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Treatment of hospital-acquired and ventilator-associated pneumonia in adults

●Hospital-acquired (or nosocomial) pneumonia (HAP) is pneumonia that occurs 48 hours


or more after admission and did not appear to be incubating at the time of admission.

●Ventilator-associated pneumonia (VAP) is a type of HAP that develops more than 48


hours after endotracheal intubation.

health care-associated pneumonia (HCAP) pneumonia acquired in health care facilities such
as nursing homes, hemodialysis centers, outpatient clinics, or during a hospitalization within
the past three months . This category was used to identify patients at risk for infection with
multidrug-resistant (MDR) pathogens. We thus manage patients who would have been
previously classified as having HCAP in a similar way to those with community-acquired
pneumonia (CAP), deciding whether to include therapy targeting MDR pathogens on a case-
by-case basis.

Empiric therapy for HAP and VAP should include agents with activity against
Staphylococcus aureus, Pseudomonas aeruginosa, and other gram-negative bacilli.

If patients have recently received antibiotics, empiric therapy should generally be with a drug
from a different class since earlier treatment may have selected for pathogens resistant

ventilator-associated pneumonia — Risk factors for MDR pathogens (including


Pseudomonas, other gram-negative bacilli, and MRSA) in patients with VAP include:●IV
antibiotic use within the previous 90 days●Septic shock at the time of VAP●Acute
respiratory distress syndrome (ARDS) preceding VAP●≥5 days of hospitalization prior to the
occurrence of VAP●Acute renal replacement therapy prior to VAP onset

Risk factors for MDR Pseudomonas and other gram-negative bacilli include:●Treatment
in an ICU in which >10 percent of gram-negative bacilli are resistant to an agent being
considered for monotherapy●Treatment in an ICU in which local antimicrobial susceptibility
rates among gram-negative bacilli are not known

Risk factors for MRSA include:●Treatment in a unit in which >10 to 20 percent of S.


aureus isolates are methicillin resistant●Treatment in a unit in which the prevalence of
MRSA is not known

●Patients with VAP who have no known risk factors for MDR pathogens and who are in a
unit in which ≤10 percent of gram-negative isolates are resistant to an agent being considered
for monotherapy and ≤20 percent of S. aureus is resistant to methicillin should receive one
agent that has activity against Pseudomonas, other gram-negative bacilli, and methicillin-
susceptible S. aureus (MSSA).

●Patients with VAP who have any of the following risk factors for MDR VAP should
receive two agents with activity against P. aeruginosa and other gram-negative bacilli and
one agent with activity against MRSA:•IV antibiotic use within the previous 90 days •Septic
shock at the time of VAP•ARDS preceding VAP•≥5 days of hospitalization prior to the
occurrence of VAP•Acute renal replacement therapy prior to VAP onset
●Any patient being treated in a unit in which >10 percent of gram-negative bacilli are
resistant to an agent being considered for monotherapy or in which the prevalence of
resistance among gram-negative bacilli is unknown should receive two agents with activity
against gram-negative bacilli. If this is the patient's only risk factor for MDR pathogens and
local MRSA resistance rates are low (ie, <20 percent), then empiric treatment for MRSA is
not needed.

●Any patient being treated in a unit in which MRSA prevalence is >20 percent or unknown
should receive one agent with activity against MRSA. If this is the patient's only risk factor
for MDR pathogens and local resistance rates among gram-negative bacilli are low (ie, <10
percent), a single agent with activity against P. aeruginosa and other gram-negative bacilli
can be given in addition to the agent active against MRSA.

The traditional intermittent dosing of each agent for VAP is described but we generally favor
prolonged infusions of certain (eg, antipseudomonal) beta-lactams to optimize
pharmacodynamics, especially in critically ill patients with infections caused by gram-
negative bacilli and for patients with infections caused by gram-negative bacilli that have
elevated but susceptible minimum inhibitory concentrations (MICs) to the chosen agent

No MDR risk factors — For patients with VAP who have no known risk factors for
multidrug-resistant pathogens and who are in a unit in which ≤10 percent of gram-negative
isolates are resistant to an agent being considered for monotherapy and ≤20 percent of S.
aureus is resistant to methicillin (table 1), we suggest one of the following intravenous
empiric antibiotic regimens: ●Piperacillin-tazobactam 4.5 g IV every 6 hours ●Cefepime 2 g
IV every 8 hours ●Levofloxacin 750 mg IV daily –

imipenem and meropenem are generally reserve these agents for patients with a high
likelihood of infection with an extended-spectrum beta-lactamase (ESBL)-producing gram-
negative bacillus or for patients in units where local antibiograms favor these agents over
other broad-spectrum beta-lactams.

MDR risk factors — Patients with VAP who have any of the following risk factors for
multidrug-resistant VAP should receive two agents with activity against P. aeruginosa and
other gram-negative bacilli and one agent with activity against MRSA:●IV antibiotic use
within the previous 90 days●Septic shock at the time of VAP●ARDS preceding VAP●≥5
days hospitalization prior to the occurrence of VAP●Acute renal replacement therapy prior to
VAP onset ONE of the following:●Piperacillin-tazobactam 4.5 g IV every six
hours●Cefepime 2 g IV every eight hours ●Ceftazidime 2 g IV every eight hours●Imipenem
500 mg IV every six hours●Meropenem 1 g IV every eight hours●Aztreonam 2 g IV every
eight hours – We use aztreonam infrequently since rates of resistance among gram-negative
bacilli are typically higher than to the other beta-lactams options

PLUS one of the following:

●An aminoglycoside – Once-daily dosing is only appropriate for patients with normal renal
function. A single serum concentration should be obtained 6 to 14 hours after the first dose,
and the dose should be adjusted as needed based upon the following nomogram •Amikacin
15 to 20 mg/kg IV daily •Gentamicin 5 to 7 mg/kg IV daily•Tobramycin 5 to 7 mg/kg IV
daily
Because the aminoglycosides have poor lung penetration, increased risk of nephrotoxicity
and ototoxicity, and poorer clinical response rates ,if they are used as part of combination
therapy and subsequent culture results indicate that the isolate is susceptible to one of the
beta-lactams, the aminoglycoside should be discontinued. We typically discontinue the
aminoglycoside after one or two days, especially in patients who have improved clinically
and in whom the pathogen (if identified) is susceptible to the beta-lactam.

●An antipseudomonal fluoroquinolone such as ciprofloxacin (400 mg IV every eight hours)


or levofloxacin (750 mg IV daily) is preferred if Legionella is likely.

The IDSA/ATS guidelines recommend either an antipseudomonal fluoroquinolone or an


aminoglycoside for the second agent for gram-negative bacilli and they also state that
aminoglycosides should be avoided if alternative agents with adequate activity against gram-
negative bacilli are available. However, we generally prefer an aminoglycoside over a
fluoroquinolone for patients with severe disease if there is not concern for Legionella, as
aminoglycosides are more likely to have in vitro activity against gram-negative bacilli in
those with risk factors for resistance.

●A polymyxin – Addition of an alternative agent, such as IV colistin or polymyxin B, may be


appropriate if highly resistant Pseudomonas spp, Acinetobacter spp, Enterobacteriaceae
(including Klebsiella pneumoniae) is suspected or established. Polymyxins are used rarely
given their significant nephrotoxicity and should be avoided if alternative agents with
adequate activity against gram-negative bacilli are available . In some cases of VAP with
highly resistant organisms, inhaled colistin may be appropriate adjunctive therapy in
combination with systemic antimicrobials,

●Aztreonam 2 g IV every eight hours – Although the use of two beta-lactams is generally
avoided, in the absence of other options, it is acceptable to use aztreonam as a second agent
for gram-negative bacteria with another beta-lactam because it has different targets within the
bacterial cell wall [1].

PLUS one of the following:

●Linezolid 600 mg IV every 12 hours, which may be administered orally

●Vancomycin 15 mg/kg (based on actual body weight) IV (maximum 2 g per dose initially)
every 8 to 12 hours for patients with normal renal function, with a target serum trough
concentration of 15 to 20 mcg/mL. In seriously ill patients, a loading dose of 25 to 30 mg/kg
(maximum 3 g) can be used to facilitate rapid attainment of the target trough concentration.

●Telavancin 10 mg/kg IV every 24 hours is an alternative agent when neither linezolid nor
vancomycin can be used, but there are several boxed warnings that must be considered

The combination of vancomycin and piperacillin-tazobactam has been associated with acute
kidney injury . In patients who require an anti-MRSA agent and an antipseudomonal beta-
lactam, options include using a beta-lactam other than piperacillin-tazobactam (eg, cefepime
or ceftazidime) or, if piperacillin-tazobactam is favored, using linezolid instead of
vancomycin.
High local prevalence of resistant gram-negatives — If the patient is being treated in an ICU
in which >10 percent of gram-negative bacilli are resistant to an agent being considered for
monotherapy or in which the prevalence of resistant gram-negative bacilli is unknown, then
two agents should be used for gram-negative coverage. Specific regimens are summarized in
the following algorithm (algorithm 1). Appropriate regimens are outlined in the previous
section. (See 'MDR risk factors' above.)

High local prevalence of MRSA — If none of the risk factors for MDR VAP are present and
the patient is in an ICU in which ≤10 percent of gram-negative isolates are resistant to an
agent being considered for monotherapy (table 1), but >20 percent of S. aureus isolates in the
unit are methicillin resistant or the local MRSA prevalence is unknown, the patient should
receive one agent with activity against P. aeruginosa and one agent with activity against
MRSA (algorithm 1).

Adding an agent with MRSA activity to the treatment regimen allows for more flexibility in
the choice of gram-negative agents since the gram-negative agent does not need to include
activity against S. aureus. Potential regimens are summarized below.

ONE of the following:

●Piperacillin-tazobactam 4.5 g IV every six hours

●Cefepime 2 g IV every eight hours

●Ceftazidime 2 g IV every eight hours

●Levofloxacin 750 mg IV daily – When the patient is clinically improved and able to take
oral medications, levofloxacin may be administered orally at the same dose as that used for
IV administration

●Ciprofloxacin 400 mg IV every eight hours – When the patient is clinically improved and
able to take oral medication, ciprofloxacin may be administered orally at 750 mg twice daily

●Aztreonam 2 g IV every eight hours

Among these agents, we generally prefer piperacillin-tazobactam, cefepime, or ceftazidime


because they are more likely to have activity against gram-negative bacilli than the
fluoroquinolones or aztreonam. The IDSA/ATS guidelines also include imipenem and
meropenem as options, but we generally reserve these agents for situations in which they are
required, such as in patients with a high likelihood of infection with an ESBL-producing
gram-negative bacillus. (See 'Gram-negative pathogens' below.)

PLUS one of the following:

●Linezolid 600 mg IV every 12 hours, which may be administered orally when the patient is
able to take oral medications. (See 'Methicillin-resistant Staphylococcus aureus' below.)

●Vancomycin 15 mg/kg (based on actual body weight) IV (maximum 2 g per dose initially)
every 8 to 12 hours for patients with normal renal function, with a target serum trough
concentration of 15 to 20 mcg/mL. In seriously ill patients, a loading dose of 25 to 30 mg/kg
(maximum 3 g) can be used to facilitate rapid attainment of the target trough concentration.

●Telavancin 10 mg/kg IV every 24 hours is an alternative agent when neither linezolid nor
vancomycin can be used, but there are several boxed warnings

The combination of vancomycin and piperacillin-tazobactam has been associated with acute
kidney injury. In patients who require an anti-MRSA agent and an antipseudomonal beta-
lactam, options include using a beta-lactam other than piperacillin-tazobactam (eg, cefepime
or ceftazidime) or, if piperacillin-tazobactam is favored, using linezolid instead of
vancomycin.

Hospital-acquired pneumonia — The appropriate regimen for HAP


depends upon the presence or absence of risk factors for MDR pathogens/ MDR pathogens
tend to be less common in patients who develop HAP outside of the intensive care unit,
particularly early in the hospitalization course. . A single agent active against both MSSA and
P. aeruginosa is often sufficient.

●Risk factors for increased mortality:•Ventilatory support for HAP•Septic shock●Risk factor
for MDR Pseudomonas, other gram-negative bacilli, and MRSA:•IV antibiotics within the
past 90 days

●Risk factors for MDR Pseudomonas and other gram-negative bacilli:•Structural lung
disease (bronchiectasis or cystic fibrosis)•A respiratory specimen Gram stain with numerous
and predominant gram-negative bacilli

●Risk factors for MRSA:•Treatment in a unit in which >20 percent of S. aureus isolates are
methicillin resistant•Treatment in a unit in which the prevalence of MRSA is not known

No MDR risk factors or increased risk of mortality — If there are no risk factors for
increased mortality, for multidrug-resistant Pseudomonas and other gram-negative bacilli, or
for MRSA, the patient should receive one agent that has activity against Pseudomonas and
MSSA. Choices include:●Piperacillin-tazobactam 4.5 g IV every six hours●Cefepime 2 g IV
every eight hours●Levofloxacin 750 mg IV daily.

imipenem and meropenem reserved for patients with a high likelihood of infection with an
ESBL-producing gram-negative bacillus.

Risk factors for MDR gram-negative bacilli and MRSA or for increased mortality — If there
are risk factors either for increased mortality (need for ventilatory support due to HAP or
septic shock) or for both multidrug-resistant Pseudomonas and other MDR gram-negative
bacilli and methicillin-resistant S. aureus, the patient should receive two agents with activity
against P. aeruginosa and other gram-negative bacilli and one agent with activity against
MRSA. Such patients should receive:

ONE of the following:●Piperacillin-tazobactam 4.5 g IV every six hours●Cefepime 2 g IV


every eight hours●Ceftazidime 2 g IV every eight hours●Imipenem 500 mg IV every six
hours●Meropenem 1 g IV every eight hours●Aztreonam 2 g IV every eight hours – We use
aztreonam infrequently since rates of resistance among gram-negative bacilli are typically
higher than to the other beta-lactams options

PLUS one of the following:

●An aminoglycoside – Once-daily dosing is only appropriate for patients with normal renal
function. A single serum concentration should be obtained 6 to 14 hours after the first dose,
and the dose should be adjusted as needed based upon the following nomogram •Amikacin
15 to 20 mg/kg IV daily•Gentamicin 5 to 7 mg/kg IV daily•Tobramycin 5 to 7 mg/kg IV
daily

●An antipseudomonal fluoroquinolone such as ciprofloxacin (400 mg IV every eight hours)


or levofloxacin (750 mg IV daily) is preferred if Legionella is likely. , we generally prefer an
aminoglycoside over a fluoroquinolone for patients with severe disease if there is not concern
for Legionella as aminoglycosides are more likely to have in vitro activity against gram-
negative bacilli in those with risk factors for resistance.
●Aztreonam 2 g IV every eight hours – Although the use of two beta-lactams is generally
avoided, in the absence of other options, it is acceptable to use aztreonam as a second agent
for gram-negative bacteria with another beta-lactam because it has different targets within the
bacterial cell wall

PLUS one of the following:

●Linezolid 600 mg IV every 12 hours ●Vancomycin ●Telavancin

Risk factors for MDR gram-negative bacilli only — If there are risk factors for methicillin-
resistant Pseudomonas and other gram-negative bacilli but not MRSA , the patient should
receive two agents with activity against P. aeruginosa; the regimen should also have activity
against MSSA. Such patients should receive ONE of the following:●Piperacillin-tazobactam
4.5 g IV every six hours●Cefepime 2 g IV every eight hours●Ceftazidime 2 g IV every eight
hours●Imipenem 500 mg IV every six hours●Meropenem 1 g IV every eight
hours●Aztreonam 2 g IV every eight hours

PLUS one of the following:

●An aminoglycoside ●An antipseudomonal fluoroquinolone such as ciprofloxacin (400 mg


IV every eight hours) or levofloxacin (750 mg IV daily) is preferred if Legionella is likely.
●Aztreonam 2 g IV every eight hours

MRSA risk factors only — If there are risk factors for methicillin-resistant S. aureus but not
MDR Pseudomonas and other gram-negative bacilli, the patient should receive one agent
with activity against P. aeruginosa and other gram-negative bacilli and one agent with
activity against MRSA. ONE of the following:●Piperacillin-tazobactam 4.5 g IV every six
hours●Cefepime 2 g IV every eight hours●Ceftazidime 2 g IV every eight
hours●Levofloxacin 750 mg IV daily. ●Ciprofloxacin 400 mg IV every eight hours.
●Aztreonam 2 g IV every eight hours

Among these agents, we generally prefer piperacillin-tazobactam, cefepime, or ceftazidime


because they are more likely to have activity against gram-negative bacilli than the
fluoroquinolones or aztreonam. The IDSA/ATS guidelines also include imipenem and
meropenem as options, but we generally reserve these agents for patients with a high
likelihood of infection with an ESBL-producing gram-negative bacillus.

PLUS one of the following:

●Linezolid ●Vancomycin ●Telavancin

●For patients who are clinically improving who do not have an identified pathogen, empiric
treatment for S. aureus or multidrug-resistant gram-negative bacilli can be discontinued if
these organisms have not grown in culture from a high-quality sputum specimen within 48 to
72 hours.

●Patients who have not improved within 72 hours of starting empiric antibiotics should be
evaluated for complications, other sites of infection, and alternate diagnoses. If the diagnosis
of pneumonia appears certain, there is no evidence of a pyogenic complication that requires
drainage (eg, empyema, lung abscess), and the patient has risk factors for drug-resistant
pathogens (eg, prolonged hospitalization, recent exposure to multiple antibiotics), additional
diagnostic pulmonary cultures should be obtained and the empiric regimen should be
expanded to cover additional resistant organisms.

treat most patients with HAP or VAP for seven days For selected patients with severe illness,
bacteremia, metastatic infection, slow response to therapy, immunocompromise, and
pyogenic complications such as empyema or lung abscess, the duration of therapy is often
individualized and courses longer than seven days may be warranted.

In critically ill patients with rapidly progressive HAP despite broad-spectrum antibiotic use,
other potential hospital-acquired infections such as respiratory viral infections or Legionella
should be considered. During outbreaks of highly drug-resistant organisms, such as
Acinetobacter species or Stenotrophomonas species, including an antibiotic that targets these
organisms in the empiric treatment regimen may be warranted. In immunocompromised
patients, the differential diagnosis should be broad and include fungal, viral, parasitic, and
less common bacterial pathogens.

Allergy to penicillins or cephalosporins — For patients who are allergic to penicillin, the type
and severity of reaction should be assessed. The great majority of patients who are allergic to
penicillin by skin testing can still receive cephalosporins (especially third-generation
cephalosporins) or carbapenems. If there is a history of a mild reaction to penicillin (not an
immunoglobulin [Ig]E-mediated reaction, Stevens-Johnson syndrome, or toxic epidermal
necrolysis), it is reasonable to administer a cephalosporin or an antipseudomonal carbapenem
using a simple graded challenge (1/10 dose followed by a one-hour period of observation; if
no symptoms, give the full dose followed by another hour of observation). Skin testing is
indicated in some situations. If a skin test is positive or if there is significant concern to
warrant avoidance of a cephalosporin or carbapenem, aztreonam (2 g intravenously [IV]
every eight hours) is recommended.

Patients with a history of allergic reactions to cephalosporins may also be treated with
aztreonam, with the possible exception of those allergic to ceftazidime. The prevalence of
cross-sensitivity has been estimated at <5 percent. Patients with past reactions to ceftazidime
that were life-threatening or suggestive of anaphylaxis (involving urticaria, bronchospasm,
and/or hypotension) should not be given aztreonam unless evaluated by an allergy specialist.
In contrast, in patients with mild past reactions to ceftazidime (eg, uncomplicated
maculopapular rash), it is reasonable to inform the patient of the low risk of cross-reactivity if
the patient is agreeable, administer aztreonam with a simple graded challenge (1/10 dose
followed by a one-hour period of observation; if no symptoms, give the full dose followed by
another hour of observation). It is important to note that aztreonam does not provide activity
against gram-positive bacteria like S. aureus. Also, ceftazidime has less activity against
methicillin-susceptible S. aureus (MSSA) than the other beta-lactams suggested above for
HAP and VAP. When one of these agents is used for empiric therapy, an additional agent
with activity against S. aureus (eg, linezolid or vancomycin) should also be used.

●Aminoglycosides are nephrotoxic and ototoxic. However, rates of susceptibility among


gram-negative bacilli are high, so we sometimes use them as part of the initial empiric
regimen in patients with septic shock or rapidly progressive disease. Given the potential
toxicity, we typically discontinue the aminoglycoside after one or two days, especially in
patients who have improved clinically and in whom the pathogen (if identified) is susceptible
to the beta-lactam. There are data suggesting that even very brief courses of aminoglycosides
increase the risk of nephrotoxicity

●Polymyxins (polymyxin B and colistin) are very nephrotoxic. ●In patients with renal
insufficiency, imipenem and cefepime have been associated with seizures. Alternative beta-
lactams should be used in patients at risk. ●The fluoroquinolones have multiple potential
toxicities, including QT interval prolongation, tendinitis and tendon rupture, and
neurotoxicity.

Methicillin-resistant Staphylococcus aureus — If MRSA is a frequent nosocomial pathogen


in the institution (ie, >20 percent local prevalence), linezolid or vancomycin should be
included as part of the initial regimen to provide antistaphylococcal coverage but should be
discontinued if MRSA is not isolated. / when all other factors are equal, we prefer linezolid
to vancomycin in patients with limited intravenous access or difficulty achieving therapeutic
serum concentrations of vancomycin. We prefer vancomycin to linezolid in patients receiving
selective serotonin-reuptake inhibitors and for patients with cytopenias.

●Daptomycin cannot be used to treat pneumonia because it is inactivated by surfactant and


does not achieve adequate concentrations in the respiratory tract.

●Ceftobiprole is a broad-spectrum cephalosporin with activity against a broad range of gram-


positive bacteria including MRSA and penicillin- and ceftriaxone-resistant pneumococci, as
well as gram-negative bacteria. It has not been approved by the FDA, but it has been
approved in Europe and Canada for treatment of HAP and CAP but not VAP.

Methicillin-susceptible Staphylococcus aureus — If a sputum culture reveals MSSA, empiric


therapy for MRSA should be replaced with nafcillin (2 g IV every four hours), oxacillin (2 g
IV every four hours), or cefazolin (2 g IV every eight hours)

Gram-negative pathogens — Although combination antimicrobial therapy for HAP and VAP
due to gram-negative bacilli (especially Pseudomonas) is commonly administered, evidence
to support this practice is limited. The most appropriate use of combination therapy is during
the empiric treatment phase before the infecting pathogen(s) has been identified and
susceptibilities reported. During this phase, the goal of combination therapy is to ensure that
at least one active agent is administered as soon as possible in patients at risk for multidrug-
resistant (MDR) pathogens (eg, if the infecting pathogen is resistant to one agent, it may be
susceptible to the other). Other commonly cited reasons for combination therapy include the
potential for synergistic efficacy as well as the potential to reduce the emergence of
resistance. Continuing combination therapy once the susceptibilities of an infecting pathogen
are known is unlikely to provide benefit.

●Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae – In settings


in which ESBL–producing Enterobacteriaceae are found, cephalosporins should be used
selectively depending on the prevalence of resistance to ceftazidime and cefepime. If local
cefepime resistance rates are high (ie, >10 percent), we generally select a carbapenem (ie,
imipenem, ertapenem, or meropenem) as part of our empiric antibiotic regimen

●Carbapenemase-producing gram-negative bacilli – The optimal treatment of infection


due to carbapenemase-producing organisms is uncertain, and antibiotic options are limited. A
combination regimen is often given, often including a polymyxin (colistin or polymyxin B).
For those with an isolate that is susceptible only to a polymyxin (colistin or polymyxin B),
one of these agents should be given intravenously together with inhaled colistin. The
combination of inhaled and IV colistin is used because IV colistin does not achieve high
concentrations in the lung

●Acinetobacter baumannii – For patients with HAP or VAP caused by A. baumannii, a


carbapenem or ampicillin-sulbactam should be used if the isolate is susceptible . If the isolate
is susceptible only to polymyxins (colistin or polymyxin B), one of these agents should be
given intravenously together with inhaled colistin since intravenous colistin yields low lung
concentrations.

We generally reserve use of ceftazidime-avibactam for patients with HAP or VAP caused by
an MDR gram-negative pathogen that is known to be susceptible to this agent but not other
cephalosporins or as part of an empiric treatment regimen for patients who are known to be
colonized by a MDR gram-negative pathogen that is susceptible to this agent.

Ceftolozane-tazobactam, a second cephalosporin-beta-lactamase inhibitor combination, has


been approved for treatment of urinary tract and intra-abdominal infections but not
pneumonia.

Meropenem-vaborbactam has been approved for the treatment of urinary tract infections and
not pneumonia

Prolonged infusions — prolonged infusions of certain beta-lactam antibiotics may be given


in critically ill patients when MDR pathogens are suspected. We favor prolonged infusions of
beta-lactams for empiric and targeted therapy of gram-negative bacilli in critically ill patients
with VAP or HAP as well as for patients with VAP or HAP caused by gram-negative bacilli
that have elevated but susceptible MICs to the chosen agent. Suitable agents for prolonged
infusions include piperacillin-tazobactam, meropenem, imipenem, and cefepime. Prolonged
infusion for intravenous beta-lactams may include either a continuous infusion (over the
entire dosing interval) or an extended infusion (over three to four hours).

Aerosolized colistin, polymyxin, or aminoglycosides can be used as adjunctive therapy (in


combination with IV antibiotics) in patients with VAP or HAP caused by MDR gram-
negative bacilli, such as A. baumannii or P. aeruginosa Aerosolization may increase
antibiotic concentrations at the site of infection and may be particularly useful for treatment
of organisms that have high MICs to systemic antimicrobial agents . However, the evidence
supporting use of aerosolized antibiotics is not strong and administration can be associated
with adverse effects, particularly in hypoxemic

Legionella — Patients who have compromised immune systems, diabetes mellitus, renal
disease, structural lung disease, or have been recently treated with glucocorticoids may
require coverage for Legionella spp (eg, with azithromycin or a fluoroquinolone).

Anaerobes — Patients who have aspirated or had recent abdominal surgery may warrant
coverage for anaerobes (clindamycin, beta-lactam-beta-lactamase inhibitor, or a
carbapenem). In general, however, anaerobes are rarely implicated in VAP,

PROGNOSIS — HAP is associated with significant increased risk of death. However, many
of these critically ill patients die from their underlying disease and not from the infection

VAP attributable mortality at 13 percent Variables associated with increased mortality


include ●Serious illness at the time of diagnosis (eg, high Acute Physiology and Chronic
Health Evaluation [APACHE] score, shock, coma, respiratory failure, acute respiratory
distress syndrome [ARDS])●Bacteremia●Severe underlying comorbid disease●Infection
caused by an organism associated with multidrug resistance (eg, P. aeruginosa,
Acinetobacter spp, and Enterobacteriaceae, including K. pneumoniae)●Multilobar, cavitating,
or rapidly progressive infiltrates on lung imaging●Delay in the institution of effective
antimicrobial therapy

, we generally prefer piperacillin-tazobactam, cefepime, or ceftazidime because they


are more likely to have activity against gram-negative bacilli than the
fluoroquinolones or aztreonam. The IDSA/ATS guidelines also include imipenem and
meropenem as options, but we generally reserve these agents for patients with a
high likelihood of infection with ESBL-producing gram-negative bacilli.
‡ The IDSA/ATS guidelines recommend either an antipseudomonal fluoroquinolone
or an aminoglycoside for the second agent for gram-negative bacilli, but we
generally prefer an aminoglycoside over a fluoroquinolone if there is not concern for
Legionella, ** We typically discontinue the aminoglycoside after one or two days,
especially in patients who have improved clinically and in whom the pathogen (if
identified) is susceptible to the beta-lactam.
¶¶ In the absence of other options, it is acceptable to use aztreonam as a second
agent for gram-negative bacilli with another beta-lactam because it has different
targets within the bacterial cell wall.
ΔΔ We use aztreonam infrequently since rates of resistance among gram-negative
bacilli are typically higher than to the other beta-lactams options.


not ventilator-associated pneumonia) in patients with normal renal function
The serum gentamicin or tobramycin concentration should be obtained 6 hours (or up to 14
hours) after the initial dose of 7 mg/kg and plotted on the above nomogram. The interval for
drug administration of subsequent doses of 7 mg/kg is then determined based on the interval
specified on the graph.
* Application of the nomogram for amikacin requires the measured concentration be divided
by two. The new value should be plotted on the nomogram in order to obtain the appropriate
dosing interval.

Dosing for prolonged infusions of beta-lactams[1-8]


Infusion
Creatinine clearance Dose Dosing interval
time
3.375 or
>20 mL/minute Every 8 hours 4 hours
4.5 g
Piperacillin- ≤20 mL/minute or 3.375 or
Every 12 hours 4 hours
tazobactam* intermittent HD or PD 4.5 g
3.375 or
CRRT¶ Every 8 hours 4 hours
4.5 g
≥50 mL/minute 2g Every 8 hours 4 hours
30 to 49 mL/minute 2g Every 12 hours 4 hours
15 to 29 mL/minute 1g Every 12 hours 4 hours
CefepimeΔ
<15 mL/minute or
1g Every 24 hours 4 hours
intermittent HD
CRRT¶ 2g Every 12 hours 4 hours
500 mg or
>70 Every 6 hours 3 hours
1g
500 mg or
41 to 70 Every 8 hours 3 hours
◊ 750 mg
Imipenem
250 or 500
21 to 40 Every 6 hours 3 hours
mg
6 to 20 or intermittent 250 or 500
Every 12 hours 3 hours
HD or PD mg
CRRT¶ 500 mg Every 6 hours 3 hours
≥50 mL/minute 1 or 2 g Every 8 hours 3 hours
25 to 49 mL/minute 1 or 2 g Every 12 hours 3 hours
500 mg or
10 to 24 mL/minute Every 12 hours 3 hours
Meropenem§ 1g
<10 mL/minute or 500 mg or Every 24 hours, given
3 hours
intermittent HD 1g after HD
CRRT¶ 1 or 2 g Every 12 hours 3 hours
>50 mL/minute 2.5 g Every 8 hours 2 hours
31 to 50 mL/minute 1.25 g Every 8 hours 2 hours
16 to 30 mL/minute 0.94 g Every 12 hours 2 hours
Ceftazidime-
6 to 15 mL/minute 0.94 g Every 24 hours 2 hours
avibactam
<5 mL/minute or Every 48 hours, given
0.94 g 2 hours
intermittent HD after HD
CRRT¶ 1.25 g Every 8 hours 2 hours
1500 or
>50 mL Every 8 hours 3 hours
3000 mg
750 or
30 to 50 mL/minute Every 8 hours 3 hours
1500 mg
Ceftolozane- 375 or 750
15 to 29 mL/minute Every 8 hours 3 hours
tazobactam mg
<15 mL/minute or 150 or 375 Every 8 hours (start
3 hours
intermittent HD mg after loading dose)
750 or
CRRT¶ Every 8 hours 3 hours
1500 mg
Estimated glomerular Infusion
Dose Dosing interval
filtration rate time
≥50 mL/minute 4g Every 8 hours 3 hours
30 to 49 mL/minute 2g Every 8 hours 3 hours
Meropenem- 15 to 29 mL/minute 2g Every 12 hours 3 hours
vaborbactam <15 mL/minute or
1g Every 12 hours 3 hours
intermittent HD
CRRT¶ 2g Every 8 hours 3 hours

* The higher dose of piperacillin-tazobactam (4.5 g) is used in certain situations, such as


expected augmented drug clearance (as with critical illness or cystic fibrosis) or in cases of
infections with pathogens that have high, but still susceptible, MICs to piperacillin-
tazobactam when alternative agents are not appropriate. .
◊ Imipenem is dosed by both weight and renal function. Dosing above is based on patient
weight >70 kg.
§ The higher dose of meropenem is used in patients with infections of the central nervous
system or other life-threatening infections such as necrotizing fasciitis.