Infectious Pulmonary

Diseases
a, b,1
Rachel Rafeq, PharmD *, Lauren A. Igneri, PharmD, BCPS, BCCCP

KEYWORDS
 Community-acquired pneumonia  Hospital-acquired pneumonia
 Ventilator-associated pneumonia  Antimicrobial stewardship  Allergies
 Cross-sensitivity  Procalcitonin  MRSA nasal screening

KEY POINTS
 Community-acquired pneumonia is most commonly caused by Streptococcus pneumo-
niae and requires various antimicrobial therapy depending on patient disposition and
severity of disease.
 Patients with hospital-acquired and ventilator-associated pneumonia are at risk for
multidrug-resistant pathogens, especially following exposure to intravenous antibiotics
within the last 90 days.
 Immunocompromised populations may require broader spectrum antimicrobial therapy to
accommodate additional organisms not typically seen in non-immunocompromised
populations.
 Although guidelines serve as an important source for appropriate treatment of pneumonia,
a shift in emphasizing individualized approaches to antibiotic therapy is needed to
improve patient outcomes.

INTRODUCTION

Pneumonia is a lower respiratory tract infection caused by the inability to clear path-
ogens from the lower airway and alveoli. Cytokines and local inflammatory markers are
released, causing further damage to the lungs through an inflammatory cascade lead-
ing to an accumulation of white blood cells and fluid congestion, leading to pus in the
parenchyma. The Infectious Diseases Society of America (IDSA) defines pneumonia
as the presence of new lung infiltrate with other clinical evidence supporting infection,

This article was previously published in Emergency Medicine Clinics 40:3 August 2022.
No commercial or financial conflicts of interest or any funding sources to disclose.
Statement of authorship – both authors contributed equally to this article.
a
Emergency Medicine, Department of Pharmacy, Cooper University Healthcare, 1 Cooper
Plaza, Camden, NJ 08103, USA; b Critical Care, Department of Pharmacy, Cooper University
Healthcare, 1 Cooper Plaza, Camden, NJ 08103, USA
1
Author contributed equally to the publication of this article
* Corresponding author.
E-mail address: rafeq-rachel@cooperhealth.edu

Infect Dis Clin N Am 38 (2024) 1–17

https://doi.org/10.1016/j.idc.2023.12.006 id.theclinics.com
0891-5520/24/Published by Elsevier Inc.

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2 Rafeq & Igneri

including new fever, purulent sputum, leukocytosis, and decline in oxygenation.

Importantly, lower respiratory infections remain the deadliest communicable disease.
Ranking as the fourth leading cause of death worldwide, 2.6 million lives were claimed
from pneumonia in 2019.

COMMUNITY-ACQUIRED PNEUMONIA

Community-acquired pneumonia (CAP) is a leading cause of hospitalization and death

in the United States with more than 1.5 million Americans hospitalized annually.1 It ac-
counts for 4.5 million outpatient and emergency department visits annually. Up to 30%
of mortality among intensive care unit (ICU) patients are related to pneumonia, with S
pneumoniae remaining the most common bacterial pathogen implicated in CAP
despite vaccine availability.2 The understanding of microbiologic studies and inflam-
matory markers, such as procalcitonin (PCT), can be used to guide management.
The American Thoracic Society (ATS) and the IDSA provide antibiotic recommenda-
tions, which will vary depending on whether outpatient or inpatient management is
required.
Etiology
Several bacterial pathogens and some viral and fungal pathogens are implicated in the
cause of CAP including:3

Bacterial
Pathogen Characteristics
Streptococcus  Aerobic, gram-positive diplococcus.
pneumonia  The most common cause of CAP; however, the incidence has decreased
over the years with the widespread use of pneumococcal vaccine.
Haemophilus  Aerobic gram-negative coccobacillus.
influenza  Spread person to person via airborne droplets or through direct contact
with respiratory secretions of an infected or colonized individual.
Legionella  Atypical pathogen
pneumophila  Gram-negative bacilli, classified as an atypical pneumonia.
 Implicated in <4% of all CAP cases.
Mycoplasma  Atypical pathogen
pneumonia  Unlike other bacteria, it does not contain a cell wall rendering beta-lactam
antimicrobial ineffective.
 Unable to be gram stained due to the lack of cell wall.
Chlamydia  Atypical pathogen
pneumonia  Obligate intracellular gram-negative bacteria.
Moraxella  Gram-negative diplococcus that commonly produces beta-lactamase,
catarrhalis rendering it mostly resistant to amoxicillin.
 Most frequently found as part of normal flora in infants and children but
decreases in adults.
Pseudomonas  Implicated in up to 8.3% of severe CAP requiring ICU admissions.
aeruginosa  Pseudomonal infection is associated with poorer clinical outcomes and
multidrug resistance.

 Viruses
 CAP pathogens include coronaviruses (in 2020, primarily SARS-CoV-2), influ-
enza A, RSV, parainfluenzea, adenovirus, human metapneumovirus, and
rhinovirus.
 The Center for Disease report of 2300 adults hospitalized with CAP showed the
most common identified pathogens were rhinovirus (9%), influenza (6%), and
S pneumoniae (5%). No pathogens were identified in 62% of cases.

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 Infectious Pulmonary Diseases 3

 Pathogens to be considered in special circumstances (eg,

immunocompromised)
 Mycobacterium tuberculosis
 Nocardia spp.
 Pneumocystis jirovecii
 Aspergillus spp.
 Mucorales spp.
 Varicella-zoster virus
 Cytomegalovirus
 Group A Streptococcus
 Neisseria meningitidis
 Anaerobes (aspiration pneumonia)

Prognosis Assessment Tools

Clinical comorbidities and social habits (eg, smoking) may worsen or increase the risk
of CAP. The pneumonia severity index (PSI) and CURB-65 are assessment tools used
to predict 30-day mortality in immunocompetent patients (Tables 1 and 2).4 PSI is rec-
ommended over CURB-65 because it has a higher discriminative power in predicting
mortality .5

Diagnostic Strategies
Microbiologic studies are integral to guiding antimicrobial treatment and vary
depending on whether outpatient or inpatient management is required. In the outpa-
tient setting, pretreatment sputum gram stain, the culture of the lower respiratory se-
cretions, and blood cultures are not recommended.5 However, these studies are
crucial in hospital patients, particularly in patients being managed for severe CAP
or the patients who are empirically treated for methicillin-resistant Staphylococcus
aureus (MRSA) or Pseudomonas aeruginosa. In addition, these tests should be per-
formed for all patients previously infected with MRSA or Pseudomonas spp., or who
were hospitalized and received intravenous antibiotics in the last 90 days. In patients
with severe CAP, urine Legionella and pneumococcal antigen testing are
recommended.5
The 2019 CAP guidelines address the use of PCT and corticosteroids, which differs
from the prior 2007 guideline. PCT, regardless of level, is not recommended to deter-
mine the need for empiric antibiotic initiation. Instead, clinical criteria and radiograph-
ically confirmed infiltrate should guide the administration of antimicrobials. Although
corticosteroids also are not recommended for routine use, they may be considered
in patients with septic shock (Table 3).5

Therapeutic Options
Antimicrobial treatment is initiated on an empiric basis and in hospitalized
patients may be streamlined once the causative organism is identified (Tables 4
and 5).
The etiology of disease is important for several reasons. As empiric therapy tends to
be broad to cover a wide range of possible pathogens, the culture results will allow
providers to narrow therapy and determine resistance if applicable.
Risk factors for MRSA or P aeruginosa:5
 Prior respiratory isolation of MRSA or P aeruginosa
 Recent hospitalization plus receipt of parenteral antibiotics in the last 90 days

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4 Rafeq & Igneri

Table 1
Pneumonia severity index

Patient Characteristics Points Assigned

Demographic Factors
Age 1 point per year
Men Age (y)
Women Age (y) – 10
Nursing home resident 1 10
Comorbid Illnesses
Neoplastic disease 130
Liver disease 120
Congestive heart disease 110
Cerebrovascular disease 110
Renal disease 110
Physical examination findings
Altered mental status 1 20
Respiratory rate  30 breaths/min 1 20
Systolic blood pressure <90 mmHg 1 20
Temperature <30 or 40 C 1 15
Pulse 125 beats/min 1 10
Laboratory findings
PH <7.35 130
blood urea nitrogen >10.7 mmol/L 120
Sodium <130 meq/L 120
Glucose >13.9 mmol/L 110
Hematocrit <30% 110
PO2 < 60 mmHg (or SaO2<90%) 110
Pleural effusion 110

Risk Points Mortality Patient Care

Class Total Rate Location
I <51 0.1% Outpatient
II 51–70 0.6% Outpatient
III 71–90 2.8% Observation
unit with
reevaluation
if possible
IV 91–130 8.2% Inpatient
V >130 29.2% Inpatient,
likely ICU

Aspiration Pneumonia
In the new 2019 guidelines, the IDSA/ATS suggest not routinely adding anaerobic
coverage for suspected aspiration pneumonia unless there is suspicion of or known
lung empyema or abscess. Many patients with aspiration pneumonia are found to
have self-limiting symptoms that resolve in 24 to 48 hours and only require supportive
care without the need for antibiotics. Avoidance of unnecessary antimicrobial therapy
has become paramount in light of the growing body of evidence for increased

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 Infectious Pulmonary Diseases 5

Table 2
CURB-65 criteria

Characteristics Points Total

Confusion 1
Increased blood urea 1
nitrogen >20 mg/dL
Respiratory rate 30 breaths/min 1
Blood pressure 1
(systolic BP <90 mmHg
or diastolic 60 mmHg)
Age >65 y 1

Total
Score Recommendation
0–1 Low risk; outpatient treatment
2 Moderately severe; short inpatient
hospitalization or closely
supervised outpatient treatment
3–5 Severe pneumonia; hospitalization
required; consider intensive care
unit admission

Clostridioides difficile infection and multidrug-resistant (MDR) pathogens associated

with broad-spectrum antimicrobials (eg, cefepime, ceftriaxone, carbapenems, fluoro-
quinolones, clindamycin, and so forth).5

Antimicrobial Dosing
Although the CAP guidelines provide clear dosing recommendations for some treat-
ment options, dosing ranges are provided for severe infection treatment options to
allow clinicians selection of an optimal dose based on patient-specific characteristics.
A systematic review and meta-analysis by Telles and colleagues evaluated the effi-
cacy of ceftriaxone 1 g versus 2 g daily for the treatment of CAP based on data pooled
from 24 randomized controlled trials. Of note, trials including critically ill patients were
excluded: 12 studies evaluated ceftriaxone 1 g and 12 studies evaluated ceftriaxone
2 g. Comparator regimens show similar efficacy ceftriaxone 1 g daily dosing [OR

Table 3
Severe community-acquired pneumonia criteria5

Severe CAP Is Defined as Having Three or More Minor Criteria OR One Major Criteria
Minor criteria  Confusion/disorientation
 Hypotension requiring aggressive fluid resuscitation
 Hypothermia (core temperature <36 C)
 Leukopenia from infection along (ie, not related to chemotherapy)
defined as white blood cell count <4000 cells/mL
 Multilobar infiltrates
 PaO2/FiO2 ratio 250
 Respiratory rate 30 breaths/min
 Uremia (blood urea nitrogen level 20 mg/dL)
Major criteria  Respiratory failure requiring mechanical ventilation
 Septic shock with the need for vasopressors

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6 Rafeq & Igneri

Table 4
Outpatient community-acquired pneumonia therapeutic options5

Patient Characteristics Antimicrobial Therapy of Choice

No comorbidities or  Amoxicillin 1 g oral three times daily OR
risk factors for MRSA  Doxycycline 100 mg oral twice daily OR
or P aeruginosa  Azithromycina 500 mg oral on day 1,
azithromycin, 250 mg oral on days 2–4
 Clarithromycina 500 mg oral twice daily
or clarithromycin ER 1000 mg oral daily
With comorbiditiesb  Combination therapy with:
 Amoxicillin/clavulanate 500 mg/125 mg
three times oral daily, amoxicillin/clavulanate
875 mg/125 mg oral twice daily, amoxicillin/
clavulanate 2000 mg/125 mg oral twice daily,
cefpodoxime 200 mg oral twice daily, or
cefuroxime 500 mg oral twice daily
AND
Azithromycin, 500 mg oral on the first day
then 250 mg oral daily, clarithromycin
500 mg oral twice daily, clarithromycin
ER 1000 mg oral daily, or doxycycline 100 mg oral twice daily
 Monotherapy with respiratory fluoroquinolone
levofloxacin 750 mg oral daily, moxifloxacin
400 mg oral daily, or gemifloxacin 320 mg oral daily
a
Use macrolides only if local pneumococcal resistance is less than 25%.
b
Chronic heart, liver, lung or renal disease, diabetes mellitus, alcoholism, malignancy, or asplenia.

1.03 (95% CI [0.88–1.20])], and dosages higher than ceftriaxone 1 g daily did not result
in improved clinical outcomes for CAP (OR 1.02, 95% CI [0.91–1.14]).6
Hasegawa and colleagues supported these findings in their evaluation of ceftriax-
one 1-g versus 2-g daily dosing. A similar rate of clinical cure was seen with ceftriax-
one 1 g (94.6%) versus 2 g (93.1%), risk difference 1.5% (95% CI 3.1–6.0, P 5 .009 for
non-inferiority). These studies prove that ceftriaxone 1 g daily is as safe and effective
as other CAP regimens, including higher ceftriaxone dosing.7 This is important as cli-
nicians look to reduce antimicrobial resistance by minimizing excessive antimicrobial
exposure.

Treatment Duration
Treatment duration varies based on the resolution of vital sign abnormalities, ability to
eat, and normal mentation. IDSA recommends no less than 5 days of therapy in un-
complicated outpatient CAP, and several meta-analysis studies have demonstrated
successful efficacy with 5 to 7 day treatment durations.5,8–10 Inpatient CAP treatment
should also be not less than 5 days unless MRSA or P aeruginosa is involved, then it is
not less than 7 days.
In patients with complicated CAP, such as those with concurrent meningitis or
endocarditis, 5 to 7 days of treatment is not sufficient, and longer durations are war-
ranted.5 PCT may be a useful biomarker to help guide treatment duration and is dis-
cussed further in the Antimicrobial Stewardship section.

HOSPITAL-ACQUIRED PNEUMONIA

The IDSA, the ATS, and international guidelines define hospital-acquired pneumonia
(HAP) as a nosocomial infection of the lung parenchyma not present at the time of

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 Infectious Pulmonary Diseases 7

Table 5
Inpatient community-acquired pneumonia therapeutic options5

NO Risk for P aeruginosa or MRSA

Non-severe Combination therapy with ampicillin–sulbactam 1.5–3 g IV every 6 h,
cefotaxime 1–2 g IV every 8 h, ceftriaxone 1–2 g IV daily, or ceftaroline
600 mg IV every 12 h
Plus Azithromycin 500 mg oral or IV daily or clarithromycin 500 mg oral twice
daily
OR monotherapy with levofloxacin 750 mg oral or IV daily or moxifloxacin
400 mg oral or IV daily
Severe Combination therapy with ampicillin–sulbactam 1.5–3 g IV every 6 h,
cefotaxime 1–2 g IV every 8 h, ceftriaxone 1–2 g IV daily, or ceftaroline
600 mg IV every 12 h
Plus Azithromycin 500 mg oral or IV daily or clarithromycin 500 mg oral twice
daily
OR Levofloxacin 750 mg oral or IV daily or moxifloxacin 400 mg oral or IV
daily

WITH Risk Factors for P aeruginosa or MRSA

MRSA If prior respiratory isolation of MRSA, IV antibiotics within the last 90 d,
suspected necrotizing pneumonia or empyema regardless of non-severe or
severe CAP
 MRSA coverage: Vancomycin 15 mg/kg IV every 12 h (adjusted with TDM)
or linezolid IV 600 mg every 12 h
 Obtain cultures/nasal MRSA PCR to allow for de-escalation or confirmation
of the need to continue therapy
P aeruginosa If prior respiratory isolation of P aeruginosa, hospitalization within the last
90 d and receipt of intravenous antibiotics within the last 90 d regardless
of non-severe or severe CAP
 Piperacillin–tazobactam 4.5 g IV every 6 h, cefepime 2 g IV every 8 h,
ceftazidime 2 g IV every 8 h, imipenem 500 mg IV every 6 h, meropenem
1 g IV every 8 h, or aztreonam 2 g IV every 8 h
 Obtain cultures to allow for de-escalation or confirmation of the need to
continue therapy

hospital admission that develops in patients after 48 hours of hospitalization. A sub-

type of HAP is ventilator-associated pneumonia (VAP), occurring in patients who
have required mechanical ventilation for at least 48 hours.11,12 Health care-
associated pneumonia (HCAP) had previously been included in the HAP and VAP
guidelines, but it was removed in the most recent update as new literature demon-
strates that patients with HCAP are not at high risk for MDR pathogens as previously
thought and are probably better categorized within the CAP guidelines.11
Diagnostic Strategies
In nosocomial pneumonia, microbiological studies should be performed before initia-
tion of antimicrobial therapy to guide definitive therapy.
Noninvasive, qualitative, or semiquantitative cultures (eg, spontaneous expectora-
tion, sputum inductions, nasotracheal suctioning, and endotracheal aspiration) are
preferred over invasive, quantitative sampling strategies (eg, bronchial-alveolar
lavage, protected specimen brush, and blind bronchial sampling) as no statistically
significant difference in mortality rates were found between quantitative and qualita-
tive cultures (RR 0.91; 95% CI 0.75–1.11).13 No difference in other clinical outcomes,
including duration of mechanical ventilation, ICU length of stay, and antibiotic change,

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8 Rafeq & Igneri

were seen with the two sampling strategies.13 In addition, noninvasive sampling can
be performed rapidly and avoid delays in the initiation of effective antimicrobial ther-
apy.11 Blood cultures should be obtained for patients with suspected HAP/VAP as
they may provide insight into the severity of illness and direct antimicrobial initiation
and ultimately play a role in determining appropriate definitive therapy.
In general, clinical criteria for pneumonia should guide the initiation of empiric anti-
microbial therapy in HAP/VAP. Although biomarkers such as PCT, c-reactive protein,
or bronchial alveolar fluid soluble triggering receptor expressed on myeloid cells
(sTREM-1) have been studied for the initiation of antimicrobial therapy in HAP/VAP,
none have been associated with acceptable sensitivity or specificity for the diagnosis
of HAP/VAP compared with using clinical criteria alone.11

Therapeutic Options
Although prior guidelines differentiated empiric treatment for nosocomial pneumonia
based on the bacteriology of disease onset, early (within 4 days) versus late (5 days
or more), recent literature indicates that patients with the early-onset disease may still
be at risk for MDR pathogens.12 Therefore, risk stratification for MDR organisms should
not be based solely on disease onset. Prior intravenous antibiotic use within the last
90 days is the major risk factor for the development of MDR (eg, MRSA, Pseudomonas
spp., and so forth), VAP (OR 12.3; 95% CI 6.48–23.35), and HAP (OR 5.17; 95% CI 2.11–
12.67).11 In addition, patients with VAP may be at increased risk of MDR pathogens
when infection occurs on hospital day 5 or later or is complicated by septic shock, acute
respiratory distress syndrome (ARDS), or need for acute renal replacement therapy.11
Empiric antimicrobial therapy selections for HAP and VAP should be stratified based
on patient risk factors for MDR pathogens, as outlined in Tables 6 and 7. Antipseudo-
monal beta-lactam therapy is the cornerstone of nosocomial pneumonia treatment.
Empiric, dual antipseudomonal coverage from different antibiotic classes is indicated
in VAP when the patient has a risk factor for MDR pathogen, greater than 10% of
gram-negative isolates are resistant to the antimicrobial being considered for mono-
therapy or local ICU susceptibilities are unavailable, and in HAP when there is a risk
for MDR pathogen, need for mechanical ventilation, or presence of shock.11 However,
dual antipseudomonal therapy is controversial, and ultimately local sensitivities should
be taken into consideration when determining empiric therapy. Intensivists should
collaborate with antimicrobial stewardship (AMS) to develop local treatment pathways
that are based on the national guidelines but are tailored to local data.14
Anti-MRSA antimicrobials are indicated for patients with HAP or VAP when there is a
risk factor for MDR organisms or if an infection develops in hospital wards whereby
greater than 10% to 20% of Staphylococcus aureus are methicillin-resistant. Other-
wise, empiric treatment for HAP or VAP should target methicillin-sensitive S aureus.11

Clinical Considerations with Antimicrobial Selection and Dosing

Patient-specific factors including allergy history, organ function, and concomitant
medications should be evaluated when selecting empiric antimicrobial regimens. His-
torically, piperacillin–tazobactam with vancomycin was recommended for empiric
HAP/VAP treatment. However, a recent literature shows the odds of acute kidney
injury with vancomycin plus piperacillin–tazobactam are significantly increased
compared with vancomycin monotherapy (OR 3.40; 95% CI 2.57–4.50), vancomycin
plus cefepime or carbapenem therapy (OR 2.68; 95% CI 1.83–3.91), or piperacillin–
tazobactam monotherapy (OR 2.70; 95% CI 1.97–3.69).15 Therefore, the use of cefe-
pime in place of piperacillin–tazobactam may be preferable to avoid potential nephro-
toxicity complications.

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Table 6
Empiric antimicrobial therapy for hospital-acquired pneumonia11

Patient Characteristics Antimicrobial Therapy Choices

High risk of mortalitya or received IV Select two of the following, avoid double beta-lactam Plus anti-MRSA therapy:
antimicrobials in the past 90 d therapy or same drug class:  Vancomycin, 25–30 mg/kg IV once followed by 15 mg/
 Piperacillin–tazobactam 4.5 g IV every 6 h kg IV every 8–12 h with TDM targeting through 15–
 Cefepime or ceftazidime 2 g IV every 8 h 20 mg/mL, or
 Levofloxacin, 750 mg IV daily or ciprofloxacin 400 mg  Linezolid 600 mg IV every 12 h
IV every 8 h
 Imipenem 500 mg IV every 6 h or meropenem 1 g IV
every 8 h
 Amikacin 15–20 mg/kg IV daily
 Gentamicin or tobramycin 5–7 mg/kg IV daily
 Aztreonam 2 g IV every 8 h
Not high risk of mortality, Select two of the following, avoid double beta-lactam Plus anti-MRSA therapy:
but MRSA risk factor(s) presentb therapy or same drug class:  Vancomycin 25–30 mg/kg IV once followed by 15 mg/
 Piperacillin–tazobactam 4.5 g IV every 6 h kg IV every 8–12 h with TDM targeting through 15–
 Cefepime or ceftazidime, 2 g IV every 8 h 20 mg/mL or
 Levofloxacin 750 mg IV daily or ciprofloxacin 400 mg  Linezolid 600 mg IV every 12 h
IV every 8 h
 Imipenem 500 mg IV every 6 h or meropenem 1 g IV

Infectious Pulmonary Diseases

every 8 h
 Aztreonam 2 g IV every 8 h
Not high risk of mortality Select one of the following:
and no MRSA risk factor(s) presentb  Piperacillin–tazobactam 4.5 g IV every 6 h
 Cefepime or ceftazidime 2 g IV every 8 h
 Levofloxacin 750 mg IV daily or
 Imipenem 500 mg IV every 6 h
 Meropenem 1 g IV every 8 h
a
High risk for mortality: requiring ventilatory support or presence of septic shock.
b
MRSA risk factors: prior intravenous antibiotic use within the last 90 d, hospital wards with greater than 10% to 20% MRSA isolates.

9
 10
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Rafeq & Igneri

Table 7
Empiric antibiotic therapy for ventilator-associated pneumonia11

Patient Characteristics Antimicrobial Therapy Choices

 Received IV antimicrobials in the past 90 d Select one agent from each category: Plus anti-MRSA therapy:
 Septic shock at onset of VAP b-lactams  Vancomycin 25–30 mg/kg IV once followed by
 ARDS preceding VAP  Piperacillin–tazobactam 4.5 g IV every 6 h 15 mg/kg IV every 8–12 h with TDM targeting
 Acute renal replacement therapy preceding VAP  Cefepime or ceftazidime 2 g IV every 8 h through 15–20 mg/mL or
 VAP onset hospital day 5 or later  Imipenem 500 mg IV every 6 h or meropenem  Linezolid 600 mg IV every 12 h
1 g IV every 8 h
 Aztreonam 2 g IV every 8 h
Non-b-lactams
 Levofloxacin 750 mg IV daily or ciprofloxacin
400 mg IV every 8 h
 Amikacin 15–20 mg/kg IV daily
 Gentamicin or tobramycin 5–7 mg/kg IV daily
 Colistin 5 mg/kg IV loading dose followed by
maintenance dose (2.5 mg*CrCl 1 30) IV every
12 h or polymyxin B 2.5–3.0 mg/kg/d divided
twice daily
 Infectious Pulmonary Diseases 11

Linezolid may increase the risk of serotonin syndrome when given with serotonergic
medications (eg, selective serotonin reuptake inhibitors, serotonin–norepinephrine re-
uptake inhibitors, serotonin receptor agonists, tricyclic antidepressants, monoamine
oxidase inhibitors, and opioid medications.)11 If linezolid is chosen as either empiric
or definitive therapy for HAP/VAP, careful screening for other serotonergic medica-
tions is needed. Temporary cessation of concurrent serotonergic medications may
be needed if linezolid remains the preferred anti-MRSA therapy.
Pharmacokinetic (PK)-optimized/pharmacodynamic (PD)-optimized antimicrobial
dosing should be used when treating serious infections. As antipseudomonal beta-
lactam therapy is the backbone of nosocomial pneumonia treatment, the time-free
drug concentrations are above the minimum inhibitory concentration (fT > MIC)
must be enhanced. Critically ill patients with altered hemodynamics and organ func-
tion may benefit from the use of prolonged or continuous infusion dosing strategies
and the emerging practice of beta-lactam TDM to ensure PK/PD goals are
met.11,14,16 In addition, vancomycin dosing and monitoring strategies have shifted
to targeting an area under the curve to a MIC ratio of 400.17 Future nosocomial pneu-
monia guidelines should be updated to reflect recommended vancomycin PD targets.

Definitive Therapy
Culture data revealing antimicrobial susceptibility testing should guide definitive antimi-
crobial therapy. In general, empiric regimens should be de-escalated to the most narrow
spectrum agent covering the pathogen to avoid complications, such as Clostridioides
difficile infection.14 However, in cases whereby pathogens express expanded-
spectrum beta-lactamases or carbapenem resistance, antimicrobial therapy should
be targeted to treat these organisms.11 Patients with pneumonia secondary to MDR
gram-negative bacilli only sensitive to aminoglycosides or colistin may benefit from
the initiation of inhaled antimicrobial therapy in addition to IV systemic therapy.11

Treatment Duration
Historically, HAP/VAP were treated for long durations up to 2 weeks, but updated ev-
idence demonstrates that 7 days of therapy is suitable for most patients.11 One pivotal
clinical trial showed that 8 days of VAP treatment was non-inferior to 15 days in that
there was no significant difference in mortality (18.8% vs 17.2%, difference 1.6%,
90% CI -3.7%–6.9%) or recurrent infection (28.9% vs 26.0%, difference 2.9%, 90%
CI -3.2%–9.1%), but increased mean  SD antimicrobial-free days in the 8 days group
(13.1  7.4 vs 8.7  5.2, P<.001).18 However, a subgroup of patients with non-lactose
fermenting pathogens (eg, P aeruginosa) had a higher rate of recurrent infections,
which was confirmed in one meta-analysis.18,19 Updated meta-analyses of HAP/
VAP treatment duration did not show a significant difference in recurrent infections
with shorter courses regardless of the causative pathogen.11,20
Ultimately, clinical criteria should guide HAP/VAP resolution and antimicrobial
discontinuation. Select populations may require an individualized duration of treat-
ment, including those with severe immunocompromised state, initially treated with
inappropriate antibiotic therapy or highly resistant pathogens, including P aeruginosa
or carbapenem-resistant Enterobacteriaceae or Acinetobacter spp.12

IMMUNOCOMPROMISED POPULATIONS

Immunocompromised populations are at increased risk of pneumonia from both com-

mon pathogens and avirulent or opportunistic organisms.21 Immunocompromised
conditions include, but are not limited to receipt of cancer chemotherapy, solid organ

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12 Rafeq & Igneri

transplantation, hematopoietic stem cell transplantation, HIV infection with a CD4

T-lymphocyte count less than 200 cells/microliter or percentage less than 14%, or
receipt of corticosteroid therapy with a dose greater than 20 mg prednisone or equiv-
alent daily for greater than 14 days or a cumulative dose greater than 600 mg of
prednisone.21
Although immunocompromised patients may develop an infection from the typical
CAP respiratory pathogens, they are also at risk for infection due to Enterobacteri-
aceae (including extended-spectrum beta-lactamase and carbapenemase-
producing organisms), mycobacteria (eg, Mycobacterium tuberculosis), viruses (eg,
Cytomegalovirus), fungi (eg, Pneumocystis jirovecii), and parasites (eg, Toxoplasma
gondii).21 Broad-spectrum therapy targeting beyond core respiratory pathogens
should be used empirically when risk factors for MDR or opportunistic pathogens
exist, and the delay in appropriate therapy will place the patient at increased risk of
mortality.
Immunocompromised patients should be managed on a case-by-case basis to
ensure pathogen-directed therapy is initiated, as shown Table 8.21 Although a discus-
sion on newer beta-lactam/beta-lactamase inhibitor combinations (eg, ceftolozane/
tazobactam, imipenem/relabactam, meropenem/vaborbactam, and so forth) for the
treatment of MDR gram-negative bacilli is beyond the scope of this review, there
may be a role for these agents in the place of systemic aminoglycoside or colistin
when treating highly resistant pathogens (eg, extended-spectrum beta-lactamase
producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae) under
the direction of an infectious disease specialist.

ANTIMICROBIAL STEWARDSHIP INITIATIVES

Beta-Lactam Allergies
Beta-lactam intolerance (eg, gastrointestinal upset) is often misconstrued as a true
allergic reaction and inappropriately documented in the patient chart. This may poten-
tially result in an inferior or unnecessarily broad-spectrum antibiotic prescribing.
Although beta-lactam antibiotics are the most common cause of drug-induced
delayed rashes, including maculopapular, they infrequently cause true IgE-mediated
reactions. Anaphylaxis is rare for penicillin: 0.001% for the parenteral route of admin-
istration and 0.0005% for the oral route of administration.22
Beta-lactam allergies documented in the medical record should be carefully
reviewed to determine if a true allergy exists or whether the allergy is, in fact, a
mislabel. Clarification of mislabeled allergies should be made in the medical record
to alert other providers of intolerances that may not preclude the use of first-line

Table 8
Pathogen-directed therapy for immunocompromised patients21

Pathogen Empiric Treatment

P jirovecci Trimethoprim–sulfamethoxazole 15–20 mg/kg/d divided every 6–8 h
Nocardia spp. Trimethoprim–sulfamethoxazole 15–20 mg/kg/d divided every 6–8 h
Aspergillus spp. Preferred: Liposomal amphotericin, 5–7.5 mg/kg/d
Alternative: Isavuconazole, 200 mg every 8 h (initial dosing)
Mucorales spp. Preferred: Liposomal amphotericin 5–7.5 mg/kg/d
Alternative: Isavuconazole 200 mg every 8 h (initial dosing)
Varicella-zoster virus Acyclovir 10–15 mg/kg IV every 8 h
Cytomegalovirus Ganciclovir 5 mg/kg IV every 12 h

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 Infectious Pulmonary Diseases 13

treatment. When a true allergy exists, cross-reactivity between beta-lactam antibiotics

must be carefully evaluated to avoid inappropriate exclusion of the entire class in the
management of pneumonia.
Cross-reactivity between beta-lactams depends on the R1 side chain of the chem-
ical structure. Therefore, an antibiotic with the same R1 side chain as the drug allergy
should not be selected, and an alternative agent should be considered. For example,
cephalexin and cefaclor have an identical side chain to amoxicillin.22
First generation cephalosporins have a higher cross-reactivity risk with penicillins
compared to fourth generation cephalosporins due to similarities in the R1 side
chain.23 The cross-reactivity between penicillins and carbapenems, as well as carba-
penems and cephalosporins, is less than 1%.23 Monobactams do not cross-react with
penicillins or carbapenems and could serve as a safe alternative agent in patients with
a true risk of IgE reaction. If the R1 side chains are the same or similar, then clinical
judgment should be used to determine if the reaction should be challenged.

Procalcitonin
PCT is a precursor hormone of calcitonin that is upregulated by cytokines released in
response to bacterial infections. With a half-life of 25 to 30 hours, a rapid rise in PCT
levels is seen within 6 to 12 hours of bacterial insult which decline as the infection re-
solves. Although PCT was first approved by the FDA in 2005 as a diagnostic aid for
sepsis, it has proven useful as a tool for antimicrobial de-escalation.24
Numerous randomized studies have examined whether PCT-based algorithms can
assist clinicians in deciding whether to start or stop antimicrobial therapy without
adversely impacting patients through delayed antimicrobial therapy or inadequate
treatment courses.24 Efficacy has been demonstrated in adult patients with suspected
respiratory infections. Improving antibiotic use in these scenarios carries the potential
for important clinical benefit as respiratory infections are the most common indication
for antibiotics in hospitalized patients, and antibiotic use is most prevalent in the ICU.
A systematic review and meta-analysis by Lam and colleagues evaluated PCT-
guided antibiotic cessation (using PCT drop of 50%–90% from baseline with an abso-
lute value <0.5–1 mcg/L) compared with standard of care in adult critically ill patients
was associated with a decrease in 30-day mortality, RR 0.87 (95% CI 0.77–0.98,
P 5 .02). However, there was no decrease in short-term mortality when PCT was
used for either initiation or initiation and cessation of antibiotics.25 In addition, they
demonstrated that PCT-guided cessation of antibiotics was associated with a signif-
icant decrease in antibiotic durations. This finding was confirmed in another meta-
analysis, which showed that PCT-guided cessation was associated with a mean anti-
biotic duration of 7.35 days versus 8.85 days in the control arm 1.49 days (95% CI
-2.27–0.71, P<.001).26
Overall, serial evaluation of PCT in patients with sepsis is associated with signifi-
cantly reduced 30-day mortality and may allow for a 1 to 3 day shorter duration of anti-
microbial therapy with no apparent compromise in clinical outcomes. Of note, there
are limitations with PCT as false positives and false negatives may be seen in some
patient populations (Table 9).24

Methicillin-Resistant Staphylococcus aureus Nasal Screening

From 2011 to 2014, Staphylococcus aureus was the most prevalent pathogen impli-
cated in VAP.27 Although there are various methods to detect MRSA colonization,
PCR assay has a faster turn-around time (<1 day) than site culture (1–3 days) and a
higher sensitivity (92.5%) than culture (86.9%).28 MRSA PCR testing detects mecA ge-
netic sequencing, the gene responsible for methicillin resistance. Therefore, it is more

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14 Rafeq & Igneri

Table 9
Common causes of false-positive and false-negative procalcitonin results

False-Positive False-Negative
Burns Abscesses
Circulatory shock Empyema
Inhalation injury Mediastinitis
Pancreatitis
Severe trauma
Surgery

likely to remain positive in patients already receiving antibiotic therapy than culture
regardless of bacterial viability.28
Anti-MRSA therapy is often prescribed empirically for pneumonia in critically ill pa-
tients and de-escalated if MRSA is not isolated in a sputum or blood culture. However,
there may be challenges with obtaining adequate respiratory cultures that may result
in longer durations of broad-spectrum antimicrobial use, especially in non-intubated
patients. Respiratory samples obtained after receipt of empiric antimicrobial therapy
may have a lower yield in identifying a causative pathogen and also result in prolonged
empiric regimens. Therefore, non-culture-based testing is an important tool for AMS
de-escalation strategies.
Several studies have demonstrated high negative predictive values (NPV) of MRSA
nares screening for MRSA pneumonia. One study out of the Veterans Affairs system
evaluated MRSA nares colonization screening at admission and transfer and data
from 561,325 cultures to determine NPV of MRSA screening in determination of sub-
sequent positive MRSA culture. Overall, the NPV of MRSA nares screening for ruling
out MRSA infection at any site of infection was 96.5% and 96.1% for respiratory infec-
tions.29 A systematic review and meta-analysis confirmed a high NPV (96.5%) in
pneumonia.30
Overall, MRSA nares screening has a high specificity and NPV for ruling out MRSA
pneumonia. Although many studies used protocols to screen for MRSA in the nares at
ICU admission, with some repeating the screening weekly, Mallidi and colleagues
demonstrated the NPV remained high (98%) even when using nares screens from
within 60 days of hospital admission, indicating MRSA nares screening from a recent
hospital admission may successfully guide empiric antimicrobial therapy in the ED and
ICU settings.31 When nares screening is negative for MRSA, it is reasonable to with-
hold or rapidly de-escalate anti-MRSA antimicrobial therapy.

CLINICS CARE POINTS

 Classification of pneumonia as either community-acquired or hospital-acquired will guide

selection of empirical antimicrobial therapy.
 5 to 7 days of treatment is generally sufficient to treat community-acquired pneumonia;
however, procalcitonin may be a useful biomarker to support cessation of therapy sooner.
 Patients with hospital-acquired and ventilator-associated pneumonia should be risk-
stratified for multidrug-resistant pathogens, with the cornerstone of therapy being a
combination of anti-pseudomonal and anti-methicillin-resistant Staphylococcus aureus
therapy.

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 Infectious Pulmonary Diseases 15

 Immunocompromised patients should be managed on a case-by-case basis to ensure

appropriate broad-spectrum antibiotics have been initiated to target certain pathogens.
 Collaboration with antimicrobial stewardship programs ensures optimization in overall
antibiotic use while minimizing the risk of adverse effects from excessive antibiotic
treatment (eg, Clostridioides difficile infection, development of antimicrobial resistance, and
so forth)

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