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

Official reprint from UpToDate® www.uptodate.com©2011 UpToDate®

AuthorThomas M File, Jr, MD

Section EditorJohn G Bartlett, MD

Deputy EditorAnna R Thorner, MD

Treatment of hospital-acquired, ventilator-associated, andhealthcare-associated pneumonia in adults

Last literature review version 19.1: enero 2011 | This topic last updated: febrero 17, 2011

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

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

DEFINITIONS

Pneumonia types — The 2005 ATS/IDSA guidelines distinguish the following types of pneumonia[2]:

Hospital-acquired (or nosocomial) pneumonia (HAP) is pneumonia that occurs 48 hours or moreafter admission and did not appear to be incubating at the time of admission.

Ventilator-associated pneumonia (VAP) is a type of HAP that develops more than 48 to 72 hoursafter endotracheal intubation.

Healthcare-associated pneumonia (HCAP) is defined as pneumonia that occurs in anon-hospitalized patient with extensive healthcare contact, as defined by one or more of thefollowing:

Intravenous therapy, wound care, or intravenous chemotherapy within the prior 30 days

Residence in a nursing home or other long-term care facility

Hospitalization in an acute care hospital for two or more days within the prior 90 days

Attendance at a hospital or hemodialysis clinic within the prior 30 days

The guidelines can be accessed through the ATS web site at http://www.thoracic.org/statements/.

Multidrug resistance — The definition of multidrug resistance (MDR) in gram-negative bacilli, whichare an important cause of HAP, VAP, and HCAP is variably defined as resistance to at least two, three,four, or eight of the antibiotics typically used to treat infections with these organisms [3].Extensively-drug resistant (XDR) gram-negative bacilli are defined by resistance to all commonly usedsystemic antibiotics except colistin, tigecycline, and aminoglycosides.

Panresistance refers to those gram-negative organisms with diminished susceptibility to all of theantibiotics recommended for the empiric treatment of VAP, including cefepime, ceftazidime,

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imipenem, meropenem, piperacillin-tazobactam, ciprofloxacin, and levofloxacin. (See 'Empirictreatment' below.)

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

TREATMENT — Appropriate antibiotic therapy significantly improves survival for patients with HAP,VAP, or HCAP [2,4]. However, establishing the diagnosis of pneumonia in such patients can bedifficult, especially those on mechanical ventilation in whom clinical, radiologic, and microbiologicfindings can be due to numerous etiologies besides pneumonia. The difficulty in diagnosis may lead toovertreatment with its attendant risks of superinfection and antibiotic toxicity. (See "Clinicalpresentation and diagnosis of ventilator-associated pneumonia".)

When therapy is given, antimicrobial selection should be based upon risk factors for MDR pathogens,including recent antibiotic therapy (if any), the resident flora in the hospital or ICU, the presence ofunderlying diseases, and available culture data (interpreted with care). For patients with risk factorsfor multidrug-resistant (MDR) pathogens, empiric broad-spectrum, multidrug therapy isrecommended. Once the results of pretherapy cultures are available, therapy should be narrowedbased upon the susceptibility pattern of the pathogens identified.

The importance of providing appropriate therapy at the time of presentation was illustrated in aretrospective study of almost 400 patients with culture-positive HCAP who survived but remainedhospitalized 48 hours after hospital admission [5]. Mortality was significantly higher among the 107patients who received inappropriate initial therapy compared with the 289 patients who receivedappropriate coverage (30 versus 18 percent); switching to an appropriate regimen did not reduce therisk of death.

In a study that assessed the microbial prediction and validated the adequacy of the 2005 AmericanThoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines for HAP in the ICU,adherence to the guidelines resulted in more adequate treatment and a trend toward a better clinicalresponse in patients who presented late (≥5 days) or had risk factors for drug-resistant bacteria, butdid not affect mortality [6]. The 2005 guidelines were worse than the 1996 guidelines for predictingdrug-resistant bacteria; this was mostly observed for cases classified as lower risk for multidrug-resistant pathogens (ie, early onset infection without specified risk factors for resistant infection),suggesting that such patients may in fact be at risk for resistant pathogens.

In a later observational study that included 303 patients at risk for MDR pathogens, 28-day mortalitywas higher among patients who were treated according to the ATS/IDSA guidelines compared withpatients whose treatment did not comply with the guidelines (34 versus 20 percent) [7]. The primaryreason for “non-compliance” was lack of a second drug for gram-negative pathogens. Criticisms of thisstudy include the observation that lower coverage for certain MDR pathogens occurred in thecompliant group (but was not commented upon by the authors), lack of assessment of the impact oftiming of antimicrobial therapy, lack of appropriate adjustment for risk of death, disregard of theimpact of treatment de-escalation on the classification of compliance, and the possibility that excessmortality may have been at least partly due to toxicity when a triple regimen is used [8]. In addition,although the authors attempted to control for higher severity of infection observed in the compliantgroup, the results may still have been confounded by patients in the compliant group who were atgreater risk of poor outcomes at presentation. Potential messages from this study are: clinicians whoare following patients and are aware of pathogen and susceptibility patterns within a specific unit maybe better able to appropriately select empiric therapy based on individual clinical judgment ratherthan using routine combination therapy (guidelines are meant to supplement clinical judgment, notsupplant judgment); the need for two-drug therapy is not necessary in many cases of gram-negative


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infection; and the definition of risk for MDR as stated in the 2005 guidelines is not precise,particularly for HCAP, and should be readdressed. (See 'Gram-negative pathogens' below and'Multidrug resistance' above.)

A retrospective study showed that HCAP is associated with more severe disease, longer hospital stay,and higher mortality rates than CAP, and that the use of antimicrobial therapy not recommended bythe ATS/IDSA guidelines was associated with increased mortality in such patients [9]. Anotherobservational study found that lack of adherence to a VAP protocol (which included considerations ofappropriate use and duration of antibiotics) resulted in longer duration of therapy, ventilation, andlength of ICU stay [10].

In a retrospective analysis of local microbiologic data on HAP pathogens from 111 consecutivepatients in 2004, investigators developed institution-specific treatment guidelines in order to improveempiric antibiotic therapy [11]. Institution guideline-directed treatment regimens were predicted toprovide adequate initial therapy for >90 percent of patients who develop HAP ≥10 days afterhospitalization (eg, those at greatest risk of multidrug resistant pathogens). In this institution, use ofa fluoroquinolone per the national guidelines, would not have provided adequate additionalantimicrobial activity for the beta-lactam resistant gram-negative bacilli (ciprofloxacin was activeagainst <10 percent of these pathogens which were also resistant to piperacillin-tazobactam andcefepime). This study illustrates the importance of using local susceptibility data to develop treatmentguidelines.

The implementation of recommendations to assess a patient's status 72 hours after the initiation oftherapy and to discontinue antibiotics or narrow the regimen (deescalate therapy) based uponappropriate culture results may reduce the selective pressure for antimicrobial resistance.

A prospective observational study of 398 intensive care unit (ICU) patients with suspected VAP foundthat mortality was significantly lower among patients in whom therapy was deescalated compared tothose whose therapy was either escalated or unchanged (17 versus 43 and 24 percent, respectively)[12]. The study was limited because of its observational nature; confirmation of these results awaits arandomized controlled study. In another study, deescalation was evaluated in surgical patients withseptic shock in a retrospective evaluation of 138 patients with VAP [13]. Deescalation of antimicrobialtherapy occurred in 55 percent of patients who had received initial therapy effective against theidentified pathogen (most common initial choice was vancomycin plus piperacillin-tazobactam). Themortality rate of patients who underwent deescalation therapy was 35 percent compared with 42percent among patients who did not have deescalation, a difference that did not reach statisticalsignificance. This study demonstrated that deescalation therapy did not lead to recurrent pneumoniaor increased mortality in this population of critically ill surgical patients.

There has been interest in the nonantibiotic antiinflammatory effects of macrolides. A randomizedtrial of 200 patients with sepsis and VAP showed that those who received clarithromycin (in additionto standard treatment including antibiotics) had significantly faster resolution of VAP (10 versus 15.5days) and weaning from mechanical ventilation (16 versus 22.5 days) compared to those whoreceived placebo [14]. Among those who died of sepsis, time to death was significantly prolonged inthose who received clarithromycin.

Specific antimicrobial considerations — In critically ill patients, in those receiving antibiotics priorto the onset of pneumonia, and in institutions where these pathogens are frequent, coverage ofmethicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa, and antibiotic-resistantgram-negative bacilli, such as Acinetobacter spp, and Legionella should be considered.

MRSA — If MRSA is a frequent nosocomial pathogen in the institution, linezolid or vancomycin is anecessary first choice for anti-staphylococcal coverage [2,15,16], but should be discontinued if MRSAis not isolated.


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An overview of the treatment of invasive MRSA infections is presented separately. (See "Treatment ofinvasive methicillin-resistant Staphylococcus aureus infections in adults".)

Linezolid and vancomycin — Several trials have compared linezolid and vancomycin, withvariable results. Two prospective, randomized trials of nosocomial pneumonia compared linezolid withvancomycin; each found no significant difference in outcomes for MRSA infections [17,18]. Asubsequent open-label trial showed only a trend towards earlier microbiologic cure, clinical cure, andsurvival rate among patients treated with linezolid for VAP compared with those treated withvancomycin [19]. A meta-analysis of nine randomized trials that compared linezolid with vancomycin(in seven trials) or teicoplanin (in two trials) for nosocomial pneumonia found no differences in ratesof clinical cure or microbiologic eradication [20]. In addition, no differences in clinical cure ormicrobiologic eradication were observed in the subgroup analysis of patients with MRSA. However, ina later randomized double-blind trial that compared linezolid to vancomycin for the treatment ofhospital-acquired pneumonia (HAP) or healthcare-associated pneumonia (HCAP) due to proven MRSA,the end of study success rate was 58 percent for linezolid and 47 percent for vancomycin [21].Linezolid was non-inferior and statistically superior to vancomycin in end of treatment clinicaloutcome, and microbiologic outcome at end of treatment and end of study.

A retrospective study suggested that vancomycin failure might be related to suboptimal dosing [22].As a result, a trough level of 15 to 20 mcg/mL is often targeted [2]. However, subsequent studiesfailed to confirm that higher vancomycin trough concentrations correlate with improved outcomes[23,24]. On the other hand, higher vancomycin MICs themselves may be associated with worseoutcomes in patients with HAP due to MRSA. This was suggested in a prospective cohort study of 95patients with MRSA HCAP who were treated with vancomycin in which the targeted troughvancomycin concentration was at least four times the MIC [23]. High MIC (≥2 mcg/mL) strains ofMRSA were detected in 54 percent of patients. Despite achieving the target trough concentration,mortality was higher among patients whose MRSA strain had a high MIC than patients whose MRSAstrain had a low MIC (24 versus 10 percent). In a later prospective study that included 158 patients inthe ICU with HAP, VAP, or HCAP, an increase in 28-day mortality was observed in patients whoseMRSA isolates had increased MICs; an increase in mortality occurred as the vancomycin MICincreased from 0.75 to 3 mcg/mL, and was present even for strains within the susceptible range [25].

The 2005 ATS/IDSA treatment guidelines on HAP, VAP, and HCAP, and a 2009 United Statespharmacy consensus review recommend target vancomycin trough concentrations of 15 to 20 mcg/mL[2,26]. However, these recommendations are based on retrospective pharmacokinetic modeling in theabsence of prospective clinical data. PK/PD analysis has suggested that lung vancomycin AUC:MIC>400 may be difficult to achieve (particularly for isolates with MIC >1) [27-29]. Clinical data havefailed to demonstrate a relationship between treatment outcome and target troughs of 15 to 20mcg/mL [2]. (See "Vancomycin dosing and serum concentration monitoring in adults".)

The 2005 ATS/IDSA guidelines on HAP, VAP, and HCAP and the 2011 IDSA guidelines for thetreatment of MRSA infections recommended either linezolid or vancomycin for infections suspected orproven to be due to MRSA [2,16]. It was noted that linezolid might be preferred in patients at risk foror with renal insufficiency in whom vancomycin is often underdosed and is associated with a risk ofnephrotoxicity. Linezolid also may reduce toxin production, although the possible benefit of this hasnot been established [30,31]. Linezolid is particularly preferred in hospitals in which a substantialproportion of MRSA isolates have a vancomycin MIC ≥2 mcg/mL. Linezolid resistance and linezolidfailure have been described rarely. An alternative to linezolid and vancomycin is clindamycin (600 mgIV or orally three times daily), provided that the isolate is known to be susceptible, although there arefewer data to supports its use [16]. (See "Epidemiology of methicillin-resistant Staphylococcus aureusinfection in adults", section on 'Linezolid resistance' and "Treatment of invasive methicillin-resistantStaphylococcus aureus infections in adults", section on 'Linezolid'.)


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The usual doses are:

Linezolid — 600 mg twice daily IV (or orally if or when the patient is able to receive oralmedications).

Vancomycin — 15 to 20 mg/kg (based on actual body weight) IV every 8 to 12 hours forpatients with normal renal function, with a target serum trough concentration of 15 to 20 mg/L[26]. In seriously ill patients, a loading dose of 25 to 30 mg/kg can be used to facilitate rapidattainment of the target trough concentration. (See "Vancomycin dosing and serumconcentration monitoring in adults".)

Telavancin — Telavancin is an intravenous semisynthetic lipoglycopeptide antibiotic that isbroadly active against both aerobic and anaerobic gram-positive bacteria, including streptococci,methicillin-susceptible S. aureus, methicillin-resistant S. aureus (MRSA), and some vancomycin-resistant enterococci [32]. In two randomized trials (the ATTAIN studies) that included 1503 patientswith HAP due to gram-positive bacteria, especially MRSA, telavancin (10 mg/kg IV daily) wasnoninferior to vancomycin in terms of clinical response (58.9 percent versus 59.5 percent) [33].Among patients with monomicrobial Staphylococcus aureus infection, the cure rates were higher inpatients who received telavancin, particularly among those with an MRSA isolate with reducedsusceptibility to vancomycin (MIC ≥1 mg/dL); the cure rate among patients with MRSA with reducedsusceptibility to vancomycin was 87 percent in those who received telavancin versus 74 percent inthose who received vancomycin. The cure rates were for all patients with monomicrobial MRSAinfection regardless of vancomycin MIC were 81.8 percent for telavancin and 74.1 percent forvancomycin (95% CI -3.5-19.3). These results suggest that telavancin is particularly useful forpatients with MRSA isolates with a vancomycin MIC ≥1 mg/dL. However, telavancin has not beenapproved by the US Food and Drug Administration for the treatment of pneumonia.

Although the overall incidence of adverse events was similar in the two groups, the incidence ofserious adverse events and/or adverse events leading to drug discontinuation was higher in thetelavancin group in both trials (31 versus 26 percent and 8 versus 5 percent, respectively). Asignificant rise in serum creatinine (>50 percent from baseline and a maximum value >1.5 mg/dL)was more common in the telavancin group than the vancomycin group (16 versus 10 percent).

Other agents — There has been interest in using other agents for the treatment of MRSApneumonia, but none of the following agents can be recommended:

Daptomycin cannot be used to treat pneumonia because it does not achieve sufficiently highconcentrations in the respiratory tract.

Data are limited on the use of quinupristin-dalfopristin. In a randomized trial of HAP thatincluded 38 patients with MRSA pneumonia, there was a nonsignificant lower rate of clinicalsuccess with quinupristin-dalfopristin compared with vancomycin (31 versus 44 percent) and ahigher rate of adverse effects that led to discontinuation of therapy [34].

Ceftaroline is a broad-spectrum cephalosporin with activity against MRSA, which has beenapproved for CAP, but not for staphylococcal pneumonia [35].

Tigecycline is a broad-spectrum antibiotic with activity against MRSA. In September 2010 theFDA issued a safety announcement regarding increased mortality risk associated with the use oftigecycline compared with that of other drugs that was observed in a pooled analysis of 13 trials[36]. The increased risk was seen most clearly in patients treated for HAP, particularly VAP.

Gram-negative pathogens — Although combination antimicrobial therapy for HAP, VAP, andHCAP due to gram-negative pathogens (especially Pseudomonas) is commonly administered, there is


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no conclusive evidence to support this practice. The best rationale for the use of combination therapyis to provide a greater spectrum of activity when there is risk for MDR pathogens (eg, if the pathogenis resistant to one agent it may be susceptible to the other) [2]. Other commonly cited reasons forcombination therapy include the potential for synergistic efficacy as well as the potential to reduce theemergence of resistance. However, it is not clear that two agents offer improved outcomes fortreating gram-negative pneumonia.

A meta-analysis and a subsequent large, randomized trial suggested that monotherapy of VAP was aseffective as combination therapy [37,38]. However, the percentage of MDR organisms was low in thetrials reviewed in the meta-analysis and in the randomized trial. In addition, the randomized trialexcluded patients known to be colonized with Pseudomonas or MRSA, and found that combinationversus monotherapy was associated with improved adequacy of initial antibiotics and microbiologicaleradication of infecting organisms in patients who had infection due to Pseudomonas, Acinetobacter,and MDR gram-negative bacilli [38]. Thus, it is difficult to extrapolate the efficacy of monotherapy toICUs with high incidences of these pathogens.

In another study of patients hospitalized in an ICU due to trauma, 84 patients with VAP caused byPseudomonas were treated with monotherapy (cefepime 2 g intravenously every 8 hours); thisresulted in microbiologic eradication (based on repeat BAL showing <103 organisms/mL) in 94percent of patients with no recurrences, suggesting that combination therapy is unnecessary whenthe initial antimicrobial therapy is active against the isolate [39].

In ICU settings in which extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae arefound, cephalosporins should be avoided as monotherapy, due to the selection of resistant organismswhen these agents are used [40]. The most reliable agent in this setting is a carbapenem (imipenem-cilastatin, ertapenem, meropenem, or doripenem) [41-43].

Legionella — Patients who have diabetes mellitus, renal disease, structural lung disease, or havebeen recently treated with glucocorticoids may require coverage for Legionella spp (azithromycin or afluoroquinolone). HAP and VAP due to Legionella spp are also more common in hospitals where theorganism is present in the hospital water supply. (See "Epidemiology and pathogenesis of Legionellainfection" and "Treatment and prevention of Legionella infection".)

Anaerobes — Patients who have aspirated or had recent abdominal surgery may warrantcoverage for anaerobes (clindamycin, beta-lactam-beta-lactamase inhibitor, or a carbapenem). (See"Aspiration pneumonia in adults" and "Anaerobic bacterial infections", section on 'Pleuropulmonaryinfections'.)

Empiric treatment — We generally agree with the American Thoracic Society/Infectious DiseasesSociety of America (ATS/IDSA) guidelines for the management of HAP, VAP, or HCAP [2]. Theseguidelines can be accessed through the ATS web site at http://www.thoracic.org/statements/.

No known MDR risk factors — We suggest one of the following intravenous antibiotic regimensfor empiric coverage of HAP, VAP, and HCAP in patients with no known risk factors for multidrug-resistant (MDR) pathogens:

Ceftriaxone (2 g intravenously daily).

Ampicillin-sulbactam (3 g intravenously every six hours).

Levofloxacin (750 mg intravenously daily) or moxifloxacin (400 mg intravenously daily). Whenthe patient is able to take oral medications, either agent may be administered orally at thesame dose as that used for IV administration.

Ertapenem (1 g intravenously daily).


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Choice of a specific agent for empiric therapy should be based on knowledge of the prevailingpathogens (and susceptibility patterns) within the healthcare setting. If there is concern forgram-negative bacilli resistant to the above options (eg, Enterobacter spp, Serratia spp, Pseudomonasspp) based upon microbiologic data at the specific institution, we feel that it is reasonable to initiatepiperacillin-tazobactam (4.5 g IV every six hours) or another agent (eg, cefepime or a carbapenem)as monotherapy for patients without known risk factors for MDR bacteria provided that theinstitution’s susceptibility data support in vitro activity.

Known MDR risk factors — Host risk factors for infection with multidrug resistant (MDR)pathogens include receipt of antibiotics within the preceding 90 days, current hospitalization of ≥5days, high frequency of antibiotic resistance in the community or in the specific hospital unit,immunosuppressive disease and/or therapy, and presence of risk factors for HCAP. (See"Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired, ventilator-associated,and healthcare-associated pneumonia in adults", section on 'MDR risk factors'.)

For patients with known MDR risk factors, we recommend empiric combination therapy including:

ONE of the following:

Antipseudomonal cephalosporin such as cefepime (2 g intravenously every eight hours) orceftazidime (2 g intravenously every 8 hours)

Antipseudomonal carbapenem such as imipenem (500 mg intravenously every six hours) ormeropenem (1 g intravenously every eight hours) or doripenem (500 mg intravenously everyeight hours; administered over one hour for HAP or HCAP, administered over four hours forVAP) [42,43]

Piperacillin-tazobactam (4.5 g intravenously every six hours)

For patients who are allergic to penicillin, the type and severity of reaction should be assessed.The great majority of patients who are allergic to penicillin by skin testing can still receivecephalosporins (especially third-generation cephalosporins) or carbapenems. If there is a historyof a mild reaction to penicillin (not an IgE-mediated reaction, Stevens Johnson syndrome ortoxic epidermal necrolysis), it is reasonable to administer a cephalosporin or carbapenem usinga simple graded challenge (eg, give 1/10 of dose, observe closely for 1 hour, then giveremaining 9/10 of dose, observe closely for 1 hour). Skin testing is indicated in some situations.If a skin test is positive or if there is significant concern to warrant avoidance of a cephalosporinor carbapenem, aztreonam (2 g intravenously every six to eight hours) is recommended.Indications and strategies for skin testing are reviewed elsewhere. (See "Penicillin-allergicpatients: Use of cephalosporins, carbapenems, and monobactams".)

Patients with past allergic reactions to cephalosporins may also be treated with aztreonam, withthe possible exception of those allergic to ceftazidime. Ceftazidime and aztreonam have similarside chain groups, and cross reactivity between the two drugs is variable. The prevalence ofcross-sensitivity has been estimated at <5 percent of patients, based upon limited data. Patientswith past reactions to ceftazidime that were life-threatening or suggestive of anaphylaxis(involving urticaria, bronchospasm, and/or hypotension) should not be given aztreonam unlessevaluated by an allergy specialist. In contrast, a reasonable approach in those with mild pastreactions to ceftazidime (eg, uncomplicated maculopapular rash) would involve informing thepatient of the low risk of cross-reactivity and administering aztreonam with a graded challenge(1/100, 1/10, full dose, each separated by 1 hour of observation). (See "Cephalosporin-allergicpatients: Subsequent use of cephalosporins and related antibiotics", section on 'Use ofcarbapenems and monobactams'.)


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PLUS one of the following:

Antipseudomonal fluoroquinolone, preferred regimen if Legionella is likely, such asciprofloxacin (400 mg intravenously every eight hours) or levofloxacin (750 mg intravenouslydaily). These agents may be administered orally when the patient is able to take oralmedications. The dose of levofloxacin is the same when given intravenously and orally, whilethe dose of ciprofloxacin is 750 mg orally twice daily.

Aminoglycoside such as gentamicin or tobramycin (7 mg/kg intravenously once daily) oramikacin (20 mg/kg intravenously once daily); once daily dosing is only appropriate for patientswith normal renal function. A single serum concentration should be obtained 6 to 14 hours afterthe first dose, and the dose should be adjusted as needed based upon the following nomogram(figure 1). The aminoglycoside can be stopped after five to seven days in responding patients.(See "Consolidated aminoglycoside dosing with gentamicin and tobramycin".)

PLUS ONE of the following (if MRSA is suspected, there are MRSA risk factors, or there is a highincidence of MRSA locally):

Linezolid (600 mg intravenously every 12 hours; may be administered orally when the patientis able to take oral medications)

Vancomycin (15 to 20 mg/kg [based on actual body weight] intravenously every 8 to 12 hoursfor patients with normal renal function, with a target serum trough concentration of 15 to 20mg/L.) In seriously ill patients, a loading dose of 25 to 30 mg/kg can be used to facilitate rapidattainment of the target trough concentration. (See "Vancomycin dosing and serumconcentration monitoring in adults".)

If patients have recently received antibiotics, empiric therapy should generally be with a drug from adifferent class since earlier treatment may have selected pathogens resistant to the initial class.

Because of increasing resistance of pathogens associated wth VAP, HAP, and HCAP, one potentialstrategy to enhance the antimicrobial potential of a given agent is to optimize the pharmacodynamiceffect. Since the beta-lactams are associated with optimal outcomes when the level of the drug isabove the minimum inhibitory concentration (MIC) for the pathogen for an appropriate percent of thedosing interval, this effect can potentially be improved with prolonged infusion of the antimicrobial.This has been demonstrated with the use of a 3 to 4 hour infusion of piperacillin-tazobactam,cefepime, or the carbapenems for the treatment of VAP due to gram-negative bacilli with higher MICsthan the usual breakpoints for susceptibility [44-46].

Aerosolized antibiotics — Aerosolized colistin, polymyxin, or aminoglycosides may beconsidered as potential additional antibiotics in patients with multidrug-resistant (MDR)gram-negative bacilli [47-51]. Aerosolization may increase antibiotic concentrations at the site ofinfection, and may be particularly useful for treatment of organisms that have high MICs to systemicantimicrobial agents [52]. In a randomized trial that included 100 patients with VAP due togram-negative bacilli (predominantly MDR Acinetobacter baumannii and/or Pseudomonas aeruginosa),patients who were treated with a combination of systemic antibiotics and nebulized colistin had ahigher rate of favorable microbiologic outcome compared with patients who were treated withsystemic antibiotics alone (microbiologic eradication or presumed eradication 61 versus 38 percent),but there was no differences in clinical outcome (51 versus 53 percent) [51].

In a retrospective case-control study that included 86 patients with VAP due to MDR gram-negativebacilli (predominantly A. baumannii) treated with a combination of IV and aerosolizedcolistin compared with IV colistin alone, there was only a trend towards improved rates of clinical


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cure, pathogen eradication, and mortality in the patients who received aerosolized and IV colistin[53]. However, this study may have been underpowered to show a benefit, adequate doses ofaerosolized colistin may not have been used, and the difficulty in diagnosing VAP may have biased theresults (ie, if patients without VAP were included) [54]. (See "Colistin: An overview".)

Antibiotic regimens — When the etiology of HAP, VAP, or HAP has been identified based uponreliable microbiologic methods and there is no laboratory or epidemiologic evidence of coinfection,treatment regimens should be simplified and directed to that pathogen. The choice of specific agentswill be dictated by the results of susceptibility testing. It is crucial to avoid broad-spectrum therapyonce a pathogen has been identified [2,8].

A novel approach may determine antimicrobial susceptibility more quickly than traditional methods.In a trial, Gram stain was performed on endotracheal aspirates from 250 patients withbacteriologically confirmed VAP [55]. The endotracheal aspirates whose Gram stain identified amicrobe were randomly assigned to either rapid testing — the endotracheal aspirates were directlyapplied to antibiotic susceptibility test strips — or standard culture. Rapid testing more quicklyidentified susceptibility than standard culture (1.4 versus 4.2 days). In addition, patients were morelikely to receive appropriate antimicrobial therapy, have fewer days of antimicrobial therapy, andhave more rapid resolution of fever. Antimicrobial selection based on this strategy has never beencompared to that based on a Gram stain or local susceptibility patterns. Nor has it been compared toempiric broad spectrum therapy based on MDR risk factors. Until further clinical studies areperformed, this approach cannot be recommended in the routine management of HAP.

Patients who are improving clinically, are hemodynamically stable, and able to take oral medicationscan be switched to oral therapy. If the pathogen has been identified, the choice of antibiotic for oraltherapy is based upon the susceptibility profile for that organism. If a pathogen is not identified, thechoice of antibiotic for oral therapy is either the same antibiotic as the intravenous antibiotic, or anagent in the same drug class, which achieves adequate lung penetration when administered orally.

Duration — The duration of therapy should be based upon the clinical response. The standardduration of therapy in the past was 14 to 21 days in part because of a concern for difficult to treatpathogens (eg, Pseudomonas spp). However, a shorter course could significantly reduce the amount ofantimicrobial drugs used in hospitals where the emergence of resistant pathogens is a concern.

The following studies found that short course treatment is effective:

A prospective, randomized, multicenter trial of 401 patients with VAP compared outcomesfollowing eight versus 15 days of treatment [56]. All patients underwent bronchoscopy forquantitative cultures and were empirically treated with a combination of an antipseudomonalbeta-lactam plus either an aminoglycoside or a fluoroquinolone. Investigators were encouragedto change the regimen to a pathogen-directed treatment based upon culture results.

There was no significant difference between patients treated for eight compared to 15 days inmortality or recurrent infection at 28 days; as expected, patients treated for eight days hadmore antibiotic-free days. Among patients who developed recurrent infections, MDR pathogenswere isolated less frequently in those treated for eight days (42 versus 62 percent for thosetreated for 15 days). However, patients with VAP caused by nonfermenting gram-negativebacilli (eg, Pseudomonas spp) had a higher pulmonary infection recurrence rate when treatedfor eight versus 15 days (41 versus 25 percent with 15 days of treatment), although mortalitywas not different. In a subanalysis of 125 patients who had S. aureus isolated as a pathogen,there was no significant difference based on treatment duration (8 or 15 days) for 28-daymortality or VAP recurrence; this was also the case when only VAP caused by MRSA wasconsidered [57].


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An ICU study evaluated clinical outcomes, including duration of treatment, followingimplementation of a clinical guideline for the treatment of VAP compared to historical controls(patients with VAP treated prior to implementation of the guideline) [58]. The clinical guidelinegroup had a shorter duration of antimicrobial therapy and was less likely to have a recurrentepisode of VAP.

A prospective study evaluated the ability of the Clinical Pulmonary Infection Score (CPIS) todetermine the duration of therapy for ICU patients with new pulmonary infiltrates (table 1)[59]. Patients were included in the study if they had new-onset pulmonary infiltrates and a CPIS<6. The patients were randomized to either a control group (standard therapy) or to theexperimental group (intravenous ciprofloxacin 400 mg every eight hours for three days).

The CPIS was reevaluated at three days and in patients with a CPIS <6, antibiotics werediscontinued in the experimental group. If the CPIS was >6, ciprofloxacin was continued orantibiotics were changed based upon the microbiologic results. Significantly more patients in thecontrol group received antibiotics beyond three days compared to those in the experimentalgroup (90 compared with 28 percent in the experimental group). In addition to reducedantibiotic use, the experimental group was less likely to have colonization/infection withresistant organisms (15 compared with 35 percent of patients in the control group) and had atrend towards lower mortality.

In a separate prospective cohort study of 312 patients who were treated with empiric antibioticsin an ICU, investigators sought to determine if the CPIS score could be used to decrease theamount or duration of antibiotic therapy [60]. The CPIS score was compared to the assessmentof a "pneumonia committee" (PC), which was comprised of investigators and cliniciansexperienced in the management of ICU patients. The CPIS score had a reasonable predictivevalue, but assessment by the PC and the CPIS score often diverged when the CPIS score was sixor less. Half of the empiric antibiotic use was for patients in whom pneumonia was suspectedbut the PC or the CPIS score indicated that pneumonia was unlikely.

Recommendations — Based upon these data, we recommend that all patients with HAP, VAP, orHCAP should be evaluated after 72 hours of initial empiric antimicrobial therapy.

If the patient has improved after 72 hours, and a pathogen is isolated, antimicrobial therapy shouldbe changed to a pathogen-directed regimen based upon the susceptibility pattern. Therapy shouldgenerally be continued to complete a total course of 7 days; we would treat up to 15 days if P.aeruginosa were the etiologic agent, and for up to 21 days for MRSA, depending upon the extent ofinfection and clinical course [16]. Based on the study of S. aureus VAP discussed above, 8 days oftherapy may be adequate if there is good clinical response early in the course of appropriate therapy[57]. If the patient has improved and no pathogen is identified, we would narrow the regimen,discontinuing therapy for Pseudomonas spp and MRSA.

If the patient has not improved at 72 hours and a resistant pathogen is identified, therapy should bechanged to pathogen-directed treatment based upon the susceptibility pattern. In addition, failure toimprove at 72 hours should prompt a search for infectious complications, other diagnoses, or othersites of infection.

PROGNOSIS — Despite high absolute mortality rates in HAP patients, the mortality attributable tothe infection is difficult to gauge. Many studies have found that HAP is associated with significantexcess risk of death. However, many of these critically ill patients die from their underlying diseaseand not from pneumonia. Case-control studies estimate that the all-cause mortality rate for HAP andVAP is in the range of 33 to 50 percent [2].


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In a retrospective cohort study that used a large inpatient database, mortality rates were 10 percentin patients with CAP, 19 percent in patients with HAP, 20 percent in patients with HCAP, and 29percent in patients with VAP [61]. In another study, HCAP was associated with a higher in-hospitalmortality rate than CAP (18 versus 7 percent) [9].

Variables associated with increased mortality include [2,62-69]:

Serious illness at the time of diagnosis (eg, high APACHE score, shock, coma, respiratoryfailure, ARDS)

Bacteremia

Severe underlying comorbid disease

Infection caused by an organism associated with multidrug resistance (Pseudomonasaeruginosa, Acinetobacter spp)

Multilobar, cavitating, or rapidly progressive infiltrates on lung imaging

Delay in the institution of effective antimicrobial therapy

The Acute Physiology and Chronic Health Evaluation II (APACHE II) score has been considered thebest system to predict mortality in patients with VAP. A group of investigators has developed asimpler scoring system to predict mortality: the IBMP-10 score based on the presence ofimmunodeficiency; blood pressure <90 mm Hg systolic; multilobar infiltrates; platelet count<100,000; and >10 days in hospital prior to onset of VAP [69]. Based on a point for each variable,the mortality rates for each score were: 0 to 2 percent; 1 to 9 percent; 2 to 24 percent; 3 to 50percent; 4 to 67 percent. In a preliminary analysis, the authors indicated that this five-point systemwas comparable to APACHE-II in its ability to predict mortality in such patients.

SUMMARY AND RECOMMENDATIONS

The choice of the antibiotic treatment regimen for HAP, VAP, and HCAP should be influenced bythe patient's recent antibiotic therapy (if any), the resident flora in the hospital or intensivecare unit, the presence of underlying diseases, available culture data (interpreted with care),and whether the patient is at risk for MDR pathogens. (See 'Treatment' above.)

For empiric coverage of HAP, VAP, and HCAP in patients with no known risk factors formultidrug-resistant (MDR) pathogens, we suggest one of the following intravenous antibioticregimens:

Ceftriaxone (2 g intravenously daily)

Ampicillin-sulbactam (3 g intravenously every six hours)

Levofloxacin (750 mg intravenously daily) or moxifloxacin (400 mg intravenously daily).When the patient is able to take oral medications, either agent may be administered orallyat the same dose as that used for IV administration.

Ertapenem (1 g intravenously daily) .

Choice of a specific agent for empiric therapy should be based upon knowledge of theprevailing pathogens (and susceptibility patterns) within the healthcare setting. If there isconcern for gram-negative bacilli resistant to the above options (eg, Enterobacter spp,Serratia spp, Pseudomonas spp) based upon microbiologic data at the specific institution, wefeel that it is reasonable to initiate piperacillin-tazobactam (4.5 g IV every six hours) oranother agent (eg, cefepime or a carbapenem) as monotherapy for patients without known


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risk factors for MDR bacteria provided that the institution’s susceptibility data support invitro activity. (See 'No known MDR risk factors' above.)

For empiric coverage of HAP, VAP, and HCAP in patients with known risk factors for MDRpathogens, we recommend empiric combination therapy including:

One of the following:

Antipseudomonal cephalosporin such as cefepime (2 g intravenously every eight hours) orceftazidime (2 g intravenously every 8 hours)

Antipseudomonal carbapenem such as imipenem (500 mg intravenously every six hours) ormeropenem (1 g intravenously every eight hours) or doripenem (500 mg intravenouslyevery eight hours; administered over one hour for HAP or HCAP, administered over fourhours for VAP)

Piperacillin-tazobactam (4.5 g intravenously every six hours)

For patients who are allergic to penicillin, the type and severity of reaction should beassessed. If a skin test is positive or if there is significant concern to warrant avoidance of acephalosporin or carbapenem, aztreonam (2 g intravenously every six to eight hours) isrecommended.

Patients with past allergic reactions to cephalosporins may also be treated with aztreonam,with the possible exception of those allergic to ceftazidime. Ceftazidime and aztreonam havesimilar side chain groups, and cross reactivity between the two drugs is variable. Theprevalence of cross-sensitivity has been estimated at <5 percent of patients, based uponlimited data. Patients with past reactions to ceftazidime that were life-threatening orsuggestive of anaphylaxis (involving urticaria, bronchospasm, and/or hypotension) shouldnot be given aztreonam unless evaluated by an allergy specialist. In contrast, a reasonableapproach in those with mild past reactions to ceftazidime (eg, uncomplicated maculopapularrash) would involve informing the patient of the low risk of cross-reactivity andadministering aztreonam with a graded challenge (1/100, 1/10, full dose, each separated by1 hour of observation). (See "Cephalosporin-allergic patients: Subsequent use ofcephalosporins and related antibiotics", section on 'Use of carbapenems and monobactams'.)

PLUS one of the following:

Antipseudomonal fluoroquinolone, such as ciprofloxacin (400 mg intravenously every eighthours) or levofloxacin (750 mg intravenously daily).

Aminoglycoside such as gentamicin or tobramycin (7 mg/kg intravenously once daily ) oramikacin (20 mg/kg intravenously once daily ). The aminoglycoside can be stopped after fiveto seven days in responding patients.

PLUS one of the following (if MRSA is suspected, there are MRSA risk factors, or there is a highincidence of MRSA locally):

Linezolid (600 mg intravenously every 12 hours; may be administered orally when thepatient is able to take oral medications)

Vancomycin (15 to 20 mg/kg [based on actual body weight] intravenously every 8 to 12hours for patients with normal renal function, with a target serum trough concentration of15 to 20 mg/L.) In seriously ill patients, a loading dose of 25 to 30 mg/kg can be used tofacilitate rapid attainment of the target trough concentration. (See 'Known MDR riskfactors' above.)


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Critical to reducing overuse of antimicrobials, "deescalation" of therapy should be consideredafter 48 to 72 hours of initial therapy, and should be based upon the results of initial culturesand the clinical response of the patient. (See 'Duration' above.)

The duration of therapy should be based upon the clinical response. A short duration of therapy(eg, seven days) is sufficient for most patients with uncomplicated HAP, VAP, or HCAP who havehad a good clinical response. (See 'Duration' above.)

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GRAPHICS

Single-dose aminoglycoside nomogram

Nomogram showing the relationship between serum gentamicin ortobramycin concentrations and time beginning at six hours after asingle dose of 7 mg/kg. The interval for drug administration variedwith estimated creatinine clearance (Ccr): every 24 hours at a Ccr≥60 mL/min; every 36 hours at a Ccr of 40 to 59 mL/min; andevery 48 hours at a Ccr of 20 to 39 mL/min. Reproduced withpermission from: Nicolau, D, Quintiliani, R, Nightingale, CH. Once-dailyaminoglycosides. Conn Med 1992; 56:561. Copyright © 1992 Connecticut StateMedical Society.


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Clinical Pulmonary Infection Score (CPIS)

Temperature

≥36.5 or ≤38.4 = 0 point

≥38.5 or ≤38.9 = 1 point

≥39 or <36.5 = 2 points

Blood leukocytes, microL

≥4000 or ≤11,000 = 0 points

<4000 or >11,000 = 1 point

Band forms ≥50 percent = add 1 point

Tracheal secretions

Absence of tracheal secretions = 0 point

Presence of non-purulent tracheal secretions = 1 point

Presence of purulent tracheal secretions = 2 points

Oxygenation

PaO2/FIO2, mmHg >240 or ARDS (defined as PaO2/FIO2 ≤200, PAWP ≤18 mmHg and acutebilateral infiltrates) = 0 points

PaO2/FIO2 ≤240 and no ARDS = 2 points

Pulmonary radiography

No infiltrate = 0 point

Diffuse (patchy) infiltrate = 1 point

Localized infiltrate = 2 points

Progression of pulmonary infiltrate

No radiographic progression = 0 point

Radiographic progression (after HF and ARDS excluded) = 2 points

Culture of tracheal aspirate

Pathogenic bacteria cultured in rare or few quantities or no growth = 0 point

Pathogenic bacteria cultured in moderate or heavy quantity = 1 point

Same pathogenic bacteria seen on Gram's stain, add 1 point

Total (a score of >6 was considered suggestive of pneumonia)

ARDS: acute respiratory distress syndrome; HF: heart failure; PAWP: pulmonary arterial wedge pressure.An initial score is based upon the first five variables. The last two variables are assessed on day 2 or 3.Adapted with permission from: Singh, N, Rogers, P, Atwood, CW, et al. Short-course empiric antibiotic therapyfor patients with pulmonary infiltrates in the intensive care unit: a proposed solution for indiscriminateantibiotic prescription. Am J Respir Crit Care Med 2000; 162:505. Copyright © 2002 American ThoracicSociety.


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Health & Medicine

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