Community acquired pneumonia


Published on

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

Community acquired pneumonia

  1. 1. in the clinic in the clinic Community- Acquired Pneumonia Prevention page ITC4-2 Diagnosis page ITC4-3 Treatment page ITC4-7 Practice Improvement page ITC4-14 CME Questions page ITC4-16Section Co-Editors The content of In the Clinic is drawn from the clinical information andChristine Laine, MD, MPH education resources of the American College of Physicians (ACP), includingSankey Williams, MD PIER (Physicians’ Information and Education Resource) and MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal MedicinePhysician Writer editors develop In the Clinic from these primary sources in collaboration withMichael Niederman, MD the ACP’s Medical Education and Publishing Division and with the assistance of science writers and physician writers. Editorial consultants from PIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult and other resources referenced in each issue of In the Clinic. CME Objectives: To review prevention, diagnosis, treatment, and practice improvement for community-acquired pneumonia. The information contained herein should never be used as a substitute for clinical judgment. © 2009 American College of Physicians
  2. 2. ommunity-acquired pneumonia (CAP) can vary from a mild out- C patient illness to a more severe disease requiring admission to a hos- pital or even an intensive care unit (ICU). Along with influenza, CAP is the eighth leading cause of death in persons older than age 65 in the United States and is the leading cause of death from infectious diseases. In contrast to hospital-acquired pneumonia, CAP occurs in the community. This distinction is becoming increasingly blurred because persons in contact with health care environments, such as nursing homes and chronic hemodial- ysis centers, and those recently discharged from the hospital may be infected with multidrug resistant organisms. These infections have been termed “health care–associated pneumonia.” The key management decisions are recognizing and treating CAP in a timely and effective manner, defining the appropriate site of care (home, hospital, or ICU), and ensuring effective prevention. Prevention Who is at increased risk for CAP? special environments, such as long- Persons with a comorbid illness and term care facilities; if they are elderly persons are at increased risk Alaskan natives or American Indi- for pneumonia and for having a ans; or if they have any of the fol- more complex illness. In 2005, 1.3 lowing chronic illnesses: congestive million hospitalizations for pneu- heart failure, other cardiovascular monia occurred in the United disease, COPD, asthma,,1. American Lung Asso- ciation. Trends in States, and approximately 60% diabetes mellitus, alcoholism, pneumonia and in- were in persons older than 65 years chronic liver disease, cerebrospinal fluenza morbidity and mortality, July (1). Comorbid illnesses that are as- fluid leaks, or functional or 2007. Accessed at sociated with an increased inci- anatomic asplenia (including sickle /cf/%7B7a8d42c2- dence of CAP include respiratory cell disease). Although vaccine effi- fcca-4604-8ade- 7f5d5e762256%7D/A disease, such as chronic obstructive cacy may be reduced, immuno- LA_LDD08_INFLUEN- pulmonary disease (COPD); car- compromised patients should be ZA_FINAL.PDF on 24 August 2009. diovascular disease; and diabetes vaccinated, including patients with2. Nuorti JP, Butler JC, Farley MM, et al. Ciga- mellitus. In addition, cigarette HIV infection, leukemia, lym- rette smoking and in- smoking and alcohol abuse are phoma, Hodgkin disease, multiple vasive pneumococcal disease. Active Bacte- quite common in those with severe myeloma, generalized malignant rial Core Surveillance forms of CAP, and cigarette smok- conditions, chronic renal disease, Team. N Engl J Med. 2000;342:681-9. ing is a risk factor for bacteremic nephrotic syndrome, and immuno- [PMID: 10706897]3. Walker FJ, Singleton pneumococcal infection (2). Other suppressive therapy (including RJ, Bulkow LR, et al. common illnesses in those with long-term corticosteroids). Reactions after 3 or more doses of pneu- CAP include malignant conditions mococcal polysac- and any neurologic illness that pre- Use the 23-valent polysaccharide charide vaccine in adults in Alaska. Clin disposes to aspiration, including vaccine in adults; the 7-valent con- Infect Dis. seizures. jugate vaccine that is used in chil- 2005;40:1730-5. [PMID: 15909258] dren has not been approved for4. Jackson LA, Neuzil Who should receive pneumococcal adults. In persons older than 65 KM, Yu O, et al. Effec- tiveness of pneumo- vaccination and when should they years, revaccinate once after 5 years coccal polysaccha- ride vaccine in older receive it? anyone who was initially vaccinated adults. N Engl J Med. All high-risk persons should be before age 65. Revaccinate 2003;348:1747-55. [PMID: 12724480] vaccinated. The timing of vaccina- immunocompromised patients once5. Fisman DN, Abrutyn E, Spaude KA, et al. tion depends on the indication. All 5 years after the initial vaccination. Prior pneumococcal persons older than 65 years should Consider vaccinating anyone hospi- vaccination is associ- ated with reduced be vaccinated, and risk factors talized for a medical illness, be- death, complications, and length of stay should be reviewed for other per- cause they are at increased risk for among hospitalized sons, with a special effort in those pneumonia. Do not worry about adults with commu- nity-acquired pneu- older than 50 years. Vaccination harm from repeat vaccination, be- monia. Clin Infect Dis. should be offered to immuno- cause less than 1% of patients who 2006;42:1093-101. [PMID: 16575726] competent patients if they live in received at least 3 pneumococcal© 2009 American College of Physicians ITC4-2 In the Clinic Annals of Internal Medicine 6 October 2009
  3. 3. vaccinations had an adverse reac- conjugate vaccine may be moretion, and no reaction was severe, immunogenic in patients with sickleeven if repeat vaccination was in cell disease than the 23-valentless than 6 years (3). polysaccharide vaccine, more data are needed, and necrotizing pneu-Vaccination reduces the frequency monia caused by nonvaccine strainsof bacteremic pneumonia in healthy, may be more frequent in childrenimmunocompetent adults. Ran- who receive this vaccine (6).domized, controlled trials (RCTs)have not found reductions in the What is the role of influenzafrequency of bacteremic pneumonia vaccination in the prevention ofin adults with chronic illness, al- CAP and its complications?though case–control studies report All patients at increased risk forreductions from 56% to 81%. influenza complications and persons who can transmit the infection toEfficacy in nonbacteremic illness is less high-risk patients, such as health carecertain. In 1 study of 47 365 patients olderthan age 65, pneumococcal vaccine re- workers, should be immunized yearly.duced the incidence of pneumococcal In 1 meta-analysis of 20 studies, influenzabacteremia (odds ratio, 0.56) but had no vaccine was shown to reduce pneumoniaimpact on the frequency of CAP treated in by 53%, hospitalization by 50%, and mor-or out of the hospital (4). In another study, tality by 68% (7). In addition, observationalpneumococcal vaccination reduced mor- studies suggest that influenza vaccine cantality, shortened the length of hospital stay, reduce all-cause mortality during influen-and decreased the frequency of respiratory za season by 27% to 54% and be cost-failure and other complications (5). effective because of its ability to reduce 6. Bender JM, Ampofo hospitalization rates for congestive heart K, Korgenski K, et al.Efficacy has not been established in Pneumococcal failure and pneumonia in elderly persons necrotizing pneumo-patients with sickle cell disease, (8). Recent analyses question these bene- nia in Utah: doeschronic renal failure, immunoglob- fits, noting that few RCTs have been serotype matter? Clin Infect Dis.ulin deficiency, Hodgkin disease, conducted in this population and that 2008;46:1346-52. [PMID: 18419434]lymphoma, leukemia, or multiple selection bias may lead to vaccination be- 7. Gross PA, Hermo-myeloma. Although the 7-valent ing given to healthier persons (9, 10). genes AW, Sacks HS, et al. The efficacy of influenza vaccine in elderly persons. A meta-analysis and re- Prevention... Elderly persons and those with a comorbid illness are at increased view of the literature. risk for pneumonia. Identify persons at risk for CAP and its complications and of- Ann Intern Med. 1995;123:518-27. fer them pneumococcal and influenza vaccination. Offer influenza vaccine yearly [PMID: 7661497] to persons at risk for the disease, including health care workers. Repeat pneumo- 8. Nichol KL, Margolis KL, Wuorenma J, et al. coccal vaccination once after 5 years in persons who received the first dose be- The efficacy and cost fore age 65 and in immunocompromised patients. Consider giving both vaccines effectiveness of vacci- to patients hospitalized with a medical illness. nation against in- fluenza among elder- ly persons living in the community. N CLINICAL BOTTOM LINE Engl J Med. 1994;331:778-84. [PMID: 8065407] 9. Centers for Medicare Diagnosis & Medicaid Services. Hospital Quality Ini- tiative Overview. Ac-Which symptoms should lead sweats, and weight loss. Fever and cessed atclinicians to consider the chills have a sensitivity of 50% to ospitalQualityInits/Dodiagnosis of CAP? 85%, but may be absent in elderly wnloads/Hospi- taloverview.pdf on 24Pneumonia usually presents with persons. Dyspnea has a sensitivity August 2009.both respiratory and systemic of 70% for the diagnosis of CAP, 10. Nelson JC, Jackson ML, Weiss NS, et al.symptoms, particularly in young whereas purulent sputum has a sen- New strategies arepatients and in those with an intact sitivity of only 50%. Hemoptysis needed to improve the accuracy of in-immune response. It should be sus- suggests necrotizing infection, such fluenza vaccine ef- fectiveness esti-pected when the patient has cough, as lung abscess, tuberculosis, or mates amongpurulent sputum, pleuritic chest gram-negative pneumonia. Many seniors. J Clin Epi- demiol 2009; 62:pain, dyspnea, chills, fever, night older patients and those with 687-694.6 October 2009 Annals of Internal Medicine In the Clinic ITC4-3 © 2009 American College of Physicians
  4. 4. chronic illness have a less-intense A cohort study of 3339 patients with invasive immune response, and the disease pneumococcal infection found that if the may go unrecognized because the patient had received penicillin, macro- lide, fluoroquinolone, or trimethoprim– patient has only nonrespiratory sulfamethoxazole in 3 months before the symptoms. These include confu- onset of bacteremia, the organism was sion, weakness, lethargy, falling, more likely to be resistant to the antibiotic poor oral intake, and decompensa- that the patient had received (11). tion of a chronic illness (for exam- Viruses also can cause CAP, and 1 ple, congestive heart failure). Most recent study found that they were patients with CAP present with an present in 18% of all patients who acute illness of 1 to 2 days’ dura- had paired serologies. The most tion, but symptoms may be present common viral organisms were in- for longer in elderly persons. fluenza and parainfluenza virus, followed by respiratory syncytial Which organisms cause CAP? virus and adenovirus. Nearly half of The most commonly identified these patients had viral infection as bacterial pathogens for CAP are part of a mixed infection, often11. Toronto Invasive Streptococcus pneumoniae (pneumo- Bacterial Disease with bacterial pathogens (12, 13). Network. Predicting coccus); Haemophilus influenzae; and antimicrobial resist- ance in invasive atypical pathogens, such as My- Gram-negative bacteria have been pneumococcal in- coplasma pneumoniae, Chlamydophila found in up to 10% of patients with fections. Clin Infect Dis. 2005;40:1288-97. pneumoniae, and Legionella. Drug- CAP, particularly in those with a [PMID: 15825031]12. de Roux A, Marcos resistant pneumococcus (DRSP) is history of chronic cardiopulmonary MA, Garcia E, et al. disease, residence in a nursing Viral community-ac- more likely to be the cause in pa- quired pneumonia home, multiple medical comorbid tients older than 65 years and in in nonimmunocom- conditions, recent antibiotic thera- promised adults. Chest. those with alcoholism, noninvasive py, renal insufficiency, chronic liver 2004;125:1343-51. disease, antibiotic therapy within 3 disease, diabetes, or active malig- [PMID: 15078744]13. Falsey AR, Hen- months, multiple medical comorbid nant conditions (14). Pseudomonas nessey PA, Formica MA, et al. Respiratory conditions, exposure to children in aeruginosa should be considered in syncytial virus infec- tion in elderly and a day care center, or immuno- persons with bronchiectasis, recent high-risk adults. N suppressive illness (Table 1). hospitalization, or recent antibiotic Engl J Med. 2005;352:1749-59. [PMID: 15858184]14. Arancibia F, Bauer TT, Ewig S, et al. Com- munity-acquired Table 1. Modifying Factors That Increase the Risk for Infection pneumonia due to gram-negative bac- With Specific Pathogens teria and Organism Modifying Factor Putting Patient at Risk pseudomonas aeruginosa: inci- Penicillin-resistant and Age >65 years dence, risk, and prognosis. Arch In- drug-resistant pneumococci β-lactam therapy within the past 3 months tern Med. Alcoholism 2002;162:1849-58. [PMID: 12196083] Immune-suppressive illness (including therapy15. El-Solh AA, Pietran- with corticosteroids) toni C, Bhat A, et al. Microbiology of se- Multiple medical comorbid conditions vere aspiration Exposure to a child in a day care center pneumonia in insti- tutionalized elderly. Am J Respir Crit Care Enteric gram-negative bacteria Residence in a nursing home Med. 2003;167:1650- 4. [PMID: 12689848] Underlying cardiopulmonary disease16. Carratalà J, Mykietiuk Multiple medical comorbid conditions A, Fernández-Sabé N, et al. Health care- Recent antibiotic therapy associated pneumo- nia requiring hospi- Pseudomonas aeruginosa Structural lung disease (bronchiectasis) tal admission: epidemiology, an- Corticosteroid therapy (prednisone, >10 mg/d) tibiotic therapy, and clinical outcomes. Broad-spectrum antibiotic therapy for >7 d Arch Intern Med. in the past month 2007;167:1393-9. Malnutrition [PMID: 17620533]© 2009 American College of Physicians ITC4-4 In the Clinic Annals of Internal Medicine 6 October 2009
  5. 5. therapy. Although anaerobic organ- pleural effusion. Specific findingsisms should be considered when that are associated with a poor out-aspiration is a possibility (for exam- come include a respiratory rateple, in elderly patients with neuro- greater than 30 breaths/min, dias-logic or swallowing disorders), in 1 tolic blood pressure less thanstudy the most common organisms 60 mm Hg, systolic blood pressureidentified in those at risk for aspi- less than 90 mm Hg, heart rateration were gram-negative bacteria greater than 125 beats/min, and(15). Klebsiella pneumoniae has been temperature less than 35°C orreported in patients with alco- greater than 40°C.holism. Although some studiessuggest that health care–associated When should clinicians use chestpneumonia pathogens are more radiography in the diagnosis ofsimilar to those in hospital-acquired CAP?pneumonia than to those in CAP, Obtain a chest radiograph in anynot all studies confirm these find- patient with clinical features sug-ings. Patients with health care– gesting CAP. Studies show that theassociated pneumonia who are clinical diagnosis of pneumonia ismost at risk for drug-resistant or- inaccurate; the clinical impressionganisms are those with poor func- of pneumonia has an overall sensi-tional status, severe illness, recent tivity ranging from 70% to 90%,antibiotic therapy, and recent hos- and a specificity ranging from 40%pitalization. Methicillin-resistant to 70% (17).S. aureus can occur in patients withhealth care–associated pneumonia When history and physical examination findings were used to predict the presence 17. Mandell LA, Marrieand also in previously healthy per- TJ, Grossman RF, etsons after influenza (15, 16). of radiographic pneumonia in a study of al. Canadian guide- lines for the initial 129 patients with lower respiratory tract in- management ofWhat is the role of history and fection (26 with pneumonia), no combina- community-ac- quired pneumonia:physical examination in the tion of findings was highly accurate. The an evidence-baseddiagnosis of CAP? positive predictive value of each finding update by the Cana- dian Infectious Dis- varied from 17% to 43% (18).History and physical examination eases Society and the Canadian Tho-are valuable for suggesting the It is especially important to have a racic Society. The Canadian Communi-presence of pneumonia, for predict- chest radiograph if the diagnosis is ty-Acquired Pneu-ing the etiologic pathogen, and for uncertain or if pleural effusion, monia Working Group. Clin Infecthelping to define the severity of lung abscess, necrotizing pneumo- Dis. 2000;31:383-421.illness. The history also should nia, or multilobar illness is suspect- [PMID: 10987698] 18. Graffelman AW, leidentify risk factors for health care- Cessie S, Knuistingh ed. If a pleural effusion is present, Neven A, et al. Canassociated pneumonia, such as hos- obtain a decubitus film or comput- history and exampitalization or antibiotic therapy in alone reliably predict ed tomography. Assume pneumonia pneumonia? J Famthe past 90 days, residence in a Pract. 2007;56:465- is present in the absence of a 70. [PMID: 17543257]long-term care facility, chronic radiographic infiltrate if the patient 19. Hopstaken RM, Wit-dialysis, outpatient wound care, or braad T, van En- has a convincing history and focal gelshoven JM, et al.home infusion therapy. The history Inter-observer varia- physical findings. A follow-upshould also focus on recent travel to tion in the interpre-the southwestern United States radiograph may show an infiltrate. tation of chest radi- ographs for(endemic fungi), or southeast Asia Interobserver variability in chest pneumonia in com- munity-acquiredor China (melioidosis, epidemic vi- radiographic interpretation was lower respiratoryral pneumonia). Exposure to birds, shown in 1 study that compared tract infections. Clin Radiol. 2004;59:743-bats, farm animals, and rabbits the readings of at least 2 radiolo- 52. [PMID: 15262550] 20. Syrjälä H, Broas M,should also be documented. gists. Positive agreement (59%) was Suramo I, et al. High- less frequent than negative agree- resolution comput- ed tomography forPhysical examination findings that ment (94%) (19). Computed the diagnosis of community-ac-suggest pneumonia include crack- tomography may show an infiltrate quired pneumonia.les, bronchial breath sounds, when the chest radiograph is Clin Infect Dis. 1998;27:358-63.tachypnea, fever, and findings of negative (20). [PMID: 9709887]6 October 2009 Annals of Internal Medicine In the Clinic ITC4-5 © 2009 American College of Physicians
  6. 6. What is the role of other is effective. For example, when laboratory tests in diagnosing CAP? pathogen-directed treatment was For outpatients, perform pulse compared with empirical treatment oximetry to assess oxygenation. using a broad-spectrum antibiotic, No other testing is needed. the 2 groups did not significantly differ in the length of hospital stay, For inpatients, additional testing is 30-day mortality, clinical failure, or done to define disease severity and to resolution of fever (22). identify pathogens. Measure arterial blood gasses in patients suspected of Measurement of serum levels of C- having carbon dioxide retention. reactive protein or procalcitonin may Collect sputum for Gram stain and be helpful, although current guide- culture before starting therapy in pa- lines do not recommend their use. tients suspected of infection with a C-reactive protein may identify drug-resistant or unusual pathogen, which patients with acute respiratory but only evaluate sputum if it is of symptoms have pneumonia; levels good quality and is processed rapidly. are higher in patients who require Collect 2 sets of blood cultures, and hospitalization and in patients with test the urine for Legionella and pneumococcal and Legionella infec- pneumococcal antigens when pa- tion. Low levels of procalcitonin tients have severe pneumonia. Limit identify patients who do not benefit blood cultures to patients with severe from antibiotic therapy whereas per- illness; they are positive in only 10% sistently high levels identify patients to 20% of all patients with CAP. who have a poor prognosis. Culture an endotracheal aspirate in patients who are intubated and me- A randomized trial of 302 patients with CAP compared patients managed by usual care chanically ventilated. The utility of with those managed by an algorithm rec- real-time polymerase chain reaction ommending the use of antibiotics and the testing of sputum samples has not duration of therapy on the basis of serial been demonstrated. measurement of procalcitonin using the highly-sensitive Kryptor assay. Procalci- One recent study of 13 043 Medicare pa- tonin was measured on admission and af- tients identified the following predictors of ter 6 to 24 hours, 4 days, 6 days, and 8 days. a true-positive blood culture: no previous The procalcitonin-guided group had signif- antibiotics, underlying liver disease, systolic icantly fewer antibiotic prescriptions on ad- blood pressure less than 90 mm Hg, fever mission and less antibiotic usage, and the less than 35°C or greater than 40°C, pulse duration of therapy was reduced from 12 to greater than 125/min, blood urea nitrogen 5 days with similar clinical success (23). greater than 10.71 mmol/L (30 mg/dL), serum sodium less than 130 mmol, and What other disorders should leukocyte count less than 5 or greater than clinicians consider in patients 20 × 109 cells/L. The diagnostic yield of suspected of having CAP? blood cultures increased in patients with 121. Metersky ML, Ma A, or more risk factor and in those who had If the patient does not respond to Bratzler DW, et al. Predicting bac- not received antibiotics before blood was empirical therapy after 48 to 72 teremia in patients with community-ac- collected (21). hours, consider the possibility of quired pneumonia. viruses or unusual bacterial Am J Respir Crit Care Med. 2004;169:342- Even with extensive diagnostic pathogens, such as Mycobacterium 7. [PMID: 14630621] testing, a specific etiologic diagno- tuberculosis, Coxiella burnetii (Q22. van der Eerden MM, Vlaspolder F, de sis is obtained in less than half of fever), Burkholderia pseudomalle Graaff CS, et al. Com- parison between all patients with CAP. Do not per- (melioidosis), Chlamydia psittaci pathogen directed form serologic tests for viruses and (psittacosis), Paragonimiasis, En- antibiotic treatment and empirical broad atypical pathogens, because they demic fungi (histoplasmosis, coc- spectrum antibiotic require convalescent titers 6 to 8 cidioidomycosis, blastomycosis), treatment in pa- tients with commu- weeks after the initial test to iden- Pasteurella multocida, Bacillus nity acquired pneu- monia: a prospective tify infection. Establishing a specific anthracis, Actinomyces Israeli, randomised study. etiologic diagnosis usually is not Francisella tularensis (tularemia), Thorax. 2005;60:672- 8. [PMID: 16061709] necessary, because empirical therapy Leptospira spp, Nocardia spp,© 2009 American College of Physicians ITC4-6 In the Clinic Annals of Internal Medicine 6 October 2009
  7. 7. Rhodococcus equi, and Yersinia pestis When should clinicians consider(plague). Also consider noninfec- specialty consultation for thetious possibilities, such as bron- diagnosis of pneumonia, andchiolitis obliterans, organizing which types of specialists shouldpneumonia, pulmonary vasculitis, they consult?hypersensitivity pneumonitis, inter- Consultation is most valuablestitial diseases, lung cancer, lym- when patients do not respond tophangitic carcinoma, lymphoma, initial therapy. An infectious dis-and congestive heart failure, par- ease specialist can help identifyticularly if the patient is younger unusual infections and infectiousthan 55 years, is a nonsmoker, and complications of pneumonia.has a nonfocal lung infiltrate. If A pulmonary specialist can helpthe patient starts to respond to identify inflammatory lung dis-therapy and then his condition ease and pulmonary embolus,deteriorates, consider pulmonary perform a bronchoscopy, andembolus, antibiotic-induced coli- perform a transbronchial biopsy.tis, empyema, meningitis, and en- A surgeon can perform an open-docarditis. lung biopsy. Diagnosis... Clinical findings are less dramatic in elderly persons. History is particularly valuable for defining risk factors for specific pathogens, whereas physical findings help define disease severity. Confirm the diagnosis of CAP with a chest radiograph, although this test is not always diagnostic early in the course of illness. Laboratory testing has limited value; its main use is to define pneumonia severity and to identify systemic and respiratory complications. Diagnosing specific pathogens early is less useful because most initial therapy is empirical. If the patient does not respond to initial therapy, consult specialists and consider bronchoscopy and lung biopsy. CLINICAL BOTTOM LINEHow should clinicians determine Treatment condensed into the “CURB-65,”whether a patient with CAP which is based on the presence ofrequires outpatient, inpatient, or Confusion, blood Urea nitrogenICU care? greater than 7.0 mmol/L (19.6Many site-of-care decisions can be mg/dL), Respiratory rate of 30facilitated with the Pneumonia breaths/min or greater, systolicSeverity Index (PSI) or the BritishThoracic Society (BTS) rule. These Blood pressure less than 90 mm Hgtools predict the risk for dying; pa- or diastolic blood pressure no greatertients with a high risk are generally than 60 mm Hg, and age 65 years ormanaged in the hospital, and those older. Patients meeting at least 2 of 23. Christ-Crain M, Stolzwith the highest risk are managed in these criteria are usually admitted to D, Bingisser R, et al. Procalcitonin guid-the ICU. The PSI stratifies patients the hospital, whereas those with at ance of antibiotic therapy in commu-into 5 categories by using a scoring least 3 criteria are considered for nity-acquired pneu-system based on patient age, comor- ICU admission. monia: a random- ized trial. Am Jbid illness, physical examination Respir Crit Care Med.findings, and laboratory data. One prospective study of 3181 patients 2006;174:84-93. [PMID: 16603606]Patients in classes IV and V are seen in 32 different emergency depart- 24. Aujesky D, Auble TE, Yealy DM, et al.generally admitted to the hospital, ments compared the PSI with the CURB Prospective compar-those in classes I and II are often and CURB-65 criteria and found that both ison of three validat- ed prediction rulestreated as outpatients, and those in approaches were successful in identifying for prognosis in community-ac-class III have the site-of-care deci- low-risk patients. The CURB-65 was better quired pneumonia.sion based on careful clinical assess- for predicting mortality risk in high-risk Am J Med. 2005;118:384-92.ment. The BTS rule has been patients (24). [PMID: 15808136]6 October 2009 Annals of Internal Medicine In the Clinic ITC4-7 © 2009 American College of Physicians
  8. 8. In another prospective study of 1651 pa- quionolone (gemifloxacin, levo- tients, measurement of serum procalcitonin floxacin, or moxifloxacin) or a supplemented the data obtained by prog- combination of a β-lactam (amoxi- nostic scoring, and patients who had a low cillin, 3 g/d; amoxicillin–clavulanate, value of procalcitonin had a low mortality, cefpodoxime, or cufuroxime) with a regardless of PSI class or number of CURB-65 points (25). macrolide or doxycycline. If the patient has received an antibiotic Current guidelines suggest ICU care in the past 3 months, avoid using an if the patient needs assisted ventila- antibiotic in the same class. tion or has septic shock requiring vasopressors or if the patient has at How long should outpatients least 3 of the following: respiratory continue antibiotic treatment? rate of 30 breaths/min or greater, Base the duration of therapy on the PaO2 /FiO2 ratio no greater than 250, patient’s clinical response, severity multilobar infiltrates, confusion or of illness, and probable pathogen. disorientation, blood urea nitrogen Treat outpatients with mild-to- 7.1 mmol/L (20 mg/dL) or greater, moderate CAP for 7 days or fewer leukocyte count less than 4 × 109 if there is a good clinical response, cells/L, platelet count less than 100 × no fever for 48 to 72 hours, and no 109 cells/L, temperature less than sign of extrapulmonary infection. 36°C, and hypotension requiring ag- Azithromycin has such a long half-25. GenIMS Investiga- tors. Risk prediction gressive fluid resuscitation (26), al- life that therapy for 1 or 3 days with procalcitonin though 1 study has questioned the may be effective. and clinical rules in community-ac- quired pneumonia. utility of using only minor criteria to A meta-analysis of 15 RCTs of mild-to- Ann Emerg Med. define the need for ICU care (27). moderate CAP found that therapy for 7 2008;52:48-58.e2. [PMID: 18342993] days or fewer was as effective as longer26. Infectious Diseases What is the role of nondrug therapy with regard to clinical failure, mor- Society of America. Infectious Diseases therapies in treating CAP? tality, adverse events, and bacteriologic Society of Ameri- In outpatients, focus nondrug therapy eradication. The trials compared only ca/American Tho- racic Society con- on encouraging oral hydration. For monotherapies, and 13 of the short-dura- sensus guidelines on the management of hospitalized patients, nondrug thera- tion trials used azithromycin, fluoro- community-ac- pies include intravenous hydration quinolones, or ketolides, which provide quired pneumonia in adults. Clin Infect and oxygen for hypoxemia. Chest coverage for both pneumococcal and Dis. 2007;44 Suppl physiotherapy has not been widely atypical pathogens. Only 2 short-duration 2:S27-72. [PMID: 17278083] studied, but it has been shown to trials used β-lactam monotherapy (29).27. Liapikou A, Ferrer M, Polverino E, et al. Se- improve the outcome of patients vere community-ac- with pneumonia who have more How should clinicians follow quired pneumonia: than 30 mL/d of sputum and im- patients during outpatient validation of the In- fectious Diseases So- paired clearance of secretions (28). treatment of CAP? ciety of Up to 10% of patients initially America/American Thoracic Society When using outpatient treatment managed at home do not respond guidelines to predict an intensive care for CAP, which antibiotics should to outpatient therapy and require unit admission. Clin Infect Dis. clinicians prescribe? hospitalization. To identify these 2009;48:377-85. For patients with no cardiopul- patients early, the physician and [PMID: 19140759]28. Graham WG, Bradley monary disease and no factors that patient should agree on a plan to DA. Efficacy of chest physiotherapy and increase risk for infection with monitor the response to therapy. intermittent posi- DRSP or enteric gram-negative Ask patients to measure an oral tive-pressure breath- ing in the resolution bacteria (Table 1), prescribe a temperature every 8 hours and to of pneumonia. N macrolide (azithromycin, clari- report if it increases higher than Engl J Med. 1978;299:624-7. thromycin, or erythromycin) or 38.3°C (101°F) or if it does not [PMID: 355879]29. Li JZ, Winston LG, doxycycline (Table 2). For outpa- decrease below 37.2°C (99°F) after Moore DH, et al. Effi- tients who have cardiopulmonary 48 hours. Encourage patients to cacy of short-course antibiotic regimens disease or factors that increase the drink at least 1 to 2 quarts of liquid for community-ac- quired pneumonia: a risk for infection with DRSP or daily, and ask them to report if they meta-analysis. Am J enteric gram-negative bacteria, cannot achieve this goal. Instruct Med. 2007;120:783- 90. [PMID: 17765048] prescribe an antipneumococcal patients to report symptoms of© 2009 American College of Physicians ITC4-8 In the Clinic Annals of Internal Medicine 6 October 2009
  9. 9. Table 2. Drug Treatment for Community-Acquired Pneumonia Agent Mechanism of Action Dosage Benefits Side Effects and Notes Macrolides Bacteriostatic, binds to Azithromycin, 500 mg on Cover pneumococcus, Nausea, vomiting, diarrhea, QT Azithromycin the 50S ribosomal subunit, day 1 (IV or PO), followed atypical pathogens, prolongation, dyspepsia Clarithromycin and inhibits bacterial by 500 mg (IV or PO) for and Haemophilus (clarithromycin). Use as protein synthesis. 7–10 d for hospitalized influenzae. monotherapy only in patients patients. 250 mg on d without cardiopulmonary disease 2–5 for outpatients. or modifying factors. Otherwise, Azithromycin in the micro- combine with a β-lactam agent. spheres oral extended- Erythromycin is less expensive but release formulation, 2 g on not recommended because of the day 1 (PO) without follow- need for more frequent dosing, up dosing for outpatients. more intestinal upset, and no Clarithromycin, 500 mg coverage of H. influenzae. bid PO, or 1000 mg/d PO (extended-release preparation) for outpatients. Penicillins Bactericidal, interferes Amoxicillin/clavulanate, Active against Anaphylaxis, rash, nausea, Amoxicillin/clavulanate with peptidoglycan 875 mg bid PO; Ampicillin, pneumococci and vomiting, diarrhea, phlebitis, Ampicillin cross-linking, and 500–1000 mg tid PO; β-lactamase-producing seizures (high doses), hypokalemia Ampicillin/sulbactam prevents formation of Ampicillin/sulbactam, H. influenzae. (high doses), elevated liver tests, the bacterial cell wall. 1–2 g q6h IV. prolonged prothrombin time (especially if on coumadin). Do not use alone in CAP. Combine with a macrolide. Antipseudomonal Bactericidal, interferes Piperacillin/tazobactam, Active against Anaphylaxis, rash, nausea, β-lactams with peptidoglycan 3.375 mg q4–6h IV; pneumococci and vomiting, diarrhea, phlebitis, Piperacillin/tazobactam cross-linking, and Cefepime, 1–2 g q12h IV; Pseudomonas seizures (high doses), hypokalemia Cefepime prevents formation of Imipenem, 1 g q8h IV aeruginosa. (high doses), elevated liver tests, Imipenem the bacterial cell wall. or 500 mg q6h IV; prolonged prothrombin time Meropenem Meropenem, 1 g q8h IV. (especially if on coumadin). Seizure potential greater with imipenem than meropenem. Only use for patients with pseudomonal risk factors, although generally ac- tive against DRSP. Can dose daily if patient has renal insufficiency. Cephalosporins Bactericidal, interferes Cefuroxime, 500 mg bid PO; Active against Anaphylaxis, rash, nausea, Cefuroxime with peptidoglycan Cefpodoxime, 400 mg bid PO; pneumococci and vomiting, diarrhea, elevated liver Cefpodoxime cross-linking, and Ceftriaxone, 1–2 g q12–24h H. influenzae, including function test results, interstitial Ceftriaxone prevents formation of (usually q24h); β-lactamase–producing nephritis, altered coagulation, Cefotaxime the bacterial cell wall. Cefotaxime, 1 g q8h. organisms. pseudomembranous colitis. Not to be used alone in CAP. Combine with a macrolide. Although cefuroxime can be used as oral therapy, it should not be used IV, because it is not as active against DRSP as other cephalosporins. Quinolones Bactericidal, interferes Ciprofloxacin, 400 mg q8-12h Ciprofloxacin and Levo- Seizures, hypersensitivity, photo- Ciprofloxacin with bacterial DNA gyrase. IV; Gemifloxacin, 320 mg/d floxacin are active against sensitivity, tendon rupture, nausea, Gemifloxacin Kills bacteria in a (PO only); Levofloxacin, P. aeruginosa, atypicals, vomiting, diarrhea, QT prolongation. Levofloxacin concentration-dependent 750 mg/d (IV or PO); and H. influenzae. Ciprofloxacin: only to be used in Moxifloxacin fashion. Moxifloxacin, 400 mg/d Levofloxacin and severe CAP. Not always reliable (IV or PO). Moxifloxacin are the against pneumococci, and should “respiratory quinolones” be combined with other agents if with activity against DRSP is possible. If used in severe DRSP, H. influenzae, CAP, do not use as monotherapy. and atypical pathogens. Tetracyclines Bacteriostatic, binds to Doxycycline, 100 mg bid Active against key Nausea, vomiting, diarrhea, Doxycycline 30S ribosomal subunit, (IV or PO). bacterial and atypical photosensitivity. Not always fully and interferes with pathogens. reliable against pneumococci. bacterial protein synthesis. bid = twice daily; CAP = community-acquired pneumonia; DNA = deoxyribonucleic acid; DRSP = drug-resistant Streptococcus pneumonia; IV = intra- venous; PO = oral; tid = three times daily.6 October 2009 Annals of Internal Medicine In the Clinic ITC4-9 © 2009 American College of Physicians
  10. 10. chest pain, severe or increasing 75.9% to 58.9% after the initiation shortness of breath, or lethargy. of a program to give more patients Encourage patients to take their antibiotics within 4 hours of arrival30. Meehan TP, Fine MJ, antibiotic therapy on schedule and in the emergency department (31). Krumholz HM, et al. Quality of care, to continue taking antibiotic thera- process, and out- py after they begin feeling better Give hospitalized patients who are comes in elderly pa- tients with pneumo- until they have taken all of it. not in the ICU intravenous nia. JAMA. azithromycin if they have no cardio- 1997;278:2080-4. [PMID: 9403422] If the response to therapy is satis- pulmonary disease and no factors31. Kanwar M, Brar N, factory, ask the patient to return for that increase the risk for DRSP or Khatib R, et al. Misdi- agnosis of commu- a repeat examination within 10 to gram-negative bacteria (26, 32). nity-acquired pneu- monia and 14 days. Give pneumococcal and For hospitalized patients not in the inappropriate utiliza- influenza vaccinations if they have ICU who have cardiopulmonary tion of antibiotics: side effects of the 4- not previously been given. Obtain a disease or factors that increase the h antibiotic adminis- tration rule. Chest. repeat chest radiograph no sooner risk for DRSP or gram-negative 2007;131:1865-9. than 1 month after starting pneu- bacteria, give an intravenous [PMID: 17400668]32. Feldman RB, Rhew monia therapy. Exclude lung can- quinolone (levofloxacin, 750 mg, DC, Wong JY, et al. cer, immunodeficiency, and other when renal function is normal or Azithromycin monotherapy for pa- possibilities during follow-up visits. moxifloxacin, 400 mg/d) or the tients hospitalized with community-ac- combination of a β-lactam (cefo- quired pneumonia: a When patients require hospital- taxime, ceftriaxone, ampicillin– 31/2-year experi- ization for CAP, how soon after ence from a veter- sulbactam, or high-dose ampicillin, ans affairs hospital. admission should antibiotics be but not cefuroxime) with a macro- Arch Intern Med. 2003;163:1718-26. started, and which antibiotics lide or doxycycline (26). The addi- [PMID: 12885688] should patients receive if they do tion of a macrolide to a β-lactam33. Gleason PP, Kapoor WN, Stone RA, et al. not need ICU care? has been associated with a reduc- Medical outcomes and antimicrobial Patients should receive initial anti- tion in mortality and length of hos- costs with the use of biotic therapy as soon as possible pital stay (33, 34) even for bac- the American Tho- racic Society guide- after the diagnosis of pneumonia is teremic pneumococcal pneumonia lines for outpatients with community-ac- established and before the patient (35). Specific β-lactams are pre- quired pneumonia. leaves the emergency department. ferred if DRSP is suspected. Cef- JAMA. 1997;278:32-9. [PMID: 9207335] A large Medicare study found that triaxone and cefotaxime are as34. Brown RB, Iannini P, Gross P, et al. Impact antibiotic administration within 4 effective against DRSP with mean of initial antibiotic hours of arrival to the hospital was choice on clinical inhibitory concentration values up associated with a lower mortality outcomes in com- to 2 mg/L as they are against non- munity-acquired and a shorter length of stay. As a pneumonia: analysis resistant organisms (36). Cefurox- result, prompt antibiotic adminis- of a hospital claims- made database. ime may not be an ideal β-lactam if tration has become a widely used Chest. DRSP is suspected, because 1 study 2003;123:1503-11. measure of the quality of pneumo- [PMID: 12740267] showed increased mortality when35. Martínez JA, Horca- nia care (9, 30). However, delayed this agent was used in patients with jada JP, Almela M, et administration of antibiotics may al. Addition of a bacteremic DRSP (37). macrolide to a beta- be only a surrogate for other factors lactam-based empir- ical antibiotic regi- that are the direct causes of in- One international study of 4337 hospital- men is associated creased mortality; for example, ized patients with CAP showed that with lower in-hospi- tal mortality for pa- immunocompromised patients approximately 20% had evidence of tients with bac- atypical pathogen infection and that teremic probably have higher mortality pneumococcal rates and have atypical presenta- therapy directed against these organisms pneumonia. Clin In- decreased the time to clinical stability, fect Dis. tions that probably delay the start 2003;36:389-95. of therapy. Too strong a focus on length of stay, total mortality, and CAP- [PMID: 12567294] related mortality (38). However, another36. Lujan M, Gallego M, timely antibiotic therapy can result Fontanals D, et al. study of 2209 hospitalized Medicare pa- Prospective observa- in unnecessary antibiotic use in pa- tients with bacteremic pneumonia found tional study of bac- tients who do not have pneumonia. that therapy directed at atypical patho- teremic pneumo- coccal pneumonia: In 1 study, the final diagnosis of gens led to reduced 30-day mortality and Effect of discordant therapy on mortality. pneumonia in patients suspected of 30-day readmission rate, but the benefits Crit Care Med. having pneumonia in the emer- occurred only with macrolides and not 2004;32:625-31. [PMID: 15090938] gency department decreased from with fluoroquinolones (39).© 2009 American College of Physicians ITC4-10 In the Clinic Annals of Internal Medicine 6 October 2009
  11. 11. Which antibiotics should be given What are the other componentsto patients admitted to an ICU? of ICU care for CAP?No patient in the ICU should receive Consider hydration, supplementalempirical monotherapy. Assess these oxygen, and chest physiotherapy, 37. International Pneu-patients for risk factors for P. aerugi- but the major issue is ventilatory mococcal Study Group. An interna-nosa. Treat those without risk factors support for respiratory failure. Use tional prospective study of pneumo-with intravenous ceftriaxone or cefo- intubation and mechanical ventila- coccal bacteremia:taxime plus either azithromycin or a tion in patients who have oxygen correlation with in vitro resistance, an-quinolone, such as levofloxacin or saturation less than 90% on maxi- tibiotics adminis- tered, and clinicalmoxifloxacin. Treat patients who mal mask oxygen, inability to clear outcome. Clin Infecthave risk factors with an intravenous, secretions, inability to protect the Dis. 2003;37:230-7. [PMID: 12856216]antipseudomonal β-lactam (cefe- airway, or hypercarbia. If the pa- 38. Community-Ac-pime, piperacillin–tazobactam, tient has only hypoxemia or hyper- quired Pneumonia Organization (CAPO)imipenem, meropenem) plus an in- carbia and is alert and cooperative, Investigators. A worldwide perspec-travenous quinolone effective against it may be possible to use noninva- tive of atypicalPseudomonas (ciprofloxacin or high- sive positive pressure ventilation, pathogens in com- munity-acquireddose levofloxacin). Alternatively, treat which may be associated with fewer pneumonia. Am J Respir Crit Care Med.patients who have risk factors with complications than endotracheal 2007; intravenous, antipseudomonal intubation, including ventilator- [PMID: 17332485] 39. Metersky ML, Ma A,β-lactam (cefepime, piperacillin– associated pneumonia. Houck PM, et al. An-tazobactam, imipenem, meropenem) tibiotics for bac- teremic pneumonia:combined with an aminoglycoside Consider systemic corticosteroids, Improved outcomes with macrolides but(amikacin, gentamicin, or tobra- especially if relative adrenal insuf- not fluoro-mycin) plus either an intravenous ficiency is suspected. Because quinolones. Chest. 2007;131:466-73.macrolide (azithromycin or erythro- many patients with severe CAP [PMID: 17296649] 40. Rello J, Catalán M,mycin) or intravenous antipneumo- also have systemic sepsis, consider Díaz E, et al. Associa-coccal quinolone (levofloxacin or using drotrecogin α, aggressive tions between em- pirical antimicrobialmoxifloxacin). In studies of patients hydration, vasopressors, and meas- therapy at the hospi-admitted to the ICU with severe urement of serum lactate. Do not tal and mortality in patients with severeCAP, mortality was reduced when use granulocyte-colony stimulating community-ac- quired pneumonia.combination therapy was used; factor routinely for patients with Intensive Care Med.monotherapy, even with a quinolone, severe CAP. 2002;28:1030-5. [PMID: 12185421]was not as effective. In general, the 41. International Pneu-addition of a macrolide to therapy In 1 study of 40 patients with severe CAP, mococcal Study Group. Combinationwith a β-lactam (either a cephalo- when random serum cortisol levels were antibiotic therapy measured in the first 72 hours, 65% of pa-sporin or β-lactam or β-lactamase lowers mortality among severely ill tients met criteria for adrenal insufficiency,inhibitor) led to the best outcomes patients with pneu- and 63% of the 19 patients with CAP and mococcal bac-(40). In patients with bacteremic septic shock also had adrenal insufficiency teremia. Am J Respir Crit Care Med.pneumococcal pneumonia and critical (43). In 4 studies, including randomized tri- 2004;170:440-4.illness, studies have found that mor- als, evidence was inconsistent for a benefit [PMID: 15184200] 42. Micek ST, Dunne M,tality was lower with combination from routine corticosteroid therapy, but if Kollef MH. Pleu- ropulmonary com-therapy than with monotherapy (41). the patient required this therapy for anoth- plications of Panton- er reason (such as underlying COPD), corti- ValentineIf community-acquired methicillin- costeroid therapy seemed to cause no leukocidin-positive community-ac-resistant S. aureus is suspected, add ei- harm (44). quired methicillin-re- sistant Staphylococ-ther linezolid alone or vancomycin in cus aureus:combination with clindamycin, be- In a randomized, placebo-controlled tri- importance of treat-cause both of these regimens are anti- al, drotrecogin α led to reduced mortality ment with antimi- crobials inhibitingbacterial and inhibit the production for patients with severe sepsis, including exotoxin production. the 35.6% of patients who had severe Chest.of bacterial toxins. Vancomycin alone 2005;128:2732-8. CAP. Patients who were vasopressor- [PMID: 16236949]is antibacterial but cannot inhibit tox- dependent and were treated with the 43. Salluh JI, Verdeal JC,in production (42). These regimens drug had a relative risk reduction in mor- Mello GW, et al. Cor- tisol levels in pa-are recommended, even though the tality of 28% at 28 days. The survival ben- tients with severe community-ac-organisms are often sensitive in vitro efit was most pronounced in patients quired trimethoprim–sulfamethoxizole with severe CAP and S. pneumoniae and Intensive Care Med. 2006;32:595-8.and quinolones. in patients with severe CAP at high risk [PMID: 16552616]6 October 2009 Annals of Internal Medicine In the Clinic ITC4-11 © 2009 American College of Physicians
  12. 12. for death as indicated by Acute Physiolo- When should a consultation be gy and Chronic Health Evaluation II score requested for hospital patients, 25 or greater, PSI score IV or greater, or and which types of specialists or CURB-65 score 3 or greater (45). subspecialists should be consulted? When can clinicians switch Ask for an infectious disease or pul- hospitalized patients from monary consultation if there are intravenous to oral antibiotics? questions about the selection of ini- Switch from intravenous to oral tial antibiotic therapy or when the antibiotics once the symptoms of patient does not respond to initial cough, sputum production, and therapy. Ask for a pulmonary or crit- dyspnea improve; the patient is ical care consultant for patients with afebrile on 2 occasions 8 hours severe illness to help select anti- apart; and the patient is able to biotics, decide about using vasopres- take medications orally. This sors, determine the appropriate site switch can be made as early as 24 of care, decide about the need for to 48 hours after admission and is ventilatory support, and aid in man- made by day 3 in up to half of all aging the mechanical ventilator. Ask patients. The switch to oral thera- for a pulmonary consultant if a pleu- py can be done safely even if ral effusion is documented and help pneumococcal bacteremia has been is needed with a thoracentesis. Ask documented, although these pa- for a pulmonary or thoracic surgical tients may take longer to respond. consultation for placement of a chest Longer durations of therapy may tube if a complicated parapneumonic be needed for patients infected effusion or empyema is found on with P. aeruginosa or S. aureus or thoracentesis, because early therapy for those with extrapulmonary can reduce hospital stay and avoid complications, such as empyema complications. A thoracic surgeon or meningitis. Select an oral regi- can perform surgical decortication men that covers all organisms iso- for advanced and loculated pleural44. Salluh JI, Póvoa P, lated in blood or sputum cultures effusion and empyema. A cardiology Soares M, et al. The role of corticos- and reflects the intravenous thera- consultation may be needed if com- teroids in severe py. For some patients, this will community-ac- plications of cardiac ischemia or con- quired pneumonia: a mean a β-lactam–macrolide com- gestive heart failure occur. In a study systematic review. Crit Care. bination or a quinolone alone. In of 170 patients with pneumococcal 2008;12:R76. [PMID: 18547407] patients who have responded to a pneumonia, 19.4% had at least 145. PROWESS Clinical β-lactam–macrolide combination, major cardiac event, including 12 Evaluation Commit- tee. Severe commu- therapy can be continued on a with acute myocardial infarction, 8 nity-acquired pneu- monia as a cause of macrolide alone unless cultures with new-onset atrial fibrillation or severe sepsis: data justify dual therapy. ventricular tachycardia, and 13 with from the PROWESS study. Crit Care Med. newly diagnosed or worsening heart 2005;33:952-61. To facilitate the switch to oral therapy, failure without other cardiac compli- [PMID: 15891319] hospitals should consider using a stand-46. Fishbane S, Nieder- cations. The patients with cardiac man MS, Daly C, et ing order set supplemented by prospec- events had a significantly higher al. The impact of tive case management. In a cohort study, standardized order mortality rate (27.3% vs. 8.8%) (47). sets and intensive patients were managed in each of 3 suc- clinical case man- agement on out- cessive time periods with conventional When can inpatients be comes in communi- therapy, a guideline-based order set sup- discharged from the hospital? ty-acquired ported by prospective case management pneumonia. Arch In- Discharge patients once the switch tern Med. that provided feedback to clinicians, and 2007;167:1664-9. to oral therapy is made, because no [PMID: 17698690] a guideline-based order set alone. In all 347. Musher DM, Rueda time periods, the time to clinical stability proven benefit exists for observa- AM, Kaka AS, et al. was similar, but prospective case man- tion in the hospital. In 1 study, The association be- tween pneumococ- agement led to the greatest reductions in two-thirds of clinically stable cal pneumonia and acute cardiac events. the time to oral antibiotics, time from patients were observed on oral Clin Infect Dis. oral therapy to discharge, and overall therapy before discharge, and no 2007;45:158-65. [PMID: 17578773] length of stay (46). deterioration occurred during this© 2009 American College of Physicians ITC4-12 In the Clinic Annals of Internal Medicine 6 October 2009