Professional Documents
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Infectious Pulmonary Diseases
Infectious Pulmonary Diseases
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,
COMMUNITY-ACQUIRED PNEUMONIA
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 505
Diagnostic Strategies
Microbiologic studies are integral to guiding antimicrobial treatment and vary depend-
ing on whether outpatient or inpatient management is required. In the outpatient
setting, pretreatment sputum gram stain, the culture of the lower respiratory secre-
tions, 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 pa-
tients who are empirically treated for methicillin-resistant Staphylococcus aureus
(MRSA) or Pseudomonas aeruginosa. In addition, these tests should be performed
for all patients previously infected with MRSA or Pseudomonas spp., or who were hos-
pitalized and received intravenous antibiotics in the last 90 days. In patients with se-
vere 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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506 Rafeq & Igneri
Table 1
Pneumonia severity index
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 Clostri-
dioides difficile infection and multidrug-resistant (MDR) pathogens associated with
broad-spectrum antimicrobials (eg, cefepime, ceftriaxone, carbapenems, fluoroqui-
nolones, clindamycin, and so forth).5
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Infectious Pulmonary Diseases 507
Table 2
CURB-65 criteria
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
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.
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
Table 4
Outpatient community-acquired pneumonia therapeutic options5
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 hos-
pital admission that develops in patients after 48 hours of hospitalization. A subtype 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 demonstrates that pa-
tients 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.
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Infectious Pulmonary Diseases 509
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, Pseu-
domonas 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 replace-
ment 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
Table 5
Inpatient community-acquired pneumonia therapeutic options5
Table 6
Empiric antimicrobial therapy for hospital-acquired pneumonia11
Table 7
Empiric antibiotic therapy for ventilator-associated pneumonia11
Definitive Therapy
Culture data revealing antimicrobial susceptibility testing should guide definitive anti-
microbial therapy. In general, empiric regimens should be de-escalated to the most
narrow spectrum agent covering the pathogen to avoid complications, such as Clos-
tridioides difficile infection.14 However, in cases whereby pathogens express
expanded-spectrum beta-lactamases or carbapenem resistance, antimicrobial ther-
apy should be targeted to treat these organisms.11 Patients with pneumonia second-
ary 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
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Infectious Pulmonary Diseases 513
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
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 treat-
ment. 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
Table 8
Pathogen-directed therapy for immunocompromised patients21
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
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.
REFERENCES
21. Ramirez JA, Musher DM, Evans SE, et al. Treatment of Community-Acquired
Pneumonia in Immunocompromised Adults: A Consensus Statement Regarding
Initial Strategies. Chest 2020;158(5):1896–911.
22. Blumenthal KG, Peter JG, Trubiano JA, et al. Antibiotic allergy. Lancet 2019;
393(10167):183–98.
23. Zagursky RJ, Pichichero ME. Cross-reactivity in b-Lactam Allergy. J Allergy Clin
Immunol Pract 2018;6(1):72–81.e1.
24. Rhee C. Using Procalcitonin to Guide Antibiotic Therapy. Open Forum Infect Dis
2016;7(4):ofw249.
25. Lam SW, Bauer SR, Fowler R, et al. Systematic review and meta-analysis of
procalcitonin-guidance versus usual care for antimicrobial management in criti-
cally ill patients: focus on subgroups based on antibiotic initiation, cessation, or
mixed strategies. Crit Care Med 2018;46:684–90.
26. Iankova I, Thompson-Leduc P, Kirson NY, et al. Efficacy and safety of procalcito-
nin guidance in patients with suspected or confirmed sepsis: a systematic review
and meta-analysis. Crit Care Med 2018;46:691–8.
27. Weiner LM, Webb AK, Limbago B, et al. Antimicrobial-resistant pathogens asso-
ciated with healthcare-associated infections: summary of data reported to the
National Healthcare Safety Network at the Centers for Disease Control and Pre-
vention, 2011-2014. Infect Control Hosp Epidemiol 2016;37(11):1288–301.
28. Carr AL, Daley MJ, Givens Merkel K, et al. Clinical Utility of Methicillin-Resistant
Staphylococcus aureus Nasal Screening for Antimicrobial Stewardship: A Review
of Current Literature. Pharmacotherapy 2018;38:1216–28.
29. Mergenhagen KA, Starr KE, Wattengel BA, et al. Determining the Utility of
Methicillin-Resistant Staphylococcus aureus Nares Screening in Antimicrobial
Stewardship. Clin Infect Dis 2020;71:1142–8.
30. Parente DM, Cunha CB, Mylonakis E, et al. The Clinical Utility of Methicillin-
Resistant Staphylococcus aureus (MRSA) Nasal Screening to Rule Out MRSA
Pneumonia: A Diagnostic Meta-analysis With Antimicrobial Stewardship Implica-
tions. Clin Infect Dis 2018;67:1–7.
31. Mallidi MG, Slocum GW, Peksa GD, et al. Impact of Prior-to-Admission Methicillin-
Resistant Staphylococcus aureus Nares Screening in Critically Ill Adults With
Pneumonia. Ann Pharmacother 2022;56(2):124–30.