The Novel Biological Action of Antimicrobial Peptides via Apoptosis Induction.

Nov 2012

Cho J, Hwang IS, Choi H, Hwang JH, Hwang JS, Lee DG.

Source

School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 702-701, Korea.

Abstract

Antimicrobial peptides (AMPs) exert antimicrobial activity against Gram-positive and Gram-negative bacteria, fungi, and viruses by various mechanisms. AMPs commonly possess particular characteristics by harboring cationic and amphipathic structures and binding to cell membranes, resulting in the leakage of essential cell contents by forming pores or disturbing lipid organization. These membrane disruptive mechanisms of AMPs are possible to explain according to the various structure forming pores in the membrane. Some AMPs inhibit DNA and/or RNA synthesis as well as apoptosis induction by reactive oxygen species (ROS) accumulation and mitochondrial dysfunction. Specifically, mitochondria play a major role in the apoptotic pathway. During apoptosis induced by AMPs, cells undergo cytochrome c release, caspase activation, phosphatidylserine externalization, plasma or mitochondrial membrane depolarization, DNA and nuclei damage, cell shrinkage, apoptotic body formation, and membrane blebbing. Even AMPs, which have been reported to exert membrane-active mechanisms, induce apoptosis in yeast. These phenomena were also discovered in tumor cells treated with AMPs. The apoptosis mechanism of AMPs is available for various therapeutics such as antibiotics for antibiotic-resistant pathogens that resist to the membrane active mechanism, and antitumor agents with selectivity to tumor cells.

PubMed

Polymyxin use associated with respiratory arrest.

Feb 2012

Wunsch H, Moitra VK, Patel M, Dzierba AL.

Source

Department of Anesthesiology, Columbia University, 622 W 168th St, PH5-527D, New York, NY 10032. hw2125@columbia.edu.

Abstract

The polymyxins (polymyxin B and E) are bactericidal polypeptide antibiotics first discovered in 1947 and used for the treatment of gram-negative bacterial infections. Renal and neurologic toxicities coupled with the increasing availability of effective alternatives led to declining use in the 1960s. The emergence of multidrug-resistant organisms in the past decade has resulted in a resurgence in the use of polymyxins in critically ill patients, yet the side effects are not well known. We report two cases of respiratory arrest likely due to polymyxin B infusions in the context of a 10-fold increase in the use of polymyxin B in our institution over the past 10 years.

PubMed

Colistin in the 21st century

Colistin in the 21st century

Curr Opin Infect Dis. 2009 Sep 30

Nation RL, Li J.

Facility for Anti-infective Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.

PURPOSE OF REVIEW: Colistin is a 50-year-old antibiotic that is being used increasingly as a 'last-line' therapy to treat infections caused by multidrug-resistant Gram-negative bacteria, when essentially no other options are available. Despite its age, or because of its age, there has been a dearth of knowledge on its pharmacological and microbiological properties. This review focuses on recent studies aimed at optimizing the clinical use of this old antibiotic.

RECENT FINDINGS: A number of factors, including the diversity in the pharmaceutical products available, have hindered the optimal use of colistin. Recent advances in understanding of the pharmacokinetics and pharmacodynamics of colistin, and the emerging knowledge on the relationship between the pharmacokinetics and pharmacodynamics, provide a solid base for optimization of dosage regimens. The potential for nephrotoxicity has been a lingering concern, but recent studies provide useful new information on the incidence, severity and reversibility of this adverse effect. Recent approaches to the use of other antibiotics in combination with colistin hold promise for increased antibacterial efficacy with less potential for emergence of resistance.

SUMMARY:Because few, if any, new antibiotics with activity against multidrug-resistant Gram-negative bacteria will be available within the next several years, it is essential that colistin is used in ways that maximize its antibacterial efficacy and minimize toxicity and development of resistance. Recent developments have improved use of colistin in the 21st century.

Infectious Diseases

Aerosol antibiotics: considerations in pharmacological and clinical evaluation.

Aerosol antibiotics: considerations in pharmacological and clinical evaluation.

Curr Opin Biotechnol. 2008 Nov 24.

Dudley MN, Loutit J, Griffith DC.
Mpex Pharmaceuticals, San Diego, CA 92121, United States.

Increasing antibiotic resistance and lack of R&D productivity of new classes of antimicrobial agents directed against Gram-negative bacteria necessitate new approaches to maximize the efficacy of existing classes of drugs. Direct administration of drugs to the lung via the inhalational route provides for high concentrations at the target site of action in patients with pulmonary infections. The efficacy of aerosol antibiotic administration has been best demonstrated with aerosolized tobramycin in the management of chronic infections because of Pseudomonas aeruginosa in cystic fibrosis (CF) patients. Unfortunately, inconvenient regimens leading to poor patient adherence to therapy, and the increasing frequency of multidrug-resistant strains have necessitated the search for additional agents. Integration of aerosol science, PK-PD and clinical trial designs are important for the development and evaluation of these new aerosol agents in both chronic infections (e.g. CF and chronic obstructive pulmonary disease (COPD)) as well as acute infections (e.g. bacterial pneumonias).

This review outlines important considerations and recent progress in this emerging area.

PubMed

Trends in Resistance to Ciprofloxacin, Cefazolin, and Gentamicin in the Treatment of Bacterial Keratitis

Trends in Resistance to Ciprofloxacin, Cefazolin, and Gentamicin in the Treatment of Bacterial Keratitis

J Ocul Pharmacol Ther. 2008 Mar 10

Afshari NA, Ma JJ, Duncan SM, Pineda R, Starr CE, Decroos FC, Johnson CS, Adelman RA.
Duke University Eye Center, Duke University Medical Center, Durham, NC.

Purpose: The aim of this study was to evaluate the microbial profile, resistance patterns, and antibiotic sensitivity of bacterial keratitis to three commonly used ocular antibiotics.

Methods: All cases of bacterial keratitis referred to the Massachusetts Eye and Ear Infirmary Microbiology Laboratory from two consecutive annual 10-month periods were reviewed. The bacterial profile and resistance to ciprofloxacin, cefazolin, and gentamicin was evaluated within the two intervals.

Results: Of the 485 cultures analyzed, 66.4% (322) were positive for bacterial isolates. Of these, 19.2% were polymicrobial, 87.5% were gram-positive, and 12.5% were gram-negative. The most prevalent isolate was coagulase-negative Staphylococcus (45.5%), followed by S. aureus (15.2%).

The resistance patterns for gram-positive bacteria for ciprofloxacin for the first versus second time interval were 12% and 22% (P = 0.04) respectively, for cefazolin 13% and 23% (P = 0.04), and for gentamicin 4% and 7% (P = 0.36). The resistance patterns for gram-negative bacteria for ciprofloxacin, cefazolin, and gentamicin were not significantly different in the two tested time periods (all P greater then 0.05).

Conclusions: There was increased resistance of gram-positive organisms to ciprofloxacin and cefazolin, but not gentamicin, in the two examined time periods. Increased resistance to these commonly used antibiotics emphasizes the need for close follow-up after initial empiric treatment, and maintaining a low threshold for selecting alternative therapy.

Liebert

Carbapenems: a potent class of antibiotics.

Carbapenems: a potent class of antibiotics.
Expert Opin Pharmacother. 2008 Jan

Nicolau DP.
Hartford Hospital, Center for Anti-Infective Research and Development, 80 Seymour Street, Hartford, Connecticut 06102-5037, USA +1 860 545 3941 ; +1 860 545 3992 ; dnicola@harthosp.org.

The purpose of this review is to assess the relative strengths and weaknesses of individual members of the carbapenem class of antibiotics. Clinical trials and review articles were identified from a Medline search (1979 - July 2006), in addition to, reference citations from identified publications, abstracts from the Interscience Conferences on Antimicrobial Agents and Chemotherapy and the 12th International Congress on Infectious Disease, and package inserts. Articles in English were reviewed, with emphasis on those containing efficacy or safety data. Carbapenems bind to critical penicillin-binding proteins, disrupting the growth and structural integrity of bacterial cell walls. They provide enhanced anaerobic and Gram-negative coverage as compared with other beta-lactams and their stability against extended-spectrum beta-lactamases (ESBLs) makes them an effective treatment option. The most common adverse effects are infusion-site complications and gastrointestinal distress.

Ertapenem has limited efficacy against non-fermenting, Gram-negative bacteria, restricting its use to community-acquired infections. Imipenem is slightly more effective against Gram-positive organisms and meropenem slightly more effective against Gram-negative organisms. However, both have broad-spectrum activity, including non-fermenting, Gram-negative bacteria. Among non-fermenting, Gram-negatives, resistance to imipenem in particular is increasing. Doripenem is in late-stage clinical development and combines the broad-spectrum coverage of imipenem and meropenem, and more potent activity against Pseudomonas aeruginosa. Due to the increasing challenges represented by ESBLs and multi-drug resistant organisms, the carbapenems are assuming a greater role in the treatment of serious infections.

Imipenem and meropenem are presently available and have been shown to be effective against nosocomial infections.

Doripenem is an investigational carbapenem that has completed Phase III clinical trials and that has the potential to improve on this efficacy and minimize the emergence of resistance to the carbapenem class.

PMID: 18076336 [PubMed - in process]

Xenorhabdus antibiotics: a comparative analysis and potential utility for controlling mastitis caused by bacteria

Xenorhabdus antibiotics: a comparative analysis and potential utility for controlling mastitis caused by bacteria

J Appl Microbiol. 2007 Nov 1

Furgani G, Böszörményi E, Fodor A, Máthé-Fodor A, Forst S, Hogan JS, Katona Z, Klein MG, Stackebrandt E, Szentirmai A, Sztaricskai F, Wolf SL.

Department of Genetics, Faculty of Natural Sciences, Eötvös University, Budapest, Hungary.

Aims: The role of antibiotics produced by bacterial symbionts of entomopathogenic nematodes is to suppress growth of microbes in the soil environment. These antibiotics are active against Gram-positive and Gram-negative bacteria, and were tested against mastitis isolates from dairy cows.

Methods and Results: Two bioassays were adapted for Xenorhabdus antibiotics; an overlay method on agar plates, and serially diluted, cell-free, Xenorhabdus cultures. The antimicrobial activities of the liquid cultures of 13 strains from five Xenorhabdus species were further evaluated. Antimicrobial activities of the type strains of X. nematophila, X. budapestensis and X. szentirmaii were tested on mastitis isolates of Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae with both bioassays. A previously reported antibiotic from X. nematophila, nematophin, was synthesized in three steps from tryptamine and 4-methyl-2-oxovaleric acid sodium salt.

Conclusions: The antibiotics of all three Xenorhabdus strains were powerful in either bioassay, but the sensitivity of the isolates differed from each other. While Kl. pneumoniae was the least susceptible, Staph. aureus had the highest sensitivity to each Xenorhabdus strain. Xenorhabdus szentirmaii and X. budapestensis were more potent antibiotic producers than X. nematophila, and raceme nematophin was ineffective against all mastitis isolates.

Significance and Impact of the Study: These results indicate that Xenorhabdus antibiotics are effective against mastitis isolates and should be further evaluated for their potential in mastitis control or prevention.

PMID: 17976177 [PubMed - as supplied by publisher]

Zymar (Gatifloxacin 0.3%) Shows Excellent Gram-Negative Activity Against Serratia marcescens and Pseudomonas aeruginosa

Zymar (Gatifloxacin 0.3%) Shows Excellent Gram-Negative Activity Against Serratia marcescens and Pseudomonas aeruginosa in a New Zealand White Rabbit Keratitis Model.

Cornea. 2007 Jun

Mah FS,
Romanowski EG,
Kowalski RP,
Yates KA,
Gordon YJ.

From the Charles T. Campbell Ophthalmic Microbiology Laboratory, UPMC Eye Center, Ophthalmology and Visual Sciences Research Center, Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

PURPOSE: Whereas gatifloxacin, a newer fluoroquinolone, was engineered to increase its Gram-positive potency, we assessed whether it still retained significant Gram-negative activity in vivo. Specifically, we compared the efficacy of Zymar (gatifloxacin 0.3%), Ciloxan (ciprofloxacin 0.3%), and fortified tobramycin (14 mg/mL) in the treatment of experimental Gram-negative bacterial infections of Serratia marcescens (SM) and Pseudomonas aeruginosa (PA) in the New Zealand White (NZW) rabbit keratitis model.

METHODS: A total of 30 NZW rabbits each were intrastromally inoculated in both eyes with approximately 1000 CFU of SM and PA. By E-test, the minimum inhibitory concentrations (MICs; mug/mL) for SM were gatifloxacin (0.125), ciprofloxacin (0.047), and tobramycin (1.5), and for PA were gatifloxacin (0.125), ciprofloxacin (0.19), and tobramycin (0.5). After 16 hours, the rabbits were divided into 4 treatment groups: (1) Zymar, (2) Ciloxan, (3) fortified tobramycin, and (4) saline control. One drop was instilled in both eyes every 15 minutes for 5 doses and then every 30 minutes for 14 doses. One hour after the final treatment, the animals were euthanized, and bacterial colony counts from the corneas were determined.

RESULTS: For SM, Zymar and Ciloxan significantly reduced the colony counts compared with tobramycin and saline control. Zymar was more effective than Ciloxan.For PA, all antibiotics reduced equivalently the colony counts compared with the saline control

CONCLUSIONS: The enhanced Gram-positive activity of gatifloxacin is not associated with any decreased Gram-negative activity in vivo. Zymar may prove useful for SM and PA keratitis.

PMID: 17525656 [PubMed - in process]