Successful use of feedback to improve antibiotic prescribing and reduce Clostridium difficile infection: a controlled interrupted time series.

OBJECTIVES: To investigate the effect of reinforcing a narrow-spectrum antibiotic policy on antibiotic prescription and Clostridium difficile infection (CDI) rates by feedback of antibiotic use to doctors, as part of a departmental audit and feedback programme. DESIGN: A prospective controlled interrupted time-series (ITS) study, with pre-defined pre- and post-intervention periods, each of 21 months. SETTING: Three acute medical wards for elderly people in a teaching hospital. PARTICIPANTS: Six thousand one hundred and twenty-nine consecutive unselected acute medical admissions aged >or=80 years. INTERVENTIONS: A 'narrow-spectrum' antibiotic policy (reinforced by an established programme of audit and feedback of antibiotic usage and CDI rates) was introduced, following an unplanned rise in amoxicillin/clavulanate (Augmentin) use. It targeted broad-spectrum antibiotics for reduction (cephalosporins and amoxicillin/clavulanate) and narrow-spectrum antibiotics for increase (benzyl penicillin, amoxicillin and trimethoprim). Changes in the use of targeted antibiotics (intervention group) were compared with those of untargeted antibiotics (control group) using segmented regression analysis. Changes in CDI rates were examined by the Poisson regression model. Methicillin-resistant Staphylococcus aureus (MRSA) acquisition rates acted as an additional control. RESULTS: There was a reduction in the use of all targeted broad-spectrum antibiotics and an increase in all targeted narrow-spectrum antibiotics, statistically significant for sudden change and/or linear trend. All other antibiotic use remained unchanged. CDI rates fell with incidence rate ratios of 0.35 (0.17, 0.73) (P=0.009). MRSA incidence did not change [0.79 (0.49, 1.28); P=0.32]. CONCLUSIONS: This is the first controlled prospective ITS study to use feedback to reinforce antibiotic policy and reduce CDI. Multicentre ITS or cluster randomized trials of this and other methods need to be undertaken to establish the most effective means of optimizing antibiotic use and reducing CDI.

Prevention of naphthalene-induced pulmonary toxicity by glutathione prodrugs: roles for glutathione depletion in adduct formation and cell injury.

Naphthalene is metabolized in the lung and liver to reactive intermediates by cytochrome P450 enzymes. These reactive species deplete glutathione, covalently bind to proteins, and cause necrosis in Clara cells of the lung. The importance of glutathione loss in naphthalene toxicity was investigated by using the glutathione prodrugs (glutathione monoethylester or cysteine-glutathione mixed disulfide) to maintain glutathione pools during naphthalene exposure. Mice given a single intraperitoneal injection of naphthalene (1.5 mmol/kg) were treated with either prodrug (2.5 mmol/kg) 30 min later. Both compounds effectively maintained glutathione levels and decreased naphthalene-protein adducts in the lung and liver. However, cysteine-glutathione mixed disulfide was more effective at preventing Clara cell injury. To study the prodrugs in Clara cells without the influence of hepatic naphthalene metabolism and circulating glutathione, dose-response and time-course studies were conducted with intrapulmonary airway explant cultures. Only the ester of glutathione raised GSH in vitro; however, both compounds limited protein adducts and cell necrosis. In vitro protection was not associated with decreased naphthalene metabolism. We conclude that (1) glutathione prodrugs can prevent naphthalene toxicity in Clara cells, (2) the prodrugs effectively prevent glutathione loss in vivo, and (3) cysteine-glutathione mixed disulfide prevents naphthalene injury in vitro without raising glutathione levels.

Glutathione depletion is a major determinant of inhaled naphthalene respiratory toxicity and naphthalene metabolism in mice.

Naphthalene (NA) is metabolized to highly reactive intermediates that are primarily detoxified by conjugation to glutathione (GSH). Intraperitoneal administration of naphthalene causes substantial loss of both hepatic and respiratory GSH, yet only respiratory tissues are injured in mice. The liver supplies GSH to other organs via the circulation, making it unclear whether respiratory GSH losses reflect in situ respiratory depletion or decreased hepatic supply. To address this concern, mice were exposed to naphthalene by inhalation (1.5-15 ppm; 2-4 h), thereby bypassing first-pass hepatic involvement. GSH levels and histopathology were monitored during the first 24 h after exposure. Half of the mice were given the GSH depletor diethylmaleate (DEM) 1 hour before naphthalene exposure. Lung and nasal GSH levels rapidly decreased (50-90%) in mice exposed to 15 ppm naphthalene, with cell necrosis throughout the respiratory tract becoming evident several hours later. Conversely, 1.5 ppm naphthalene caused moderate GSH loss and only injured the nasal olfactory epithelium. Neither naphthalene concentration depleted hepatic GSH. Animals pretreated with DEM showed significant GSH loss and injury in nasal and intrapulmonary airway epithelium at both naphthalene concentrations. DEM treatment, perhaps by causing significant GSH loss, decreased water-soluble naphthalene metabolite formation by 48% yet increased NA-protein adducts 193%. We conclude that (1) GSH depletion occurs in airways independent of hepatic function; (2) sufficient GSH is not supplied by the liver to maintain respiratory GSH pools, or to prevent injury from inhaled naphthalene; and (3) GSH loss precedes injury and increases protein adduct formation.