Infect Dis Clin N Am

18 (2004) 883897

Nonresponses and treatment failures

with conventional empiric regimens
in patients with community-acquired
pneumonia
James S. Tan, MD, MACPa,b,*
a

Section of Infectious Disease, Department of Internal Medicine, Northeastern Ohio

Universities College of Medicine, Rootstown, OH, USA
b
Department of Internal Medicine, Summa Health System, 75 Arch Street, Suite 303,
Akron, OH 44304, USA

Pneumonia is one of the leading causes of death throughout the world.

Community-acquired pneumonias (CAPs) usually are treated empirically
without an initial culture or established cause. These cases respond
satisfactorily to the empiric antimicrobial regimen that is recommended in
the guidelines from dierent major professional societies [1,2]. Among
hospitalized cases, approximately 10% to 25% do not resolve within the
anticipated time [35], and an additional 10% may develop progressive lifethreatening pneumonia [6,7]. Among ambulatory patients, the failure rates
of pneumonia treatment are much lower. Malcolm and Marrie [8] reported
a 2.2% hospitalization rate within 3 weeks of an initial emergency department
visit. Two other reports with a slightly dierent denition of treatment failure
showed about 7% of patients who initially were treated in an ambulatory
setting required hospitalization within 30 days [9,10]. In a large prospective
study of CAP, in which treatment failure was dened as a lack of response or
worsening of clinical or radiologic status at 48 to 72 hours that required
changes in antimicrobial therapy or performance of an invasion procedure,
Roson et al [11] observed a 6% early failure rate. Delayed resolution,
however, has been associated with host factors such as advanced age,
alcoholism, and comorbid diseases [12,13].
Treatment failure may result in prolonged hospitalization, progressive
pneumonia, contiguous or metastatic infection, and increased mortality rate.
* 75 Arch Street, Suite 303, Akron, OH 44304.
E-mail address: tanj@summa-health.org
0891-5520/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.idc.2004.07.009

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J.S. Tan / Infect Dis Clin N Am 18 (2004) 883897

Causes of treatment failure include inadequate or inappropriate antimicrobial therapy, unusual pathogens, purulent complications of pneumonia, and
noninfectious illness (Box 1). An improved understanding of the causes of
treatment failure can improve the outcome and the cost eectiveness of
treatment [5].This article reviews the reasons for failure to respond among
patients with CAP who failed initial empiric therapy.

Box 1. Reasons for poor response to conventional empiric

treatment in patients with pneumonia
Pneumonia present
Host related
Overwhelming pneumonia
Undetected infection sites, such as empyema or metastatic
diseases
Infectious agent related
Antimicrobial-resistant organism
Unusual organism
Co-infection or sequential infection
Incorrect diagnosis
Pulmonary infiltrates caused by a noninfectious process
Bronchiolitis obliterans organizing pneumonia
Acute and chronic eosinophilic pneumonia
Hypersensitivity pneumonitis
Pulmonary vasculitis, including Wegeners granulomatosis,
Churg-Strauss syndrome
Pulmonary sarcoidosis
Lupus pneumonitis
Drug-induced pulmonary infiltrates
Aspiration pneumonialipoid pneumonia
Acute sickle cell syndrome
Occupational-related lung infiltrates
Radiation pneumonitis
Pulmonary neoplasms (obstructing)
Pulmonary embolus or infarction
Acute respiratory distress syndrome
Alveolar hemorrhage
Pulmonary alveolar proteinosis
Congestive heart failure
Data from Refs. [12,78,80].

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Clinical response to treatment

Despite the increasing number of new eective antimicrobial agents,
(macrolides, uoroquinolones, cephalosporins), the overall mean mortality
rate for CAP, ranging from 4% to 14% in hospitalized patients, has not
changed over the past decades [6,7,1418]. The appropriate response rate of
CAP is patient dependent and may be related to age, comorbid conditions
(particularly lung disease), alcohol abuse, and social strata [19]. The clinical
cure rate in published CAP trials is approximately 80% and does not exceed
90% [16].
In general, after pneumonia is treated, resolution of fever usually occurs
within 3 to 5 days. Leukocytosis may persist for 4 more days after the start
of therapy. Crackles may last for more than a week. Improvement of chest
radiographic ndings may take weeks. slow radiologic resolution without
clinical deterioration does not imply treatment failure, especially among
elderly patients [13].
Treatment failure or slow response to treatment is considered if there is
inadequate clinical response after 7 days of therapy, the fever persists, the
patient is not clinically stable in 72 hours, or there is clinical deterioration
after 24 hours of therapy [1,5]. For the sake of simplicity, treatment failure
and slow response to treatment are referred to as treatment failure. The
causes of treatment failure can be classied under the following categories:
(1) host related, (2) microbe related, (3) antimicrobial related, and (4) other.
Few studies have analyzed the causes of treatment failure [5,11,2022].
The following studies observed that antimicrobial resistance is responsible
for a small number of patients with treatment failures.
Arancibia et al [20] reported that 11% (49 of 444) of patients with CAP
had treatment failure. They divided treatment failures into nonresponding
pneumonia and progressive pneumonia. Nonresponding pneumonia was
dened as persistence of fever (>38 C) or clinical symptoms (malaise, cough
expectoration, dyspnea) for at least 72 hours after the start of antimicrobial
therapy. Progressive pneumonia was dened as clinical deterioration, such as
the development of acute respiratory failure requiring ventilatory support or
septic shock, after 72 hours of antimicrobial therapy. Table 1 shows the
denitions of the causes of treatment failure. Primary, persistent, or
nosocomial infection was the cause of failure in about three quarters of
patients. Most nonresponders had primary or persistent infections, whereas
nosocomial infections were associated more frequently with progressive
pneumonias. Less than 20% of patients subsequently were shown to have
noninfectious processes. An infectious or noninfectious diagnosis was not
made in almost one quarter of patients.
Roson et al [11] reported their prospective observational analysis for
factors associated with early treatment failures in 1383 nonimmunosuppressed adults who were hospitalized for CAP. Early failure was considered
when there was a lack of response at 48 or 72 hours and the patient required a

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J.S. Tan / Infect Dis Clin N Am 18 (2004) 883897

Table 1
Denitions and causes of treatment failures
Causes

No. of patients

Primary infection
Persistent infection
Denite
Probable
Nosocomial infection
Noninfectious
Nondiagnostic

10
13
6
7
11
9
11

Total

54a

1. Primary infection is dened as nding a pathogen that was not detected in the initial
investigation (eg, atypical pneumonia agents, unusual pathogens, or pathogens associated with
the development of empyema).
2. Persistent infection
a. Denite persistent infection is dened as nding the same pathogens in initial and
repeated investigations.
b. Probable persistent infection is dened as nding a pathogen in the initial but not the
subsequent investigation.
3. Nosocomial infection is dened as the demonstration of a pathogen from the respiratory
specimen of a patient with early- or late-onset ventilator-associated pneumonia. This pathogen
was not present in the initial evaluation.
4. A noninfectious cause is dened as the presence of pulmonary inltrates in a case conict
a denite noninfectious diagnosis has been established.
5. Nondiagnosis is dened as the absence of criteria to establish an infectious or
noninfectious diagnosis.
a
Five patients had more than one cause.
Adapted from Arancibia F, Ewig S, Martinez JA, et al. Antimicrobial treatment failures in
patients with community-acquired pneumonia: causes and prognostic implications. Am J
Respir Crit Care Med 2000;162:15460.

change in antibiotic therapy or performance of bronchoscopy for diagnostic

or therapeutic reasons, such as institution of mechanical ventilation or chest
tube drainage. Among the early treatment failures in 81 hospitalized patients
with CAP, 67% were caused by progressive pneumonia as demonstrated by
radiographic progression. The etiologic agent of the 81 early failures was
unknown in 32%, Streptococcus pneumoniae in 22%, Legionella spp in 21%,
and various organisms in the rest. Compared with the early-response group,
the early-failure group had a higher rate of Legionella infection. The
investigators suggested that early treatment failure is associated with highrisk pneumonia (patients with a pneumonia severity index score [90) [23],
multilobar inltrates, Legionella pneumonia, gram-negative pneumonia, and
discordant antimicrobial therapy. Antimicrobial resistance, unusual pathogens, other complications from pneumonia, and drug-related adverse eects
contribute to a minor number of failures [11]. Unlike the observation of
Waterer et al [24], the patients who received combination therapy did not
have a lower treatment failure rate.

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Mortality
When investigators in the Pneumonia Outcome Research Team Cohort
Study analyzed the causes of death among their patients with CAP, they
found that the factors associated with mortality were the presence of shock
and multilobar consolidation at the time of admission rather than penicillin
resistance [14]. In a large, international, prospective study on pneumococcal
bacteremia by Yu et al [25], the mortality rate was 16.9%. Mortensen et al
[26] stated that only half of all deaths are attributable to acute illness. In
their study, they found that CAP had a stronger association with early
mortality (more than three quarters of pneumonia-related deaths occurred
within the rst 30 days) and that prognosis beyond 45 days of presentation
is most likely related to nonpneumonia factors, such as age, sex, and other
comorbid conditions. Among patients with pneumonia-unrelated death,
comorbid conditions such as malignancy, immunosuppression and dementia
independently were associated with death.
Approximately 50% of patients hospitalized for CAP do not have an
identied etiologic agent. By and large, treatment of CAP is empiric and
involves the use of antimicrobial agents with activities against the S
pneumoniae, Haemophilus inuenzae, Moraxella catarrhalis, and the atypical
pneumonia agents (eg, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila).
The infecting organism (eg, Staphylococcus aureus, enteric gram-negative
pathogens) has a role in resolution. Legionella infection takes the longest
to resolve (up to months) [27], Mycoplasma infection resolves the earliest
(24 weeks) [28], and Chlamydia infection has an intermediate resolution
rate [29]. This knowledge is useful to determine whether the patient has a
slowly resolving process (ie, \50% resolution in 1 month), the emergence of
resistance, or treatment of the wrong pathogen or process.

Radiographic resolution
Radiographic ndings commonly lag behind clinical ndings and do not
correlate well with clinical improvement. Radiographic worsening should not
be used as the only indicator of treatment failure. Radiographic resolution is
host and organism dependent. Several reviews on slowly resolving pneumonia
listed age and underlying pulmonary disease and infecting organisms as
important determinants [12,13,30]. Among the common causes of CAP, S
pneumoniae, and Legionella spp are most likely to have persisting inltrates,
especially among the elderly. Among otherwise healthy patients, however,
radiographic resolution is expected within 6 weeks. Mycoplasma infections
generally resolve quicker [31].
Among patients with Legionnaires disease, worsening of inltrates and
pleural eusion during hospitalization were shown to occur in more than
half of the patients in spite of clinical improvement [32]. In another study,

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complete radiographic clearing of pneumonia occurred in 50% of patients

at 2 weeks and in 66.7% at 4 weeks [33]. Other studies have shown complete resolution at 2 weeks in only 12.5% of patients and at 4 weeks in only
41% [34].

Treatment failure and slow response to treatment

When treatment failure is suspected, a common reex response is to
suspect prescription of inadequate or inappropriate antibiotic, and an
antibiotic with a wider spectrum or of a dierent class is substituted or added.
This approach to management lacks rationale and literature support. Roson
et al [11] found that inappropriate antimicrobial treatment is a less frequent
cause of failure. Most treatment failures within the rst 72 hours of inhospital antimicrobial therapy are seen in patients with progressive
pneumonia and its complications [11,35]. Genne et al [5] performed a Medline
search of clinical trials and CAPs from 1990 to 1997 that were published in
English or French. Eighty-two trials involving a total of 3048 patients with
CAP were included. Treatment failure occurred in 479 cases (16%). The
cause of failure could not be determined in more than half of the patients. In
only 28 patients (6%), failure was attributed to antimicrobial resistant
bacteria. As a rule, patients who are recruited to join clinical trials are not
seriously ill, and this fact may be the cause of the higher cure rate. In contrast,
in a prospective study of bacteremic pneumococcal pneumonia, Lujan et al
[36] observed poor clinical outcomes among patients who received
antimicrobial therapy that was reported to be ineective by in vitro testing.
Up to 10% of patients with bacteremic pneumococcal pneumonia can have
metatastic infections, which include meningitis, arthritis, endocarditis,
pericarditis, peritonitis, and empyema [37].
Host factors and treatment failure
Advanced age and comorbid conditions (eg, alcohol abuse, leukopenia,
multilobar involvement, extrapulmonary foci) are important host factors
that inuence the resolution of pneumonia and mortality (Box 2) [12]. In
a study of elderly patients with pneumonia, an independent association with
mortality was associated with inadequate empiric antibiotic therapy;
however, there were inadequate number of microbiologic studies to show
an association with specic etiologic agent [38]. In the study by Mortensen
et al, the underlying causes of death included pulmonary embolus,
respiratory failure, chronic pulmonary conditions, cardiac disease, neoplastic, neurologic conditions, multisystemic organ failure, and other less
common conditions [26]. These less common conditions included acute
surgical abdomen, renal failure, liver disease, postoperative complications,
rheumatologic disorders, diabetes mellitus, hemoptysis, peripheral vascular
conditions, and depression.

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Box 2. Host factors affecting resolution of pneumonia

Age related
Ineffective cough
Loss of lung elasticity
Decreased mucociliary clearance
Increase in functional residual capacity
Flattening of diaphragms
Decreased T-cell function
Decreased interleukin 1 (IL-1), IL-2, and IgM levels
Smoking related
Impaired mucociliary clearance
Recent infection
Impaired mucociliary clearance caused by recent infection,
such as influenza, Mycoplasma infection, Chlamydia
infection
Comorbid factors
Congestive heart failure
Diabetes mellitus
Chronic obstructive pulmonary disease
Renal failure
Cerebrovascular disease
Ethanol abuse
Corticosteroid use
Immunosuppression
Malignancy
Adapted from Rome L, Murali G, Lippmann M. Nonresolving pneumonia and
mimics of pneumonia. Med Clin North Am 2001;85:151130.

Pneumococcal bacteremia in older patients has been associated with

higher mortality rates [39,40]. A mortality rate of 24.1% was reported in
a community hospital setting [40] and 38% in a study on hospitals in a large
county in central Ohio [39]. Severity of illness and underlying comorbid
conditions, such as diabetes, chronic lung disease, malignancy, empyema
[37], and renal failure, contributed to higher mortality rates [40].
Antimicrobial resistance and treatment failure
Drug resistance to S pneumoniae has increased over the past years. A
growing percentage of S pneumoniae isolates are resistant to penicillin and
macrolides, and uoroquinolone (FQ) resistance increasingly has been
detected worldwide [41]. In a review of clinical trials, however, antibioticresistant pathogens accounted for less than 6% of the cause of treatment

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failure [5]. Metlay oers a more detailed discussion of this topic elsewhere
in this issue. Previous antibiotic exposure is one of the most important
predictors for acquisition of drug-resistant S pneumoniae [25,42]. In one
study, the use of b-lactams, sulfonamides, or macrolides (but not FQ) within
the previous 1 to 6 months increased the risk for antibiotic resistance [42].
Past exposure to FQ has been reported to increase the risk for FQ-resistant
S pneumoniae (FQRSP), however [43,44]. Other risk factors for antimicrobial resistance include environmental factors such as exposure to day care
centers, nursing homes, and hospitals; alcoholism; underlying chronic lung
disease; immunosuppression; very young and old age [1,44].
The documentation of antimicrobial resistance in the respiratory isolate
does not necessarily translate into clinical treatment failure of primary CAP
[45]. The impact of drug resistance on morbidity and mortality is still
controversial. The number of patients who failed b-lactam therapy for
nonmeningeal pneumococcal disease has been small [46]. Many investigators cannot demonstrate any dierence in clinical response between
infection caused by penicillin-susceptible S pneumoniae (PSSP) and
penicillin-resistant S pneumoniae (PRSP), especially when the severity of
disease is stratied [4753]. Other studies have shown that strains of S
pneumoniae with higher minimal inhibitory concentrations (MICs) have no
eect on mortality rates but have higher rates of suppurative complications
and bacteremia [47,53,54]. The association of increased mortality rate and
PRSP has been reported by several investigators [54,55]. Feikin et al [54]
reported signicantly higher mortality rates among patients infected with
PRSP strains (MIC, 4 lg/mL) if deaths that occurred within the rst
4 days were excluded from the analysis. A higher rate of suppurative
complications also has been reported among patients with PRSP infection
[47,54,55]. Metlay et al [47] found that patients with bacteremic
pneumococcal pneumonia caused by nonpenicillin-susceptible strains had
a higher risk for treatment failure or death.
Other investigators have doubted the clinical relevance of PRSP in
nonmeningeal infections. In an international observational study of 844
hospitalized patients with S pneumoniae bacteremia, Yu et al [25] showed
that the time required for defervescence and frequency of suppurative
complications were not associated with the use of b-lactam antibiotic for the
treatment of PSSP or PRSP; however, patients with PRSP who received
cefuroxime had a signicantly higher mortality rate. Higher frequency of
suppurative complications was observed among patients treated with
a discordant antimicrobial agent, but this nding was not statistically
signicant [25]. Microbiologic conrmed failure of penicillin therapy has not
been reported [56].
Numerous guidelines consider macrolides to be rst-line treatment for
CAP. In certain areas of Europe and Asia [5759], the rate macrolide
resistance has been reported to be greater than 50%. Surveillance studies
suggest that the rate of resistance to macrolides is high and still increasing

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891

[60,61]. In spite of increasing worldwide resistance, macrolide treatment

failures have not been reported proportionally in the literature. Treatment
failures using macrolides have been summarized [62]. The available clinical
data are not adequate to predict treatment outcomes based on macrolides
resistance [63,64]; however, resistance that is detected in a clinical specimen
should be a cause for concern. Lynch et al [65] showed that the development
of breakthrough bacteremia during macrolide therapy is more likely to
occur in patients with macrolides-resistant pneumococcus, regardless of
mechanism of resistance (namely eux or methylase related). Azithromycin
therapeutic failures were reported by Fogarty et al [66,67]. These patients
were cured with levooxacin.
Klugman [46] believes that the MIC is more important than the presence
of the gene in predicting the clinical relevance of macrolide resistance.
Patients with lower levels of resistance (MIC, \8 lg/mL) still may respond
to macrolide therapy. Alveolar macrophage levels of macrolides, such as
clarithromycin and azithromycin, exceed blood levels of macrolides by
many folds [68]. Development of resistance to quinupristindalfopristin and
telithromycin in S pneumoniae during or after treatment with a macrolide or
a combination of macrolide and quinolone antibiotics has not been reported
[69].
Ketolides and quinupristindalfopristin belong to the macrolide-lincosamide-streptogramin B class of antimicrobial agents. Members of these
families of antibiotics retain activity against most resistant pneumococcal
isolates [70].

FQ resistance
FQRSP isolates increasingly are encountered in the literature, but the
number remains low [43,7174]. Rare cases of FQ treatment failure among
patients with pneumococcal pneumonia have been reported [69,71,72,75,76].
Von Gottberg et al [77] reported an African child who had a FQRSP while
in a tuberculosis treatment facility. This report raises the concern of the
possible use of an FQ as single-agent therapy in respiratory tract infection
among patients at risk for tuberculosis or in patients with active
tuberculosis. Treatment failure in pneumococcal pneumonia was observed
in an elderly man who had isolates that were initially susceptible to FQ,
macrolides, clindamycin, quinupristindalfopristin, and telithromycin but
became resistant during treatment [69].

Incorrect diagnosis
Noninfectious causes or unusual infections presenting with pulmonary
radiographic inltrates, fever, and cough can be mistaken for CAP (see
Box 1). These problems usually are suspected only after treatment failures.

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Alves dos Santos et al [78] identied 16 hospitalized patients who were suspected to have CAP and treatment failure. Eight patients had the following
noninfectious diseases: pulmonary embolism, cryptogenic organizing pneumonia, Wegeners granulomatosis, hypersensitivity pneumonitis, bronchocentric granuylomatosis, neoplastic disease, and acute leukemia.
Unusual pathogens may not have been considered because of a low index
of suspicion. Patients with chronic lung lesion may have tuberculosis,
endemic fungal infection, or pneumocystis. Patients with immunosuppression, such as those with AIDS or those who are receiving chemotherapy or
anti-tumor necrosis factor agents, are more susceptible to these infections.
With the recommendation of empiric treatment of patients with suspected
CAP without any microbiologic workup, it is easy to miss these unusual
pathogens. Mycobacterium tuberculosis is partially sensitive to erythromycin, and patients with active tuberculosis initially may improve clinically
with erythromycin therapy then clinically deteriorate, even when macrolide
treatment is continued. These same patients may have been treated with
a uoroquinolone for 10 days and then discontinued treatment. This partial
therapy often results in failure and possible induction of antimicrobial
resistance. Examples of less common and unusual infectious agents include:
M tuberculosis, Cryptococcus neoformans, Histoplasma capsulatum, Coccidiodes immitis, pneumocystis, actinomycetes, Coxiella spp, and Chlamydia
psittasii.
A thorough history for travel and animal exposure is important.
Zoonotic infections, such as tularemia, Q-fever, psittacosis, and pneumonic
plague, may not have been considered in the initial diagnosis, because many
of these infections may have fever and acute pulmonary inltrates. A disease
that may be associated with travel to southeast Asia is melioidosis.
Management
The American Thoracic Society recommends that action should be taken if
clinical deterioration is observed after 24 hours of antimicrobial therapy, the
patient is not clinically stable within 72 hours, or there is no explanation for
a slow response after 7 days [1]. Poor response to therapy may be categorized
in the following four common groups: antibiotic selection, unusual
pathogens, complications of pneumonia, or noninfectious illness. It is
worthwhile to consider the value of certain tests for patients who are already
taking antibiotics. Workup should include a search for unusual or resistant
microorganisms that may be involved in superinfection or co-infection and
the presence of obstruction to pulmonary drainage and a noninfectious agent
that mimics pneumonia. Further testing to be considered includes microbiologic examination (respiratory sample and blood cultures, antigen detection
tests, serologic tests); bronchoscopic examination with protected specimen
brush and bronchoalveolar lavage for culture, cytology, and tissue biopsy;
and radiologic examination (including spiral CT scan) searching for

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893

pulmonary sites of infection or obstruction, empyema, or extrapulmonary

sites of infection. Cultures and serologic testing for unusual pathogens should
be dependent on the local epidemiology and travel history. Change of
antimicrobial therapy should be instituted only after the cultures have been
performed.
The value of extensive microbiologic workup among patients with
treatment failure has not been established. Ortqvist et al [35] studied the
usefulness of bronchoscopic examination in patients with CAP who had
failed empiric antimicrobial therapy. Bronchoscopy was performed in 277
patients with therapeutic failures: seven patients (2.5%) had early failures,
and 11 (4%) had late failures (initial improvement followed by deterioration). Bronchoscopy was found to be helpful in establishing the
bacterial (mycobacteria, Legionella spp, a-streptococcus, Moraxella spp,
anaerobes), viral (adenovirus), or noninfectious causes in all but two cases.
El-Solh et al [79] performed an invasive study using beroptic bronchoscopy in 52 elderly, institutionalized patients with severe pneumonia who had
failed treatment. Twenty patients had denitely dened pneumonia, 28
patients had unveried pneumonia, and four patients had no respiratory
infection. Antimicrobial therapy was changed or discontinued in 50% of
patients with denite pneumonia. Antimicrobial therapy was discontinued
in 39% of patients with unveried pneumonia. In the four patients without
respiratory infection, antimicrobial therapy was discontinued in 75%.
Although bronchoscopic studies provide more reliable information, there is
no signicant eect on the overall mortality rate among these older patients
with severe pneumonia, which in part is likely because of the small number
of study patients. Because of the high mortality rate (42%) among this
group of patients [79], a bronchoscopic evaluation may be diagnostically
and therapeutically helpful in patients with treatment failure.
Open lung biopsy is most useful for identifying noninfectious conditions
and less common or chronic infectious causes, such as tuberculosis and
fungal infections. In patients with CAP and treatment failure, this approach
is seldom necessary.

Summary
Although most patients with suspected CAP respond to empiric therapy,
a small number of patients do not respond in the expected fashion. Age and
underlying comorbid conditions have a strong inuence on the course of
illness. Less common causes of treatment failures include overwhelming
infection, antimicrobial resistance, and misdiagnosis. It is a common
practice for empiric antimicrobial treatment of CAP to be initiated without
microbiologic studies. Clinicians carefully should observe these patients for
unusual or slow responses and should be ready to pursue a more extensive
search for the cause of treatment failure.

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