Two survival strategies are utilized by S. pneumoniae.
noninvasive phenotype that uses surface adhesions, immune evasion strategies, and
secretory defenses to promote long-term carriage within the nasopharynx. Deficits in
host defense, such as an immunocompromised state, allow colonizing strains of low
virulence to cause invasive disease. The second survival strategy depends on
efficient person-to-person transmission and associated rapid disease induction by an
invasive phenotype. Age younger than 2 or older than 64 years, asplenia, alcoholism,
diabetes mellitus, antecedent influenza, defects in humoral immunity, and human
immunodeficiency virus infection are risk factors for the invasive pneumococcal
40 Other risk factors less likely to be associated with invasive disease
include poverty and crowding, cigarette smoking, chronic lung disease, severe liver
disease, recent exposure to antibiotics, and chronic proton-pump inhibitor use.
Following the introduction of the first pneumococcal conjugate vaccine in 2000
to a significant pneumonia decline in high-risk pediatric patients, specifically
children younger than 5 years with moderate-to-severe asthma, or asthma with one or
more of the following comorbid conditions: heart disease, lung disease, diabetes, or
40 The effect of the newly approved pneumococcal
polysaccharide vaccine (PPSV23) on the high-risk populations has yet to be realized.
Atypical pathogens, including L. pneumophila, C. pneumoniae, and M.
pneumoniae, account for approximately 25% of CAP worldwide.
atypical pathogens may be present in up to 60% of CAP episodes because of
42 Polymicrobial infection including atypical pathogens may lead to a
more complicated course with extended lengths of stay. Several studies have shown
that antibiotic regimens that include coverage against these pathogens demonstrate a
survival benefit over regimens that do not.
43–47 Legionnaires’ disease, caused
primarily by L. pneumophila serogroup 1, accounts for 2% to 7% of CAP.
caused by L. pneumophila is considered to be more severe among hospitalized
patients, and it may present with high fever, nonproductive cough, low serum sodium
concentration, high concentration of lactate dehydrogenase, and low platelet
Microorganisms Common in Community-Acquired Pneumonia
Ambulatory Hospitalized, Non-ICU Hospitalized, ICU
Streptococcus pneumoniae S. pneumoniae S. pneumoniae
Mycoplasma pneumoniae M. pneumoniae S. aureus
Haemophilus influenzae C. pneumoniae Legionella species
Chlamydophila pneumoniae Staphylococcus aureus Gram-negative bacilli
Influenza A and B, adenovirus, respiratory syncytial virus, and parainfluenza.
Source: Mandell LA et al. Infectious Diseases Society of America/American Thoracic Society consensus
Community-Acquired Pneumonia: Underlying Conditions and Commonly
Condition Commonly Encountered Pathogen(s)
Alcoholism Oral anaerobes, Klebsiella pneumoniae, Acinetobacter
sp., Mycobacterium tuberculosis
COPD or smoking Pseudomonas aeruginosa, Legionella sp.
Aspiration Gram-negative enteric pathogens, oral anaerobes
Lung abscess CA-MRSA, oral anaerobes, endemic fungal
pneumonia, M. tuberculosis, atypical mycobacteria
Exposure to bat or bird droppings Histoplasma capsulatum
Exposure to birds Chlamydophila psittaci (if poultry: avian influenza)
Exposure to rabbits Francisella tularensis
Exposure to farm animals or parturient cats Coxiella burnetii (Q fever)
HIV infection (early) M. tuberculosis
HIV infection (late) M. tuberculosis, Pneumocystis jiroveci, Cryptococcus
sp., Histoplasma sp., Aspergillus sp., atypical
mycobacteria (especially Mycobacterium kansasii),
Hotel or cruise ship stay in previous 2 weeks Legionella sp.
Travel to or residence in southwestern United States Coccidioides sp., hantavirus
Travel to or residence in Southeast and East Asia Burkholderia pseudomallei, avian influenza, SARS
Cough >2 weeks with whoop or post-tussive vomiting Bordetella pertussis
Structural lung disease (e.g., bronchiectasis) P. aeruginosa, Burkholderia cepacia, Staphylococcus
Injection drug use S. aureus, anaerobes, M. tuberculosis
Endobronchial obstruction Anaerobes, S. aureus
In context of bioterrorism Bacillus anthracis (anthrax), Yersinia pestis (plague), F.
CA-MRSA, community-acquired methicillin-resistant Staphylococcus aureus; COPD, chronic obstructive
pulmonary disease; HIV, human immunodeficiency virus; SARS, severe acute respiratory syndrome.
Source: Mandell LA et al. Infectious Diseases Society of America/American Thoracic Society consensus
Epidemiologic factors may favor the presence of certain bacterial pathogens and
32 This highlights the importance of the performance of a
thorough patient history to assist in the direction of therapy. Additional factors such
as chronic oral steroid use (≥10 mg prednisone/day), immunosuppression, and
frequent antibiotic therapy will likely place the patient into the category of health
care–associated pneumonia (HCAP), which will require augmented therapy
S. aureus is recognized as a major cause of nosocomial pneumonia; however, its
significance in CAP is less clear. Traditionally, S. aureus has not been considered a
common cause of CAP (approximately 2.5% of cases), but it is most likely to occur
in association with influenza or in patients with lung abscess.
(e.g., clindamycin and doxycycline) and clinical syndrome (necrotizing radiographic
presentation, empyema formation, hemoptysis, and profound hypoxemia) associated
with toxins including Panton–Valentine leukocidin.
51 Toxin-producing strains are
also part of methicillin-sensitive S. aureus’s (MSSA) virulence.
patients with MRSA and MSSA CAP are similarly poor with prolonged length of
hospital stay and a nearly 25% mortality.
The influenza A H1N1 outbreak in 2009 highlighted the contribution of respiratory
viruses as an etiology of CAP. Respiratory virus can be the primary cause of CAP,
but it can also be a major contributing factor that predisposes the patient to infection
by another pathogen, often bacterial (11%–15%). Using contemporary nucleic acid
amplification tests, the incidence of viral CAP ranges from 19% to 32%.
Respiratory viruses that cause CAP include influenza A and B, respiratory syncytial
virus, rhinovirus, parainfluenza, adenovirus, human metapneumovirus, and
coronavirus. In patients coinfected with both viral and bacterial pathogens, the most
common bacteria are S. pneumoniae, S. aureus, and atypicals.
Possible microbes causing J.T.’s CAP include S. pneumoniae, M. pneumoniae, C.
pneumonia, S. aureus, H. influenzae, Legionella species, and respiratory viruses.
CASE 67-3, QUESTION 5: Which antimicrobial agent(s) should be chosen for the initial management of
An approach to the patient with CAP, and recommended antibiotic regimens based
on the patient’s site of care and severity of illness, are provided in Figure 67-1.
Delayed antibiotic therapy has been associated with an increased length of hospital
stay and decreased survival in CAP; therefore, a rapid and correct diagnosis is
58 The most recent IDSA/ATS CAP treatment guidelines recommend the
first dose of antibiotic be given in the ED in an effort to avoid treatment delays
associated with the hospital admission process.
All patients should be empirically treated for pneumococcus and atypical
pathogens. The choice of the initial regimen should be based on medical
Macrolide antibiotics (e.g., azithromycin and clarithromycin) or doxycycline are
preferred as monotherapy for noncomplicated outpatient treatment and are used in
combination with β-lactams for complicated outpatients and those treated on inpatient
32 Macrolides should not be employed as monotherapy for inpatient care, as
nearly 30% of pneumococcal isolates demonstrate resistance.
are responsible for macrolide resistance, including ribosomal modification mediated
by erm (B), efflux from the bacterial cell controlled by mef (A), or a combination of
Risk Factors for α-Lactam-Resistant Streptococcus pneumoniae
β-Lactam therapy within the previous 3 months (also at risk for organisms associated with HCAP)
Immunosuppressive illness or therapy (also at risk for organisms associated with HCAP)
Exposure to a child in a day-care center
HCAP, health care–associated pneumonia.
Source: Mandell LA et al. Infectious Diseases Society of America/American Thoracic Society consensus
Patients with comorbidities, exposure to antibiotics within the past 3 months,
DRSP risk factors, or who live in an area with a high prevalence of DRSP should
receive a combination β-lactam and macrolide regimen or a respiratory
fluoroquinolone (e.g., levofloxacin, moxifloxacin, and gemifloxacin).
32 Preferred βlactams include high-dose amoxicillin (1 g PO TID), amoxicillin-clavulanate (2 g PO
BID), or ceftriaxone (1–2 g IV daily). β-lactam resistance occurs through alteration
of one or more of the penicillin-binding proteins that mediate the bacterial cell wall
60 Penicillin-binding protein alterations in resistant strains decrease the
affinity to all β-lactams such that higher concentrations are required for binding and
inhibition of the enzyme. Thus, appropriate dosing of β-lactams in the treatment of
CAP minimizes development of resistance and promotes optimal clinical
gyrase gene gyrA and the topoisomerase IV genes parC and parE, as well as efflux
pump–mediated, has increased because of their widespread use; however, overall
pneumococcal resistance rates are low.
IDSA/ATS guideline-concordant therapy
for hospitalized patients has been associated with improved patient outcomes
including decreases in time to achieve clinical stability, total duration of parenteral
therapy, and hospital length of stay, as well as improved in-hospital survival.
J.T.’s treatment should be started in the ED after obtaining a respiratory specimen
and pretreatment blood cultures for Gram stain and culture. J.T. does not possess risk
factors for specific bacteria, such as Enterobacteriaceae or P. aeruginosa; therefore,
a β-lactam (ceftriaxone) plus a macrolide (azithromycin) should be initiated
empirically, both initially given parenterally. Consideration of CA-MRSA infection
should be made given J.T.’s recent incarceration and profound hypoxemia, although
the rest of her clinical presentation is not compatible with this etiology.
CASE 67-3, QUESTION 6: What is the appropriate length of therapy for J.T.?
A definitive duration of treatment for CAP has not been well established.
Significant variation in duration of treatment exists and is independent of severity of
66 The IDSA/ATS guidelines recommend treatment for a minimum of 5 days,
and patients should be afebrile for 48 to 72 hours before therapy is discontinued. In
addition, patients should not have therapy discontinued if they have two or more
CAP-associated signs of clinical instability, including temperature of greater than
37.8°C, heart rate of greater than 100 beats/minute, respiratory rate of greater than 24
breaths/minute, SBP of less than 90 mm Hg, arterial oxygen saturation of less than
90% or Pao2 of less than 60 mm Hg on room air, inability to maintain oral intake, or
abnormal mental status. Evidence suggests that longer courses of therapy (>7 days)
are no more effective than shorter courses (3–7 days).
Serial monitoring of infection biomarkers may guide duration of antibiotic therapy.
A fall in procalcitonin (PCT), a calcitonin precursor elevated in infection, trauma,
and burns, has been associated with a significant reduction in total duration of
antibiotic use compared with standard care and may be a useful indicator of adequate
oxygen saturation of 93% on 2 L. Laboratory results include the following:
most likely reason for F.E.’s influenza infection?
Influenza viruses spread when an infected person coughs or sneezes near a
69 The usual incubation period for influenza is 1 to 4 days, and the
time between onset among patients who have come into contact with one another is
70 Adults can shed influenza virus from the day before
symptoms begin through 5 to 10 days after illness onset.
several days before illness onset, and they can be infectious for 10 days or more after
onset of symptoms. Prolonged viral replication can occur in adults with severe
disease, including those with comorbidities or those receiving corticosteroid
73 Severely immunocompromised persons can shed virus for weeks to
CASE 67-4, QUESTION 2: Should F.E. be treated with antiviral agents?
Patients with laboratory-confirmed influenza virus or high-risk patients suspected
of infection (Table 67-6) should receive antiviral therapy within 48 hours of
symptom onset whether or not they are hospitalized. Non-improving high-risk
patients or those with symptoms greater than 48 hours and requiring hospitalization
should also be treated. F.E. falls into the latter category and should be treated for
38 Antibiotic treatment is recommended for hospitalized patients with
CAP, even if influenza is suspected, and therapy should be directed at likely
bacterial pathogens associated with influenza such as S. pneumoniae, S. pyogenes,
and S. aureus, including MRSA.
CASE 67-4, QUESTION 3: Which antiviral agent(s) should F.E. be treated with?
Patients at High Risk of Complications from Influenza
Unvaccinated infants aged 12–24 months
Persons with asthma or other chronic pulmonary diseases (e.g., COPD, cystic fibrosis)
Persons with hemodynamically significant cardiac disease
Persons with immunosuppressive disorders or who are receiving immunosuppressive therapy
Persons with sickle cell anemia and other hemoglobinopathies
Persons with chronic renal dysfunction
Persons with chronic metabolic disease, such as diabetes mellitus
Persons with central nervous system disorders that may compromise the handling of secretions such as
neuromuscular disorders, cerebral vascular accidents, or seizure disorders
Residents of any age of nursing homes or other long-term care institutions
COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus.
Comparison of Current Neuraminidase Inhibitors for Influenza
Influenza activity A and B A and B
Route of administration Oral Oral inhalation
Treatment dosage Adults: 75 mg PO BID
Children ≥12 months: ≤15 kg: 30 mg PO BID
Side effects Nausea, vomiting, abdominal pain Nasal and throat
BID, two times a day; PO, by mouth.
Influenza susceptibility profiles to antiviral agents evolve rapidly, and treating
clinicians should be familiar with updated resistance data found at the Centers for
Disease Control and Prevention website: www.cdc.gov/flu. Neuraminidase
inhibitors including oseltamivir or zanamivir are the primary antiviral agents
recommended for the treatment of influenza (Table 67-7).
neuraminidase prevents cleavage of sialic acid residues on the cell surface of the
virus, thereby preventing the release of virus from infected cells. Considering the
high rate of resistance, adamantines (amantadine and rimantadine) are not currently
recommended for treatment of influenza. FE should be treated with either oseltamivir
75 mg PO BID or zanamivir 10 mg inhaled every 12 hours. Both medications should
be used for a total of 5 days.
Neuraminidase inhibitors should be initiated as soon as possible after illness
onset, ideally within 48 hours, as this is when the majority of viral replication
occurs. However, treatment of any person with confirmed or suspected influenza
requiring hospitalization is recommended for up to 96 hours post-illness onset.
For patients whose illness is prolonged, treatment regimens may need to be extended
Development of resistance to zanamivir or oseltamivir has been identified during
treatment of seasonal influenza.
78 Oseltamivir resistance is caused by a specific
mutation leading to a histidine to tyrosine substitution (H275Y) in neuraminidase.
Oseltamivir resistance, which can occur within one week of treatment initiation, has
been reported particularly among immunocompromised patients infected with the
HOSPITAL-ACQUIRED PNEUMONIA, AND
VENTILATOR-ASSOCIATED PNEUMONIA
Despite advances in therapy and prevention, hospital-acquired pneumonia (HAP) and
ventilator-associated pneumonia (VAP) are associated with significant morbidity and
mortality. HAP is defined as pneumonia that occurs at least 48 hours after hospital
admission. VAP refers to pneumonia that arises 48 to 72 hours after endotracheal
intubation. HCAP occurs within 48 hours of admission in patients with previous risk
factors for infection caused by potentially drug-resistant pathogens, including
hospitalization in an acute-care hospital for 2 or more days within 90 days of
infection; residence in a nursing home or long-term care facility; receipt of recent IV
antibiotic therapy, chemotherapy, or wound care within the past 30 days of the
current infection; living in close contact with a person with a multidrug-resistant
pathogen; or attending a hospital or hemodialysis clinic.
HAP is the second most common nosocomial infection in the United States, with
urinary tract infections as the most common.
49 Based on a prospective cohort study,
approximately 7% of ICU patients developed HAP and over 75% of them had VAP.
A retrospective cohort study of 4,543 hospitalized patients with culture-positive
pneumonia observed that HCAP accounted for 21.7% of the cases, HAP for 18.4%,
and VAP for 11%. Mortality rates associated with HAP groups were comparable
(19.8% and 18.8%, respectively) and both were significantly lower than those for
VAP (29.3%). Mean lengths of stay differed with pneumonia category: HAP patients
for 15.2 ± 13.6 days, and VAP patients for 23 ± 20.2 days.
The disease onset is an important epidemiologic variable and risk factor for
specific pathogens and outcomes in patients with HAP and VAP. Early-onset HAP
and VAP are defined as occurring within the first 4 days of hospitalization, usually
carry a better prognosis, and are more likely caused by antibiotic-sensitive bacteria.
Late-onset HAP and VAP (occurring after ≥5 days of hospitalization) are more likely
to be caused by multidrug-resistant (MDR) pathogens and are associated with
increased morbidity and mortality.
Microorganisms gain access into the lower respiratory tract via aspiration of
oropharyngeal pathogens and leakage of secretions around the endotracheal tube cuff
Invasive-care devices, contaminated equipment, and transfer
of microorganisms among staff and patients serve as the primary pathogen sources,
and although more controversial, the gastrointestinal tract may also play a role in
Clinical Presentation and Diagnosis
HAP and VAP are all diagnosed on the basis of radiographic findings, clinical
features, and health care setting when there is initial evidence of infection. Patients
must demonstrate new or progressive infiltrates on imaging as well as two of three of
the following signs: fever greater than 38°C, leukopenia or leukocytosis, and purulent
sputum. Patients will often experience
declines in oxygen saturation, but this finding is less specific for determining the need
for empiric antimicrobial agents.
Respiratory cultures may be taken from endotracheal aspirates, bronchoalveolar
lavage, or protected-specimen brush samples. Blood cultures lack sensitivity, and
when positive, consideration should also be given to a potential extrapulmonary
The IDSA/ATS have published guidelines for the treatment of HAP.
principles underlying the management of HAP and VAP include the following: (a)
failure to initiate prompt, appropriate therapy is associated with increased mortality;
(b) the variability of bacteriology from one institution to another, as well as within
specific sites in a hospital, can be significant; (c) the overuse of antibiotics should be
avoided by focusing on accurate diagnosis; (d) therapy should be tailored based on
lower respiratory tract cultures and the duration of therapy should be shortened; and
(e) prevention strategies directed at modifiable risk factors should be applied. The
likelihood of an infection with a potential pathogen is based largely on the time to
onset of HAP, severity of the condition, and underlying risk factors. In general,
patients with early-onset disease who are not severely ill and have no risk factors for
MDR organisms can be treated with a single agent including a non-antipseudomonal
third-generation cephalosporin or an antipneumococcal fluoroquinolone (Table 67-
8). Empiric therapy in those with late-onset or severe disease should include a
combination of antibiotics active against Pseudomonas. This regimen usually
includes an antipseudomonal β-lactam, such as cefepime, imipenem, meropenem,
doripenem, or piperacillin-tazobactam, plus either an aminoglycoside or
ciprofloxacin/levofloxacin. Vancomycin or linezolid should be added if MRSA risk
factors are present or there is a high institutional incidence (Table 67-9).
The major difference in the bacteriology between CAP and HAP, HCAP, or VAP is a
shift to gram-negative pathogens, MDR pathogens, and MRSA. Gram-negative bacilli
commonly colonize oropharyngeal secretions of patients with moderate-to-severe
(acute and chronic) diseases without exposure to broad-spectrum antibiotics.
Patients admitted to the hospital with acute illnesses are rapidly colonized with
gram-negative organisms. Approximately 20% are colonized on the first hospital day,
and this number increases with the duration of hospitalization and severity of illness.
Approximately 35% to 45% of hospitalized patients and up to 100% of critically ill
patients will be colonized within 3 to 5 days of admission.
In the past, gram-negative bacteria accounted for 50% to 70% of all cases of HAP
; however, gram-positive organisms have become increasingly
common, with S. aureus responsible for upward of 40% of cases of HAP and VAP.
This is in stark contrast to CAP bacteriology, in which S. aureus represents 25% or
less of cases. P. aeruginosa remains the most prevalent gram-negative organism in
HAP and VAP, accounting for approximately 20% to 25% of infections.
who are ventilator dependent, Acinetobacter species is an increasingly common
gram-negative pathogen. Other organisms with special risk factors include
Legionella, which is associated with high-dose corticosteroid use and outbreaks
secondary to water supplies and cooling systems,
associated with neutropenia or organ transplantation.
Risk factors for MDR pathogens include patient-specific factors such as
antimicrobial therapy in the previous 90 days, current hospitalization of 5 days or
more, and immunosuppressive disease or therapy. Coverage for MDR organisms
should also be initiated if there is a high frequency of community, hospital, or health
care facility (i.e., nursing home) antibiotic resistance.
QUESTION 1: M.L. is a 71-year-old man admitted to the hospital for a deep vein thrombosis. His past
Empiric Therapy for Hospital-Acquired Pneumonia and Ventilator-Associated
Pneumonia in Patients with No Known Risk Factors for Multidrug Resistant
Possible Pathogens Recommended Therapy Dosage
Antibiotic-sensitive enteric GNB
Ceftriaxone 1–2 g IV every 24 hours
Levofloxacin 750 mg IV every 24 hours
Moxifloxacin 400 mg IV every 24 hours
Ampicillin-sulbactam 3 g IV q6 hours
levofloxacin or moxifloxacin are preferred to ciprofloxacin.
GNB, gram-negative bacilli; IV, intravenous; MSSA, methicillin-sensitive Staphylococcus aureus.
Empiric Therapy for Hospital-Acquired Pneumonia and Ventilator-Associated
Pneumonia in Patients with Late-Onset Infection (≥5 days) or Risk Factors for
β-Lactam/β-Lactamase inhibitor
Antipseudomonal fluoroquinolone
500 mg IV every 6 hours or 1 g IV
g Azithromycin 500 mg IV every 24 hours
aDosages are based on normal renal and hepatic function.
cStudied infusion times range from 30 minutes to 4 hours.
If MRSA risk factors are present, or there is a high incidence locally.
fTrough levels for vancomycin should be 15–20 mcg/mL.
fluoroquinolone (e.g., ciprofloxacin or levofloxacin) should be used.
Several risk factors for HAP have been identified, including intubation and
mechanical ventilation, aspiration, a patient’s body position, the administration of
enteral feeding, prior use of antibacterial agents, gastrointestinal bleeding
prophylaxis (i.e., histamine type 2 antagonists and proton-pump inhibitors),
immunosuppressive therapy, and poor nutrition status or glucose control. Other
nonmodifiable risk factors associated with developing HAP include age older than
70 years and chronic lung disease.
An important factor in the cause of pneumonia is colonization of the oropharynx,
common in alcoholism and with prolonged hospitalization, and previous
49 Several factors may contribute to the colonization of M.L.’s
oropharynx with gram-negative bacteria. In addition to his pulmonary disease, an
altered immune response in diabetics and the elderly can predispose M.L. to
respiratory infection. The use of drugs that inhibit the production of gastric acid, such
as famotidine and omeprazole, increases the possibility of oropharyngeal
colonization and pneumonia; yet acid suppressive medications are commonly used to
prevent gastric stress ulcers in mechanically ventilated patients.
CASE 67-5, QUESTION 2: Three days after admission, while receiving anticoagulation for the deep vein
hours, his respiratory function declined significantly requiring intubation (Pao2
antibiotics. How should antimicrobial therapy be managed for M.L.?
Because delays in the administration of appropriate therapy have been associated
with increased hospital mortality from HAP, the prompt administration of empiric
therapy is essential. Importantly, changing therapy once culture results are available
may not reduce the excess risk of hospital mortality if inappropriate initial therapy is
49 To this end, local bacteriologic patterns and in vitro susceptibility data
should be made available and updated
as frequently as possible to allow for appropriate selection of initial empirical
therapy. In addition to the selection of an appropriate agent, the selection of adequate
dosing regimens will optimize the pharmacodynamic properties of the antibacterial
agent(s) and improve clinical outcomes and mortality rates.
Resolution of HAP can be defined both clinically and microbiologically. Clinical
improvement usually is apparent after the first 48 to 72 hours of therapy. During this
time, the selected antibacterial regimen should not be changed unless progressive
deterioration takes place or microbiologic studies confirm the pathogen.
If culture results are negative or inconclusive (because of known specimen
contamination with mouth flora), the patient’s response to the initial antibiotic
therapy should be used to evaluate modification of the antibiotic regimen. If the
patient responds to the initial regimen, consideration should be given to narrowing
coverage to the most likely causative pathogens.
If the patient is not responding to the initial antibiotic therapy, one should consider
whether (a) the pathogen is not covered in the initial choice of antibiotic therapy, (b)
the dose of antibiotic is insufficient, and (c) any other factors are responsible for the
failure to respond to therapy. Such factors include poor pulmonary clearance of
necrotic tissue and cellular debris, lung abscesses or empyema, and severely altered
host defenses leading to a rapidly fatal underlying disease.
Of note, if one of the following organisms is isolated (Serratia, Pseudomonas,
indole-positive Proteus, Citrobacter, or Enterobacter species), in vitro reports
indicating susceptibility should be carefully evaluated, as these organisms often
possess an inducible β-lactamase gene (also referred to as a type I β-lactamase
In vitro testing may demonstrate susceptibility to third-generation
cephalosporins and extended-spectrum penicillins, but this may not translate into
efficacy in the clinical setting. As a possible scenario of infection with these
organisms, after initiation with one of the above agents, the patient may initially
respond; however, after approximately 1 week, the patient’s condition begins to
worsen. Because treatment with the β-lactam agent induces the expression of the type
I enzyme, a subsequent sputum specimen sent after approximately 1 week is now
105 Although cefepime is more likely to be active against these
isolates, a large inoculum of organisms (e.g., that present in pneumonia) can result in
β-lactamase degradation of this agent as well.
106 Considering that this phenomenon
will not be identified by using usual in vitro testing, cefepime should be used
107 The preferred therapy in these patients includes
trimethoprim–sulfamethoxazole, a fluoroquinolone, or a carbapenem.
Acinetobacter species are increasingly resistant to many commonly used antibacterial
agents. Treatment of this often multiply-resistant pathogen requires the use of very
high doses of ampicillin–sulbactam (up to 24 g/day) or colistin.
CASE 67-5, QUESTION 3: Seventy-two hours after empiric antibiotics were initiated, the microbiology
dose and aggressive maintenance regimen, vancomycin trough concentrations have been 17 to 22 mcg/mL.
cultures again grow only S. aureus with susceptibility to vancomycin, sulfamethoxazole–trimethoprim,
daptomycin, and linezolid. Should M.L.’s antibiotic therapy be modified?
The first IDSA MRSA infection treatment guidelines
and are discussed subsequently in collaboration with the first vancomycin therapeutic
monitoring guidelines jointly developed by the American Society of Health-System
Pharmacists, the Society of Infectious Diseases Pharmacists, and the IDSA.
For MRSA pneumonia, IV vancomycin, or linezolid 600 mg by mouth (PO) or IV
twice daily, or clindamycin 600 mg PO or IV 3 times daily (if the strain is
susceptible) is recommended for 7 to 21 days, depending on the extent of infection.
Daptomycin should not be used for the treatment of MRSA pneumonia, because its
activity is inhibited by pulmonary surfactant, rendering it inactive in the treatment of
The recommended dosing of IV vancomycin is 15 to 20 mg/kg/dose (actual body
weight) every 8 to 12 hours, not to exceed 2 g/dose, for patients with normal renal
function. A loading dose of 25 to 30 mg/kg (actual body weight) may be considered.
Some patients may experience an adverse event during the infusion of vancomycin
known as red man syndrome. Extending the infusion time to 2 hours for larger doses
or premedicating patients who have experienced this phenomenon with an
antihistamine may alleviate this adverse event.
Vancomycin trough concentrations of 15 to 20 mcg/mL are recommended for the
110 as higher trough serum concentrations should increase the
likelihood of optimizing the area under the curve (AUC) and minimum inhibitory
concentration (MIC) and, therefore, take into account higher vancomycin MIC values
appreciated in some isolates. It has also been postulated that targeting higher trough
values may help to overcome vancomycin’s inherent impaired penetration into
epithelial lining fluid and respiratory secretions.
111 Of note, there are no data
confirming that achievement of more aggressive trough levels is associated with
Linezolid achieves higher concentrations in lung epithelial fluid than in plasma
serves as an alternative to vancomycin for the treatment of MRSA pneumonia. A
retrospective analysis of two prospective trials
for the treatment of HAP found
that patients in the subgroup of MRSA cases randomly assigned to linezolid
experienced higher cure rates and lower mortality compared with vancomycin.
contrast, a meta-analysis of eight randomized control trials comparing glycopeptide
antibiotics to linezolid for suspected MRSA pneumonia found no evidence to support
117 The ZEPHyR study compared linezolid with vancomycin
in patients with proven nosocomial MRSA pneumonia in a randomized, double-blind
fashion. This is the largest trial conducted in this population to date, and it showed a
statistical improvement with linezolid in clinical outcomes at the end of study; yet the
confidence interval was close to no significance and only showed a benefit with
linezolid in identified nosocomial MRSA pneumonia.
difficult for initial selection over vancomycin for empiric therapy of MRSA
coverage. Therefore, it remains uncertain whether linezolid or vancomycin should be
M.L. is at risk for MDR pathogens (current hospitalization of 5 days or more and
immunosuppressive diseases) and should be started empirically with an anti-MRSA
agent (vancomycin), and double coverage for resistant gram-negative pathogens
(cefepime and gentamicin or ciprofloxacin). (Table 67-9) Dosing and frequency of
antimicrobial agents will require renal adjustments because of M.L.’s chronic renal
issues. When culture results are known, the antibiotic regimen can be modified and
individualized. For patients with uncomplicated HAP or VAP, who have received
appropriate empiric antibiotics with a satisfactory subsequent
clinical response, 7 to 10 days of therapy is recommended.
infected with nonfermenting gram-negative bacilli (i.e., pseudomonas and
acinetobacter) may benefit from longer courses (14 days or greater) to prevent
119 M.L.’s clinical response should be monitored to determine whether the
selected antibiotics are effective in treating this infection. These parameters include
the ability to discontinue mechanical intubation and decreases in temperature and
WBC count with resolution of the left shift.
Since M.L. remains febrile despite MRSA sensitivities to vancomycin with
appropriate trough concentrations, it is appropriate to consider alternative MRSA
coverage. Despite MRSA susceptibility to daptomycin, the drug does not penetrate
lung surfactant, and therefore it is not appropriate to use in the treatment of
pneumonia. Sulfamethoxazole–trimethoprim is a less appealing option owing to the
patient’s dialysis requirement. M.L. should be switched to linezolid. Linezolid
quickly reaches high lung concentrations and is safe to use in the setting of acute renal
failure. Linezolid has been associated with thrombocytopenia and neutropenia.
Platelet counts and WBC should be monitored at baseline and at least every 7 days
Doxycycline, clindamycin, and sulfamethoxazole–trimethoprim are not reliably
active against MRSA strains, and recent research has focused on novel agents.
Although active against MRSA, tigecycline has been associated with worsened
clinical outcomes when used for the treatment of HAP, including MRSA
120 Telavancin has been compared with vancomycin in the treatment of
HAP caused by gram-positive pathogens. Treatment with telavancin achieved higher
clinical cure rates in patients with monomicrobial S. aureus infection and in those
with isolates that demonstrated a vancomycin MIC of at least 1 mcg/mL. However,
lower cure rates were observed in the telavancin group in those who had mixed
infections. Telavancin use was also associated with a higher incidence in serum
creatinine elevation; yet the drug was approved by the US Food and Drug
Administration in 2013 for HAP when other alternatives are not suitable.
Individualization of aminoglycoside dosing is imperative as the therapeutic outcome
(efficacy and toxicity) of aminoglycosides correlates with plasma concentrations in
patients with gram-negative pneumonia.
In patients receiving multiple daily
doses of gentamicin or tobramycin and achieving a 1-hour postinfusion peak plasma
concentration of greater than 7 mcg/mL, a successful outcome occurs more often than
in those with lower plasma concentrations.
The aminoglycosides are concentration-dependent killing antibiotics. The rate and
extent of killing organisms is maximized by increasing their peak serum concentration
relative to the MIC of the pathogen. In addition to maximizing bactericidal activity, in
vitro evidence has demonstrated that this concentration goal also minimizes the
development of resistance. The use of once-daily dosing strategies to minimize
nephrotoxicity of the aminoglycosides has been studied extensively. Single doses of
gentamicin and tobramycin (5–7 mg/kg/day) and of amikacin (15–20 mg/kg/day) have
been reported to be as effective as standard dosing (smaller single doses given every
8 or every 12 hours) of these agents in controlled clinical trials. However, none of
the trials has enrolled a sufficient number of patients required to demonstrate a lower
incidence of nephrotoxicity. There are several advantages of once-daily dose
aminoglycoside therapy: (a) it is no more nephrotoxic than traditional dosing, (b)
clinicians are ensured that a therapeutic peak serum level will be achieved with the
first dose, (c) it is the only safe and effective way to achieve serum peak levels of 10
to 20 times the MIC for difficult-to-treat organisms such as P. aeruginosa, and (d) it
is a more efficient dosing regimen (fewer doses and administration times per day;
fewer serum level measurements are required).
Despite the use of individualized aminoglycoside dosing, morbidity and mortality
rates attributable to gram-negative pneumonia remain high. This is because the
success of antibiotic therapy depends on the ability of the antibiotic to reach the site
of infection and remain biologically active.
125 Concentrations of the aminoglycosides
in bronchial secretions range from 1 to 5 mcg/mL (30%–40% of serum
concentrations) 2 to 4 hours after parenteral administration.
concentrations may be insufficient to inhibit the growth of many gram-negative
organisms, especially Pseudomonas.
Lastly, aminoglycosides bind to purulent exudates and cellular debris and are
In summary, the aminoglycosides penetrate poorly
into bronchial secretions and are less active at the site of infection because of local
pH effects and binding to cellular debris. These properties may result in the need for
increased dosages, placing patients at increased risk for ototoxicity and
nephrotoxicity. Therefore, unless no reasonable alternative exists, aminoglycoside
monotherapy for the treatment of pneumonia should be avoided.
INHALED AGENTS FOR MULTIDRUG-RESISTANT PATHOGENS
Because of the growing incidence of pneumonia caused by MDR gram-negative
organisms, interest has been renewed in the use of inhaled aminoglycosides and
polymyxin products. When given systemically, both classes have been associated
with poor pulmonary penetration and with nephrotoxicity, with polymyxin carrying
the additional risk of neurotoxicity, and with aminoglycosides ototoxicity. However,
the proposed high drug concentrations at the site of pulmonary infection, minimal
systemic exposure after nebulized administration, and data showing benefit in both
the prevention and treatment of Pseudomonas pulmonary infection in cystic fibrosis
patients make aerosolized antibiotic therapy an appealing strategy for the treatment of
VAP. The IDSA/ATS guidelines state that aerosolized antimicrobials may be
considered in patients with MDR organisms not responding well to IV therapy.
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