Investigational treatments for postoperative surgical site infections

Surgical site infections rank third among nosocomial infections, representing a global threat, associated with the emergence of multi-drug-resistant bacteria. The pharmaceutical industry has recently curtailed developmental programmes; however, the need for new compounds is extremely important. This article reviews new antimicrobials and immunointerventional targets for their potential to treat surgical site infections in comparison with recently licensed compounds. Daptomycin, dalbavancin, oritavancin, telavancin, iclaprim and ranbezolid seem to be promising agents against infections caused by Gram-positive pathogens and effectively address the present problems of multi-resistance in Gram-positive infections. Peptide deformylase inhibitors and immunostimulating agents open new perspectives in this field; however, very few compounds targeting Gram-negative problematic pathogens are in the pipeline of the future. Tigecycline (recently marketed) ceftobiprole, ceftaroline and doripenem seem to possess an extended anti-Gram-positive and -negative spectrum. Among these compounds, only doripenem demonstrates activity against Pseudomonas aeruginosa, for which there is a clear unmet need for new compounds, focusing on new targets.     

High throughput screening of small molecule libraries for modifiers of radiation responses

Purpose:?An unbiased approach of drug discovery through high-throughput screening (HTS) of libraries of chemically defined and bioactive small molecule compounds was used to identify modulators of radiation injury with an emphasis on radioprotectors and mitigators rather than radiosensitisers. Assay system endpoints included radiation-induced genotoxicity and DNA damage in yeast and apoptosis in murine lymphocytes. Large-scale data mining of chemically diverse libraries identified agents that were effective with all endpoints. HTS of bioactive compound libraries against murine lymphocytes profiled tetracycline and fluoroquinolone antibiotics and cyclopiazonic acid as having activity, and structure-activity analysis showed a common pharmacophore. Purine nucleosides, the interferon inducer tilorone, and linoleic acid were also identified as potential mitigators of radiation damage that often were also radioprotective. Many of these compounds enhance DNA repair, have anti-inflammatory activity, and stimulate hematopoiesis. Selected compounds within these initial verified hits from both types of libraries identified potent mitigators of lethal whole body irradiation (WBI) in mice.

Conclusion:?In spite of the fact that in vitro HTS has limitations and is unable to fully recapitulate all aspects of the complex in vivo acute radiation response, it identified several classes of molecules that had activity as radioprotectors and radiomitigators of the hematopoietic system in vivo. In the future, addition of 3-dimensional (3-D) or stem cell cultures or pathway analysis, may improve the power of HTS, but our findings indicate that common, evolutionary conserved, canonical pathways can be identified that could be exploited to mitigate radiation-induced defects.     

Infectious diarrhea

Diarrhea caused by enteric infections is a major factor in morbidity and mortality worldwide. An estimated 2-4 billion episodes of infectious diarrhea occur each year and are especially prevalent in infants. This review highlights the cellular and molecular mechanisms underlying diarrhea associated with the three classes of infectious agents, i.e. bacteria, viruses and parasites. Several bacterial pathogens have been chosen as model organisms, including Vibrio cholerae as a classical example of secretory diarrhea, Clostridium difficile and Shigella species as agents of inflammatory diarrhea and selected strains of pathogenic Escherichia coli (E. coli) to discuss the recent advances in alteration of epithelial ion absorption. Many of the recent studies addressing epithelial ion transport and barrier function have been carried out using viruses and parasites. Here, we focus on the rapidly developing field of viral diarrhea including rotavirus, norovirus and astrovirus infections. Finally we discuss Giardia lamblia and Entamoeba histolytica as examples of parasitic diarrhea. Parasites have a greater complexity than the other pathogens and are capable of creating molecules similar to those produced by the host, such as serotonin and PGE2. The underlying mechanisms of infectious diarrhea discussed include alterations in ion transport and tight junctions as well as the virulence factors, which alter these processes either through direct effects or indirectly through inflammation and neurotransmitters.     

Inhaled ciprofloxacin for chronic airways infections caused by Pseudomonas aeruginosa

Chronic infection of the airways with Pseudomonas aeruginosa represents a therapeutic challenge. Currently existing approaches are particularly based on systemic approaches and this increases the risk of strain resistance selection and is frequently associated with side effects. Therefore, local delivery of antibiotics may reduce these risks and may provide sustained sterilization of the respiratory tract. In fact, this approach was found to be effective with inhaled tobramycin in cystic fibrosis. Inhaled ciprofloxacin (dry powder inhaled formulation or liposomal inhaled formulation) is currently being investigated in chronic infections of the airways in cystic fibrosis, non-cystic fibrosis bronchiectasis and chronic obstructive pulmonary disease, and the initial clinical data are encouraging. This paper presents a perspective on the potential role of inhaled ciprofloxacin in such infections.     

An update on the use of C. elegans for preclinical drug discovery: screening and identifying anti-infective drugs

Introduction: The emergence of antibiotic-resistant and -tolerant bacteria is a major threat to human health. Although efforts for drug discovery are ongoing, conventional bacteria-centered screening strategies have thus far failed to yield new classes of effective antibiotics. Therefore, new paradigms for discovering novel antibiotics are of critical importance. Caenorhabditis elegans, a model organism used for in vivo, offers a promising solution for identification of anti-infective compounds.

Areas covered: This review examines the advantages of C. elegans-based high-throughput screening over conventional, bacteria-centered in vitro screens. It discusses major anti-infective compounds identified from large-scale C. elegans-based screens and presents the first clinically-approved drugs, then known bioactive compounds, and finally novel small molecules.

Expert opinion: There are clear advantages of using a C. elegans-infection based screening method. A C. elegans-based screen produces an enriched pool of non-toxic, efficacious, potential anti-infectives, covering: conventional antimicrobial agents, immunomodulators, and anti-virulence agents. Although C. elegans-based screens do not denote the mode of action of hit compounds, this can be elucidated in secondary studies by comparing the results to target-based screens, or conducting subsequent target-based screens, including the genetic knock-down of host or bacterial genes.     

Aerosolized antibiotics: the past,present and future,with a special emphasis on inhaled colistin

Inhaled antibiotics, such as TOBI (a tobramycin solution), gentamicin, colistin and aztreonam lysine (Cayston) have been effectively administered with safety and efficacy in patients with cystic fibrosis and bronchiectasis. In addition, inhaled antibiotics have been administered with safety and efficacy for the prevention and treatment of patients with ventilator-associated tracheobronchitis or pneumonia due to multidrug-resistant Gram-negative bacteria (mainly Pseudomonas aeruginosa or Acinetobacter baumannii). Original studies showed that inhaled colistin resulted in treatment success of nosocomial pneumonia or ventilator-associated pneumonia (VAP) due to multidrug-resistant Gram-negative bacteria. However, although aerosolized colistin seems to be safe and effective for the eradication of P. aeruginosa and the management of pneumonia in cystic fibrosis patients, hospital-acquired pneumonia and VAP due to multidrug-resistant Gram-negative bacteria, it is still unclear if it provides additional benefit in all-cause hospital mortality, or VAP-related mortality rates. For this reason, randomized controlled trials (RCTs) are necessary to validate the efficacy and safety of aerosolized colistin, mainly in patients with nosocomial pneumonia or VAP. In addition, RCTs are necessary to determine the appropriate inhaled colistin dose and the optimal delivery device.     

Optimal airway antimicrobial therapy for cystic fibrosis: the role of inhaled aztreonam lysine

Importance of the field: Chronic endobronchial infection in cystic fibrosis (CF) leads to progressive lung function loss and respiratory failure. Most adult CF patients are infected with Pseudomonas aeruginosa, an important predictor of mortality. Suppressing chronic P. aeruginosa infection with inhaled antibiotics is standard of care for CF patients.

Areas covered in this review: This review describes the development (2003 – 2010) of aztreonam lysine 75 mg powder and solvent for nebulizer solution (AZLI; Cayston^®), an aerosolized formulation of the monobactam antibiotic aztreonam.

What the reader will gain: AZLI was studied in patients with CF and chronic P. aeruginosa airway infection. In placebo-controlled trials, AZLI improved respiratory symptoms, increased forced expiratory volume in 1 sec (FEV₁), decreased sputum P. aeruginosa density, and was well tolerated. An open-label follow-on trial of nine ‘on/off’ courses showed that AZLI was safe and the effect durable with repeated administration. AZLI was recently approved for use in CF patients in Australia and the USA, and conditionally approved in Canada and the European Union. AZLI is given three times daily for 28 days (2 – 3 min/dose), followed by 28 days off-drug. AZLI is used only with the Altera Nebulizer System?, which provides appropriate particle size and small airway deposition, and has excellent portability.

Take home message: AZLI is a new therapy that is safe and effectively improves respiratory symptoms and FEV₁ in patients with CF.     

Current recommendations for Helicobacter pylori therapies in a world of evolving resistance

Occurrence of resistance, especially to clarithromycin, renders the standard triple therapy used to cure Helicobacter pylori infection ineffective. This review presents the bacteriological and pharmacological basis for H. pylori therapy and the current recommendations. The third-line treatment must be based on clarithromycin susceptibility testing. If the bacteria are still susceptible, failure may come from problems of compliance, hyperacidity or high bacterial load which can be overcome. If the bacteria are resistant, different regimens must be considered, including bismuth and non-bismuth-based quadruple therapies (sequential or concomitant), as well as triple therapies where amoxicillin is administered several times a day to obtain an optimal concentration at the gastric mucosal level. The treatments are becoming more and more complex and ecologically unsatisfactory, waiting for new agents or vaccines.     

Otitis media

Bacterial pathogens are isolated from middle ear fluid in up to 90% of children with acute otitis media (OM). Streptococcus pnuemoniae, Haemophilus influenzae and Moraxella catarrhalis predominate. Acute OM can be classified as uncomplicated, persistent, recurrent or chronic. Patient age, symptom severity, prior treatment history and exposure through day-care attendance in children influences pathogen distribution, antimicrobial susceptibility and anticipated clinical and microbiological responses to empirical and pathogen-directed therapies. The natural history of acute OM without intervention is favourable. However, meta-analysis of clinical trials shows an improvement in symptom and middle ear effusion resolution with antimicrobials. Aminopenicillins, cephalosporins and macrolides are often selected as therapy for acute OM. The various agents have differing activity against acute OM pathogens, particularly organisms with resistance mechanisms and they differ in dosing schedule, side effects and compliance enhancing factors. Consideration should be given to pharmacokinetic and pharmacodynamic principles in antibiotic selection. Selection criteria include antibiotic activity against drug-resistant S. pneumoniae and efficacy against β-lactamase-producing Gram-negative organisms. The necessary duration of treatment for acute OM varies according to multiple factors, including local preferences, but there is growing, compelling data to support short-course therapy. Tympanocentesis has been endorsed in various guidelines as a diagnostic and therapeutic procedure. Best-practice for management of acute OM continues to advocate antibiotic therapy with careful, accurate diagnosis and consideration of the major pathogens and their mechanisms of resistance.