Official reprint from UpToDate

www.uptodate.com 2013 UpToDate

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

Author
Thomas M File, Jr, MD

Section Editor
John G Bartlett, MD

Deputy Editor
Anna R Thorner, MD

Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2013. | This topic last updated: Aug 27, 2013.
INTRODUCTION Hospital-acquired (or nosocomial) pneumonia (HAP), ventilator-associated pneumonia (VAP),
and healthcare-associated pneumonia (HCAP) are important causes of morbidity and mortality despite improved
antimicrobial therapy, supportive care, and prevention [1].
The treatment of HAP, VAP, and HCAP will be reviewed here. The diagnosis, epidemiology, pathogenesis,
microbiology, risk factors, and prevention of HAP, VAP, and HCAP are discussed separately. (See "Clinical
presentation and diagnosis of ventilator-associated pneumonia" and "Epidemiology, pathogenesis, microbiology,
and diagnosis of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults" and
"Risk factors and prevention of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in
adults".)
DEFINITIONS
Pneumonia types The 2005 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA)
guidelines distinguish the following types of pneumonia [2]:
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 to 72 hours after
endotracheal intubation.
Healthcare-associated pneumonia (HCAP) is defined as pneumonia that occurs in a non-hospitalized patient
with extensive healthcare contact, as defined by one or more of the following:
Intravenous therapy, wound care, or intravenous chemotherapy within the prior 30 days
Residence in a nursing home or other long-term care facility
Hospitalization in an acute care hospital for two or more days within the prior 90 days
Attendance at a hospital or hemodialysis clinic within the prior 30 days
HCAP was added as a category of pneumonia in the 2005 ATS/IDSA guidelines in order to identify patients at
increased risk for MDR pathogens coming from community settings; such individuals would previously have been
classified as having community-acquired pneumonia [2,3]. However, the definition of HCAP is being reevaluated
since some authorities have argued that it is an overgeneralization to consider all HCAP patients at increased risk
for MDR pathogens. The challenge for clinicians is to correctly identify the HCAP patient who is most likely to
benefit from empiric treatment with broad-spectrum antibiotics with activity against MDR pathogens. The clinical
issues surrounding HCAP are discussed in greater detail below. (See 'Approach to therapy' below.)

The guidelines can be accessed through the ATS web site at http://www.thoracic.org/statements/.
Multidrug resistance The definition of multidrug resistance (MDR) in gram-negative bacilli, which are an
important cause of HAP, VAP, and HCAP, is variably defined as resistance to at least two, three, four, or eight of
the antibiotics typically used to treat infections with these organisms [4]. Extensively-drug resistant (XDR) gramnegative bacilli are defined by resistance to all commonly used systemic antibiotics except colistin, tigecycline,
and aminoglycosides. Awareness of local resistance patterns is critical for decisions regarding empiric therapy for
HAP, VAP, and HCAP.
Panresistance refers to those gram-negative organisms with diminished susceptibility to all of the antibiotics
recommended for the empiric treatment of VAP, including cefepime, ceftazidime, imipenem, meropenem,
piperacillin-tazobactam, ciprofloxacin, and levofloxacin. (See 'Empiric treatment' below.)
Risk factors for multidrug resistance are discussed separately. (See "Epidemiology, pathogenesis, microbiology,
and diagnosis of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults", section
on 'MDR risk factors'.)
TREATMENT
Approach to therapy Appropriate antibiotic therapy significantly improves survival for patients with hospitalacquired (or nosocomial) pneumonia (HAP), ventilator-associated pneumonia (VAP), or healthcare-associated
pneumonia (HCAP) [2,5]. However, establishing the diagnosis of pneumonia in such patients can be difficult,
especially those on mechanical ventilation in whom clinical, radiologic, and microbiologic findings can be due to
numerous etiologies besides pneumonia. The difficulty in diagnosis may lead to overtreatment with its attendant
risks of superinfection and antibiotic toxicity. (See "Clinical presentation and diagnosis of ventilator-associated
pneumonia".)
When therapy is given, antimicrobial selection should be based upon risk factors for multidrug-resistant (MDR)
pathogens, including recent antibiotic therapy (if any), the resident flora in the hospital or intensive care unit (ICU),
the presence of underlying diseases, and available culture data (interpreted with care). For patients with risk factors
for MDR pathogens, empiric broad-spectrum, multidrug therapy is recommended. Once the results of pretherapy
cultures are available, therapy should be narrowed based upon the susceptibility pattern of the pathogens identified.
(See 'Tailoring the regimen' below.)
The importance of providing appropriate therapy at the time of presentation was illustrated in a retrospective study of
almost 400 patients with culture-positive HCAP who survived but remained hospitalized 48 hours after hospital
admission [6]. Mortality was significantly higher among the 107 patients who received inappropriate initial therapy
compared with the 289 patients who received appropriate coverage (30 versus 18 percent); switching to an
appropriate regimen did not reduce the risk of death.
In a study that assessed the microbial prediction and validated the adequacy of the 2005 American Thoracic
Society/Infectious Diseases Society of America (ATS/IDSA) guidelines for HAP in the ICU, adherence to the
guidelines resulted in more adequate treatment and a trend toward a better clinical response in patients who
presented late (5 days) or had risk factors for drug-resistant bacteria, but did not affect mortality [7]. The 2005
guidelines were worse than the 1996 guidelines for predicting drug-resistant bacteria; this was mostly observed for
cases classified as lower risk for multidrug-resistant pathogens (ie, early onset infection without specified risk
factors for resistant infection), suggesting that such patients may in fact be at risk for resistant pathogens.
In a survey of physicians at academic medical centers, respondents selected guideline-concordant antibiotic
regimens only 9 percent of the time for HCAP compared with 78 percent of the time for CAP [8]. A retrospective
study showed that HCAP is associated with more severe disease, longer hospital stay, and higher mortality rates
than community-acquired pneumonia (CAP), and that the use of antimicrobial therapy not recommended by the
ATS/IDSA guidelines was associated with increased mortality in such patients [9]. Another observational study
found that lack of adherence to a VAP protocol (which included considerations of appropriate use and duration of

antibiotics) resulted in longer duration of therapy, ventilation, and length of ICU stay [10].
In an observational study that included 303 patients at risk for MDR pathogens, 28-day mortality was higher among
patients who were treated according to the ATS/IDSA guidelines compared with patients whose treatment did not
comply with the guidelines (34 versus 20 percent) [11]. The primary reason for non-compliance was lack of a
second drug for gram-negative pathogens. Criticisms of this study include the observation that lower coverage for
certain MDR pathogens occurred in the compliant group (but was not commented upon by the authors), lack of
assessment of the impact of timing of antimicrobial therapy, lack of appropriate adjustment for risk of death,
disregard of the impact of treatment deescalation on the classification of compliance, and the possibility that
excess mortality may have been at least partly due to toxicity when a triple regimen is used [12]. In addition,
although the authors attempted to control for higher severity of infection observed in the compliant group, the results
may still have been confounded by patients in the compliant group who were at greater risk of poor outcomes at
presentation.
Potential messages from this study are [11]:
Clinicians who are following patients and are aware of pathogen and susceptibility patterns within a specific
unit may be better able to appropriately select empiric therapy based on individual clinical judgment rather
than using routine combination therapy (guidelines are meant to supplement clinical judgment, not supplant
judgment).
The need for two-drug therapy is not necessary in many cases of gram-negative infection.
The definition of risk for MDR as stated in the 2005 guidelines is not precise, particularly for HCAP, and
should be readdressed.
Various editorials and studies have reported that it is an overgeneralization to consider all HCAP patients at
increased risk for MDR pathogens [13-18]. The challenge for clinicians is to correctly identify the HCAP patient who
is most likely to benefit from empiric treatment with broad-spectrum antibiotics with activity against MDR
pathogens. The definition of HCAP is being reevaluated, and future investigations are required to better define
patients with HCAP who are likely to be infected with MDR pathogens. (See 'Gram-negative pathogens' below and
'Multidrug resistance' above.)
Given the concerns about the lack of precision of the definition of HCAP for detecting patients infected with
resistant organisms, a validation study of a clinical scoring system for predicting resistant bacteria was performed,
which compared the definition of HCAP to the scoring system [19]. The risk score was calculated using the
following weighted points:
Recent hospitalization of at least 48 hours during the preceding 90 days 4 points
Residence in a nursing home 3 points
Chronic hemodialysis 2 points
Critical illness 1 point
The risk score was higher in patients with pneumonia caused by a resistant pathogen than in those without a
resistant pathogen (median score 4 versus 1) and was more accurate than the definition of HCAP for detecting
patients with pneumonia caused by resistant bacteria, including methicillin-resistant Staphylococcus aureus,
Pseudomonas aeruginosa, and extended-spectrum beta-lactamase producing gram-negative bacilli. A risk score >0
had a negative predictive value of 85 percent; thus, a risk score of 0 could lead to fewer patients unnecessarily
receiving broad-spectrum antibiotics if it is used to guide the choice of therapy. Another study of patients requiring
hospitalization for pneumonia who came from the community found that hospitalization in the preceding 90 days
(odds ratio [OR] 4.87, 95% CI 1.90-12.4) and residency in a nursing home (OR 3.55, 95% CI 1.12-11.24) were
independent predictors of infection with a resistant pathogen; these factors were also independent predictors of inhospital mortality [20].

In a retrospective analysis of local microbiologic data on HAP pathogens from 111 consecutive patients in 2004,
investigators developed institution-specific treatment guidelines in order to improve empiric antibiotic therapy [21].
Institution guideline-directed treatment regimens were predicted to provide adequate initial therapy for >90 percent
of patients who develop HAP 10 days after hospitalization (eg, those at greatest risk of multidrug resistant
pathogens). In this institution, use of a fluoroquinolone per the national guidelines, would not have provided
adequate additional antimicrobial activity for the beta-lactam resistant gram-negative bacilli (ciprofloxacin was active
against <10 percent of these pathogens which were also resistant to piperacillin-tazobactam and cefepime). This
study illustrates the importance of using local susceptibility data to develop treatment guidelines.
The implementation of recommendations to assess a patient's status 72 hours after the initiation of therapy and to
discontinue antibiotics or narrow the regimen (deescalate therapy) based upon appropriate culture results may
reduce the selective pressure for antimicrobial resistance. A prospective observational study of 398 intensive care
unit (ICU) patients with suspected VAP found that mortality was significantly lower among patients in whom therapy
was deescalated compared to those whose therapy was either escalated or unchanged (17 versus 43 and 24
percent, respectively) [22]. The study was limited because of its observational nature; confirmation of these results
awaits a randomized controlled study. In another study, deescalation was evaluated in surgical patients with septic
shock in a retrospective evaluation of 138 patients with VAP [23]. Deescalation of antimicrobial therapy occurred in
55 percent of patients who had received initial therapy effective against the identified pathogen (most common initial
choice was vancomycin plus piperacillin-tazobactam). The mortality rate of patients who underwent deescalation
therapy was 35 percent compared with 42 percent among patients who did not have deescalation, a difference that
did not reach statistical significance. This study demonstrated that deescalation therapy did not lead to recurrent
pneumonia or increased mortality in this population of critically ill surgical patients. (See 'Tailoring the regimen'
below.)
Antimicrobial stewardship programs have been shown to reduce rates of nosocomial infections (including
Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococcal infections)
and antimicrobial expenditures without affecting mortality or length of hospital stay [24].
Specific antimicrobial considerations In critically ill patients, in those receiving antibiotics prior to the onset
of pneumonia, and in institutions where these pathogens are frequent, coverage of methicillin-resistant
Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and antibiotic-resistant gram-negative bacilli, such as
Acinetobacter spp, and Legionella should be considered.
Methicillin-resistant Staphylococcus aureus If MRSA is a frequent nosocomial pathogen in the institution,
linezolid or vancomycin is a necessary first choice for anti-staphylococcal coverage [2,25,26], but should be
discontinued if MRSA is not isolated.
An overview of the treatment of invasive MRSA infections is presented separately. (See "Treatment of invasive
methicillin-resistant Staphylococcus aureus infections in adults".)
Linezolid and vancomycin Several trials have compared linezolid and vancomycin, with variable results:
A meta-analysis of nine randomized trials that compared linezolid with vancomycin (in seven trials) or
teicoplanin (in two trials) for nosocomial pneumonia found no differences in rates of clinical cure or
microbiologic eradication [27]. In addition, no differences in clinical cure or microbiologic eradication were
observed in the subgroup analysis of patients with MRSA. Linezolid was associated with a higher risk of
thrombocytopenia (relative risk [RR] 1.93, 95% CI 1.30-2.87) and gastrointestinal events (RR 2.02, 95% CI
1.10-3.70), but there was no difference in the risk of renal dysfunction.
Another meta-analysis, which included eight trials that compared linezolid to vancomycin or teicoplanin for
the treatment of suspected MRSA pneumonia, found no differences in clinical success, microbiologic
success, or mortality [28].
It should be noted that the studies included in the meta-analyses described above used a dosing regimen for

vancomycin that is significantly lower than what is recommended by the ATS and the IDSA [2,26,29,30].
(See 'Dosing and vancomycin troughs' below.)
In a later randomized double-blind trial that compared linezolid to vancomycin for the treatment of HAP or
HCAP due to proven MRSA, the end of study success rate was 58 percent for linezolid and 47 percent for
vancomycin [31]. Among patients who had a respiratory specimen available for culture at the end of
treatment, 16 of 92 patients (17 percent) who received linezolid had cultures that were persistently positive
for MRSA compared with 50 of 109 patients (46 percent) who received vancomycin. In this study,
vancomycin dosing was adjusted to achieve target trough levels. Linezolid was non-inferior and statistically
superior to vancomycin in end of treatment clinical outcome, and microbiologic outcome at end of treatment
and end of study, but there were no differences in all-cause 60-day mortality or overall adverse events.
Nephrotoxicity occurred more commonly with vancomycin than linezolid (18 versus 8 percent).
Dosing and vancomycin troughs A retrospective study suggested that vancomycin failure might be
related to suboptimal dosing [32]. As a result, a trough level of 15 to 20 mcg/mL is targeted [2]. However,
subsequent studies failed to confirm that higher vancomycin trough concentrations correlate with improved
outcomes [33,34]. On the other hand, higher vancomycin MICs themselves may be associated with worse
outcomes in patients with HAP due to MRSA. This was suggested in a prospective cohort study of 95 patients with
MRSA HCAP who were treated with vancomycin in which the targeted trough vancomycin concentration was at
least four times the MIC [33]. High MIC (2 mcg/mL) strains of MRSA were detected in 54 percent of patients.
Despite achieving the target trough concentration, mortality was higher among patients whose MRSA strain had a
high MIC than patients whose MRSA strain had a low MIC (24 versus 10 percent). In a later prospective study that
included 158 patients in the ICU with HAP, VAP, or HCAP, an increase in 28-day mortality was observed in
patients whose MRSA isolates had increased MICs; an increase in mortality occurred as the vancomycin MIC
increased from 0.75 to 3 mcg/mL, and was present even for strains within the susceptible range [35].
The 2005 ATS/IDSA treatment guidelines on HAP, VAP, and HCAP; the 2011 IDSA guidelines for the treatment of
MRSA infections; and a 2009 United States pharmacy consensus review recommend target vancomycin trough
concentrations of 15 to 20 mcg/mL [2,26,29,30]. However, these recommendations are based on retrospective
pharmacokinetic modeling in the absence of prospective clinical data. PK/PD analysis has suggested that lung
vancomycin AUC:MIC >400 may be difficult to achieve (particularly for isolates with MIC >1) [36-38]. Clinical data
have failed to demonstrate a relationship between treatment outcome and target troughs of 15 to 20 mcg/mL [2].
(See "Vancomycin dosing and serum concentration monitoring in adults".)
The 2005 ATS/IDSA guidelines on HAP, VAP, and HCAP and the 2011 IDSA guidelines for the treatment of MRSA
infections recommended either linezolid or vancomycin for infections suspected or proven to be due to MRSA
[2,26]. It was noted that linezolid might be preferred in patients at risk for or with renal insufficiency in whom
vancomycin is often underdosed and is associated with a risk of nephrotoxicity. Linezolid also may reduce toxin
production, although the possible benefit of this has not been established [39,40]. Linezolid is particularly preferred
in hospitals in which a substantial proportion of MRSA isolates have a vancomycin MIC 2 mcg/mL. Linezolid
resistance and linezolid failure have been described rarely. An alternative to linezolid and vancomycin is
clindamycin (600 mg IV or orally three times daily), provided that the isolate is known to be susceptible, although
there are fewer data to supports its use [26]. (See "Epidemiology of methicillin-resistant Staphylococcus aureus
infection in adults", section on 'Linezolid resistance' and "Treatment of invasive methicillin-resistant Staphylococcus
aureus infections in adults", section on 'Linezolid'.)
The usual doses are:
Linezolid 600 mg twice daily IV (or orally if or when the patient is able to receive oral medications).
Vancomycin 15 to 20 mg/kg (based on actual body weight) IV every 8 to 12 hours for patients with normal
renal function, with a target serum trough concentration of 15 to 20 mg/L. In seriously ill patients, a loading
dose of 25 to 30 mg/kg can be used to facilitate rapid attainment of the target trough concentration. (See

"Vancomycin dosing and serum concentration monitoring in adults".)

Other agents There has been interest in using other agents for the treatment of MRSA pneumonia, but
none of the following agents can be recommended:
Daptomycin cannot be used to treat pneumonia because it does not achieve sufficiently high concentrations
in the respiratory tract.
Data are limited on the use of quinupristin-dalfopristin. In a randomized trial of HAP that included 38 patients
with MRSA pneumonia, there was a nonsignificant lower rate of clinical success with quinupristin-dalfopristin
compared with vancomycin (31 versus 44 percent) and a higher rate of adverse effects that led to
discontinuation of therapy [41].
Ceftaroline is a broad-spectrum cephalosporin with activity against MRSA, which has been approved by the
US Food and Drug Administration (FDA) for CAP, but not for CAP caused by MRSA, or for HAP, VAP, or
HCAP [42].
Tigecycline is a broad-spectrum antibiotic with activity against MRSA. In September 2010, the FDA issued a
safety announcement regarding an increased mortality risk associated with the use of tigecycline compared
with that of other drugs that was observed in a pooled analysis of 13 trials [43]. The increased risk was seen
most clearly in patients treated for HAP, particularly VAP. In a randomized trial of 945 patients with HAP,
tigecycline with or without ceftazidime was compared to imipenem-cilastatin with or without vancomycin
[44]. In the clinically evaluable population, the cure rate for tigecycline was significantly lower than for
imipenem (68 versus 78 percent). Cure rates in clinically evaluable patients with VAP were 48 percent for
tigecycline and 70 percent for imipenem. Cure rates for MRSA infection (HAP and VAP) were 44 percent for
tigecycline and 77 percent for imipenem plus vancomycin.
A 2012 meta-analysis of 10 published and 3 unpublished randomized noninferiority trials also found that
tigecycline was associated with an absolute mortality increase of 0.7 percent (95% CI 0.1-1.2 percent)
compared with other agents [45]. In addition, tigecycline was associated with an absolute increase in
noncure rate of 2.9 percent (95% CI 0.6-5.2 percent). These effects were not isolated to a specific type of
infection or comparator antibiotic regimen.
Telavancin is an antibiotic with activity against MRSA. In two randomized trials (the ATTAIN studies), among
patients with HAP due to monomicrobial infection with MRSA, the cure rate (regardless of vancomycin MIC)
was 82 percent for telavancin and 74 percent for vancomycin (95% CI -3.5-19.3) [46]. The cure rate among
patients with MRSA with reduced susceptibility to vancomycin (MIC 1 mg/dL) was 87 percent in those who
received telavancin versus 74 percent in those who received vancomycin (95% CI 0.5-23.0). It is important to
note that the dose of vancomycin that was used in these studies was lower than the dose that is currently
recommended. Telavancin has not been approved by the FDA for the treatment of pneumonia. Furthermore,
it is unavailable globally due to manufacturing problems [47].
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) or oxacillin (2 g IV every four hours).
Gram-negative pathogens Although combination antimicrobial therapy for HAP, VAP, and HCAP due to
gram-negative pathogens (especially Pseudomonas) is commonly administered, there is no conclusive evidence to
support this practice. The best rationale for the use of combination therapy is to provide a greater spectrum of
activity when there is risk for MDR pathogens (eg, if the pathogen is resistant to one agent it may be susceptible to
the other) [2]. Other commonly cited reasons for combination therapy include the potential for synergistic efficacy
as well as the potential to reduce the emergence of resistance. However, it is not clear that two agents offer
improved outcomes for treating gram-negative pneumonia.

A meta-analysis and a subsequent large, randomized trial suggested that monotherapy of VAP was as effective as
combination therapy [48,49]. However, the percentage of MDR organisms was low in the trials reviewed in the metaanalysis and in the randomized trial. In addition, the randomized trial excluded patients known to be colonized with
Pseudomonas or MRSA, and found that combination versus monotherapy was associated with improved adequacy
of initial antibiotics and microbiologic eradication of infecting organisms in patients who had infection due to
Pseudomonas, Acinetobacter, and MDR gram-negative bacilli [49]. Thus, it is difficult to extrapolate the efficacy of
monotherapy to ICUs with high incidences of these pathogens.
In another study of patients hospitalized in an ICU due to trauma, 84 patients with VAP caused by Pseudomonas
were treated with monotherapy (cefepime 2 g intravenously every 8 hours); this resulted in microbiologic eradication
(based on repeat BAL showing <103 organisms/mL) in 94 percent of patients with no recurrences, suggesting that
combination therapy is unnecessary when the initial antimicrobial therapy is active against the isolate [50].
In ICU settings in which extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are found,
cephalosporins should be avoided as monotherapy, due to the selection of resistant organisms when these agents
are used [51]. The most reliable agent in this setting is a carbapenem (imipenem-cilastatin, ertapenem,
meropenem, or doripenem) [52-54].
Legionella Patients who have diabetes mellitus, renal disease, structural lung disease, or have been
recently treated with glucocorticoids may require coverage for Legionella spp (azithromycin or a fluoroquinolone).
HAP and VAP due to Legionella spp are also more common in hospitals where the organism is present in the
hospital water supply. (See "Epidemiology and pathogenesis of Legionella infection" and "Treatment and prevention
of Legionella infection".)
Anaerobes Patients who have aspirated or had recent abdominal surgery may warrant coverage for
anaerobes (clindamycin, beta-lactam-beta-lactamase inhibitor, or a carbapenem). (See "Aspiration pneumonia in
adults" and "Anaerobic bacterial infections", section on 'Pleuropulmonary infections'.)
Antiinflammatory effects of macrolides There has been interest in the nonantibiotic antiinflammatory
effects of macrolides. A randomized trial of 200 patients with sepsis and VAP showed that those who received
clarithromycin (in addition to standard treatment including antibiotics) had significantly faster resolution of VAP (10
versus 15.5 days) and weaning from mechanical ventilation (16 versus 22.5 days) compared to those who received
placebo [55]. Among those who died of sepsis, time to death was significantly prolonged in those who received
clarithromycin.
Empiric treatment We generally agree with the ATS/IDSA guidelines for the management of HAP, VAP, or
HCAP [2]. These guidelines can be accessed through the ATS website at http://www.thoracic.org/statements/.
Knowledge of the predominant pathogens, and particularly their susceptibility patterns, should greatly impact the
choice of empiric therapy; in some cases, the appropriate regimen will differ from the regimens recommended in the
ATS/IDSA guidelines.
No known multidrug resistance risk factors We suggest one of the following intravenous antibiotic
regimens for empiric coverage of HAP and VAP in patients with no known risk factors for multidrug-resistant (MDR)
pathogens:
Ceftriaxone (2 g intravenously daily).
Ampicillin-sulbactam (3 g intravenously every six hours).
Levofloxacin (750 mg intravenously daily) or moxifloxacin (400 mg intravenously daily). When the patient is
able to take oral medications, either agent may be administered orally at the same dose as that used for IV
administration.
Ertapenem (1 g intravenously daily).

Choice of a specific agent for empiric therapy should be based on knowledge of the prevailing pathogens (and
susceptibility patterns) within the healthcare setting. If there is concern for gram-negative bacilli resistant to the
above options (eg, Enterobacter spp, Serratia spp, Pseudomonas spp) based upon microbiologic data at the
specific institution, we feel that it is reasonable to initiate piperacillin-tazobactam (4.5 g IV every six hours) or
another agent (eg, cefepime or a carbapenem) as monotherapy for patients without known risk factors for MDR
bacteria provided that the institutions susceptibility data support in vitro activity.
Known multidrug resistance risk factors Host risk factors for infection with multidrug-resistant (MDR)
pathogens include receipt of antibiotics within the preceding 90 days, current hospitalization of 5 days, high
frequency of antibiotic resistance in the community or in the specific hospital unit, immunosuppressive disease
and/or therapy, and presence of risk factors for HCAP. (See "Epidemiology, pathogenesis, microbiology, and
diagnosis of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults", section on
'MDR risk factors'.)
Traditional dosing The traditional dosing of each agent is described in the following discussion, but
extended infusions may be considered to optimize pharmacokinetics and pharmacodynamics, especially in
critically ill patients. (See 'Extended infusions' below.)
For patients with known MDR risk factors, we recommend empiric combination therapy including:
ONE of the following:
Antipseudomonal cephalosporin such as cefepime (2 g intravenously every eight hours) or ceftazidime (2 g
intravenously every 8 hours).
Antipseudomonal carbapenem such as imipenem (500 mg intravenously every six hours) or meropenem (1 g
intravenously every eight hours) or doripenem (500 mg intravenously every eight hours; administered over one
hour for HAP or HCAP, administered over four hours for VAP) [53,54].
Piperacillin-tazobactam (4.5 g intravenously every six hours).
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
IgE-mediated reaction, Stevens Johnson syndrome or toxic epidermal necrolysis), it is reasonable to
administer a cephalosporin or carbapenem using a simple graded challenge (eg, give 1/10 of dose, observe
closely for 1 hour, then give remaining 9/10 of dose, observe closely for 1 hour). 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 every six to eight hours) is recommended.
Indications and strategies for skin testing are reviewed elsewhere. (See "Penicillin-allergic patients: Use of
cephalosporins, carbapenems, and monobactams".)
Patients with past allergic reactions to cephalosporins may also be treated with aztreonam, with the
possible exception of those allergic to ceftazidime. Ceftazidime and aztreonam have similar side chain
groups, and cross reactivity between the two drugs is variable. The prevalence of cross-sensitivity has been
estimated at <5 percent of patients, based upon limited data. 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, a
reasonable approach in those with mild past reactions to ceftazidime (eg, uncomplicated maculopapular
rash) would involve informing the patient of the low risk of cross-reactivity and administering aztreonam with a
graded challenge (1/100, 1/10, full dose, each separated by 1 hour of observation). (See "Cephalosporinallergic patients: Subsequent use of cephalosporins and related antibiotics", section on 'Use of
carbapenems and monobactams'.)

PLUS consider adding one of the following (if microbiologic data from the institution or the patients
previous cultures suggest that one of the following agents provides necessary additional coverage for
gram-negative bacilli [GNB] in combination with the selected beta-lactam). In light of the results of several
studies suggesting comparable outcomes with monotherapy compared with combination therapy of GNB and the
potential for added toxicity of the aminoglycosides, it may not be beneficial to add one of the following agents (see
'Approach to therapy' above):
Antipseudomonal fluoroquinolone, preferred regimen if Legionella is likely, such as ciprofloxacin (400 mg
intravenously every eight hours) or levofloxacin (750 mg intravenously daily). These agents may be
administered orally when the patient is able to take oral medications. The dose of levofloxacin is the same
when given intravenously and orally, while the dose of ciprofloxacin is 750 mg orally twice daily.
Aminoglycoside such as gentamicin or tobramycin (7 mg/kg intravenously once daily) or amikacin (20 mg/kg
intravenously once daily); 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 (figure 1). The aminoglycoside can be stopped after
five to seven days in responding patients. (See "Dosing and administration of parenteral aminoglycosides".)
Addition of an alternative agent, such as intravenous colistin, may be appropriate if highly resistant
Pseudomonas spp or Acinetobacter spp is suspected (see "Treatment of Pseudomonas aeruginosa
infections", section on 'Alternative therapy in multidrug resistant infections' and "Acinetobacter infection:
Treatment and prevention", section on 'Pneumonia' and "Colistin: An overview", section on 'Systemic
administration') [56]. In some cases, inhaled colistin may be appropriate as adjunctive therapy in
combination with systemic antimicrobials, as discussed below. (See 'Aerosolized antibiotics' below.)
PLUS ONE of the following (if MRSA is suspected, there are MRSA risk factors, or there is a high
incidence of MRSA locally):
Linezolid (600 mg intravenously every 12 hours; may be administered orally when the patient is able to take
oral medications)
Vancomycin (15 to 20 mg/kg [based on actual body weight] intravenously every 8 to 12 hours for patients
with normal renal function, with a target serum trough concentration of 15 to 20 mg/L.) In seriously ill
patients, a loading dose of 25 to 30 mg/kg can be used to facilitate rapid attainment of the target trough
concentration. (See "Vancomycin dosing and serum concentration monitoring in adults".)
If patients have recently received antibiotics, empiric therapy should generally be with a drug from a different class
since earlier treatment may have selected pathogens resistant to the initial class.
Extended infusions Because of increasing resistance of pathogens associated with VAP, HAP, and
HCAP, one potential strategy to enhance the antimicrobial potential of a given agent is to optimize the
pharmacodynamic effect. Based upon the pharmacokinetic and pharmacodynamic properties of each agent,
optimization of antimicrobial effect can be achieved with increased doses (for concentration-dependent antibiotics
such as aminoglycosides and fluoroquinolones) or with prolonged or continuous infusions (for time-dependent
antibiotics such as beta-lactams) [57]. Such regimens can potentially provide effective therapy for pathogens with
higher minimum inhibitory concentration (MICs), and may impede the emergence of resistance, and potentially
provide a pharmacoeconomic benefit. Extended infusions are generally more practical than continuous infusions,
since dedicated intravenous catheters are required for continuous infusions.
Since the beta-lactams are associated with optimal outcomes when the level of the drug is above the MIC for the
pathogen for an appropriate percent of the dosing interval, this effect can potentially be improved with prolonged
infusion of the antimicrobial. This has been demonstrated with the use of a 3 to 4 hour infusion of piperacillintazobactam, cefepime, or the carbapenems, meropenem and doripenem, for the treatment of VAP due to gram-

negative bacilli with higher MICs than the usual breakpoints for susceptibility [58-65]. An extended infusion of
imipenem is not appropriate, since it does not remain stable for prolonged periods.
Dosing guidelines for extended infusions have not been published; we use the following dosing regimens for
extended infusions of piperacillin-tazobactam, cefepime, meropenem, and doripenem based on
pharmacokinetic/pharmacodynamic modeling [58-65]. For patients with normal renal function, we use the following
initial dosing:
Piperacillin-tazobactam 4.5 g infused IV over three hours, administered every six hours. An alternative to
the extended infusion is to administer piperacillin-tazobactam as a continuous infusion of 18 g IV over 24
hours.
Meropenem 1 to 2 g infused IV over three hours, administered every eight hours.
Doripenem 1 g infused IV over four hours, administered every eight hours. Of note, this dose is higher than
the approved dose that is used in traditional dosing regimens.
Cefepime 2 g infused IV over three hours, administered every eight hours.
The patient can be transitioned to traditional dosing if the MIC is low.
In a 2013 meta-analysis of observational studies and randomized trials, patients with pneumonia receiving an
extended or continuous infusion of a carbapenem (mostly meropenem) or piperacillin-tazobactam had lower
mortality than patients receiving intermittent bolus dosing (risk ratio 0.5, 95% CI 0.26-0.96), although there were no
differences in clinical cure [66]. Previously published meta-analyses that included only randomized trials did not
detect a difference in mortality between extended infusions and intermittent bolus dosing [67-69]. A possible reason
for this difference is that the disease severity in the randomized trials was low, which is reflected by the low
mortality rates in these studies [70]. In contrast, many of the patients in the 2013 meta-analysis were critically ill
patients with nosocomial pneumonia. Such patients might be more likely to benefit from extended infusions.
In a separate Cochrane meta-analysis, which included 29 randomized trials published between 1977 and 2012 of
patients receiving antibiotics for severe acute infections (16 of which involved patients with pneumonia), there were
no differences in mortality, infection recurrence, clinical cure, superinfection post-therapy, or safety outcomes when
comparing continuous infusions of intravenous antibiotics to traditional intermittent infusions of antibiotics [71].
However, the utility for MDR pathogens or those with higher MICs was not well-defined.
In a randomized trial of 60 patients with severe sepsis (nearly half of whom had pneumonia) that was published after
the 2013 meta-analysis was performed, plasma antibiotic concentrations exceeded the MIC in 82 percent of
patients who received a continuous infusion of piperacillin-tazobactam, meropenem, or ticarcillin-clavulanate
compared with 29 percent of patients who received intermittent bolus dosing [72]. The rate of clinical cure was
significantly higher in those who received a continuous infusion compared with those who received intermittent
bolus dosing (70 versus 43 percent). There was a non-significant trend towards increased survival to hospital
discharge in patients who received a continuous infusion (90 versus 80 percent), but this study was not powered to
detect a survival benefit.
In a single center study of extended infusion of cefepime, piperacillin-tazobactam, or meropenem (administered over
three hours) for suspected gram-negative infections in critically ill patients, many of whom had pneumonia, there
was no advantage compared with intermittent infusion with regard to treatment success, mortality, or length of
hospital stay [73]. The paucity of isolates with elevated MICs in this study may in part explain the lack of benefit of
extended infusion.
Aerosolized antibiotics Aerosolized colistin, polymyxin, or aminoglycosides may be considered as
potential additional antibiotics in patients with multidrug-resistant (MDR) gram-negative bacilli [74-78].
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 [79]. In a randomized trial that
included 100 patients with VAP due to gram-negative bacilli (predominantly MDR Acinetobacter baumannii and/or
Pseudomonas aeruginosa), patients who were treated with a combination of systemic antibiotics and nebulized
colistin had a higher rate of favorable microbiologic outcome compared with patients who were treated with
systemic antibiotics alone (microbiologic eradication or presumed eradication 61 versus 38 percent), but there was
no differences in clinical outcome (51 versus 53 percent) [78].
In a retrospective case-control study that included 86 patients with VAP due to MDR gram-negative bacilli
(predominantly A. baumannii) treated with a combination of IV and aerosolized colistin compared with IV colistin
alone, there was only a trend towards improved rates of clinical cure, pathogen eradication, and mortality in the
patients who received aerosolized and IV colistin [80]. However, this study may have been underpowered to show a
benefit, adequate doses of aerosolized colistin may not have been used, and the difficulty in diagnosing VAP may
have biased the results (ie, if patients without VAP were included) [81]. (See "Colistin: An overview".)
In a trial that included 37 patients with VAP due to P. aeruginosa, patients were randomly assigned to receive
either ceftazidime plus amikacin administered intravenously (ceftazidime 90 mg/kg per day via continuous infusion
for eight days plus amikacin 15 mg/kg daily for three days) or by aerosolization (ceftazidime 15 mg eight times
daily for eight days and amikacin 25 mg/kg daily for three days) [82]. Bacterial eradication occurred more often and
more rapidly in the patients who received aerosolized antibiotics. However, no significant clinical differences were
detected between the treatment groups, which may have been due at least in part to the small number of patients.
Clinical success was achieved in 70 percent of the aerosolized antibiotic group and 55 percent of the IV antibiotic
group. No antibiotic resistance developed in patients who received aerosolized antibiotics, but three patients who
received IV antibiotics developed resistance to ceftazidime. There were three adverse events related to obstruction
of the respiratory filter in the aerosolized antibiotic group; one of these resulted in a nonfatal cardiorespiratory
arrest.
Tailoring the regimen When the etiology of HAP, VAP, or HCAP has been identified based upon reliable
microbiologic methods and there is no laboratory or epidemiologic evidence of coinfection, treatment regimens
should be simplified and directed to that pathogen. The choice of specific agents will be dictated by the results of
susceptibility testing. It is important to avoid broad-spectrum therapy once a pathogen has been identified [2,12,83].
Staphylococcus aureus and gram-negative bacilli are easy to grow in culture. Thus, if these organisms are not
isolated from a good quality sputum specimen, coverage for methicillin-resistant S. aureus and multidrug-resistant
gram-negative bacilli can be discontinued.
Patients who are improving clinically, are hemodynamically stable, and able to take oral medications can be
switched to oral therapy. If the pathogen has been identified, the choice of antibiotic for oral therapy is based upon
the susceptibility profile for that organism. If a pathogen is not identified, the choice of antibiotic for oral therapy is
either the same antibiotic as the intravenous antibiotic, or an agent in the same drug class, which achieves
adequate lung penetration when administered orally.
Duration The duration of therapy should be based upon the clinical response. The standard duration of therapy
in the past was 14 to 21 days in part because of a concern for difficult to treat pathogens (eg, Pseudomonas spp).
However, a shorter course could significantly reduce the amount of antimicrobial drugs used in hospitals where the
emergence of resistant pathogens is a concern.
The following studies found that short course treatment is effective:
A prospective randomized multicenter trial of 401 patients with VAP compared outcomes following eight
versus 15 days of treatment [84]. All patients underwent bronchoscopy for quantitative cultures and were
empirically treated with a combination of an antipseudomonal beta-lactam plus either an aminoglycoside or a
fluoroquinolone. Investigators were encouraged to change the regimen to a pathogen-directed treatment
based upon culture results.

There was no significant difference between patients treated for eight compared to 15 days in mortality or
recurrent infection at 28 days; as expected, patients treated for eight days had more antibiotic-free days.
Among patients who developed recurrent infections, MDR pathogens were isolated less frequently in those
treated for eight days (42 versus 62 percent for those treated for 15 days). However, patients with VAP
caused by nonfermenting gram-negative bacilli (eg, Pseudomonas spp) had a higher pulmonary infection
recurrence rate when treated for eight versus 15 days (41 versus 25 percent with 15 days of treatment),
although mortality was not different. In a subanalysis of 125 patients who had S. aureus isolated as a
pathogen, there was no significant difference based on treatment duration (8 or 15 days) for 28-day mortality
or VAP recurrence; this was also the case when only VAP caused by MRSA was considered [85].
In a 2011 meta-analysis that evaluated 508 patients with VAP showed that a short (seven to eight day)
course of antibiotics compared with a longer (10 to 15 day) course increased antibiotic-free days during the
28 days following enrollment (odds ratio [OR] 4.02, 95% CI 2.26-5.78) and reduced recurrence of VAP due to
MDR pathogens (OR 0.44, 95% CI 0.21-0.95) [86]. However, for cases of VAP due to non-fermenting gramnegative bacilli, pneumonia recurrence was greater after short-course therapy (OR 2.18, 95% CI 1.14-4.16).
The majority of the patients included in the meta-analysis derived from the trial described above [84], and the
remainder were from two other smaller studies. An ICU study evaluated clinical outcomes, including duration
of treatment, following implementation of a clinical guideline for the treatment of VAP compared with
historical controls (patients with VAP treated prior to implementation of the guideline) [87]. The clinical
guideline group had a shorter duration of antimicrobial therapy and was less likely to have a recurrent
episode of VAP.
A prospective study evaluated the ability of the Clinical Pulmonary Infection Score (CPIS) to determine the
duration of therapy for ICU patients with new pulmonary infiltrates (table 1) [88]. Patients were included in the
study if they had new-onset pulmonary infiltrates and a CPIS <6. The patients were randomized to either a
control group (standard therapy) or to the experimental group (intravenous ciprofloxacin 400 mg every eight
hours for three days).
The CPIS was reevaluated at three days and in patients with a CPIS <6, antibiotics were discontinued in the
experimental group. If the CPIS was >6, ciprofloxacin was continued or antibiotics were changed based upon
the microbiologic results. Significantly more patients in the control group received antibiotics beyond three
days compared to those in the experimental group (90 compared with 28 percent in the experimental group).
In addition to reduced antibiotic use, the experimental group was less likely to have colonization/infection
with resistant organisms (15 compared with 35 percent of patients in the control group) and had a trend
towards lower mortality.
Another relevant finding in the 2011 meta-analysis described above was that discontinuation strategies using
procalcitonin led to a reduction in the duration of therapy without adversely affecting other outcomes,
including mortality [86]. (See "Clinical presentation and diagnosis of ventilator-associated pneumonia",
section on 'Other diagnostic tests'.)
Based upon these data, we recommend that all patients with HAP, VAP, or HCAP should be evaluated after 72
hours of initial empiric antimicrobial therapy. If the patient has improved after 72 hours, and a pathogen is isolated,
antimicrobial therapy should be changed to a pathogen-directed regimen based upon the susceptibility pattern.
Therapy should generally be continued to complete a total course of 7 days; we would treat up to 15 days if P.
aeruginosa were the etiologic agent, and for up to 21 days for MRSA, depending upon the extent of infection and
clinical course [26]. Based on the study of S. aureus VAP discussed above, 8 days of therapy may be adequate if
there is good clinical response early in the course of appropriate therapy [85]. If the patient has improved and no
pathogen is identified, we would narrow the regimen, discontinuing therapy for Pseudomonas spp and MRSA.
If the patient has not improved at 72 hours and a resistant pathogen is identified, therapy should be changed to
pathogen-directed treatment based upon the susceptibility pattern. In addition, failure to improve at 72 hours should

prompt a search for infectious complications, other diagnoses, or other sites of infection.
PROGNOSIS Despite high absolute mortality rates in hospital-acquired (or nosocomial) pneumonia (HAP)
patients, the mortality attributable to the infection is difficult to gauge. Many studies have found that HAP is
associated with significant excess risk of death. However, many of these critically ill patients die from their
underlying disease and not from pneumonia. Case-control studies estimate that the all-cause mortality rate for HAP
and ventilator-associated pneumonia (VAP) is in the range of 33 to 50 percent [2]. In contrast, a systematic review
of randomized trials for the prevention of VAP has estimated that the attributable mortality of VAP is approximately
9 percent (range 3 to 17 percent) [89].
In a retrospective cohort study that used a large inpatient database, mortality rates were 10 percent in patients with
community-acquired pneumonia (CAP), 19 percent in patients with HAP, 20 percent in patients with healthcareassociated pneumonia (HCAP), and 29 percent in patients with VAP [3]. In another study, HCAP was associated
with a higher in-hospital mortality rate than CAP (18 versus 7 percent) [9].
Variables associated with increased mortality include [2,90-97]:
Serious illness at the time of diagnosis (eg, high APACHE score, shock, coma, respiratory failure, ARDS)
Bacteremia
Severe underlying comorbid disease
Infection caused by an organism associated with multidrug resistance (Pseudomonas aeruginosa,
Acinetobacter spp)
Multilobar, cavitating, or rapidly progressive infiltrates on lung imaging
Delay in the institution of effective antimicrobial therapy
The Acute Physiology and Chronic Health Evaluation II (APACHE II) score has been considered the best system to
predict mortality in patients with VAP. A group of investigators has developed a simpler scoring system to predict
mortality: the IBMP-10 score based on the presence of immunodeficiency; blood pressure <90 mm Hg systolic;
multilobar infiltrates; platelet count <100,000; and >10 days in hospital prior to onset of VAP [97]. Based on a point
for each variable, the mortality rates for each score were: 0 to 2 percent; 1 to 9 percent; 2 to 24 percent; 3 to 50
percent; 4 to 67 percent. In a preliminary analysis, the authors indicated that this five-point system was comparable
to APACHE-II in its ability to predict mortality in such patients.
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and
Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the
10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with
some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
patient info and the keyword(s) of interest.)
Basics topic (see "Patient information: Hospital-acquired pneumonia (The Basics)")
SUMMARY AND RECOMMENDATIONS The choice of the antibiotic treatment regimen for hospital-acquired (or
nosocomial) pneumonia (HAP), ventilator-associated pneumonia (VAP), and healthcare-associated pneumonia

(HCAP) should be influenced by the patient's recent antibiotic therapy (if any), the resident flora in the hospital or
intensive care unit, the presence of underlying diseases, available culture data (interpreted with care), and whether
the patient is at risk for multidrug-resistant (MDR) pathogens. (See 'Treatment' above.)
Empiric coverage for patients WITHOUT risk factors for MDR pathogens For empiric coverage of HAP and
VAP in patients with no known risk factors for MDR pathogens, we suggest one of the following intravenous
antibiotic regimens:
Ceftriaxone (2 g intravenously daily)
Ampicillin-sulbactam (3 g intravenously every six hours)
Levofloxacin (750 mg intravenously daily) or moxifloxacin (400 mg intravenously daily). When the patient is
able to take oral medications, either agent may be administered orally at the same dose as that used for IV
administration.
Ertapenem (1 g intravenously daily).
Choice of a specific agent for empiric therapy should be based upon knowledge of the prevailing pathogens
(and susceptibility patterns) within the healthcare setting. If there is concern for gram-negative bacilli
resistant to the above options (eg, Enterobacter spp, Serratia spp, Pseudomonas spp) based upon
microbiologic data at the specific institution, we feel that it is reasonable to initiate piperacillin-tazobactam
(4.5 g IV every six hours) or another agent (eg, cefepime or a carbapenem) as monotherapy for patients
without known risk factors for MDR bacteria provided that the institutions susceptibility data support in vitro
activity. (See 'No known multidrug resistance risk factors' above.)
Empiric coverage for patients WITH risk factors for MDR pathogens For empiric coverage of HAP, VAP,
and HCAP in patients with known risk factors for MDR pathogens, we recommend empiric combination therapy
including:
One of the following:
Antipseudomonal cephalosporin such as cefepime (2 g intravenously every eight hours) or ceftazidime (2
g intravenously every eight hours)
Antipseudomonal carbapenem such as imipenem (500 mg intravenously every six hours) or meropenem
(1 g intravenously every eight hours) or doripenem (500 mg intravenously every eight hours; administered
over one hour for HAP or HCAP, administered over four hours for VAP)
Piperacillin-tazobactam (4.5 g intravenously every six hours)
For patients who are allergic to penicillin, the type and severity of reaction should be assessed. If a skin
test is positive or if there is significant concern to warrant avoidance of a cephalosporin or carbapenem,
aztreonam (2 g intravenously every six to eight hours) is recommended.
Patients with past allergic reactions to cephalosporins may also be treated with aztreonam, with the
possible exception of those allergic to ceftazidime. Ceftazidime and aztreonam have similar side chain
groups, and cross reactivity between the two drugs is variable. The prevalence of cross-sensitivity has
been estimated at <5 percent of patients, based upon limited data. 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, a reasonable approach in those with mild past reactions to ceftazidime (eg, uncomplicated
maculopapular rash) would involve informing the patient of the low risk of cross-reactivity and
administering aztreonam with a graded challenge (1/100, 1/10, full dose, each separated by 1 hour of
observation). (See "Cephalosporin-allergic patients: Subsequent use of cephalosporins and related
antibiotics", section on 'Use of carbapenems and monobactams'.)

PLUS consider one of the following (if microbiologic data from the institution or the patients previous
cultures suggest that one of the following agents provides necessary additional coverage for gram-negative
bacilli in combination with the selected beta-lactam):
Antipseudomonal fluoroquinolone, such as ciprofloxacin (400 mg intravenously every eight hours) or
levofloxacin (750 mg intravenously daily).
Aminoglycoside such as gentamicin or tobramycin (7 mg/kg intravenously once daily) or amikacin (20
mg/kg intravenously once daily). The aminoglycoside can be stopped after five to seven days in
responding patients.
Addition of an alternative agent, such as intravenous colistin, may be appropriate if highly resistant
Pseudomonas spp or Acinetobacter spp is suspected. In some cases, inhaled colistin may be
appropriate as adjunctive therapy in combination with systemic antimicrobials. (See "Treatment of
Pseudomonas aeruginosa infections", section on 'Alternative therapy in multidrug resistant infections'
and "Acinetobacter infection: Treatment and prevention", section on 'Pneumonia' and 'Aerosolized
antibiotics' above.)
PLUS one of the following (if MRSA is suspected, there are MRSA risk factors, or there is a high incidence
of MRSA locally):
Linezolid (600 mg intravenously every 12 hours; may be administered orally when the patient is able to
take oral medications)
Vancomycin (15 to 20 mg/kg [based on actual body weight] intravenously every 8 to 12 hours for
patients with normal renal function, with a target serum trough concentration of 15 to 20 mg/L.) In
seriously ill patients, a loading dose of 25 to 30 mg/kg can be used to facilitate rapid attainment of the
target trough concentration. (See 'Known multidrug resistance risk factors' above.)
Extended infusions As an alternative to the traditional dosing regimens described above, extended infusions of
certain agents (piperacillin-tazobactam, cefepime, meropenem, doripenem) may be considered to optimize
pharmacokinetics and pharmacodynamics when MDR pathogens are suspected. (See 'Extended infusions' above.)
Duration of therapy Critical to reducing overuse of antimicrobials, "deescalation" of therapy should be
considered after 48 to 72 hours of initial therapy, and should be based upon the results of initial cultures and the
clinical response of the patient. (See 'Duration' above.)
The duration of therapy should be based upon the clinical response. A short duration of therapy (eg, seven days) is
sufficient for most patients with uncomplicated HAP, VAP, or HCAP who have had a good clinical response. (See
'Duration' above.)
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Topic 6993 Version 19.0

GRAPHICS
Extended-interval dosing nomogram for gentamicin and
tobramycin*

The serum gentamicin or tobramycin concentration should be

obtained six 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.
Reproduced with permission from: Nicolau, D, Quintiliani, R, Nightingale, CH.
Once-daily aminoglycosides. Conn Med 1992; 56:561. Copyright 1992
Connecticut State Medical Society.

Clinical Pulmonary Infection Score (CPIS)

Temperature
36.5 or 38.4 = 0 point
38.5 or 38.9 = 1 point
39 or <36.5 = 2 points

Blood leukocytes, microL

4000 or 11,000 = 0 points
<4000 or >11,000 = 1 point
Band forms 50 percent = add 1 point

Tracheal secretions
Absence of tracheal secretions = 0 point
Presence of non-purulent tracheal secretions = 1 point
Presence of purulent tracheal secretions = 2 points

Oxygenation
PaO2/FIO2, mmHg >240 or ARDS (defined as PaO2/FIO2 200, PAWP 18 mmHg and
acute bilateral infiltrates) = 0 points
PaO2/FIO2 240 and no ARDS = 2 points

Pulmonary radiography
No infiltrate = 0 point
Diffuse (patchy) infiltrate = 1 point
Localized infiltrate = 2 points

Progression of pulmonary infiltrate

No radiographic progression = 0 point
Radiographic progression (after HF and ARDS excluded) = 2 points

Culture of tracheal aspirate

Pathogenic bacteria cultured in rare or few quantities or no growth = 0 point
Pathogenic bacteria cultured in moderate or heavy quantity = 1 point
Same pathogenic bacteria seen on Gram's stain, add 1 point
Total (a score of >6 was considered suggestive of pneumonia)

An initial score is based upon the first five variables. The last two variables are
assessed on day 2 or 3.

ARDS: acute respiratory distress syndrome; HF: heart failure; PAWP: pulmonary arterial wedge
pressure.
Adapted with permission from: Singh N, Rogers P, Atwood CW, et al. Short-course empiric antibiotic
therapy for patients with pulmonary infiltrates in the intensive care unit: a proposed solution for
indiscriminate antibiotic prescription. Am J Respir Crit Care Med 2000; 162:505. Copyright 2002
American Thoracic Society.