C5a-mediated neutrophil phagocytic dysfunction is RhoA-dependent and predicts nosocomial infection in critically ill patients.

Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3Kd. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P = .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P = .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection.

Modelling the impact of antibiotic use and infection control practices on the incidence of hospital-acquired methicillin-resistant Staphylococcus aureus: a time-series analysis

Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen worldwide. A wide range of factors have been suggested to influence the spread of MRSA. The objective of this study was to evaluate the effect of antimicrobial drug use and infection control practices on nosocomial MRSA incidence in a 426-bed general teaching hospital in Northern Ireland.

Methods: The present research involved the retrospective collection of monthly data on the usage of antibiotics and on infection control practices within the hospital over a 5 year period (January 2000–December 2004). A multivariate ARIMA (time-series analysis) model was built to relate MRSA incidence with antibiotic use and infection control practices.

Results: Analysis of the 5 year data set showed that temporal variations in MRSA incidence followed temporal variations in the use of fluoroquinolones, third-generation cephalosporins, macrolides and amoxicillin/clavulanic acid (coefficients = 0.005, 0.03, 0.002 and 0.003, respectively, with various time lags). Temporal relationships were also observed between MRSA incidence and infection control practices, i.e. the number of patients actively screened for MRSA (coefficient = -0.007), the use of alcohol-impregnated wipes (coefficient = -0.0003) and the bulk orders of alcohol-based handrub (coefficients = -0.04 and -0.08), with increased infection control activity being associated with decreased MRSA incidence, and between MRSA incidence and the number of new patients admitted with MRSA (coefficient = 0.22). The model explained 78.4% of the variance in the monthly incidence of MRSA.

Conclusions: The results of this study confirm the value of infection control policies as well as suggest the usefulness of restricting the use of certain antimicrobial classes to control MRSA.

Photodynamic antimicrobial polymers for infection control

Hospital-acquired infections pose both a major risk to patient wellbeing and an economic burden on global healthcare systems, with the problem compounded by the emergence of multidrug resistant and biocide tolerant bacterial pathogens. Many inanimate surfaces can act as a reservoir for infection, and adequate disinfection is difficult to achieve and requires direct intervention. In this study we demonstrate the preparation and performance of materials with inherent photodynamic, surface-active, persistent antimicrobial properties through the incorporation of photosensitizers into high density poly(ethylene) (HDPE) using hot-melt extrusion, which require no external intervention except a source of visible light. Our aim is to prevent bacterial adherence to these surfaces and eliminate them as reservoirs of nosocomial pathogens, thus presenting a valuable advance in infection control. A two-layer system with one layer comprising photosensitizer-incorporated HDPE, and one layer comprising HDPE alone is also described to demonstrate the versatility of our approach. The photosensitizer-incorporated materials are capable of reducing the adherence of viable bacteria by up to 3.62 Log colony forming units (CFU) per square centimeter of material surface for methicillin resistant Staphylococcus aureus (MRSA), and by up to 1.51 Log CFU/cm2 for Escherichia coli. Potential applications for the technology are in antimicrobial coatings for, or materials comprising objects, such as tubing, collection bags, handrails, finger-plates on hospital doors, or medical equipment found in the healthcare setting.

Rifampicin and sodium fusidate reduces the frequency of methicillin-resistant Staphylococcus aureus (MRSA) isolation in adults with cystic fibrosis and chronic MRSA infection

Nosocomial transmission of methicillin-resistant Staphylococcus aureus (MRSA) to patients with cystic fibrosis (CF) frequently results in chronic respiratory tract carriage. This is an increasing problem, adds to the burden of glycopeptide antibiotic use in hospitals, and represents a relative contraindication to lung transplantation. The aim of this study was to determine whether it is possible to eradicate MRSA with prolonged oral combination antibiotics, and whether this treatment is associated with improved clinical status. Adult CF patients (six male, one female) with chronic MRSA infection were treated for six months with rifampicin and sodium fusidate. Outcome data were examined for six months before treatment, on treatment and after treatment. The patients had a mean age of 29.3 (standard deviation=6.3) years and FEV(1) of 36.1% (standard deviation=12.7) predicted. The mean duration of MRSA isolation was 31 months. MRSA isolates identified in these patients was of the same lineage as the known endemic strain at the hospital when assessed by pulsed-field gel electrophoresis. Five of the seven had no evidence of MRSA during and for at least six months after rifampicin and sodium fusidate. The proportion of sputum samples positive for MRSA was lower during the six months of treatment (0.13) and after treatment (0.19) compared with before treatment (0.85) (P<0.0001). There was a reduction in the number of days of intravenous antibiotics per six months with 20.3+/-17.6 on treatment compared with 50.7 before treatment and 33.0 after treatment (P=0.02). There was no change in lung function. Gastrointestinal side effects occurred in three, but led to therapy cessation in only one patient. Despite the use of antibiotics with anti-staphylococcal activity for treatment of respiratory exacerbation, MRSA infection persists. MRSA can be eradicated from the sputum of patients with CF and chronic MRSA carriage by using rifampicin and sodium fusidate for six months. This finding was associated with a significant reduction in the duration of intravenous antibiotic treatment during therapy.

Elective versus symptomatic antibiotic treatment in cystic fibrosis patients with chronic Pseudomonas infection of the lungs

BACKGROUND:
A previous retrospective study suggested that a policy of regular anti-pseudomonal antibiotic treatment improved pulmonary function and increased survival in patients with cystic fibrosis chronically infected with Pseudomonas species. The results of a prospective multicentre study to compare the effects on pulmonary function and mortality of three monthly elective anti-pseudomonal antibiotic treatment with conventional symptomatic treatment are reported.

METHODS:
Sixty patients with cystic fibrosis, chronically infected with P aeruginosa, were randomised to the two treatment arms (elective or symptomatic) and followed clinically at yearly reviews. The major end points were changes in forced expiratory volume in one second (FEV(1)) and forced vital capacity (FVC). Survival was a secondary end point.

RESULTS:
Patients in the symptomatic group received a mean of three antibiotic treatments each year and those in the elective group received four antibiotic treatments during each year of the study. No significant differences in FEV(1) and FVC were found between the two groups after three years. There was a statistically non-significant higher rate of deaths in the elective group (n = 4), three of which were associated with B cepacia infection, compared with the symptomatic group (n = 0).

CONCLUSIONS:
This study did not demonstrate an advantage of a policy of elective antibiotic treatment over symptomatic treatment in patients with cystic fibrosis chronically infected with Pseudomonas species.