SECTION 1
Introduction
Behavioral Objectives
SECTION 2
Normal
Respiratory Tract Defenses
Clinical Presentation
Risk
Stratification of CAP
Determination
of Etiologic Agent
Treatment
Ambulatory Setting
Hospital Setting
Alternative
Antimicrobial Therapy
Response to Therapy
SECTION 3
Summary
References
Quiz Preview
Accreditation
|
|
Brought to you by an unrestricted educational grant from
Roche Pharmaceuticals Inc.
An Update on the Treatment of Community-Acquired Pneumonia
Cynthia A. Burman, PharmD; Staci Pacetti, PharmD, and Steven P. Gelone, PharmD
Dr. Burman is Assistant Clinical Professor and Dr. Pacetti is Infectious Diseases Specialty Resident, Temple University School of Pharmacy. Dr. Gelone is Associate Professor of Pharmacy, Assistant Professor of Medicine, Temple University Schools of Pharmacy
Infection of the respiratory tract continues to be the most frequent and important cause of short-term illness in the United States. Pneumonia, an inflammation of the lung parenchyma caused by acute infection, is the sixth leading cause of death and the number one cause of death as a result of infectious diseases in the United
States.1,2 Because pneumonia is not a reportable disease and most community-acquired infections are treated on an outpatient basis, it is difficult to determine the true incidence of this infection and its related morbidity. Approximately 2 million to 3 million cases of community-acquired pneumonia (CAP) occur annually, resulting in 10 million physician visits, 500,000 hospitalizations, and 45,000
deaths.3 Of those patients hospitalized for pneumonia, the average mortality rate is 10% to
14%.3-5 Mortality depends on the kind and number of underlying diseases, age of the patient, complications during hospitalization, and type of bacteria causing the pneumonia. The aggregate cost of care in the United States for CAP is in excess of $4.4 billion
annually.4,6-9
Over the past decade, diagnostic modalities and treatment options have become abundant as a result of an increase in pathogen resistance and the aging of the population. At the same time, managed care organizations have forced practitioners to reevaluate their practices, specifically regarding antibiotic route of administration and site of care. In addition, differences exist among the current guidelines for the management of CAP, further reflecting the diversity of CAP management.
Preservation of normal respiratory tract function involves a complex system of local pulmonary lung defenses. Anatomic, functional, and mechanical barriers protect the tracheobronchial tree from inert particle and microbial invasion. In addition, an intricate system of cellular and humoral immune host defenses contributes to maintaining the respiratory tract free of infection. Intrinsic defects in these normal defenses predispose the patient to respiratory
infections.10,11
The hairs lining the nasal passages, ciliated epithelial cells on mucosal surfaces, production of mucus, salivary enzymes, and the mechanical process of swallowing help decrease and prevent the passage of foreign material into the lower respiratory tract. Control of epiglottal and laryngeal function is necessary to prevent aspiration of upper airway secretions. A functioning mucociliary transport system, which traps and removes foreign material from the lower respiratory tract, is critical to the protection of the lungs. Finally, cellular and humoral defenses, such as immunoglobulin and complement, enhance the body’s defense against bacterial pathogens.
In the normal state, the lungs are repeatedly inoculated with micro-organisms from the upper airway and inhaled aerosols, but pneumonia rarely
occurs.12 If as a result of defects in one or more of the above mechanisms the lung is exposed to an increased inoculum of micro-organisms for a sufficient period of time, marked inflammatory changes result in pneumonia.
Nearly all patients with pneumonia have fever and cough (with or without sputum
production).9 Patients may complain of a history of pleuritic (knife-like) chest pain or may be hypoxemic and tachypnic. On physical examination and auscultation of the chest, decreased breath sounds, dullness on chest percussion, vowel tone changes (E to A changes also called egophony), chest splinting, and an inspiratory lag highly suggest a lung consolidation. All of these signs suggest a pneumonic process and usually are present on the affected lung.
In addition to a thorough physical examination, a complete blood count with differential should be evaluated. An elevated white blood cell count with a left shift in the cell differential (predominance of polymorphonuclear cells [PMNs] and bands) is consistent with a bacterial infection. The chest radiograph is important in identifying and/or confirming a pulmonary infiltrate in patients with respiratory infections. Although a number of tests are used to document pneumonia, a chest radiograph most clearly distinguishes pneumonia from other diseases. Congestive heart failure, pulmonary embolism, and other diseases may mimic the signs and symptoms of pneumonia. In the majority of cases, a chest radiograph is the test that differentiates between acute bronchitis—an infection that does not require antibiotics—and pneumonia, which benefits from antimicrobial therapy. Consequently, a chest radiograph is recommended for all patients hospitalized for presumed pneumonia. The radiograph also may be useful in evaluating the severity of disease (multilobar versus single-lobe involvement).
Historically, clinicians have attempted to classify pneumonia as typical or atypical. This categorization originated from the presumption that the presenting symptoms of pneumonia secondary to pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and enteric gram-negative bacteria (typical) are different from those observed for Mycoplasma, Legionella, and Chlamydia (atypical). However, both the American Thoracic Society and the Infectious Diseases Society of America (IDSA) caution that this categorization is flawed. S pneumoniae and viruses have been documented to cause a syndrome indistinguishable from that caused by Mycoplasma pneumoniae. Consequently, reliance on the presence of specific symptoms in the etiology of pneumonia may be unreliable. This difficulty with a pathogen-specific diagnosis commonly results in the empiric use of antibacterials in the treatment of pneumonia.
The site of care has become critically important in the era of managed health care because hospitalizations account for 89% to 96% of pneumonia
costs.6 Risk factors for mortality have been derived by Fine et al using age, gender, laboratory data on admission, and comorbidities
(Figure 1).13 Patients in risk categories I and II have extremely low mortality associated with pneumonia and should be treated as outpatients. Patients in risk stratum III may require brief hospitalization; those in categories IV and V should be hospitalized. It is important to note that these data did not include patients with human immunodeficiency virus (HIV) or other immunocompromised states and did not take into account social issues such as home support and the likelihood of compliance with treatment requirements, all of
which may necessitate hospitalization. A recent study demonstrated that implementation of a risk stratification scheme or critical pathway decreased the use of hospital resources and length of stay without affecting the quality of patient
care.14 Severity stratification guides the initial decision on site of care and prospectively identifies patients who are most likely to be treated with oral antibiotics after initial parenteral therapy.
Figure 1.
Temple University Health System Community-Acquired Pneumonia Severity of
Disease Assessment Tool
Gram’s stain and sputum culture of appropriately collected sputum are the mainstays in identifying the etiologic organisms of acute pneumonia. The sputum should be examined for color, consistency, quantity, and odor. Most often, sputum is collected by having the patient cough and expectorate lower respiratory tract secretions into a collection container; however, because the secretions must pass through the mouth, they may become contaminated with mouth flora. Acceptable specimens should contain less than 10 epithelial cells and >25 PMNs/low power
field.15 If there is a predominant organism on Gram’s stain, empiric therapy can be directed toward the most probable organism. Patients with risk factors for pneumonia (eg, the elderly or hospitalized or chronically ill patients) frequently are colonized by multiple pathogens and a sputum culture is seldom helpful in identifying the specific causative
organism.16 In those cases, physical examination, chest X ray, and changes in sputum production and quality continue to be the cornerstone for the diagnosis of pneumonia. In patients with moderate-to-severe disease, blood cultures also may be helpful in the diagnosis. In this patient group, approximately 12% to 25% will have a positive blood culture with a respiratory pathogen.
If a patient is unable to give an acceptable sputum specimen after three or four attempts, transtracheal aspiration, bronchoscopy, or open lung biopsy can be used to obtain sputum or tissue samples for laboratory analysis. However, these procedures are not without risk and should be used only when the etiology is crucial for diagnosis.
The major pathogens for CAP are summarized in Table
1.9,17-21 Published reports are biased because most are based on studies of hospitalized patients. In addition, there is great variation in the recovery of atypical pathogens, which include viruses (influenza A and B), Legionella species, C pneumoniae, and M pneumoniae. In evaluating patients with suspected CAP, it is important to realize that even with extensive diagnostic studies, the causative organism is identified in only 30% to 50% of cases. Several factors contribute to this low yield: 20% to 30% of patients do not provide sputum samples; 20% to 30% have received prior antimicrobial therapy; and some pathogens can only be detected with special techniques.
Table 1. Major Pathogens of Community-Acquired
Pneumonia
The atypical pathogens of CAP are theoretically associated with an atypical clinical presentation, including subacute onset, nonproductive cough, extrapulmonary manifestations, and a chest radiograph characteristically worse than the patient’s clinical appearance. However, as discussed earlier, a clear association between these organisms and an atypical presentation is debatable. Atypical pathogens account for 10% to 20% of all cases; however, frequency varies based on temporal and geographic epidemiologic patterns. Diagnostic tests for Legionella include culture, direct fluorescent antigen stain, or urinary antigen assays that are adequate for a presumptive diagnosis and empiric therapy.
Epidemiologic factors may favor the presence of certain
pathogens.3,4 Patients with poor dental hygiene are more likely to have anaerobic involvement; HIV-coinfected individuals are more likely to be infected by Pneumocystis carinii. A thorough travel and animal contact history is important. Exposure to birds can be associated with Chlamydia psittaci (the cause of psitticosis); exposure to cattle or a parturient cat can be associated with Coxiella burnetii (the cause of Q fever); and travel to the southwestern United States can be associated with Coccidioides immitis infections.
S pneumonia, the most common cause of pneumonia in all age groups, is identified in 25% to 60% of all community-acquired bacterial
pneumonias.19 The sudden, rapid onset of dramatic rigors, pleuritic chest pain, rust-colored sputum with gram-positive diplococci, and leukocytosis are consistent with pneumococcal
pneumonia.
H influenzae has been a significant pulmonary pathogen in infants and children. In recent years, H influenzae also has been recognized as a significant pulmonary
pathogen in adults. This trend may be related to the fact that the population is growing older and the number of patients with chronic lung diseases is increasing. The incidence of beta-lactamase-producing H influenzae has increased over the past several years (30% to 40%), complicating antimicrobial
selection.22,23
M catarrhalis now is recognized to be a significant pulmonary pathogen in patients with chronic pulmonary diseases. The recovery of this organism shows a seasonal distribution that is encountered largely during the late fall and winter months. More than 75% of
M catarrhalis strains are beta-lactamase producing.22
Legionella pneumophila contributes significantly to the incidence of
CAP.21 Patients with altered immunologic function (eg, the elderly) and chronic disease (eg, chronic obstructive pulmonary disease [COPD]) are most susceptible to infection with this organism. Legionella is more common in middle-age and elderly adults and has the highest mortality rate of the atypical pathogens. Its presentation differs slightly from that of the more typical pathogenic organisms and is associated with significant gastrointestinal complaints (nausea, vomiting) and electrolyte abnormalities. Legionella is similar to serious pneumococcal pneumonia: The clinical course of many patients is progressive despite administration of appropriate antibiotic therapy. The reported mortality is 15% to 25%, even with effective
therapy.6,24
Mycoplasma (also referred to as “walking pneumonia”) is more common in young
adults.9,25 Diagnostic tests are available (the most useful is an immunoglobulin M enzyme immunoassay), but most laboratories do not provide those tests. Mycoplasma carries virtually no mortality.
C pneumoniae, an important cause of CAP, accounts for 5% to 10% of all
cases.9,26 It has been associated with atherosclerotic disease; however, cause and effect continue to be debated. Diagnostic tests for this pathogen are not offered by most clinical laboratories.
Gram-negative pneumonia in the community setting is increasing in
incidence.9,21 Most cases occur in patients who reside in nursing homes and long-term care facilities. In addition, alcoholic individuals are predisposed to gram-negative pneumonia, often with K pneumoniae.
An approach to the patient with CAP and empiric antibiotic regimens are presented in
Figure 2.3 Initial antimicrobial therapy is largely empirical and should be guided by the results of the sputum Gram’s stain, patient age, prior medical history, concomitant diseases, prior place of residence, and clinical signs and symptoms. If no sputum is available for Gram’s stain, antibiotics active against the most probable bacterial pathogens are selected.
Figure 2.
Approach to Treating the Patient with Community-Acquired Pneumonia
For low-risk patients who may be safely treated in an ambulatory setting, the IDSA-updated guidelines recommend doxycycline, a macrolide, or an antipneumococcal fluoroquinolone as preferred agents because these agents have activity against the most likely pathogens in this setting (S pneumoniae, M pneumoniae, and C pneumoniae).3 The IDSA has adopted the new antipneumococcal fluoroquinolones, levofloxacin, sparfloxacin, moxifloxacin, and gatifloxacin, as preferred agents for the treatment of both ambulatory and hospitalized patients with CAP and for penicillin-resistant pneumococcal
pneumonia.3 All of these compounds have excellent activity against pneumococcus while maintaining much of their gram-negative aerobic activity and possess favorable dosing schedules and side-effect profiles. Multiple trials have demonstrated these agents to be clinically effective in treating CAP, including pneumococcal bacteremia and pneumonia involving penicillin-resistant
strains.27-29
These IDSA recommendations differ from those of the Centers for Disease Control and Prevention (CDC) Working Group on drug-resistant S
pneumoniae.30 The Working Group suggests that penicillin-resistant S pneumoniae isolates are uncommon, and activity against such organisms is unnecessary for empiric treatment. Their recommendations for first-line therapy of CAP include a macrolide, doxycycline, or an oral beta-lactam such as cefuroxime, amoxicillin, or amoxicillin/ clavulanate. The CDC recommends reserving the use of fluoroquinolones for treatment of gram-negative pathogens, patients with beta-lactam allergy, or treatment of penicillin-resistant pneumococcal pneumonia.
Most hospitalized patients with pneumonia should be initiated on intravenous antibiotics. The timing of initial antimicrobial administration may be an important predictor of outcome. Meehan et al examined approximately 65,000 hospitalized Medicare recipients over age 65 with
CAP.31 Mortality gradually increased, with progressive delays between the time a patient presented and the time the initial dose of an antibiotic was administered. This difference reached statistical significance when the delay exceeded 8 hours. Based on these results, antibiotics should be initiated in less than 8 hours after patient presentation and continued for 7 to 14
days.3
For empiric treatment of the moderately ill hospitalized patient, the IDSA recommends an extended-spectrum cephalosporin (cefotaxime, ceftriaxone) plus a macrolide or monotherapy with a fluoroquinolone. This recommendation differs from their 1998 guidelines, in which the addition of the macrolide had been an option. In part, this change is based on two recent retrospective studies demonstrating that the use of a macrolide plus a second- or third-generation nonantipseudomonal cephalosporin or an antipneumococcal fluoroquinolone alone in the elderly resulted in a decreased length of hospital stay and 30-day
mortality.32,33
For hospitalized patients admitted to the intensive care unit, the IDSA prefers agents that include combination therapy with an extended spectrum cephalosporin plus a macrolide or a fluoroquinolone. Monotherapy with a fluoroquinolone is not recommended because data with seriously ill CAP patients are limited.
Differences exist among groups about the role of the fluoroquinolones. The major concern is the potential that extensive use may result in increased
resistance.34,35 Although this argument may be raised regarding any antibiotic, the concern with the fluoroquinolones is that resistance to one agent affects all agents to some degree. Currently, pneumococcal resistance to the fluoroquinolones is low, but a report from Canada has demonstrated an association between increased fluoroquinolone use and resistance in S
pneumoniae.36 In addition, the potential for development of resistance in other organisms (especially Pseudomonas aeruginosa) as a result of the indiscriminate use of fluoroquinolones poses a more ominous threat to this drug
class.37 The CDC Working Group on drug-resistant S pneumoniae has addressed these concerns and, as previously stated, recommends reserving the use of the fluoroquinolones for specific situations.
Pneumococcal susceptibility has changed significantly over the past decade. Despite 4 decades of using penicillin, only modest rates of reduced susceptibility to penicillin were reported in the 1980s. Strains with minimum inhibitory concentrations (MICs) >0.1 mg/mL accounted for 3.8% of isolates in the 1980s; by 1994 to 1995, the rate was 24%, and by 1997 it was
43.8%.22,23,38,39
Penicillin resistance is also associated with resistance to other antimicrobial classes, including cephalosporins, macrolides, tetracyclines, and trimethoprim/sulfamethoxazole (TMP/SMZ). Antibiotics less affected by this broad-spectrum resistance include vancomycin, the fluoroquinolones, clindamycin, chloramphenicol, and
rifampin.22,23,38,39 Penicillin susceptibility should be tested in all significant pneumococcal isolates. Strains are considered sensitive if the MIC is <0.1 mg/mL.
Practitioners frequently are reluctant to modify therapy once culture and sensitivity results are in hand, especially if a patient is improving. However, a change may be justified if the redirected therapy is less likely to disrupt normal flora, has fewer side effects, is less likely to influence institutional resistance patterns, and costs less. Antibiotics usually are administered for 10 to 14 days or for at least 5 days after the patient becomes afebrile in this setting.
Based on the IDSA guidelines for treating
CAP,3 the preferred regimen for pneumococcal pneumonia with an MIC <2 mg/mL is penicillin G or ampicillin. If an isolate is resistant (ie, MIC
<2 mg/mL), treatment with a nonbeta-lactam, such as one of the antipneumococcal fluoroquinolones or vancomycin, is recommended. We note that the decision not to use a beta-lactam such as ceftriaxone for isolates with an MIC between 0.1 and 1.0 mg/mL is currently unjustified by the data. In the two largest trials published to date of patients infected with intermediately susceptible S pneumoniae pneumonia, the mortality of those treated with a beta-lactam did not differ among patients infected with susceptible strains and those infected with strains of intermediate
susceptibility.40,41
Additional recommendations for pathogen-directed therapy are provided in
Table 2 for the other common CAP organisms.
Table 2.
Recommended Treatment for Community-Acquired Pneumonia
For patients allergic to penicillin, alternative antibiotics should be prescribed. If the patient’s allergic reaction to penicillin was mild (ie, a maculopapular rash without difficult breathing), the likelihood of cross-reactivity to a cephalosporin is low. Ceftriaxone 1 g/day would be an appropriate alternative in this situation. For patients with a history of more severe allergic reactions, intravenous azithromycin 500 mg/day is an appropriate alternative for patients with mild disease. With more severe disease, an antipneumococcal fluoroquinolone, clindamycin, or vancomycin may be substituted.
The response and outcome of patients with CAP largely depend on the microbial agent involved and the patient status at presentation. Poor prognostic factors include age >65 years; a coexisting disease such as diabetes, renal failure, heart failure, or COPD; clinical and laboratory findings outlined in Figure 1; and recovery of S pneumoniae or
Legionella.4,6,13
Most patients with pneumonia will begin to improve clinically (decreased temperature and systemic toxicity) 24 to 48 hours after the initiation of effective antibiotic therapy. Chest radiograph resolution will lag, taking 3 weeks in
otherwise healthy, young adults and up to 12 weeks in elderly patients and those with complicated
infections.42,43
A subset of patients with pneumococcal pneumonia will do poorly. Factors associated with a poor outcome include involvement of multiple lobes of the lung, bacteremia, a past history of alcoholism, older than 60 years of age, and neutropenia. It is important to note that antibiotic therapy has not affected the mortality rate of pneumococcal pneumonia with bacteremia, which remains at 20% to
30%.6,44
When the patient is clinically stable for 24 hours (temperature <38
degrees C, respiratory rate
<24/minutes, and pulse <100 beats per minute), conversion to the oral route should be considered. The patient must be able to take oral medications and have adequate gastrointestinal function to absorb the agent selected. Diarrhea is not a reason to avoid the oral route; it rarely causes significant reduction in absorption of
medications.4 Selecting an oral agent is simplified if culture and sensitivity data are available and if the parenteral agent is available in an oral formulation.
CAP is a common cause of morbidity and mortality in the United States. An accurate diagnosis of CAP is difficult and complicated because of the methodology involved. Guidelines for the management of CAP have been put forth by several organizations; however, the
recommendations differ regarding the therapy. The role of the pharmacist in CAP is important and multifaceted. The pharmacist should take an active role to assure that the appropriate antimicrobial agent and route of administration are selected, follow the patient’s progress to assess when conversion of an intravenous therapy to oral therapy is recommended, and counsel the patient on the importance of adhering to the medication regimen prescribed.
1. Dixon RE. Economic costs of respiratory tract infections in the United States. Am J Med. 1985;78(Suppl. 6B):45.
2. U.S. Department of Commerce, Bureau of the Census: Statistical Abstract of the United States. 113th ed. Washington, D.C.: U.S. Government Printing Office; 1993.
3. Bartlett JG, Dowell SF. Practice Guidelines for the Management of Community Acquired Pneumonia in Adults. Clin Infect Dis 2000;31:347-82.
4. Bartlett JG, Breiman RF, Mandell LA, File TM. Community-acquired pneumonia in adults: guidelines for management. Clin Infect Dis 1998;26:811.
5. Garibaldi RA. Epidemiology of community-acquired respiratory tract infections in adults: incidence, etiology, and impact. Am J Med 1985;78:32S.
6. Fine MJ, Smith MA, Carson CA, Mutha SS, Sankey SS, Weissfield LA, Kapoor WN. Prognosis and outcomes of patients with community-acquired pneumonia. JAMA 1996;275:134.
7. Centers for Disease Control and Prevention. Pneumonia and influenza death rates- United States, 1979-1994. Morb Mort Wkly Rep 1995;44:535.
8. Niederman MS, McCombs JS, Unger AN, Kumar A, Popovian R. The cost of treating community-acquired pneumonia. Clin Ther 1998;20:820.
9. Bartlett JG, Mundy LM. Community-acquired pneumonia. N Engl J Med 1995;333:1618.
10. Pennington JE. Respiratory tract infections: intrinsic risk factors. Am J Med. 1984;76(Suppl. 5A):34.
11. Skerett SJ. Host defenses against respiratory infections. Med Clin North Am. 1994;78:941.
12. Toews GB. Pulmonary clearance of infectious agents. In: Pennington JE, ed. Respiratory Infections: Diagnosis and Management. New York: Raven Press; 1983:31.
13. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336:243.
14. Marrie TJ, Lau CY, Wheeler SL, Wong CJ, Vendervoort MK, Feagen BG. A Controlled trial of a critical pathway for treatment of community acquired pneumonia. JAMA 2000;283:749-755.
15. Murray PR, Washington JA. Microscopic and bacteriologic analysis of expectorated sputum. Mayo Clin Proc. 1975;50:339.
16. Dal Nogare AR. Nosocomial pneumonia in the medical and surgical patient. Med Clin North Am. 1994;78:1081.
17. Mundy LM, Auwaerter PG, Oldach D, Warner ML, Burton A, Vance E. Community-acquired pneumonia: impact of immune status. Am J Respir Crit Care Med 1995;152:1309.
18. Fekety FR Jr, Caldwell J, Gump D, Johnson JE, Maxson W, Mulholland J, Thoburn R. Bacteria, viruses, and mycoplasmas in acute pneumonia in adults. Am Rev Respir Dis 1971;104:499.
19. Marrie TJ, Durant H, Yates L. Community-acquired pneumonia requiring hospitalization: a 5-year prospective study. Rev Infect Dis 1989;11:586.
20. Farr BM, Sloman AJ, Fisch MJ. Predicting death in patients hospitalized with community-acquired pneumonia. Ann Intern Med 1991;115:428.
21. Fang GD, Fine M, Orloff J et al. New and emerging etiologies for community-acquired pneumonia with implications for therapy: a prospective multi-center study of 359 cases. Medicine 1990;69:307.
22. Thornsberrry C, Agilvie P, Kahn J, Mawriz Y. Surveillance of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the United States in 1996-1997 respiratory season. Diag Microbiol Infect Dis 1997;29:249.
23. Thornsberry C et al. International surveillance of resistance among respiratory tract pathogens in the United States, 1997-1998. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego. Sept 24, 1998. Abstract E-22.
24. Edelstein PH. Legionnaires’ disease. Clin Infect Dis 1993;16:741
25. Brook I. Percutaneous transtracheal aspiration in the diagnosis and treatment of aspiration pneumonia in children. J Pediatr. 1980;96:1000.
26. Grayston JT, Kuo CC, Chen HH, Wang SP. A new Chlamydia psittaci strain, TWAR, isolated in acute respiratory tract infections. N Engl J Med 1986 315:161.
27. File T, File TM Jr, Segreti J, Dunbar L et al. A multicenter, randomized study comparing the efficacy and safety of intravenous and/ or oral levofloxacin versus ceftriaxone and/ or cefuroxime axetil in the treatment of adults with community-acquired pneumonia. Antimicrob Agents Chemother 1997;41:1965.
28. Ortqvist A, Valtonen M, Cars O, Wahl M, Saikku P, Jean C. Oral empiric treatment of community-acquired pneumonia: a multi-center, double blind, randomized study comparing sparfloxacin and roxithromycin. Chest. 1996;110:1499-1506
29. Dowell ME et al. A randomized, double-blind, multicenter comparative study of gatifloxacin 400 mg IV and PO versus ceftriaxone +/- erythromycin in treatment of community-acquired pneumonia requiring hospitalization. Abstract # 2241. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Sept. 26, 1999.
30. Heffelfinger JD, Dowell SF, Jorgensen JH et al Management of community-acquired pneumonia in the era of pneumococcal resistance. A report of the drug-resistant Streptococcus pneumoniae therapeutic working group. Arch Intern Med 2000;160:1399-1408.
31. Gleason PP, Meehan TP, Fine JM, Galusha DH, Fine MJ. Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia. Arch Intern Med 1999;159:2562.
32. Stahl JE, Barza M, DesJardin J, Martin R, Eckman MH. Effect of macrolides as part of the initial therapy on length of stay in patients hospitalized with community-acquired pneumonia. Arch Intern Med 1999;159:2576.
33. Meehan TP, Fine MJ, Krumholz HM et al. Quality of care, process, and outcomes in elderly patients with pneumonia. JAMA 1997; 278: 2080-84.
34. Hooper DC. Expanding uses of fluoroquinolones: opportunities and challenges. Ann Intern Med 1998;129:908.
35. Applebaum PC et al. Role of the newer fluoroquinolones against penicillin-resistant Streptococcus pneumoniae. Infect Dis Clin Pract 1999;8:374.
36. Chen DK, McGeer A, DeAzavedo JC, Low DE. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. Canadian Bacterial Surveillance Network. N Engl J Med 1999;34:233.
37. Low DE, Scheld WM. Strategies for stemming the tide of antimicrobial resistance. JAMA 1998;273;394.
38. Doern GV, Pfaller MA, Kugler K, Freeman J, Jones RN. Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program. Clin Infect Dis 1998;27:764.
39. Mufson MA. Penicillin-resistant Streptococcus pneumoniae increasingly threatens the patient and challenges the physician. Clin Infect Dis 1998;27:771.
40. Pallares R, Linares J, Vadillo M et al. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcellona, Spain. N Engl J Med 1995;333:474.
41. Kaplan SL, Mason EO Jr. Management of infections due to antibiotic resistant Streptococcus pneumoniae. Clin Microbiol Rev 1998;11:628.
42. Mittl RL Jr, Schwab RJ, Duchin JS, Goin JE, Albeida SM, Miller WT. Radiographic resolution of community-acquired pneumonia. Am J Respir Crit Care Med 1994;149:630.
43. Jay SJ, Johanson WG Jr, Pierce AK et al. The radiographic resolution of Streptococcus pneumoniae pneumonia. N Engl J Med 1975;293:798.
44. Austriam R, Gold J. Pneumococcal bacteremia with special reference to bacteremic pneumococcal pneumonia. Ann Intern Med 1964;60:759.
|
