Publications

Pseudomonas aeruginosa is one of the major causative agents of mortality and morbidity in hospitalized patients due to a multiplicity of virulence factors associated with both chronic and acute infections. Acute P. aeruginosa infection is primarily mediated by planktonic bacteria expressing the type III secretion system (TTSS), a surface-attached needle-like complex that injects cytotoxins directly into eukaryotic cells, causing cellular damage. Lipopolysaccharide (LPS) is the principal surface-associated virulence factor of P. aeruginosa. This molecule is known to undergo structural modification (primarily alterations in the A- and B-band O antigen) in response to changes in the mode of life (e.g., from biofilm to planktonic). Given that LPS exhibits structural plasticity, we hypothesized that the presence of LPS lacking O antigen would facilitate eukaryotic intoxication and that a correlation between the LPS O-antigen serotype and TTSS-mediated cytotoxicity would exist. Therefore, strain PAO1 (A+ B+ O-antigen serotype) and isogenic mutants with specific O-antigen defects (A+ B-, A- B+, and A- B-) were examined for TTSS expression and cytotoxicity. A strong association existed in vitro between the absence of the large, structured B-band O antigen and increased cytotoxicity of these strains. In vivo, all three LPS mutant strains demonstrated significantly increased lung injury compared to PAO1. Clinical strains lacking the B-band O antigen also demonstrated increased TTSS secretion. These results suggest the existence of a cooperative association between LPS O-antigen structure and the TTSS in both laboratory and clinical isolates of P. aeruginosa.

RATIONALE

One-quarter to one-third of individuals with asthma smoke, which may affect response to therapy and contribute to poor asthma control.

OBJECTIVES

To determine if the response to an inhaled corticosteroid or a leukotriene receptor antagonist is attenuated in individuals with asthma who smoke.

METHODS

In a multicenter, placebo-controlled, double-blind, double-dummy, crossover trial, 44 nonsmokers and 39 light smokers with mild asthma were assigned randomly to treatment twice daily with inhaled beclomethasone and once daily with oral montelukast.

MEASUREMENTS AND MAIN RESULTS

Primary outcome was change in prebronchodilator FEV(1) in smokers versus nonsmokers. Secondary outcomes included peak flow, PC(20) methacholine, symptoms, quality of life, and markers of airway inflammation. Despite similar FEV(1), bronchodilator response, and sensitivity to methacholine at baseline, subjects with asthma who smoked had significantly more symptoms, worse quality of life, and lower daily peak flow than nonsmokers. Adherence to therapy did not differ significantly between smokers and nonsmokers, or between treatment arms. Beclomethasone significantly reduced sputum eosinophils and eosinophil cationic protein (ECP) in both smokers and nonsmokers, but increased FEV(1) (170 ml, p = 0.0003) only in nonsmokers. Montelukast significantly increased a.m. peak flow in smokers (12.6 L/min, p = 0.002), but not in nonsmokers.

CONCLUSIONS

In subjects with mild asthma who smoke, the response to inhaled corticosteroids is attenuated, suggesting that adjustments to standard therapy may be required to attain asthma control. The greater improvement seen in some outcomes in smokers treated with montelukast suggests that leukotrienes may be important in this setting. Larger prospective studies are required to determine whether leukotriene modifiers can be recommended for managing asthma in patients who smoke.

BACKGROUND

The rise in community-onset methicillin-resistant Staphylococcus aureus (MRSA) infections potentially complicates the empiric management of cellulitis. The threshold at which drugs active against MRSA, such as clindamycin and trimethoprim/sulfamethoxazole (TMP/SMX), should be incorporated into empiric therapy is unknown.

OBJECTIVE

To evaluate the cost-effectiveness of using cephalexin, TMP/SMX, or clindamycin for outpatient empiric therapy of cellulitis, given various likelihoods of infection due to MRSA.

METHODS

A decision analysis of the empiric treatment of cellulitis was performed from the perspective of a third-party payer. The model included initial therapy with cephalexin, clindamycin, or TMP/SMX, followed by treatment with linezolid in cases of clinical failure. Probability and cost estimates were obtained from clinical trials, epidemiologic data, and publicly available cost data and were subjected to sensitivity analysis.

RESULTS

Under the base-case scenario (37% probability of infection by S. aureus and a 27% MRSA prevalence), cephalexin was the most cost-effective option. Clindamycin became a more cost-effective therapy at MRSA probabilities from 41-80% when the probability of staphylococcal infection was greater than 40%. TMP/SMX was cost-effective only at very high likelihoods of MRSA infection. Variables with the most influence in the model were probability of S. aureus being methicillin-resistant, cost of linezolid, probability of a cure with cephalexin for a non-MRSA infection, and probability of infection due to S. aureus.

CONCLUSIONS

Cephalexin remains a cost-effective therapy for outpatient management of cellulitis at current estimated MRSA levels. Cephalexin was the most cost-effective choice over most of the modeled range of probabilities, with clindamycin becoming more cost-effective at high likelihoods of MRSA infection. TMP/SMX is unlikely to be cost-effective for treatment of simple cellulitis. Further studies of the microbiology of cellulitis, the epidemiology of MRSA, and the clinical effectiveness of clindamycin and TMP/SMX in skin and soft tissue infections are needed.

This highlight article summarizes the current published literature of ion channels and ion transport in type I cells. Twenty years ago, the general theory of ion and fluid transport in the lung was that the alveolar type II cells, known to contain ion channels, governed ion transport and that the type I cells, believed to be incapable of ion transport, only allowed passive movement of water. Unable to reconcile the extraordinarily large surface area covered by type I cells (95% of the internal surface area of the lung) with such minimal biological activity, investigators set out to demonstrate that type I cells were capable of ion transport and played a role in regulating lung fluid balance. Various methods were employed to show that type I cells contained ENaC (HSC and NSC channels), CNG and K(+) channels, and CFTR, further necessitating a revision of the current theories of ion and fluid transport in the lung.