905

Principles of Antibiotic Management of

Community-Acquired Pneumonia
Michael T. Bender, MD1 Michael S. Niederman, MD2,3

1 NewYork-Presbyterian Hospital, Weill Cornell Medicine, New York,
New York
2 Department of Medicine, Weill Cornell Medical College, New York,
New York
3 Division of Pulmonary and Critical Care Medicine, Department of
Medicine, Weill Cornell Medicine, New York, New York
Address for correspondence Michael S. Niederman, MD, Division of
Pulmonary and Critical Care Medicine, Department of Medicine, Weill
Cornell Medicine, 425 East 61st Street, 4th Floor, New York, NY 10065
(e-mail: msn9004@med.cornell.edu).

Semin Respir Crit Care Med 2016;37:905912.

Downloaded by: State University of New York at Stony Brook. Copyrighted material.
Abstract Community-acquired pneumonia (CAP) encompasses a broad spectrum of disease
severity and may require outpatient, inpatient, or intensive care management. Suc-
cessful treatment hinges on expedient delivery of appropriate antibiotic therapy
tailored to both the likely offending pathogens and the severity of disease. This review
summarizes key principles in starting treatment and provides recommended empiric
Keywords therapy regimens for each site of care. In addition, we discuss the antimicrobial and anti-
pneumonia inammatory role macrolides play in CAP, as well as specic information for managing
initiation of individual CAP pathogens such as community-acquired methicillin-resistant Staphylo-
antibiotics coccus aureus and drug-resistant Streptococcus pneumoniae. We also examine several
duration of antibiotics novel antibiotics being developed for CAP and review the evidence guiding duration of
macrolides therapy and current best practices for the transition of hospitalized patients from
clinical outcomes intravenous antibiotics to oral therapy.

Community-acquired pneumonia (CAP) is the leading cause Timely Initiation of Antibiotics

of death from infectious diseases and is encountered by
clinicians in both the outpatient and inpatient setting. CAP
is responsible for signicant patient morbidity and mortality,
thus adding to healthcare expenditure. This review focuses on
approaches to the optimal antibiotic management of CAP,
including strategies to ensure timely institution of treatment,
appropriate initial antibiotic selection incorporating treat-
ment algorithms tailored to the spectrum of CAP severity, and
specic approaches to commonly encountered pneumonia
pathogens. The discussion also focuses on duration of therapy
and methods that can be employed to guide safe transitions
from intravenous to oral therapy. This review provides clini-
cian with tools required to improve patient outcomes in CAP
and also provides a look at the development of novel agents
for the treatment of CAP that may be available in the near
future.
Optimal CAP outcomes stem not only from the correct
antibiotic choice but also from the initiation of antibiotic
therapy as soon as the diagnosis has been established.
Preferably, antibiotics for admitted patients should be started
in the emergency department1; however, the exact time
frame has been a topic of debate. A recent systematic review2
of clinical data spanning the years between 1995 and 2015
concluded that antibiotics should be given within 4 to 8 hours
of arrival to hospitalized adults with radiographically con-
rmed CAP, especially if they present with moderate to high
illness severity. This recommendation is mainly supported by
retrospective data,37 although two prospective cohort stud-
ies8,9 and one secondary analysis of a randomized trial10
reached similar conclusions. Of note, the authors rated the
quality of evidence supporting this recommendation as poor

Issue Theme Community-Acquired Copyright 2016 by Thieme Medical DOI http://dx.doi.org/

Pneumonia: A Global Perspective; Guest Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0036-1592133.
Editors: Charles Feldman, MBBCh, DSc, New York, NY 10001, USA. ISSN 1069-3424.
PhD, FRCP, FCP (SA), and James D. Tel: +1(212) 584-4662.
Chalmers, MBChB, PhD, FRCPE
906 Principles of Antibiotic Management of CAP
with only four of the aforementioned trials concluding a
modest, but statistically signicant adjusted odds ratio favor-
ing earlier therapy. The remainder of the trials showed no
difference between earlier or less early treatment. The largest
retrospective study to address this question included
1,170,022 adults
65 years and reported a relative reduction
in mortality of 5% when antibiotics were initiated within 6
hours of hospital arrival. Two prior retrospective studies4,6
found a 15% relative reduction in 30-day mortality when
antibiotics were initiated within either 4 or 8 hours. CAP
treatment in critically ill patients with sepsis and shock
should be distinguished from the treatment of less severe
forms of CAP as survival rates decrease by 8% for each hour of
delayed antibiotic administration in those with septic shock.
Antibiotics should therefore be given as soon as possible in
cases of severe CAP.11,12
It is important to emphasize that efforts to achieve early
antibiotic administration should not come at the expense of a
detailed consideration of alternative diagnoses that mimic
bacterial CAP, including acute bronchitis, inuenza, conges-
tive heart failure with associated viral syndrome, aspiration
pneumonitis, pulmonary embolism and infarction, and other
inammatory lung diseases. Attempting to shorten the time
to rst antibiotic dose can have adverse effects. Studies have
detailed that an undue emphasis on antibiotic timing has led
to increased CAP admission diagnoses that were not associ-
ated with radiographic abnormalities and increased antibiot-
ic usage without improvements in mortality,13 along with
reduced accuracy of the emergency department physician to
diagnose CAP.14 Outbreaks of severe Clostridium difcile
disease have been related to unnecessary antibiotic use for
the treatment of presumed CAP.15 Lastly, given the current
focus on processes of care, clinicians should be mindful not to
attribute all improvements in CAP outcomes to timely thera-
py. A prospective study16 from the United Kingdom showed
that while in the majority of the study 13,725 subjects
received antibiotics within 4 hours of presentation, the
data could not prove that reduced 30-day inpatient mortality
(adjusted odds ratio [OR]: 0.84; 95% condence interval [CI]:
0.740.94; p 0.003) resulted from early initiation of anti-
biotics or from other concomitant benecial processes of care.
Empiric Therapy Regimens for CAP in
Relation to Site of Care
Successful selection of empiric CAP treatment hinges on
knowledge of common causative pathogens, host risk factors,
and comorbidities that contribute to infection with specic
organisms. This information paired with the severity of illness
dictates the appropriate therapy choice associated with each
site of CAP care. Although empiric therapy may seem unsat-
isfying, even sputum Gram stain obtained from a good quality
specimen and interpreted by a skilled examiner using objec-
tive criteria1 may not identify a causative agent in the
majority of CAP patients.17,18 Streptococcus pneumoniae is
the most common CAP pathogen, an observation that holds
across the spectrum of CAP severities. In the outpatient
setting, Haemophilus inuenzae, Moraxella catarrhalis, the
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 6/2016
Bender, Niederman
atypical pneumonia pathogens, Mycoplasma pneumoniae and
Chlamydophila pneumoniae, and respiratory viruses have also
been identied as CAP pathogens.19,20 In trials attempting to
characterize outpatient CAP bacteriology, pathogens were
not identied in 51.9 to 68.7% of cases.
Therefore, in outpatients without comorbidities and with no
recent antibiotic use, who reside in low prevalence macrolide-
resistant S. pneumoniae areas (minimum inhibitor concentration
[MIC]
16 g/mL in <25% of isolates), the optimal outpatient
regimens should include azithromycin, clarithromycin, or doxy-
cycline. Outpatients in high prevalence macrolide-resistant
areas, who have recent antibiotic exposure or have signicant
comorbidities (chronic obstructive pulmonary disease [COPD],
bronchiectasis, liver or renal disease, cancer, diabetes, congestive
heart failure, alcoholism, asplenia, chronic prednisone use, or
other immunosuppressing condition) should receive a respira-
tory uoroquinolone alone (levooxacin or moxioxacin), or
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combination therapy with a -lactam effective against S. pneu-
moniae (cefpodoxime, cefuroxime, amoxicillin/clavulanate) and
a macrolide. Additional risk factors for drug-resistant S. pneumo-
niae (DRSP) include age > 65 years old, antibiotic use within the
prior 3 to 6 months, and exposure to a child in a daycare
center.2123 If a patient is unable to use a macrolide, doxycycline
can be used in its place. With the advent of new microbiological
diagnostic tests, including reverse transcriptase polymerase
chain reaction for respiratory viruses, antimicrobial therapy
may be able to be directed against the causative pathogen
when it is identied, but the utility of these tests in clinical
practice is still under evaluation.
For patients managed in the inpatient setting, the bacteri-
ology and virology of CAP change. S. pneumoniae is still the
most common pathogen, but atypical pathogens (including
Legionella pneumophila species), and occasionally both methi-
cillin-sensitive and methicillin-resistant Staphylococcus aureus
(MRSA; especially following inuenza infection), as well as
gram-negative organisms and respiratory viruses should also
be considered. One recent population-based surveillance
study18 of 2,488 patients with CAP requiring hospitalization
employed broad diagnostic testing to accurately account for
CAP pathogens. Despite this effort, a pathogen was identied in
only 38% of cases. At least one respiratory virus was the
presumed causative pathogen in 23% of cases, whereas a
bacterial pathogen was identied in only 11% of cases. Coin-
fection occurred in 3% cases, whereas a fungal or mycobacterial
pathogen was diagnosed in 1% of cases. For each pathogen, the
incidence increased with patient age. These data underscore
the importance of knowing the likely etiologic pathogen when
selecting the optimal empiric therapy for CAP.
Inpatients not requiring intensive care24 can be infected with
gram-negative enteric bacilli and Pseudomonas aeruginosa.
These organisms are even more common in patients admitted
to the intensive care unit (ICU) with CAP. The antibiotic recom-
mendations for inpatients not requiring intensive care include
treatment with a respiratory uoroquinolone alone, or the
combination of an antipneumococcal -lactam (cefotaxime or
ceftriaxone) and a macrolide. Infection with L. pneumophila
should be considered in patients admitted with high fever,
gastrointestinal symptoms, hyponatremia, renal failure, and
 Principles of Antibiotic Management of CAP
elevated liver enzyme tests. Treatment with an intravenous
respiratory uoroquinolone, ideally levooxacin or moxioxa-
cin, for 7 to 10 days is effective, but may need to be given longer
in immunocompromised patients. Quinolone therapy may be
more effective than macrolide regimens based on prospective,
observational, but nonrandomized studies of L. pneumophila
treatment, which found more rapid defervescence, fewer com-
plications, and shorter hospital stays in patients receiving
quinolones.25,26
As mentioned earlier, patients with CAP requiring intensive
care are more likely to be infected with resistant organisms,
including P. aeruginosa and MRSA, as well as L. pneumophila
and S. pneumoniae. Risk factors for P. aeruginosa pneumonia
include recent broad-spectrum antibiotic therapy, bronchiec-
tasis, corticosteroids, malnutrition, and the presence of health
care associated pneumonia (HCAP) risks (nursing home resi-
dence, recent hospitalization, hemodialysis, poor functional
status, and immune suppressive therapy). The approach to CAP
treatment in the ICU is designed to ensure activity against the
aforementioned pathogens. In patients without risk factors for
P. aeruginosa or MRSA, a potent antipneumococcal -lactam
combined with a macrolide is recommended. However,
patients with risk factors for P. aeruginosa require an alterna-
tive approach using an antipseudomonal -lactam (imipenem,
meropenem, piperacillin/tazobactam, or cefepime) combined
with an antipseudomonal quinolone (ciprooxacin or levo-
oxacin). Alternatively, antipseudomonal -lactams combined
with an aminoglycoside plus either a macrolide or an anti-
pneumococcal quinolone should be employed. The approach
to management of community-associated MRSA (CA-MRSA)
pneumonia is discussed in the following section.
Benets of Specic Antibiotic Choices in CAP
Macrolides
One topic that has led to renewed interest and debate is the
role of macrolide therapy in CAP. The benecial impact of
macrolides on CAP outcomes is probably related to both
antibacterial and anti-inammatory effects. Azithromycin
and clarithromycin are antibacterial macrolides with a special
tropism for atypical pneumonia pathogens. Tacrolimus and
sirolimus are anti-inammatory macrolides that interact
with FKBP-12 and inhibit calcineurin phosphatase activity
resulting in T cell suppression to prevent solid organ trans-
plant rejection. Macrolides exert their antibacterial effects by
inhibiting ribonucleic acid synthesis, reducing bacterial pro-
tein and biolm production, while also attenuating bacterial
virulence factors. Macrolide antibiotics also inhibit host cell
cytokine production and release, promote macrophage
phagocytosis of apoptotic cells, and limit neutrophil chemo-
taxis, survival, and oxidative burst.27
The impact of adjunctive macrolide therapy in CAP was
recently evaluated in two prospective studies, with each study
reaching different conclusions. In the CAP-START study,28 a
cluster-randomized trial, patients were randomly assigned to
-lactam monotherapy (n 656), -lactammacrolide combi-
nation therapy (n 739), and uoroquinolone monotherapy
(n 888) during distinct 4-month time intervals, among 6
Bender, Niederman 907
hospitals in the Netherlands. A nonstatistically signicant trend
toward lower 90-day mortality was associated with the uoro-
quinolone and -lactam monotherapy groups (8.8 and 9.0%,
respectively) compared with the -lactammacrolide combina-
tion group (11.1%). The authors concluded that -lactam mono-
therapy was noninferior to -lactammacrolide combination
therapy. Critiques of this paper make this conclusion question-
able. One troubling aspect of the trial was that atypical patho-
gens accounted for an unusually small number of infections
(2.1%) in the study population, whereas L. pneumophila,
M. pneumoniae, and C. pneumoniae were responsible for 6.1%
of infections encountered in hospitalized patients treated
outside of the ICU in one large observational trial.20 Further-
more, CAP was not conrmed radiographically in 25% of the
study population. Approximately 38.7% of the patients treated in
the -lactam group later received antibiotics directed against
atypical organisms during the trial, essentially creating similar
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treatment groups and biasing results. Lastly, although the study
excluded patients managed in the ICU, an aspect that may have
contributed to the low severity of illness seen in the trial (median
CURB-65a score of 1), mortality was not higher when more
severely ill patients were given combination therapy.
These limitations make it difcult to conclude that the
combination of a -lactam and a macrolide is not better than
monotherapy with a -lactam for hospitalized patients with
CAP. In contrast to the CAP-START trial, the study by Garin
et al29 did not nd -lactam monotherapy to be noninferior to
a -lactammacrolide combination therapy for the endpoint
of time to clinical stability after 7 days of treatment in patients
with moderately severe CAP requiring hospitalization.
Approximately 41.2% of the patients in the monotherapy
group did not reach clinical stability compared with 33.6%
of patients in the combination group, with an absolute
difference of 7.6%. Importantly, patients infected with atypi-
cal pathogens (hazard ratio [HR]: 0.33; 95% CI: 0.130.85) or
with pneumonia severity index category IV pneumonia
(HR: 0.81; 95% CI: 0.591.10) were both less likely to reach
clinical stability and more likely to be readmitted within
30 days if treated with monotherapy compared with the
combination therapy group (7.9 vs. 3.1%, p 0.01).
Looking at a wealth of data from other studies, there may
be some question of the value of adding a macrolide in
patients without severe illness, but in those who are severely
ill, the data support the use of macrolide therapy in combi-
nation with -lactam antibiotics, especially if S. pneumoniae
bacteremia is present and there is a need for intensive care. A
meta-analysis30 of 28 observational studies including 9,850
patients with severe CAP found that mortality risk was lower
when patients received macrolides as part of their antibiotic
regimen (risk ratio: 0.82; 95% CI: 0.700.97; p 0.02) with a
trend toward improved mortality when patients were given a
-lactammacrolide combination therapy compared with
those treated with a combination of a -lactam and
uoroquinolone. One prospective, multicenter, international
a
CURB-65 is an acronym for: confusion, elevated blood urea
nitrogen, elevated respiratory rate, low blood pressure, and age of
65 or greater.
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 6/2016
908 Principles of Antibiotic Management of CAP
observation study of 844 adults with S. pneumoniae bacter-
emia found that 14-day mortality was lower (23.4 vs. 55.3%)
when critically ill patients were treated with combination
antibiotics including a macrolide, although the benet was
absent in patients with less severe illness.31 Another study of
CAP complicated by severe sepsis found that the use of
macrolides was associated with decreased 30-day (HR: 0.3;
95% CI: 0.207) and 90-day (HR: 0.3; 95% CI: 0.20.6) mor-
tality.32 Surprisingly, this trend toward improved outcomes
remained when the data were analyzed in patients with
macrolide-resistant pathogens (HR: 0.1; 95% CI: 0.020.5).
Interestingly, a retrospective study33 found improved 30-day
survival when macrolides were added to quinolones com-
pared with quinolone monotherapy (2.91 vs. 4.94%;
p < 0.05). These results and others suggest immune-modu-
latory benets of macrolides in the treatment of CAP.34
The routine use of macrolide therapy for CAP raised
concerns about macrolides causing increased rates of cardio-
vascular adverse events. However, a recent retrospective
study of 73,690 patients admitted to acute care Veterans
Affairs hospitals found signicantly lower 90-day mortality in
patients treated with azithromycin compared with matched
controls (17.4 vs. 22.3%), despite a slight increase risk of
myocardial infarction in patients treated with a macrolide
(5.1 vs. 4.4%). Importantly, there were no differences in the
rates of arrhythmia and congestive heart failure. These data
suggest that the cardiac effects of azithromycin should be
weighed against the benets of an overall favorable impact on
pneumonia outcome. As an alternative in select cases, doxy-
cycline, which is not associated with signicant QT prolonga-
tion,35 can be used in place of azithromycin for patients at risk
of prolonged QT interval. This rationale may extend to
patients with CAP, concomitant bradyarrhythmias, and
uncompensated heart failure, as well as patients receiving
antiarrhythmic medications known to prolong the QT inter-
val. Unfortunately, studies of doxycycline for the treatment of
severe CAP are not robust and doxycycline remains a preg-
nancy category D medication.
Community-Associated Methicillin-Resistant
Staphylococcus aureus Therapy
MRSA pneumonia can occur in previously healthy patients as
CA-MRSA and can also occur in patients with HCAP risk
factors with strains similar to nosocomial MRSA. CA-MRSA
pneumonia is uncommon, but when present, it tends to
complicate inuenza infection or other viral illnesses.
CA-MRSA also appears to be more virulent than nosocomial
MRSA.36 Patients with CA-MRSA are often young and healthy,
but present with serious illness during the summer months
or after inuenza infection. CA-MRSA risk factors include
prior colonization as well as activities associated with expo-
sure to CA-MRSA (contact sports players, injection drugs
users, men who have sex with men, those living in crowded
conditions, and prisoners). An erythematous skin rash,
pustules, or gross hemoptysis can also accompany CA-
MRSA. Neutropenia may be found on routine laboratory
analysis, and imaging can reveal a cavitary lung inltrate or
necrosis. A rapidly increasing pleural effusion may also occur.
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 6/2016
Bender, Niederman
When compared with nosocomial MRSA, CA-MRSA typically
has different pulsed-eld gel electrophoresis patterns
(USA300, USA400), staphylococcal cassette chromosome
mec types (IV, V), and a vancomycin MIC less than 1 g/mL.
CA-MRSA organisms are also sensitive to trimethoprim/sul-
famethoxazole and clindamycin. Most importantly, CA-MRSA
and many strains of CA methicillin-susceptible S. aureus
produce the PantonValentine leukocidin (PVL) toxin as
well as other exotoxins,37 which may be responsible for
some of the necrotizing manifestations of disease.
The optimal treatment of CA-MRSA is uncertain because
the traditional therapy, vancomycin, which is slowly bacteri-
cidal against MRSA, still allows for continued toxin produc-
tion. While a mouse model suggests that PVL may not account
entirely for the virulence of CA-MRSA,38 linezolid in compar-
ison to vancomycin not only reduced PVL toxin production,
but also improved mortality in a rabbit model of USA300
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MRSA necrotizing pneumonia.39 Regardless, a recent retro-
spective study highlighted the danger of continued toxin
production in humans as a dramatic reduction in mortality
(6.1 vs. 52.3%) was seen among the patients with PVL positive
S. aureus pneumonia treated with antibiotics directed against
toxin production (linezolid, rifampin, or clindamycin) com-
pared with patients managed without this approach.40 In
addition, vancomycin has limited penetration into lung tissue
(12% of serum levels) and dosing to achieve consistently
therapeutic levels carries the risk of nephrotoxicity even
when optimal trough levels are achieved. Linezolid inhibits
MRSA toxin production in experimental studies41,42 and has
good lung penetration. While linezolid does not require renal
dose adjustments, side effects include thrombocytopenia,
optic neuritis, and lactic acidosis with prolonged therapy.
Linezolid also interacts with other medications, which may
result in the onset of serotonin syndrome. Other agents for
the treatment of CA-MRSA are under evaluation, and ceftaro-
line, although not approved for MRSA pneumonia, has been
reported to show efcacy in treating MRSA pneumonia and
bacteremia unresponsive to vancomycin.43
Drug-Resistant Streptococcus pneumonia
The advent of DRSP strains continues to complicate empiric
antibiotic decisions for CAP. Current estimates place nearly
40% of S. pneumoniae isolates as resistant to penicillin or
macrolides. Risk factors for drug resistance, as mentioned
previously, include age greater than 65 years, alcoholism,
medical comorbidities, immunosuppressive illness or ther-
apy, exposure to a child in a daycare center, and treatment
in the past 3 to 6 months with -lactam, macrolide, or
uoroquinolone antibiotics. Prior antibiotic treatment
increases the chance for the development of resistance to
other antibiotics within the same class.44,45 S. pneumoniae
develops resistance to -lactam antibiotics when changes
occur in penicillin-binding proteins, resulting in decreased
afnity of the antibiotic to its bacterial binding site. In most
instances, in vitro resistance can be overcome with optimal
dosing levels of most -lactam antibiotics. In patients with
CAP without distant sites of infection (such as meningitis),
multiple studies have shown that currently recommended
 Principles of Antibiotic Management of CAP
doses for CAP therapy are sufcient to overcome resistance
and treat infection.4648
As a result of such data, the MIC breakpoint for suscepti-
bility testing of S. pneumoniae isolated in non-meningeal
infections was increased to 2 g/mL in 2008, reecting the
fact that few organisms have clinically relevant levels of
resistance. One instance where discordant therapy may be
problematic is when cefuroxime is selected. One prospective
trial47 including 844 patients with S. pneumoniae bacteremia
found a higher mortality rate when patients with cefuroxime-
resistant pneumococcus were treated with cefuroxime than
with alternative therapies. Interestingly, in cases of DRSP
bacteremia, the addition of azithromycin to an active
-lactam agent improved mortalitya nding that is likely application for skin or soft-tissue infection, as the antibiotic is
related to anti-inammatory properties of the macrolide.31
Quinolones and Their Role in Community-Acquired
Pneumonia
Based on several large randomized trials, quinolone monother-
apy is effective for non-ICU CAP patients when compared with
-lactam therapy with or without the use of a macrolide.49,50 In
the elderly, quinolone monotherapy is safe and effective, but
moxioxacin may lead to a more rapid clinical response than
levooxacin.51 While one meta-analysis52 of 23 randomized
trials concluded that respiratory uoroquinolones were more
likely to lead to treatment success than -lactam and macrolide
combination therapy (OR: 1.39; 95% CI: 1.021.90), a review53
completed afterward could not demonstrate the superiority of
either regimen. Based on these results, it seems reasonable to
treat milder forms of CAP with a uoroquinolone after consid-
ering adverse effects such as the risk of developing tendon injury,
diarrhea, QT prolongation, and the possibility that overuse can
promote resistance of S. pneumoniae to this class of antibiotics.54
Although there is no role for uoroquinolone monotherapy, or
monotherapy with any antibiotic for that matter, in the treat-
ment of severe forms of CAP, one clearly established benecial
role for uoroquinolones in CAP is in the treatment of
L. pneumophila pneumonia, as discussed previously.
Novel Antibiotics for Community-Acquired Pneumonia
The development of novel antibiotics to treat CAP has been
hampered by issues with discovering new agents and classes
of therapy, lack of economic incentives for pharmaceutical
companies especially when antibiotic stewardship programs
discourage the use of new agents, the efforts of clinicians to
use shorter antibiotic courses, and inherent regulatory and
trial design barriers, which lengthen the time needed for drug
approval.55 However, despite these hurdles, the need for new
treatments in CAP is paramount, as resistance to current
therapy continues to occur.
The ketolides represent a subclass of macrolide antibiotics
designed to be effective against macrolide-resistant respira-
tory pathogens. An efcacy and safety trial56 of oral solithro-
mycin versus oral moxioxacin in a population of 860
patients with CAP found that solithromycin was noninferior
to the control group in the treatment of community-acquired
bacterial pneumonia with similar rates of adverse effects and
high rates of early clinical response. The most frequently
Bender, Niederman 909
encountered adverse events were gastrointestinal disorders.
Another drug under development for CAP is omadacycline, an
aminomethylcycline active against DRSP and MRSA, as well as
some gram-negative pathogens. Lefamulin is a member of a
new class of antibiotics known as the pleuromutilins, which
have activity against common CAP pathogens along with
MRSA and its vancomycin-resistant strains, and is currently
under evaluation.
Novel quinolone antibiotics designed to overcome resis-
tance include nemonoxacin57 and zabooxacin,58 both of
which have been studied in safety and efcacy trials for
treatment of CAP, as well as isothiazoloquinolone,59 which
is active against MRSA. Its role may be limited to topical
extensively metabolized when dosed systemically. Tedizolid,
an oxazolidinone, is active against linezolid-resistant MRSA
and does not appear to interact with other serotonergic
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agents, thus potentially avoiding serotonin syndrome. Addi-
tionally, multiple new therapies for antibiotic-resistant gram-
negative bacilli, including extended spectrum -lactam-
resistant Enterobacteriacae and Acinetobacter baumanni, are
under active investigation.60
Duration of Therapy and Converting to Oral
Therapy
Three international guidelines1,61,62 have evaluated the dura-
tion of antibiotic treatment in CAP and the consensus is that a
5- to 7-day course of antibiotics is recommended for patients
who show good clinical response to therapy assessed after 2 to
3 days of treatment. Patients should be afebrile for 48 to 72
hours, breathing at baseline oxygen level (either ambient air or
the ow rate required to compensate for preexisting disease),
and vital signs should not include more than two abnormal
clinical instability factors (dened as heart rate > 100 beats
per minutes, respiratory rate > 24 breaths per minute, and
systolic blood pressure < 90 mm Hg) prior to discontinuing
antibiotics. Additional evidence supporting antibiotic courses
less than 7 days stems from a meta-analysis,63 which included
15 (however, only 2 focused on hospitalized patients) random-
ized controlled trials of 2,796 subjects with mild to moderate
CAP. The authors found no difference in the risk of clinical
failure between short-course ( 7 days) and extended-course
(> 7 days) regimens (0.89; 95% CI: 0.781.02), no difference in
mortality risk (0.81; 95% CI: 0.461.43), or bacterial eradica-
tion (1.11; 95% CI: 0.761.62). However, longer durations of
therapy are warranted in situations when the pneumonia is
due to P. aeruginosa, S. aureus (especially MRSA), Legionella
species, or other unusual pathogens, especially if the initial
treatment was not active against the subsequently identied
pathogen, or if the pneumonia is complicated by empyema,
lung abscess, lung necrosis, or extrapulmonary infection, such
as endocarditis or meningitis. The length of therapy for MRSA
pneumonia without evidence of distant infection depends not
only on the extent of disease, but also on clinical severity, with
typical treatment duration lasting anywhere from 7 to 21 days.
Recent research efforts have focused on shorter duration of
therapy for MRSA, keeping with the theme of attempting to
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 6/2016
910 Principles of Antibiotic Management of CAP Bender, Niederman

Table 1 Summary of key points in CAP antibiotic management

1. Timely initiation of therapy: treatment (within 48 h) for hospitalized patients with CAP can improve outcome and should
be used. In patients with severe pneumonia, therapy should be started even sooner because any delay in therapy
has deleterious consequences.
2. Empiric treatment: antibiotic choice varies according the site of care decision, which is based on illness severity.
Hospitalized patients may benet more from a combination regimen that includes a macrolide with a -lactam rather
than -lactam monotherapy. In patients with Legionella pneumonia, a quinolone is preferable to a macrolide.
3. Specic pathogens: CA-MRSA pneumonia is best treated with medications that afford both antibactericidal and
antitoxin effects; DRSP remains a problem, however, current doses of antibiotics are sufcient to overcome resistance.
4. Duration of therapy: 57 d of treatment is effective in the treatment of CAP; however, longer durations may be required
based on the pathogen identied, especially if the pathogen is resistant to the initial treatment selected, as well as if
the patient had a suboptimal response to therapy or evidence of extrapulmonary infection.
5. Converting from oral to intravenous therapy: the use of objective criteria combined with integrated case management
may lead to shorter hospitalizations, without compromising clinical outcomes or leading to increased readmission rates
related to pneumonia.

Abbreviations: CA-MRSA, community-associated methicillin-resistant Staphylococcus aureus; CAP, community-acquired pneumonia; DRSP, drug-

Downloaded by: State University of New York at Stony Brook. Copyrighted material.
resistant Streptococcus pneumoniae.

reduce antibiotic exposure without compromising clinical
outcomes.64 Finally, procalcitonin measurement in CAP may
assist clinicians in reducing antibiotic exposure without
sacricing patient safety. A 2012 Cochrane meta-analysis65
of 14 randomized controlled trials with a total of 4,221 patients
found no increased risk for all-cause mortality or treatment
failure when procalcitonin was used to guide both the initia-
tion and duration of antibiotic treatments in immunocompe-
tent patients (analysis excluded HIV positive patients and
patients receiving immunosuppressive therapy or chemother-
apy) with acute respiratory infections. Total antibiotic expo-
sure was also signicantly reduced from a median of 8 days
(interquartile range [IQR]: 5 to 12) to 4 days (IQR: 0 to 8).
Procalcitonin may have its greatest value when clinicians are
considering durations of therapy greater than 7 days or there is
uncertainty if a lung inltrate is truly infectious in origin.
It is also important to determine the optimal timing of the
switch from intravenous to oral therapy for hospitalized
patients. One large multicenter randomized controlled trial66
concluded that with the use of a protocol, intravenous anti-
biotics could be safely transitioned to oral antibiotics 3.5 days
earlier, reducing hospital length of stay by nearly 2 days,
without compromising a composite endpoint of death, con-
tinued hospitalization at 28 days, or clinical deterioration.
Criteria for switching to oral therapy include respiratory
rate < 25 breaths per minute, oxygen saturation > 90% or
partial pressure of arterial oxygen > 55 mm Hg, no hemody-
namic instability, greater than 1C decrease in temperature in
patients with fever, the absence of mental confusion, and the
ability to tolerate oral medications. These results conrm the
ndings of prior studies that show the benet of using
objective criteria to guide the transition from intravenous
to oral antibiotics,67,68 as well as assist clinicians with
discharge decisions.69,70 One recent study71 showed that an
intervention designed to include automatic stop dates, guid-
ing the duration of antibiotics by CURB-65 score, and multi-
disciplinary discussions with pharmacists signicantly
reduced the duration of treatment from 8.3 to 6.8 days,
resulting in fewer adverse antibiotic events without affecting
mortality or hospital length of stay. Indeed, an implementa-
tion strategy that incorporates objective measures guiding
transition from intravenous to oral therapy has added bene-
ts. One prospective trial72 concluded that intensive clinical
case management, paired with objective measures, led to a
substantial reduction in length of stay, improved progressive
ambulation, and improved preventative pneumonia care,
without differences in mortality or hospital readmission
rates.
Conclusions
Successful antibiotic management in the treatment of CAP
encompasses fundamental knowledge of the causative patho-
gens in different settings and adjusting therapy to both the
severity of illness and site of care (Table 1). These tasks
cannot be completed without an understanding of risk factors
for specic CAP pathogens and considering resistance trends
when selecting therapy. Furthermore, improved outcomes are
optimized not only when treatment is initiated in a timely
fashion, but also when the optimal duration of therapy is
chosen. Tailoring therapy to an identied pathogen and
converting antibiotics from intravenous to oral routes in a
safe and efcient manner contributes to antibiotic steward-
ship. These strategies have the potential to decrease antibiotic
resistance without sacricing benecial outcomes in the man-
agement of CAP. Regardless, novel antibiotics are required to
overcome existing resistance and ensure continued success in
the treatment of CAP.
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