Nasia Safdar

Clinical and economic consequences of ventilator-associated pneumonia: a systematic review.

Background:Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in critically ill patients. The clinical and economic consequences of VAP are unclear, with a broad range of values reported in the literature Objective:To perform a systematic review to determine the incidence of VAP and its attributable mortality rate, length of stay, and costs. Data Source:Computerized PUBMED and MEDLINE search supplemented by manual searches for relevant articles, limited to articles published after 1990. Study Selection:English-language observational studies and randomized trials that provided data on the incidence of VAP were included. Matched cohort studies were included for calculation of attributable mortality rate and length of stay. Data Extraction:Data were extracted on patient population, diagnostic criteria for VAP, incidence, outcome, type of intensive care unit, and study design. Data Synthesis:The cumulative incidence of VAP was calculated by combining the results of several studies using standard formulas for combining proportions, in which the weighted average and variance are calculated. Results from studies comparing intensive care unit and hospital mortality due to VAP, additional length of stay, and additional days of mechanical ventilation were pooled using a random effects model, with assessment of heterogeneity. Results:Our findings indicate a) between 10% and 20% of patients receiving >48 hrs of mechanical ventilation will develop VAP; b) critically ill patients who develop VAP appear to be twice as likely to die compared with similar patients without VAP (pooled odds ratio, 2.03; 95% confidence interval, 1.16–3.56); c) patients with VAP have significantly longer intensive care unit lengths of stay (mean = 6.10 days; 95% confidence interval, 5.32–6.87 days); and d) patients who develop VAP incur ≥

Diagnosis of invasive aspergillosis using a galactomannan assay:a meta-analysis

10,019 in additional hospital costs. Conclusions:Ventilator-associated pneumonia occurs in a considerable proportion of patients undergoing mechanical ventilation and is associated with substantial morbidity, a two-fold mortality rate, and excess cost. Given these findings, strategies that effectively prevent VAP are urgently needed. LEARNING OBJECTIVESOn completion of this article, the reader should be able to: Define the incidence of ventilator-associated pneumonia (VAP) in mechanically ventilated patients. Explain the economic consequences of VAP. Use this information in a clinical setting. All authors have disclosed that they have no financial relationships or interests in any commercial companies pertaining to this educational activity. Wolters Kluwer Health has identified and resolved all faculty conflicts of interest regarding this educational activity. Visit the Critical Care Medicine Web site (www.ccmjournal.org) for information on obtaining continuing medical education credit.

Impact of Treatment Strategy on Outcomes in Patients with Candidemia and Other Forms of Invasive Candidiasis: A Patient-Level Quantitative Review of Randomized Trials

BACKGROUND A double-sandwich enzyme-linked immunosorbent galactomannan assay has been approved for surveillance for invasive aspergillosis in immunocompromised patients. We undertook a meta-analysis to assess the accuracy of a galactomannan assay for diagnosing invasive aspergillosis. METHODS Studies of the galactomannan assay that used the European Organization for Research and Treatment of Cancer or similar criteria as a reference standard and provided data to calculate sensitivity and specificity were included. Pooled sensitivity and specificity and summary measures of accuracy, Q* (the upper left-most point on the summary receiver-operating characteristic curve), mean D (a log odds ratio), and Youden index were calculated. Subgroup analyses were performed to explore heterogeneity. RESULTS Twenty-seven studies from 1966 to 28 February 2005 were included. Overall, the galactomannan assay had a sensitivity of 0.71 (95% confidence interval [CI], 0.68-0.74) and specificity of 0.89 (95% CI, 0.88-0.90) for proven cases of invasive aspergillosis. The Youden index, mean D, and Q* were 0.54 (95% CI, 0.41-0.65), 2.74 (95% CI, 21.12-3.36), and 0.80 (95% CI, 0.74-0.86), respectively, indicating moderate accuracy. Subgroup analyses showed that the performance of the test differed by patient population and type of reference standard used. Significant heterogeneity was present. CONCLUSIONS The galactomannan assay has moderate accuracy for diagnosis of invasive aspergillosis in immunocompromised patients. The test is more useful in patients who have hematological malignancy or who have undergone hematopoietic cell transplantation than in solid-organ transplant recipients. Further studies with attention to the impact of antifungal therapy, rigorous assessment of false-positive test results, and assessment of the utility of the test under nonsurveillance conditions are needed.

Voriconazole Therapeutic Drug Monitoring

BACKGROUND Invasive candidiasis (IC) is an important healthcare-related infection, with increasing incidence and a crude mortality exceeding 50%. Numerous treatment options are available yet comparative studies have not identified optimal therapy. METHODS We conducted an individual patient-level quantitative review of randomized trials for treatment of IC and to assess the impact of host-, organism-, and treatment-related factors on mortality and clinical cure. Studies were identified by searching computerized databases and queries of experts in the field for randomized trials comparing the effect of ≥2 antifungals for treatment of IC. Univariate and multivariable analyses were performed to determine factors associated with patient outcomes. RESULTS Data from 1915 patients were obtained from 7 trials. Overall mortality among patients in the entire data set was 31.4%, and the rate of treatment success was 67.4%. Logistic regression analysis for the aggregate data set identified increasing age (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00-1.02; P = .02), the Acute Physiology and Chronic Health Evaluation II score (OR, 1.11; 95% CI, 1.08-1.14; P = .0001), use of immunosuppressive therapy (OR, 1.69; 95% CI, 1.18-2.44; P = .001), and infection with Candida tropicalis (OR, 1.64; 95% CI, 1.11-2.39; P = .01) as predictors of mortality. Conversely, removal of a central venous catheter (CVC) (OR, 0.50; 95% CI, .35-.72; P = .0001) and treatment with an echinocandin antifungal (OR, 0.65; 95% CI, .45-.94; P = .02) were associated with decreased mortality. Similar findings were observed for the clinical success end point. CONCLUSIONS Two treatment-related factors were associated with improved survival and greater clinical success: use of an echinocandin and removal of the CVC.

Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis

ABSTRACT We report on 28 patients who underwent voriconazole monitoring because of disease progression or toxicity. A relationship (P < 0.025) between disease progression and drug concentration was detected. Favorable responses were observed in 10/10 patients with concentrations above 2.05 μg/ml, while disease progressed in 44% (n = 18) of patients with concentrations below 2.05 μg/ml.

Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study.

The use of combination antimicrobial therapy for bacteraemia caused by Gram-negative bacilli is controversial. We did a meta-analysis of published studies to determine whether a combination of two or more antimicrobials reduces mortality in patients with Gram-negative bacteraemia. Criteria for inclusion were: analytic studies of patients with documented Gram-negative bacteraemia that included patients receiving a single antibiotic (monotherapy) and patients receiving two or more antibiotics (combination therapy). Data on mortality (outcome) had to be provided. A pooled odds ratio was calculated with the random effects model of DerSimonian and Laird. Assessment of heterogeneity was done with the Breslow-Day test and reasons for heterogeneity were explored. 17 studies met the inclusion criteria, five prospective cohort studies, two prospective randomised trials, and ten retrospective cohort studies. Most studies used beta-lactams or aminoglycosides alone and in combination. The summary odds ratio was 0.96 (95% CI 0.70-1.32), indicating no mortality benefit with combination therapy. Subgroup analyses adjusting for year of publication, study design, and severity of illness did not change the results. Considerable heterogeneity was present in the main analyses. Analysis of only Pseudomonas aeruginosa bacteraemias showed a significant mortality benefit (OR 0.50, 95% CI 0.30-0.79). Our analysis does not support the routine use of combination antimicrobial therapy for Gram-negative bacteraemia, beyond settings where infection by P aeruginosa is strongly suspected or more than one drug would be desirable to assure in-vitro efficacy.

The Risk of Infection after Nasal Colonization with Staphylococcus Aureus

Background. The efficacy of the combination of voriconazole and caspofungin when used as primary therapy for invasive aspergillosis in organ transplant recipients has not been defined. Methods. Transplant recipients who received voriconazole and caspofungin (n=40) as primary therapy for invasive aspergillosis (proven or probable) in a prospective multicenter study between 2003 and 2005 were compared to a control group comprising a cohort of consecutive transplant recipients between 1999 and 2002 who had received a lipid formulation of AmB as primary therapy (n=47). In vitro antifungal testing of Aspergillus isolates to combination therapy was correlated with clinical outcome. Results. Survival at 90 days was 67.5% (27/40) in the cases, and 51% (24/47) in the control group (HR 0.58, 95% CI, 0.30–1.14, P=0.117). However, in transplant recipients with renal failure (adjusted HR 0.32, 95% CI: 0.12–0.85, P=0.022), and in those with A. fumigatus infection (adjusted HR 0.37, 95% CI: 0.16–0.84, P=0.019), combination therapy was independently associated with an improved 90-day survival in multivariate analysis. No correlation was found between in vitro antifungal interactions of the Aspergillus isolates to the combination of voriconazole and caspofungin and clinical outcome. Conclusions. Combination of voriconazole and caspofungin might be considered preferable therapy for subsets of organ transplant recipients with invasive aspergillosis, such as those with renal failure or A. fumigatus infection.

The pathogenesis of catheter-related bloodstream infection with noncuffed short-term central venous catheters

PURPOSE Nasal, axillary, or inguinal colonization with Staphylococcus aureus generally precedes invasive infection. Some studies have found that colonization with methicillin-resistant S. aureus (MRSA) poses a greater risk of clinical infection than colonization with methicillin-susceptible S. aureus (MSSA). However, the magnitude of risk is unclear. METHODS We undertook a systematic review to provide an overall estimate of the risk of infection following colonization with MRSA compared with colonization by MSSA. Ten observational studies, with a total of 1170 patients, were identified that provided data on both MSSA and MRSA colonization and infection. A random-effects model was used to obtain pooled estimates of the odds ratio and 95% confidence interval. RESULTS Overall, colonization by MRSA was associated with a 4-fold increase in the risk of infection (odds ratio 4.08, 95% confidence interval, 2.10-7.44). Studies differed in the choice of patient population, severity of illness, and frequency of sampling to detect colonization. CONCLUSION Further research is needed to identify effective methods for sustained eradication of MRSA carriage to reduce the high risk of subsequent infection.

In Vivo Pharmacodynamic Activity of Daptomycin

ObjectiveShort-term, noncuffed, percutaneously inserted central venous catheters (CVCs) are widely used and cause more than 250,000 bloodstream infections (BSIs) in hospitals each year in the United States. We report a prospective study undertaken to determine the pathogenesis of CVC-related BSI.Design and settingProspective cohort study in a university hospital 24-bed medical-surgical intensive care unit.Patients and participantsPatients participating in two randomized trials during 1998–2000—one studying the efficacy of a 1% chlorhexidine–75% alcohol solution for cutaneous antisepsis and the other a novel chlorhexidine-impregnated sponge dressing—formed the study population; CVC-related BSIs were considered to be extraluminally acquired if concordance was identified solely between isolates from catheter segments, skin, and blood cultures and intraluminally acquired if concordance was demonstrated only between hub or infusate and blood culture isolates, as confirmed by DNA subtyping of isolates from blood and catheter sites or infusate.ResultsOf 1,263 catheters (6075 CVC days) prospectively studied, 35 (2.7%) caused BSI (5.9 per 1000 CVC days); 27 were caused by coagulase-negative staphylococci. Overall, 45% of infections were extraluminally acquired, 26% were intraluminally derived, and the mechanism of infection was indeterminate in 29%. In the pooled control groups of the two trials, 25 CVC-related BSIs occurred (7.0 per 1000 CVC days), of which 60% of infections were extraluminally acquired, 12% were intraluminally derived and 28% were indeterminate. In contrast, CVC-related BSIs in the treatment groups were most often intraluminally derived (60%, p=0.006).ConclusionsMost catheter-related BSIs with short-term percutaneously inserted, noncuffed CVCs were extraluminally acquired and derived from the cutaneous microflora. Strategies achieving successful suppression of cutaneous colonization can substantially reduce the risk of catheter-related BSI with short-term CVCs.

Meta-Analysis: Methods for Diagnosing Intravascular Device–Related Bloodstream Infection

ABSTRACT Daptomycin is a lipopeptide antibiotic with activity against a wide range of gram-positive bacteria. We used the neutropenic murine thigh model to characterize the pharmacodynamics of daptomycin. ICR/Swiss mice were rendered neutropenic with cyclophosphamide; and the thigh muscles of the mice were infected with strains of Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecium. Animals were treated by subcutaneous injection of daptomycin at doses of 0.20 to 400 mg/kg of body weight/day divided into one, two, four, or eight doses over 24 h. Daptomycin exhibited linear pharmacokinetics, with an area under the concentration-time curve (AUC) from time zero to infinity/dose of 9.4 and a half-life of 0.9 to 1.4 h. The level of protein binding was 90%. Free daptomycin exhibited concentration-dependent killing and produced in vivo postantibiotic effects (PAEs) of 4.8 to 10.8 h. Nonlinear regression analysis was used to determine which pharmacokinetic (PK) or pharmacodynamic (PD) parameter was important for efficacy by using free drug concentrations. The peak concentration/MIC (peak/MIC) ratio and 24-h AUC/MIC ratio were the PK and PD parameters that best correlated with in vivo efficacy (R2 = 83 to 87% for peak/MIC and R2 = 86% for the AUC/MIC ratio, whereas R2 = 47 to 50% for the time that the concentration was greater than the MIC) against standard strains of S. aureus and S. pneumoniae. The peak/MIC ratios required for a bacteriostatic effect ranged from 12 to 36 for S. pneumoniae, 59 to 94 for S. aureus, and 0.14 to 0.25 for E. faecium. The AUC/MIC ratios needed for a bacteriostatic effect ranged from 75 to 237 for S. pneumoniae, 388 to 537 for S. aureus, and 0.94 to 1.67 for E. faecium. The free daptomycin concentrations needed to average from one to two times the MIC over 24 h to produce a bacteriostatic effect and two to four times the MIC over 24 h to produce greater than 99% killing. The long PAE and potent bactericidal activity make daptomycin an attractive option for the treatment of infections caused by gram-positive bacteria.