Value of β-d-glucan and Candida albicans germ tube antibody for discriminating between Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Purpose

To assess the value of (1→3)-β-d-glucan (BDG), Candida albicans germ tube antibody (CAGTA), C-reactive protein (CRP), and procalcitonin (PCT) levels for the diagnosis of invasive candidiasis (IC) and for differentiating Candida spp. colonization from infection in ICU patients with severe abdominal conditions (SAC).

Methods

Prospective study of 176 non-neutropenic patients, with SAC at ICU admission, and expected to stay at least 7?days. Surveillance cultures and BDG, CAGTA, CRP, and PCT levels were performed on the third day of ICU stay and twice a week for four consecutive weeks. Patients were grouped into invasive candidiasis (IC), Candida colonization, and neither colonized/nor infected. The classification and regression tree (CART) analysis was used to predict IC in colonized patients. The discriminatory ability of the obtained prediction rule was assessed by the area under the ROC curve (AUC).

Results

The probabilities of IC were 59.3?% for the terminal node of BDG greater than 259?pg/mL and 30.8?% for BDG less than 259?pg/mL and CAGTA positivity, whereas there was a 93.9?% probability in predicting the absence of IC for BDG less than 259?pg/mL and negative CAGTA. Using a cutoff of 30?% for IC probability, the prediction rule showed 90.3?% sensitivity, 54.8?% specificity, 42.4?% positive predictive value, and 93.9?% negative predictive value with an AUC of 0.78 (95?% confidence interval 0.76–0.81). Significant differences in CRP (p?=?0.411) and PCT (p?=?0.179) among the studied groups were not found.

Conclusions

BDG with a positive test for CAGTA accurately differentiated Candida colonization from IC in patients with SAC, whereas CRP and PCT did not.     

Candida in the respiratory tract secretions of critically ill patients and the impact of antifungal treatment: a randomized placebo controlled pilot trial (CANTREAT study)

Purpose

Candida spp. are frequently recovered from endotracheal secretions in critically ill patients suspected of having ventilator-associated pneumonia. Observational studies reported an association with worse clinical outcomes but the effect of antifungal therapy in these patients remains unclear. We designed this pilot study to assess the feasibility of a larger trial and to evaluate inflammatory profiles and clinical outcomes in these patients.

Methods

We conducted a double-blind, placebo-controlled, multicenter pilot randomized trial of antifungal therapy in critically ill patients with a clinical suspicion of ventilator-associated pneumonia with positive airway secretion specimens for Candida spp. We also included an observational group without Candida spp. in their airway secretions. We measured recruitment rate, inflammatory and innate immune function profiles over time, and clinical outcomes.

Results

We recruited 60 patients into the randomized trial and 29 patients into the observational study. Markers of inflammation and all clinical outcomes were comparable between placebo and antifungal treatment group at baseline and over time. At baseline, plasma TNF-α levels were higher in patients with VAP and Candida compared to the observational group (mean ± SD) (21.8 ± 23.1 versus 12.4 ± 9.3 pg/ml, p = 0.02) and these patients had lower innate immune function as evidenced by reduced whole blood ex vivo LPS-induced TNF-α production capacity (854.8 ± 855.2 versus 1,559.4 ± 1,290.6 pg/ml, p = 0.01).

Conclusions

This study does not provide evidence to support a larger trial examining the efficacy of empiric antifungal treatment in patients with a clinical suspicion of ventilator-associated pneumonia and Candida in the endotracheal secretions. The presence of Candida in the lung may be associated with persistent inflammation and immunosuppression.     

Pathophysiology of Escherichia coli ventilator-associated pneumonia: implication of highly virulent extraintestinal pathogenic strains

Purpose

To characterize Escherichia coli ventilator-associated pneumonia (VAP) in intensive care unit (ICU) patients by determining antibioresistance and genotypic characteristics of E.?coli isolates responsible for VAP or lung colonization, by comparing them with their oropharyngeal and rectal counterparts and by assessing representative isolates’ virulence in a pneumonia mouse model.

Methods

Patients under mechanical ventilation for more than 72?h were screened for simultaneous presence of E.?coli in rectal, oropharyngeal, and respiratory samples (colonization or VAP). If present, E.?coli isolates were characterized by antimicrobial susceptibility, phylogenetic grouping, and virulence factor (VF) gene content determination. BALB/c mice were challenged intranasally with 3.6?×?10⁸ colony-forming units (CFU) of patients’ E.?coli isolates.

Results

Multisite E.?coli colonization was observed in 19?% of patients (25 patients, 12 with E.?coli VAP). One hundred fifteen distinct E.?coli isolates were analyzed. B2 phylogenetic group was predominant, with high VF gene content and low antimicrobial resistance. Antimicrobial resistance diversity was observed in four patients with VAP. E.?coli isolates from VAP patients were more frequently B2 isolates, with significantly greater VF gene content than lung colonization isolates. Among screened VF genes, iroN and sfa appeared important for lung infection. A very strong correlation (R ²?=?0.99) was found between VF gene content and mortality in the mouse model.

Conclusions

This is the first study establishing antibioresistance and genotypic characteristics of E.?coli isolates responsible for VAP in adult ICU patients. These isolates are highly virulent specific extraintestinal pathogenic E.?coli strains expressing virulence factors, representing potential targets for new therapies.     

Value of lower respiratory tract surveillance cultures to predict bacterial pathogens in ventilator-associated pneumonia: systematic review and diagnostic test accuracy meta-analysis

Purpose

In ventilator-associated pneumonia (VAP), early appropriate antimicrobial therapy may be hampered by involvement of multidrug-resistant (MDR) pathogens.

Methods

A systematic review and diagnostic test accuracy meta-analysis were performed to analyse whether lower respiratory tract surveillance cultures accurately predict the causative pathogens of subsequent VAP in adult patients. Selection and assessment of eligibility were performed by three investigators by mutual consideration. Of the 525 studies retrieved, 14 were eligible for inclusion (all in English; published since 1994), accounting for 791 VAP episodes. The following data were collected: study and population characteristics; in- and exclusion criteria; diagnostic criteria for VAP; microbiological workup of surveillance and diagnostic VAP cultures. Sub-analyses were conducted for VAP caused by Staphylococcus aureus, Pseudomonas spp., and Acinetobacter spp., MDR microorganisms, frequency of sampling, and consideration of all versus the most recent surveillance cultures.

Results

The meta-analysis showed a high accuracy of surveillance cultures, with pooled sensitivities up to 0.75 and specificities up to 0.92 in culture-positive VAP. The area under the curve (AUC) of the hierarchical summary receiver-operating characteristic curve demonstrates moderate accuracy (AUC: 0.90) in predicting multidrug resistance. A sampling frequency of >2/week (sensitivity 0.79; specificity 0.96) and consideration of only the most recent surveillance culture (sensitivity 0.78; specificity 0.96) are associated with a higher accuracy of prediction.

Conclusions

This study provides evidence for the benefit of surveillance cultures in predicting MDR bacterial pathogens in VAP. However, clinical and statistical heterogeneity, limited samples sizes, and bias remain important limitations of this meta-analysis.     

Azithromycin to prevent Pseudomonas aeruginosa ventilator-associated pneumonia by inhibition of quorum sensing: a randomized controlled trial

Purpose

Anti-virulence strategies have not been evaluated for the prevention of bacterial infections. Prolonged colonization of intubated patients with Pseudomonas aeruginosa isolates producing high-levels of the quorum sensing (QS)-regulated virulence factor rhamnolipids has been associated with ventilator-associated pneumonia (VAP). In this pathogen, azithromycin reduces QS-regulated virulence. We aimed to assess whether azithromycin could prevent VAP in patients colonized by rhamnolipids producing isolates.

Methods

In a randomized, double-blind, multicenter trial, intubated colonized patients received either 300?mg/day azithromycin or placebo. Primary endpoint was the occurrence of P. aeruginosa VAP. We further identified those patients persistently colonized by isolates producing high-levels of rhamnolipids and therefore at the highest risk to develop VAP linked to this QS-dependent virulence factor.

Results

Ninety-two patients were enrolled; 43 azithromycin-treated and 42 placebo patients were eligible for the per-protocol analysis. In the per-protocol population, the occurrence of P. aeruginosa VAP was reduced in the azithromycin group but without reaching statistical significance (4.7 vs. 14.3?% VAP, p?=?0.156). QS-dependent virulence of colonizing isolates was similarly low in both study groups, and only five patients in each arm were persistently colonized by high-level rhamnolipids producing isolates. In this high-risk subgroup, the incidence of VAP was reduced fivefold in azithromycin versus placebo patients (1/5 vs. 5/5 VAP, p?=?0.048).

Conclusions

There was a trend towards reduced incidence of VAP in colonized azithromycin-treated patients. In addition, azithromycin significantly prevented VAP in those patients at high risk of rhamnolipid-dependent VAP, suggesting that virulence inhibition is a promising anti-microbial strategy.     

Non-adherence to guidelines: an avoidable cause of failure of empirical antimicrobial therapy in the presence of difficult-to-treat bacteria

Purpose

To identify the risk factors of ventilator-associated pneumonia (VAP) due to difficult-to-treat (DTT) bacteria (i.e., Pseudomonas aeruginosa, Acinetobacter baumannii and oxacillin-resistant Staphylococcus aureus), and to assess the rate and the causes of inappropriateness of empirical antimicrobial therapy.

Methods

In an intensive care unit of a university hospital, patients with VAP were empirically treated with antibiotics without activity against DTT bacteria if the patients had no prior hospitalization or prior administration of antibiotics, according to local guidelines.

Results

Overall, the empirical antimicrobial therapy was appropriate in 190 (87%) out of 218 patients with VAP. Fifty (23%) patients developed problems due to DTT bacteria. The risk factors for VAP due to DTT bacteria were shock state, prior antimicrobial therapy, prior stay in long-term care facilities and late-onset VAP. Empirical antimicrobial therapy was inappropriate in 20 (40%) patients with VAP due to DTT bacteria and 8 (5%) patients with VAP due to non-DTT (P?=?0.001). Guidelines violations (nine patients), bacteria not included in antibiotic spectrum (eight patients) and bacterial resistance (three patients) were the causes of inappropriateness in case of DTT bacteria.

Conclusion

Despite the abundant information for the treatment of VAP and the establishment of guidelines, too many patients with DTT bacteria received inappropriate antimicrobial therapy. Since 45% of the cases are related to non-adherence to the local protocol, there is room for improvement by implementing educational programs. Also, since DTT bacteria are found in 23% of late-onset VAP, empirical antibiotic treatment should be directed against these pathogens.     

Clinical impact and risk factors for colonization with extended-spectrum β-lactamase-producing bacteria in the intensive care unit

Purpose

The changed epidemiology of extended spectrum beta-lactamases (ESBL), the spread to the community and the need for prudent use of carbapenems require updated knowledge of risk factors for colonization with ESBL-producing enterobacteriaceae (ESBL-PE).

Methods

An 8-month prospective study in the medical ICU of an 850-bed general and university-affiliated hospital.

Results

Of 610 patients admitted, 531 (87?%) had a rectal swab obtained at admission, showing a 15?% (82 patients) ESBL-PE carriage rate, mostly of E. coli (n?=?51, 62?%); ESBL-PE caused 9 (3?%) infections on admission. By multivariable analysis, transfer from another ICU (OR?=?2.56 [1, 22]), hospital admission in another country [OR?=?5.28 (1.56–17.8)], surgery within the past year [OR?=?2.28 (1.34–3.86)], prior neurologic disease [OR?=?2.09 (1.1–4.0)], and prior administration of third generation cephalosporin (within 3–12?months before ICU admission) [OR?=?3.05 (1.21–7.68)] were independent predictive factors of colonization by ESBL-PE upon ICU admission. Twenty-eight patients (13?% of those staying for more than 5?days) acquired ESBL carriage in ICU, mostly with E. cloacae (n?=?13, 46?%) and K. pneumoniae (n?=?10, 36?%). In carriers, ESBL-PE caused 10 and 27?% of first and second episodes of ICU-acquired infections, respectively.

Conclusion

We found a high prevalence of ESBLE-PE colonization on admission to our ICU, even in the subgroup admitted from the community, but few first infections. Identifying risk factors for ESBL-PE colonization may help identifying which patients may warrant empiric ESBL-targeted antimicrobial drug therapy as a means to limit carbapenem use.     

Serum β-d-glucan of critically ill patients with suspected ventilator-associated pneumonia: Preliminary observations

Background

The purpose of this pilot study was to determine whether β-d-glucan (BG) was associated with Candida in the lung and risk of death in patients with suspected ventilator-associated pneumonia (VAP).

Methods

In a single-center observational study, we enrolled eligible adults within 24 hours of intensive care unit admission. Patients who developed suspected VAP were divided into 3 groups according to culture results. Serum BG levels and clinical outcomes were collected.

Results

Fifty-seven patients were included; 26 had no growth, 19 patients grew pathogenic bacteria only, and 12 patients grew only Candida. The proportion of patients with a positive BG tended to be greater in the Candida group (66.7% vs 26.3% in bacteria group vs 50.0% in culture-negative group, P = .09). The BG-positive patients were much more likely to die by day 28 than the BG-negative patients (odds ratio, 4.2; 95% confidence limits, 1.1-15.7; P = .03). Patients with both BG positivity and Candida in their lung secretions were much more likely to die compared with patients who did not.

Conclusions

β-d-Glucan positivity in patients with a suspected VAP may be a marker for Candida in the lung and worse outcomes. Further validation of this postulate is warranted.     

Tracheal suction by closed system without daily change versus open system

Background

Tracheal suctioning costs are higher with a closed tracheal suction system (CTSS) than with an open system (OTSS), due to the need for complete daily change as recommended by the manufacturer. However, is it necessary to change the closed system daily?

Objective

To evaluate the tracheal suctioning costs and incidence of ventilator-associated pneumonia (VAP) using closed system without daily change vs OTSS.

Design

Prospective and randomised study.

Setting

An Intensive Care Unit in a university hospital.

Patients

Patients requiring mechanical ventilation.

Interventions

Patients were randomly assigned to CTSS without daily change or OTSS. We used a CTSS that allowed partial or complete change.

Measurements and results

There were no significant differences between both groups of patients (236 with CTSS and 221 with OTSS) in gender, age, diagnosis, APACHE-II score, mortality, number of aspirations per day, percentage of patients who developed VAP (13.9 vs 14.1%) or the number of ventilator-associated pneumonia per 1000 days of mechanical ventilation (14.1 vs 14.6). There were not significant differences in tracheal suctioning costs per patient/day between CTSS vs OTSS (2.3?±?3.7 vs 2.4?±?0.5 Euros; p?=?0.96); however, when length of mechanical ventilation was lower than 4?days, the cost was higher with CTSS than with OTSS (7.2?±?4.7 vs 1.9?±?0.6?Euros; p?p?Conclusion CTSS without daily change is the optimal option for patients needing tracheal suction longer than 4?days.     

Effect of probiotics on the incidence of ventilator-associated pneumonia in critically ill patients: a randomized controlled multicenter trial

Purpose

To evaluate the potential preventive effect of probiotics on ventilator-associated pneumonia (VAP).

Methods

This was an open-label, randomized, controlled multicenter trial involving 235 critically ill adult patients who were expected to receive mechanical ventilation for ≥48 h. The patients were randomized to receive (1) a probiotics capsule containing live Bacillus subtilis and Enterococcus faecalis (Medilac-S) 0.5 g three times daily through a nasogastric feeding tube plus standard preventive strategies or (2) standard preventive strategies alone, for a maximum of 14 days. The development of VAP was evaluated daily, and throat swabs and gastric aspirate were cultured at baseline and once or twice weekly thereafter.

Results

The incidence of microbiologically confirmed VAP in the probiotics group was significantly lower than that in the control patients (36.4 vs. 50.4 %, respectively; P = 0.031). The mean time to develop VAP was significantly longer in the probiotics group than in the control group (10.4 vs. 7.5 days, respectively; P = 0.022). The proportion of patients with acquisition of gastric colonization of potentially pathogenic microorganisms (PPMOs) was lower in the probiotics group (24 %) than the control group (44 %) (P = 0.004). However, the proportion of patients with eradication PPMO colonization on both sites of the oropharynx and stomach were not significantly different between the two groups. The administration of probiotics did not result in any improvement in the incidence of clinically suspected VAP, antimicrobial consumption, duration of mechanical ventilation, mortality and length of hospital stay.

Conclusion

Therapy with the probiotic bacteria B. Subtilis and E. faecalis are an effective and safe means for preventing VAP and the acquisition of PPMO colonization in the stomach.

     

Risk factors for infection byPseudomonas aeruginosa in patients with ventilator-associated pneumonia

Objective

to investigate the epidemiology of infection byPseudomonas aeruginosa in patients with ventilator-associated pneumonia (VAP).

Design

prospective clinical study.

Setting

a medical-surgical ICU in a university hospital.

Patients

we followed-up 568 mechanically ventilated patients and 83 episodes of VAP with etiologic diagnosis in 72 patients were retained for analysis.

Results

Ps. aeruginosa was isolated in 22 (26.5%) episodes in 18 patients. Of these episodes 7 were directly responsible for death. Using logistic regression analysis, the risk of VAP due toPs. aeruginosa was increased in patients with chronic obstructive pulmonary disease (relative risk (RR)=29.9, 95% confidence interval (CI)=4.86-184.53), a mechanical ventilation period longer than 8 days (RR=8.1, 95% CI=1.01-65.40) and prior use of antibiotics (RR=5.5, 95% CI=0.88-35.01).

Conclusions

patients with VAP and these factors have a greater risk of infection byPs. aeruginosa and empirical therapy for these episodes should include anti-pseudomonal activity until etiologic diagnosis is established.     

Neutrophil extracellular traps (NETs) are increased in the alveolar spaces of patients with ventilator-associated pneumonia

Background

Neutrophils release neutrophil extracellular traps (NETs) in response to invading pathogens. Although NETs play an important role in host defense against microbial pathogens, they have also been shown to play a contributing mechanistic role in pathologic inflammation in the absence of infection. Although a role for NETs in bacterial pneumonia and acute respiratory distress syndrome (ARDS) is emerging, a comprehensive evaluation of NETs in the alveolar space of critically ill patients has yet to be reported. In this study, we evaluated whether markers of NET formation in mechanically ventilated patients are associated with ventilator-associated pneumonia (VAP).

Methods

We collected bronchoalveolar lavage fluid from 100 critically ill patients undergoing bronchoscopy for clinically suspected VAP. Subjects were categorized by the absence or presence of VAP and further stratified by ARDS status. NETs (myeloperoxidase (MPO)-DNA complexes) and the NET-associated markers peroxidase activity and cell-free DNA were analyzed by enzyme-linked immunosorbent assay and colorimetric assays, respectively. Quantitative polymerase chain reaction of nuclear and mitochondrial DNA was used to determine the origin of the extruded DNA. Interleukin (IL)-8 and calprotectin were assayed as measures of alveolar inflammation and neutrophil activation. Correlations between NETs and markers of neutrophil activation were determined using Spearman’s correlation. We tested for associations with VAP and bacterial burden by logistic and linear regression, respectively, using log₁₀-transformed NETs.

Results

MPO-DNA concentrations were highly correlated with other measures of NET formation in the alveolar space, including cell-free DNA and peroxidase activity (r?=?0.95 and r?=?0.87, p?<?0.0001, respectively). Alveolar concentrations of MPO-DNA were higher in subjects with VAP and ARDS compared with those with ARDS alone (p?<?0.0001), and higher MPO-DNA was associated with increased odds of VAP (odds ratio 3.03, p?<?0.0001). In addition, NET concentrations were associated with bacterial burden (p?<?0.0001) and local alveolar inflammation as measured by IL-8 (r?=?0.89, p?<?0.0001).

Conclusions

Alveolar NETs measured by MPO-DNA complex are associated with VAP, and markers of NETosis are associated with local inflammation and bacterial burden in the lung. These results suggest that NETs contribute to inflammatory responses involved in the pathogenesis of VAP.

     

Does the surface-treated AN69 membrane prolong filter survival in CRRT without anticoagulation?

Purpose

The need for continuous anticoagulation remains a significant drawback in continuous renal replacement therapy (CRRT), especially in patients with increased bleeding risk. Polyethyleneimine treatment of the AN69 membrane (AN69ST) reduces thrombogenicity through decreased contact activation and promotion of heparin binding. The aim of this study is to evaluate whether this membrane prolongs filter survival in CRRT without anticoagulation.

Methods

A single-center, prospective, randomized, double-blind controlled trial with cross-over design comparing filter survival with the AN69ST membrane and the original AN69 membrane in 39 patients treated with continuous venovenous hemofiltraton (CVVH) without additional heparin.

Results

Filter survival with the AN69ST membrane (n?=?75) was 14.2?±?8.2?h, which is not significantly different from the 13.3?±?10.3?h for the original AN69 membrane (n?=?76; p?=?0.59). Limiting the analysis to those treatments that were interrupted for filter clotting yielded similar results: 14.4?±?8.2?h for the AN69 ST membrane (n?=?62) versus 14.1?±?7.5?h for the original AN69 membrane (n?=?56) (p?=?0.93).

Conclusions

Compared with the original AN69 membrane, the surface-treated AN69ST membrane does not prolong filter survival during CVVH without systemic anticoagulation and with the CRRT settings used in this study.     

Non-invasive pressure support ventilation and CPAP in cardiogenic pulmonary edema: a multicenter randomized study in the emergency department

Introduction

Noninvasive pressure support ventilation (NIPSV) and continuous positive airway pressure (CPAP) are both advocated in the treatment of cardiogenic pulmonary edema (CPE); however, the superiority of one technique over the other has not been clearly demonstrated. With regard to its physiological effects, we hypothesized that NIPSV would be better than CPAP in terms of clinical benefit.

Methods

In a prospective, randomized, controlled study performed in four emergency departments, 200 patients were assigned to CPAP (n?=?101) or NIPSV (n?=?99). Primary outcome was combined events of hospital death and tracheal intubation. Secondary outcomes included resolution time, myocardial infarction rate, and length of hospital stay. Separate analysis was performed in patients with hypercapnia and those with high B-type natriuretic peptide (>500?pg/ml).

Results

Hospital death occurred in 5 (5.0%) patients receiving NIPSV and 3 (2.9%) patients receiving CPAP (p?=?0.56). The need for intubation was observed in 6 (6%) patients in the NIPSV group and 4 (3.9%) patients in the CPAP group (p?=?0.46). Combined events were similar in both groups. NIPSV was associated to a shorter resolution time compared to CPAP (159?±?54 vs. 210?±?73?min; p?Conclusions During CPE, NIPSV accelerates the improvement of respiratory failure compared to CPAP but does not affect primary clinical outcome either in overall population or in subgroups of patients with hypercapnia or those with high B-type natriuretic peptide.     

Selective decontamination of the digestive tract: the mechanism of action is control of gut overgrowth

Purpose

Gut overgrowth is the pathophysiological event in the critically ill requiring intensive care. In relation to the risk of developing a clinically important outcome, gut overgrowth is defined as?≥10⁵ potential pathogens including ‘abnormal’ aerobic Gram-negative bacilli (AGNB), ‘normal’ bacteria and yeasts, per mL of digestive tract secretion. Surveillance samples of throat and gut are the only samples to detect overgrowth. Gut overgrowth is the crucial event which precedes both primary and secondary endogenous infection, and a risk factor for the development of de novo resistance. Selective decontamination of the digestive tract (SDD) is an antimicrobial prophylaxis designed to control overgrowth.

Methods

There have been 65 randomised controlled trials of SDD in 15,000 patients over 25?years and 11 meta-analyses, which are reviewed.

Results and conclusions

These trials demonstrate that the full SDD regimen using parenteral and enteral antimicrobials reduces lower airway infection by 72?%, blood stream infection by 37?%, and mortality by 29?%. Resistance is also controlled. Parenteral cefotaxime which reaches high salivary and biliary concentrations eradicates overgrowth of ‘normal’ bacteria such as Staphylococcus aureus in the throat. Enteral polyenes control ‘normal’ Candida species. Enteral polymyxin and tobramycin, eradicate, or prevent gut overgrowth of ‘abnormal’ AGNB. Enteral vancomycin controls overgrowth of ‘abnormal’ methicillin-resistant S. aureus. SDD controls overgrowth by achieving high antimicrobial concentrations effective against ‘normal’ and ‘abnormal’ potential pathogens rather than by selectivity.     

Comparison of pegfilgrastim on day?2 vs. day?4 as primary prophylaxis of intense dose-dense chemotherapy in patients with node-positive primary breast cancer within the prospective, multi-center GAIN study: (GBG 33)

Background

Preliminary data suggest that pegfilgrastim given on day?4 (P4) might be superior to pegfilgrastim on day?2 (P2) in reducing grade 4 leucopenia.

Methods

Patients with node-positive primary breast cancer receiving epirubicin?Cpaclitaxel?Ccyclophosphamide chemotherapy were randomized to receive P2 versus P4. Primary endpoint was leucopenia grade 4, assuming a risk reduction of 50% with P4 from 50% in P2 to 25% with P4.

Results

Three-hundred fifty-one patients were randomized to P2 (n?=?174) versus P4 (n?=?177). The rate of leucopenia (grade 4) was 47.1% with P2 and 42.0% with P4 (p?=?0.387), neutropenia (grade 3?+?4) was 47.9% versus 40.8% (p?=?0.337), FN was 4.7% versus 8.0% (p?=?0.271), and infections was 29.9% versus 25.4% (p?=?0.404), respectively.

Conclusion

This study failed to demonstrate that pegfilgrastim on day?4 was more efficacious than on day?2 with respect to grade 4 leucopenia (the primary endpoint), febrile neutropenia, or infections.     

Efficacy and safety of intravenous voriconazole and intravenous itraconazole for antifungal prophylaxis in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome

Purpose

To compare the efficacy and safety of voriconazole with itraconazole as prophylaxis in leukemia patients.

Methods

Open-label, randomized study. Patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome undergoing induction chemotherapy or first salvage were eligible. Patients received voriconazole (400?mg intravenous (IV) every 12?h for two doses, followed by 300?mg BID) or itraconazole (200?mg IV twice daily for 2?days, followed by 200?mg IV daily).

Results

A total of 127 patients were enrolled. Four were excluded because they did not receive study drug (n?=?3) or received two antifungal agents during the first week on study (n?=?1), leaving 123 patients for analysis. None of the 71 patients receiving voriconazole developed proven or probable invasive fungal infection, compared to two (4%) of the 52 patients receiving itraconazole (P?=?0.17). Drug discontinuation because of adverse events occurred in 15 patients (21%) receiving voriconazole and six (11%) receiving itraconazole (P?=?0.23).

Conclusions

Voriconazole is a good alternative for prophylaxis in patients with leukemia. Elevated baseline bilirubin levels were associated with a higher risk of side effects in patients receiving IV voriconazole or IV itraconazole. Monitoring of liver function and drug levels should be considered for some patients.     

Impact of ureido/carboxypenicillin resistance on the prognosis of ventilator-associated pneumonia due to Pseudomonas aeruginosa

Introduction

Although Pseudomonas aeruginosa is a leading pathogen responsible for ventilator-associated pneumonia (VAP), the excess in mortality associated with multi-resistance in patients with P. aeruginosa VAP (PA-VAP), taking into account confounders such as treatment adequacy and prior length of stay in the ICU, has not yet been adequately estimated.

Methods

A total of 223 episodes of PA-VAP recorded into the Outcomerea database were evaluated. Patients with ureido/carboxy-resistant P. aeruginosa (PRPA) were compared with those with ureido/carboxy-sensitive P. aeruginosa (PSPA) after matching on duration of ICU stay at VAP onset and adjustment for confounders.

Results

Factors associated with onset of PRPA-VAP were as follows: admission to the ICU with septic shock, broad-spectrum antimicrobials at admission, prior use of ureido/carboxypenicillin, and colonization with PRPA before infection. Adequate antimicrobial therapy was more often delayed in the PRPA group. The crude ICU mortality rate and the hospital mortality rate were not different between the PRPA and the PSPA groups. In multivariate analysis, after controlling for time in the ICU before VAP diagnosis, neither ICU death (odds ratio (OR) = 0.73; 95% confidence interval (CI): 0.32 to 1.69; P = 0.46) nor hospital death (OR = 0.87; 95% CI: 0.38 to 1.99; P = 0.74) were increased in the presence of PRPA infection. This result remained unchanged in the subgroup of 87 patients who received adequate antimicrobial treatment on the day of VAP diagnosis.

Conclusions

After adjustment, and despite the more frequent delay in the initiation of an adequate antimicrobial therapy in these patients, resistance to ureido/carboxypenicillin was not associated with ICU or hospital death in patients with PA-VAP.     

Impact of a multifaceted prevention program on ventilator-associated pneumonia including selective oropharyngeal decontamination

Purpose

We describe the impact of a multifaceted program for decreasing ventilator-associated pneumonia (VAP) after implementing nine preventive measures, including selective oropharyngeal decontamination (SOD).

Methods

We compared VAP rates during an 8-month pre-intervention period, a 12-month intervention period, and an 11-month post-intervention period in a cohort of patients who received mechanical ventilation (MV) for?>?48 h. The primary objective was to assess the effect on first VAP occurrence, using a Cox cause-specific proportional hazards model. Secondary objectives included the impact on emergence of antimicrobial resistance, antibiotic consumption, duration of MV, and ICU mortality.

Results

Pre-intervention, intervention and post-intervention VAP rates were 24.0, 11.0 and 3.9 VAP episodes per 1000 ventilation-days, respectively. VAP rates decreased by 56% [hazard ratio (HR) 0.44, 95% CI 0.29–0.65; P?<?0.001] in the intervention and by 85% (HR 0.15, 95% CI 0.08–0.27; P?<?0.001) in the post-intervention periods. During the intervention period, VAP rates decreased by 42% (HR 0.58, 95% CI 0.38–0.87; P?<?0.001) after implementation of eight preventive measures without SOD, and by 70% after adding SOD (HR 0.30, 95% CI 0.13–0.72; P?<?0.001) compared to the pre-intervention period. The incidence density of intrinsically resistant bacteria (to colistin or tobramycin) did not increase. We documented a significant reduction of days of therapy per 1000 patient-days of broad-spectrum antibiotic used to treat lower respiratory tract infection (P?<?0.028), median duration of MV (from 7.1 to 6.4 days; P?<?0.003) and ICU mortality (from 16.2 to 13.5%; P?<?0.049) for patients ventilated?>?48 h between the pre- and post-intervention periods.

Conclusions

Our preventive program produced a sustained decrease in VAP incidence. SOD provides an additive value.