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

Author:: Michael Klompas, MD, MPH
Section Editor:: Thomas M File, Jr, MD
Deputy Editor:: Milana Bogorodskaya, MD

Literature review current through: Dec 2022. | This topic last updated: Aug 03, 2022.

INTRODUCTION — Hospital-acquired (or nosocomial) pneumonia (HAP) and ventilator-associated pneumonia (VAP) are important causes of morbidity and mortality despite improved prevention, antimicrobial therapy, and supportive care [1].

The treatment of HAP and VAP will be reviewed here. The diagnosis, epidemiology, pathogenesis, microbiology, risk factors, and prevention of HAP and VAP are discussed separately. (See "Clinical presentation and diagnostic evaluation of ventilator-associated pneumonia" and "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults" and "Risk factors and prevention of hospital-acquired and ventilator-associated pneumonia in adults".)

DEFINITIONS

Pneumonia types — Pneumonia is frequently categorized based on site of acquisition (table 1).

●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.

The category of health care-associated pneumonia (HCAP) was included in the 2005 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines and referred to pneumonia acquired in health care facilities such as nursing homes, hemodialysis centers, outpatient clinics, or during a hospitalization within the past three months [2]. This category was used to identify patients at risk for infection with multidrug-resistant (MDR) pathogens. However, this categorization may have been overly sensitive and may have led to increased, inappropriately broad antibiotic use. Although patients with recent contact with health care facilities are at increased risk for infection with MDR pathogens, this risk is small for most patients and the overall incidence of MDR pathogens in this population is low [3-9]. Thus, the category of HCAP was purposefully not included in the 2016 ATS/IDSA guidelines. For similar reasons, the combined 2017 European and Latin American guidelines on the management of HAP and VAP did not categorize HCAP as a distinct type of pneumonia [10].

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 depending upon each patient’s specific risk factors and severity of illness. Specific risk factors for resistance that should be assessed include known colonization with MDR pathogens, recent receipt of antimicrobials, comorbidities, functional status, and severity of illness [11,12]. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting" and "Treatment of community-acquired pneumonia in adults who require hospitalization".)

Antimicrobial resistance — The United States Centers for Disease Control and Prevention (CDC) and the European Centre for Disease Prevention and Control (ECDC) have developed standard terminology for antimicrobial-resistant gram-negative bacilli, which are important causes of HAP and VAP [13]:

●MDR refers to acquired nonsusceptibility to at least one agent in three different antimicrobial classes.

●Extensively drug resistant (XDR) refers to nonsusceptibility to at least one agent in all but two antimicrobial classes.

●Pandrug resistant (PDR) refers to nonsusceptibility to all antimicrobial agents that can be used for treatment.

Awareness of local resistance patterns is critical for decisions regarding empiric therapy for HAP and VAP [14]. All hospitals should regularly create and disseminate a local antibiogram, ideally one that is specific to the different units in the hospital (although small numbers of cases per unit may preclude this) [1].

Risk factors for multidrug resistance are discussed separately. (See "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults", section on 'MDR risk factors'.)

EMPIRIC THERAPY — Empiric therapy for HAP and VAP should include agents with activity against Staphylococcus aureus, Pseudomonas aeruginosa, and other gram-negative bacilli. The choice of a specific regimen for empiric therapy should be based upon knowledge of the prevailing pathogens and susceptibility patterns within the patient’s health care setting as well as the patient's individual risk factors for multidrug resistance, including their prior microbiology data. A good-quality Gram stain can also be useful for guiding the choice of initial therapy. As an example, in a multicenter randomized trial of 206 patients with VAP, clinical cure (response) was noninferior in the group whose empiric antibiotic regimen was guided by Gram stain results compared with the group whose treatment was guided by guidelines (77 versus 72 percent; risk difference 0.05, 95% CI -0.07 to 0.17) [15]. Furthermore, the Gram stain group had reduced use of empiric anti-pseudomonal (70 versus 100 percent) and anti-MRSA agents (61 versus 100 percent) without significant difference in 28-day intensive care unit (ICU)-free days, ventilator-free days, or mortality between the two groups.

The recommendations below are generally in keeping with the 2016 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) guidelines on the management of HAP and VAP [1] (see 'Society guideline links' below). Modifications to these recommendations may be needed based on the local prevalence of pathogens and local and hospital antimicrobial resistance patterns. The 2017 combined European and Latin American guidelines differ somewhat in their approach to initial antibiotic selection, opting to reserve empiric treatment for Pseudomonas species for those who are critically ill or have specific risk factors in an effort to reduce antimicrobial resistance [10].

Approach to therapy — Once HAP or VAP is suspected clinically, diagnostic specimens should be obtained as soon as possible in all patients and antimicrobial therapy started as soon as possible in patients with signs of septic shock or rapidly progressive organ dysfunction [1]. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Empiric antibiotic therapy (first hour)'.)

Delaying treatment and failing to give a regimen with activity against the causative pathogens are both associated with higher mortality rates in patients with sepsis due to HAP or VAP [16-19]. However, broader regimens and longer treatment courses increase the risks of adverse drug effects, Clostridioides difficile infections, and antimicrobial resistance [20,21]. An appropriate compromise is to pair early and aggressive treatment for patients with signs of sepsis or septic shock with early and aggressive de-escalation once the causative pathogen and susceptibilities are known or an alternative diagnosis is established. Establishing the diagnosis of HAP and VAP can be difficult, especially for hospitalized patients in whom clinical, radiologic, and microbiologic findings can be due to numerous etiologies besides pneumonia. The difficulty in diagnosis may lead to overtreatment and its attendant risks of superinfection and antibiotic toxicity. If the diagnosis of HAP and VAP is uncertain and the patient is not in sepsis or septic shock, then it appears to be safe and potentially beneficial to gather more data and await culture results before treating [22-24]. (See "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults" and "Clinical presentation and diagnostic evaluation of ventilator-associated pneumonia".)

Empiric treatment choices should be informed by the local distribution of pathogens causing HAP and VAP and their antimicrobial susceptibility patterns [14]. As noted above, all hospitals should regularly create and disseminate local antibiograms, ideally ones that are specific to their different units. In addition to awareness of local pathogen distribution, antimicrobial selection should also be based upon risk factors for multidrug-resistant (MDR) pathogens [1,25], including recent antibiotic therapy (if any), the presence of underlying diseases associated with increased risk for resistant organisms (eg, bronchiectasis, cystic fibrosis), and both current and historic culture data (interpreted with care). For patients with risk factors for MDR pathogens, empiric broad-spectrum multidrug therapy is recommended (table 2 and table 3).

Additional considerations include Gram stain results, potential toxicities, potential drug interactions, cost, availability, and clinician familiarity with different antibiotics. Once microbiologic results are available, therapy should be narrowed based upon the susceptibility pattern of the pathogens identified and the potential toxicities of the regimens. (See 'Antimicrobial resistance' above and 'Specific antimicrobial considerations' below and 'Potential toxicities' below and 'Tailoring therapy' below.)

The choice of which of the following agents to select should be based in part upon knowledge of local pathogen susceptibility patterns and whether or not the agent is likely to be active against suspected pathogens. Because patients experience worse outcomes if initial antimicrobial therapy is ineffective against the causative pathogen, the 2016 HAP and VAP guidelines have chosen a goal of trying to assure that ≥95 percent of patients with VAP receive empiric therapy with activity against the most likely pathogens [1].

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 to the initial class. For patients with highly resistant or pan-resistant gram-negative bacilli, consultation with a specialist with expertise in antimicrobial management of antibiotic-resistant infections is recommended.

Risk factors for MDR VAP have been addressed in several studies. In a meta-analysis that included 15 studies, factors associated with an increased risk of MDR VAP were use of intravenous (IV) antibiotics in the past 90 days (odds ratio [OR] 12.3, 95% CI 6.48-23.35), ≥5 days of hospitalization prior to the occurrence of VAP, septic shock at the time of VAP (OR 2.01, 95% CI 1.12-3.61), acute respiratory distress syndrome before VAP (OR 3.1, 95% CI 1.88-5.1), and renal replacement therapy prior to VAP (OR 2.5, 95% CI 1.14-5.49) [1]. Coma present at the time of ICU admission was associated with lower risk of MDR VAP (OR 0.21, 95% CI 0.08-0.52). In a meta-analysis of three small observational studies of patients with VAP, inappropriate therapy was associated with significantly increased odds of mortality (OR 3.03, 95% CI 1.12-8.19) [16].

Reassessing a patient's status 48 to 72 hours after the initiation of therapy with consideration of discontinuing antibiotics or narrowing the regimen (de-escalating therapy) based upon appropriate culture results may reduce the selective pressure for antimicrobial resistance and appears to be safe [26]. (See 'Tailoring therapy' below.)

Antimicrobial stewardship reduces rates of nosocomial infections (ie, C. difficile, methicillin-resistant S. aureus [MRSA], vancomycin-resistant enterococcal infections, and MDR gram-negative infections) and antimicrobial expenditures without increasing mortality or extending length of hospital stay [27-31]. (See "Antimicrobial stewardship in hospital settings".)

Ventilator-associated pneumonia — Empiric regimens for VAP are outlined in the following algorithm (algorithm 1).

Determining coverage based on risk of resistance — The selection of an empiric regimen depends upon risk factors for MDR pathogens, local antimicrobial resistance rates, and the individual patient's prior microbiology data (table 2) [1].

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 associated with VAP 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

●Colonization with OR prior isolation of MDR Pseudomonas or other gram-negative bacilli

Risk factors for MRSA include:

●Treatment in a unit in which >10 to 20 percent of S. aureus isolates associated with VAP are methicillin resistant

●Treatment in a unit in which the prevalence of MRSA is not known

●Colonization with OR prior isolation of MRSA

Our approach to selecting a regimen based upon these risk factors:

●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 associated with VAP 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 associated with VAP 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.

Ideally, local resistance rates should be determined for each hospital unit and derived from pulmonary culture results from patients with VAP [32]. The resistance rate calculation should account for both the frequency of pathogens causing VAP and their resistance rates, resulting in a blended estimate of the probability that any given antibiotic will be active [1,33]. Because most hospitals do not have sufficient numbers of VAP isolates and data management support to generate such estimates, unit-wide MRSA and P. aeruginosa resistance rates are acceptable, albeit conservative, proxies.

Specific regimens are presented in the following section.

Regimens — As noted above, the choice of regimen depends upon risk factors for MDR pathogens, including local pathogen susceptibility patterns and the individual patient's prior microbiology data. (See 'Determining coverage based on risk of resistance' above.)

The dosing provided below is intended for patient with normal renal function; dosing will need to be adjusted in those with renal dysfunction.

The traditional intermittent dosing of each agent for VAP is described in the following discussion, but we favor prolonged infusions of 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 (table 4). (See 'Prolonged infusions' below.)

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 associated with VAP is resistant to methicillin (table 2), 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 – 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

Among these agents, we generally prefer piperacillin-tazobactam or cefepime because they are more likely to have activity against gram-negative bacilli than the fluoroquinolones. 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 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. (See 'Gram-negative pathogens' below.)

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

Such patients should receive (algorithm 1):

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 compared with 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 (figure 1) (see "Dosing and administration of parenteral aminoglycosides"):

•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 compared with other antibiotic classes, aminoglycosides are not recommended as monotherapy for gram-negative infections. 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 will also discontinue the aminoglycoside after two or three days in patients who have improved clinically and in whom cultures are negative. There are data suggesting that even very brief courses of aminoglycosides increase the risk of nephrotoxicity [34]. (See 'Potential toxicities' below.)

●An antipseudomonal fluoroquinolone such as ciprofloxacin (400 mg IV every eight hours) or levofloxacin (750 mg IV daily) is preferred if Legionella is likely. 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. In many institutions, addition of a fluoroquinolone as the second gram-negative agent confers minimal additional activity against local pathogens.

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 [1]. 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. When possible, clinicians should consult their local antibiogram to help determine whether similar resistance patterns exist at their institutions.

●A polymyxin – Addition of an alternative agent, such as intravenous colistin or polymyxin B, may be appropriate if highly resistant Pseudomonas spp, Acinetobacter spp, Enterobacteriaceae (including Klebsiella pneumoniae) is suspected or established [35]. Polymyxins are used rarely given their significant nephrotoxicity and should be avoided if alternative agents with adequate activity against gram-negative bacilli are available [36,37]. When they are required, an infectious disease physician and/or pharmacist with expertise using these agents should be consulted. Dosing recommendations are provided separately. (See "Polymyxins: An overview", section on 'Intravenous administration' and 'Potential toxicities' below and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Antibiotic selection' and "Acinetobacter infection: Treatment and prevention", section on 'Pneumonia' and "Clinical features, diagnosis, and treatment of Klebsiella pneumoniae infection", section on 'Treatment' and "Overview of carbapenemase-producing gram-negative bacilli", section on 'Treatment'.)

In some cases of VAP with highly resistant organisms, inhaled colistin may be appropriate adjunctive therapy in combination with systemic antimicrobials, as discussed below. (See 'Aerosolized antibiotics' below.)

●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].

●Since publication of the IDSA/ATS guidelines, additional antimicrobials active against MDR pathogens have been approved by the US Food and Drug Administration (FDA) including ceftazidime-avibactam, ceftolozane-tazobactam, cefiderocol, imipenem-cilastatin-relebactam, and meropenem-vaborbactam. These agents may provide alternative single-agent options to cover potential MDR gram-negative bacteria in patients for whom two gram-negative agents would otherwise be indicated. Gram-negative monotherapy is reasonable if local gram-negative resistance rates to the planned agent are <10 percent.

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 S. aureus' below.)

●Vancomycin dosing as summarized in the following table (table 5). (See 'Methicillin-resistant S. aureus' below and "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults".)

●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 before choosing it. (See 'Telavancin' below.)

The combination of vancomycin and piperacillin-tazobactam has been associated with acute kidney injury [41]. 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. (See "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults", section on 'Acute kidney injury'.)

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 or clinicians should use a single agent more likely to be active against MDR gram negatives (eg, ceftazidime-avibactam, ceftolozane-tazobactam, cefiderocol, imipenem-cilastatin-relebactam, or meropenem-vaborbactam). 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 associated with VAP are resistant to an agent being considered for monotherapy (table 2), but >20 percent of S. aureus isolates associated with VAP 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

●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 S. aureus' below.)

●Vancomycin dosing as summarized in the following table (table 5). (See 'Methicillin-resistant S. aureus' below and "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults".)

Hospital-acquired pneumonia — The appropriate regimen for HAP depends upon the presence or absence of risk factors for MDR pathogens, knowledge of the predominant pathogens (and susceptibility patterns) within the health care setting, and the individual patient's prior microbiology data. In general, HAP patients who are not in the ICU tend to be less severely ill than VAP patients, and, therefore, the negative consequences of initial inappropriate antibiotic therapy may be less pronounced with HAP than with VAP. In addition, MDR pathogens tend to be less common in patients who develop HAP outside of the intensive care unit, particularly early in the hospitalization course. (See "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Microbiology'.)

For this reason, the 2016 HAP and VAP guidelines suggest that a smaller subset of patients with HAP as compared with VAP require empiric treatment for MRSA and MDR gram-negative organisms [1]. A single agent active against both MSSA and P. aeruginosa is often sufficient.

Description of risk factors — Risk factors for MDR pathogens and/or mortality in patients with HAP include the following (table 3):

●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

•Colonization with OR prior isolation of MDR Pseudomonas or other gram-negative bacilli

●Risk factors for MRSA:

•Treatment in a unit in which >20 percent of S. aureus isolates associated with HAP are methicillin resistant

•Treatment in a unit in which the prevalence of MRSA is not known

•Colonization with OR prior isolation of MRSA

Regimens — Empiric regimens for HAP are outlined in the following algorithm (algorithm 2). As noted above, the appropriate regimen depends upon the presence or absence of risk factors for MDR pathogens, including local pathogen susceptibility patterns and the individual patient's prior microbiology data.

The dosing described below is intended for patients with normal renal function and represents traditional intermittent dosing; dosing will need to be adjusted in those with renal dysfunction.

As an alternative to the traditional dosing regimens described below, prolonged infusions of certain beta-lactams may be given to optimize pharmacodynamics; we favor prolonged infusions in critically ill patients with infections caused by gram-negative bacilli and in patients with infections caused by gram-negative bacilli that have elevated but susceptible minimum inhibitory concentrations to the chosen agent (table 4). (See 'Prolonged infusions' below.)

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. Risk factors for increased mortality and for MDR pathogens are outlined above. (See 'Description of risk factors' above.)

Choices include:

●Piperacillin-tazobactam 4.5 g IV every six hours

●Cefepime 2 g IV every eight hours

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

Among these agents, we generally prefer piperacillin-tazobactam or cefepime because they are more likely to have activity against hospital-acquired gram-negative bacilli than the fluoroquinolones.

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. (See 'Gram-negative pathogens' below.)

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 (table 3), 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 (figure 1). (See "Dosing and administration of parenteral aminoglycosides".)

•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 compared with other antibiotic classes, aminoglycosides are not recommended as monotherapy for gram-negative infections. 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 also discontinue the aminoglycoside after two or three days in patients who have improved clinically and in whom cultures are negative. There are data suggesting that even very brief courses of aminoglycosides increase the risk of nephrotoxicity [34].

●An antipseudomonal fluoroquinolone such as ciprofloxacin (400 mg IV every eight hours) or levofloxacin (750 mg IV daily) is preferred if Legionella is likely. 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. In many institutions, addition of a fluoroquinolone adds minimal additional in vitro activity against other local pathogens.

The IDSA/ATS guidelines recommend either an antipseudomonal fluoroquinolone or an aminoglycoside as a 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. When possible, clinicians should consult their local antibiogram to help determine whether similar resistance patterns exist at their institutions.

●Since publication of the IDSA/ATS guidelines, additional antimicrobials active against MDR pathogens have been approved by the FDA including ceftazidime-avibactam, ceftolozane-tazobactam, cefiderocol, imipenem-cilastatin-relebactam, and meropenem-vaborbactam. These agents may provide alternative single-agent options to cover potential MDR gram-negative bacteria in patients for whom two gram-negative agents would otherwise be indicated. Gram-negative monotherapy is reasonable if local gram-negative resistance rates to the planned agent are <10 percent.

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 S. aureus' below.)

●Vancomycin dosing as summarized in the following table (table 5). (See 'Methicillin-resistant S. aureus' below and "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults".)

●Tedizolid 200 mg IV once daily, which may be administered orally when the patient is able to take oral medications.

●Telavancin 10 mg/kg IV every 24 hours is an alternative agent when linezolid, tedizolid, or vancomycin cannot be used, but there are several boxed warnings that must be considered before choosing it. (See 'Telavancin' below.)

Because clinical outcomes appear to be similar for linezolid and vancomycin [38,39], we select between these agents based on other factors such as renal function, monitoring convenience, potential drug interactions, blood cell counts, and quality of IV access. (See 'Linezolid and vancomycin' below.)

Risk factors for MDR gram-negative bacilli only — If there are risk factors for multidrug-resistant Pseudomonas and other gram-negative bacilli but not MRSA (table 3), the patient should receive two agents with activity against P. aeruginosa; the regimen should also have activity against MSSA. Such patients should receive (algorithm 2):

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:

•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 compared with other antibiotic classes, aminoglycosides are not recommended as monotherapy for gram-negative infections. 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 also discontinue the aminoglycoside after two or three days in patients who have improved clinically and in whom cultures are negative. There are data suggesting that even very brief courses of aminoglycosides increase the risk of nephrotoxicity [34].

●An antipseudomonal fluoroquinolone such as ciprofloxacin (400 mg IV every eight hours) or levofloxacin (750 mg IV daily) is preferred if Legionella is likely. 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. In many institutions, addition of a fluoroquinolone adds minimal additional in vitro activity against other local pathogens.

The IDSA/ATS guidelines recommend either an antipseudomonal fluoroquinolone or an aminoglycoside as a 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. When possible, clinicians should consult their local antibiogram to help determine whether similar resistance patterns exist at their institutions.

MRSA risk factors only — If there are risk factors for methicillin-resistant S. aureus but not MDR Pseudomonas and other gram-negative bacilli (table 3), the patient should receive one agent with activity against P. aeruginosa and other gram-negative bacilli and one agent with activity against MRSA. Adding an agent with MRSA activity to the treatment regimen allows for more flexibility in the choice of gram-negative agent because the selected gram-negative agent does not need to include activity against S. aureus.

Patients with risk factors for MRSA only 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

●Levofloxacin 750 mg IV daily. When the patient is clinically improved and able to take oral medications, it 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 patients with a high likelihood of infection with an ESBL-producing gram-negative bacillus. Optimally, local antibiograms should indicate that ≤10 percent of gram-negative isolates are resistant to an agent being considered for monotherapy. (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 S. aureus' below.)

●Vancomycin dosing as summarized in the following table (table 5). (See 'Methicillin-resistant S. aureus' below and "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults".)

●Tedizolid 200 mg IV once daily, which may be administered orally when the patient is able to take oral medications. (See 'Methicillin-resistant S. aureus' below.)

TAILORING THERAPY — All patients with HAP or VAP should be evaluated for clinical response and results of microbiologic studies after initial empiric antimicrobial therapy.

●For patients in whom a pathogen has been identified, the empiric regimen should be tailored to the pathogen's susceptibility pattern [1,42,43]. Tailoring antibiotic therapy has not been associated with increased mortality [26,44-46], recurrent pneumonia [26,45], or longer intensive care unit admission [26,46]. (See 'Specific antimicrobial considerations' below.)

●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), no evidence of untreated infections elsewhere in the body, 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 can be expanded to cover additional resistant organisms.

DURATION — We treat most patients with HAP or VAP for seven days, in agreement with the 2016 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) guidelines and the combined 2017 European and Latin American guidelines on HAP and VAP [1,10]. Seven days appears to be as effective as longer durations in most circumstances and may reduce the emergence of resistant organisms [1,3].

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 should be individualized and courses longer than seven days may be warranted. (See "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Duration of therapy' and "Pseudomonas aeruginosa pneumonia", section on 'Directed antimicrobial therapy'.)

Monitoring serial procalcitonin levels can help guide the decision to discontinue antibiotics. While the optimal approach to using procalcitonin in patients with HAP or VAP has not been determined, a low or declining procalcitonin level (eg, <0.25 ng/mL or ≥80 percent decrease from peak) in a patient who has clinically responded to antibiotics provides additional reassurance that antibiotics can be safely stopped [47-54]. (See "Procalcitonin use in lower respiratory tract infections", section on 'Ventilator-associated pneumonia'.)

A seven-day course of antimicrobial therapy is supported by two meta-analyses of six randomized trials evaluating over 1000 patients with HAP or VAP, in which short courses (7 to 8 days) of therapy were as effective as longer courses (10 to 15 days) [1,55]. In subgroup analysis of one of the meta-analyses [55], a higher rate of recurrent pneumonia was observed in patients with pneumonia caused by nonfermenting gram-negative rods, such as P. aeruginosa, who received shorter courses of therapy. This finding was primarily driven by a single large trial that used a microbiologic definition of pneumonia [56]; hence, this finding may have indicated microbiologic persistence rather than clinical failure. No differences in ventilator-free days, organ failure-free days, length of stay, or mortality were detected in patients with nonfermenting gram-negative bacillus infections randomized to short versus long courses [1,55,57]. Another multicenter, randomized trial of 186 patients with VAP due to P. aeruginosa demonstrated similar findings [58].

Although a retrospective cohort study suggested that patients with suspected VAP who have stable and minimal ventilator settings (positive-end expiratory pressure <5 cm H₂O and FiO₂ ≤40 percent) have similar outcomes whether they are treated with ≤3 days or >3 days of antibiotics [59], these observations must be confirmed in a randomized trial before this strategy can be broadly applied.

CONVERSION TO ORAL ANTIBIOTICS — Generally, patients can be switched to oral therapy when they are hemodynamically stable, clinically improving, and able to tolerate oral medications. If a pathogen has been identified, the choice of antibiotic for oral therapy should be based on the organism's susceptibility pattern. If a pathogen has not been identified, the oral antibiotic selected should have similar antimicrobial coverage as the intravenous agent and should have good lung penetration.

SPECIFIC ANTIMICROBIAL CONSIDERATIONS — 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. (See "Epidemiology of pulmonary infections in immunocompromised patients".)

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. Indications and strategies for skin testing are reviewed elsewhere. (See "Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics".)

Patients with a history of 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 possible. 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, 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, and 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). (See "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics", section on 'Carbapenems and monobactams' and "An approach to the patient with drug allergy", section on 'Graded challenge'.)

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.

Potential toxicities — Clinicians should consider the potential toxicities of their antimicrobial choices when selecting a regimen [21]. All antibiotics increase the risk of C. difficile infection; among the agents used for HAP and VAP, the fluoroquinolones and broad-spectrum cephalosporins are most commonly implicated. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Antibiotic use'.)

Other potential toxicities of antibiotics used for HAP and VAP include the following:

●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 [34]. (See "Aminoglycosides", section on 'Toxicity'.)

●Polymyxins (polymyxin B and colistin) are nephrotoxic. Polymyxins are therefore used rarely and should be avoided if alternative agents with adequate activity against gram-negative bacilli are available [1,36,37]. When they are required, an infectious disease physician and/or pharmacist with expertise using these agents should be consulted. (See "Polymyxins: An overview", section on 'Nephrotoxicity'.)

●The combination of vancomycin and piperacillin-tazobactam has been associated with acute kidney injury [41]. In patients who require an anti-methicillin-resistant S. aureus (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. (See "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults", section on 'Acute kidney injury'.)

●In patients with renal insufficiency, imipenem and cefepime have been associated with seizures. Alternative beta-lactams should be used in patients at risk. (See "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects", section on 'Neurologic reactions'.)

●The fluoroquinolones have multiple potential toxicities, including QT interval prolongation, tendinitis and tendon rupture, and neurotoxicity. (See "Fluoroquinolones", section on 'Adverse effects'.)

Methicillin-resistant S. 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 [1,60,61] but should be discontinued if MRSA is not isolated. Note that the prevalence of MRSA has been decreasing worldwide [62-64], which serves as an important reminder to consider the local prevalence when determining whether or not to include coverage for MRSA in an empiric regimen.

Observational studies [65-67] and at least one randomized trial [68] suggest that testing nasal swabs or bronchoalveolar lavage fluid for MRSA via culture or polymerase chain reaction (PCR) can help decrease utilization of anti-MRSA therapy if negative results are used as a trigger to stop anti-MRSA treatment. Early discontinuation of MRSA coverage in patients with negative cultures and/or PCRs may be associated with better outcomes, including less renal failure and possibly lower mortality rates [68,69].

Because clinical outcomes appear to be similar for linezolid and vancomycin [38-40], we select between these agents based on other factors such as renal function, monitoring convenience, potential drug interactions, blood cell counts, and quality of IV access. As examples, when all other factors are equal, we prefer linezolid to vancomycin in patients with limited IV 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.

Telavancin, tedizolid, and ceftaroline are alternatives when neither linezolid nor vancomycin can be used. However, tedizolid was associated with lower clinical cure rates compared with linezolid in a randomized trial, though mortality rates were similar [70]. There are several boxed warnings that must be considered before choosing telavancin (see 'Telavancin' below). Ceftaroline is not US Food and Drug Administration (FDA) approved for the treatment of HAP or VAP. Clindamycin (600 mg IV or orally three times daily) is an additional alternative for patients with susceptible MRSA isolates; however, data supporting clindamycin use for HAP and VAP are limited [61].

Our approach to the treatment of HAP or VAP caused by MRSA is largely similar to the 2016 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) guidelines on HAP and VAP and the 2011 IDSA guidelines for the treatment of MRSA infections, which recommend either linezolid or vancomycin for infections suspected or proven to be due to MRSA [1,61].

Linezolid and vancomycin — The dosing of linezolid and vancomycin is presented above. (See 'Ventilator-associated pneumonia' above and 'Hospital-acquired pneumonia' above.)

Several trials have compared linezolid and vancomycin for the treatment of HAP and VAP; clinical outcomes appear to be similar when comparing these two agents [38-40]. As an example, in a meta-analysis of nine randomized trials that compared linezolid to vancomycin for HAP, no differences in mortality, clinical response, microbiologic eradication, or MRSA eradication were detected [40]. Linezolid was associated with a higher rate of gastrointestinal adverse effects, but there were no differences in rates of acute kidney injury, thrombocytopenia, or drug discontinuation due to adverse effects.

Several trials included in this meta-analysis used lower doses for vancomycin than those recommended by the ATS and IDSA [1,61,71,72], which may have resulted in lower efficacy rates for this agent. In one trial that did use optimal vancomycin dosing, clinical success rates were lower for vancomycin when compared with linezolid in the per-protocol analysis (47 versus 58 percent, p<0.05) [73]. However, higher rates of mechanical ventilation, renal dysfunction, and bacteremia in the vancomycin per-protocol group may account for this difference. No differences in all-cause 60-day mortality or overall adverse events were detected in this trial, although nephrotoxicity did occur more frequently with vancomycin than linezolid (18 versus 8 percent, p value not reported).

Vancomycin failure might also be related to vancomycin minimum inhibitory concentrations (MICs). Pharmacokinetic and pharmacodynamic analyses suggest that lung vancomycin area under time-concentration curve to minimum inhibitory concentration ratio (AUC:MIC) >400 may be difficult to achieve (particularly for isolates with MIC >1) [74-76]. Cohort studies have also reported worse outcomes in patients with HAP due to MRSA with higher MICs. In one prospective cohort of 95 patients, patients with MRSA isolates with MICs ≥2 mcg/mL had higher mortality rates than those with lower MICs (24 percent versus 10 percent) [77]. Another study of 158 intensive care patients reported a stepwise increase in mortality as the vancomycin MIC increased from 0.75 to 3 mcg/mL and was present even for strains within the susceptible range [78]. These findings are controversial, however, because studies of MSSA bacteremia have also correlated higher vancomycin MICs with higher mortality rates even though all patients were treated with beta-lactams [79,80]. These studies suggest that worse outcomes in patients with higher MICs may be due to clinical factors other than vancomycin failure alone. In addition, there are no data as of yet demonstrating better outcomes with linezolid or other alternatives compared to vancomycin in patients infected with MRSA with high vancomycin MICs. Some clinicians nonetheless favor using an alternative to vancomycin for treatment of pneumonia caused by MRSA strains with vancomycin MICs ≥2 mcg/mL.

Tedizolid — Tedizolid is an antibiotic from the same family as linezolid that inhibits bacterial protein synthesis. It is active against gram-positive bacteria including MRSA. In a randomized trial comparing tedizolid with linezolid, 726 ventilated patients with HAP or VAP suspected to be due to a gram-positive pathogen were randomized to tedizolid 200 mg IV daily for 7 days versus linezolid 600 mg IV twice a day for 10 days [70]. Adjunctive coverage for gram negatives was permitted per clinicians’ discretion. Tedizolid was found to be noninferior to linezolid with regard to all-cause mortality (28.1 versus 26.4 percent; 1.8 percent difference, 95% CI -8.2 to 4.7) but was associated with a lower rate of clinical cure (56.3 versus 63.9%; 7.6 percent difference, 97.5% CI -15.7 to 0.5). It is unclear whether the difference in clinical cure rates was due to the difference in drugs or difference in duration of treatment. Drug-related adverse events occurred in 8.1 percent of patients who received tedizolid versus 11.9 percent of those who received linezolid. Thrombocytopenia was more common in patients randomized to linezolid (38 versus 28 percent).

Telavancin — Telavancin is an antibiotic with activity against MRSA [81]. In 2013, telavancin was approved by the FDA for the treatment of HAP and VAP caused by S. aureus but not for other bacterial causes of HAP or VAP; it is recommended only when alternative agents cannot be used and should ideally be reserved for patients with normal renal function [82]. In patients with normal renal function, the dose of telavancin is 10 mg/kg IV every 24 hours.

The FDA has included the following boxed warnings for telavancin [83]:

●Patients with pre-existing moderate or severe renal impairment (creatinine clearance [CrCl] ≤50 mL/minute) who were treated with telavancin for HAP or VAP had increased mortality compared with vancomycin. Use of telavancin in patients with pre-existing moderate or severe renal impairment (CrCl ≤50 mL/minute) should therefore be considered only when the potential benefit to the patient outweighs the potential risk.

●New-onset or worsening renal impairment has occurred in patients receiving telavancin. Renal function should be monitored in all patients receiving telavancin.

●Adverse developmental outcomes were observed in three animal species at clinically relevant doses. These findings raise concerns about potential adverse developmental outcomes in humans. Women of childbearing potential should have a serum pregnancy test prior to administration of telavancin, and its use should be avoided during pregnancy unless the potential benefit to the patient outweighs the potential risk to the fetus.

The data on the performance of telavancin for HAP and VAP come from two randomized trials (the ATTAIN trials) comparing telavancin versus vancomycin for hospitalized patients with HAP or VAP (29 percent had VAP) caused by gram-positive pathogens, particularly S. aureus. Pooled results from these two studies revealed no differences in overall cure rates or mortality in the vancomycin versus telavancin groups [84]. However, in a subgroup analysis of patients with renal impairment (CrCl <50 mL/minute), cure rates were lower in patients who received telavancin when compared with vancomycin (47 versus 55 percent; 8 percent difference, 95% CI -17.5 to 1.9) [85].

Other agents — There has been interest in using other agents for the treatment of MRSA pneumonia, but none of the following agents are recommended as first-line options for MRSA pneumonia:

●Daptomycin cannot be used to treat pneumonia because it is inactivated by surfactant and does not achieve adequate concentrations in the respiratory tract.

●Ceftaroline is a broad-spectrum cephalosporin with activity against MRSA. It has been approved by the FDA for community-acquired pneumonia (CAP) but not for CAP caused by MRSA, nor for HAP or VAP. Clinical success with ceftaroline use for the treatment of MRSA pneumonia has been reported in cases series but comparative studies are lacking [86-88]

●Tigecycline is a broad-spectrum antibiotic with activity against MRSA. It has been approved by the FDA for skin and skin structure infections and intra-abdominal infections caused by MRSA. It has also been approved for CAP but not for CAP caused by MRSA or for HAP or VAP. In 2010, the FDA issued a safety announcement regarding an increased mortality risk associated with the use of tigecycline compared with other drugs observed in a pooled analysis of 13 trials [89]. The increased risk was seen most clearly in patients treated for HAP, particularly VAP. In 2013, the FDA added a boxed warning in reaction to an additional analysis showing an increased risk of death associated with tigecycline use [90]. The boxed warning states that tigecycline should be reserved for use in situations when alternative agents are not suitable. In an analysis of 10 trials conducted for FDA-approved uses (CAP, complicated skin and skin structure infections, complicated intra-abdominal infections), tigecycline was associated with increased mortality compared with other antibacterial agents (2.5 versus 1.8 percent, adjusted risk difference 0.6 percent, 95% CI 0.0-1.2 percent). Most deaths resulted from worsening infections, complications of infection, or underlying comorbidities. Randomized trials of patients with HAP have reported similar results [91,92].

●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. In a trial of patients with HAP, 781 patients with HAP (including 210 with VAP) were randomly assigned to receive either ceftobiprole or linezolid plus ceftazidime [93]. In the intention-to-treat population, overall cure rates for ceftobiprole versus linezolid plus ceftazidime were similar (50 versus 53 percent). Cure rates in HAP (excluding VAP) patients were also similar (60 versus 59 percent). However, cure rates in VAP patients were substantially lower in those who received ceftobiprole (23 versus 37 percent). Microbiologic eradication rates in HAP (excluding VAP) patients were 63 versus 68 percent (microbiologically evaluable [ME], 95% CI -16.7 to 7.6) and in VAP patients were 30 versus 50 percent (ME, 95% CI -38.8 to -0.4) [94].

Methicillin-susceptible S. 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) [1].

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 with severe disease 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 but there are no definitive data confirming these purported benefits.

The IDSA/ATS 2016 guidelines include a meta-analysis of seven randomized controlled trials of combination gram-negative versus monotherapy for VAP [1]. There were no differences in mortality, clinical response, adverse effects, or acquired resistance with combination therapy versus monotherapy. However, many of the trials in the analysis excluded patients at high risk for MDR pathogens. Thus, this analysis does not adequately address whether providing empiric combination therapy to patients at risk for MDR pathogens improves outcomes, but it does suggest that continuing combination therapy once the susceptibilities of an infecting pathogen are known is unlikely to provide benefit.

Our recommendations for empiric therapy (ie, before the causative pathogen has been identified and/or antimicrobial susceptibility results are available) are presented above. (See 'Ventilator-associated pneumonia' above and 'Hospital-acquired pneumonia' above.)

The approach to therapy for specific gram-negative pathogens is summarized briefly below and discussed in greater detail separately:

●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 among gram-negatives associated with HAP or VAP are high (ie, >10 percent), we generally select a carbapenem (ie, imipenem, ertapenem, or meropenem) as part of our empiric antibiotic regimen [95]. (See "Extended-spectrum beta-lactamases".)

Among carbapenems, doripenem should not be used for treatment of VAP when other carbapenems are available. Doripenem is not approved by the FDA for the treatment of VAP, and a warning about increased mortality with doripenem use in patients with VAP was added to its label in 2014 [96]. The warning is based on a randomized trial which compared doripenem administered as 1 g via a four-hour infusion every eight hours for seven days with imipenem administered as a 1 g infusion over one hour every eight hours for 10 days [97]. In the intention-to-treat analysis, 28-day all-cause mortality was numerically higher among patients receiving doripenem when compared with imipenem (22 versus 15 percent, 95% CI -5.0 to 18.5). It is unclear whether the difference was due to the differing duration of therapy, the lack of a loading dose with doripenem, doripenem inferiority, or other factors. Doripenem has since been withdrawn from the United States and European markets.

The novel agents ceftazidime-avibactam and ceftolozane-tazobactam are additional options that are active against many ESBLs (see below) [98,99].

●Carbapenemase-producing gram-negative bacilli – The optimal treatment of infection due to carbapenemase-producing organisms is uncertain, and antibiotic options are limited. Management of patients with infections due to carbapenemase-producing organisms should be done in consultation with an expert in the treatment of multidrug-resistant bacteria. The novel agents ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-relebactam cilastatin, and cefiderocol are active against many carbapenemase-producing strains. Alternatively, combination regimens can be 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 two agents should be given intravenously together with inhaled colistin. The combination of inhaled and intravenous (IV) colistin is used because IV colistin does not achieve high concentrations in the lung [1] (see 'MDR risk factors' above and "Overview of carbapenemase-producing gram-negative bacilli"). Combination therapy with ceftazidime-avibactam has not been associated with better outcomes compared with monotherapy [100].

●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 [1]. 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. (See "Acinetobacter infection: Treatment and prevention", section on 'Pneumonia'.)

Ceftazidime-avibactam is a cephalosporin-beta-lactamase inhibitor combination approved by the FDA for treatment of nosocomial pneumonia. The approval was based on the REPROVE trial, a multicenter, international randomized trial evaluating 879 patients with HAP or VAP [99]. Clinical cure and mortality rates were similar when comparing 2 g ceftazidime and 500 mg avibactam by intravenous two-hour infusion every eight hours versus meropenem 1 g by intravenous 30-minute infusion every eight hours for 7 to 14 days. However, the rate of serious adverse events was higher in patients treated with ceftazidime-avibactam (19 percent versus 13 percent, p value not reported). Approximately one-third of gram-negative pathogens in this study were resistant to ceftazidime but susceptible to ceftazidime-avibactam, affirming ceftazidime-avibactam's capacity to provide broader coverage compared with ceftazidime alone. 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 to 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 also been approved for treatment of HAP and VAP [101]. The potential utility of ceftolozane-tazobactam to treat nosocomial pneumonia was demonstrated in the ASPECT-NP trial [98]. In this trial, 726 mechanically ventilated patients with HAP or VAP were randomized to ceftolozane-tazobactam 3 g IV every 8 hours versus meropenem 1 g IV every 8 hours. Clinical cure (54 versus 53 percent) and 28-day mortality rates (24 versus 25 percent) were similar in both arms. Adverse event rates were also similar for both agents.

Cefiderocol, a novel siderophore cephalosporin with activity against some carbapenem-resistant gram-negative bacilli, has also been approved for HAP and VAP treatment based on a randomized trial demonstrating noninferiority to high-dose extended infusion meropenem [102,103].

Imipenem-cilastatin-relebactam combines the carbapenem imipenem-cilastatin with the beta-lactamase inhibitor relebactam. The combination restores imipenem’s activity against some carbapenem-resistant Enterobacterales and Pseudomonas isolates. It was approved for the treatment of hospital-acquired bacterial pneumonia (including VAP) following a trial in which 537 patients were randomized to imipenem-cilastatin-relebactam 500 mg IV every 6 hours versus piperacillin-tazobactam 4.5 g IV every 6 hours for 7 to 14 days. Clinical response rates (61 percent versus 56 percent), 28-day mortality rates (16 percent versus 21 percent), and serious adverse event rates (27 percent versus 32 percent) were similar between the two treatment arms. On subgroup analysis, patients with severe disease (APACHE II score ≥15) and those with VAP treated with imipenem-cilastatin-relebactam had lower mortality rates than those treated with piperacillin-tazobactam but these subgroups were small and so should be interpreted with caution.

Meropenem-vaborbactam has been approved for the treatment of nosocomial pneumonia in Europe but not in the United States. In the United States, it is only approved for treatment of complicated urinary tract infections [104]. Meropenem-vaborbactam is active against some carbapenem-resistant Enterobacterales but clinical data on its performance in the treatment of HAP and VAP in particular are sparse [105]. Further study is necessary to determine the role of this agent in the treatment of HAP and VAP. (See "Combination beta-lactamase inhibitors, carbapenems, and monobactams", section on 'Ceftolozane-tazobactam' and "Combination beta-lactamase inhibitors, carbapenems, and monobactams", section on 'Ceftazidime-avibactam'.)

Prolonged infusions — Because of increasing resistance of pathogens associated with VAP and HAP, one potential strategy to enhance the antimicrobial potential of a given agent is to optimize the pharmacodynamic effect. As an alternative to traditional intermittent dosing (eg, administered over 30 minutes), 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 (table 4). Suitable agents for prolonged infusions include piperacillin-tazobactam, meropenem, imipenem, and cefepime. The decision to use this dosing strategy should also take into account logistical issues such as staffing or IV access availability.

Beta-lactam antibiotics demonstrate a time-dependent effect on bacterial eradication. Prolonged infusions achieve pharmacodynamic efficacy targets defined for beta-lactam antibiotics more effectively than short infusions. A prolonged infusion may therefore improve microbiologic and clinical cure, especially for pathogens with high MICs. 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).

Pharmacologic and clinical data indicate that patients who have an elevated risk of drug-resistant pathogens or who are critically ill in the setting of a severe infection are most likely to benefit from prolonged infusions. In a patient-level meta-analysis of 22 randomized trials comparing prolonged versus rapid infusions of antipseudomonal beta-lactams in patients with sepsis, mortality was 30 percent lower in patients receiving prolonged infusions (risk ratio [RR] 0.70, 95% CI 0.56-0.87) [106]. Further discussion of prolonged infusions of beta-lactams is provided separately. (See "Prolonged infusions of beta-lactam antibiotics".)

Aerosolized antibiotics — 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 [1,107-113].

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 [114]. However, the evidence supporting use of aerosolized antibiotics is not strong [115-117] and administration can be associated with adverse effects, particularly in hypoxemic patients [115,116]. Overall, knowledge on the most appropriate use of aerosolized antibiotics is evolving.

For example, in a meta-analysis of 13 randomized trials [118], adding aerosolized amikacin to IV antibiotics for gram-negative pneumonia versus treating with IV antibiotics alone was associated with higher rates of clinical cure in unblinded studies (9 studies, 700 patients; risk ratio 1.46, 95% CI 1.31-1.63) but not in blinded studies (4 studies, 750 patients; risk ratio 1.01, 95% CI 0.89-1.16). Similarly, adding aerosolized amikacin to IV treatment versus IV treatment alone was associated with no difference in duration of mechanical ventilation, intensive care unit length-of-stay, or mortality. However, adjunctive aerosolized amikacin was associated with more bronchospasm, sometimes with hypoxemia (6.4 versus 2.4 percent of patients; risk ratio 2.55, 95% CI 1.40-4.66). There was no difference in the rate of renal dysfunction between treatment strategies. Other studies have reported occasional episodes of cardiac arrest when aerosolizing antibiotics due to obstruction of the ventilator circuit expiratory filter [107,109].

Another meta-analysis analyzed the potential impact of adding aerosolized colistin to intravenous colistin in particular [119]. The meta-analysis included seven observational studies and one randomized trial. The investigators reported better clinical outcomes and microbiologic eradication rates associated with aerosolized colistin. There was a nonsignificant trend toward lower mortality rates with aerosolized colistin (odds ratio 0.74, 95% CI 0.54-1.01, p = 0.06) but no difference in nephrotoxicity rates. The overall quality of evidence was deemed low.

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). Nosocomial cases of HAP and VAP due to Legionella spp attributable to contamination of the hospital water supply have been reported. (See "Microbiology, 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). In general, however, anaerobes are rarely implicated in VAP, and some retrospective analyses suggest little difference in outcomes in patients with aspiration pneumonitis treated with and without anaerobic coverage [120]. (See "Aspiration pneumonia in adults" and "Anaerobic bacterial infections".)

PROGNOSIS — Despite high absolute mortality rates in hospital-acquired (or nosocomial) pneumonia patients, the mortality attributable to the infection is difficult to gauge. Many studies have found that HAP is associated with significant increased risk of death. However, many of these critically ill patients die from their underlying disease and not from pneumonia. While crude all-cause mortality associated with VAP has ranged from 20 to 50 percent in different studies [1], a meta-analysis of randomized trials of VAP prevention estimated the attributable mortality at 13 percent [121]. Another study estimated that eliminating VAP would lead to a relative decrease in 60-day intensive care unit mortality of 3.6 percent [122].

Variables associated with increased mortality include [1,123-132]:

●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

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hospital-acquired pneumonia and ventilator-associated pneumonia in adults".)

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 5^th to 6^th 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 10^th to 12^th 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 email 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 education: Hospital-acquired pneumonia (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Approach to empiric therapy − The choice of the antibiotic treatment regimen for hospital-acquired (or nosocomial) pneumonia (HAP) and ventilator-associated pneumonia (VAP) should be informed by the patient's recent antibiotic therapy (if any), the resident flora and resistance rates in the hospital or intensive care unit (ICU), the presence of underlying diseases, severity of illness, available culture data (including past microbiology data) and Gram stain, and additional risk factors for multidrug-resistant (MDR) pathogens. Further considerations include potential toxicities, potential drug interactions, cost, availability, and clinician familiarity with the medications. (See 'Empiric therapy' above.)

●Empiric regimens for VAP − Empiric regimens for VAP are outlined in the following algorithm (algorithm 1). Risk factors for MDR pathogens are summarized in the following table and influence the choice of regimen (table 2):

•Patients with VAP who have no known risk factors for MDR pathogens (table 2) and who are in a unit in which ≤10 percent of gram-negative isolates associated with VAP are resistant to an agent being considered for monotherapy and ≤20 percent of S. aureus associated with VAP is methicillin resistant, should receive one agent that has activity against Pseudomonas, other gram-negative bacilli, and methicillin-susceptible Staphylococcus 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 methicillin-resistant S. aureus (MRSA):

-Intravenous 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

•Patients being treated in a location in which >10 percent of gram-negative bacilli associated with VAP 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.

•Patients being treated in a location in which >20 percent of S. aureus isolates associated with VAP are resistant to methicillin or in which the prevalence of methicillin resistance is unknown should receive an agent with activity against MRSA.

●Empiric regimens for HAP − Empiric regimens for HAP are outlined in the following algorithm (algorithm 2). Risk factors for MDR pathogens and/or for increased mortality are summarized in the following table (table 3) and influence the choice of regimen:

•If there are no risk factors for increased mortality, for resistant gram-negative bacilli, or for MRSA, the patient should receive one agent that has activity against Pseudomonas and MSSA. (See 'No MDR risk factors or increased risk of mortality' above.)

•If there are risk factors for either increased mortality (need for ventilatory support due to HAP or septic shock) or for MDR gram-negative bacilli, and MRSA, the patient should receive two agents with activity against P. aeruginosa and other gram-negative bacilli and one agent with activity against MRSA.

•If there are risk factors for MDR Pseudomonas and other gram-negative bacilli but not MRSA, the patient should receive two agents with activity against P. aeruginosa and MSSA.

•If there are risk factors for MRSA but not MDR gram-negative bacilli, the patient should receive one agent with activity against P. aeruginosa and one agent with activity against MRSA. Optimally, local antibiograms should indicate that ≤10 percent of gram-negative isolates associated with VAP are resistant to an agent being considered for monotherapy against gram-negative bacilli. (See 'Regimens' above.)

●Use of prolonged infusions of beta-lactam antibiotics − Prolonged infusions of antipseudomonal beta-lactam antibiotics may optimize pharmacodynamic effects against MDR pathogens (table 4). Pharmacologic and clinical data indicate that patients who have an elevated risk of drug-resistant pathogens or who are critically ill in the setting of a severe infection are most likely to benefit. When piperacillin-tazobactam, meropenem, imipenem, or cefepime is chosen for treatment in such patients, we favor a prolonged infusion dosing strategy. The decision to use this dosing strategy should also take into account logistical issues such as staffing or intravenous access availability. (See 'Prolonged infusions' above and "Prolonged infusions of beta-lactam antibiotics".)

●Tailoring therapy − De-escalation of therapy is critical to reduce overuse of antimicrobials and their potential adverse effects. De-escalation should be considered after 48 to 72 hours of empiric therapy and should be based upon culture results and the patient's clinical response to treatment. (See 'Tailoring therapy' above.)

●Duration of therapy − Most patients with HAP or VAP should receive a seven-day course of antibiotics, but a shorter or longer duration may be indicated, depending upon the rate of improvement of clinical, radiologic, and laboratory parameters. (See 'Duration' above.)

ACKNOWLEDGMENT — We are saddened by the death of John G Bartlett, MD, who passed away in January 2021. UpToDate gratefully acknowledges his tenure as the founding Editor-in-Chief for UpToDate in Infectious Diseases and his dedicated and longstanding involvement with the UpToDate program.

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Topic 6993 Version 75.0

References

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4 : The challenge of identifying resistant-organism pneumonia in the emergency department: still navigating on the erie canal?

5 : Is healthcare-associated pneumonia a distinct entity needing specific therapy?

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7 : Is the present definition of health care-associated pneumonia the best way to define risk of infection with antibiotic-resistant pathogens?

8 : Should nursing home-acquired pneumonia be treated as nosocomial pneumonia?

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33 : Weighted-incidence syndromic combination antibiograms to guide empiric treatment of critical care infections: a retrospective cohort study.

34 : Short-Course Adjunctive Gentamicin as Empirical Therapy in Patients With Severe Sepsis and Septic Shock: A Prospective Observational Cohort Study.

35 : What is the efficacy and safety of colistin for the treatment of ventilator-associated pneumonia? A systematic review and meta-regression.

36 : Ceftolozane/Tazobactam vs Polymyxin or Aminoglycoside-based Regimens for the Treatment of Drug-resistant Pseudomonas aeruginosa.

37 : Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial.

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40 : Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis.

41 : Vancomycin Plus Piperacillin-Tazobactam and Acute Kidney Injury in Adults: A Systematic Review and Meta-Analysis.

42 : Nosocomial pneumonia: de-escalation is what matters.

43 : De-escalation therapy: is it valuable for the management of ventilator-associated pneumonia?

44 : Clinical characteristics and treatment patterns among patients with ventilator-associated pneumonia.

45 : Does de-escalation of antibiotic therapy for ventilator-associated pneumonia affect the likelihood of recurrent pneumonia or mortality in critically ill surgical patients?

46 : De-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial.

47 : Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study.

48 : Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial.

49 : Usefulness of procalcitonin for the diagnosis of ventilator-associated pneumonia.

50 : Diagnostic utility of plasma procalcitonin for nosocomial pneumonia in the intensive care unit setting.

51 : Sequential measurements of procalcitonin levels in diagnosing ventilator-associated pneumonia.

52 : Value of the serum procalcitonin level to guide antimicrobial therapy for patients with ventilator-associated pneumonia.

53 : Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections.

54 : Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial.

55 : Short-course versus prolonged-course antibiotic therapy for hospital-acquired pneumonia in critically ill adults.

56 : Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial.

57 : Set a short course but follow the patient's course for ventilator-associated pneumonia.

58 : Comparison of 8 versus 15 days of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia in adults: a randomized, controlled, open-label trial.

59 : Ultra-Short-Course Antibiotics for Patients With Suspected Ventilator-Associated Pneumonia but Minimal and Stable Ventilator Settings.

60 : Pneumonia caused by methicillin-resistant Staphylococcus aureus.

61 : Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.

62 : Vital Signs: Trends in Staphylococcus aureus Infections in Veterans Affairs Medical Centers - United States, 2005-2017.

63 : Multidrug-Resistant Bacterial Infections in U.S. Hospitalized Patients, 2012-2017.

64 : Prevalence and Outcomes of Infection Among Patients in Intensive Care Units in 2017.

65 : A trial of discontinuation of empiric vancomycin therapy in patients with suspected methicillin-resistant Staphylococcus aureus health care-associated pneumonia.

66 : Nasal Methicillin-Resistant Staphylococcus aureus (MRSA) PCR Testing Reduces the Duration of MRSA-Targeted Therapy in Patients with Suspected MRSA Pneumonia.

67 : Association between a rapid diagnostic test to detect methicillin-resistant Staphylococcus Aureus pneumonia and decreased vancomycin use in a medical intensive care unit over a 30-month period.

68 : Rapid Detection of Methicillin-Resistant Staphylococcus aureus in BAL: A Pilot Randomized Controlled Trial.

69 : Empirical Anti-MRSA vs Standard Antibiotic Therapy and Risk of 30-Day Mortality in Patients Hospitalized for Pneumonia.

70 : A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate and Linezolid for Treatment of Ventilated Gram-Positive Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia.

71 : Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists.

72 : Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists.

73 : Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study.

74 : Vancomycin in vitro bactericidal activity and its relationship to efficacy in clearance of methicillin-resistant Staphylococcus aureus bacteremia.

75 : Point: Vancomycin is not obsolete for the treatment of infection caused by methicillin-resistant Staphylococcus aureus.

76 : Pharmacodynamic comparison of linezolid, teicoplanin and vancomycin against clinical isolates of Staphylococcus aureus and coagulase-negative staphylococci collected from hospitals in Brazil.

77 : High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity.

78 : Relationship of vancomycin minimum inhibitory concentration to mortality in patients with methicillin-resistant Staphylococcus aureus hospital-acquired, ventilator-associated, or health-care-associated pneumonia.

79 : Antibiotic choice may not explain poorer outcomes in patients with Staphylococcus aureus bacteremia and high vancomycin minimum inhibitory concentrations.

80 : Effect of vancomycin minimal inhibitory concentration on the outcome of methicillin-susceptible Staphylococcus aureus endocarditis.

81 : The role of telavancin in hospital-acquired pneumonia and ventilator-associated pneumonia.

82 : The role of telavancin in hospital-acquired pneumonia and ventilator-associated pneumonia.

83 : The role of telavancin in hospital-acquired pneumonia and ventilator-associated pneumonia.

84 : Telavancin versus vancomycin for hospital-acquired pneumonia due to gram-positive pathogens.

85 : Telavancin for hospital-acquired pneumonia: clinical response and 28-day survival.

86 : Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia.

87 : Experience with ceftaroline for treatment of methicillin-resistant Staphylococcus aureus pneumonia in a community hospital.

88 : Ceftaroline fosamil for the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia.

89 : Ceftaroline fosamil for the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia.

90 : Ceftaroline fosamil for the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia.

91 : Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia.

92 : Excess deaths associated with tigecycline after approval based on noninferiority trials.

93 : A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia.

94 : A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia.

95 : Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: a multicenter, randomized study.

96 : Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: a multicenter, randomized study.

97 : A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia.

98 : Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial.

99 : Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial.

100 : Ceftazidime-Avibactam Combination Therapy Compared to Ceftazidime-Avibactam Monotherapy for the Treatment of Severe Infections Due to Carbapenem-Resistant Pathogens: A Systematic Review and Network Meta-Analysis.

101 : Ceftazidime-Avibactam Combination Therapy Compared to Ceftazidime-Avibactam Monotherapy for the Treatment of Severe Infections Due to Carbapenem-Resistant Pathogens: A Systematic Review and Network Meta-Analysis.

102 : Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial.

103 : Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial.

104 : Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial.

105 : Effect and Safety of Meropenem-Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial.

106 : Prolonged versus short-term intravenous infusion of antipseudomonalβ-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials.

107 : Nebulized colistin in the treatment of pneumonia due to multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa.

108 : Aerosolized colistin as adjunctive treatment of ventilator-associated pneumonia due to multidrug-resistant Gram-negative bacteria: a prospective study.

109 : Aerosolized antibiotics to treat ventilator-associated pneumonia.

110 : Adjunctive aerosolized antibiotics for treatment of ventilator-associated pneumonia.

111 : Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonia caused by Gram-negative bacteria.

112 : Adjunctive aerosolized colistin for multi-drug resistant gram-negative pneumonia in the critically ill: a retrospective study.

113 : Effect of aerosolized colistin as adjunctive treatment on the outcomes of microbiologically documented ventilator-associated pneumonia caused by colistin-only susceptible gram-negative bacteria.

114 : Role of inhaled antibacterials in hospital-acquired and ventilator-associated pneumonia.

115 : Nebulization of Antiinfective Agents in Invasively Mechanically Ventilated Adults: A Systematic Review and Meta-analysis.

116 : Key considerations on nebulization of antimicrobial agents to mechanically ventilated patients.

117 : Nebulized antibiotics for ventilator-associated pneumonia: a systematic review and meta-analysis.

118 : Amikacin nebulization for the adjunctive therapy of gram-negative pneumonia in mechanically ventilated patients: a systematic review and meta-analysis of randomized controlled trials.

119 : The role of aerosolized colistin in the treatment of ventilator-associated pneumonia: a systematic review and metaanalysis.

120 : Prophylactic Antimicrobial Therapy for Acute Aspiration Pneumonitis.

121 : Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies.

122 : Attributable Mortality of Ventilator-associated Pneumonia. Replicating Findings, Revisiting Methods.

123 : Appropriateness and delay to initiate therapy in ventilator-associated pneumonia.

124 : Survival in patients with nosocomial pneumonia: impact of the severity of illness and the etiologic agent.

125 : Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients.

126 : Nosocomial pneumonia. A multivariate analysis of risk and prognosis.

127 : Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia.

128 : Predictors of 30-day mortality and hospital costs in patients with ventilator-associated pneumonia attributed to potentially antibiotic-resistant gram-negative bacteria.

129 : Impact of adequacy of initial antimicrobial therapy on the prognosis of patients with ventilator-associated pneumonia.

130 : Predicting mortality in patients with ventilator-associated pneumonia: The APACHE II score versus the new IBMP-10 score.

131 : Predicting mortality in patients with ventilator-associated pneumonia: The APACHE II score versus the new IBMP-10 score.

132 : Managing transmission of carbapenem-resistant enterobacteriaceae in healthcare settings: a view from the trenches.