COMMUNITY-ACQUIRED PNEUMONIA

ANTIBIOTIC THERAPY, PART I1

0025-7125/01 $15.00

+ .OO

COMMUNITY-ACQUIRED PNEUMONIA Diagnostic and Therapeutic Approach Burke A. Cunha, MD

Community-acquired pneumonia (CAP) is one of the most common infectious diseases encountered by physicians. Mild or walking pneumonia is treated in the ambulatory setting, whereas sicker patients with CAP usually require hospitalization. CAP may be defined as an infectious disease confined to or involving the lungs, caused by microorganisms. CAP is important from a public health standpoint because of the frequency of this infectious disease and its attendant morbidity and mortality. Optimal antimicrobial therapy of CAP depends on an accurate assessment of the presumed or known pathogens and detailed knowledge of the spectrum, pharmacokinetics, resistance potential, side-effect profile, and cost of the antimicrobial agent selected to treat CAP. DIAGNOSTIC CONSIDERATIONS Typical Community-Acquired Pneumonia

The most common causes of CAP are bacterial pulmonary pathogens. The bacterial causes of CAP have not changed over the years and remain Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella cat~rrhalis.~, *, 75, 87, lZo Knowledge of the pathogens causing CAP is important and determines appropriate antimicrobial therapy. Knowing

From the State University of New York School of Medicine, Stony Brook, and the Infectious Disease Division, Winthrop-University Hospital, Mineola, New York

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that only these three pathogens cause bacterial pneumonia is important, to avoid covering organisms that do not cause CAP except under special circumstances (e.g., Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonus aer~ginosa).~~, K. pneumoniae as a cause of CAP occurs almost exclusively in chronic alcoholics. S. aureus may complicate viral influenza pneumonia but otherwise rarely, if ever, causes CAP. P. aeruginosa virtually never causes CAP even in compromised hosts. Community-acquired P. aeruginosa pneumonia is seen usually in the subset of patients with chronic bronchiectasis or cystic fibrosis. Other organisms (e.g., Acinetobacter) are such rare causes of CAP as not to require specific coverage in 39, 49 empiric therapy regimens for CAP.22, The best and definitive study recently conducted by Spanish investigators has settled several questions about pathogens in CAP.123Spanish investigators conducted a large study of patients with CAP and using invasive techniques (e.g.,lung biopsy and sophisticated diagnostic methods, such as polymerase chain reaction) were able to determine accurately the cause of CAP in all patients in the study. Using conventional diagnostic techniques, in approximately 25% of patients no specific pathogenic agent can be identified. This study showed the no easily demonstrated pathogen group had the same pathogen distribution, although smaller, as the CAP group with easily demonstrable pathogens, using the usual diagnostic methods (e.g., sputum, blood cultures). Clinicians can now be assured that if a specific microbiologic diagnosis cannot be obtained in a patient with CAP, it can be assumed confidently that these patients have the same pathogen distribution as in the demonstrable pathogen group as determined by the usual diagnostic metho d ~These . ~ ~ findings ~ are clinically important because this means that there are no unknown organisms that need to be covered when the causative organism cannot be determined using the usual diagnostic methods. The series included a small number of normal and compromised In normal and immunocompromised hosts, the causes of CAP are the same: Approximately 85% of the cases are caused by S. pneumoniae, H. infuenzae, or M. catarrhalis, and the remaining 15% are distributed among Legionella, Mycoplasma pneumoniae, and Chlamydia pneumoni~ze.~~, 54 The Spanish study also included patients with human immunodeficiency virus (HIV) who were mildly to moderately advanced, as evidenced by low CD, counts. Such HIV patients with CAP also had the same pathogen distribution as in normal and other compromised hosts!, lo,15, 67, Io6, lo8,lZ2, 132 Such data are critically important in determining an appropriate therapeutic regimen, which must be based on an accurate knowledge of the pathogen distribution in CAP.38,lZ3 The Spanish study settles several other questions about the cause of CAP. Some have suggested that multiple pathogens are common in CAP. Such data are based on seroprevalence surveys and have no clinical relevance. The Spanish study also demonstrated using the best available diagnostic techniques, that single pathogens, not copathogens, are responsible in CAP. Patients do not present with multiple bacterial patho-

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gens or with aspiration pneumonia or with multiple atypical pathogens, and they do not present with a mixture of typical or atypical pathogens. The Spanish study proves what was known from clinical experienceone pathogen is responsible for each case of CAP, aspiration pneumonia excluded.16,17,29.49.58. 123 Three important concepts vital in designing appropriate therapeutic regimens for CAP emerge from the Spanish data. First, the relative proportion of typical (approximately 85%) and atypical (approximately 150/,)pathogens as a cause of CAP has been defined. The study also determined that undiagnosed pathogens, using usual diagnostic methods, are the same and are in the same proportion as those in which a specific microbiologic diagnosis is possible using conventional diagnostic metho d ~The . ~second ~ ~ important finding in the Spanish study is that there is a monomicrobial cause of CAP; copathogens do not cause CAP. A third important finding is that the pathogen distribution of typical and atypical pulmonary pathogens is the same in normal and compromised hosts, including those with early to moderately advanced HIV. The Spanish investigators reconfirmed that the pathogen distribution in CAP is not related to severity.", 66* 95, 96, 99, lol, lo9 Moderately ill patients with CAP have the same pathogen distribution as those with severe CAP. These definitive data finally permit a unifying concept of treatment for patients with CAP.123Based on clinical experience and the crucial data from the Spanish study, the treatment of CAP may be unified into a single therapeutic approach for normal and compromised hosts regardless of degree of severity (Table 1). Atypical Community-Acquired Pneumonia

The patient with CAP usually presents with an acute febrile illness accompanied by pulmonary symptoms. Most patients have a dry or productive cough, which may be accompanied by pleuritic chest pain.98,lo4 The frequency and intensity of rigors depends on the infecting pathogen causing CAP.113With the typical bacterial pneumonias caused by bacterial pulmonary pathogens, the findings except for fever and chills are confined solely to the lungs.7,133 In contrast, CAP with extrapulmonary findings should suggest CAP resulting from atypical pathog e n ~ . ~90*Atypical , pathogens are systemic infectious diseases that have a pulmonary component. This fact permits clinical differentiation from the typical bacterial causes of CAP (Fig. 1).Atypical pulmonary pathogens may be differentiated further from a diagnostic standpoint by the pattern of extrapulmonary organ involvement of extrapulmonary findings because each atypical pulmonary pathogen has its own characteristic pattern of organ involvement. Although individual symptoms and signs are not pathognomonic of any particular pathogen, the pattern of organ involvement is sufficiently characteristic to permit a rapid and accurate presumptive clinical diagnosis (Table 2).21,29 Although M . pneumoniae and C. pneurnoniae are as frequent causes

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Table 1. COMMON RESPIRATORY PATHOGENS AND NONPATHOGENS IN COMMUNITY-ACQUIRED PNEUMONIA

Typical bacterial pathogens approximately (85%) Streptococcus pneumoniae Penicillin-sensitive S. pneumoniae Pencillin-resistant S. pneumoniae Haemophilus influenzae Ampicillin-sensitive H. influenzae Ampicillin-resistant H. infuenzae Moraxella catarrhalis All strains penicillin resistant Atypical respiratory pathogens (approximately 15%) Legionella Mycoplasma pneumoniae Chlamydia pneumoniae Rare bacterial pathogens KIebsiella pneumoniae-only in chronic alcoholics Staphylococcus aureus-nly in post-viral influenza setting Pseudomonas aeruginosa-nly in cystic fibrosis or bronchiectasis Non-pulmonary pathogens Non-aeruginosa pseudomonads Stentrophomonas (Xanthomonas) maltophilia Burkholderia (Pseudomonas) cepacia Enterobacter E. cloacae E. agglomerans Enterococcus Citrobacter C. freundii C. koseri Flavobacterium F. meningosepticum Nosocomial pulmonary pathogens Pseudomonas aeruginosa Acinetobacter baumanii Klebsiella pneumoniae Aerobic gram negative bacilli From Cunha BA: Severe community-acquired pneumonia. Crit Care Clin 14:105-118;1998; with permission.

as is Legionella in CAP, Legionella is the most important nonzoonotic atypical pulmonary pathogen on the basis of mortality and morbidity.21* 29, 58, lZ9 It is important to be able to recognize legionnaires’ disease clinically. Legionnaires’ disease may be differentiated from the typical bacterial pneumonias as well as the atypical pneumonias based on its characteristic pattern of extrapulmonary involvement (Table 3, Fig. 2).90 Clinicians should appreciate that selected signs and symptoms are more important than others because of their diagnostic specificity. A weighted diagnostic scoring system that permits the clinician to diagnose legionnaires’ disease rapidly and accurately has been developed (Table 4).4,45

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Clinical pneumonia (confirmed by chest x-ray)

I I

I

No exm-pulmonary features

Extra-pulmonary features

I

I

Typical bacterial pneumonia

Positive zoonotic contact history

I

Streptococcus pneumoniae Haemophilusiniluenzae Moraxella cata~~halis Grp A streptococci Aspiration pneumonia

- Zoonotic coitact history

+ Zoonotic coitact history

Mycoplasma Chlamydia pneumoniae Tularemia

-RB

Mycoplasma C. pneumoniae

+RE4

Psittacosis Q fever Tularemia

-RB

m

Legionnaires’ Tularemia

disease

+RB

Psittacosis Q fever

Figure 1. The clinical diagnostic approach to community-acquired pneumonia. (From Cunha BA: Clinical diagnosis of Legionnaire’s Disease. Semin Respir Infect 13:116, 1998; with permission.)

Mimics of Community-Acquired Pneumonia CAP must be differentiated from other pulmonary conditions mimicking pneumonia as well as systemic disorders with pulmonary manifestations. Mild CAP seen in the ambulatory setting may be confused with tracheobronchitis, acute bronchitis, or exacerbation of chronic bronchitis. The differential diagnosis of CAP in hospitalized patients includes congestive heart failure, pulmonary embolism or infarction, pulmonary drug reactions, asthma, systemic lupus erythematosus (SLE), pneumonitis, noncardiac pulmonary edema, radiation pneumonitis, and bronchogenic carcinomas. The past medical history of these disorders, the findings of extrapulmonary manifestations of the systemic diseases mentioned, and the chest radiograph appearance usually are sufficient to differentiate the mimics of pneumonia from CAP.13,16, 39, 49, 70 Diagnostic Approach The diagnostic approach consists of verifying the presence of CAP. The clinician should be sure the patient has CAP and not an upper respiratory infection or tracheobronchitis. The infiltrates on chest radiograph may suggest a noninfectious cause. It is important to recognize disorders that may mimic CAP, to treat the underlying disorder, and to avoid mistreating CAP. Patients presenting with CAP should be evaluated appropriately for the most likely diagnostic possibility. Even though the diagnostic process may not affect empiric therapy, the diagnostic workup is essential for accurate diagnosis, which predicts prognosis,

Splenomegaly Relative bradycardia

Raynaud’s phenomenon Nonexudative pharyngitis Hemoptysis Lobar consolidation Cardiac involvement

Symptoms Mental confusion Prominent headache Meningismus Myalgias Ear pain Pleuritic pain Abdominal pain Diarrhea Signs Rash

Key Characteristics

f (Myocarditis)

+ +

+ +

+-

f (Endocarditis)

f

-

+ +

(Myocarditis, heart block pericarditis)

f f

-

+

f

-

-

f

+

Mycoplasma pneumoniae

(E. multforme)

Tularemia

2

0 Fever

+

-

(Endocarditis, myocarditis)

-

f 2

f

Legionnaires’ Disease

Chlamydia pneumoniae

Nonzoonotic Atypical Pneumonias

(Horder’s spots)

Psittacosis

Zoonotic Atypical Pneumonias

Table 2. DIFFERENTIAL DIAGNOSTIC FEATURES OF ATYPICAL PNEUMONIAS

+

-

-

2

-

t

CF -

CF -

-

+

-

t -/ N

-

-

(Patchy/ consolidation)

1-/ N

-

-

(Patchy/ consolidation)

f CF -

-

-

t

-

+

-

TA

-

-

-

t -/ N

(Small)

(Bloody)

t -/ N

f

-

(Patchy)

+ +

(Ovoid bodies)

T

t

IFA

f

T

+ + +

(Small/ moderate)

f

-

(Patchy/ consolidation)

CF

+ t -

-

-

-

-

N

f

-

(Single circumscribed lesions)

Datafrom Cunha BA, Ortega A M Atypical pneumonias. In Borer WZ, et a1 (eds): Current Diagnosis 9. Philadelphia, WB Saunders, 1996; and Cunha BA Clinical features of Legionnaires’ Disease. Semin Respir Infect 13:116127, 1998.

WBC = White blood cell; SGOT/SGPT = serum glutamic-oxaloacetictransaminase/serum glutamic-pyruvic transaminase; N = normal; CF = complement fixation; TA = tube agglutination; IFA = indirect fluorescent antibody.

Laboratory abnormalities WBC count Hyponatremia/ hypophosphatemia Increase in SGOT/SGPT Cold agglutinins Microscopic hematuria Diagnostic tests Direct isolation (culture) Serology (specific) Psittacosis CF titers Legionella IFA titers

Bilateral hilar adenopathy Pleural effusion

Chest radiograph Infiltrate

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Table 3. RELATIVE BRADYCARDIA AS A DIAGNOSTIC SIGN IN LEGIONNAIRE'S DISEASE Determinationof Relative Bradycardia Inclusive criteria Patient must be an adult Temperature ~ 1 0 2 ° F Pulse must be taken simultaneously with temperature elevation Exclusive criteria Patient has NSR without arrhythmia, second- or third-degree heart block, or pacemaker-induced rhythm Patient must not be on P-blocker medication Appropriate Temperature-Pulse Relationships Temperature and corresponding pulse (beats/min) 41.1"C (106°F) 150 40.6"C (105°F) 140 40.0"C (104°F) 130 39.5"C (103°F) 120 110 389°C (102°F) Causes of Relative Bradycardia Infectious causes Legionella Psittacosis Q fever Typhoid fever Typhus Malaria Babesiosis Leptospirosis Yellow fever Dengue fever Rocky Mountain spotted fever Noninfectious causes P-Blockers CNS lesions Lymphomas Factitious fever Drug fever NSR = Normal sinus rhythm; CNS = central nervous system. Datafrom Cunha BA: Clinical diagnosis of Legionnaire's Disease. Semin Respir Infect 13116,1998.

predicts complications, and has public health implications (Table 5 ) . The severity of CAP is determined by host not microbial factors. Severity predicts length of stay and complications, but has no bearing on the choice of empiric antimicrobial therapy. See Table 6 for differential diagnosis of severe CAP presenting with shock. THERAPEUTIC CONSIDERATIONS Factors in the Selection of Antimicrobial Therapy for Community-Acquired Pneumonia

The selection of an antimicrobial to treat CAP depends on several factors, including spectrum, pharmacokinetics, resistance potential,

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ANCEF AMIKACIN DOXVCVCLINE

1 gm [ I V ) 5OOmg[IV)

2Wmg [ I V ) ql2h 16.0 13.1

m4 CREAT.

51

2.5 1.3

1.2

10.9

6.8

2.4 1.2

10.8

1.2 1.0

~lWlrIlVlql2h~100~(K))qlZh 9.0

9.2

10.4

0.7

Figure 2. Clinical features of a patient with legionnaires’disease and characteristicextrapulmonary findings. The pulse temperature record demonstrates relative bradycardia as an important sign in legionnaires’disease. (From Cunha BA: Clinical diagnosis of Legionnaire’s Disease. Sernin Respir Infect 13:116, 1998; with permission.)

safety profile, and cost. Optimal selection is based on a compilation of these factors, and for this reason, it is better to refer to an antimicrobial agent as being preferred for a given infectious disease rather than drug of choice.1,37,48 Drug of choice is based on in vitro activity and does not take into account all the other factors that are essential in a real life selection, and for this reason, the term preferred antimicrobial should be used in place of drug of choice.l8,19,28 Appropriate Antibiotic Spectrum

Empiric therapy of CAP is based on providing coverage against the most likely pathogens responsible for CAP. Previously the importance of the atypical pathogens relative to the typical pathogens was debated (i.e., should coverage for atypical pathogens be routinely included in an empiric antibiotic regimen or not).2,57, 58 Although it is possible, using the diagnostic approach presented, to differentiate typical from atypical pneumonias and to identify specifically Legionella among the atypical pathogens, it is nonetheless prudent for most clinicians, especially those unfamiliar with this method, to cover typical and atypical pathogens in the empiric coverage of CAP. Because the Spanish study convincingly

Table 4. WINTHROP-UNIVERSITY HOSPITAL INFECTIOUS DISEASE DIVISION POINT SYSTEM FOR DIAGNOSING LEGIONNAIRES DISEASE Findings

Clinical Headache Mental confusion, encephalopathic Lethargy Ear pain Nonproductive cough, sore throat Hoarseness Sputum Hemoptysis Chest pain Loose stools, watery diarrhea Abdominal pain Relative bradycardia Lack of response to plactam therapy Acute renal failure Laboratory .1 Na J PO4

t

SGOT/SGPT

T t

Total bilirubin Cold agglutinin titer

t

Qualifying Conditions

Point Score

Acute onset Acute onset

+1

Acute onset Acute onset Acute onset

+3 -3 -3

Acute onset Purulent Mild/moderate Pleuritic Not secondary to diarrhea-causing drugs With or without diarrhea Adults with temperature ?102"F, no pblockers, pacemaker, or arrhythmias After 72 hours

-3 -2 -1 -2 +3

Excluding other causes of renal insufficiency

+5

+2

Excluding other causes of hypophosphatemia Excluding pre-existing elevations or other causes of T serum transaminases

+5 +5 +5

+1 +4 +4 +2 -3

'1:64

Creatinine

Microscopic hematuria

Excluding pre-existing or other causes of renal insufficiency Otherwise unexplained

+1 +2

Diagnostic Point Score

Legionella highly probable: >10

Legionella probable: 5-10

Legionella unlikely: <5

Na = sodium; PO, = phosphate; SGOT/SGFT = serum glutamic-oxaloacetic transaminase/serum glutamic-pyruvic transaminase. Datafrom Cunha BA: Clinical features of Legionnaires' Disease. Semin Respir Infect 13:116, 1998.

shows that organisms that are not shown by the usual diagnostic methods are in fact the same ones that are easily demonstrable with conventional microbiologic techniques, the desired spectrum is not altered in such patients, and there is no need to add additional coverage with the presumption that these organisms are unusual or exotic gram-negative aerobic pathogens.68,lZ3 For all of these reasons, empiric coverage should be directed against S. pneumoniae, H . injuenzae, and M . catarrhalis among the typical bacterial

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Table 5. DIAGNOSTIC APPROACH TO COMMUNITY-ACQUIRED PNEUMONIA

Diagnosis Rule out tracheobronchitis and upper respiratory infections Establish diagnosis by physical examination and chest radiograph Rule out mimics of CAP by chest film or CT scan Diflermtiate typical from atypical CAP Typical CAP-no extrapulmonary features Atypical CAP-extrapulmonary features Rule out or rule in zoonotic atypical pathogens from nonzoonotic atypical pathogens by positive or negative history of recent close contact with appropriate vector Diagnostic workup Typical CAP Sputum Gram’s stain/culture (except in chronic bronchitis) Blood cultures Thoracentesis if otherwise unexplained pleural effusion present Atypical CAP Zoonotic atypical pathogens Do not send blood cultures Appropriate acute serology (followed by convalescent titers in 6-8 weeks) Serum transaminases Non-zoonotic atypical pathogens Determine if relative bradycardia is present or absent Serum transaminases Serum phosphorus If Legionella suspected Direct fluorescent antibody of sputum for Legionella (if productive cough or no previous anti-legionella antibiotics) Urinalysis for microscopic hematuria If Mycoplasma suspected Acute IgM Mycoplasma titer followed by convalescent IgM and IgG titers in fj-8 weeks Cold agglutinin titers If Chlamydia pneumoniae suspected Acute specific IgM and IgG C. pneumoniae titers followed by convalescent IgM and IgG titers in 4-5 weeks Assess sensitivity Mild CAP Treat as outpatient Mild + moderate to severe CAP Admit for workup and therapy Severe CAP Admit to intensive care unit for workup and therapy Rule out underlying new or acute exacerbation of pre-existing cardiac or pulmonary disease to explain CAP severity If no cardiopulmonary explanation, evaluate patient for disorders associated with decreased splenic function to explain severity of CAP Antimicrobial therapy same regardless of severity of CAP Assess host defenses Most compromised hosts have common pathogens causing CAP Compromised hosts often have a more severe or prolonged clinical course of CAP Antimicrobial therapy same as for normal hosts

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Table 6. DIFFERENTIAL DIAGNOSIS OF SEVERE COMMUNITY-ACQUIRED PNEUMONIA PRESENTING WITH SHOCK

CAP does not present with shock in normal hosts Look for cardiopulmonary cause or decreased splenic function if CAP presents with shock Disorders associated with impaired splenic function Hyposplenism of the elderly Chronic alcoholism Amyloidosis Chronic active hepatitis Fanconi’s syndrome IgA deficiency Intestinal lymphangiectasia Myeloproliferative disorders Waldenstrom’s macroglobulinemia Non-Hodgkin’s lymphoma Celiac disease Regional enteritis Ulcerative colitis Sezary’s syndrome Congenital asplenia Sickle cell trait/disease Splenic infarcts Splenic malignancies Systemic mastocystosis Rheumatoid arthritis Systemic necrotizing vasculitis Thyroiditis Steroid therapy Gamma globulin deficiency Splenectomy If CAP presents with shock in the absence of conditions associated with hyposplenism, look for mimics of pneumonia that present with pulmonary infiltrates, fever, leukocytosis, and hypotension, such as acute myocardial infarction or acute pulmonary embolism If CAP presents with shock and without evidence of hyposplenia or acute myocardial infarction or acute pulmonary embolism, consider an exacerbation of pre-existing cardiopulmonay disease that may present with hypotension (e.g., coronary insufficiency, hypoxemia with emphysema) CAP severity is not related to microbial virulence factors or unusual gram-negative organisms. CAP, if severe, is related to the cardiac, pulmonay, or splenic dysfunction of the host Datafrom Cunha B A Strategies for managing severe community-acquired pneumonia. J Crit Illness 12711-721, 1997; with permission.

pathogens and should include coverage of the nonzoonotic atypical pathogens, particularly Legionella?,18, 2o Most antibiotics with anti-legionella spectrum also are effective against M. pneumoniae and C. pneumon i ~ e . 241,~52~ Because the zoonotic atypical pathogens causing tularemia, psittacosis, and Q fever are geographically limited or require specific vector contact, routine empiric coverage need not include activity against these organism^.^^ Aspiration pneumonia presenting as CAP does not require any special therapeutic consideration. Although multiple species of anaerobic organisms that normally colonize the oropharynx cause community-

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acquired aspiration pneumonia, all of these anaerobes are sensitive to penicillin, p-lactams, and virtually all antibiotics that would be used to treat respiratory tract infections. Penicillin is effective against Bucteroides species causing aspiration pneumonia. The so-called oral pigmented Bucteroides (e.g., Prevotellu (Bucteroides) rneluninogenicus) are important pathogens in aspiration pneumonia but do not require specific anti-B. frugilis coverage (e.g., metronidazole, clindamycin, trovafloxacin, moxifloxacin, penicillin, p-lactamase inhibitor combinations, or carbapenems).13,17, In terms of spectrum, these anti-B. frugilis antimicrobials should be used primarily below the waist in anaerobic infections involving the abdomen or pelvis, where B. frugilis is a key pathogen.28, 49, 57 Clinical experience and the Spanish study re-emphasize that CAP pathogens are the same in normal and compromised hosts. Patients presenting with lymphomas, solid-tumor malignancies, and leukemias have the same pathogen distribution as immunocompetent patients with CAP.'" Similarly, nonleukopenic compromised hosts (i.e., patients with diabetes mellitus, patients with uremia, choronic alcoholics, patients with SLE, and patients with impaired or absent splenic function) have the same pathogen distribution as normal hosts., Patients who have become leukopenic recently secondary to chemotherapy have the same pathogen distribution as normal patients when presenting with CAP. This situation is in contrast to patients with febrile leukopenia in the absence of pneumonia, whose major infectious problems are gram-negative bacillary bacteremias, or after 2 weeks of antibiotic-treated neutropenia, when fungemias become a potential problem. From an antimicrobial spectrum standpoint, any of the antibiotics selected for empiric coverage of CAP should have a high degree of activity against S. pneumoniue, H. influenzue, M . cuturrhalis, L. pneurnophilu, M . pneurnoniue, and C. pneurnoniue. Coverage against oral anaerobic organisms in community-acquired aspiration pneumonia is achieved readily with any antibiotic active against these organisms, and anti-B. frugilis coverage should not be included in an empiric CAP treatment regimen.

Multiple Pathogens

Usually, one microbial species is responsible for each infectious disease.l8< 19,l" In pulmonary infections, this relationship holds true with the exception of aspiration pneumonia or anaerobic lung abscess. Anaerobic infections of the lungs are due to a mixed oropharyngeal anaerobic flora that is polymicrobial. Anaerobic oropharyngeal flora, when aspirated, becomes the pathogenic flora responsible for anaerobic lung infectiolls*18. 19 *References9, 32, 54, 64, 73, 84, 87, 96, 98, 105, 110.

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Severity Factors

The severity of CAP depends on the extent and severity of preexisting lung disease and cardiac function and on the degree of impaired splenic function (i.e., decreased B lymphocyte function). These host factors, singly or in combination, are the primary determinants of severity in CAP.59Relatively avirulent pulmonary pathogens (e.g., M . catarrhalis) are capable of causing severe pneumonia when infecting severely damaged lungs of a patient with advanced chronic bronchitis? Although it is true that pneumococci are more virulent than other communityacquired pulmonary pathogens, virulence is a minor determinant of severity in CAP.30,83, lo9 The clinical severity of a patient with CAP depends on the host factors mentioned and does not depend on the infecting organism. For this reason, overwhelming pneumococcal sepsis in an asplenic patient is treated the same as in an immunocompetent patient with pneumococcal infection. No additional antibiotic coverage is needed or desired in patients with severe CAP because the severity of the infection is host factor dependent and is not corrected by increasing number or spectrum of antibiotics. The therapeutic concept is simple: The treatment, in terms of the agent and dosing regimen, is the same for mild-to-moderate CAP as for severe CAP.34,37 A variety of indices of severity have been devised to quantitate the severity of CAP. These indices are useful as prognostic indicators and predict a prolonged clinical course, duration of hospital stay, and poten81, 95, 99, lol Severity indicators have no place in the tial complications.60, selection of an antibiotic for CAP. Because empiric antibiotic selection is based primarily on spectrum and antimicrobial activity, expanded coverage and double-drug coverage are unnecessary and wasteful and should be discouraged because they cannot correct the host factors that are the major determinants of CAP severity.34,35, 76, 96 747

Pharmacodynamic Considerations

Because antibiotics concentrate in the lungs, virtually all antibiotics used to treat pulmonary infections achieve therapeutic concentrations in the lungs. Because the lungs are vast capillary beds, antibiotic concentrations in the lungs approximate simultaneous serum levels. Certain antibiotics, such as aminoglycosides, reach the lungs in adequate concentrations but are less active in areas of pulmonary infection because aminoglycoside activity is decreased in the presence of white cell exudate, local hypoxia, and local acidosis.19,25, 28, 37 In an attempt to predict antibiotic effectiveness data, several in vitro indices have been devised. The most useful predictor of clinical efficacy is the ratio of serum and tissue levels to the minimal inhibitory concentration (MIC) of the organism. This ratio has been variably termed the kill ratio, inhibitory index, or inhibitory quotient. A ratio of area under the curve (AUC) to MIC also has been

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used to predict efficacy. Clinical experience compared with AUC/MIC9,, predictors does not seem to be better than kill ratios (i.e., serum concentration/MICgO).This ratio also has been applied to predict the resistance potential of antibiotics, with low ratios of less than or equal to 45. Fluoroquinolones with higher ratios have exactly the same outcomes as levofloxacin.ll2z114, Il5, 130 Neither clinical failures nor resistance has been reported with levofloxacin in the treatment of CAP. Similarly, with plactam antibiotics used to treat pulmonary infections, the AUC/MIC ratio may predict efficacy but not resistance potential. AUC/MIC does not predict resistance potential among cephalosporins any more than among fluoroquinolones (e.g., ceftazidime). Ceftazidime, regardless of dosing regimen, is associated with the development of P. aeruginosa resistance. Because antibiotic resis tance is ugent specific, resistance potential remains in spite of modifying the dosing regimen to improve AUC/ MIC ratios.37, 43 Bacteriostatic Versus Bacteriocidal Antibiotics

Using in vitro kill time studies, there are no differences in the rates of microbial elimination or differences in efficacy of microbial cell death between bacteriostatic and bacteriocidal agents. Using therapeutic concentrations against pulmonary pathogens (e.g., s. pneurnoniae, H. infuenzae, M . catarrhalis), bacteriostatic drugs, such as doxycycline, kill with the same rapidity and efficacy as bacteriocidal drugs, such as p-lactams. Attention should be paid to dosing regimens that vary with concentration-dependent or time-dependent antibiotic killing kinetics. A dose of 200 mg every 12 hours of doxycycline provides optimal concentration52 dependent killing kinetics and maximal bacterial killing.51* Concentration-d~endent killing kinetics is defined as an increase in bacterial killing as the concentration exceeds 4 to 6 times the MIC of the organism in a dose-dependent fashion. Time-dependent kinetics show that bacterial eradication with serum concentrations 4 times the MIC does not enhance bacterial killing. These pharmacodynamic parameters are not related to mechanism of action (i.e., bacteriostatic versus bacteri43 cidal action).41, Antibiotic Resistance Potential

There is concern about antibiotic resistance to typical CAP pathogens. Since the 1970s, virtually all strains of M . catarrhalis have become p-lactamase producers. Ampicillin-resistant H. infuenzue are prevalent in many geographic locations.* The main concern is with S. pneurnoniue, however, which remains the most important bacterial pathogen causing upper and lower respiratory tract infections.2,11, 36* 55, 65, 88 *References 55, 63, 72, 85, 86, 89, 92, 103, 107, 124.

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Penicillin-resistant S. pneumoniae rates depend on the definition used to establish breakpoints for sensitive and resistant strains. Currently, pneumococcal strains with an MIC less than 1 pg/mL are termed sensitive strains. S. pneumoniae isolates with a sensitivity of 1 to 2 pg/mL are termed intermediate strains. Pharmacokinetically, these strains should be considered as sensitive and grouped with the sensitive strains, but usually they are grouped with the resistant strains. Because most strains of penicillin-resistant pneumococci are in the intermediate susceptibility group, this causes the number of penicillin-resistant strains to appear large. Relatively pencillin-resistant strains also means that these same strains are relatively penicillin sensitive. Antibiotic susceptibilities are concentration dependent, including relatively penicillin-resistant streptococci. Strains of S. pneumoniae showing intermediate sensitivity are eradicated easily using conventional dosing regimens that achieve serum and tissue concentrations greater than 1 to 2 pg/mL needed to eradicate these organisms from the blood and serum. Strains that are termed resistant (i.e., with an MIC 22 pg/mL) are eradicated easily from most infected sites because serum and tissue concentrations are achieved readily that are 2 to 4 times greater than the MIC of such resistant 77 strains.50* Depending on the breakpoints selected, the percentage of penicillinresistant pneumococcal strains varies widely. If the breakpoint of 2 pg/ mL is used to divide sensitive from resistant strains, the number of penicillin-resistant strains greatly diminishes from 30% to 50% to 5% or less. Among the penicillin-resistant strains using the 2 pg/mL breakpoint, most of these strains are susceptible to clinically achievable therapeutic concentrations in serum and lung.n Although penicillin-resistant pneumococci are not a therapeutic problem at present, the potential for the emergence of truly highly penicillin-resistant strains should be kept in mind. The selection of an antibiotic with little or no resistance potential to treat CAP is crucial, to minimize the emergence of highly penicillin-resistant pneumococci. The increase in intermediate and resistant strains of S. pneurnoniae may be due to the overuse of p-lactam antibiotics. Because p-lactam antibiotics act on bacterial cell wall synthesis, and penicillin resistance is mediated through altered penicillin binding proteins, it would be prudent to shift the bulk of antibiotic use to non-cell wall active agents that act intracellularly. Doxycycline and the respiratory fluoroquinolones should continue to prevent further pneumococcal penicillin resistance. The literature regarding fluoroquinolone resistance with S. pneurnoniae is related to ciprofloxacin, but not the other fluoroq~inolones.4~~ 79, 82, ll1 Most article titles do' not specify which fluoroquinolone is responsible for the resistance problem so that the misconception that fluoroquinolone use per se is associated with penicillin-resistant pneumococci is perpetuated falsely.47,50, With respect to resistance, the fluoroquinolone that has been studied most intensely over time is levofloxacin. Thousands of strains from hundreds of U.S. hospitals have been analyzed over time to detect resistance among respiratory pathogens, and expect-

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edly no resistance problems were found.'ll Levofloxacin, a respiratory quinolone, is one antibiotic, similar to doxycycline, that has not been associated with resistance problems regardless of volume of use as lI4, lz6 lo2, shown in U.S. and Canadian studies.82, Doxycycline has been used extensively worldwide for 3 decades and remains effective against P-lactamase-producing strains of M . catarrhah, ampicillin-sensitive strains of H. influenzae, and penicillin-resistant S. pneumoniae. Doxycycline has been shown to be effective against highly resistant strains of S. pneumoniae. Certain antimicrobials, not classes of antibiotics (e.g., tetracyclines), have been associated with antimicrobial resistance.46,50 Among the tetracyclines, only tetracycline has been associated with penicillin-resistant pneumococci, but not doxycycline or minocycline.12, Among the fluoroquinolones, ciprofloxacin is the only fluoroquinolone associated with S. pneumoniae resistance problems as well as resistance to other organisms (e.g., P. aeruginosa, aerobic gram-negative 40 Certain agents in each antibiotic class have been associated ba~illi).~, with resistance problems, but other antibiotics within the class have not been associated historically with resistance problems. The unrestricted use of antibiotics not associated with resistance problems (e.g., cefprozil, doxycycline, levofloxacin, cefepime, meropenem) has not resulted in the emergence of penicillin-resistant pneumococci or other organisms.40,47, Macrolides should not be used as monotherapy in CAP. All macrolides (i.e., erythromycin, clarithromycin, azithromycin) are naturally resistant to approximately 25% of strains of S. pneumoniae. Macrolide use increases acquired resistance to S. pneumoniae and H. influenz~e.~~, 28* 34* The selection of an antibiotic for CAP should take into account resistance potential, especially with regard to penicillin-resistant pneumococci. The antibiotic selected should have little or no potential for increasing penicillin-resistance among pneumococcal strains (Table 7)!", 116

Table 7. PENICILLIN-RESISTANT STREPTOCOCCUS PNEUMONIAE: ANTIBIOTIC RESISTANCE POTENTIAL Natural Resistance

Acquired Resistance

All macrolides (-25% resistant)

Some p-lactams TMP-SMX Tetracyclines Ciprofloxacin Clarithromycin Azithromycin

~~

~

TMP-SMX

~~~

=

Trimethoprim-sulfamethoxazole.

Little/No Resistance Potential Preferred Therapy Levofloxacin Alternate Therapy Doxycyc1ine Clindamycin Imipenem Meropenem Cefepime Vancomycin Linezolid

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Antibiotic Side Effects

The side effects of antimicrobial agents should be taken into account in selecting an agent in CAP. Side effects have untoward effects on the patient, the hospital, and the health care system. Aside from minimizing adverse effects on patients to decrease their discomfort and enhance well-being, adverse side effects have medicolegal significance for the physician as well as the hospital. Avoiding life-threatening side effects is important. Non-life-threatening side effects prolong hospitalization and have important economic implications. Any side effect that prolongs hospitalization increases the cost of health care for the hospital and for health care in genera1.Q 43 The most important side effects from an institutional and economic perspective include seizures, phlebitis, hepatotoxicity, drug fevers, cutaneous drug reactions, isolated cytopenias (e.g., leukopenia, anemia, or thrombocytopenia), and antibiotic-associated diarrhea.14,23,24, 41 Other side effects are encountered occasionally, but these are the most common and the most important from a pharmacoeconomic standpoint.'j,48 Clinicians preferentially should avoid agents with an adverse safety profile and select another agent with a good safety profile for CAP (Table 8)?7,42,43 Table 8. COMMUNITY-ACQUIRED PNEUMONIA: THERAPEUTIC PRINCIPLES

Pathogens Single pathogens cause CAP Multiple pathogens rarely, if mer, cause CAP CAP is rarely due to more than one typical or two atypical organisms or multiple typical and atypical organisms. Studies describing multiple pathogens are flawed and demonstrate one organism microbiologically with serologic evidence of prior exposure to the other pathogen. CAP is usually due to a single pathogen as clinical experience has shown for decades The only cause of multiple-pathogen CAP is aspiration pneumonia Comorbid conditions Comorbid conditions do not affect selection of antimicrobial therapy Monotherapy is as effective as multiple-drug therapy The addition or change of antibiotics because of severity of illness or comorbidities makes little sense Antimicrobial therapy is directed against the pathogen, not comorbid conditions Comorbidity is an important prognostic factor but has no place in antibiotic selection Severity The severity of CAP is determined by the underlyingfunctional capacity of the lungs, heart, and spleen Do not change antibiotics or use additional antibiotics to treat severe CAP Additional antibiotics do not affect pulmonary, cardiac, or splenic dysfunction, which determines clinical severity CAP presenting with hypotension or shock is usually due to underlying lung disease, cardiac disease, acute myocardial infarction, or exacerbation of congestive heart failure Antibiotic monotherapy is the same for mild, moderate, or severe CAP Appropriate empiric coverage No need to cover S. aureus, Klebsiella, or P. aeruginosa in CAP (most CAP regimens include K. pneumoniae coverage) Table continued on opposite page

COMMUNITY-ACQUIRED PNEUMONIA

61

Table 8. COMMUNITY-ACQUIRED PNEUMONIA: THERAPEUTIC PRINCIPLES (Continued)

No need to cover oral anaerobes in community-acquired aspiration pneumonia Virtually all antibiotics used to treat community-acquired aspiration pneumonia are effective against oral anaerobes. B. fragilis coverage, with metronidazole, clindamycin, or moxifloxacin is unnecessary Coverage should include typical (S. pneumoniae, H. influenzae, M . catarrhah) and atypical (Legionella,Mycoplasrna, C. pneumoniae) pathogens Nursing homeacquired pneumonia should be treated as CAP. Nursing home-acquired pneumonia pathogens most closely resemble CAP, not hospitalacquired pneumonia pathogens (e.g., P. aeruginosa) Therapeutic considerations Monotherapy coverage of typical and atypical pathogens in CAP is preferred to double-drug therapy Monotherapy is less expensive and as effective as double-drug regimens Avoid empiric macrolide monotherapy because approximately 25% of S. pneumoniae are naturally resistant to all macrolides Preferred monotherapy for CAP is levofloxacin or doxycycline Least expensive way to treat CAP optimally No increased resistance with extensive use No serious side effects; well tolerated IV or PO Ideal monotherapy for IV-to-PO switch from a patient compliance, safety, and cost perspective In CAP patients able to take PO medication, switch from IV to PO if clinically improved after 48 hours to antibiotic with the appropriate spectrum, high bioavailability, few gastrointestinal side effects, little or no resistance potential, and relatively low cost, (eg., levofloxacin) Penicillin-resistant S. pneumoniae Most penicillin resistance is relative resistance and is caused by overuse of P-lactams Penicillin-resistant S. pneumoniae (MIC 2 2 pg/mL) may be treated with levofloxacin, cefipime, meropenem, or linezolid Vancomycin rarely needed. Highly penicillin-resistant S. pneumoniae (MIC 210 &mL) remain uncommon MICs and minimal inhibitory concentrations If an organism is susceptible to an antibiotic, provided that achievable serum concentrations are 2 2 X the MIC, MIC differences are not clinically relevant. Respiratory Quinolones

S. pneumoniae MIC

Achievable Serum Concentrations

Clinical Outcome

Levofloxacin Gatifloxacin

1.0 pg/mL 0.5 pg/mL

6 pg/mL 6 pg/mL

Gold standard Same as standard

Respiratory quinolones against S. pneumoniae Respiratory Quinolones

Relative AUClMlC Ratios

Clinical Outcome

Levofloxacin Gatifloxacin Gemifloxacin

+++ ++++ +++++

Gold standard Same as standard Same as standard

Antibiotics with high AUC/MlC ratios have no clinical advantage or decreased resistance over those with lower ratios Serum concentration: MIC ratios ( 2 2 X MIC) remain the time-tested predictor of clinical effectiveness with quinolones (concentration dependent killing kinetics) AUC-to-MIC ratios are not a better predictor of outcome than serum concentration-toMIC ratios

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Monotherapy Versus Combination Therapy Monotherapy always is preferred to combination therapy. Polypharmacy using two or more antibiotics increases the chances of missed doses, increases the potential for adverse drug reactions, increases the potential for drug interactions, and is always more expensive than properly selected equivalent monotherapy. Combination therapy may be used when the spectrum of each antibiotic is inadequate in the clinical situation (e.g., ceftriaxone plus erythromycin or azithromycin for the treatment of CAP). Macrolides are active against the atypical pathogens, particularly Legionella, but approximately 25% of S. pneumoniue strains are naturally resistant to all macrolides (e.g., erythromycin, clarithromycin, and azithromycin). Because S. pneumoniue is the most important organism causing upper and lower respiratory tract infections, macrolides should not be used for monotherapy for respiratory tract infections unless the organism is known not to be S. pneumoniue. Macrolide-resistant S. pneumoniue is not an acquired resistance problem. Macrolides are deficient in their spectrum against S. pneumoniue, and this is independent of volume of use. The use of macrolides may increase resistance to other organisms but not S. pneumoniue. Because of this defect in gram-positive coverage against S. pneumoniue, macrolides often are combined with plactams (e.g., ceftriaxone). Ceftriaxone as a p-lactam antibiotic has no activity against atypical pathogens and should not be used alone because of the increasing importance of atypical pathogens (e.g., Legionella, Mycoplasma, and C. pneumoniue). Ceftriaxone/macrolide combination therapy regimens have been used to treat CAP, but have several disadvant a g e ~ .43~ ~ , There are disadvantages to using ceftriaxone plus azithromycin for CAP. First, in terms of adverse effects, ceftriaxone commonly is associated with Clostridium dificile and non-C. dificile diarrhea. Ceftriaxone also may cause pseudobiliary lithiasis. Azithromycin has fewer gastrointestinal side effects than the other macrolides but has a higher incidence of gastrointestinal side effects than most non-macrolide antibiotics. If erythromycin is used with ceftriaxone, intravenous erythromycin therapy often is complicated by phlebitis or diarrhea. Intravenous erythromycin has been associated with cardiac abnormalities (e.g., QT, interval abnormalities, torsades de pointes).23,24, 43,93 Some p-lactams may increase penicillin resistance among pneumococci, and macrolides increase cephalosporin resistance to S. pneumoniue and H. influenzue. In this era of managed health care, ceftriaxone plus erythromycin or azithromycin is much more expensive than equivalent monotherapy. Doxycycline monotherapy is associated with fewer side effects, has little or no resistance potential, and is less expensive than parenteral erythromycin alone or the combination of ceftriaxone plus azithromycin. In CAP, among the respiratory fluoroquinolones, levofloxacin is less expensive than ceftriaxone/azithromycin combination 427

COMMLTNITY-ACQUIRED PNEUMONIA

63

therapy. Respiratory quinolones are not associated with resistance problems, have few if any side effects, and are substantially less expensive than combination therapy.40,46, 47 Monotherapy has an additional advantage in intravenous (IV)-tooral (PO) switch 53 Patients who are not severely ill who are admitted to the hospital with CAP usually are switched to oral therapy after clinical defervescence, usually within 48 hours of admission.12*The oral equivalent of ceftriaxone and azithromycin is suboptimal in terms of inconvenience, side effects, and higher cost. Because there is no oral equivalent of ceftriaxone, a relatively expensive oral third-generation cephalosporin must be used in its place. Oral erythromycin and clarithromycin have too high an incidence of side effects to consider for oral transition therapy. Azithromycin has the best side-effect profile among the macrolides but still has a relatively high incidence of nausea, vomiting, abdominal discomfort, and diarrhea. In addition, the patient is still required to take two antibiotics, which together are more expensive than a monotherapy equivalent. Doxycycline, levofloxacin, and gatifloxacin are ideal agents for CAP PI-to-PO switch programs. These antibiotics offer the advantages of a single antibiotic that may be taken once or twice a day (e.g., doxycycline) or once daily (e.g., levofloxacin or gatifloxacin) with fewer side effects. Monotherapy reduces pressure on IV teams and decreases the cost of treatment of CAP in hospitalized patients. In ambulatory patients with CAP, patient compliance is enhanced with one rather than two antibiotics. The patient is more likely to take an antibiotic once daily than three or four times daily. Appropriate monotherapy is less expensive and always preferred to combination therapy (Table 9).ll8,119 Antibiotic Costs

In hospitalized patients, the cost of an antibiotic to the institution and the health care system is based on several factors. Best known is the acquisition price of the antibiotic to the hospital pharmacy. This price often is used as the basis for comparing costs among antibiotics. Acquisition cost is a relatively unimportant part of the cost calculations. Often overlooked in cost comparisons is the cost of administration of antibiotic therapy. The cost of administering an antibiotic intravenously is dose dependent. In the United States the average cost per dose of intravenously administered antibiotics to the hospital is $10. Although this figure may vary in different locations, it is the national average. If a drug has a short dosing interval (e.g., penicillin G) that requires administration every 4 hours, the cost of administering intravenous penicillin per day is 6 X $10 = $60 for administration of the antibiotic alone. Compared with the daily administration cost of IV penicillin (< $5/d), the acquisition cost of the drug is a minor cost factor. Given antibiotics with similar spectrum of activity, resistance potential, and side-effect profile, the clinician should choose the IV antibiotic with the

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Table 9. COMMUNITY-ACQUIRED PNEUMONIA AND EMPlRlC ANTIMICROBIAL THERAPY IN NORMAL AND COMPROMISED HOSTS CAP Hosts

Normal hosts

Compromised hosts Diabetes mellitus SLE/collagen vascular diseases Cirrhosis Uremia Solid-tumor malignancies CLL/CML Lymphomas Multiple myeloma HIV* Focal/segmental pulmonary infiltrates with mild/moderate 1 CD, counts (negative sputum for AFB) Special populations Elderly

Nursing homeacquired pneumonia (NHAP)

Intravenous drug abuserst

Cystic fibrosis or bronchiectasis Post-viral influenza

Usual Pathogens

Optimal Empiric Monotherapy

Typical S. pneumoniae H.influenzae M.catarrhalis Atypical Legionella M.pneumoniae C. pneumoniae Typical S. pneumoniae H. influenzae M.catarrhalis Atypical Legionella M.pneumoniae C. pneumoniae

Levofloxacin or Doxycyc1ine

Typical S. pneumoniae H.influenzae Salmonella Atypical Legionella M.pneumoniae C. pneumoniae

Levofloxacin

Typical S. pneumoniae H. influenzae M.catarrhalis Atypical Legionella C. pneumoniae Typical S. pneumoniae H. influenzae M. catarrhalis Atypical Legionella C. pneumoniae Typical S. pneumoniae H. influenzae M. catarrhalis P. aeruginosa

Levofloxacin or Doxycycline

S. maltophilia B. cepacia S. aureus S. pneumoniae H. influenzae

TMP-SMX

Levofloxacin or Doxycyc1ine

Levofloxacin or Doxycycline

Cefepime or Meropenem Cefepime

Nafcillin plus Levofloxacin Table continued on opposite page

COMMUNITY-ACQUIREDPNEUMONIA

65

Table 9. COMMUNITY-ACQUIRED PNEUMONIA AND EMPlRlC ANTIMICROBIAL THERAPY IN NORMAL AND COMPROMISED HOSTS (Continued) CAP Hosts

Bone marrow transplants

Solid-organ transplants

Febrile neutropenia

Usual Pathogens

Optimal Empiric Monotherapy

Typical S. pneumoniae H. influenzae P.aeruginosa Atypical Legionella Typical S. pneumoniae H. influenzae P.aeruginosa Atypical Legionella Typical P.aeruginosa**

Cefepime plus Levofloxacin

Cefepime plus Levofloxacin

Cefepime or Meropenem

*Bilateral diffuse or perihilar infiltrates with mild-to-moderate decreased CD, counts should suggest Pneurnocystis carinii pneumonia and not typical or atypical causes of CAP. Empiric therapy is with TMP-SMX or pentamidine. Caution: HIV patients with focal or diffuse infiltrates with low CD, counts do not suggest any specific organism. Tuberculosis or Mycobacteriurn avium-intracellulare should be ruled out. If AFB sputum smears are negative, then lung biopsy is needed for a specific diagnosis and therapy. **Withleukopenia postchemotherapy. tPulmonary infiltrates secondary to tricuspid valve endocarditis is not a CAP but represents septic pulmonary emboli. CAP = Community-acquired pneumonia; SLE = systemic lupus erythematosus; CLL = chronic lymphocytic leukemia; CML = chronic myelogenous leukemia; HIV = human immunodeficiency virus; AFB = acid-fast bacilli; TMP-SMX = trimethoprim-sulfamethoxazole.

longest half-life and dosing interval to decrease the institutional cost related to frequency of administration. Polypharmacy increases costs related to frequency of administrati~n.~~. 94 Using a common regimen as an example (ceftriaxone/macrolide regimens), ceftriaxone administered as 1 g intravenously every 24 hours costs $27 (acquisition cost) plus $10 (administration cost) for a total daily cost to the institution of $37 per day. Erythromycin commonly is administered with ceftriaxone; the acquisition cost of erythromycin is $10 per day. Erythromycin lactobionate administered intravenously is 1 g every 6 hours. The IV administration of erythromycin results in an administration cost of $40, which must be added to the $10 acquisition cost of the antibiotic; this results in a total cost per day to the institution of $50 for IV erythromycin. If one uses ceftriaxone/erythromycin combination therapy for the treatment of CAP, the cost to the institution is $87 per day. IV azithromycin costs approximately $20 per 500 mg dose, and $10 per dose is the administration cost, resulting in a total daily cost of $30 per day for intravenously administered azithromycin. The substitution of azithromycin in place of erythromycin results in some cost reduction, but the combination is still needlessly expensive at $67/day.

Monotherapy with levofloxacin 500 mg ($19) administered intravenously every 24 hours (administrative cost = $10) results in a total cost of $29 per day.4143. 118,119 Other cost factors are difficult to calculate but add to the hospital's cost of administering antibiotics and impact on the health care system in general. The cost of antibiotic side effects should not be minimized. Side effects that prolong hospitalization result in decreased reimbursement. Antibiotic side effects that have important economic implications are phlebitis, antibiotic-associated diarrhea (C. dijjicile and non-C. dijjicile), drug fevers, cutaneous drug reactions, hepatotoxic reactions, neurotoxicity, cytopenias (e.g., pancytopenia, leukopenia, anemia, thrombocytopenia), and drug-induced pancreatitis. Drug-associated diarrhea requires placing the patient on enteric precautions, then obtaining the appropriate diagnostic tests, which usually include a variety of stool examinations, including C. dijjiciZe toxin assays. The empiric treatment usually is initiated with oral metronidazole or vancomycin in the case of C. dijjicile diarrhea. IV metronidazole must be used if C. dijjicile colitis is present. In C. dijjicile colitis, a variety of radiographic examinations must be added to the cost of administering the causative antibiotic. The therapeutic cost must be added to the cost of the diagnostic workup.6,20 The cost of therapeutic failure often is overlooked as a cost determinant. For example, if empiric monotherapy for CAP is initiated with a drug with an inadequate spectrum (e.g., azithromycin) and S. pneurnoniae is the pathogen, the patient may not improve clinically, and prolonged hospitalization may result. The delay in effective therapy may have important implications in terms of morbidity, which also have cost implications. The potential therapeutic failures have to be re-treated with an antibiotic that is effective against the organism not covered with the initial inadequate antibiotic. Acquisition and administrative costs must be added to the cost of using a suboptimal antibiotic initially. It has long been appreciated that the earlier that CAP is treated, particularly penumococcal pneumonia, the better the prognosis. Delay in initiation of therapy or initiation of suboptimal therapy has important implications for the individual patient, and affects health care Although the side effects mentioned earlier do not occur in every case, they are cost-additive factors to health care. These factors multiply the cost of antibiotic therapy by requiring additional laboratory tests for long hospitalization, additional therapies or interventions, and consultations, which should be considered when attempting to assess the true cost of an antibiotic, which is far more complex than simple analysis of the acquisition cost of the drug would indicate.31,42, 43 Wherever possible, bsing PO antibiotic therapy has important cost implications. In switching from IV to PO therapy, not only does the acquisition cost of the antibiotic become much less, but also the IV administration costs are eliminated. PO antibiotic therapy has the additional advantage of eliminating the costs associated with potential IV side effects (e.g., phlebitis, IV line (See Table 10.)

COMMUNITY-ACQUIRED PNEUMONIA

67

Table 10. EMPlRlC THERAPY OF HOSPITALIZED PATIENTS WITH COMMUNITYACQUIRED PNEUMONIA IN NORMAL AND MOST COMPROMISED HOSTS

Optimal regimens Monotherapy Doxycycline Effective against all typical and atypical pathogens, including penicillin-resistant S. pneumoniae Side effects PO-gastrointestinal upset IV-phlebitis if volume/diluent inadequate Inexpensive: 100-200 mg (IV) q12h-$5 (antibiotic cost) + $20 (IV charge)* = $25/d (total cost to institution) IV-to-PO switch therapy: excellent bioavailability (e.g., >90%) Most inexpensive regimen: compliance advantages of monotherapy 100 mg (PO) q12h = $6.44 (brand) 100 mg (PO) q12h = $0.20 (generic) Levofloxacin Highly active against all typical and atypical pathogens, including highly penicillinresistant s. pneumoniae Side effects: none Most cost-effective regimen: 500 mg (IV) q24h-$19 (antibiotic cost) + $10 (IV charge) = $29/d (total cost to institution) No need of additional coverage in normal or compromised hosts or those with severe CAP IV-to-PO switch Excellent bioavailability (e.g., 99-100%) Compliance advantages of monotherapy Relatively inexpensive: 500 mg (PO) q24h = $7.11/d Suboptimal regimens Monotherapy Ceftriaxone Covers typical pathogens, misses atypical pathogens Side effects Non-C. difficile diarrhea Pseudobiffary lithiasis Relatively expensive: 1 g (IV) q24h-$27 (antibiotic cost) $10 (IV charge) = $37/d (cost to institution) Azithromycin Misses approximately 25% of S. pneumoniae, should not be used alone, covers atypical pathogens Side effects Nausea vomiting Non-C. dificile diarrhea Low serum levels-slow onset/delayed therapeutic effect in CAP Relatively inexpensive: $20 (antibiotic cost) + $10 (IV charge) = $30/d (cost to institution) Combination therapy Ceftriaxone plus erythromycin-most expensive regimen Covers typical and atypical pathogens Side effects Nausea Vomiting Non-C. dificile diarrhea Phlebitis Cardiac effects (prolonged QT, interval) Pseudobiliary lithiasis Table continued on following page

+

68

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Table 10. EMPlRlC THERAPY OF HOSPITALIZED PATIENTS WITH COMMUNITYACQUIRED PNEUMONIA IN NORMAL AND MOST COMPROMISED HOSTS

(Continued) Most expensive dual drug combination: Ceftriaxone 1 g (IV) q24h ($27 $10) = $37/d plus Erythromycin 1 g (IV) q6h ($40 $10) = $50/d Total cost = $87/d (cost to institution) IV-to-PO switch therapy: disadvantage of double-drug therapy, relatively expensive and inconvenient Ceftriaxone plus azithromycin-most commonly used dual drug regimen Covers typical and atypical pathogens Side effects Nausea Vomiting Non-C. dzfficile diarrhea Phlebitis Cardiac effects (prolonged QT, interval) Pseudobiliary lithiasis Expensive: Ceftriaxone 1 g (IV) q24h ($27 $10) = $37/d plus Azithromvcin 500 mg (IV)q24h ($20 $10) = $30/d Total cost = $67/d Gost toainstiktion) IV-to-PO switch therapy: disadvantage of double-drug therapy, relatively expensive and inconvenient

+ +

+

*Intravenousadministration of antibiotics

+

=

$10/dose (national average) cost to the institution

Intravenous-to-Oral Switch Therapy

Patients that are moderately ill with CAP may be treated exclusively with appropriate oral antibiotic^.^^, 78 Patients who are hospitalized and do not require oxygen therapy, respiratory support, or other therapeutic interventions may be treated orally in the hospital setting. Severely ill patients with CAP and patients unable to absorb drug orally should be treated initially with IV antibiotic therapy.61The non-critically ill patients should be switched to equivalent PO therapy after 48 hours or as soon as the patient defervesces. Switching from IV to PO therapy has many advantages, but is particularly important from the standpoint of decreasing antibiotic costs, eliminating IV complications, and permitting earlier discharge.128 Some clinicians have been reluctant to use PO antibiotic therapy in a variety of infectious diseases, including CAP, because of the erroneous belief that IV antibiotics are more efficacious than PO equivalents. An antibiotic selected for PO antibiotic therapy used alone or as part of an IV-to-PO switch program should have the same spectrum, pharmacokinetics, low resistance potential, and excellent side-effect profile of its IV equivalent. The antibiotics selected for oral use must have excellent bioavailability so that serum and tissue levels approximate those achieved when administering IV antibiotics. Most IV antibiotics do not have oral equivalents (e.g., ceftriaxone), which limits options in IV-to27 PO switch program.26,

COMMLTNITY-ACQUIRED PNEUMONIA

69

Antibiotics that have excellent bioavailability but an inappropriate spectrum for CAP include clindamycin and metronidazole. Antibiotics that do not have good bioavailability include erythromycin and most p-lactams. Antibiotics that have excellent bioavailability include trimethoprim-sulfamethoxazole (TMP-SMX), doxycycline, minocycline, chloramphenicol, and the respiratory quinolones. Chloramphenicol and TMPSMX may be eliminated from consideration because of potential adverse effects and resistance potential. Certain antibiotics meet all the criteria, having proper spectrum, excellent bioavailability, low resistance potential, and good safety profile, but have no IV equivalent (e.g., cefprozil). Most cephalosporins have a lower bioavailability than other classes of antibiotics (e.g., doxycycline, respiratory quinolones). The ideal agents for the oral treatment of CAP and for use in IV-toPO switch programs include doxycycline or a respiratory quinolone (e.g., levofloxacin, gatifloxacin). These antibiotics possess an appropriate spectrum for treating all of the pathogens in CAP, including penicillinresistant pneumococci and atypical pathogens. These antibiotics have an excellent safety profile, have minimal resistance potential, and are relatively inexpensive. In terms of patient compliance, they may be administered on a once-daily or twice-daily basis (doxycycline) or on a once-daily basis (respiratory quinolones). Their widespread use (e.g., doxycycline, levofloxacin) has not resulted in increased antibiotic resistance to respiratory pathogens, particularly S. pneumoniue.26,27, 31-33 Duration of Treatment

CAP has traditionally been treated for 14 days. In the past, when courses of antibiotic therapy were achieved solely using the IV route, the duration of therapy had important economic implications. If a patient has to remain in the hospital for no other reason than to receive IV antibiotics for CAP, the cost implications for managed care are substantial. With the advent of IV-to-PO switch programs, the duration of antimicrobial therapy is a less important consideration. After switching to PO therapy, patients may be discharged earlier from the hospital, which has important cost implications on managed health care. Not only is PO therapy less expensive than equivalent IV antibiotic therapy, but also IV administration costs are eliminated. PO antibiotic therapy virtually eliminates added cost and hospital days resulting from phlebitis or IV line infection. If patients are discharged from the hospital, total duration of antibiotic therapy is relatively unimportant. Immunocompetent hosts usually are treated for 14 days of IV/PO therapy. Mild cases of CAP in healthy young hosts or elderly patients often require a longer course of therapy, (i.e., L 14 days of IV/PO therapy), which may be completed at home or at a nursing h0me.5~. 97, 128 Legionnaires’ disease usually is treated for 4 weeks to prevent replase. All other typical and atypical pulmonary pathogens are treated 94 as described.29*

THERAPEUTIC FAILURE

Properly selected and dosed antibiotics used to treat CAP should not result in therapeutic failure. Patients not responding to appropriate antibiotic therapy may be hosts with unrecognized underlying host defense defects (e.g., hyposplenism, lung disease, or heart disease). These are the same host factors in CAP that predict a complicated, prolonged, or severe course. The most common clinical problem is recognizing apparent therapy failure. Apparent therapy failure rarely is due to the emergence of resistant organisms but often is due to inadequate spectrum or treating usually noninfectious disorders mimicking CAP that appear to represent antibiotic failure incidence.47,50 Common disorders mimicking CAP include pulmonary infection resulting from pulmonary drug reactions, collagen vascular diseases (e.g., SLE), heart failure, bronchogenic carcinomatosis, lymphangitis spread or leukemia infiltrate (e.g., leukostasis), pulmonary emboli, atelectasis, or a previously existing pulmonary infiltrate of unknown cause. Repeated aspiration pneumonia often presents as antibiotic therapy failure. The cause of respiratory aspiration should be corrected, if possible, rather than adding or changing antibiotic the rap^?^^^, 35 SUMMARY

Optimal empiric therapy of CAP is with appropriate monotherapy (e.g., doxycycline, levofloxacin). Combination therapy is problematic because of potential side effects and high cost. Empiric coverage should have a high degree of activity against both typical and atypical pathogens. The antibiotic selected should have an excellent side-effect profile and be relatively inexpensive. Clinicians should be selective in their choice of antibiotic for CAP and choose an antimicrobial that has little or no resistance potential, is relatively inexpensive, and permits WtoPO switch monotherapy. References 1. Acar J: Broad- and narrow-spectrum antibiotics: An unhelpful categorization. Clin Microbiol Infect 3:395, 1997 2. Ailani RK, Agastya G, Ailani RK, et al: Doxycycline is a cost-effective therapy for hospitalized patients .with community-acquired penumonia. Arch Intern Med 159:266, 1999 3. Appelbaum PC: Antimicrobial resistance in Streptococcus pneumonia: An overview. Clin Infect Dis 1557, 1992 4. Appelbaum PC, Klepser ME: Role of the newer fluoroquinolons against penicillinresistant Streptococcus pneurnoniue. Infect Dis Clin Pract 8374, 1999 5. Baril L, Astagneau P, Nguyen J, et al: Pyogenic bacterial pneumonia in human immunodeficiency virus-infected inpatients: A clinical, radiological, microbiological and epidemiological study. Clin Infect Dis 26:964, 1998

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