Community-acquired pneumonia (CAP) is one of our most important diseases, and recent studies have shown that the annual incidence of CAP is 4.7 cases per 1000 adults in Spain and 7–10 cases per 1000 population in the United States, with >500,000 associated hospitalizations and 45,000 associated deaths occurring each year in the United States [1, 2]. More than 1.3 million patients with CAP were hospitalized in 1998, and 3.9 million ambulatory care visits to physician offices, outpatient departments, and emergency departments were made in 1997 in the United States [3, 4]. The estimated cost of an episode of CAP in an inpatient is $6000–$7000, compared with <\$200 for a case of CAP in a nonhospitalized patient [5]. Macrolides, which include the closely related azalides, are frequently prescribed for the treatment of outpatients with CAP [6].

Lonks et al. [7] described 19 patients who developed breakthrough pneumococcal bacteremia due to macrolide-resistant strains while receiving empirical treatment with orally administered macrolides. These 19 patients included 13 adults and 6 children seen at 3 US centers and 1 Spanish center in 1991–2000. The patients were receiving empirical treatment for CAP or other febrile illnesses. The macrolides administered included azithromycin, clarithromycin, erythromycin, and josamycin. Seventeen of the patients developed breakthrough bacteremia after receiving oral therapy for 2–9 days (mean duration of therapy before bacteremia developed, 3.9 days), and 1 patient developed bacteremia after receiving macrolides intravenously for 3 days (2 doses of cefuroxime were also administered intravenously), followed by azithromycin given orally for 2 days. The remaining patient had been receiving clarithromycin daily for >30 days. Fifteen patients had lobar pulmonary infiltrates noted at the time of breakthrough bacteremia, whereas 4 had no focus of infection. In addition, empyema was present in 2 patients and meningitis was present in another patient. All patients subsequently were successfully treated with intravenously administered β-lactams (18 patients) or vancomycin (1 patient).

Lonks et al. [7] also performed a case-control study of patients with pneumococcal bacteremia to determine whether any “controls” (i.e., patients with bacteremia due to a macrolide-susceptible pneumococcus) had experienced failure of macrolide therapy. This was achieved by matching each “case patient” (i.e., a patient with bacteremia due to a macrolide-nonsusceptible pneumococcus) with up to 2 controls on the basis of hospital location, sex, age, and year of presentation. If any controls had received macrolides, this would suggest that treatment failure was not directly related to macrolide susceptibility. Lonks and colleagues identified 141 case-matched controls, who were compared with 86 case patients. Whereas only 19 of the 86 case patients included in their report had received oral macrolides, as shown in the analysis discussed above, none of the controls had received macrolides before presentation with bacteremia (P < .001). This finding elegantly demonstrated that taking a macrolide was highly likely to be associated with treatment failure as a consequence of macrolide resistance. The only other statistically significant differences between the 2 groups were black race (none of the case patients vs. 11% of the controls; P = .015) and meningitis (12% of the case patients vs. 4% of the controls; P = .0059). The higher incidence of meningitis among case patients could be related to the virulence of the pneumococcal serogroups associated with macrolide resistance (macrolide resistance is predominantly found in serogroups 6, 9, 14, 19, and 23), whereas the pneumococcal serogroups associated with macrolide susceptibility (in the controls) were likely to be more widely distributed.

Evaluation of the significance of these findings needs to take the following factors into consideration: (1) the spectrum of pathogens associated with CAP and outcome on the basis of severity of disease; (2) the natural history of CAP, pneumococcal pneumonia, and bacteremia in various age groups; (3) the in vitro susceptibility of pneumococci to macrolides; and (4) the pharmacokinetic and pharmacodynamic properties of macrolides and the outcome of macrolide-susceptible and -resistant pneumococcal infections in animal models and in humans. Finally, these factors need to be integrated into recommendations for empirical treatment of CAP. These issues will be discussed in turn.

## Spectrum of Pathogens Associated with CAP and Outcome According to Severity of Disease

A review of 16 studies of CAP, each of which involved >100 patients, showed that Streptococcus pneumoniae was the most common cause of CAP identified in 14 of these studies [8]. Haemophilus influenzae was the second most common cause in 6 studies, followed by Legionella pneumophila and Mycoplasma pneumoniae. Allowing for the failure of older studies to recognize atypical or intracellular pathogens, a reasonable estimate of the distribution of pathogens in outpatients with CAP is 40%–60% for S. pneumoniae and 10%–20% each for H. influenzae, atypical or intracellular species, and other bacterial pathogens.

Disease severity also has a marked influence on the outcome of CAP. In the Pneumonia Outcome Research Team (PORT) study, 14,199 patients with CAP were stratified into 5 classes on the basis of disease severity [9]. Patients <50 years of age who had no underlying diseases, normal mental status, a pulse rate of <125 beats/min, a respiratory rate of <30 breaths/min, a systolic blood pressure of >90 mm Hg, and a temperature of 35°C–40°C were assigned to class I, whereas those who did not meet these criteria were assigned to classes II–V on the basis of a scoring system. This stratification was correlated with the mortality rate, which was 9.8% overall and increased by class: 0.1% for class I, 0.6% for class II, 2.8% for class III, 8.2% for class IV, and 29.6% for class V. This classification was recently validated by a study of 533 patients with CAP in Spain, where mortality rates, both overall and as stratified by PORT class, were very similar to those found in the PORT study [10].

## Natural History of CAP and of Pneumococcal Pneumonia and Bacteremia

Although these are important issues, there is a lack of adequate information about the untreated natural history of each major etiologic agent in CAP. The PORT study showed that the mortality rate correlates more closely with age, severity of disease, and presence of underlying diseases than with the pathogen involved. A report of the only CAP study to include a no-treatment arm was published in 1938: the mortality rate among untreated, hospitalized patients with acute-onset lobar pneumonia was 27%, compared with 8% among patients treated with sulfonamidopyridine, an early sulfonamide [11]. It is interesting to note that, even in this 1938 publication, the mortality rate was associated with age; in the treatment group, the mortality rate was 2.9% among patients 8–39 years of age and 19.4% among patients ⩾40 years of age, compared with rates of 16.2% and 50%, respectively, among patients in the untreated group. The mortality rate among hospitalized patients with pneumococcal bacteremia is currently still 10%–25% and is thought to result from irreversible disease processes and older age [12–14]. Conversely, death among outpatients with CAP essentially does not occur, because patients who do not respond to therapy are hospitalized [9]. However, the frequency of hospitalization of outpatients who do not respond to therapy is not well documented, although it has been estimated that 20% of patients for whom first-line therapy fails are hospitalized [15].

Data on variation in the outcome of CAP according to the pathogen involved are also difficult to find, particularly for outpatients, because disease resolves in virtually all outpatients and because placebo-controlled studies are not conducted for ethical reasons. Nevertheless, we can glean some information from CAP outpatient studies in which such agents as β-lactams were used to treat infections, such as M. pneumoniae infection, that are not affected by these agents. Several studies have shown no difference in outcome between treatment with antibiotics that do not provide coverage for these bacteria and those that do [16–18]. Factors that could discriminate among agents, such as speed of resolution, unfortunately are not included in these publications.

## In Vitro Susceptibility of Pneumococci to Macrolides

Pneumococci were initially highly susceptible to macrolides, with the MICs of erythromycin, clarithromycin, and azithromycin ⩽0.12 µg/mL [19]. However, resistant strains have emerged during the past 25 years, and 2 patterns of resistance are now common with the worldwide spread of resistant clones [6]. First, some strains have acquired the erm gene, which codes for a ribosomal methylase, and are usually highly resistant to macrolides, lincosamides, and streptogramin B agents (MLSB phenotype; MICs of >64 µg/mL), although MICs can be lower in inducible variants. Second, other strains have acquired the mef gene, which codes for a macrolide efflux pump, which does not affect lincosamides or streptogramin B agents (M phenotype; macrolide MICs of 1–64 µg/mL). On occasion, strains are also found that have other mechanisms of resistance, such as mutations in ribosomal binding sites of macrolides or in ribosomal proteins associated with amino acid chain elongation [20–23]. Isolates with the M phenotype predominate among macrolide-resistant pneumococci in the United States, whereas isolates with the MLSB phenotype predominate in most other countries [24]. Recent US studies have shown that 20%–30% of S. pneumoniae isolates are macrolide resistant, with two-thirds of resistant strains having the M phenotype and one-third having the MLSB phenotype [6, 25].

Current macrolide MIC breakpoints for pneumococci allow for good discrimination between susceptible and resistant strains. However, some investigators have suggested that M phenotype strains may be susceptible under selected circumstances (see the following section). Of note, macrolide resistance among pneumococci has increased in parallel with the increase in use of newer long-acting macrolides [6, 26]. In the United States, this increase has been associated with strains with the M phenotype, whereas in other countries, this increase has been associated with strains with the MLSB phenotype. A promising development for pneumococcal therapy has been the introduction of ketolides, such as telithromycin, which are related to macrolides; these agents appear to be active in vitro and in vivo against macrolide-resistant pneumococci, but they are not as active against H. influenzae [27].

## Pharmacokinetic and Pharmacodynamic Properties of Macrolides

Determinations of in vitro susceptibility have to be interpreted to be clinically meaningful, and this is done by establishing interpretative criteria for MICs, which denote susceptible, intermediate, and resistant categories. The upper limit of susceptibility is generally determined on the basis of the pharmacokinetic and pharmacodynamic properties of each agent in animal models and in humans [28, 29]. Unbound serum levels have been found to be the best reflection of pharmacokinetic properties. The time when such unbound serum levels exceed MICs best reflects the pharmacodynamic properties of time-dependent agents (e.g., macrolides and β-lactams), and the ratios of the unbound serum area under the curve to MIC or the ratios of peak unbound serum levels to MIC best reflect the pharmacodynamic properties of concentration-dependent agents (e.g., quinolones and aminoglycosides). On the basis of studies that correlate pharmacokinetic and pharmacodynamic parameters with bacteriologic eradication in patients or in animal models, susceptibility breakpoints for macrolides have been determined as ⩽0.5 µg/mL for erythromycin, azithromycin, and clarithromycin [30, 31]. These breakpoints are based on the dosing regimen used and the site of infection, and they apply to approved oral dosing regimens and to infections other than meningitis and urinary tract infections; for the latter infections, the concentration profiles of the infection site differ substantially from the serum concentration profiles. They may not apply to intracellular pathogens, because drug distribution within intracellular compartments is much more variable.

Application of the aforementioned macrolide MIC breakpoints to the 2 most common extracellular pathogens associated with CAP, S. pneumoniae and H. influenzae results in 20%–30% of strains of the former organism and >95% of strains of the latter organism being classified as macrolide resistant in the United States [6, 25]. These interpretations are in agreement with numerous animal models of infections due to these pathogens as well as with bacteriologic outcome studies of acute otitis media and sinusitis in humans [30–34]. These studies show that macrolide-susceptible pneumococci respond to macrolide therapy, whereas macrolide-resistant pneumococci of both phenotypes, as well as all H. influenzae isolates, do not respond to therapy. A successful clinical outcome for community-acquired acute respiratory tract infection does not necessarily reflect antimicrobial efficacy, because of the high rate of spontaneous resolution of such disease in outpatients [9, 10] and because of the poor correlation between bacteriologic and clinical outcome in acute otitis media (referred to as the “Pollyanna phenomenon”) [35].

Some investigators have invented a new body compartment for drugs, such as macrolides and quinolones, that are concentrated intracellularly. This compartment is named alveolar or epithelial lining fluid (ELF), and drug concentrations in such fluids are postulated to correlate with the outcome of pneumonia. This theory is used to explain why macrolides, which have inadequate pharmacokinetic properties on the basis of unbound serum levels, are actually active in vivo against isolates with “low-level resistance,” such as S. pneumoniae with the M phenotype and all H. influenzae. ELF consists of alveolar lining fluid, which is obtained bronchoscopically by intrabronchial lavage [36–39]. After centrifugation of the fluid to remove macrophages, drug levels in ELF are determined and corrected for dilution on the basis of urea concentrations in blood and ELF. This theory has several associated problems that need to be explained. First, drug is predominantly concentrated within alveolar macrophages in ELF, rather than in the aqueous phase of the fluid, in which drug concentrations are low. Extracellular pathogens are exposed only to these aqueous-phase levels. Second, drug in ELF may prevent alveolar epithelial penetration of bacteria, but it is hard to envision how this fluid affects pathogens that have penetrated beyond the alveolar epithelium. Third, drug levels in ELF have mainly been determined in healthy volunteers, whereas ELF levels in actual patients have not been documented. Finally, animal models have been unable to show correlations between bacterial eradication and ELF levels, whereas correlation with unbound serum levels has repeatedly been demonstrated. With the use of dosing regimens equivalent to dosing regimens for humans, bacterial eradication of macrolide-resistant pneumococci with erm- or mef-mediated resistance, as well as eradication of H. influenzae, does not occur in rodent pneumonia models, whereas bacterial eradication does occur with macrolide-susceptible pneumococci [32–34].

## Empirical Treatment of CAP in the ERA of Macrolide Resistance

The aforementioned factors need to be considered in relation to the spectrum of pathogens associated with CAP and to the development of guidelines for the empirical treatment of these infections. Current guidelines continue to recommend oral administration of macrolides for the treatment of outpatients with CAP [2, 40–43]. If macrolides are active against S. pneumoniae with M phenotype in vivo, then macrolides are reasonable choices in areas in which such strains are common. However, in light of the evidence discussed above, macrolides may not be as attractive an option.

Although the number of cases of breakthrough pneumococcal bacteremia specified in the article by Lonks et al. [7] is not large (19 cases) considering the large number of cases of pneumococcal pneumonia that occur, and although, fortunately, there were no deaths among these patients, the patients all had considerable morbidity, which was reflected by their need for hospitalization as well as by the development of empyema in 2 patients and meningitis in 1. In addition, Lonks and colleagues show that some patients could have been treated more aggressively, on the basis of such risk factors as age >50 years, immunosuppression, or underlying chronic pulmonary, renal, or hepatic disease. In areas in which the prevalence of macrolide-resistant pneumococci is high, oral administration of macrolides would be a reasonable option only for patients in PORT class I or II who have no high-risk factors for drug-resistant S. pneumoniae infections, such as recent antibiotic use, recent hospitalization, and day care exposure. However, macrolides have no advantage over β-lactams, unless patients are allergic to β-lactams. In the era of antibiotic-resistant pneumococci, it is somewhat ironic to note that amoxicillin, 875–1000 mg given orally twice daily, is active against ⩾90% of pneumococci worldwide, whereas macrolides are active against <80% of isolates in most countries, with the prevalence of resistance exceeding 80% in some countries in the Far East [24]. On the basis of the high incidence of CAP, we need answers to questions about the real efficacy of antimicrobials in CAP, according to the pathogen involved, the patient age group, the severity of disease, whether outpatients with pneumonia due to “atypical” pathogens actually benefit from receiving antibiotics, and the most cost-effective approach to treating this disease.

## References

1
Almirall
J
Bolibar
I
Vidal
J
, et al.  .
Epidemiology of community-acquired pneumonia in adults: a population-based study
Eur Respir J
,
2000
, vol.
15
(pg.
757
-
63
)
2
Bartlett
JG
Dowell
SF
Mandell
LA
File
TM
Jr
Musher
DM
Fine
MJ
Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America
Clin Infect Dis
,
2000
, vol.
31
(pg.
347
-
82
)
3
Popovic
J
Kozak
L
National Hospital Discharge Survey: annual summary, 1998. National Center for Health Statistics
Vital Health Stat 13
,
2000
(pg.
1
-
194
Sep(148)
4
Schappert
SM
Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States, 1997
Vital Health Stat 13
,
1999
(pg.
i
-
iv
Nov(143)
5
Niederman
MS
McCombs
JS
Unger
AN
Kumar
A
Popovian
R
The cost of treating community-acquired pneumonia
Clin Ther
,
1998
, vol.
20
(pg.
820
-
37
)
6
Hyde
TB
Gay
K
Stephens
DS
, et al.  .
Macrolide resistance among invasive Streptococcus pneumoniae isolates
JAMA
,
2001
, vol.
286
(pg.
1857
-
62
)
7
Lonks
JR
Garau
J
Gomez
L
, et al.  .
Failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycin-resistant Streptococcus pneumoniae
Clin Infect Dis
,
2002
, vol.
35
(pg.
556
-
64
(in this issue)
8
Fang
GD
Fine
M
Orloff
J
, et al.  .
New and emerging etiologies for community-acquired pneumonia with implications for therapy: a prospective multicenter study of 359 cases
Medicine (Baltimore)
,
1990
, vol.
69
(pg.
307
-
16
)
9
Fine
MJ
Auble
TE
Yealy
DM
, et al.  .
A prediction rule to identify low-risk patients with community-acquired pneumonia
N Engl J Med
,
1997
, vol.
336
(pg.
243
-
50
)
10
Roson
B
Carratala
J
Dorca
J
Casanova
A
Manresa
F
Gudiol
F
Etiology, reasons for hospitalization, risk classes, and outcomes of community-acquired pneumonia in patients hospitalized on the basis of conventional admission criteria
Clin Infect Dis
,
2001
, vol.
33
(pg.
158
-
65
)
11
Evans
G
Gainsford
W
Treatment of pneumonia with 2-(p-aminobenzenesulfonamido)pyridine
Lancet
,
1938
, vol.
2
(pg.
14
-
9
)
12
Brandenburg
JA
Marrie
TJ
Coley
CM
, et al.  .
Clinical presentation, processes, and outcomes of care for patients with pneumococcal pneumonia
J Gen Intern Med
,
2000
, vol.
15
(pg.
638
-
46
)
13
Ekdahl
K
Martensson
A
Kamme
C
Bacteraemic pneumococcal infections in Southern Sweden 1981–96: trends in incidence, mortality, age-distribution, serogroups, and penicillin-resistance
Scand J Infect Dis
,
1998
, vol.
30
(pg.
257
-
62
)
14
Marrie
TJ
Pneumococcal pneumonia: epidemiology and clinical features
Semin Respir Infect
,
1999
, vol.
14
(pg.
227
-
36
)
15
Backhouse
R
Kapasi
M
Noble
I
Modelling the use of three antibiotics in the management of community-acquired pneumonia
British Journal of Medical Economics
,
1995
, vol.
8
(pg.
195
-
210
)
16
Donowitz
GR
Brandon
ML
Salisbury
JP
, et al.  .
Sparfloxacin versus cefaclor in the treatment of patients with community-acquired pneumonia: a randomized, double-masked, comparative, multicenter study
Clin Ther
,
1997
, vol.
19
(pg.
936
-
53
)
17
Lode
H
Garau
J
Grassi
C
, et al.  .
Treatment of community-acquired pneumonia: a randomized comparison of sparfloxacin, amoxycillin-clavulanic acid, and erythromycin
Eur Respir J
,
1995
, vol.
8
(pg.
1999
-
2007
)
18
Mundy
LM
Oldach
D
Auwaerter
PG
, et al.  .
Implications for macrolide treatment in community-acquired pneumonia. Hopkins CAP Team
Chest
,
1998
, vol.
113
(pg.
1201
-
6
)
19
Fasola
EL
Bajaksouzian
S
Appelbaum
PC
Jacobs
MR
Variation in erythromycin and clindamycin susceptibilities of Streptococcus pneumoniae by four test methods
Antimicrob Agents Chemother
,
1997
, vol.
41
(pg.
129
-
34
)
20
Nagai
K
Appelbaum
PC
Davies
TA
, et al.  .
Susceptibilities to telithromycin and six other agents and prevalence of macrolide resistance due to L4 ribosomal protein mutation among 992 pneumococci from 10 central and eastern European countries
Antimicrob Agents Chemother
,
2002
, vol.
46
(pg.
371
-
7
)
21
A
Davies
T
Appelbaum
PC
, et al.  .
Two new mechanisms of macrolide resistance in clinical strains of Streptococcus pneumoniae from eastern Europe and North America
Antimicrob Agents Chemother
,
2000
, vol.
44
(pg.
3395
-
401
)
22
Canu
A
Malbruny
B
Coquemont
M
Davies
TA
Appelbaum
PC
Leclercq
R
Diversity of ribosomal mutations conferring resistance to macrolides, clindamycin, streptogramin, and telithromycin in Streptococcus pneumoniae
Antimicrob Agents Chemother
,
2002
, vol.
46
(pg.
125
-
31
)
23
Musher
DM
Dowell
ME
Shortridge
VD
, et al.  .
Emergence of macrolide resistance during treatment of pneumococcal pneumonia
N Engl J Med
,
2002
, vol.
346
(pg.
630
-
1
)
24
Hoban
DJ
Doern
GV
Fluit
AC
Roussel-Delvallez
M
Jones
RN
Worldwide prevalence of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the SENTRY Antimicrobial Surveillance Program, 1997–1999
Clin Infect Dis
,
2001
, vol.
32

Suppl 2
(pg.
S81
-
93
)
25
Jacobs
MR
Bajaksouzian
S
Zilles
A
Lin
G
Pankuch
GA
Appelbaum
PC
Susceptibilities of Streptococcus pneumoniae and Haemophilus influenzae to 10 oral antimicrobial agents based on pharmacodynamic parameters: 1997 U.S. Surveillance Study
Antimicrob Agents Chemother
,
1999
, vol.
43
(pg.
1901
-
8
)
26
Garcia-Rey
C
Aguilar
L
Baquero
F
Casal
J
Dal-Re
R
Importance of local variations in antibiotic consumption and geographical differences of erythromycin and penicillin resistance in Streptococcus pneumoniae
J Clin Microbiol
,
2002
, vol.
40
(pg.
159
-
64
)
27
Leclercq
R
Overcoming antimicrobial resistance: profile of a new ketolide antibacterial, telithromycin
J Antimicrob Chemother
,
2001
, vol.
48

Suppl T1
(pg.
9
-
23
)
28
Craig
WA
Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men
Clin Infect Dis
,
1998
, vol.
26
(pg.
1
-
10
11–2 [quiz]
29
Drusano
GL
Craig
WA
Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections
J Chemother
,
1997
, vol.
9

Suppl 3
(pg.
38
-
44
)
30
Dagan
R
Klugman
KP
Craig
WA
Baquero
F
Evidence to support the rationale that bacterial eradication in respiratory tract infection is an important aim of antimicrobial therapy
J Antimicrob Chemother
,
2001
, vol.
47
(pg.
129
-
40
)
31
Jacobs
MR
Optimisation of antimicrobial therapy using pharmacokinetic and pharmacodynamic parameters
Clin Microbiol Infect
,
2001
, vol.
7
(pg.
589
-
96
)
32
Mitten
MJ
Meulbroek
J
Nukkala
M
, et al.  .
Efficacies of ABT-773, a new ketolide, against experimental bacterial infections
Antimicrob Agents Chemother
,
2001
, vol.
45
(pg.
2585
-
93
)
33
Okamoto
H
Miyazaki
S
Tateda
K
Ishii
Y
Yamaguchi
K
In vivo efficacy of telithromycin (HMR3647) against Streptococcus pneumoniae and Haemophilus influenzae
Antimicrob Agents Chemother
,
2001
, vol.
45
(pg.
3250
-
2
)
34
Tessier
PR
Kim
MK
Zhou
W
, et al.  .
Pharmacodynamic assessment of clarithromycin in a murine model of pneumococcal pneumonia
Antimicrob Agents Chemother
,
2002
, vol.
46
(pg.
1425
-
34
)
35
Marchant
CD
Carlin
SA
Johnson
CE
Shurin
PA
Measuring the comparative efficacy of antibacterial agents for acute otitis media: the “Pollyanna phenomenon”
J Pediatr
,
1992
, vol.
120
(pg.
72
-
7
)
36
Amsden
GW
Pneumococcal macrolide resistance—myth or reality?
J Antimicrob Chemother
,
1999
, vol.
44
(pg.
1
-
6
)
37
Bergogne-Berezin
E
Predicting the efficacy of antimicrobial agents in respiratory infections—is tissue concentration a valid measure?
J Antimicrob Chemother
,
1995
, vol.
35
(pg.
363
-
71
)
38
Carcas
AJ
Garcia-Satue
JL
Zapater
P
Frias-Iniesta
J
Tobramycin penetration into epithelial lining fluid of patients with pneumonia
Clin Pharmacol Ther
,
1999
, vol.
65
(pg.
245
-
50
)
39
Conte
JE
Jr
Golden
J
Duncan
S
McKenna
E
Lin
E
Zurlinden
E
Single-dose intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime in volunteer subjects
Antimicrob Agents Chemother
,
1996
, vol.
40
(pg.
1617
-
22
)
40
Nelson
JD
Community-acquired pneumonia in children: guidelines for treatment
Pediatr Infect Dis J
,
2000
, vol.
19
(pg.
251
-
3
)
41
Mandell
LA
Marrie
TJ
Grossman
RF
Chow
AW
Hyland
RH
Summary of Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Disease Society and the Canadian Thoracic Society
Can Respir J
,
2000
, vol.
7
(pg.
371
-
82
)
42
File
TJ
Jr
Community-acquired pneumonia: new guidelines for management
Curr Opin Infect Dis
,
2001
, vol.
14
(pg.
161
-
4
)
43
Niederman
MS
Mandell
LA
Anzueto
A
, et al.  .
Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention
Am J Respir Crit Care Med
,
2001
, vol.
163
(pg.
1730
-
54
)

## Author notes

(See the article by Lonks et al. on pages 556–64)