Chest physiotherapy for the prevention of ventilator-associated pneumonia: A meta-analysis.

BACKGROUND: Ventilator-associated pneumonia (VAP) remains a frequent and severe complication in mechanically ventilated patients. We undertook a meta-analysis to evaluate the efficacy of chest physiotherapy (CPT) for the prevention of VAP. METHODS: A systematic literature search of PubMed and Embase databases were searched up until November 25, 2018 for published studies of mechanically ventilated patients comparing CPT with controls and reporting on the occurrence of VAP. Two authors independently selected studies and abstracted data on study quality and outcomes. We pooled data using random-effects models. RESULTS: A total of 6 randomized (n = 704) controlled trials were identified. CPT did not significantly reduce the incidence of VAP (risk ratio = 1.02; 95% confidence interval, 0.82-1.26; P = .87), but reduced hospital mortality (risk ratio = 0.68; 95% confidence interval, 0.48-0.95; P = .02). No significant differences were observed regarding intensive care unit mortality, length of intensive care unit stay, and duration of mechanical ventilation. CONCLUSIONS: CPT may not significantly reduce the incidence of VAP and alter other important clinical outcomes in adult patients receiving mechanical ventilation. However, the results should be interpreted cautiously owing to the heterogeneity and the limited trials. Further large-scale, well-designed randomized controlled trials are needed.

Healthcare-Associated Pneumonia and Hospital-Acquired Pneumonia: Bacterial Aetiology, Antibiotic Resistance and Treatment Outcomes: A Study From North India.

BACKGROUND: Data regarding the comparative profiling of HCAP and HAP from developing countries like India are scant. We set out to address the microbial aetiology, antibiotic resistance and treatment outcomes in patients with HCAP and HAP. METHODS: 318 consenting patients with HCAP (n = 165, aged 16-90 years; median 60 years; 97 males) or HAP (n = 153; aged 16-85 years; median 45 years; 92 males) presenting to a tertiary care hospital in North India from 2013 to 2015 were prospectively recruited for the study. Data on patient characteristics, microbial aetiology, APACHE II scores, treatment outcomes and mortality were studied. Clinical outcomes were compared with various possible predictors employing logistic regression analysis. RESULTS: Patients in HCAP had more comorbidity. Escherichia coli (30, 18%) and Acinetobacter baumannii (62, 41%) were the most commonly isolated bacteria in HCAP and HAP, respectively. Multidrug-resistant bacteria were isolated more frequently in HCAP, only because the incidence of extensively drug-resistant bacteria was markedly high in HAP (p = 0.00). The mean APACHE II score was lower in HCAP (17.55 ± 6.406, range 30) compared to HAP (19.74 ± 8.843, range 37; p = 0.013). The length of stay ≥ 5 days (p = 0.036) and in-hospital mortality was higher in HAP group (p = 0.002). The most reliable predictors of in-hospital mortality in HCAP and HAP were APACHE II score ≥ 17 (OR = 14, p = 0.00; HAP: OR = 10.8, p = 0.00), and septic shock (OR = 4.5, p = 0.00; HAP: OR = 6.9, p = 0.00). CONCLUSION: The patient characteristics in HCAP, treatment outcomes, bacterial aetiology, and a higher incidence of antibiotic-resistant bacteria, suggest that HCAP although not as severe as HAP, can be grouped as a separate third entity.

The clinical significance of pneumonia in patients with respiratory specimens harbouring multidrug-resistant Pseudomonas aeruginosa: a 5-year retrospective study following 5667 patients in four general ICUs.

Pseudomonas aeruginosa is the leading cause of pneumonia in intensive care units (ICUs), with multidrug-resistant (MDR) strains posing a serious threat. The aim of this study was to assess the clinical relevance of MDR Pseudomonas isolates in respiratory clinical specimens. A 5-year retrospective observational study in four medical-surgical ICUs from a referral hospital was carried out. Of 5667 adults admitted to the ICU, 69 had MDR-PA in respiratory samples: 31 were identified as having pneumonia (HAP/VAP): 21 ventilator-associated pneumonia (VAP) and ten hospital-acquired pneumonia (HAP). Twenty-one (67.7%) adults with MDR-PA HAP/VAP died after a median of 4 days (18 of the 21 deaths within 8 days), compared with one (2.6%) without pneumonia at day 8. In a Cox proportional regression model, MDR-PA pneumonia was an independent variable [adjusted hazard ratio (aHR) 5.92] associated with 30-day ICU mortality. Most strains (85.1%) were susceptible to amikacin and colistin. Resistance to beta-lactams (third-generation cephalosporins and piperacillin-tazobactam) ranged from 44.1% to 45.3%. Meropenem showed poor overall activity (MIC[50/90] 16/32 mg/dL), with 47.0% having a minimum inhibitory concentration (MIC) breakpoint >8 mg/L. Twenty-four (77.4%) HAP/VAP episodes received inappropriate empirical therapy. Although empirical combination therapy was associated with less inappropriate therapy than monotherapy (16.7% vs. 88.3%, p < 0.01), there was no difference in survival (30% vs. 33.3%, p = 0.8). Pneumonia was identified in one-third of adult ICU patients harbouring MDR-PA in respiratory clinical specimens. These patients have a 6-fold risk of (early) death compared to ventilator-associated tracheobronchitis (VAT) and respiratory colonisation. New antibiotics and adjuvant therapies are urgently needed to prevent and treat MDR-PA HAP/VAP.

Patterns of antimicrobial resistance in intensive care unit patients: a study in Vietnam.

BACKGROUND: Antimicrobial resistance has emerged as a major concern in developing countries. The present study sought to define the pattern of antimicrobial resistance in ICU patients with ventilator-associated pneumonia. METHODS: Between November 2014 and September 2015, we enrolled 220 patients (average age ~ 71 yr) who were admitted to ICU in a major tertiary hospital in Ho Chi Minh City, Vietnam. Data concerning demographic characteristics and clinical history were collected from each patient. The Bauer-Kirby disk diffusion method was used to detect the antimicrobial susceptibility. RESULTS: Antimicrobial resistance was commonly found in ceftriaxone (88%), ceftazidime (80%), ciprofloxacin (77%), cefepime (75%), levofloxacin (72%). Overall, the rate of antimicrobial resistance to any drug was 93% (n = 153/164), with the majority (87%) being resistant to at least 2 drugs. The three commonly isolated microorganisms were Acinetobacter (n = 75), Klebsiella (n = 39), and Pseudomonas aeruginosa (n = 29). Acinetobacter baumannii were virtually resistant to ceftazidime, ceftriaxone, piperacilin, imipenem, meropenem, ertapenem, ciprofloxacin and levofloxacin. High rates (>70%) of ceftriaxone and ceftazidime-resistant Klebsiella were also observed. CONCLUSION: These data indicated that critically ill patients on ventilator in Vietnam were at disturbingly high risk of antimicrobial resistance. The data also imply that these Acinetobacter, Klebsiella, and Pseudomonas aeruginosa and multidrug resistance pose serious therapeutic problems in ICU patients. A concerted and systematic effort is required to rapidly identify high risk patients and to reduce the burden of antimicrobial resistance in developing countries.

Antibiotic de-escalation for bloodstream infections and pneumonia: systematic review and meta-analysis.

Antibiotic de-escalation is an appealing strategy in antibiotic stewardship programmes. We aimed to assess its safety and effects using a systematic review and meta-analysis. We included randomized controlled trials (RCTs) and observational studies assessing adults with bacteraemia, microbiologically documented pneumonia or severe sepsis, comparing between antibiotic de-escalation and no de-escalation. De-escalation was defined as changing an initially covering antibiotic regimen to a narrower spectrum regimen based on antibiotic susceptibility testing results within 96 hours. The primary outcome was 30-day all-cause mortality. A search of published articles and conference proceedings was last updated in September 2015. Crude and adjusted ORs with 95% CI were pooled in random-effects meta-analyses. Sixteen observational studies and three RCTs were included. Risk of bias related to confounding was high in the observational studies. De-escalation was associated with fewer deaths in the unadjusted analysis (OR 0.53, 95% CI 0.39-0.73), 19 studies, moderate heterogeneity. In the adjusted analysis there was no significant difference in mortality (adjusted OR 0.83, 95% CI 0.59-1.16), 11 studies, moderate heterogeneity and the RCTs showed non-significant increased mortality with de-escalation (OR 1.73, 95% 0.97-3.06), three trials, no heterogeneity. There was a significant unadjusted association between de-escalation and survival in bacteraemia/severe sepsis (OR 0.45, 95% CI 0.30-0.67) and ventilator-associated pneumonia (OR 0.49, 95% CI 0.26-0.95), but not with other pneumonia (OR 0.97, 95% CI 0.45-2.12). Only two studies reported on the emergence of resistance with inconsistent findings. Observational studies suggest lower mortality with antibiotic susceptibility testing-based de-escalation for bacteraemia, severe sepsis and ventilator-associated pneumonia that was not demonstrated in RCTs.

[THE UTILITY OF BRONCHOSCOPY IN INTENSIVE CARE UNIT PATIENTS WITH VENTILATOR ASSOCIATED PNEUMONIA].

BACKGROUND: Ventilator associated pneumonia (VAPI is a common complication leading to lengthier hospitalizations and higher mortality. Prompt adequate initial antibiotic coverage is the crucial issue affecting survival. Currently, there is no gold standard diagnostic test. No conclusive data regarding the benefit of bronchoscopy exists in the literature reviewed. AIM: This study aims to evaluate the change of prognosis for patients who developed VAP, following a positive culture from bronchoalveolar lavage (BAL). DESIGN: This is a retrospective cohort study. SETTING: General intensive care unit in a tertiary university healthcare center. PARTICIPANTS: All patients who were admitted to Surgical ICU and developed VAP and who then underwent diagnostic bronchoscopy with BAL between the period 01/02/2007 - 31/02/2011. MEASUREMENTS AND RESULTS: A total of 66 patients who were admitted to the ICU, developed VAP and underwent bronchoscopy while ventilated; 30 patients were excluded. The positive BAL culture group was compared to the negative BAL culture group; there was no difference between demographic and clinical characteristics, mortality rates (for 30 days) or therapy change between the two groups. No complications were reported regarding the bronchoscopy procedure. CONCLUSIONS: Our findings demonstrate that performing y a diagnostic bronchoscopy with BAL does not improve the prognosis of patients with VAP. Furthermore, expanded prospective studies will be needed to conclude regarding its benefit in diagnosis and subsequent rectifying of therapy.

Effectiveness and safety of high-dose tigecycline-containing regimens for the treatment of severe bacterial infections.

Here we review the effectiveness and safety of high-dose tigecycline (200mg daily). A systematic search was performed in PubMed and Scopus databases as well as of abstracts presented at scientific conferences. Eight studies (263 patients; 58% critically ill) were included, comprising one randomised controlled trial (RCT), four non-randomised cohorts and three case reports. Klebsiella pneumoniae was the most commonly isolated pathogen (reported in seven studies). In the RCT, response in the clinically evaluable patients was 85.0% (17/20) in the 100mg every 12h (q12h) group and 69.6% (16/23) in the 75mg q12h group (P=0.4). More episodes of diarrhoea, treatment-related nausea and vomiting developed in the high-dose group (14.3% vs. 2.8%, 8.6% vs. 2.8% and 5.7% vs. 2.8%, respectively; P>0.05 for all comparisons). Three (8.6%) and 7 (19.6%) patients died in the 200mg and 150mg daily dose groups, respectively. The cohort studies enrolled patients with severe infections, including ventilator-associated pneumonia and complicated intra-abdominal infections. Mortality with high-dose tigecycline (100mg q12h) in the cohort studies ranged from 8.3% to 26%; mortality in the low-dose groups (50mg q12h) ranged from 8% to 61% and depended on the severity of the underlying infection. There are limited available data regarding the effectiveness and safety of high-dose tigecycline. Most of the data come from critically ill patients with difficult-to-treat infections. Pharmacokinetic/pharmacodynamic properties of tigecycline suggest that high-dose regimens may be more effective than low-dose regimens. Candidates for administration of high-dose tigecycline should be also defined.

In vivo efficacy of biapenem with ME1071, a novel metallo-ß-lactamase (MBL) inhibitor, in a murine model mimicking ventilator-associated pneumonia caused by MBL-producing Pseudomonas aeruginosa.

ME1071, a maleic acid derivative, is a novel, specific inhibitor of metallo-ß-lactamases (MBLs). In vitro, ME1071 can potentiate the activity of carbapenems against MBL-producing Pseudomonas aeruginosa. To confirm the clinical efficacy of ME1071 in ventilator-associated pneumonia (VAP) caused by MBL-producing P. aeruginosa, a mouse model that mimics VAP by placement of a plastic tube in the bronchus was used. Biapenem (100 mg/kg) or ME1071 plus biapenem (each 100 mg/kg) was administered intraperitoneally every 12 h beginning at 12 h after inoculation. Survival was evaluated over 7 days. At 30 h post infection, mice were sacrificed and the numbers of viable bacteria in the lungs and bronchoalveolar lavage fluid (BALF) were compared. Histopathological analysis of lung specimens was also performed. The pharmacokinetics of ME1071 was analysed after initial treatment. The ME1071 plus biapenem combination group displayed significantly longer survival compared with the control and biapenem monotherapy groups (P<0.05). Furthermore, the number of viable bacteria in the lungs was significantly lower in the combination group (P<0.05). Histopathological examination of lung specimens indicated that progression of lung inflammation was prevented in the combination group. Furthermore, total cell and neutrophil counts, as well as cytokine levels, in BALF were significantly decreased (P<0.05) in the combination group. The percentage time above the MIC (%T>MIC) for biapenem without ME1071 was 0% in plasma; however, this value was elevated to 10.8% with ME1071. These results suggest that ME1071 is potent and effective for treatment of VAP caused by MBL-producing P. aeruginosa.

Empiric antibiotics pending bronchoalveolar lavage data in patients without pneumonia significantly alters the flora, but not the resistance profile, if a subsequent pneumonia develops.

INTRODUCTION: Ventilator-associated pneumonia (VAP) occurs in up to 25% of mechanically ventilated patients, with an associated mortality up to 50%. Early diagnosis and appropriate empiric antibiotic coverage of VAP are crucial. Given the multitude of noninfectious clinical and radiographic anomalies within trauma patients, microbiology from bronchioalveolar lavage (BAL) is often needed. Empiric antibiotics are administered while awaiting BAL culture data. Little is known about the effects of these empiric antibiotics on patients with negative BAL microbiology if a subsequent VAP occurs during the same hospital course. METHODS: This is a retrospective chart review of intubated trauma patients undergoing BAL for suspected pneumonia over a 3-y period at a Level 1 trauma center. All patients with suspected VAP undergoing a BAL receive empiric antibiotics. If microbiology data are negative at 72 h, all antibiotics are stopped; however, if the BAL returns with ≥10(5) colony-forming units per milliliter, the diagnosis of VAP is confirmed. We divided patients into three groups. Group 1 consisted of patients in whom the initial BAL was positive for VAP. Group 2 consisted of patients with an initial negative BAL, who subsequently developed VAP at a later point in the hospital course. Group 3 consisted of patients with negative BAL who did not develop a subsequent VAP. RESULTS: We obtained 499 BAL specimens in 185 patients over the 3-y period. A total of 14 patients with 23 BAL specimens initially negative for VAP subsequently developed VAP later during the same hospital stay. These patients did not have an increase in the hospital length of stay, intensive care unit days, ventilator days, or mortality compared with those who had a positive culture on the first suspicion of VAP. There was a significant increase in the percentage of Enterobacter (21% versus 8%) and Morganella (8% versus 0%) as the causative organism in these 14 patients when the VAP occurred. Furthermore, the profile of the top two organisms in each group changed. Enterobacter (21%) and Pseudomonas (17%) were the principal organisms in the initial BAL-negative group, whereas the two predominant strains in the initial positive BAL group were methicillin-sensitive Staphylococcus aureus (21%) and Haemophilus influenza (11%). Interestingly, methicillin-resistant S. aureus remained the third most common organism in both groups. Empiric antibiotics also did not seem to induce the growth of multidrug-resistant organisms, and there was no increased rate of secondary infections such as Clostridium difficile. CONCLUSIONS: Ventilator-associated pneumonia remains a significant cause of morbidity and mortality in mechanically ventilated trauma patients. The diagnosis and treatment of VAP continue to be challenging. Once clinically suspected, empiric coverage decreases morbidity and mortality. Our data demonstrate that patients who receive empiric coverage exhibit a significantly different microbiologic profile compared with those who had an initial positive BAL culture. Initial empiric antibiotics in BAL-negative patients were not associated with an increase in multidrug-resistant organisms, hospital, or intensive care unit length of stay, ventilator days, and mortality or secondary infections.

The adequacy of timely empiric antibiotic therapy for ventilator-associated pneumonia: an important determinant of outcome.

OBJECTIVE: The individual impact of timeliness vs adequacy of empiric antibiotic therapy for a clinical suspicion of ventilator-associated pneumonia (CSVAP) is unknown. Accordingly, in patients with CSVAP and timely initiation of empiric antibiotic therapy, we determined the impact of inadequate therapy (IT). METHODS: Analysis of a randomized trial of CSVAP treated empirically with meropenem or meropenem plus ciprofloxacin was done. Adequate therapy (AT) was considered present if all pathogens in the index culture were sensitive to the empiric antibiotics; IT was defined as the presence of pathogens resistant to the empiric antibiotics. A priori, for Pseudomonas sp, 2 antibiotics with activity against the organisms were required for AT to be considered present. RESULTS: Of 739 patients with CSVAP, 350 had positive cultures: 313 (89.4%) had AT, and 37 (10.6%), IT. The IT group had higher intensive care unit (35.1% vs 11.8%, P = .0001) and hospital mortalities (48.7% vs 19.5%, P < .0001), increased mechanical ventilation (15.8 vs 6.8 days, P = .0005), intensive care unit stay (13.5 vs 8.4 days, P = .02), and hospital stay (42.2 vs 27.9 days, P = .04). In multivariate analysis and a separate case control analysis, the odds ratio of hospital mortality with IT was 3.05 (95% confidence interval, 1.25-7.45; P = .01) and 3.00 (95% confidence interval, 1.24-7.24; P = .01), respectively. CONCLUSION: In the context of early administration of empiric broad spectrum antibiotics for CSVAP, IT is associated with higher morbidity and mortality.

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

To compare efficacy and safety of a tigecycline regimen with an imipenem/cilastatin regimen in hospital-acquired pneumonia patients, a phase 3, multicenter, randomized, double-blind, study evaluated 945 patients. Coprimary end points were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure. Cure rates were 67.9% for tigecycline and 78.2% for imipenem (CE patients) and 62.7% and 67.6% (c-mITT patients), respectively. A statistical interaction occurred between ventilator-associated pneumonia (VAP) and non-VAP subgroups, with significantly lower cure rates in tigecycline VAP patients compared to imipenem; in non-VAP patients, tigecycline was noninferior to imipenem. Overall mortality did not differ between the tigecycline (14.1%) and imipenem regimens (12.2%), although more deaths occurred in VAP patients treated with tigecycline than imipenem. Overall, the tigecycline regimen was noninferior to the imipenem/cilastatin regimen for the c-mITT but not the CE population; this difference appears to have been driven by results in VAP patients.

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

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and health-care-associated pneumonia (HCAP). These infections are associated with significant morbidity, mortality, and cost. The impact of vancomycin minimum inhibitory concentration (MIC) on mortality for patients with MRSA pneumonia has not been determined. METHODS: Adult patients in ICUs with a diagnosis of MRSA HAP, VAP, or HCAP were entered in the study. Clinical and laboratory information were prospectively collected. Vancomycin MIC and heteroresistance were determined for each MRSA isolate. Data were collected from February 2006 through August 2007. The primary outcome variable was all-cause mortality at day 28. A propensity score approach was used to adjust for confounding variables. RESULTS: The study sample consisted of 158 patients. All-cause mortality at day 28 was 32.3%. The majority of MRSA isolates had a vancomycin MIC ≥ 1.5 mg/mL (115/158, 72.8%). Propensity score analysis demonstrated an increase in 28-day mortality as vancomycin MIC increased from 0.75 to 3 mg/mL (P ≤ .001). Heteroresistance to vancomycin, demonstrated in 21.5% isolates, was not associated with mortality. CONCLUSIONS: Mortality in patients with MRSA HAP, VAP, and HCAP increases as a function of the vancomycin MIC, even for strains with MIC values within the susceptible range. Evaluation of vancomycin MICs should be contemplated at the institutional level and for individual cases of MRSA pneumonia. The use of vancomycin therapy in patients with MRSA pneumonia caused by isolates with MICs between 1 and 2 mg/mL should be undertaken with caution, and alternative therapies should be considered.

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

BACKGROUND: Ventilator-associated pneumonia (VAP) is a leading cause of mortality in critically ill patients. Although previous studies have shown that de-escalation therapy (DT) of antibiotics may decrease costs and the development of resistant pathogens, minimal data have shown its effect in surgical patients or in any patients with septic shock. We hypothesized that DT for VAP was not associated with an increased rate of recurrent pneumonia (RP) or mortality in a high acuity cohort of critically ill surgical patients. METHODS: All surgical intensive care unit (SICU) patients from January 2005 to May 2007 with VAP diagnosed by quantitative bronchoalveolar lavage with a positive threshold of 10,000 CFU/mL were identified. Data collected included age, gender, Acute Physiologic and Chronic Health Evaluation Score III (A3), type of bacterial or other pathogen, antibiotics used for initial and final therapy, mortality, RP, and appropriateness of initial therapy (AIT). Patients were designated as receiving AIT, DT, or escalation of antibiotic therapy based on microbiology for their VAP. RESULTS: One hundred thirty-eight of 1,596 SICU patients developed VAP during the study period (8.7%). For VAP patients, the mean Acute Physiologic and Chronic Health Evaluation III score was 82.7 points with a mean age of 63.8 years. The RP rate was 30% and did not differ between patients receiving DT (27.3%) and those who did not receive DT (35.1%). Overall mortality was 37% (55% predicted by A3 norms) and did not differ between those receiving DT (33.8%) or not (42.1%). The most common pathogens for primary VAP were methicillin-resistant Staphylococcus aureus (14%), Escherichia coli (11%), and Pseudomonas aeruginosa (9%) whereas P. aeruginosa was the most common pathogen in RP. The AIT for all VAP was 93%. De-escalation of therapy occurred in 55% of patients with AIT whereas 8% of VAP patients required escalation of antibiotic therapy. The most commonly used initial antibiotic choice was vancomycin/piperacillin-tazobactam (16%) and the final choice was piperacillin-tazobactam (20%). Logistic regression demonstrated no specific parameter correlated with development of RP. Higher A3 (Odds ratio, 1.03; 95% confidence interval, 1.01-1.05) was associated with mortality whereas lack of RP (odds ratio, 0.31; 95% confidence interval, 0.12-0.80), and AIT reduced mortality (odds ratio, 0.024; 95% confidence interval, 0.007-0.221). Age, gender, individual pathogen, individual antibiotic regimen, and the use of DT had no effect on mortality. CONCLUSION: De-escalation therapy did not lead to RP or increased mortality in critically ill surgical patients with VAP. De-escalation therapy was also shown to be safe in patients with septic shock. Because of its acknowledged benefits and lack of demonstrable risks, de-escalation therapy should be used whenever possible in critically ill patients with VAP.

Correlates of clinical failure in ventilator-associated pneumonia: insights from a large, randomized trial.

PURPOSE: Our objective was to determine clinical variables measured at baseline and day 3 that may relate to failure of resolution of ventilator-associated pneumonia (VAP). MATERIALS AND METHODS: In patients with confirmed VAP derived from a large, randomized controlled trial comparing different modalities for the diagnosis and treatment of VAP, we identified risk factors associated with clinical failure. Clinical failure was prospectively defined in this trial as death, persistence of clinical and radiographic features of infection throughout the study period requiring additional antibiotics, superinfection, or relapsing infection. We examined the relationship between VAP resolution and clinical characteristics measured both at study enrollment and at day 3. We used logistic regression to identify independent factors associated with clinical failure and conducted a sensitivity analysis focusing only on patients who met the definition for clinical failure but who nonetheless survived until day 28. RESULTS: Of 563 subjects with VAP, 179 (31.8%) were classified as clinical failures. Death was the most common reason for clinical failure. At baseline, clinical failure patients were older, more severely ill, had been on mechanical ventilation for a longer period, and had higher Clinical Pulmonary Infection Score values and lower Pao2/Fio2 ratios. By day 3, patients defined as clinical failures remained more severely ill and continued to have worse oxygenation. In multivariate analysis, 4 factors were independently associated with clinical failure: older age, duration of ventilation before enrollment, presence of neurologic disease at admission, and failure of the Pao2/Fio2 ratio to improve by day 3. Repeating this multivariable model in only surviving patients suggested that persistence of fever was the only variable associated with clinical failure. CONCLUSIONS: Clinical characteristics correlate with eventual outcomes in VAP. Failure of the Pao2/Fio2 ratio and fever to improve are independently associated with clinical failure. We suggest that clinicians follow these measures and consider integrating them in their decisions as to when to reevaluate persons with VAP who are not improving.

Should the currently recommended twice-daily dosing still be considered the most appropriate regimen for treating MRSA ventilator-associated pneumonia with vancomycin?

Methicillin-resistant (methicillin-resistant) Staphylococcus aureus causes unacceptably high mortality from ventilator-associated pneumonia, even when appropriate early therapy with vancomycin is administered at a dosage of 15 mg/kg every 12 hours. However, because of the poor penetration of vancomycin in epithelial lining fluid, it is unlikely that this dosing schedule always achieves optimal vancomycin exposure in the lung. Conversely, there is probably enough evidence to suggest that continuous infusion enhances vancomycin efficacy with the standard 30 mg/kg daily dosage, thus avoiding the need to use higher daily dosages that could increase the risk of nephrotoxicity. It is worth noting that in the case of fully susceptible pathogens with a minimum inhibitory concentration (MIC) of < or =1 mg/L, the strategy of targeting a steady-state vancomycin concentration of 15 mg/L during continuous infusion may simultaneously enable an area under the plasma concentration-time curve (AUC)/MIC ratio of > or =360, so that both pharmacodynamic efficacy targets may be optimized.