Recent Patents on Anti-Infective Drug Discovery (v.4, #1)

Progress Towards Recombinant Anti-Infective Antibodies by Jennifer Pai, Jamie Sutherland, Jennifer Maynard (1-17).
The global market for monoclonal antibody therapeutics reached a total of $11.2 billion in 2004, with an impressive 42and#x25; growth rate over the previous five years and is expected to reach and#x223C;$34 billion by 2010. Coupled with this growth are stream-lined product development, production scale-up and regulatory approval processes for the highly conserved antibody structure. While only one of the 21 current FDA-approved antibodies, and one of the 38 products in advanced clinical trials target infectious diseases, there is increasing academic, government and commercial interest in this area. Synagis, an antibody neutralizing respiratory syncitial virus (RSV), garnered impressive sales of $1.1 billion in 2006 in spite of its high cost and undocumented effects on viral titres in human patients. The success of anti-RSV passive immunization has motivated the continued development of anti-infectives to treat a number of other infectious diseases, including those mediated by viruses, toxins and bacterial/ fungal cells. Concurrently, advances in antibody technology suggest that cocktails of several monoclonal antibodies with unique epitope specificity or single monoclonal antibodies with broad serotype specificity may be the most successful format. Recent patents and patent applications in these areas will be discussed as predictors of future anti-infective therapeutics.

Doripenem: A New Addition to the Carbapenem Class of Antimicrobials by Jason Schafer, Debra Goff, Julie Mangino (18-28).
Doripenem (DPM) is the newest antimicrobial in the carbapenem class. It is a broad spectrum agent with activity against gram-positive, gram-negative and anaerobic bacteria. in vitro Susceptibility testing has demonstrated potent activity for many drug resistant gram-negative pathogens including some that are resistant to imipenem and meropenem. It appears to be less likely to induce resistance for certain pathogens compared to the other carbapenems. The purpose of this review is to introduce DPM and describe its potential role in managing infections due to multi-drug resistant gram-negative bacteria. This article also reviews recent patents related to the carbapenem class of antimicrobials.

Percutaneous Treatment of Hydatid Liver Cyst by Antonio Giorgio, Antonella Sarno, Giorgio de Stefano, Nunzia Farella, Paolo Matteucci, Umberto Scognamiglio, Valentina Giorgio (29-36).
Percutaneous treatment of Hydatid Liver Cyst (HLC) with scolicidal agent under ultrasound guidance is now worldwide used after the advent of Percutaneous-Aspiration-Injection and Re-Aspiration (PAIR) and its modifications. Although HLC represent a benign disease, treatment has to be considered mandatory in symptomatic cysts and recommended in viable cysts because of the risk of severe complications. In this article, clinical indications, PAIR technique with results and complications are discussed. Finally, clinical flow-chart of active and inactive HLCs is reported. The present article is a review of some patents in the Hydatid liver cyst.

Inhibitors of Multidrug Resistant Efflux Systems in Bacteria by Barbara Zechini, Ilaria Versace (37-50).
Resistance of bacteria to many classes of antibiotics is an increasing problem worldwide. Multidrug resistance efflux pumps are recognized as an important component of resistance in both Gram-positive and Gram-negative bacteria. Some bacterial efflux pumps may be selective for one substrate, such as tetracycline, or transport antibiotics of different classes, conferring a multiple drug resistance (MDR) phenotype. Efflux pump inhibitors (EPIs) are promising therapeutic agents, as they should restore the activity of standard antibiotics. The efflux pump inhibitor-antibiotic combination is expected to increase the intracellular concentration of antibiotics that are expelled by efflux pumps, decrease the intrinsic bacterial resistance to antibiotics, reverse the acquired resistance associated with efflux pumps overexpression, and reduce the frequency of the emergence of resistant mutant strains. In recent years, different classes of EPIs have been described and tested, including analogues of antibiotic substrates and new molecules. This review focuses on the families of MDR efflux pumps, and on the current progress for the clinical use of EPIs. The present article is a good review of the recent patents related to efflux pump inhibitors.

The Triggering Receptors Expressed on Myeloid cells (TREM) are a family of activating receptors with some homology with activating natural killer cell receptors. TREM-1 is an activating receptor on neutrophils and monocytes that plays an important role in the amplification of inflammation. TREM-1 blockade significantly decreases mortality from bacterial sepsis. Altered TREM-1 expression on neutrophils in response to bacterial stimuli may be an important factor in susceptibility to bacterial infection. However the natural TREM-1 ligand is unknown although Toll-like receptor agonists stimulate TREM-1 upregulation and function. TREM-2 regulates dendritic cell function by inducing CCR7 expression on peripheral dendritic cells and directing them from the periphery to the draining lymph node. These receptors may potentially be manipulated to alter the inflammatory response to severe sepsis and chronic inflammation and possible therapies and patents are explored in this review.

Management of Severe Abdominal Infections by Dietrich Hasper, Joerg Schefold, Daniel Baumgart (57-65).
Abdominal infections are associated with significant morbidity and mortality. Nearly all bacteria causing abdominal infections are derived from the endogenous flora of the alimentary tract. The resulting infection is typically polymicrobial and comprised of both aerobic and anaerobic microbes. They can be classified by their severity as uncomplicated and complicated or by their origin as community or hospital acquired. Escherichia coli and Bacteroides fragilis are the most frequently isolated bacteria in community-acquired abdominal infections. Nosocomial infections typically involve a more resistant flora (e.g. Pseudomonas spp., Acinetobacter spp., Gram-negative bacilli producing extended-spectrum and#946;-lactamases [ESBL], vancomycin-resistant enterococci [VRE] and methicillin-resistant Staphylococcus aureus [MRSA]). Antimicrobial therapy should be guided by microbiological testing and frequently requires other interventions as well. In uncomplicated infections antimicrobial prophylaxis for andlt; 24h may be considered. Patients with underlying or acquired immunodeficiency, i.e. organ transplant recipients and other patients on complex immunosuppressant regimens require special attention and antimicrobial coverage. We discuss the relevant microbiota, a rational diagnostic and therapeutic approach including strategies to handle challenging infections. The application of novel compounds and/or drug classes for abdominal infections such as glycylcyclines (i.e. tigecycline), glycopeptides (i.e. dalbavancin, telavancin, oritavancin), carbapenems (i.e. doripenem), and forth generation cephalosporins (i.e. ceftaroline, ceftobiprole) as well as patents on metalloproteinase and caspase inhibitors, interleukin antagonists, fusion proteins and nitric oxide donators is critically reviewed. The information is summarized in flow charts and algorithms for use in daily clinical practice and the review article also shows the useful information of the patents for the treatment of abdominal infections.

Isolation of Bacteria from Remote High Altitude Andean Lakes Able to Grow in the Presence of Antibiotics by Julian Dib, Annika Weiss, Anna Neumann, Omar Ordonez, Maria Estevez, Maria Farias (66-76).
High altitude Andean lakes are placed in Puna desert over 4400 above sea level. Completely isolated, they are exposed to extreme environmental factors like high levels of salinity, UV radiation and heavy metals and low concentrations of phosphorus. Nevertheless, they are the habitat of enormous populations of three flamingo species that migrate among these Lakes. Previous reports have determined that bacteria isolated from these environments present high levels of resistance to antibiotics. The aim of this work was to determine the diversity of antibiotic resistant bacteria in water from Andean Lakes and their connection with flamingo enteric biota. Bacteria from water and birds faeces from high altitude Lakes: Laguna (L.) Aparejos, L. Negra, L. Vilama and L. Azul (all are located between 4,200 and 4,600 m altitude) were isolated by plating in five different Antibiotics (ampicillin, 100 and#956;g ml-1; chloramphenicol, 170 and#956;g ml-1; colistin , 20 and#956;g ml-1; erythromycin, 50 and#956;g ml-1and tetracycline 50 and#956;g ml-1). 56 bacteria were isolated and identified by 16 S rDNA sequencing. Antibiotic resistance profiles of isolated bacteria were determined for 22 different antibiotics. All identified bacteria were able to growth in multiple ATBs. Colistin, ceftazidime, ampicillin/sulbactam, cefotaxime, cefepime, cefalotin, ampicillin and erythromycin were the most distributed resistances among the 56 tested bacteria The current results demonstrated that antibiotic resistance was abundant and diverse in high altitude Lakes. Also the present article indicates some useful patents regarding the isolation of bacteria able to grow in the present of antibiotics.

Patent Selections by Publishers (77-80).
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