No evidence of expression of two classes of natural antibiotics (cathelicidins and defensins) in a sample of platypus milk

Marsupial neonates are born without a fully functioning immune system, and are known to be protected in part by natural antimicrobial peptides present in their mother's milk. Monotreme neonates hatch at a similar stage in development, and it has been hypothesised that their survival in a non-sterile burrow also relies on the presence of natural antibiotics in their mother's milk. Here we review the field of monotreme lactation and the antimicrobial peptide complement of the platypus (Ornithorhynchus anatinus). Using reverse transcriptasepolymerase chain reaction of milk cell RNA from a sample of platypus milk, we found no evidence for the expression of cathelicidins or defensins in the milk. This was unexpected. We hypothesise that these natural antibiotics may instead be produced by the young platypuses themselves.

Beta-lactam antibiotics as a possible novel therapy for managing epilepsy and autism, a case report and review of literature

Autism is a disorder of unknown etiology. There are few FDA approved medications for treating autism. Co-occurring autism and epilepsy is common, and glutamate antagonists improve some symptoms of autism. Ceftriaxone, a beta-lactam antibiotic, increases the expression of the glutamate transporter 1 which decreases extracellular glutamate levels. It is hypothesized that modulating astrocyte glutamate transporter expression by ceftriaxone or cefixime might improve some symptoms of autism. This case report of a child with autism and epilepsy suggests a decrease in seizures after taking cefixime

Synthesis of norbornane bisether antibiotics via silver-mediated alkylation

A small series of norbornane bisether diguanidines have been synthesized and evaluated as antibacterial agents. The key transformation-bisalkylation of norbornane diol 6-was not successful using Williamson methodology but has been accomplished using Ag2O mediated alkylation. Further functionalization to incorporate two guanidinium groups gave rise to a series of structurally rigid cationic amphiphiles; several of which (16d, 16g and 16h) exhibited antibiotic activity. For example, compound 16d was active against a broad range of bacteria including Pseudomonas aeruginosa (MIC = 8 µg/mL), Escherichia coli (MIC = 8 µg/mL) and methicillin-resistant Staphylococcus aureus (MIC = 8 µg/mL).

Antimicrobial activity of Eucalyptus tereticornis and comparison with daily life antibiotics

Eucalyptus is a fast growing tree which has shown to possess high degree of resistance against stressed environmental conditions. Eucalyptus tereticornis is widely cultivated in various parts of the world even in Pakistan. The medicinal properties of this tree reside in its oil. The main aim of our study is to check the antimicrobial activity of this valuable tree and to compare it with commercially available antibiotics. Eucalyptus tereticornis oil was extracted from the fresh leaves and branch tips during flowering season from surrounding areas of Hazara University, Pakistan. Different concentrations of oil were checked against Gram positive bacteria Staphylococcus aureus (ATCC 6538), Enterococcus faecalis (ATCC 49452), Gram negative bacteria including Escherichia coli (ATCC 25922), Salmonella typhimurium (ATCC 14028) and Pseudomonas aeruginosa (ATCC 27853), and also against yeast Candiada albican (ATCC 2091). The oil was significantly active against all the microbes studied. The activity of E. tereticornis oil was compared with standard antibiotics Ciprofloxacin (CIP-5 μg), Chloramphenicol (C-30 μg), Tetracycline (TE-30 μg) and Ampicillin (AMP 25-μg). The comparison gives the significant results and proves the antimicrobial efficiency of this valuable plant.

Use of in vitro critical inhibitory concentration, a novel approach to predict in vivo synergistic bactericidal effect of combined amikacin and piperacillin against pseudomonas aeruginosa in a systemic rat infection model

PURPOSE: This study was undertaken to explore the use of in vitro critical inhibitory concentration (CIC) as a surrogate marker relating the pharmacokinetic (PK) parameters to in vivo bactericidal synergistic effect [pharmacodynamic (PD)] of amikacin + piperacillin combination against Pseudomonas aeruginosa in a systemic rat infection model. METHODS: The in vitro antibacterial activities of amikacin and piperacillin, alone and in combinations at various ratios of the concentrations, were tested against a standard [5 x 10(5) colony-forming units (CFU)/ml] and a large (1.5 x 10(8) CFU/ml) inoculum of P. aeruginosa ATCC 9027 using a modified survival-time method. The CIC of each individual antibiotic for the different combinations was determined using a cup-plate method. In vivo studies were performed on Sprague-Dawley rats using a systemic model of infection with P. aeruginosa ATCC 9027. PK profiles and in vivo killing effects of the combination at different dosing ratios were studied. RESULTS: An inoculum effect was observed with the antibiotics studied. Synergy was seen against both the inocula at the following concentration ratios: 70% C(ami) + 30% C(pip) and 75% C(ami) + 25% C(pip), where C(ami) and C(pip) are the concentrations of amikacin and piperacillin to produce a 1000-fold decrease in bacterial population over 5 h, respectively. The CIC values determined corroborated with the order of in vitro bacterial killing observed for the antibiotic combinations. The dosing ratio of 12.6 mg/kg amikacin + 36 mg/kg piperacillin (a 70:30 ratio of the individual doses) exhibited the greatest killing in vivo when compared to the other ratios. The PK-PD relationships were described by simple, linear regression equations using the area under the in vivo killing curve as a PD marker and the AUCIC(ami)/CIC(ami) + AUCIC(pip)/CIC(pip), AUC(ami)/CIC(ami) + AUC(pip)/CIC(pip), C(max,ami)/CIC(ami) + C(max,pip)/CIC(pip), and AUCIC(ami)/MIC(ami) + AUCIC(pip)/MIC(pip) as PK markers for the amikacin + piperacillin combination. CONCLUSION: The combination of amikacin and piperacillin exhibited synergistic killing effect on P. aeruginosa that could be modeled using CIC as a surrogate marker relating the PK parameters to in vivo bactericidal effect.

Novel agents that potentially inhibit irinotecan-induced diarrhea

Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or ≥ 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Lateonset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na⁺ and Cl^-. Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-agr (TNF-α) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea.

Drug bioactivation, covalent binding to target proteins and toxicity relevance

A number of therapeutic drugs with different structures and mechanisms of action have been reported to undergo metabolic activation by Phase I or Phase II drug-metabolizing enzymes. The bioactivation gives rise to reactive metabolites/intermediates, which readily confer covalent binding to various target proteins by nucleophilic substitution and/or Schiff's base mechanism. These drugs include analgesics (e.g., acetaminophen), antibacterial agents (e.g., sulfonamides and macrolide antibiotics), anticancer drugs (e.g., irinotecan), antiepileptic drugs (e.g., carbamazepine), anti-HIV agents (e.g., ritonavir), antipsychotics (e.g., clozapine), cardiovascular drugs (e.g., procainamide and hydralazine), immunosupressants (e.g., cyclosporine A), inhalational anesthetics (e.g., halothane), nonsteroidal anti-inflammatory drugs (NSAIDSs) (e.g., diclofenac), and steroids and their receptor modulators (e.g., estrogens and tamoxifen). Some herbal and dietary constituents are also bioactivated to reactive metabolites capable of binding covalently and inactivating cytochrome P450s (CYPs). A number of important target proteins of drugs have been identified by mass spectrometric techniques and proteomic approaches. The covalent binding and formation of drug-protein adducts are generally considered to be related to drug toxicity, and selective protein covalent binding by drug metabolites may lead to selective organ toxicity. However, the mechanisms involved in the protein adduct-induced toxicity are largely undefined, although it has been suggested that drug-protein adducts may cause toxicity either through impairing physiological functions of the modified proteins or through immune-mediated mechanisms. In addition, mechanism-based inhibition of CYPs may result in toxic drug-drug interactions. The clinical consequences of drug bioactivation and covalent binding to proteins are unpredictable, depending on many factors that are associated with the administered drugs and patients. Further studies using proteomic and genomic approaches with high throughput capacity are needed to identify the protein targetsof reactive drug metabolites, and to elucidate the structure-activity relationships of drug's covalent binding to proteins and their clinical outcomes.

Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease

Background & Aims: Mycobacterium avium subspecies paratuberculosis has been proposed as a cause of Crohn’s disease. We report a prospective, parallel, placebo-controlled, double-blind, randomized trial of 2 years of clarithromycin, rifabutin, and clofazimine in active Crohn’s disease, with a further year of follow-up. Methods: Two hundred thirteen patients were randomized to clarithromycin 750 mg/day, rifabutin 450 mg/day, clofazimine 50 mg/day or placebo, in addition to a 16-week tapering course of prednisolone. Those in remission (Crohn’s Disease Activity Index ≤150) at week 16 continued their study medications in the maintenance phase of the trial. Primary end points were the proportion of patients experiencing at least 1 relapse at 12, 24, and 36 months. Results: At week 16, there were significantly more subjects in remission in the antibiotic arm (66%) than the placebo arm (50%; P = .02). Of 122 subjects entering the maintenance phase, 39% taking antibiotics experienced at least 1 relapse between weeks 16 and 52, compared with 56% taking placebo (P = .054). At week 104, the figures were 26% and 43%, respectively (P = .14). During the following year, 59% of the antibiotic group and 50% of the placebo group relapsed (P = .54). Conclusions: Using combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for up to 2 years, we did not find evidence of a sustained benefit. This finding does not support a significant role for Mycobacterium avium subspecies paratuberculosis in the pathogenesis of Crohn’s disease in the majority of patients. Short-term improvement was seen when this combination was added to corticosteroids, most likely because of nonspecific antibacterial effects.

Community onset staphylococcus aureus infections in Melbourne

Objective: To investigate the relative importance of methicillin resistant Staphylococcus aureus (MRSA) in the community in Melbourne by describing circulating S. aureus strains and infection characteristics.

Methods: Patients with any community-onset S. aureus infection were identified via clinical specimens submitted to a community-based pathology service in 2006. The referring doctors confirmed community onset and defined site and severity of each infection. Patient isolates were characterised by antibiotic resistance subtype and presence of the Panton-Valentine leukocidin gene (pvl).

Results: Between April and September 2006, 2,094 S. aureus isolates were processed. Of these, 133 (6.4%) were multiresistant MRSA (mMRSA) and 110 (5.3%) were resistant to less than 3 non-betalactam antibiotics (non-multiresistant MRSA or nmMRSA). We followed-up all nmMRSA (34) and mMRSA (15) confirmed community-onset infections, and a random subset of eligible patients with MSSA infections (57), for whom clinical data were available from referring doctors (82% response).

The majority of isolates were from skin infections (99/106), but drainage was performed in less than one third of cases (29/99). Antibiotics were prescribed for 89% (95%CI: 82, 94) of infections. The isolates were resistant to the prescribed antibiotic 100% of the time for mMRSA infections and 80% for nmMRSA. Those with infections caused by MRSA had on average one additional visit to their doctor compared with MSSA infections.

Ten nmMRSA clones were identified, including one new pvl positive nmMRSA. Of the 29 nmMRSA isolates, 14 were pvl positive (48%; 95%CIs: 30%, 66%) compared with 16% of MSSA and 0% mMRSA.

Patients with an infection caused by pvl positive strains (23) were younger ((mean age 23 years (95%CI: 16, 30) compared with the 55 years (95%CI: 50, 61)). Infection site also varied with presence of pvl; more pvl positive infections were found in the axilla (17.9% compared with 0%) and head and neck (35.7% compared with 8.2%), and less for the leg or foot (21.4% compared with 55.7%).

Conclusions: We estimate that 3.5% of community-onset S. aureus infections in Melbourne in 2006 were caused by MRSA, and 70 to 90% of patients with MRSA infections were treated initially with antibiotics to which their isolate was resistant. pvl positive isolates of S. aureus were associated with younger age and axillary or head and neck infections.

Death and late-stage dementia in institutions : a cultural analysis

The first purpose of this study was to describe the deaths of fifteen nursing home residents with late-stage dementia. The devastating effect of dementia on a person has been called a ‘living death’ (Woods, 1989). The caring which occurs when someone is going through this process in a nursing home was recorded and analysed. In analysing this act of caring, the second purpose was to look for the origins of the structures and the sources of pressure that shaped the context and therefore helped determine the behaviour of the various groups under observation. These groups were residents and their relatives, the staff of the nursing home and the treating doctors. Before commencing observations and carrying out this study, an understanding needed to be developed of: the condition of dementia as it is perceived by health professionals and presented in the media; the institutions in which the majority of people with dementia end their days; the background and conditions of the staff who nurse in them; the models of care that guide and determine policies; and the conceptions of life and death which underpin relevant laws and moral standpoints. Accordingly, in part 1. chapter 1 the history, causes, pathology and effects of dementing conditions are examined. Relevant medical and lay literature including media influences are examined which pertain to the subject of death and dementia and nursing home care. The history of this institutional care is briefly examined together with the growth of the discipline of gerontological nursing. Chapter 2 discusses some of the effects of this history on present day care and the concept of emotional work being carried out within the present day aged care public policy regulations. The moral arguments surrounding illness and dying in Australian society today are briefly discussed. Chapter 3 describes the conceptual framework for the study, the ethnographic method that has been employed and an outline of critical theory as the basis for analysis. The chapter concludes by recounting the practical steps taken to arrange the field work, secure the consent of participants, record data and gather documents, and outlines the ethical considerations given to the undertaking of the study. Chapter 4 describes the context in which the study took place and the first tentative exploration of the culture from an etic perspective. Part 2 describes the death trajectories observed and raises some questions about alternative strategies that may have been considered within a different paradigm of caring. In chapter 5 the death trajectories of each of the fifteen residents in the study are described, each written with a particular emphasis to illustrate aspects of the culture of care that emerged through thematic analysis. Observations, comments and feelings from staff and family are wound in and around these case studies. Chapter 6 looks more closely at the impact of policy and institutional pressure on the milieu in which these deaths took place. Part 3 draws conclusions from the observations and makes suggestions for emancipatory change as viewed from the author's standpoint of critical ethnographic analysis. In the final chapter an argument is presented for policy change that leads a movement towards palliative care practices for people with late-stage dementia. Approaches to implementation of palliative care will need to take account of any expression by the resident such as an advanced directive, indicating a preferred approach to treatment in the period prior to death; a need for a better understanding of such issues as the significance of body breakdown, the manifestations of pain and electrolyte imbalances; the surrounding ethical complexities and shift in public opinion, and perhaps, most of ail, the culture of the institutions in which this dying will take place. A definition of late-stage dementia which might be used in determining patterns of care is set out. A discussion about changes in practice which relate lo communication with treating doctors, the administering of antibiotics, the relief of pain, the mobilisation of residents and the provision of food and water takes place in light of the evidence found. The discussion of these issues is raised in the form of debate. Each aspect needs more rigorous analysis and information so that evidence-based practice, rather than care which is value-laden and emotional, can be used when treatment decisions are made for people with late-stage dementia.

Applications of nanomedicine in antibacterial medical therapeutics and diagnostics

The need for new and effective/efficient antibacterial therapeutics and diagnostics is necessary if we want to be able to maintain and improve the protection against pathogenic bacteria. Bacteria are becoming increasingly resistant to traditionally used antibiotics and as a result are a major health concern. The number of deaths and hospitalizations due to bacteria is increasing. Current methods of bacterial diagnostics are inefficient as they lack speed and ultra sensitivity and cannot be performed on site. This is where nanomedicine is playing a vital role. The discovery of new and innovative materials through the improvement in fabrication techniques has seen the establishment of an influx of novel antibacterial therapeutics and diagnostics. The goal of this review is to highlight the research that has been done through the implementation of nanomaterials and nanotechnologies for antibacterial medical therapeutic and diagnostic.

Unintentional needlestick injuries in livestock production : a case series and review

Livestock producers and their employees sometimes experience unintentional needlestick injury (NSI) while vaccinating or injecting medications into animals. There is little published regarding the medical complications that can develop from this occupational exposure. The objectives of this study were to (1) perform a retrospective review of animal-related NSIs treated at a tertiary medical center of a rural state; and (2) review the risks of NSI and measures to decrease their occurrence. Medical records of patients with NSI related to animal injection were identified from the University of Iowa Hospitals and Clinics database from 2002 to 2008 and reviewed. Nine patients received medical care for NSI that occurred while vaccinating farm animals. Most common NSI site was the nondominant hand and most occurred while attempting to inject the animal. Soft tissue infection was common and all nine received oral and/or intravenous antibiotics. Two thirds required hospital admission. Three required surgery and one had a bedside incision and drainage procedure. One patient had a serious inflammatory reaction with necrosis in the leg due to the oil adjuvant in the animal vaccine. Another case had a probable mycetoma with osteomyelitis and soft tissue infection due to the bacteria Streptomyces, which is a NSI complication not previously reported. Although medical complications from farm-related NSIs do not appear to be common, this case series illustrates how these injuries can be debilitating, costly, and lead to loss of work time and productivity. Producers and employees who inject livestock need to be aware of the risks and utilize measures to decrease unintentional NSI.

Efflux pumps of Mycobacterium tuberculosis play a significant role in antituberculosis activity of potential drug candidates

Active efflux of drugs mediated by efflux pumps that confer drug resistance is one of the mechanisms developed by bacteria to counter the adverse effects of antibiotics and chemicals. To understand these efflux mechanisms in Mycobacterium tuberculosis, we generated knockout (KO) mutants of four efflux pumps of the pathogen belonging to different classes. We measured the MICs and kill values of two different compound classes on the wild type (WT) and the efflux pump (EP) KO mutants in the presence and absence of the efflux inhibitors verapamil and L-phenylalanyl-L-arginyl-β-naphthylamide (PAβN). Among the pumps studied, the efflux pumps belonging to the ABC (ATP-binding cassette) class, encoded by Rv1218c, and the SMR (small multidrug resistance) class, encoded by Rv3065, appear to play important roles in mediating the efflux of different chemical classes and antibiotics. Efflux pumps encoded by Rv0849 and Rv1258c also mediate the efflux of these compounds, but to a lesser extent. Increased killing is observed in WT M. tuberculosis cells by these compounds in the presence of either verapamil or PAβN. The efflux pump KO mutants were more susceptible to these compounds in the presence of efflux inhibitors. We have shown that these four efflux pumps of M. tuberculosis play a vital role in mediating efflux of different chemical scaffolds. Inhibitors of one or several of these efflux pumps could have a significant impact in the treatment of tuberculosis. The identification and characterization of Rv0849, a new efflux pump belonging to the MFS (major facilitator superfamily) class, are reported.