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1.  Clinical and economic consequences of hospital-acquired resistant and multidrug-resistant Pseudomonas aeruginosa infections: a systematic review and meta-analysis 
Background
Increasing rates of resistant and multidrug-resistant (MDR) P. aeruginosa in hospitalized patients constitute a major public health threat. We present a systematic review of the clinical and economic impact of this resistant pathogen.
Methods
Studies indexed in MEDLINE and Cochrane databases between January 2000-February 2013, and reported all-cause mortality, length of stay, hospital costs, readmission, or recurrence in at least 20 hospitalized patients with laboratory confirmed resistant P. aeruginosa infection were included. We accepted individual study definitions of MDR, and assessed study methodological quality.
Results
The most common definition of MDR was resistance to more than one agent in three or more categories of antibiotics. Twenty-three studies (7,881 patients with susceptible P. aeruginosa, 1,653 with resistant P. aeruginosa, 559 with MDR P. aeruginosa, 387 non-infected patients without P. aeruginosa) were analyzed. A random effects model meta-analysis was feasible for the endpoint of all-cause in-hospital mortality. All-cause mortality was 34% (95% confidence interval (CI) 27% – 41%) in patients with any resistant P. aeruginosa compared to 22% (95% CI 14% – 29%) with susceptible P. aeruginosa. The meta-analysis demonstrated a > 2-fold increased risk of mortality with MDR P. aeruginosa (relative risk (RR) 2.34, 95% CI 1.53 – 3.57) and a 24% increased risk with resistant P. aeruginosa (RR 1.24, 95% CI 1.11 – 1.38), compared to susceptible P. aeruginosa. An adjusted meta-analysis of data from seven studies demonstrated a statistically non-significant increased risk of mortality in patients with any resistant P. aeruginosa (adjusted RR 1.24, 95% CI 0.98 – 1.57). All three studies that reported infection-related mortality found a statistically significantly increased risk in patients with MDR P. aeruginosa compared to those with susceptible P. aeruginosa. Across studies, hospital length of stay (LOS) was higher in patients with resistant and MDR P. aeruginosa infections, compared to susceptible P. aeruginosa and control patients. Limitations included heterogeneity in MDR definition, restriction to nosocomial infections, and potential confounding in analyses.
Conclusions
Hospitalized patients with resistant and MDR P. aeruginosa infections appear to have increased all-cause mortality and LOS. The negative clinical and economic impact of these pathogens warrants in-depth evaluation of optimal infection prevention and stewardship strategies.
Electronic supplementary material
The online version of this article (doi:10.1186/2047-2994-3-32) contains supplementary material, which is available to authorized users.
doi:10.1186/2047-2994-3-32
PMCID: PMC4219028  PMID: 25371812
Pseudomonas aeruginosa; Resistance; All-cause mortality
2.  Influence of real-world characteristics on outcomes for patients with methicillin-resistant Staphylococcal skin and soft tissue infections: a multi-country medical chart review in Europe 
BMC Infectious Diseases  2014;14(1):476.
Background
Patient-related (demographic/disease) and treatment-related (drug/clinician/hospital) characteristics were evaluated as potential predictors of healthcare resource use and opportunities for early switch (ES) from intravenous (IV)-to-oral methicillin-resistant Staphylococcus aureus (MRSA)-active antibiotic therapy and early hospital discharge (ED).
Methods
This retrospective observational medical chart study analyzed patients (across 12 European countries) with microbiologically confirmed MRSA complicated skin and soft tissue infections (cSSTI), ≥3 days of IV anti-MRSA antibiotics during hospitalization (July 1, 2010-June 30, 2011), and discharged alive by July 31, 2011. Logistic/linear regression models evaluated characteristics potentially associated with actual resource use (length of IV therapy, length of hospital stay [LOS], IV-to-oral antibiotic switch), and ES and ED (using literature-based and expert-verified criteria) outcomes.
Results
1542 patients (mean ± SD age 60.8 ± 16.5 years; 61.5% males) were assessed with 81.0% hospitalized for MRSA cSSTI as the primary reason. Several patient demographic, infection, complication, treatment, and hospital characteristics were predictive of length of IV therapy, LOS, IV-to-oral antibiotic switch, or ES and ED opportunities. Outcomes and ES and ED opportunities varied across countries. Length of IV therapy and LOS (r = 0.66, p < 0.0001) and eligibilities for ES and ED (r = 0.44, p < 0.0001) showed relatively strong correlations. IV-to-oral antibiotic switch patients had significantly shorter length of IV therapy (−5.19 days, p < 0.001) and non-significantly shorter LOS (−1.86 days, p > 0.05). Certain patient and treatment characteristics were associated with increased odds of ES (healthcare-associated/ hospital-acquired infection) and ED (patient living arrangements, healthcare-associated/ hospital-acquired infection, initiating MRSA-active treatment 1–2 days post cSSTI index date, existing ED protocol), while other factors decreased the odds of ES (no documented MRSA culture, ≥4 days from admission to cSSTI index date, IV-to-oral switch, IV line infection) and ED (dementia, no documented MRSA culture, initiating MRSA-active treatment ≥3 days post cSSTI index date, existing ES protocol).
Conclusions
Practice patterns and opportunity for further ES and ED were affected by several infection, treatment, hospital, and geographical characteristics, which should be considered in identifying ES and ED opportunities and designing interventions for MRSA cSSTI to reduce IV days and LOS while maintaining the quality of care.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2334-14-476) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2334-14-476
PMCID: PMC4164818  PMID: 25182029
IV-to-oral antibiotic switch; Length of stay; Clinical criteria; Antibiotic therapy
3.  Cost-effectiveness analysis of fidaxomicin versus vancomycin in Clostridium difficile infection 
Journal of Antimicrobial Chemotherapy  2014;69(11):2901-2912.
Objectives
Fidaxomicin was non-inferior to vancomycin with respect to clinical cure rates in the treatment of Clostridium difficile infections (CDIs) in two Phase III trials, but was associated with significantly fewer recurrences than vancomycin. This economic analysis investigated the cost-effectiveness of fidaxomicin compared with vancomycin in patients with severe CDI and in patients with their first CDI recurrence.
Methods
A 1 year time horizon Markov model with seven health states was developed from the perspective of Scottish public healthcare providers. Model inputs for effectiveness, resource use, direct costs and utilities were obtained from published sources and a Scottish expert panel. The main model outcome was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY), for fidaxomicin versus vancomycin; ICERs were interpreted using willingness-to-pay thresholds of £20 000/QALY and £30 000/QALY. One-way and probabilistic sensitivity analyses were performed.
Results
Total costs were similar with fidaxomicin and vancomycin in patients with severe CDI (£14 515 and £14 344, respectively) and in patients with a first recurrence (£16 535 and £16 926, respectively). Improvements in clinical outcomes with fidaxomicin resulted in small QALY gains versus vancomycin (severe CDI, +0.010; patients with first recurrence, +0.019). Fidaxomicin was cost-effective in severe CDI (ICER £16 529/QALY) and dominant (i.e. more effective and less costly) in patients with a first recurrence. The probability that fidaxomicin was cost-effective at a willingness-to-pay threshold of £30 000/QALY was 60% for severe CDI and 68% in a first recurrence.
Conclusions
Fidaxomicin is cost-effective in patients with severe CDI and in patients with a first CDI recurrence versus vancomycin.
doi:10.1093/jac/dku257
PMCID: PMC4195473  PMID: 25096079
economic; model; antibacterials
4.  Modeling the economic impact of linezolid versus vancomycin in confirmed nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus 
Critical Care  2014;18(4):R157.
Introduction
We compared the economic impacts of linezolid and vancomycin for the treatment of hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA)–confirmed nosocomial pneumonia.
Methods
We used a 4-week decision tree model incorporating published data and expert opinion on clinical parameters, resource use and costs (in 2012 US dollars), such as efficacy, mortality, serious adverse events, treatment duration and length of hospital stay. The results presented are from a US payer perspective. The base case first-line treatment duration for patients with MRSA-confirmed nosocomial pneumonia was 10 days. Clinical treatment success (used for the cost-effectiveness ratio) and failure due to lack of efficacy, serious adverse events or mortality were possible clinical outcomes that could impact costs. Cost of treatment and incremental cost-effectiveness per successfully treated patient were calculated for linezolid versus vancomycin. Univariate (one-way) and probabilistic sensitivity analyses were conducted.
Results
The model allowed us to calculate the total base case inpatient costs as $46,168 (linezolid) and $46,992 (vancomycin). The incremental cost-effectiveness ratio favored linezolid (versus vancomycin), with lower costs ($824 less) and greater efficacy (+2.7% absolute difference in the proportion of patients successfully treated for MRSA nosocomial pneumonia). Approximately 80% of the total treatment costs were attributed to hospital stay (primarily in the intensive care unit). The results of our probabilistic sensitivity analysis indicated that linezolid is the cost-effective alternative under varying willingness to pay thresholds.
Conclusion
These model results show that linezolid has a favorable incremental cost-effectiveness ratio compared to vancomycin for MRSA-confirmed nosocomial pneumonia, largely attributable to the higher clinical trial response rate of patients treated with linezolid. The higher drug acquisition cost of linezolid was offset by lower treatment failure–related costs and fewer days of hospitalization.
doi:10.1186/cc13996
PMCID: PMC4220084  PMID: 25053453
5.  From intermittent antibiotic point prevalence surveys to quality improvement: experience in Scottish hospitals 
Background
In 2008, the Scottish Antimicrobial Prescribing Group (SAPG) was established to coordinate a national antimicrobial stewardship programme. In 2009 SAPG led participation in a European point prevalence survey (PPS) of hospital antibiotic use. We describe how SAPG used this baseline PPS as the foundation for implementation of measures for improvement in antibiotic prescribing.
Methods
In 2009 data for the baseline PPS were collected in accordance with the European Surveillance of Antimicrobial Consumption [ESAC] protocol. This informed the development of two quality prescribing indicators: compliance with antibiotic policy in acute admission units and duration of surgical prophylaxis. From December 2009 clinicians collected these data on a monthly basis. The prescribing indicators were reviewed and further modified in March 2011. Data for the follow up PPS in September 2011 were collected as part of a national PPS of healthcare associated infection and antimicrobial use developed using ECDC protocols.
Results
In the baseline PPS data were collected in 22 (56%) acute hospitals. The frequency of recording the reason for treatment in medical notes was similar in Scotland (75.9%) and Europe (75.7%). Compliance with policy (81.0%) was also similar to Europe (82.5%) but duration of surgical prophylaxis <24hr (68.6%), was higher than in Europe (48.1%, OR: 0.41, p<0.001). Following the development and implementation of the prescribing indicators monthly measurement and data feedback in admission units illustrated improvement in indication documented of ≥90% and compliance with antibiotic prescribing policy increasing from 76% to 90%. The initial prescribing indicator in surgical prophylaxis was less successful in providing consistent national data as there was local discretion on which procedures to include. Following a review and a focus on colorectal surgery the mean proportion receiving single dose prophylaxis exceeded the target of 95% and the mean proportion compliant with policy was 83%. In the follow up PPS of 2011 indication documented (86.8%) and policy compliant (82.8%) were higher than in baseline PPS.
Conclusions
The baseline PPS identified priorities for quality improvement. SAPG has demonstrated that implementation of regularly reviewed national prescribing indicators, acceptable to clinicians, implemented through regular systematic measurement can drive improvement in quality of antibiotic use in key clinical areas. However, our data also show that the ESAC PPS method may underestimate the proportion of surgical prophylaxis with duration <24hr.
doi:10.1186/2047-2994-2-3
PMCID: PMC3573889  PMID: 23320479
Antimicrobial stewardship; Quality improvement; Prescribing indicators; Point prevalence survey; Antibiotic; Hospital prescribing; Surgical prophylaxis
6.  MRSA: treating people with infection 
Clinical Evidence  2010;2010:0922.
Introduction
Methicillin-resistant Staphylococcus aureus (MRSA) has a gene that makes it resistant to methicillin as well as to other beta-lactam antibiotics including flucloxacillin, beta-lactam/beta-lactamase inhibitor combinations, cephalosporins, and carbapenems. MRSA can be part of the normal body flora (colonisation), especially in the nose, but it can cause infection, especially in people with prolonged hospital admissions, with underlying disease, or after antibiotic use. About 20% of S aureus in blood cultures in England, Wales, and Northern Ireland is resistant to methicillin.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatment for MRSA infections at any body site? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 11 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: clindamycin, daptomycin, fusidic acid, glycopeptides (teicoplanin, vancomycin), linezolid, macrolides (azithromycin, clarithromycin, erythromycin), quinolones (ciprofloxacin, levofloxacin, moxifloxacin), quinupristin–dalfopristin, pristinamycin, rifampicin, tetracyclines (doxycycline, minocycline, oxytetracycline), tigecycline, trimethoprim, and trimethoprim–sulfamethoxazole (co-trimoxazole).
Key Points
Methicillin-resistant Staphylococcus aureus (MRSA) has a gene that makes it resistant to methicillin as well as other beta-lactam antibiotics including flucloxacillin, cephalosporins, and carbapenems. MRSA can be part of the normal body flora (colonisation), especially in the nose, but it can cause infection, especially in people with prolonged hospital admissions, with underlying disease, or after antibiotic use.About 20% of S aureus in blood cultures in England, Wales, and Northern Ireland is resistant to methicillin.
Glycopeptides (teicoplanin, vancomycin) and linezolid seem to have similar efficacy at curing MRSA infection. However, they have all been associated with adverse effects.
We found limited evidence that tigecycline may have similar cure rates as vancomycin, however effectiveness is not yet clear.
Trimethoprim–sulfamethoxazole (co-trimoxazole; TMP-SMX) may be as effective as vancomycin at curing MRSA infection in injecting drug users, with similar toxicity. However, we cannot draw conclusions on the effects of this drug in other populations.
We don’t know whether macrolides (azithromycin, clarithromycin, erythromycin), quinolones (ciprofloxacin, levofloxacin, moxifloxacin), tetracyclines (doxycycline, minocycline, oxytetracycline), clindamycin, daptomycin, fusidic acid, pristinamycin, quinupristin–dalfopristin, rifampicin, and trimethoprim are effective at curing MRSA infection, because we found no adequate RCTs. Ciprofloxacin has been used in combination with rifampicin or fusidic acid for MRSA bone and joint infections but we cannot confirm its effectiveness from adequate studies. Fusidic acid or rifampicin should not be used as monotherapy because resistance rapidly develops.Clindamycin may be used in preference to macrolides in susceptible MRSA infections, as bioavailability may be better and resistance less likely, however we found no adequate trials.Oral tetracyclines may be recommended for minor MRSA infections, however we found no adequate trials.
PMCID: PMC3217712  PMID: 21418679
7.  Antimicrobial stewardship in Scotland: impact of a national programme 
Backgound
The Scottish Antimicrobial Prescribing Group (SAPG) was established by the Scottish Government in 2008 to lead the first national initiative to actively address antimicrobial stewardship. Healthcare associated infection (HAI) is a priority in Scotland and the work of SAPG contributes to the national HAI Delivery Plan. SAPG's early work has focused on restricting the use of antibiotics associated with a high risk of Clostridium difficile infection (CDI) and development of national prescribing indicators to support reduction of CDI.
Findings
Scottish Antimicrobial Prescribing Group has developed prescribing indicators for hospital and primary care, which are measured and reported in all 14 NHS board areas. Improvement in compliance with the indicators has been demonstrated with resultant reductions in CDI rates and no adverse effect on mortality or antimicrobial resistance patterns.
Conclusions
The establishment of a Scottish national antimicrobial stewardship programme has made a significant contribution to the HAI agenda, particularly in relation to CDI. The programme is supported by local antimicrobial teams, a national framework for education, surveillance of antimicrobial use and resistance and sharing of data for improvement. Antimicrobial stewardship has been integrated with other national programmes on patient safety and quality improvement.
doi:10.1186/2047-2994-1-7
PMCID: PMC3436612  PMID: 22958296
Antimicrobial stewardship; Clostridium difficile infection; prescribing indicators; quality improvement
8.  A randomized trial of the efficacy and safety of sequential intravenous/oral moxifloxacin monotherapy versus intravenous piperacillin/tazobactam followed by oral amoxicillin/clavulanate for complicated skin and skin structure infections 
Journal of Antimicrobial Chemotherapy  2011;66(11):2632-2642.
Objectives
The primary aim of the RELIEF study was to evaluate the efficacy and safety of two sequential intravenous (iv)/oral regimens: moxifloxacin iv/oral versus piperacillin/tazobactam (TZP) iv followed by oral amoxicillin/clavulanate (AMC).
Patients and methods
The study had a prospective, randomized, double-dummy, double-blind, multicentre design. Patients ≥18 years were prospectively stratified according to complicated skin and skin structure infection (cSSSI) subtype/diagnosis (major abscess, diabetic foot infection, wound infection or infected ischaemic ulcer), surgical intervention and severity of illness. Diagnoses and disease severity were based on predetermined criteria, documented by repeated photographs, and confirmed by an independent data review committee. Patients were randomized to receive either 400 mg of moxifloxacin iv once daily followed by 400 mg of moxifloxacin orally once daily or 4.0/0.5 g of TZP iv thrice daily followed by 875/125 mg of AMC orally twice daily for 7–21 days. The primary efficacy variable was clinical response at test of cure (TOC) for the per-protocol (PP) population. Clinical efficacy was assessed by the data review committee based on repeated photographs and case descriptions. Clinical trials registry number: NCT 00402727.
Results
A total of 813 patients were randomized. Clinical success rates at TOC were similar for moxifloxacin and TZP–AMC in the PP [320/361 (88.6%) versus 275/307 (89.6%), respectively; P = 0.758] and intent-to-treat (ITT) [350/426 (82.2%) versus 305/377 (80.9%), respectively; P = 0.632] populations. Thus, moxifloxacin was non-inferior to TZP–AMC. Bacteriological success rates were high in both treatment arms [moxifloxacin: 432/497 (86.9%) versus TZP–AMC: 370/429 (86.2%), microbiologically valid (MBV) population]. Moxifloxacin was non-inferior to TZP–AMC at TOC in both the MBV and the ITT populations. Both treatments were well tolerated.
Conclusions
Once-daily iv/oral moxifloxacin monotherapy was clinically and bacteriologically non-inferior to iv TZP thrice daily followed by oral AMC twice daily in patients with cSSSIs.
doi:10.1093/jac/dkr344
PMCID: PMC3191944  PMID: 21896561
β-lactams; randomized controlled trials; soft tissue infections; fluoroquinolones; sequential therapy
9.  Medical resource utilization among patients with ventilator-associated pneumonia: pooled analysis of randomized studies of doripenem versus comparators 
Critical Care  2010;14(3):R84.
Introduction
Ventilator-associated pneumonia (VAP) is associated with increased medical resource utilization, but few randomized studies have been conducted to evaluate the effect of initial antibiotic therapy. To assess medical resource utilization in patients with VAP, we conducted a pooled analysis of two prospective, randomized, open-label, multicenter, phase III studies, which also showed that doripenem was clinically noninferior to comparators.
Methods
We assessed durations of mechanical ventilation, intensive care unit (ICU) stay, and hospitalization in patients with VAP who received at least 1 dose of doripenem or a comparator in the phase III studies. Comparators were piperacillin/tazobactam (study 1) and imipenem (study 2). We analyzed between-group differences in medical resource utilization endpoints by comparison of Kaplan-Meier curves with generalized Wilcoxon test and in microbiologic eradication rates by two-sided Fisher's exact test.
Results
625 patients with VAP were evaluated and received at least 1 dose of doripenem (n = 312) or a comparator (n = 313). Median durations of mechanical ventilation (7 versus 10 days; P = 0.008) and hospitalization (22 versus 26 days; P = 0.010) were shorter for doripenem than comparators; corresponding ICU stays were 12 and 13 days (P = 0.065). All-cause, overall mortality rates were similar (51/312 [16%] versus 47/313 [15%]; P = 0.648). MIC90 values against Pseudomonas aeruginosa for doripenem versus imipenem were 4 versus 16 μg/mL in study 2. P. aeruginosa was eradicated from 16/24 (67%) doripenem recipients and 10/24 (42%) comparator recipients (P = 0.147). In patients with P. aeruginosa at baseline, median durations of mechanical ventilation (7 versus 13 days; P = 0.031) and ICU stay (13 versus 21 days; P = 0.027) were shorter for doripenem; corresponding hospital stays were 24 and 35 days (P = 0.129).
Conclusions
Doripenem was associated with lower medical resource utilization than comparators. Differences in antipseudomonal activity may have contributed to these findings.
Trial registration
ClinicalTrials.gov number NCT00211003 (study 1) and NCT00211016 (study 2).
doi:10.1186/cc9012
PMCID: PMC2911715  PMID: 20459721
10.  The CURB65 pneumonia severity score outperforms generic sepsis and early warning scores in predicting mortality in community‐acquired pneumonia 
Thorax  2006;62(3):253-259.
Background
The performance of CURB65 in predicting mortality in community‐acquired pneumonia (CAP) has been tested in two large observational studies. However, it has not been tested against generic sepsis and early warning scores, which are increasingly being advocated for identification of high‐risk patients in acute medical wards.
Method
A retrospective analysis was performed of data prospectively collected for a CAP quality improvement study. The ability to stratify mortality and performance characteristics (sensitivity, specificity, positive predictive value, negative predictive value and area under the receiver operating curve) were calculated for stratifications of CURB65, CRB65, the systemic inflammatory response syndrome (SIRS) criteria and the standardised early warning score (SEWS).
Results
419 patients were included in the main analysis with a median age of 74 years (men = 47%). CURB65 and CRB65 stratified mortality in a more clinically useful way and had more favourable operating characteristics than SIRS or SEWS; for example, mortality in low‐risk patients was 2% when defined by CURB65, but 9% when defined by SEWS and 11–17% when defined by variations of the SIRS criteria. The sensitivity, specificity, positive predictive value and negative predictive value of CURB65 was 71%, 69%, 35% and 91%, respectively, compared with 62%, 73%, 35% and 89% for the best performing version of SIRS and 52%, 67%, 27% and 86% for SEWS. CURB65 had the greatest area under the receiver operating curve (0.78 v 0.73 for CRB65, 0.68 for SIRS and 0.64 for SEWS).
Conclusions
CURB65 should not be supplanted by SIRS or SEWS for initial prognostic assessment in CAP. Further research to identify better generic prognostic tools is required.
doi:10.1136/thx.2006.067371
PMCID: PMC2117168  PMID: 16928720
11.  Reducing door‐to‐antibiotic time in community‐acquired pneumonia: controlled before‐and‐after evaluation and cost‐effectiveness analysis 
Thorax  2006;62(1):67-74.
Background
Practice guidelines suggest that all patients hospitalised with community‐acquired pneumonia (CAP) should receive antibiotics within 4 h of admission. An audit at our hospital during 1999–2000 showed that this target was achieved in less than two thirds of patients with severe CAP.
Methods
An experienced multidisciplinary steering group designed a management pathway to improve the early delivery of appropriate antibiotics to patients with CAP. This was implemented using a multifaceted strategy. The effect of implementation was evaluated using a controlled before‐and‐after study design over two winter seasons (November–April 2001–2 and 2002–3). Cost‐effectiveness analyses were performed from the hospital's perspective.
Results
The proportion of patients receiving appropriate antibiotics within 4 h of admission to hospital increased from 33% to 56% at the intervention site, and from 32% to 36% at the control site (absolute change adjusted for differences in severity of illness 17%, p = 0.035). The cost per additional patient receiving appropriate antibiotics within 4 h was £132 with no post‐implementation evaluation, and £456 for a limited post‐implementation evaluation. Simple modelling from the results of a large observational study suggests that the cost per death prevented could be £3003 with no post‐implementation evaluation, or £16 632 with a limited post‐implementation evaluation.
Conclusions
The intervention markedly improved door‐to‐antibiotic time, albeit at considerable cost. It might still be a cost‐effective strategy, however, to reduce mortality in CAP. Uncertainty about the cost effectiveness of such interventions is likely to be resolved only by a well‐designed, cluster randomised trial.
doi:10.1136/thx.2005.056689
PMCID: PMC2111288  PMID: 16928714

Results 1-12 (12)