Topical therapy for refractory rhinosinusitis caused by methicillin-resistant Staphylococcus aureus: First report in a prospective series.

OBJECTIVE: The incidence of refractory chronic rhinosinusitis (CRS) associated with methicillin-resistant Staphylococcus aureus (MRSA) is rising and remains a therapeutic challenge. The goal of this study is to demonstrate the efficacy of a non-invasive topical therapy against MRSA in these patients. METHODS: Seventeen patients with refractory CRS caused by MRSA were treated with a topical therapy protocol. Treatment consisted of weekly endoscopic sinus debridement followed by intra-sinus installation of a hydroxyl-ethylcellulose gel that releases mometasone and a culture-directed antibiotic for a period of 6 weeks, along with daily nasal nebulization of mometasone with the same antibiotic and saline rinses. Clinical outcome was assessed using the Lund-Kennedy (LK) symptom and endoscopic appearance scores. Sinus mucosal tissue was homogenized and cultured, and microbial biofilm burden was assessed based on colony forming units (CFUs) counts. RESULTS: Rhinotopic therapy resulted in clearance of MRSA in 13 of 16 patients (81.2%). Treated patients also demonstrated significant improvement clinically as measured by the LK scores. In addition, a significant decrease in mucosal CFUs was observed post-therapy. CONCLUSION: Our findings demonstrate that topical therapy is an effective method for treating MRSA-associated refractory CRS.

Therapeutic vaccination against relevant high virulence clinical isolates of Mycobacterium tuberculosis.

The purpose of this study was to attempt to develop therapeutic or post-exposure vaccines that could slow progressive disease in guinea pigs infected by low dose aerosol with very high virulence Beijing isolates of Mycobacterium tuberculosis, currently classified as Category C biodefense pathogens by the NIH and CDC. After screening several candidates we focused on the use of three candidates; these were a pool of bacterial iron acquisition proteins, a pool of antigens recognized by T cells from chronically infected mice thought to represent proteins made by the bacillus in response to decreases in local oxygen tension, and a bacterial lipoprotein that is a potent TLR2 agonist. When delivered in a potent GLA-based adjuvant [targeting TLR4 and TLR9], in most cases we were unable to reduce the bacterial load in the lungs. However, the pathologic appearance of lungs from these animals showed that, while primary lesions were most unaffected and had become necrotic, the development of large, lung consolidating secondary lesions seemed to have been mostly prevented. In animals given both a priming vaccination and a boost the effects were prominent, and almost certainly contributed to significantly prolonged survival in these animals. In a biodefense situation, this prolonged survival would be potentially long enough to allow for the organism to be identified and a drug susceptibility profile determined.

Phosphatidylinositol di-mannoside and derivates modulate the immune response to and efficacy of a tuberculosis protein vaccine against Mycobacterium bovis infection.

Mycobacterium bovis infects a wide range of hosts, including domestic livestock, wildlife, and humans. Development of an effective vaccine protecting against bovine tuberculosis would provide a cost-effective tuberculosis control strategy. The objective of this study was to investigate the ability of phosphatidylinositol di-mannoside (PIM(2)) and its derivatives to modulate cell-mediated immunity in vivo in a bovine tuberculosis mouse model in response to a relevant antigen, namely a fusion protein of mycobacterial proteins Ag85A and ESAT-6. The addition of synthetic PIM(2) to the vaccine resulted in a significant reduction in lung bacterial counts and a cytokine profile indicating a Th 1 type immune response. The addition of the other PIM(2) derivatives to the vaccine or the fusion protein alone did not result in reduced lung bacterial counts; moreover, the addition of PIM(2)ME appeared to negate the induction of an antigen-specific interferon-γ response and protection against tuberculosis. In conclusion, this study provides further evidence that PIMs can function as potent adjuvants for protein or sub-unit vaccines, but subtle structural differences among PIMs can markedly alter the type of immune response induced.

Experimental tuberculosis: the role of comparative pathology in the discovery of improved tuberculosis treatment strategies.

The use of laboratory animals is critical to the discovery and in vivo pre-clinical testing of new drugs and drug combinations for use in humans. M. tuberculosis infection of mice, rats, guinea pigs, rabbits and non-human primates are the most commonly used animal models of human tuberculosis. While granulomatous inflammation characterizes the most fundamental host response to M. tuberculosis aerosol infection in humans and animals, there are important species differences in pulmonary and extra-pulmonary lesion morphology which may influence responses to drug therapy. Lesions that progress to necrosis or cavitation are common, unfavorable host responses in naturally occurring tuberculosis of humans, but are not seen consistently in experimental infections in most animal model species. The importance of these unique lesion morphologies is that they represent irreversible tissue damage that can harbor persistent bacilli which are difficult to treat with standard therapies. Understanding the differences in host response to experimental tuberculosis infections may aid in selecting the most appropriate animal models to test drugs that have been rationally designed to have specific mechanisms of action in vivo. A better understanding of lesion pathogenesis across species may also aid in the identification of novel therapeutic targets or strategies that can be used alone or in combination with more conventional tuberculosis treatments in humans.