Treatment of hospital-acquired, ventilator-associated, and healthcare-asso... http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilat... imipenem, meropenem, piperacillin-tazobactam, ciprofloxacin, and levofloxacin. (See Empiric treatment below.) Risk factors for multidrug resistance are discussed separately. (See "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults", section on MDR risk factors.) TREATMENT — 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 be difficult, especially those on mechanical ventilation in whom clinical, radiologic, and microbiologic findings can be due to numerous etiologies besides pneumonia. The difficulty in diagnosis may lead to overtreatment with its attendant risks of superinfection and antibiotic toxicity. (See "Clinical presentation and diagnosis of ventilator-associated pneumonia".) When therapy is given, antimicrobial selection should be based upon risk factors for MDR pathogens, including recent antibiotic therapy (if any), the resident flora in the hospital or ICU, the presence of underlying diseases, and available culture data (interpreted with care). For patients with risk factors for multidrug-resistant (MDR) pathogens, empiric broad-spectrum, multidrug therapy is recommended. Once the results of pretherapy cultures are available, therapy should be narrowed based upon the susceptibility pattern of the pathogens identified. The importance of providing appropriate therapy at the time of presentation was illustrated in a retrospective study of almost 400 patients with culture-positive HCAP who survived but remained hospitalized 48 hours after hospital admission . Mortality was significantly higher among the 107 patients who received inappropriate initial therapy compared with the 289 patients who received appropriate coverage (30 versus 18 percent); switching to an appropriate regimen did not reduce the risk of death. In a study that assessed the microbial prediction and validated the adequacy of the 2005 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines for HAP in the ICU, adherence to the guidelines resulted in more adequate treatment and a trend toward a better clinical response in patients who presented late (≥5 days) or had risk factors for drug-resistant bacteria, but did not affect mortality . The 2005 guidelines were worse than the 1996 guidelines for predicting drug-resistant bacteria; this was mostly observed for cases classified as lower risk for multidrug- resistant pathogens (ie, early onset infection without specified risk factors for resistant infection), suggesting that such patients may in fact be at risk for resistant pathogens. In a later observational study that included 303 patients at risk for MDR pathogens, 28-day mortality was higher among patients who were treated according to the ATS/IDSA guidelines compared with patients whose treatment did not comply with the guidelines (34 versus 20 percent) . The primary reason for “non-compliance” was lack of a second drug for gram-negative pathogens. Criticisms of this study include the observation that lower coverage for certain MDR pathogens occurred in the compliant group (but was not commented upon by the authors), lack of assessment of the impact of timing of antimicrobial therapy, lack of appropriate adjustment for risk of death, disregard of the impact of treatment de-escalation on the classification of compliance, and the possibility that excess mortality may have been at least partly due to toxicity when a triple regimen is used . In addition, although the authors attempted to control for higher severity of infection observed in the compliant group, the results may still have been confounded by patients in the compliant group who were at greater risk of poor outcomes at presentation. Potential messages from this study are: clinicians who are following patients and are aware of pathogen and susceptibility patterns within a specific unit may be better able to appropriately select empiric therapy based on individual clinical judgment rather than using routine combination therapy (guidelines are meant to supplement clinical judgment, not supplant judgment); the need for two-drug therapy is not necessary in many cases of gram-negative2 de 19 15/04/2011 07:30 p.m.
Treatment of hospital-acquired, ventilator-associated, and healthcare-asso... http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilat... 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 by the ATS/IDSA guidelines was associated with increased mortality in such patients . Another observational study found that lack of adherence to a VAP protocol (which included considerations of appropriate use and duration of antibiotics) resulted in longer duration of therapy, ventilation, and length of ICU stay . In a retrospective analysis of local microbiologic data on HAP pathogens from 111 consecutive patients in 2004, investigators developed institution-specific treatment guidelines in order to improve empiric antibiotic therapy . Institution guideline-directed treatment regimens were predicted to provide adequate initial therapy for >90 percent of patients who develop HAP ≥10 days after hospitalization (eg, those at greatest risk of multidrug resistant pathogens). In this institution, use of a fluoroquinolone per the national guidelines, would not have provided adequate additional antimicrobial activity for the beta-lactam resistant gram-negative bacilli (ciprofloxacin was active against <10 percent of these pathogens which were also resistant to piperacillin-tazobactam and cefepime). This study illustrates the importance of using local susceptibility data to develop treatment guidelines. The implementation of recommendations to assess a patients status 72 hours after the initiation of therapy and to discontinue antibiotics or narrow the regimen (deescalate therapy) based upon appropriate culture results may reduce the selective pressure for antimicrobial resistance. A prospective observational study of 398 intensive care unit (ICU) patients with suspected VAP found that mortality was significantly lower among patients in whom therapy was deescalated compared to those whose therapy was either escalated or unchanged (17 versus 43 and 24 percent, respectively) . The study was limited because of its observational nature; confirmation of these results awaits a randomized controlled study. In another study, deescalation was evaluated in surgical patients with septic shock in a retrospective evaluation of 138 patients with VAP . Deescalation of antimicrobial therapy occurred in 55 percent of patients who had received initial therapy effective against the identified pathogen (most common initial choice was vancomycin plus piperacillin-tazobactam). The mortality rate of patients who underwent deescalation therapy was 35 percent compared with 42 percent among patients who did not have deescalation, a difference that did not reach statistical significance. This study demonstrated that deescalation therapy did not lead to recurrent pneumonia or increased mortality in this population of critically ill surgical patients. There has been interest in the nonantibiotic antiinflammatory effects of macrolides. A randomized trial of 200 patients with sepsis and VAP showed that those who received clarithromycin (in addition to standard treatment including antibiotics) had significantly faster resolution of VAP (10 versus 15.5 days) and weaning from mechanical ventilation (16 versus 22.5 days) compared to those who received placebo . Among those who died of sepsis, time to death was significantly prolonged in those who received clarithromycin. Specific antimicrobial considerations — In critically ill patients, in those receiving antibiotics prior to the onset of pneumonia, and in institutions where these pathogens are frequent, coverage of methicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa, and antibiotic-resistant gram-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 a necessary first choice for anti-staphylococcal coverage [2,15,16], but should be discontinued if MRSA is not isolated.3 de 19 15/04/2011 07:30 p.m.
Treatment of hospital-acquired, ventilator-associated, and healthcare-asso... http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilat... An overview of the treatment of invasive MRSA infections is presented separately. (See "Treatment of invasive methicillin-resistant Staphylococcus aureus infections in adults".) Linezolid and vancomycin — Several trials have compared linezolid and vancomycin, with variable results. Two prospective, randomized trials of nosocomial pneumonia compared linezolid with vancomycin; each found no significant difference in outcomes for MRSA infections [17,18]. A subsequent open-label trial showed only a trend towards earlier microbiologic cure, clinical cure, and survival rate among patients treated with linezolid for VAP compared with those treated with vancomycin . A meta-analysis of nine randomized trials that compared linezolid with vancomycin (in seven trials) or teicoplanin (in two trials) for nosocomial pneumonia found no differences in rates of clinical cure or microbiologic eradication . In addition, no differences in clinical cure or microbiologic eradication were observed in the subgroup analysis of patients with MRSA. However, in a later randomized double-blind trial that compared linezolid to vancomycin for the treatment of hospital-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 . Linezolid was non-inferior and statistically superior to vancomycin in end of treatment clinical outcome, and microbiologic outcome at end of treatment and end of study. A retrospective study suggested that vancomycin failure might be related to suboptimal dosing . As a result, a trough level of 15 to 20 mcg/mL is often targeted . However, subsequent studies failed 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 worse outcomes in patients with HAP due to MRSA. This was suggested in a prospective cohort study of 95 patients with MRSA HCAP who were treated with vancomycin in which the targeted trough vancomycin concentration was at least four times the MIC . High MIC (≥2 mcg/mL) strains of MRSA were detected in 54 percent of patients. Despite achieving the target trough concentration, mortality was higher among patients whose MRSA strain had a high MIC than patients whose MRSA strain had a low MIC (24 versus 10 percent). In a later prospective study that included 158 patients in the ICU with HAP, VAP, or HCAP, an increase in 28-day mortality was observed in patients whose MRSA isolates had increased MICs; an increase in mortality occurred as the vancomycin MIC increased from 0.75 to 3 mcg/mL, and was present even for strains within the susceptible range . The 2005 ATS/IDSA treatment guidelines on HAP, VAP, and HCAP, and a 2009 United States pharmacy 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 the absence of prospective clinical data. PK/PD analysis has suggested that lung vancomycin AUC:MIC >400 may be difficult to achieve (particularly for isolates with MIC >1) [27-29]. Clinical data have failed to demonstrate a relationship between treatment outcome and target troughs of 15 to 20 mcg/mL . (See "Vancomycin dosing and serum concentration monitoring in adults".) The 2005 ATS/IDSA guidelines on HAP, VAP, and HCAP and the 2011 IDSA guidelines for the treatment of MRSA infections recommended either linezolid or vancomycin for infections suspected or proven to be due to MRSA [2,16]. It was noted that linezolid might be preferred in patients at risk for or with renal insufficiency in whom vancomycin is often underdosed and is associated with a risk of nephrotoxicity. Linezolid also may reduce toxin production, although the possible benefit of this has not been established [30,31]. Linezolid is particularly preferred in hospitals in which a substantial proportion of MRSA isolates have a vancomycin MIC ≥2 mcg/mL. Linezolid resistance and linezolid failure have been described rarely. An alternative to linezolid and vancomycin is clindamycin (600 mg IV or orally three times daily), provided that the isolate is known to be susceptible, although there are fewer data to supports its use . (See "Epidemiology of methicillin-resistant Staphylococcus aureus infection in adults", section on Linezolid resistance and "Treatment of invasive methicillin-resistant Staphylococcus aureus infections in adults", section on Linezolid.)4 de 19 15/04/2011 07:30 p.m.
Treatment of hospital-acquired, ventilator-associated, and healthcare-asso... http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilat... The usual doses are: Linezolid — 600 mg twice daily IV (or orally if or when the patient is able to receive oral medications). Vancomycin — 15 to 20 mg/kg (based on actual body weight) IV every 8 to 12 hours for patients with normal renal function, with a target serum trough concentration of 15 to 20 mg/L . In seriously ill patients, a loading dose of 25 to 30 mg/kg can be used to facilitate rapid attainment of the target trough concentration. (See "Vancomycin dosing and serum concentration monitoring in adults".) Telavancin — Telavancin is an intravenous semisynthetic lipoglycopeptide antibiotic that is broadly 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 . In two randomized trials (the ATTAIN studies) that included 1503 patients with HAP due to gram-positive bacteria, especially MRSA, telavancin (10 mg/kg IV daily) was noninferior to vancomycin in terms of clinical response (58.9 percent versus 59.5 percent) . Among patients with monomicrobial Staphylococcus aureus infection, the cure rates were higher in patients who received telavancin, particularly among those with an MRSA isolate with reduced susceptibility to vancomycin (MIC ≥1 mg/dL); the cure rate among patients with MRSA with reduced susceptibility to vancomycin was 87 percent in those who received telavancin versus 74 percent in those who received vancomycin. The cure rates were for all patients with monomicrobial MRSA infection regardless of vancomycin MIC were 81.8 percent for telavancin and 74.1 percent for vancomycin (95% CI -3.5-19.3). These results suggest that telavancin is particularly useful for patients with MRSA isolates with a vancomycin MIC ≥1 mg/dL. However, telavancin has not been approved 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 of serious adverse events and/or adverse events leading to drug discontinuation was higher in the telavancin group in both trials (31 versus 26 percent and 8 versus 5 percent, respectively). A significant 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 MRSA pneumonia, but none of the following agents can be recommended: Daptomycin cannot be used to treat pneumonia because it does not achieve sufficiently high concentrations in the respiratory tract. Data are limited on the use of quinupristin-dalfopristin. In a randomized trial of HAP that included 38 patients with MRSA pneumonia, there was a nonsignificant lower rate of clinical success with quinupristin-dalfopristin compared with vancomycin (31 versus 44 percent) and a higher rate of adverse effects that led to discontinuation of therapy . Ceftaroline is a broad-spectrum cephalosporin with activity against MRSA, which has been approved for CAP, but not for staphylococcal pneumonia . Tigecycline is a broad-spectrum antibiotic with activity against MRSA. In September 2010 the FDA issued a safety announcement regarding increased mortality risk associated with the use of tigecycline compared with that of other drugs that was observed in a pooled analysis of 13 trials . The increased risk was seen most clearly in patients treated for HAP, particularly VAP. Gram-negative pathogens — Although combination antimicrobial therapy for HAP, VAP, and HCAP due to gram-negative pathogens (especially Pseudomonas) is commonly administered, there is5 de 19 15/04/2011 07:30 p.m.
Treatment of hospital-acquired, ventilator-associated, and healthcare-asso... http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilat... no conclusive evidence to support this practice. The best rationale for the use of combination therapy is to provide a greater spectrum of activity when there is risk for MDR pathogens (eg, if the pathogen is resistant to one agent it may be susceptible to the other) . Other commonly cited reasons for combination therapy include the potential for synergistic efficacy as well as the potential to reduce the emergence of resistance. However, it is not clear that two agents offer improved outcomes for treating gram-negative pneumonia. A meta-analysis and a subsequent large, randomized trial suggested that monotherapy of VAP was as effective as combination therapy [37,38]. However, the percentage of MDR organisms was low in the trials reviewed in the meta-analysis and in the randomized trial. In addition, the randomized trial excluded patients known to be colonized with Pseudomonas or MRSA, and found that combination versus monotherapy was associated with improved adequacy of initial antibiotics and microbiological eradication of infecting organisms in patients who had infection due to Pseudomonas, Acinetobacter, and MDR gram-negative bacilli . Thus, it is difficult to extrapolate the efficacy of monotherapy to ICUs with high incidences of these pathogens. In another study of patients hospitalized in an ICU due to trauma, 84 patients with VAP caused by Pseudomonas were treated with monotherapy (cefepime 2 g intravenously every 8 hours); this resulted in microbiologic eradication (based on repeat BAL showing <103 organisms/mL) in 94 percent of patients with no recurrences, suggesting that combination therapy is unnecessary when the initial antimicrobial therapy is active against the isolate . In ICU settings in which extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are found, cephalosporins should be avoided as monotherapy, due to the selection of resistant organisms when these agents are used . 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 have been recently treated with glucocorticoids may require coverage for Legionella spp (azithromycin or a fluoroquinolone). HAP and VAP due to Legionella spp are also more common in hospitals where the organism is present in the hospital water supply. (See "Epidemiology and pathogenesis of Legionella infection" and "Treatment and prevention of Legionella infection".) Anaerobes — Patients who have aspirated or had recent abdominal surgery may warrant coverage for anaerobes (clindamycin, beta-lactam-beta-lactamase inhibitor, or a carbapenem). (See "Aspiration pneumonia in adults" and "Anaerobic bacterial infections", section on Pleuropulmonary infections.) Empiric treatment — We generally agree with the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines for the management of HAP, VAP, or HCAP . These guidelines 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 regimens for 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). When the patient is able to take oral medications, either agent may be administered orally at the same dose as that used for IV administration. Ertapenem (1 g intravenously daily).6 de 19 15/04/2011 07:30 p.m.
Treatment of hospital-acquired, ventilator-associated, and healthcare-asso... http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilat... Choice of a specific agent for empiric therapy should be based on knowledge of the prevailing pathogens (and susceptibility patterns) within the healthcare setting. If there is concern for gram-negative bacilli resistant to the above options (eg, Enterobacter spp, Serratia spp, Pseudomonas spp) based upon microbiologic data at the specific institution, we feel that it is reasonable to initiate piperacillin-tazobactam (4.5 g IV every six hours) or another agent (eg, cefepime or a carbapenem) as monotherapy for patients without known risk factors for MDR bacteria provided that the institution’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 ≥5 days, high frequency of antibiotic resistance in the community or in the specific hospital unit, immunosuppressive disease and/or therapy, and presence of risk factors for HCAP. (See "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults", section on MDR risk factors.) For patients with known MDR risk factors, we recommend empiric combination therapy including: ONE of the following: Antipseudomonal cephalosporin such as cefepime (2 g intravenously every eight hours) or ceftazidime (2 g intravenously every 8 hours) Antipseudomonal carbapenem such as imipenem (500 mg intravenously every six hours) or meropenem (1 g intravenously every eight hours) or doripenem (500 mg intravenously every eight hours; administered over one hour for HAP or HCAP, administered over four hours for VAP) [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 receive cephalosporins (especially third-generation cephalosporins) or carbapenems. If there is a history of a mild reaction to penicillin (not an IgE-mediated reaction, Stevens Johnson syndrome or toxic epidermal necrolysis), it is reasonable to administer a cephalosporin or carbapenem using a simple graded challenge (eg, give 1/10 of dose, observe closely for 1 hour, then give remaining 9/10 of dose, observe closely for 1 hour). Skin testing is indicated in some situations. If a skin test is positive or if there is significant concern to warrant avoidance of a cephalosporin or carbapenem, aztreonam (2 g intravenously every six to eight hours) is recommended. Indications and strategies for skin testing are reviewed elsewhere. (See "Penicillin-allergic patients: Use of cephalosporins, carbapenems, and monobactams".) Patients with past allergic reactions to cephalosporins may also be treated with aztreonam, with the possible exception of those allergic to ceftazidime. Ceftazidime and aztreonam have similar side chain groups, and cross reactivity between the two drugs is variable. The prevalence of cross-sensitivity has been estimated at <5 percent of patients, based upon limited data. Patients with past reactions to ceftazidime that were life-threatening or suggestive of anaphylaxis (involving urticaria, bronchospasm, and/or hypotension) should not be given aztreonam unless evaluated by an allergy specialist. In contrast, a reasonable approach in those with mild past reactions to ceftazidime (eg, uncomplicated maculopapular rash) would involve informing the patient of the low risk of cross-reactivity and administering aztreonam with a graded challenge (1/100, 1/10, full dose, each separated by 1 hour of observation). (See "Cephalosporin-allergic patients: Subsequent use of cephalosporins and related antibiotics", section on Use of carbapenems and monobactams.)7 de 19 15/04/2011 07:30 p.m.
Treatment of hospital-acquired, ventilator-associated, and healthcare-asso... http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilat... PLUS one of the following: Antipseudomonal fluoroquinolone, preferred regimen if Legionella is likely, such as ciprofloxacin (400 mg intravenously every eight hours) or levofloxacin (750 mg intravenously daily). These agents may be administered orally when the patient is able to take oral medications. The dose of levofloxacin is the same when given intravenously and orally, while the dose of ciprofloxacin is 750 mg orally twice daily. Aminoglycoside such as gentamicin or tobramycin (7 mg/kg intravenously once daily) or amikacin (20 mg/kg intravenously once daily); once daily dosing is only appropriate for patients with normal renal function. A single serum concentration should be obtained 6 to 14 hours after the first dose, and the dose should be adjusted as needed based upon the following nomogram (figure 1). The aminoglycoside can be stopped after five to seven days in responding patients. (See "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 high incidence of MRSA locally): Linezolid (600 mg intravenously every 12 hours; may be administered orally when the patient is able to take oral medications) Vancomycin (15 to 20 mg/kg [based on actual body weight] intravenously every 8 to 12 hours for patients with normal renal function, with a target serum trough concentration of 15 to 20 mg/L.) In seriously ill patients, a loading dose of 25 to 30 mg/kg can be used to facilitate rapid attainment of the target trough concentration. (See "Vancomycin dosing and serum concentration monitoring in adults".) If patients have recently received antibiotics, empiric therapy should generally be with a drug from a different class since earlier treatment may have selected pathogens resistant to the initial class. Because of increasing resistance of pathogens associated wth VAP, HAP, and HCAP, one potential strategy to enhance the antimicrobial potential of a given agent is to optimize the pharmacodynamic effect. Since the beta-lactams are associated with optimal outcomes when the level of the drug is above the minimum inhibitory concentration (MIC) for the pathogen for an appropriate percent of the dosing interval, this effect can potentially be improved with prolonged infusion of the antimicrobial. This has been demonstrated with the use of a 3 to 4 hour infusion of piperacillin-tazobactam, cefepime, or the carbapenems for the treatment of VAP due to gram-negative bacilli with higher MICs than the usual breakpoints for susceptibility [44-46]. Aerosolized antibiotics — Aerosolized colistin, polymyxin, or aminoglycosides may be considered as potential additional antibiotics in patients with multidrug-resistant (MDR) gram-negative bacilli [47-51]. 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 . In a randomized trial that included 100 patients with VAP due to gram-negative bacilli (predominantly MDR Acinetobacter baumannii and/or Pseudomonas aeruginosa), patients who were treated with a combination of systemic antibiotics and nebulized colistin had a higher rate of favorable microbiologic outcome compared with patients who were treated with systemic antibiotics alone (microbiologic eradication or presumed eradication 61 versus 38 percent), but there was no differences in clinical outcome (51 versus 53 percent) . In a retrospective case-control study that included 86 patients with VAP due to MDR gram-negative bacilli (predominantly A. baumannii) treated with a combination of IV and aerosolized colistin compared with IV colistin alone, there was only a trend towards improved rates of clinical8 de 19 15/04/2011 07:30 p.m.
Treatment of hospital-acquired, ventilator-associated, and healthcare-asso... http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilat... cure, pathogen eradication, and mortality in the patients who received aerosolized and IV colistin . However, this study may have been underpowered to show a benefit, adequate doses of aerosolized colistin may not have been used, and the difficulty in diagnosing VAP may have biased the results (ie, if patients without VAP were included) . (See "Colistin: An overview".) Antibiotic regimens — When the etiology of HAP, VAP, or HAP has been identified based upon reliable microbiologic methods and there is no laboratory or epidemiologic evidence of coinfection, treatment regimens should be simplified and directed to that pathogen. The choice of specific agents will be dictated by the results of susceptibility testing. It is crucial to avoid broad-spectrum therapy once 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 with bacteriologically confirmed VAP . The endotracheal aspirates whose Gram stain identified a microbe were randomly assigned to either rapid testing — the endotracheal aspirates were directly applied to antibiotic susceptibility test strips — or standard culture. Rapid testing more quickly identified susceptibility than standard culture (1.4 versus 4.2 days). In addition, patients were more likely to receive appropriate antimicrobial therapy, have fewer days of antimicrobial therapy, and have more rapid resolution of fever. Antimicrobial selection based on this strategy has never been compared to that based on a Gram stain or local susceptibility patterns. Nor has it been compared to empiric broad spectrum therapy based on MDR risk factors. Until further clinical studies are performed, this approach cannot be recommended in the routine management of HAP. Patients who are improving clinically, are hemodynamically stable, and able to take oral medications can be switched to oral therapy. If the pathogen has been identified, the choice of antibiotic for oral therapy is based upon the susceptibility profile for that organism. If a pathogen is not identified, the choice of antibiotic for oral therapy is either the same antibiotic as the intravenous antibiotic, or an agent in the same drug class, which achieves adequate lung penetration when administered orally. Duration — The duration of therapy should be based upon the clinical response. The standard duration of therapy in the past was 14 to 21 days in part because of a concern for difficult to treat pathogens (eg, Pseudomonas spp). However, a shorter course could significantly reduce the amount of antimicrobial drugs used in hospitals where the emergence of resistant pathogens is a concern. The following studies found that short course treatment is effective: A prospective, randomized, multicenter trial of 401 patients with VAP compared outcomes following eight versus 15 days of treatment . All patients underwent bronchoscopy for quantitative cultures and were empirically treated with a combination of an antipseudomonal beta-lactam plus either an aminoglycoside or a fluoroquinolone. Investigators were encouraged to change the regimen to a pathogen-directed treatment based upon culture results. There was no significant difference between patients treated for eight compared to 15 days in mortality or recurrent infection at 28 days; as expected, patients treated for eight days had more antibiotic-free days. Among patients who developed recurrent infections, MDR pathogens were isolated less frequently in those treated for eight days (42 versus 62 percent for those treated for 15 days). However, patients with VAP caused by nonfermenting gram-negative bacilli (eg, Pseudomonas spp) had a higher pulmonary infection recurrence rate when treated for eight versus 15 days (41 versus 25 percent with 15 days of treatment), although mortality was not different. In a subanalysis of 125 patients who had S. aureus isolated as a pathogen, there was no significant difference based on treatment duration (8 or 15 days) for 28-day mortality or VAP recurrence; this was also the case when only VAP caused by MRSA was considered .9 de 19 15/04/2011 07:30 p.m.
Treatment of hospital-acquired, ventilator-associated, and healthcare-asso... http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilat... An ICU study evaluated clinical outcomes, including duration of treatment, following implementation of a clinical guideline for the treatment of VAP compared to historical controls (patients with VAP treated prior to implementation of the guideline) . The clinical guideline group had a shorter duration of antimicrobial therapy and was less likely to have a recurrent episode of VAP. A prospective study evaluated the ability of the Clinical Pulmonary Infection Score (CPIS) to determine the duration of therapy for ICU patients with new pulmonary infiltrates (table 1) . Patients were included in the study if they had new-onset pulmonary infiltrates and a CPIS <6. The patients were randomized to either a control group (standard therapy) or to the experimental group (intravenous ciprofloxacin 400 mg every eight hours for three days). The CPIS was reevaluated at three days and in patients with a CPIS <6, antibiotics were discontinued in the experimental group. If the CPIS was >6, ciprofloxacin was continued or antibiotics were changed based upon the microbiologic results. Significantly more patients in the control group received antibiotics beyond three days compared to those in the experimental group (90 compared with 28 percent in the experimental group). In addition to reduced antibiotic use, the experimental group was less likely to have colonization/infection with resistant organisms (15 compared with 35 percent of patients in the control group) and had a trend towards lower mortality. In a separate prospective cohort study of 312 patients who were treated with empiric antibiotics in an ICU, investigators sought to determine if the CPIS score could be used to decrease the amount or duration of antibiotic therapy . The CPIS score was compared to the assessment of a "pneumonia committee" (PC), which was comprised of investigators and clinicians experienced in the management of ICU patients. The CPIS score had a reasonable predictive value, but assessment by the PC and the CPIS score often diverged when the CPIS score was six or less. Half of the empiric antibiotic use was for patients in whom pneumonia was suspected but the PC or the CPIS score indicated that pneumonia was unlikely. Recommendations — Based upon these data, we recommend that all patients with HAP, VAP, or HCAP should be evaluated after 72 hours of initial empiric antimicrobial therapy. If the patient has improved after 72 hours, and a pathogen is isolated, antimicrobial therapy should be changed to a pathogen-directed regimen based upon the susceptibility pattern. Therapy should generally be continued to complete a total course of 7 days; we would treat up to 15 days if P. aeruginosa were the etiologic agent, and for up to 21 days for MRSA, depending upon the extent of infection and clinical course . Based on the study of S. aureus VAP discussed above, 8 days of therapy may be adequate if there is good clinical response early in the course of appropriate therapy . If the patient has improved and no pathogen is identified, we would narrow the regimen, discontinuing therapy for Pseudomonas spp and MRSA. If the patient has not improved at 72 hours and a resistant pathogen is identified, therapy should be changed to pathogen-directed treatment based upon the susceptibility pattern. In addition, failure to improve at 72 hours should prompt a search for infectious complications, other diagnoses, or other sites of infection. PROGNOSIS — Despite high absolute mortality rates in HAP patients, the mortality attributable to the infection is difficult to gauge. Many studies have found that HAP is associated with significant excess risk of death. However, many of these critically ill patients die from their underlying disease and not from pneumonia. Case-control studies estimate that the all-cause mortality rate for HAP and VAP is in the range of 33 to 50 percent .10 de 19 15/04/2011 07:30 p.m.
Treatment of hospital-acquired, ventilator-associated, and healthcare-asso... http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilat... In a retrospective cohort study that used a large inpatient database, mortality rates were 10 percent in patients with CAP, 19 percent in patients with HAP, 20 percent in patients with HCAP, and 29 percent in patients with VAP . In another study, HCAP was associated with a higher in-hospital mortality rate than CAP (18 versus 7 percent) . Variables associated with increased mortality include [2,62-69]: Serious illness at the time of diagnosis (eg, high APACHE score, shock, coma, respiratory failure, ARDS) Bacteremia Severe underlying comorbid disease Infection caused by an organism associated with multidrug resistance (Pseudomonas aeruginosa, Acinetobacter spp) Multilobar, cavitating, or rapidly progressive infiltrates on lung imaging Delay in the institution of effective antimicrobial therapy The Acute Physiology and Chronic Health Evaluation II (APACHE II) score has been considered the best system to predict mortality in patients with VAP. A group of investigators has developed a simpler scoring system to predict mortality: the IBMP-10 score based on the presence of immunodeficiency; blood pressure <90 mm Hg systolic; multilobar infiltrates; platelet count <100,000; and >10 days in hospital prior to onset of VAP . Based on a point for each variable, the mortality rates for each score were: 0 to 2 percent; 1 to 9 percent; 2 to 24 percent; 3 to 50 percent; 4 to 67 percent. In a preliminary analysis, the authors indicated that this five-point system was comparable to APACHE-II in its ability to predict mortality in such patients. SUMMARY AND RECOMMENDATIONS The choice of the antibiotic treatment regimen for HAP, VAP, and HCAP should be influenced by the patients recent antibiotic therapy (if any), the resident flora in the hospital or intensive care unit, the presence of underlying diseases, available culture data (interpreted with care), and whether the patient is at risk for MDR pathogens. (See Treatment above.) For empiric coverage of HAP, VAP, and HCAP in patients with no known risk factors for multidrug-resistant (MDR) pathogens, we suggest one of the following intravenous antibiotic regimens: Ceftriaxone (2 g intravenously daily) Ampicillin-sulbactam (3 g intravenously every six hours) Levofloxacin (750 mg intravenously daily) or moxifloxacin (400 mg intravenously daily). When the patient is able to take oral medications, either agent may be administered orally at the same dose as that used for IV administration. Ertapenem (1 g intravenously daily) . Choice of a specific agent for empiric therapy should be based upon knowledge of the prevailing pathogens (and susceptibility patterns) within the healthcare setting. If there is concern for gram-negative bacilli resistant to the above options (eg, Enterobacter spp, Serratia spp, Pseudomonas spp) based upon microbiologic data at the specific institution, we feel that it is reasonable to initiate piperacillin-tazobactam (4.5 g IV every six hours) or another agent (eg, cefepime or a carbapenem) as monotherapy for patients without known11 de 19 15/04/2011 07:30 p.m.
Treatment of hospital-acquired, ventilator-associated, and healthcare-asso... http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilat... risk factors for MDR bacteria provided that the institution’s susceptibility data support in vitro activity. (See No known MDR risk factors above.) For empiric coverage of HAP, VAP, and HCAP in patients with known risk factors for MDR pathogens, we recommend empiric combination therapy including: One of the following: Antipseudomonal cephalosporin such as cefepime (2 g intravenously every eight hours) or ceftazidime (2 g intravenously every 8 hours) Antipseudomonal carbapenem such as imipenem (500 mg intravenously every six hours) or meropenem (1 g intravenously every eight hours) or doripenem (500 mg intravenously every eight hours; administered over one hour for HAP or HCAP, administered over four hours for VAP) Piperacillin-tazobactam (4.5 g intravenously every six hours) For patients who are allergic to penicillin, the type and severity of reaction should be assessed. If a skin test is positive or if there is significant concern to warrant avoidance of a cephalosporin or carbapenem, aztreonam (2 g intravenously every six to eight hours) is recommended. Patients with past allergic reactions to cephalosporins may also be treated with aztreonam, with the possible exception of those allergic to ceftazidime. Ceftazidime and aztreonam have similar side chain groups, and cross reactivity between the two drugs is variable. The prevalence of cross-sensitivity has been estimated at <5 percent of patients, based upon limited data. Patients with past reactions to ceftazidime that were life-threatening or suggestive of anaphylaxis (involving urticaria, bronchospasm, and/or hypotension) should not be given aztreonam unless evaluated by an allergy specialist. In contrast, a reasonable approach in those with mild past reactions to ceftazidime (eg, uncomplicated maculopapular rash) would involve informing the patient of the low risk of cross-reactivity and administering aztreonam with a graded challenge (1/100, 1/10, full dose, each separated by 1 hour of observation). (See "Cephalosporin-allergic patients: Subsequent use of cephalosporins and related antibiotics", section on Use of carbapenems and monobactams.) PLUS one of the following: Antipseudomonal fluoroquinolone, such as ciprofloxacin (400 mg intravenously every eight hours) or levofloxacin (750 mg intravenously daily). Aminoglycoside such as gentamicin or tobramycin (7 mg/kg intravenously once daily ) or amikacin (20 mg/kg intravenously once daily ). The aminoglycoside can be stopped after five to seven days in responding patients. PLUS one of the following (if MRSA is suspected, there are MRSA risk factors, or there is a high incidence of MRSA locally): Linezolid (600 mg intravenously every 12 hours; may be administered orally when the patient is able to take oral medications) Vancomycin (15 to 20 mg/kg [based on actual body weight] intravenously every 8 to 12 hours for patients with normal renal function, with a target serum trough concentration of 15 to 20 mg/L.) In seriously ill patients, a loading dose of 25 to 30 mg/kg can be used to facilitate rapid attainment of the target trough concentration. (See Known MDR risk factors above.)12 de 19 15/04/2011 07:30 p.m.
Treatment of hospital-acquired, ventilator-associated, and healthcare-asso... http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilat... Critical to reducing overuse of antimicrobials, "deescalation" of therapy should be considered after 48 to 72 hours of initial therapy, and should be based upon the results of initial cultures and the clinical response of the patient. (See Duration above.) The duration of therapy should be based upon the clinical response. A short duration of therapy (eg, seven days) is sufficient for most patients with uncomplicated HAP, VAP, or HCAP who have had a good clinical response. (See Duration above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Guideline for prevention of nosocomial pneumonia. Centers for Disease Control and Prevention. Respir Care 1994; 39:1191. 2. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171:388. 3. Paterson DL. The epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species. Clin Infect Dis 2006; 43 Suppl 2:S43. 4. Meduri GU, Johanson WG Jr. International Consensus Conference: clinical investigation of ventilator-associated pneumonia. Introduction. Chest 1992; 102:551S. 5. Zilberberg MD, Shorr AF, Micek ST, et al. Antimicrobial therapy escalation and hospital mortality among patients with health-care-associated pneumonia: a single-center experience. Chest 2008; 134:963. 6. Ferrer M, Liapikou A, Valencia M, et al. Validation of the American Thoracic Society-Infectious Diseases Society of America guidelines for hospital-acquired pneumonia in the intensive care unit. Clin Infect Dis 2010; 50:945. 7. Kett DH, Cano E, Quartin AA, et al. Implementation of guidelines for management of possible multidrug-resistant pneumonia in intensive care: an observational, multicentre cohort study. Lancet Infect Dis 2011. 8. Ewig S. Nosocomial pneumonia: de-escalation is what matters. Lancet Infect Dis 2011. 9. Venditti M, Falcone M, Corrao S, et al. Outcomes of patients hospitalized with community- acquired, health care-associated, and hospital-acquired pneumonia. Ann Intern Med 2009; 150:19. 10. Nachtigall I, Tamarkin A, Tafelski S, et al. Impact of adherence to standard operating procedures for pneumonia on outcome of intensive care unit patients. Crit Care Med 2009; 37:159. 11. Beardsley JR, Williamson JC, Johnson JW, et al. Using local microbiologic data to develop institution-specific guidelines for the treatment of hospital-acquired pneumonia. Chest 2006; 130:787. 12. Kollef MH, Morrow LE, Niederman MS, et al. Clinical characteristics and treatment patterns among patients with ventilator-associated pneumonia. Chest 2006; 129:1210. 13. Eachempati SR, Hydo LJ, Shou J, Barie PS. Does de-escalation of antibiotic therapy for ventilator-associated pneumonia affect the likelihood of recurrent pneumonia or mortality in critically ill surgical patients? J Trauma 2009; 66:1343. 14. Giamarellos-Bourboulis EJ, Pechère JC, Routsi C, et al. Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia. Clin Infect Dis 2008; 46:1157. 15. Rubinstein E, Kollef MH, Nathwani D. Pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2008; 46 Suppl 5:S378. 16. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society13 de 19 15/04/2011 07:30 p.m.
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