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News Article | March 17, 2016

In a study using mice, the Johns Hopkins University School of Medicine infectious disease experts have added to evidence that statin drugs — known primarily for their cholesterol-lowering effects — can significantly reduce the time it takes to clear tuberculosis infection. “If our results hold up in humans, the use of statins as adjuncts to standard drug treatment could confer substantial benefits to public health and the nearly nine million new TB patients diagnosed worldwide each year,” said study author Petros Karakousis, M.D., associate professor of medicine in the Division of Infectious Diseases at the Johns Hopkins University School of Medicine. “Because statins like the one we tested are already approved by the U.S. Food and Drug Administration and have a long history of safety in patients, the new data might substantially accelerate their repurposing for tuberculosis patients.” First-line treatment for tuberculosis, which consists of a combination of four antibiotics, should in theory cure all drug-susceptible infections if strict compliance can be assured. However, said Karakousis, a curative course of treatment usually requires six to nine months, with a minimum of 18 months for drug-resistant forms of the lung disease. To assure compliance, most patients in developed countries undergo directly observed therapy, in which a trained health care worker provides the prescribed drugs and watches patients swallow every dose — a strategy that mitigates spread of the disease but diverts resources from other needed medical care. In many developing countries, patients stop taking their antibiotics early when their symptoms abate, contributing to continued spread of tuberculosis in the community and the emerging problem of drug resistance. Because new drugs that might shorten treatment duration are few in number and years from clinical use, Karakousis said his team’s focus has been on repurposing already approved medicines that bolster the first-line regimen. Toward that goal, the researchers focused on simvastatin, used by millions in the U.S. alone to reduce heart disease risk. In recent years, evidence has emerged that statins work, in part, by reducing inflammation by modulating the immune system, said Karakousis’ colleague and study author Noton Dutta, Ph.D., research associate in the Division of Infectious Diseases at the Johns Hopkins University School of Medicine. In a report published just days before World TB Day by the Journal of Antimicrobial Chemotherapy, the Johns Hopkins team described its initial experiments with TB-infected cells growing in petri dishes. The researchers found that statins didn’t directly kill the tuberculosis bacterium, but the addition of statin to infected cells helps stop bacterial growth. The combination of statins and standard drugs cleared the tuberculosis bacteria more efficiently than cells receiving just the usual drugs. Moving to infected mice, the researchers gave either the first-line regimen or those drugs plus simvastatin to animals six weeks after they were exposed to the tuberculosis bacteria in doses analogous to those standard for human patients. By counting the number of bacteria that remained in the animals’ lungs over the course of treatment, the researchers found that adding the statin reduced the time to infection-free lungs from 4.5 months to 3.5 months. Similarly, after 2.5 months, 3.5 months and 4.5 months of the standard treatment, mice had infection relapse rates of 100 percent, 50 percent and 0 percent. Adding simvastatin lowered the relapse rate to 50 percent after 2.5 months and to 20 percent after 3.5 months. Together, said Karakousis, the results suggest that simvastatin could be an attractive candidate drug to reduce the amount of time patients with tuberculosis must be treated with the standard regimen, and he adds that preliminary data also suggest that other statins have similar effects. Consequently, he and his colleagues are currently studying other members of this class of drugs to identify the most effective statin for adjunctive therapy and the most effective dose. Other important considerations in selecting the optimal statin, he adds, include cost and the potential for drug interactions with antiretroviral drugs used to treat HIV infection, which is common in patients with tuberculosis in many parts of the world. The World Health Organization estimates that the cost of standard tuberculosis treatment is about $2,000 per patient in industrialized countries, but that amount rises more than a hundredfold for patients with drug-resistant strains of the disease. Statins vary widely in cost, with some generic versions costing as little as $4 per month through discount programs run by major chain stores to more than $600 per month for name-brand drugs not covered by insurance. In general, statins are well-tolerated by most patients. Severe side effects, such as liver or muscle damage, are extremely rare. Michael Pinn of Johns Hopkins also participated in this research. The study also includes researchers from the Public Health Research Institute, New Jersey Medical School, Rutgers University and the State University of New Jersey. Funding support for this study was provided by the National Institute of Allergy and Infectious Diseases, the AIDS Clinical Trials Group, and the Johns Hopkins University Center for AIDS Research.

News Article | August 31, 2016

New Jersey researchers have identified what is believed to be the first strain of Escherichia coli bacteria from a patient in the United States that harbored two mobile genes making it resistant to both broad spectrum carbapenem antibiotics as well as colistin, an older antibiotic increasingly used as a last resort for multidrug-resistant infections. Their report is published this week in mBio®, an online open-access journal of the American Society for Microbiology. The strain of bacteria, isolated in 2014 from a 76-year-old man with a complicated urinary tract infection but further analyzed in 2016, was found to carry the genes mcr-1 and blaNDM-5, which confer resistance to colistin and carbapenems, respectively. These genes exist on plasmids, small segments of DNA that are capable of moving from one bacterium to another, potentially spreading antibiotic resistance to other bacterial species. While this strain did respond to other antimicrobial agents and was treated successfully, investigators say the case presents a sound reminder to monitor and track multidrug-resistant organisms. "The good news is that this did not cause a major outbreak of drug-resistant infection," said senior study author Barry N. Kreiswirth, Ph.D., founding director of the Public Health Research Institute (PHRI) Tuberculosis Center at New Jersey Medical School, part of Rutgers University in Newark, N.J. "The bad news is that since this occurred two years ago, there are clearly other strains out there we haven't detected yet. Both the carbapenem resistance and the colistin resistance genes are on separate plasmids, which means in principle they could spread to other bacteria." In August 2014, the patient presented to University Hospital in Newark, N.J., with fever and pain in his side. He had emigrated from India to the United States a year prior to experiencing these symptoms. The man had a history of prostate cancer treated with radiation therapy and subsequently developed recurrent urinary tract infections. He had recently undergone a procedure called cystoscopy to examine the bladder. The procedure was complicated by a bladder perforation, requiring surgery to place rubber tubes to help drain the kidneys. Laboratory testing suggested the man had pyuria, or pus in the urine. The man was started on the antimicrobial drugs piperacillin/tazobactam and vancomycin. A urine sample tested positive for the bacteria Pseudomonas aeruginosa, Citrobacter koseri, and Enterococcus faecium; another urine sample from the tube tested positive for P. aeruginosa, E. coli, Klebsiella pneumoniae, Enterococcus spp., and methicillin-resistant Staphylococcus aureus (MRSA). After six days of antimicrobial therapy, a urine sample was clear of bacteria; the man returned home after another procedure to create a new conduit for urine flow. Kreiswirth's lab, which analyzes bacterial isolates from University Hospital, used various molecular techniques to identify and compare bacteria in the man's urine samples. Investigators found that the E. coli strain from the man's urine sample carried both mcr-1 and blaNDM-5 and harbored resistance to several classes of antibiotics, including aminoglycosides, beta-lactams, chloramphenicol, fluoroquinolones, rifampin, sulfonamides, and tetracycline. Additional testing found that the plasmids isolated were highly similar to others that have been reported to be associated with clinical infection in China. The lab identified the E. coli strain as a variant of ST405, one of the main disease-causing strains of the bacteria. "Worrisomely, ST405 has frequently been associated with community-onset urinary tract infections," Kreiswirth said. Most mcr-1 cases appear to be happening in E. coli, the most common cause of urinary tract infections, said lead study author José R. Mediavilla, MBS, MPH, a research teaching specialist at PHRI. "These strains are probably already in the community and could spread further, essentially building toward a situation where you're going to have difficult if not impossible to treat urinary infections," he said. "Active surveillance efforts involving all colistin- and carbapenem-resistant organisms are imperative to determine mcr-1 prevalence and prevent further dissemination."

Prideaux B.,Novartis | Prideaux B.,Public Health Research Institute | Stoeckli M.,Novartis
Journal of Proteomics | Year: 2012

Since its introduction mass spectrometry imaging (MSI) has proven to be a powerful tool for the localization of molecules in biological tissues. In drug discovery and development, understanding the distribution of both drug and its metabolites is of critical importance. Traditional methods suffer from a lack of spatial information (tissue extraction followed by LCMS) or lack of specificity resulting in the inability to resolve parent drug from its metabolites (whole body autoradiography). MSI is a sensitive and label-free approach for imaging drugs and metabolites in tissues. In this article we review the different MSI technologies that have been applied to the imaging of pharmaceuticals. Recent technical advances, applications and current analytical limitations are discussed.This article is part of a Special Issue entitled: Imaging Mass Spectrometry: A User's Guide to a New Technique for Biological and Biomedical Research. © 2012 Elsevier B.V.

Dartois V.,Public Health Research Institute | Barry C.E.,U.S. National Institutes of Health
Bioorganic and Medicinal Chemistry Letters | Year: 2013

Tuberculosis is a bacterial disease that predominantly affects the lungs and results in extensive tissue pathology. This pathology contributes to the complexity of drug development as it presents discrete microenvironments within which the bacterium resides, often under conditions where replication is limited and intrinsic drug susceptibility is low. This consolidated pathology also results in impaired vascularization that limits access of potential lead molecules to the site of infection. Translating these considerations into a target-product profile to guide lead optimization programs involves implementing unique in vitro and in vivo assays to maximize the likelihood of developing clinically meaningful candidates. © 2013 Elsevier Ltd. All rights reserved.

Diamond G.,UMDNJ New Jersey Dental School | Ryan L.K.,Public Health Research Institute
Oral Diseases | Year: 2011

Initially identified as broad-spectrum antimicrobial peptides, the members of the β-defensin family have increasingly been observed to exhibit numerous other activities, both in vitro and in vivo, that do not always relate directly to host defense. Much research has been carried out in the oral cavity, where the presence of commensal bacteria further complicates the definition of their role. In addition to direct antimicrobial activity, β-defensins exhibit potent chemotactic activity for a variety of innate immune cells, as well as stimulating other cells to secrete cytokines. They can also inhibit the inflammatory response, however, by the specific binding of microbe-associated molecular patterns. These patterns are also able to induce the expression of β-defensins in gingival epithelial cells, although significant differences are observed between different species of bacteria. Together these results suggest a complex model of a host-defense related function in maintenance of bacterial homeostasis and response to pathogens. This model is complicated, however, by numerous other observations of β-defensin involvement in cell proliferation, wound healing and cancer. Together, the in vitro, in vivo and human studies suggest that these peptides are important in the biology of the oral cavity; exactly how is still subject to speculation. © 2011 John Wiley & Sons A/S.

Perlin D.S.,Public Health Research Institute
Future Microbiology | Year: 2011

It has been nearly a decade since caspofungin was approved for clinical use as the first echinocandin class antifungal agent, followed by micafungin and anidulafungin. The echinocandin drugs target the fungal cell wall by inhibiting the synthesis of β-1,3-D-glucan, a critical cell wall component of many pathogenic fungi. They are fungicidal for Candida spp. and fungistatic for moulds, such as Aspergillus fumigatus, where they induce abnormal morphology and growth properties. The echinocandins have a limited antifungal spectrum but are highly active against most Candida spp., including azole-resistant strains and biofilms. As they target glucan synthase, an enzyme absent in mammalian cells, the echinocandins have a favorable safety profile. They show potent MIC and epidemiological cutoff values against susceptible Candida and Aspergillus isolates, and the frequency of resistance is low. When clinical breakthrough occurs, it is associated with high MIC values and mutations in Fks subunits of glucan synthase, which can reduce the sensitivity of the enzyme to the drug by several thousand-fold. Such strains were not adequately captured by an early clinical breakpoint for susceptibility prompting a revised lower value, which addresses the FKS resistance mechanism and new pharmacokinetic/pharmacodynamic studies. Elevated MIC values unlinked to therapeutic failure can occur and result from adaptive cell behavior, which is FKS-independent and involves the molecular chaperone Hsp90 and the calcineurin pathway. Mutations in FKS1 and/or FKS2 alter the kinetic properties of glucan synthase, which reduces the relative fitness of mutant strains causing them to be less pathogenic. The echinocandin drugs also modify the cell wall architecture exposing buried glucans, which in turn induce a variety of important host immune responses. Finally, the future for glucan synthase inhibitors looks bright with the development of new orally active compounds. © 2011 Future Medicine Ltd.

Perlin D.S.,Public Health Research Institute
Clinical Infectious Diseases | Year: 2015

Invasive fungal infections are an important infection concern for patients with underlying immunosuppression. Antifungal therapy is a critical component of patient care, but therapeutic choices are limited due to few drug classes. Antifungal resistance, especially among Candida species, aggravates the problem. The echinocandin drugs (micafungin, anidulafungin, and caspofungin) are the preferred choice to treat a range of candidiasis. They target the fungal-specific enzyme glucan synthase, which is responsible for the biosynthesis of a major cell wall polymer. Therapeutic failure involves acquisition of resistance, although it is a rare event among most Candida species. However, in some settings, higher-level resistance has been reported among Candida glabrata, which is also frequently resistant to azole drugs, resulting in difficult-to-treat multidrug-resistant strains. The mechanism of echinocandin resistance involves amino acid changes in "hot spot" regions of FKS-encoded subunits of glucan synthase, which decreases the sensitivity of enzyme to drug, resulting in higher minimum inhibitory concentration values. The cellular processes promoting the formation of resistant FKS strains involve complex stress response pathways that yield a variety of adaptive compensatory genetic responses. Standardized broth microdilution techniques can be used to distinguish FKS mutant strains from wild type, but testing C. glabrata with caspofungin should be approached cautiously. Finally, clinical factors that promote echinocandin resistance include prophylaxis, host reservoirs including biofilms in the gastrointestinal tract, and intra-abdominal infections. An understanding of clinical and molecular factors that promote echinocandin resistance is critical to develop better diagnostic tools and therapeutic strategies to overcome resistance. © 2015 The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Perlin D.S.,Public Health Research Institute
Annals of the New York Academy of Sciences | Year: 2015

Fungal infections due to Candida and Aspergillus species cause extensive morbidity and mortality, especially among immunosuppressed patients, and antifungal therapy is critical to patient management. Yet only a few drug classes are available to treat invasive fungal diseases, and this problem is compounded by the emergence of antifungal resistance. Echinocandin drugs are the preferred choice to treat candidiasis. They are the first cell wall-active agents and target the fungal-specific enzyme glucan synthase, which catalyzes the biosynthesis of β-1,3-glucan, a key cell wall polymer. Therapeutic failures occur rarely among common Candida species, with the exception of Candida glabrata, which is frequently multidrug resistant. Echinocandin resistance in susceptible species is always acquired during therapy. The mechanism of resistance involves amino acid changes in hot-spot regions of Fks subunits of glucan synthase, which decrease the sensitivity of the enzyme to drug. Cellular stress response pathways lead to drug adaptation, which promotes the formation of resistant fks strains. Clinical factors promoting echinocandin resistance include empiric therapy, prophylaxis, gastrointestinal reservoirs, and intra-abdominal infections. A better understanding of the echinocandin-resistance mechanism, along with cellular and clinical factors promoting resistance, will facilitate more effective strategies to overcome and prevent echinocandin resistance. © 2015 The New York Academy of Sciences.

Arendrup M.C.,Statens Serum Institute | Perlin D.S.,Public Health Research Institute
Current Opinion in Infectious Diseases | Year: 2014

Purpose of review Echinocandin resistance in Candida is a great concern, as the echinocandin drugs are recommended as first-line therapy for patients with invasive candidiasis. Here, we review recent advances in our understanding of the epidemiology, underlying mechanisms, methods for detection and clinical implications. Recent findings Echinocandin resistance has emerged over the recent years. It has been found in most clinically relevant Candida spp., but is most common in C. glabrata with rates exceeding 10% at selected institutions. It is most commonly detected after 3-4 weeks of treatment and is associated with a dismal outcome. An extensive list of mutations in hot spot regions of the genes encoding the target has been characterized and associated with species and drug-specific loss of susceptibility. The updated antifungal susceptibility testing reference methods identify echinocandin-resistant isolates reliably, although the performance of commercial tests is somewhat more variable. Alternative technologies are being developed, including molecular detection and matrix-assisted laser desorption ionization-time of flight. Summary Echinocandin resistance is increasingly encountered and its occurrence makes susceptibility testing essential, particularly in patients with prior exposure. The further development of rapid and user-friendly commercially available susceptibility platforms is warranted. Antifungal stewardship is important in order to minimize unnecessary selection pressure. Copyright © 2014 Lippincott Williams & Wilkins.

Perlin D.S.,Public Health Research Institute
Current Fungal Infection Reports | Year: 2011

We now have a decade of experience with echinocandin drugs. Large-scale epidemiologic antifungal surveillance studies have demonstrated that caspofungin, micafungin, and anidulafungin retain high potency on clinical isolates of Candida, and resistance remains relatively low. Yet reports of breakthrough infections involving strains with a high minimum inhibitory concentration (MIC) are mounting. Mechanism-specific resistance involving amino acid substitutions in the Fks subunit(s) of the drug target glucan synthase results in reduced enzyme sensitivity to drug and high MICs. The mechanism affects all three drugs and is encountered in all Candida species, as well as in Aspergillus. An initial susceptibility testing breakpoint failed to adequately distinguish wild-type susceptible isolates from fks mutant resistant strains. Considering data from epidemiologic, microbiologic, pharmacokinetic/ pharmacodynamic, biochemical, and genetic studies that better capture resistant isolates with fks genotypes has resulted in a proposed new breakpoint which provides a more reliable measure of probable therapeutic success. © Springer Science+Business Media, LLC 2011.

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