATS Consensus Guideline Recommendations also include advanced generation macrolides as initial therapy for outpatient CAP.
In this regard, two safe and effective advanced generation macrolides, azithromycin and clarithromycin, currently are available for outpatient, oral-based treatment of CAP (IV azithromycin also is indicated for in-hospital management of patients who are risk-stratified as having more serious diseases). Based on outcome-sensitive criteria such as cost, daily dose frequency, duration of therapy, side effects, and drug interactions, the ASCAP Consensus Panel recommends azithromycin as first-line, preferred initial therapy in CAP, with clarithromycin or doxycycline as an alternative agents; and moxifloxacin, gatifloxacin, or levofloxacin as second-line therapy when appropriate, according to CDC guidelines and other association-based protocols. Among the advanced generation fluoroquinolones, moxifloxacin is preferred by the ASCAP Consensus Panel because it has the most favorable MICs against S. pneumoniae, and a more focused spectrum of coverage against gram-positive organisms than levofloxacin or gatifloxacin.
Physicians are urged to prescribe antibiotics in CAP at the time of diagnosis and to encourage patients to fill and begin taking their prescriptions for CAP on the day of diagnosis. Ideally, patients should initiate their first course of oral therapy within eight hours of diagnosis, a time frame that appears reasonable based on studies in hospitalized patients indicating improved survival in patients who received their first IV dose within eight hours of diagnosis. Physicians also are urged to instruct patients in medication compliance, and in the case of short (five-day) courses of therapy, educate their patients that, although they are only consuming medications for a five-day period, the antibiotic remains at the tissue site of infection for about 7-10 days and continues to deliver therapeutic effects during that period.
Either verbal or on-site, reevaluation of patients is recommended within a three-day period following diagnosis and initiation of antibiotic therapy. Follow-up in the office or clinic within three days is recommended in certain risk-stratified patients, especially the elderly, those with co-morbid illness, and those in whom medication compliance may be compromised. More urgent follow-up may be required in patients with certain increasing symptoms, including dyspnea, fever, and other systemic signs or symptoms. Follow-up chest x-rays generally are not recommended in patients with outpatient CAP, except in certain high-risk groups, such as those with right middle lobe syndrome, and in individuals in whom the diagnosis may have been uncertain.
In-Hospital Management of CAP—Monotherapy vs. Combination Therapy: Outcomes Analysis and ASCAP Treatment Guidelines
As emphasized earlier, prompt administration of IV antibiotics in the emergency department (ED) can improve clinical outcomes in patients with CAP. Consequently, once diagnostic tests, including cultures and radiographs (when appropriate), 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, sites where the infection was acquired, and other modifying factors play a role, institutional protocols, hospital-based critical pathways, resistance features, and other factors also will influence antibiotic selection. Despite variations in hospital or departmental protocols, certain requirements regarding drug selection for CAP are relatively consistent.
When combination cephalosporin/macrolide therapy is the accepted hospital protocol, among the beta-lactams available, IV ceftriaxone is recommended by the ASCAP 2002 Consensus Panel because of its evidence-based efficacy in moderate to severe CAP, once-daily administration, and spectrum of coverage, and because it is supported by all major guideline panels. One study evaluated antibiotic resistance using data derived from community-based medical practices. Data were gathered from July 1999 to April 2000. Four of the most common isolates were: M. catarrhalis (27%), H. influenzae (25%), Staphylococcus aureus (14%), and S. pneumoniae (12%); atypical organisms were not assessed.
Among S. pneumoniae isolates, levofloxacin exhibited a 4.8% level of resistance; for ceftriaxone, the resistance rate was only 5.8% (based on pre-2002 NCCLS MIC breakpoint). For Staphylococcus aureus, both ceftriaxone and levofloxacin inhibited all isolates. And for M. catarrhalis and H. influenzae, no resistance was observed for either levofloxacin or ceftriaxone. The investigators concluded that levofloxacin and ceftriaxone exhibited equivalent susceptibility/resistance patterns to organisms encountered in CAP.3
Although ceftriaxone was introduced to the market in 1985, and despite 18 years of use, its susceptibility to multiple gram-positive and gram-negative isolates has not changed significantly. In this regard, ceftriaxone has retained potent activity against the most commonly encountered enteric species (i.e., Escherichia coli, Klebsiella pneumoniae, Klebsiella xytocia, and Proteus mirabilis), at a level of 93-99%.3
Azithromycin is recommended as the co-therapeutic macrolide agent (i.e., in combination with ceftriaxone) in patients with CAP for the following reasons: 1) it can be administered on a once-daily basis, thereby minimizing human resource costs associated with drug administration; 2) it is the only macrolide indicated for in-hospital, IV-to-oral step-down, monotherapeutic management of CAP caused by S. pneumoniae, H. influenzae, M. catarrhalis, L. pneumophila, M. pneumoniae, C. pneumoniae, or S. aureus—an important efficacy and spectrum of coverage benchmark; 3) at $19-22 per day for the IV dose of 500 mg azithromycin, its cost is reasonable; 4) the IV-to-oral step-down dose of 500 mg has been established as effective in clinical trials evaluating hospitalized patients with CAP; and 5) azithromycin has excellent activity against L. pneumophila, a pathogen commonly implicated in the geriatric patient 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 intrainstitutional pathways and protocols, based on consensus recommendations and association guidelines as presented in this article.
Critical Pathways and Protocols. When patients with CAP are hospitalized in the intensive care unit (ICU) or there is a significant likelihood of gram-negative infection (i.e., Klebsiella, E. coli, or Pseudomonas aeruginosa), monotherapy with a macrolide is not appropriate, and the CDC-DRSPWG’s recent consensus report stresses the importance of using an IV macrolide in combination with other agents—in particular, third-generation cephalosporins such as ceftriaxone.4 In these patients, a macrolide should be used in combination with a cephalosporin (i.e., ceftriaxone), and when anti-pseudomonal coverage is necessary, an anti-pseudomonal cephalosporin and/or an aminoglycoside also may be required. Alternatively, an extended spectrum fluoroquinolone such as levofloxacin should be considered, although combination therapy that includes a cephalosporin such as ceftriaxone also has been advocated with this agent in severely ill patients.4 When anaerobic organisms are suspected, clindamycin or a beta-lactam/beta-lactamase inhibitor is appropriate.
Accordingly, a number of critical pathways for pneumonia therapy recommend use of two-drug therapy for CAP. The therapy typically is the combination of an IV cephalosporin such as ceftriaxone plus a macrolide, which usually is administered, initially, by the IV route when the patient’s condition so warrants. Perhaps the important change in CAP treatment since publication of the ATS guidelines in 1993 is the current general consensus, including guidelines presented at the 2001 ATS Scientific Conference, 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 now is felt that coverage of the atypical spectrum, along with coverage of S. pneumoniae, H. influenzae, and M. catarrhalis, is mandatory.2 New guidelines from the IDSA, ATS, ASCAP, and CDC now reflect this strategy.
Although virtually all protocols using combination cephalosporin/macrolide therapy specify IV administration of the cephalosporin, guidelines specifying whether initial macrolide therapy should occur via the IV or oral route are less concrete. Recent CDC-DRSPWG guidelines recommend an IV macrolide therapy for patients hospitalized in the ICU, while oral therapy is permissible in conjunction with an IV cephalosporin in the medical ward patient.4 Because atypical infections such as 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, advisable that initial macrolide therapy in the hospital be administered by the IV route. The ASCAP Consensus Panel, therefore, recommends IV azithromycin therapy as the preferred initial, empiric agent in combination with ceftriaxone. The Panel acknowledges, however, that some institutions will use IV ceftriaxone in combination with an oral macrolide in non-ICU patients, an approach supported by a number of national panels. In patients on combination cephalosporin/macrolide therapy, step-down to oral therapy with azithromycin can be accomplished when the patient’s clinical status so dictates, or when culture results suggest this is appropriate.
Monotherapy vs. Combination Therapy. It should be pointed out that while some consensus panels (ATS Guidelines, 2001) support the use of IV azithromycin monotherapy in very carefully selected hospitalized CAP patients (i.e., those with mild disease), other panels, such as CDC-DRSPWG and the IDSA 2000 Guidelines, support its use specifically as the macrolide component of combination therapy (i.e., to be used in combination with such agents as ceftriaxone).
As emphasized, advanced generation fluoroquinolones also provide a monotherapeutic option for management of CAP, and advocates of this approach argue that these agents, on an empiric basis, provide an adequate spectrum of coverage against expected respiratory pathogens at lower drug acquisition costs. Other experts make the case that although monotherapy for pneumococcal pneumonia is standard practice in many institutions, and is identified as a treatment option in many national association guidelines, there may be a survival benefit from using a combination beta-lactam and macrolide therapy.5 To address this issue, a group of investigators evaluated a patient database to determine whether initial empirical therapy with a combination of effective antibiotic agents would have a better outcome than a single effective antibiotic agent in patients with bacteremic pneumococcal pneumonia.
The investigators conducted a review of adult bacteremic pneumococcal pneumonia managed in the Methodist Healthcare System, Memphis, TN, between Jan. 1, 1996, and July 31, 2000. Empirical therapy was defined as all antibiotic agents received in the first 24 hours after presentation. On the basis of culture results, empirical therapy was classified as single effective therapy (SET), dual effective therapy (DET), or more than DET (MET). Acute Physiology and Chronic Health Evaluation II (APACHE II)-based predicted mortality (PM), and Pneumonia Severity Index (PSI) scores were calculated.5
Two hundred twenty-five subjects met the inclusion criteria for analysis. An additional seven cases of CAP with pneumococcal bacteremia were identified but were excluded from the study because the isolate was resistant to the empirical therapy the patients received. Investigators noted that the subjects who received MET were significantly sicker than the subjects who received SET or DET, as measured by the PSI (P = 0.04) and APACHE II-based PM (P = 0.03). Of special significance was the fact that there was no statistically significant difference in the prevalence of chronic disease states between the SET and DET groups.
Levofloxacin was the most commonly chosen fluoroquinolone (70.4%), with only four subjects treated with ciprofloxacin (one in the SET group, two in the DET group, and one in the MET group, all with no fatalities). Eight subjects who received more than one antibiotic agent as empirical therapy were classified as SET on the basis of the isolate being resistant to azithromycin (five subjects), cefotaxime (two subjects), or combined ticarcillin-clavulanate potassium (one subject). Twenty-nine subjects (12.9%) died. A Kaplan-Meier plot of mortality over time for each antibiotic therapy group demonstrated that mortality with the SET group was significantly higher than with the DET group (P = 0.02; odds ratio [OR], 3.0 [95% confidence interval (CI), 1.2-7.6]). Even when the DET and MET groups are combined, the mortality still was significantly higher in the SET group (P = 0.04; OR, 2.3 [95% CI, 1.0-5.2]). Because only a few subjects received MET and the subjects who received MET were significantly sicker than the other subjects, subsequent analysis is confined to the SET and DET groups.
Because subjects who received SET had a lower PM than those who received DET, a logistic regression model was used to calculate the OR for death of SET vs. DET adjusted for PM, which was 6.4 (95% CI, 1.9-21.7). All deaths occurred in patients with a PSI score higher than 90 (PSI classes IV and V). In subjects with PSI class IV or V CAP who were given SET, the PM-adjusted OR for death was 5.5 (95% CI, 1.7-17.5). Because antibiotic therapy would be expected to have little influence on early deaths, the investigators reanalyzed SET vs. DET groups after excluding all deaths that occurred within 48 hours of presentation (n = 4, 3 in the SET group and 1 in the DET group). Univariate analysis of this subgroup showed a trend to better outcome with DET compared with SET (94% survival vs 85%, respectively; P = 0.06). Multivariate analysis again confirmed that SET was an independent predictor of worse outcome (P = 0.01), with the PM-adjusted odds ratio for death in subjects given SET being 4.9 (95% CI, 1.6-18.3). Subgroup analysis did not show any significant trends to suggest any advantage or disadvantage of any specific antibiotic agents or combinations of antibiotic agents within the SET or DET groups.
While acknowledging its limitations, the results of this retrospective study strongly suggest that bacteremic patients with pneumococcal CAP who receive at least two effective antibiotic agents within the first 24 hours after presentation to a hospital have a significantly lower mortality than patients who receive only one effective antibiotic agent. In fact, among high-risk patients (PSI classes IV or V), receiving only one effective antibiotic agent increases mortality by more than five-fold as compared with patients receiving two effective antibiotic agents. Although these findings need to be confirmed by a prospective study, the authors suggest that current approaches to the empirical therapy of severe CAP may need to be reevaluated.5 Accordingly, the ASCAP 2002 Consensus Panel evaluated this study and found its results and conclusions—as well as its clinical implications—to be sufficiently compelling to recommend combination therapy with ceftriaxone plus a macrolide as the initial approach-of-choice in managing moderately to severely ill patients suspected of having bacteremia associated with pneumococcal pneumonia.
Extended Spectrum Fluoroquinolones: Intensification of Coverage and Patient Selection
The extended spectrum quinolones moxifloxacin, levofloxacin, and gatifloxacin are indicated for treatment of CAP. Each of these agents is available as an oral and IV preparation. Quinolones have been associated with cartilage damage in animal studies. They are not approved for use in children, adolescents, and pregnant and nursing women.
Moxifloxacin. Among the new fluoroquinolones, moxifloxacin has the lowest MICs against S. pneumoniae and more specific gram-positive coverage; therefore, it is recommended by the ASCAP Consensus Panel as the fluoroquinolone of choice—when a fluoroquinolone is indicated—for managing patients with CAP. Moxifloxacin generally is well-tolerated. In clinical trials, the most common adverse events were nausea (8%), diarrhea (6%), dizziness (3%), headache (2%), abdominal pain (2%), and vomiting (2%). The agent is contraindicated in persons with a history of hypersensitivity to moxifloxacin or any quinolone antibiotic. The safety and effectiveness of moxifloxacin in pediatric patients, young adults (older than age 18 years), pregnant women, and lactating women have not been established.
Although reports of clinical problems are rare, moxifloxacin has been shown to prolong the QTc interval of the electrocardiogram in some patients. The drug should be avoided in patients with known prolongation of the QTc interval, patients with uncorrected hypokalemia, and patients receiving Class lA (e.g., quinidine, procainamide) or Class lll (e.g., amiodarone, sotalol) antiarrhythmic agents due to the lack of clinical experience with the drug in these patient populations. Pharmacokinetic studies between moxifloxacin and other drugs that prolong the QTc interval, including cisapride, erythromycin, antipsychotics, and tricyclic antidepressants, have not been performed. An additive effect of moxifloxacin and these drugs cannot be excluded; therefore, moxifloxacin should be used with caution when given concurrently with these drugs.
Because of limited clinical experience, moxifloxacin should be used with caution in patients with ongoing proarrhythmic conditions, such as clinically significant bradycardia or acute myocardial ischemia. As with all quinolones, moxifloxacin should be used with caution in patients with known or suspected central nervous system (CNS) disorders or in the presence of other risk factors that may predispose the patient to seizures or lower the patient’s seizure threshold.
Gatifloxacin. Gatifloxacin, a broad-spectrum 8-methoxy fluoroquinolone antibiotic, is approved for community-acquired respiratory tract infections, such as bacterial exacerbation of chronic bronchitis (ABE/COPD); acute sinusitis; and CAP. The recommended dose for gatifloxacin is 400 mg once daily for individuals with normal renal function. Dosage adjustment is required in patients with impaired renal function (creatinine clearance less than 40 mL/min).
Gatifloxacin is excreted primarily through the kidneys, and less than 1% is metabolized by the liver. Gatifloxacin may have the potential to prolong the QTc interval in some patients, and due to limited clinical experience, gatifloxacin should be avoided in patients with known prolongation of the QTc interval, in patients with uncorrected hypokalemia, and in patients receiving Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic agents. Gatifloxacin should be used with caution when given together with drugs that may prolong the QTc interval (e.g., cisapride, erythromycin, antipsychotics, and tricyclic antidepressants), and in patients with ongoing proarrhythmic conditions (e.g., clinically significant bradycardia or acute myocardial ischemia).
Levofloxacin. Levofloxacin, the S-enantiomer of ofloxacin, is a fluoroquinolone antibiotic that, when compared with older quinolones, also has improved activity against gram-positive organisms, including S. pneumoniae. This has important drug selection implications for the management of patients with CAP and exacerbations of chronic obstructive pulmonary disease (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 well-tolerated, with the most common side effects including nausea, diarrhea, headache, and constipation.
Although no significant effect of levofloxacin on plasma concentration of theophylline was detected in 14 healthy volunteers studied, because other quinolones have produced increases in patients taking concomitant theophylline, theophylline levels should be monitored closely in patients on levofloxacin, and dosage adjustments made as necessary. Monitoring also is recommended for patients taking warfarin and quinolones.
When given orally, levofloxacin is dosed once daily, is well-absorbed orally, and penetrates well into lung tissue.6 It is active against a wide range of respiratory pathogens, including atypical pathogens and many species of S. pneumoniae resistant to penicillin.7,8 In general, levofloxacin has greater activity against gram-positive organisms than ofloxacin and is slightly less active than ciprofloxacin against gram-negative organisms.9,10
Levofloxacin is available in both oral and parenteral forms, and the oral and IV routes are interchangeable (i.e., same dose). Levofloxacin generally is well-tolerated (incidence of adverse reactions is less than 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.
Levofloxacin is indicated for the treatment of adults (older than 18 years) with mild, moderate, and severe pulmonary infections, including acute bacterial exacerbation of chronic bronchitis and CAP.11 It is active against many gram-positive organisms that may infect the lower respiratory tract, including S. pneumoniae (including DRSP) and S. aureus, and it also covers atypical pathogens, including C. pneumoniae, L. pneumophila, and M. pneumoniae. It also is active against gram-negative organisms, including E. coli, H. influenzae, H. parainfluenzae, K. pneumoniae, and M. catarrhalis. Although it is active against P. aeruginosa in vitro and carries an indication for treatment of complicated UTI caused by P. aeruginosa, levofloxacin does not have an official indication for CAP caused by this gram-negative organism.
Several studies and surveillance data suggest that some newly available, expanded spectrum fluoroquinolones, including levofloxacin (which is approved for PRSP), are efficacious for the treatment of S. pneumoniae, including penicillin-resistant strains.4,12,13 In one study, microbiologic eradication from sputum was reported among all 300 patients with pneumococcal pneumonia treated with oral levofloxacin.12 In a study of in vitro susceptibility of S. pneumoniae clinical isolates to levofloxacin, none of the 180 isolates (including 60 isolates with intermediate susceptibility to penicillin and 60 penicillin-resistant isolates) was resistant to this agent.13 In addition, a surveillance study of antimicrobial resistance in respiratory tract pathogens found levofloxacin was active against 97% of 9190 pneumococcal isolates and found no cross-resistance with penicillin, amoxicillin-clavulanate, ceftriaxone, cefuroxime, or clarithromycin.
Fluoroquinolones: Resistance Concerns and Over-Extended Spectrum of Coverage. Despite high-level activity against pneumococcal isolates and a formal indication for levofloxacin use in suspected DRSP lower respiratory tract infection, the CDC-DRSPWG recent guidelines do not advocate the use of extended spectrum fluoroquinolones (among them, levofloxacin) for first-line, empiric treatment of pneumonia.
This is because of the following: 1) their broad spectrum of coverage that includes a wide range of gram-negative organisms; and 2) concern that resistance among pneumococci will emerge if there is widespread use of this class of antibiotics. Population-based surveillance in the United States has shown a statistically significant increase in ofloxacin resistance among pneumococcal isolates between Jan. 1, 1995, and Dec. 31, 1997 (unpublished data, Active Bacterial Core Surveillance, CDC).4
The CDC-DRSPWG concerns about inducing fluoroquinolone resistance apply not only to S. pneumoniae, but also to other pathogenic organisms.14,15 Fluoroquinolone use in U.S. hospitals, as measured by inpatient dispensing, is changing over time. Selective pressure exerted by fluoroquinolone use may be related causally to the prevalence of ciprofloxacin-resistant P. aeruginosa. In fact, databases support growing concern about emerging fluoroquinolone resistance. In this regard, recent surveillance data indicate that resistance for P. aeruginosa to fluoroquinolones is increasing, possibly due to increased use of this drug class.14,15 To shed light on this possible association, the SCOPE-MMIT network of 35 hospitals tracked inpatient fluoroquinolone dispensing since 1999, and obtained hospital antibiograms to assess for associations between use and resistance rates.
MediMedia Information Technology (MMIT, North Wales, PA) collected data of inpatient-dispensed drugs from each participating hospital information system. Grams of individual fluoroquinolones are converted each quarter to defined daily dose/1000 patient days (DDD/1000PD). Antibiograms testing susceptibility of P. aeruginosa to ciprofloxacin were available from 22 hospitals. The relationship between total fluoroquinolone use and percentage resistance for P. aeruginosa to ciprofloxacin was assessed by linear regression. Results indicated that total fluoroquinolone use between 1999 and 2001 remained at approximately 140 DDD/1000PD, although mean levofloxacin increased significantly and ciprofloxacin use declined slightly. There was a significant positive relationship between total fluoroquinolone use and resistance to P. aeruginosa (r = 0.54, P = 0.01).
Investigators concluded that mean total fluoroquinolone dispensing in the 35 hospitals studied was stable, although there were significant differences in use between individual fluoroquinolones. It was not yet possible to determine if the relationship was causal or which fluoroquinolones are most likely responsible. The SCOPE-MMIT network will continue to evaluate the quantitative relationships between antibiotic use and resistance as antibiotic use changes over time, and as resistance rates respond to these changes in selective pressure.14,15
Fluoroquinolones and MRSA. Methicillin-resistant S. aureus (MRSA) represents a persistent problem in antibiotic therapy.16 There are a variety of well-known risk factors for the development of MRSA in the hospital, including extensive prior broad-spectrum antibiotic use, admission to an ICU, prolonged hospitalization, presence of an indwelling catheter, severe comorbid diseases, surgery, and exposure to MRSA-colonized patients. However, there has arisen a substantial amount of new data that fluoroquinolones are a risk factor for the increase in MRSA. Given the widespread use of oral fluoroquinolones in the community during the past several years, and the increase in community-acquired MRSA, it is prudent to consider the possibility that fluoroquinolone overuse may be associated with increasing emergence of MRSA.17
To address this question, one study evaluated prior antibiotic exposure and the development of nosocomial MRSA bacteremia in patients admitted to a 750-bed tertiary care hospital.17 All patients with nosocomial bacteremias from Jan. 1, 1996, to June 30, 1999, were evaluated. For each patient, investigators documented all antibiotics administered prior to the development of the bacteremia. They performed a case-controlled evaluation comparing fluoroquinolone-exposed patients to non-fluoroquinolone-exposed patients in relation to the development of MRSA bacteremia. A chi-squared analysis and relative risk (RR) were calculated.
A total of 514 nosocomial bacteremias occurred during the study period, with 78 (15%) MRSA cases. The percentage of MRSA bacteremias/nosocomial bacteremias increased from 10% in 1996 to 22% in 1999 (P < 0.05). MRSA as a percentage of all S. aureus clinical isolates increased from 29% to 40%. Prior fluoroquinolone exposure and MRSA bacteremia rose significantly from 25% of cases in 1986 to 65% of cases in 1999 (40% fluoroquinolone alone and 25% fluoroquinolone and other antibiotics) (P < 0.05). Cephalosporin exposure alone and the development of MRSA bacteremia dropped significantly from 50% of cases in 1996 to 0% of cases in 1999 (P < 0.01). Overall, 52% of fluoroquinolone-exposed patients developed MRSA bacteremia vs. 8% methicillin-sensitive S. aureus (MSSA) bacteremia (P < 0.05). In 1996 the RR of fluoroquinolone exposure and the development of MRSA bacteremia was 2.27 (ns), whereas during 1997-99 the RR of fluoroquinolone exposure was significant, ranging from 3.25 to 4.68 (P < 0.05). Fluoroquinolone usage increased hospital-wide during the study period.17
The study group noted a significant increase in nosocomial MRSA bacteremias in fluoroquinolone-exposed patients and a significant decrease in patients with cephalosporin exposure during the study period. Fluoroquinolone-exposed patients had a 3-4 times greater risk of developing nosocomial MRSA bacteremia than non-fluoroquinolone-exposed patients. Because increasing fluoroquinolone usage may have contributed to the increased selection and development of MRSA bacteremias, the study group implemented policies to limit fluoroquinolone utilization to attempt to control the selection and development of nosocomial MRSA bacteremias in the future.17
Selective Fluoroquinolone Use. Based on surveillance data and published studies, the CDC-DRSPWG has recommended that fluoroquinolones be reserved for selected patients with CAP. These experts have identified specific patient subgroups that are eligible for initial treatment with extended spectrum fluoroquinolones. For hospitalized patients, these include adult patients for whom one of the first-line regimens (cephalosporin plus a macrolide) has failed, those who are allergic to the first-line agents, or those who have a documented infection with highly drug-resistant pneumococci (i.e., penicillin MIC = 4 mcg/mL).18
Morbidity and Mortality Weekly Report recently reported the increasing levels of fluoroquinolone resistance among S. pneumoniae. Ofloxacin-resistance of 3.1% in 1995 had increased to 4.5% in 1997 (P = 0.02), whereas levofloxacin-resistance of 0.2% in 1998 was reported to be 0.3% in 1999 (P value not significant).19 The Morbidity and Mortality Weekly Report concluded that, "appropriate use of antibiotics is crucial for slowing the emergence of fluoroquinolone resistance."
Empiric Antibiotic Coverage for CAP: Matching Drugs with Patient Profiles
A variety of antibiotics are available for outpatient management of pneumonia. 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 ATS.20 This classification scheme helps make clinical assessments useful for guiding therapy, but it also is predictive of ultimate prognosis and mortality outcome.
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.21 H. influenzae and M. catarrhalis both are 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 of 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 based on the expected pathogens.22,23
Therefore, for the vast majority of otherwise healthy patients who have CAP but who do not have comorbid conditions and who are deemed well enough to be managed as outpatients, therapy directed toward S. pneumoniae, H. influenzae, M. pneumoniae, C. pneumoniae, L. pneumophila, and M. catarrhalis is appropriate. From an intensity and spectrum of coverage perspective, coverage of both the aforementioned bacterial and atypical species has become mandatory.
In these cases, one of the newer macrolides should be considered one of the initial agents of choice. The other monotherapeutic agents available consist of the extended spectrum quinolones, which provide similar coverage and carry an indication for 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 also may 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.23 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 trimethoprim-sulfamethoxazole (TMP-SMX) or doxycycline usually provides adequate coverage against S. pneumoniae and H. influenzae, but TMP-SMX will not cover atypical pathogens.
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) generally should 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.24 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 when 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, IV ceftriaxone plus azithromycin IV 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.
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 also 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.
Finally, there is an increasing problem in the United States concerning the emergence among hospitalized pneumonia patients of S. pneumoniae that is relatively resistant to penicillin and, less commonly, to extended spectrum cephalosporins. These isolates also may be resistant to sulfonamides and tetracyclines.20,25,26 Except for vancomycin, the most favorable in vitro response rates to S. pneumoniae are seen with extended spectrum quinolones. (See Table 1 for a summary of current recommendations for initial management of outpatient and in-hospital management of patients with CAP.)
Antimicrobial Therapy and Medical Outcomes. A recent study has helped assess the relationship between initial antimicrobial therapy and medical outcomes for elderly patients hospitalized with pneumonia.27 In this retrospective analysis, hospital records for 12,945 Medicare inpatients (65 years of age) with pneumonia were reviewed. Associations were identified between the choice of the initial antimicrobial regimen and three-day mortality, adjusting for baseline differences in patient profiles, illness severity, and process of care. Comparisons were made between the antimicrobial regimens and a reference group consisting of patients treated with a non-pseudomonal third-generation cephalosporin alone.
Of the 12,945 patients, 9751 (75.3%) were community-dwelling, and 3194 (24.7%) were admitted from a long-term care facility (LCF). Study patients had a mean age of 79.4 years ± 8.1 years, 84.4% were white, and 50.7% were female. As would be expected, the majority (58.1%) of patients had at least one comorbid illness; and 68.3% were in the two highest severity risk classes (IV and V) at initial examination. The most frequently coded bacteriologic pathogens were S. pneumoniae (6.6%) and H. influenzae (4.1%); 10.1% of patients were coded as having aspiration pneumonia, and in 60.5% the etiologic agent for the pneumonia was unknown.
The three most commonly used initial, empiric antimicrobial regimens in the elderly patient with pneumonia consisted of the following: 1) a non-pseudomonal third-generation cephalosporin only (ceftriaxone, cefotaxime, ceftizoxime) in 26.5%; 2) a second-generation cephalosporin only (cefuroxime) in 12.3%; and 3) a non-pseudomonal third-generation cephalosporin (as above) plus a macrolide in 8.8%. The 30-day mortality was 15.3% (95% CI, 14.6%-15.9%) in the entire study population, ranging from 11.2% (95% CI, 10.6%-11.9%) in community-dwelling elderly patients to 27.5% (95% CI, 26%-29.1%) among patients admitted from a long-term care facility.27
As might be predicted, this study of elderly patients with hospitalization for pneumonia demonstrated significant differences in patient survival depending upon the choice of the initial antibiotic regimen. In particular, this national study demonstrated that, compared to a reference group receiving a non-pseudomonal third-generation cephalosporin alone, initial therapy with a non-pseudomonal plus a macrolide, a second-generation cephalosporin plus a macrolide, or a fluoroquinolone alone was associated with 26%, 29%, and 36% lower 30-day mortality, respectively. Despite the fact that these regimens are compatible with those recommended by the IDSA and CDC, only 15% of patients received one of the three aforementioned regimens associated with reduced mortality rates.
For reasons that are not entirely clear, patients treated with a beta-lactam/beta-lactamase inhibitor plus a macrolide or an aminoglycoside plus another agent had mortality rates that were 77% and 21% higher than the reference group, respectively.
Role of Specific Pathogens in CAP. Prospective studies evaluating the causes of CAP in elderly 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 in the elderly is S. 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), M. pneumoniae, C. pneumoniae, S. aureus, Streptococcus pyogenes, Neisseria meningitidis, M. catarrhalis, K. 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’s 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.
Consensus Guidelines for Antibiotic Therapy
Consensus Report Guidelines: Infectious Disease Society of America. The 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 when 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 2000. (See Table 2.)
Centers for Disease Control Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group (CDC-DRSPWG) Guidelines. One of the important issues in selecting antibiotic therapy for the elderly patient is the emerging problem of DRSP. To address this problem and provide practitioners with specific guidelines for initial antimicrobial selection in these patients, the CDC-DRSPWG convened and published its recommendations in May 2000.4 Some of the important clinical issues they addressed included the following: 1) what empirical antibiotic combinations (or monotherapeutic options) constituted reasonable initial therapy in outpatients, in hospitalized (non-ICU) patients, and in hospitalized intubated or ICU patients; 2) what clinical criteria, patient risk factors, or regional, epidemiological features constituted sufficient trigger points to include agents with improved activity against DRSP as initial agents of choice; and 3) what antibiotic selection strategies were most appropriate for limiting the emergence of fluoroquinolone-resistant strains.
Their conclusions with respect to antibiotic recommendations overlap significantly with the IDSA recommendations and the existing ATS guidelines. The specific differences contained in the CDC-DRSPWG primarily involve the sequence in which antibiotics should be chosen to limit the emergence of fluoroquinolone-resistant strains, a preference for using combination drug therapy, cautionary notes about using fluoroquinolones as monotherapy in critically ill patients, reserving use of fluoroquinolones for specific patient populations, and detailed guidance regarding the comparative advantages among agents in each class. (See Table 3.)
Oral macrolide (azithromycin, clarithromycin, or erythromycin) or beta-lactam monotherapy is recommended by the CDC working group as initial therapy in patients with pneumonia who are considered to be amenable to outpatient management. For inpatients not in an ICU (i.e., medical ward disposition), this group recommends for initial therapy the combination of a parenteral beta-lactam (ceftriaxone or cefotaxime) plus a macrolide (azithromycin, erythromycin, etc.).4 Hence, one of the most important, consistent changes among recent recommendations for initial, empiric management of patients with CAP is mandatory inclusion of a macrolide (which covers atypical pathogens) when a cephalosporin (which has poor activity against atypical pathogens) is selected as part of the initial combination regimen.
For critically ill patients, first-line therapy should include an intravenous beta-lactam, such as ceftriaxone, and an intravenous macrolide such as azithromycin. The option of using a combination of a parenteral beta-lactam (ceftriaxone, etc.) plus a fluoroquinolone with improved activity against DRSP also is presented. Once again, however, this committee issues clarifying, and sometimes cautionary, statements about the role of fluoroquinolone monotherapy in the critically ill patient, stating that caution should be exercised because the efficacy of the new fluoroquinolones as monotherapy for critically ill patients has not been determined.4
Clearly, fluoroquinolones are an important part of the antimicrobial arsenal in the elderly, and the CDC-DRSPWG has issued specific guidelines governing their use in the setting of outpatient and inpatient CAP. It recommends fluoroquinolones be reserved for selected patients with CAP, among them: 1) adults, including elderly patients, for whom one of the first-line regimens (cephalosporin plus a macrolide) has failed; 2) those who are allergic to the first-line agents; or 3) those patients who have a documented infection with highly drug-resistant pneumococci (i.e., penicillin MIC > 4 mcg/mL).
Prevention of Deep Venous Thromboembolism (DVT)
Background. Although antibiotic therapy, oxygenation, and maintenance of hemodynamic status are the primary triad of emergency interventions in elderly patients with pneumonia, there has been an increasing recognition of the risk for venous thromboembolic disease (VTED) incurred by immobilized elderly patients with infections such as pneumonia, especially when accompanied by congestive heart failure (CHF) and/or respiratory failure. Emergency physicians, as well as attending physicians admitting such patients to the hospital, should be aware that the risk of VTED is significant enough to require prophylaxis in elderly patients with CAP who are likely to be immobilized for a period of three days or more (i.e., can ambulate fewer than 10 meters per day), and who have such risk factors as obesity, previous history of VTED, cancer, varicose veins, hormone therapy, chronic heart failure (NYHA Class III-IV), or chronic respiratory failure.28
From a practical perspective, this subset of patients should be considered strongly for prophylaxis to reduce the risk of VTED. Based on recent studies, the presence of pneumonia in a patient age 75 years or older is, in itself, a criterion for prophylaxis against VTED; when these factors are accompanied by CHF (Class III-IV) or respiratory failure, prophylaxis should be considered mandatory if there are no significant contraindications.28 It should be added that The American College of Chest Physicians (ACCP) guidelines29 and International Consensus Statement30 also cite risk factors for VTED and emphasize their importance when assessing prophylaxis requirements for medical patients.
Evidence for Prophylaxis. The data to support a prophylactic approach to VTED for serious infections in the elderly are growing. The studies with subcutaneous unfractionated heparin (UFH) are inconclusive, although this agent is used for medical prophylaxis. Despite the recognition of risk factors and the availability of effective means for prophylaxis, DVT and pulmonary embolism (PE) remain common causes of morbidity and mortality. It is estimated that approximately 600,000 patients per year are hospitalized for DVT in North America.31 In the United States, symptomatic PE occurs in more than 600,000 patients and causes or contributes to death in up to 200,000 patients annually.32
With respect to the risk of VTED in older patients with infection, one study group randomized infectious disease patients older than age 55 to UFH 5000 IU bid or placebo for three weeks. Autopsy was available in 60% of patients who died. Deaths from PE were delayed significantly in the UFH group, but the six-week mortality rate was similar in both groups. Non-fatal VTED was reduced by UFH. The findings of previous trials of prophylaxis in medical patients have been controversial, as the patient populations and methods used to detect thromboembolism and the dose regimens vary, undermining the value of the findings. Therefore, comparative studies with clearly defined populations and reliable end points were required to determine appropriate patient subgroups for antithrombotic therapy.33
The MEDENOX Trial. In response to the need for evidence to clarify the role of prophylaxis in specific non-surgical patient subgroups, the MEDENOX (prophylaxis in MEDical patients with ENOXaparin) trial was conducted using the low molecular weight heparin (LMWH) enoxaparin in a clearly identified risk groups.131 In contrast to previous investigations, the MEDENOX trial included a clearly defined patient population (patients immobilized with severe chest [cardiopulmonary] disease), and was designed to answer questions about the need for prophylaxis in this group of medical patients and to determine the optimal dose of LMWH.28
Patients in the MEDENOX trial were randomized to receive enoxaparin, 20 or 40 mg subcutaneously, or placebo once daily, beginning within 24 hours of randomization. They were treated for 10 days (4 days in the hospital and followed up in person or by telephone contact on day 90 [range, day 83-110]). During follow-up, patients were instructed to report any symptoms or signs of VTED or any other clinical events. The primary and secondary efficacy end points for MEDENOX were chosen to allow an objective assessment of the risk of VTED in the study population and the extent of any benefit of prophylaxis. The primary end point was any venous thromboembolic event between day 1 and day 14. All patients underwent systematic bilateral venography at day 10 or earlier if clinical signs of DVT were observed. Venous ultrasonography was performed if venography was not possible. Suspected PE was confirmed by high probability lung scan, pulmonary angiography, helical computerized tomography, or at autopsy.28 The primary safety end points were hemorrhagic events, death, thrombocytopenia, or other adverse events or laboratory abnormalities.28
A total of 1102 patients were included in the MEDENOX trial, in 60 centers and nine countries. The study excluded patients who were intubated or in septic shock. Overall, the mean age was 73.4 years, the gender distribution was 50:50, and the mean body mass index was 25.0. The mean patient ages, gender distribution, and body mass index were similar in all three treatment groups; there were slightly more males than females in the placebo and enoxaparin 20 mg groups, and more females than males in the enoxaparin 40 mg group, but this difference was not significant. The reasons for hospitalization of randomized patients varied.
The majority of patients were hospitalized for acute cardiac failure, respiratory failure, or infectious disease, with pneumonia being the most common infection in those older than 70 years. For the study population as a whole, the most prevalent risk factor in addition to the underlying illness was advanced age (50.4%). By day 14, the incidence of VTED was 14.9% in the placebo group and 5.5% in the enoxaparin 40 mg group, representing a significant 63% relative risk reduction in VTED (97% CI: 37-78%; P = 0.0002).
The primary conclusions of the MEDENOX trial can be applied directly to clinical practice. First, acutely ill elderly medical patients with cardiopulmonary or infectious disease are at significant risk of VTED. Second, enoxaparin, given once daily at a dose of 40 mg for 6-14 days, reduces the risk of VTED by 63%; and third, the reduction in thromboembolic risk is achieved without increasing the frequency of hemorrhage, thrombocytopenia, or any other adverse event compared with placebo. This study strongly suggests that elderly, immobilized patients admitted to the hospital with severe pneumonia, especially if accompanied by respiratory failure or Class III-IV CHF, should, if there are no contraindications to the use of anticoagulants, be considered candidates for prophylaxis with enoxaparin, 40 mg subcutaneously qd upon admission to the hospital to prevent VTED.
— Acknowledgement: The ASCAP 2002 Panel Members sincerely thank Dr. Donald Low, Mount Sinai Hospital and Toronto Medical Laboratories, Department of Microbiology, for his analysis, research, and contributions to the sections on emerging fluoroquinolone resistance and its clinical implications.
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