A rapid, low-cost, and microfluidic chip-based system for parallel identification of multiple pathogens related to clinical pneumonia.

An air-insulated microfluidic chip was designed for the automatic centrifugal distribution of samples to 24-test cells, enabling the parallel identification of multiple clinical pneumonia-related pathogens in 1.45-µL reactions without cross-contamination in 45 min. A portable nucleic acid analyzer that integrates mechanical, confocal optical, electronic, and software functions was also developed to collect fluorescence data in a Ø3 mm imaging field near the optical diffraction limit for highly sensitive fluorescence detection of nucleic acid amplification in real time. This microfluidic chip-based portable nucleic acid analyzer could detect low abundance nucleic acids present at as few as 10 copies. In a blinded experiment, specific identification of Mycoplasma pneumoniae, Staphylococcus aureus, and methicillin-resistant S. aureus was achieved with 229 clinical patient sputum samples. The total coincidence rate of our system and traditional RT-PCR with an ABI 7500 was 99.56%. Four samples accounting for the 0.44% inconformity were retested by gene sequencing, revealing that our system reported the correct results. This novel microfluidic chip-based detection system is cost-effective, rapid, sensitive, specific, and has a relatively high throughput for parallel identification, which is especially suitable for resource-limited facilities/areas and point-of-care testing.

The economic burden of methicillin-resistant Staphylococcus aureus in community-onset pneumonia inpatients.

BACKGROUND: The quantitative effect of multidrug-resistant bacterial infections on real-world health care resources is not clear. This study aimed to estimate the burden of methicillin-resistant Staphylococcus aureus (MRSA) infections in pneumonia inpatients in Japan. METHODS: Using a nationwide administrative claims database, we analyzed pneumonia patients who had been hospitalized in 1,063 acute care hospitals. Patients who received anti-MRSA drugs were categorized into an anti-MRSA drug group, and the remaining patients comprised the control group. We estimated the burden of length of stay, in-hospital mortality, total antibiotic agent costs, and total hospitalization costs. Risk adjustments were conducted using propensity score matching. RESULTS: The study sample comprised 634 patients administered anti-MRSA drugs and 87,427 control patients. In propensity score-matching analysis (1 to 1), the median length of stay, antibiotic costs, and hospitalization costs of the anti-MRSA drug group were significantly higher than those of the control group (21 days vs 14 days [P < .001], $756 vs $172 [P < .001] and $8,741 vs $5,063 [P < .001], respectively); the attributable excess of these indicators were 9.0 ± 1.6 days, $1,044 ± $101, and $5,548 ± $580, respectively. CONCLUSIONS: These findings may serve as a reference to support further research on multidrug-resistant bacterial infections and eventually inform policy formulation.

Estimation of the incidence of MRSA patients: evaluation of a surveillance system using health insurance claim data.

Because sentinel surveillance systems cannot obtain information about patients who visit non-sentinel medical facilities, the characteristics of patients identified by these systems may be biased. In this study, we evaluated the representativeness of a methicillin-resistant Staphylococcus aureus (MRSA) surveillance system using health insurance claim (HIC) data, which does not depend on physician notification. We calculated the age-specific incidence of MRSA patients using data from the Japan Nosocomial Infections Surveillance (JANIS) programme, which is based on sentinel surveillance systems, and inpatient HICs submitted to employee health insurance organizations in 2011, and then computed age-specific incidence ratios between the HIC and JANIS data. Age-specific MRSA incidence in both datasets followed J-shaped curves with similar shapes. For all age groups, the ratios between HIC and JANIS data were around 10. These findings indicate that JANIS notification of MRSA cases was not affected by patients' age.

Estimating the cost-effectiveness of linezolid for the treatment of methicillin-resistant Staphylococcus aureus nosocomial pneumonia in Taiwan.

BACKGROUND/PURPOSE: Methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia (NP) is associated with higher resource utilization, increased hospital stays, and mortality. We present a health economics model to understand the impact of using linezolid as the first-line treatment of MRSA NP in Taiwan. METHODS: We developed a cost-effectiveness model to estimate the costs and clinical outcomes of using linezolid 600 mg b.i.d. versus vancomycin 15 mg/kg b.i.d. as the first-line treatment of MRSA NP in Taiwan. The model is a decision-analytic analysis in which a MRSA-confirmed patient is simulated to utilize one of the treatments, using data from a clinical trial. Within each treatment arm, the patient can or cannot achieve clinical cure. Regardless of whether the clinical cure was achieved or not, the patient may or may not have experienced an adverse event. The per-protocol results for clinical cure were 57.6% and 46.6% for linezolid and vancomycin, respectively. RESULTS: The total cost of linezolid was $376 more per patient than that of vancomycin. Drug costs were higher for linezolid than for vancomycin ($1108 vs. $233), and hospitalization costs were lower ($4998 vs. $5496). With higher cost and higher cure rates for linezolid, the incremental cost per cure was $3421. CONCLUSION: This study projects linezolid to have higher drug costs, lower hospital costs, and higher overall costs compared with vancomycin. This is balanced against the higher clinical cure rate for linezolid. Depending on the willingness to pay for clinical cure, linezolid could be cost effective as the first-line treatment of NP in Taiwan.

Linezolid Versus Vancomycin in the Empiric Treatment of Nosocomial Pneumonia: A Cost-Utility Analysis Incorporating Results from the ZEPHyR Trial.

OBJECTIVE: To examine the cost-effectiveness of vancomycin versus linezolid in the empiric treatment of nosocomial pneumonias incorporating results from a recent prospective, double-blind, multicenter, controlled trial in adults with suspected methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. METHODS: A decision-analytic model examining the cost-effectiveness of linezolid versus vancomycin for the empiric treatment of nosocomial pneumonia was created. Publicly available cost, efficacy, and utility data populated relevant model variables. A probabilistic sensitivity analysis varied parameters in 10,000 Monte-Carlo simulations, and univariate sensitivity analyses assessed the impact of model uncertainties and the robustness of our conclusions. RESULTS: Results indicated that the cost per quality-adjusted life-year (QALY) increased 6% ($22,594 vs. $23,860) by using linezolid versus vancomycin for nosocomial pneumonia. The incremental cost per QALY gained by using linezolid over vancomycin was $6,089, and the incremental cost per life saved was $68,615 with the use of linezolid. Vancomycin dominated linezolid in the subset of patients with documented MRSA. The incremental cost per QALY gained using linezolid if no mortality benefit exists between agents or a 60-day time horizon was analyzed was $19,608,688 and $443,662, respectively. CONCLUSIONS: Linezolid may be a cost-effective alternative to vancomycin in the empiric treatment of patients with suspected MRSA nosocomial pneumonia; however, results of our model were highly variable on a number of important variables and assumptions including mortality differences and time frame analyzed.

Managing skin and soft-tissue infection and nosocomial pneumonia caused by MRSA: a 2014 follow-up survey.

As a follow-up to our 2009 survey, in order to explore opinion and practice on the epidemiology and management of meticillin-resistant Staphylococcus aureus (MRSA) in Europe, we conducted a second survey to elicit current opinions on this topic, particularly around antibiotic choice, dose, duration and route of administration. We also aimed to further understand how the management of MRSA has evolved in Europe during the past 5 years. Members of an expert panel of infectious diseases specialists convened in London (UK) in January 2014 to identify and discuss key issues in the management of MRSA. Following this meeting, a survey was developed comprising 36 questions covering a wide range of topics on MRSA complicated skin and soft-tissue infection and nosocomial pneumonia management. The survey instrument, a web-based questionnaire, was sent to the International Society of Chemotherapy for distribution to registered European infection societies and their members. This article reports the survey results from the European respondents. At the time of the original survey, the epidemiology of MRSA varied significantly across Europe and there were differing views on best practice. The current findings suggest that the epidemiology of healthcare-associated MRSA in Europe is, if anything, even more polarised, whilst community-acquired MRSA has become much more common. However, there now appears to be a much greater knowledge of current treatment/management options, and antimicrobial stewardship has moved forward considerably in the 5 years since the last survey.

Substantial shifts in ranking of California hospitals by hospital-associated methicillin-resistant Staphylococcus aureus infection following adjustment for hospital characteristics and case mix.

BACKGROUND: States have established public reporting of hospital-associated (HA) infections-including those of methicillin-resistant Staphylococcus aureus (MRSA)-but do not account for hospital case mix or postdischarge events. OBJECTIVE: Identify facility-level characteristics associated with HA-MRSA infection admissions and create adjusted hospital rankings. METHODS: A retrospective cohort study of 2009-2010 California acute care hospitals. We defined HA-MRSA admissions as involving MRSA pneumonia or septicemia events arising during hospitalization or within 30 days after discharge. We used mandatory hospitalization and US Census data sets to generate hospital population characteristics by summarizing across admissions. Facility-level factors associated with hospitals' proportions of HA-MRSA infection admissions were identified using generalized linear models. Using state methodology, hospitals were categorized into 3 tiers of HA-MRSA infection prevention performance, using raw and adjusted values. RESULTS: Among 323 hospitals, a median of 16 HA-MRSA infections (range, 0-102) per 10,000 admissions was found. Hospitals serving a greater proportion of patients who had serious comorbidities, were from low-education zip codes, and were discharged to locations other than home were associated with higher HA-MRSA infection risk. Total concordance between all raw and adjusted hospital rankings was 0.45 (95% confidence interval, 0.40-0.51). Among 53 community hospitals in the poor-performance category, more than 20% moved into the average-performance category after adjustment. Similarly, among 71 hospitals in the superior-performance category, half moved into the average-performance category after adjustment. CONCLUSIONS: When adjusting for nonmodifiable facility characteristics and case mix, hospital rankings based on HA-MRSA infections substantially changed. Quality indicators for hospitals require adequate adjustment for patient population characteristics for valid interhospital performance comparisons.

Health economic evaluation of patients treated for nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus: secondary analysis of a multicenter randomized clinical trial of vancomycin and linezolid.

PURPOSE: Results from studies comparing health care resource use (HCRU), costs of treatment, and cost-effectiveness of linezolid compared with vancomycin therapy in the treatment of hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia are limited in the published literature. We therefore conducted an analysis to compare the HCRU, costs of treatment, and cost-effectiveness of linezolid compared with vancomycin in the treatment of hospitalized patients with MRSA nosocomial pneumonia using data from a Phase IV clinical trial. The economic effect of moderate to severe adverse events (MSAEs) and the development of renal failure were also evaluated. METHODS: We performed a post hoc analysis of data from a Phase IV, double-blind, randomized, comparator-controlled, multicenter trial that compared linezolid and vancomycin treatment in patients with MRSA nosocomial pneumonia. HCRU and costs were compared based on treatment, development of MSAEs, and development of renal failure using data from the modified intent-to-treat population. Predictors of costs were evaluated using generalized linear models. A piggyback cost-effectiveness analysis was conducted to assess the incremental cost-effectiveness ratio of linezolid versus vancomycin, given the significantly higher clinical success of linezolid compared with vancomycin found in the trial. FINDINGS: Overall, HCRU and costs were similar between the linezolid and vancomycin treatment groups; drug costs were significantly higher and dialysis costs significantly lower for linezolid- compared with vancomycin-treated patients. Total treatment costs were approximately $8000 higher (P = .046) for patients who developed renal failure compared with those who did not. Renal failure occurred more commonly in patients randomized to receive vancomycin (15%) compared with linezolid (4%; P < .001). Region, ventilator-associated pneumonia, clinical failure, and development of renal failure were associated with significantly higher total costs. The point estimate incremental cost-effectiveness ratio for linezolid compared with vancomycin was $16,516 per treatment success, with linezolid dominant in 24% and dominated in <2% of bootstrapped samples. IMPLICATIONS: This phase 4 clinical trial conducted in patients with MRSA-confirmed nosocomial pneumonia reveals that linezolid- compared with vancomycin-treated patients had similar HCRU and total overall costs. Fewer patients developed renal failure during the study while taking linezolid compared with vancomycin, and patients with a documented MSAE or renal failure had increased HCRU and costs. In summary, linezolid may be a cost-effective treatment strategy in MRSA-confirmed nosocomial pneumonia.

European perspective and update on the management of nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus after more than 10 years of experience with linezolid.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of antimicrobial-resistant hospital-acquired infections worldwide and remains a public health priority in Europe. Nosocomial pneumonia (NP) involving MRSA often affects patients in intensive care units with substantial morbidity, mortality and associated costs. A guideline-based approach to empirical treatment with an antibacterial agent active against MRSA can improve the outcome of patients with MRSA NP, including those with ventilator-associated pneumonia. New methods may allow more rapid or sensitive diagnosis of NP or microbiological confirmation in patients with MRSA NP, allowing early de-escalation of treatment once the pathogen is known. In Europe, available antibacterial agents for the treatment of MRSA NP include the glycopeptides (vancomycin and teicoplanin) and linezolid (available as an intravenous or oral treatment). Vancomycin has remained a standard of care in many European hospitals; however, there is evidence that it may be a suboptimal therapeutic option in critically ill patients with NP because of concerns about its limited intrapulmonary penetration, increased nephrotoxicity with higher doses, as well as the emergence of resistant strains that may result in increased clinical failure. Linezolid has demonstrated high penetration into the epithelial lining fluid of patients with ventilator-associated pneumonia and shown statistically superior clinical efficacy versus vancomycin in the treatment of MRSA NP in a phase IV, randomized, controlled study. This review focuses on the disease burden and clinical management of MRSA NP, and the use of linezolid after more than 10 years of clinical experience.

Assessment of an anti-alpha-toxin monoclonal antibody for prevention and treatment of Staphylococcus aureus-induced pneumonia.

Alpha-toxin (AT) is a major virulence factor in the disease pathogenesis of Staphylococcus aureus. We previously identified a monoclonal antibody (MAb) against AT that reduced disease severity in a mouse dermonecrosis model. Here, we evaluate the activity of an affinity-optimized variant, LC10, in a mouse model of S. aureus pneumonia. Passive immunization with LC10 increased survival and reduced bacterial numbers in the lungs and kidneys of infected mice and showed protection against diverse S. aureus clinical isolates. The lungs of S. aureus-infected mice exhibited bacterial pneumonia, including widespread inflammation, whereas the lungs of mice that received LC10 exhibited minimal inflammation and retained healthy architecture. Consistent with reduced immune cell infiltration, LC10-treated animals had significantly lower (P < 0.05) proinflammatory cytokine and chemokine levels in the bronchoalveolar lavage fluid than did those of the control animals. This reduction in inflammation and damage to the LC10-treated animals resulted in reduced vascular protein leakage and CO2 levels in the blood. LC10 was also assessed for its therapeutic activity in combination with vancomycin or linezolid. Treatment with a combination of LC10 and vancomycin or linezolid resulted in a significant increase (P < 0.05) in survival relative to the monotherapies and was deemed additive to synergistic by isobologram analysis. Consistent with improved survival, the lungs of animals treated with antibiotic plus LC10 exhibited less inflammatory tissue damage than those that received monotherapy. These data provide insight into the mechanisms of protection provided by AT inhibition and support AT as a promising target for immunoprophylaxis or adjunctive therapy against S. aureus pneumonia.

Pharmacotherapy for methicillin-resistant Staphylococcus aureus nosocomial pneumonia.

OBJECTIVE: To review the evidence for pharmacologic agents available in the treatment of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. DATA SOURCES: A search of PubMed (1975-July 2012) was conducted using a combination of the terms methicillin-resistant Staphylococcus aureus, pneumonia, nosocomial, vancomycin, linezolid, telavancin, ceftaroline, tigecycline, and quinupristin/dalfopristin. STUDY SELECTION AND DATA EXTRACTION: Randomized comparative clinical trials, meta-analyses, and review articles published in English were included. A manual review of the bibliographies of available literature was conducted and all relevant information was included. Observational and in vitro studies were incorporated as indicated. DATA SYNTHESIS: Pharmacotherapy for the treatment of nosocomial MRSA pneumonia is limited. Vancomycin has been the treatment of choice for several years. Linezolid has demonstrated similar efficacy to vancomycin in randomized clinical trials and recent data have suggested that it may be superior in some cases, although there are limitations to this conclusion. Telavancin has also demonstrated similar clinical efficacy to vancomycin; however, the drug is not commercially available in the US. Other agents with MRSA activity include ceftaroline, clindamycin, quinupristin/dalfopristin, and tigecycline, although the evidence for their use in nosocomial pneumonia is limited. CONCLUSIONS: Based on the currently available evidence and cost-effectiveness, vancomycin should continue to be the drug of choice for most patients with nosocomial MRSA pneumonia. Linezolid is a reasonable alternative for patients with treatment failure while receiving vancomycin, isolates with vancomycin minimum inhibitory concentrations over 2 µg/mL, allergic reactions, or vancomycin-induced nephrotoxicity.

Telavancin penetration into human epithelial lining fluid determined by population pharmacokinetic modeling and Monte Carlo simulation.

Telavancin is an investigational bactericidal lipoglycopeptide with a multifunctional mechanism of action, as demonstrated against methicillin-resistant Staphylococcus aureus. While the plasma pharmacokinetics have been described, the extent of the penetration of the drug into the lung, measured by the epithelial lining fluid (ELF), remains unknown. Population modeling and Monte Carlo simulation were employed to estimate the penetration of telavancin into ELF. Plasma and ELF pharmacokinetic data were obtained from 20 healthy volunteers, and the pharmacokinetic samples were assayed by a validated liquid chromatography-tandem mass spectrometry technique. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer. The model parameters were identified in a population pharmacokinetic analysis (BigNPAG). Monte Carlo simulation of 9,999 subjects was performed to calculate the ELF/plasma penetration ratios by estimating the area under the concentration-time curve (AUC) for the drug in ELF (AUC(ELF)) and for the free drug in plasma (free AUC(plasma)) from zero to infinity after a single dose. After the Bayesian step, the overall fits of the model to the data were good, and plots of predicted versus observed concentrations in plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. The median AUC(ELF)/free AUC(plasma) penetration ratio was 0.73, and the 25th and 75th percentile value ratios were 0.43 and 1.24, respectively. In uninfected lung tissue, the median AUC(ELF) is approximately 75% of the free AUC(plasma).

Cost-effectiveness of linezolid versus vancomycin in mechanical ventilation-associated nosocomial pneumonia caused by methicillin-resistant staphylococcus aureus.

UNLABELLED: Linezolid, an oxazolidinone-class antimicrobial agent, is a new drug; its use has frequently been questioned due to its high price. However, recent trials have demonstrated that the use of linezolid in mechanical ventilation-associated nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus (VAP-MRSA) may be justified due to its improved efficacy compared to vancomycin. Price and cost have different magnitudes, and clinical efficacy should always be considered in the decision-making process. Our objective was to determine whether linezolid treatment was more cost-effective than vancomycin for treating VAP-MRSA. METHODOLOGY: Elaboration of an economic model from a metanalysis of previous clinical trials comparing both drugs, through a cost-effectiveness analysis. Costs of the treatments were calculated using Brazilian parameters and were compared to the results obtained in the metanalysis. In order to compare the results with real life conditions, costs were calculated for both name brand and for generic vancomycin. RESULTS: The cost (May/2004) per unit (vial, ampoule or bag) was R$ 47.73 for the name-brand vancomycin, R$ 14.45 for generic vancomycin and R$ 214.04 for linezolid. Linezolid's efficacy in VAP-MRSA according to the metanalysis was 62.2% and vancomycin's efficacy was 21.2%. The total cost per cured patient was R$ 13,231.65 for the name-brand vancomycin, R$ 11,277.59 for generic vancomycin and R$ 7,764.72 for linezolid. CONCLUSION: Despite the higher price per unit, linezolid was more cost-effective than vancomycin.

Acute respiratory infections in Nigerian children: prospective cohort study of incidence and case management.

A community-based prospective surveillance and case management study of acute respiratory infection (ARI) in children aged 2-60 months of age was carried out over a 12-month period in Pakata, a semi-urban community in Ilorin, Kwara State, Nigeria. A cohort of 481 children was followed by trained community health assistants with thrice weekly home visits to record all symptoms and signs of ARI, and institute treatment based on WHO recommendations. There were three episodes of mild, moderate, or severe ARI per child per year, including 1.3 pneumonia episodes per child per year. The peak of infection corresponded to the rainy season (July-November), and a smaller peak to the dry season (February-April). Most of the health worker decisions were considered appropriate, although there was a tendency toward over-treatment with antibiotic drugs. An effective referral system was established from the community to a tertiary centre. There were no ARI-related deaths during the study period. These data indicate that a system of case management using trained community health workers can improve case management of ARI and may prevent severe ARI-related disease and deaths.