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A Novel Antifungal Is Active against Candida albicans Biofilms and Inhibits Mutagenic Acetaldehyde Production In Vitro.

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A Novel Antifungal Is Active against Candida albicans Biofilms and Inhibits Mutagenic Acetaldehyde Production In Vitro.

PLoS One. 2014;9(5):e97864

Authors: Nieminen MT, Novak-Frazer L, Rautemaa V, Rajendran R, Sorsa T, Ramage G, Bowyer P, Rautemaa R

Abstract
The ability of C. albicans to form biofilms is a major virulence factor and a challenge for management. This is evident in biofilm-associated chronic oral-oesophageal candidosis, which has been shown to be potentially carcinogenic in vivo. We have previously shown that most Candida spp. can produce significant levels of mutagenic acetaldehyde (ACH). ACH is also an important mediator of candidal biofilm formation. We have also reported that D,L-2-hydroxyisocaproic acid (HICA) significantly inhibits planktonic growth of C. albicans. The aim of the present study was to investigate the effect of HICA on C. albicans biofilm formation and ACH production in vitro. Inhibition of biofilm formation by HICA, analogous control compounds or caspofungin was measured using XTT to measure biofilm metabolic activity and PicoGreen as a marker of biomass. Biofilms were visualised by scanning electron microscopy (SEM). ACH levels were measured by gas chromatography. Transcriptional changes in the genes involved in ACH metabolism were measured using RT-qPCR. The mean metabolic activity and biomass of all pre-grown (4, 24, 48 h) biofilms were significantly reduced after exposure to HICA (p<0.05) with the largest reductions seen at acidic pH. Caspofungin was mainly active against biofilms pre-grown for 4 h at neutral pH. Mutagenic levels (>40 µM) of ACH were detected in 24 and 48 h biofilms at both pHs. Interestingly, no ACH production was detected from D-glucose in the presence of HICA at acidic pH (p<0.05). Expression of genes responsible for ACH catabolism was up-regulated by HICA but down-regulated by caspofungin. SEM showed aberrant hyphae and collapsed hyphal structures during incubation with HICA at acidic pH. We conclude that HICA has potential as an antifungal agent with ability to inhibit C. albicans cell growth and biofilm formation. HICA also significantly reduces the mutagenic potential of C. albicans biofilms, which may be important when treating bacterial-fungal biofilm infections.

PMID: 24867320 [PubMed – in process]

Pharmacokinetics and Pharmacodynamics of Antibacterials, Antifungals, and Antivirals Used Most Frequently in Neonates and Infants.

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Pharmacokinetics and Pharmacodynamics of Antibacterials, Antifungals, and Antivirals Used Most Frequently in Neonates and Infants.

Clin Pharmacokinet. 2014 May 29;

Authors: Roberts JK, Stockmann C, Constance JE, Stiers J, Spigarelli MG, Ward RM, Sherwin CM

Abstract
Antimicrobials and antivirals are widely used in young infants and neonates. These patients have historically been largely excluded from clinical trials and, as a consequence, the pharmacokinetics and pharmacodynamics of commonly used antibacterials, antifungals, and antivirals are incompletely understood in this population. This review summarizes the current literature specific to neonates and infants regarding pharmacokinetic parameters and changes in neonatal development that affect antimicrobial and antiviral pharmacodynamics. Specific drug classes addressed include aminoglycosides, aminopenicillins, cephalosporins, glycopeptides, azole antifungals, echinocandins, polyenes, and guanosine analogs. Within each drug class, the pharmacodynamics, pharmacokinetics, and clinical implications and future directions for prototypical agents are discussed. β-Lactam antibacterial activity is maximized when the plasma concentration exceeds the minimum inhibitory concentration for a prolonged period, suggesting that more frequent dosing may optimize β-lactam therapy. Aminoglycosides are typically administered at longer intervals with larger doses in order to maximize exposure (i.e., area under the plasma concentration-time curve) with gestational age and weight strongly influencing the pharmacokinetic profile. Nonetheless, safety concerns necessitate therapeutic drug monitoring across the entire neonatal and young infant spectrum. Vancomycin, representing the glycopeptide class of antibacterials, has a long history of clinical utility, yet there is still uncertainty about the optimal pharmacodynamic index in neonates and young infants. The high degree of pharmacokinetic variability in this population makes therapeutic drug monitoring essential to ensure adequate therapeutic exposure. Among neonates treated with the triazole agent fluconazole, it has been speculated that loading doses may improve pharmacodynamic target attainment rates. The use of voriconazole necessitates therapeutic drug monitoring and dose adjustments for patients with hepatic dysfunction. Neonates treated with lipid-based formulations of the polyene amphotericin B may be at an increased risk of death, such that alternative antifungal agents should be considered for neonates with invasive fungal infections. Alternative antifungal agents such as micafungin and caspofungin also exhibit unique pharmacokinetic considerations in this population. Neonates rapidly eliminate micafungin and require nearly three times the normal adult dose to achieve comparable levels of systemic exposure. Conversely, peak caspofungin concentrations have been reported to be similar among neonates and adults. However, both of these drugs feature favorable safety profiles. Recent studies with acyclovir have suggested that current dosing regimens may not result in therapeutic central nervous system concentrations and more frequent dosing may be required for neonates at later postmenstrual ages. Though ganciclovir and valganciclovir demonstrate excellent activity against cytomegalovirus, they are associated with significant neutropenia. In summary, many pharmacokinetic and pharmacodynamic studies have been conducted in this vulnerable population; however, there are also substantial gaps in our knowledge that require further investigation. These studies will be invaluable in determining optimal neonatal dosing regimens that have the potential to improve clinical outcomes and decrease adverse effects associated with antimicrobial and antiviral treatments.

PMID: 24871768 [PubMed – as supplied by publisher]

Eight More Ways To Deal with Antibiotic Resistance.

Eight More Ways To Deal with Antibiotic Resistance.
Antimicrob Agents Chemother. 2014 May 27;
Authors: Metz M, Shlaes DM
Abstract
The fight against antibiotic resistance must be strengthened. We pro…

Antifungal resistance to fluconazole and echinocandins is not emerging in yeast isolates causing fungemia in a Spanish tertiary care center.

Antifungal resistance to fluconazole and echinocandins is not emerging in yeast isolates causing fungemia in a Spanish tertiary care center.

Antimicrob Agents Chemother. 2014 May 27;

Authors: Marcos-Zambrano LJ, Escribano P, Sánchez C, Muñoz P, Bouza E, Guinea J

Abstract
Accurate knowledge of the fungemia epidemiology requires identification of strains to molecular level. Various studies have shown that the rate of resistance to fluconazole ranges from 2.5% to 9% in Candida spp. isolated from blood samples. However, trends in antifungal resistance have received little attention and have only been studied using CLSI M27-A3 methodology. We assessed the fungemia epidemiology in a large tertiary institution in Madrid, Spain by identifying isolates to molecular level and performing antifungal susceptibility testing according to the updated breakpoints of EUCAST EDEF 7.2. We studied 613 isolates causing 598 episodes of fungemia in 544 patients admitted to our hospital (January 2007 to December 2013). Strains were identified after amplification and sequencing of the ITS1-5.8S-ITS2 region and further tested for in vitro susceptibility to amphotericin B, fluconazole, posaconazole, voriconazole, micafungin, and anidulafungin. Resistance was defined using EUCAST species-specific breakpoints, and ECOFFs were applied as tentative breakpoints. Most episodes were caused by C. albicans (46%), C. parapsilosis (28.7%), C. glabrata (9.8%), and C. tropicalis (8%). Molecular identification enabled us to better detect cryptic species of C. guilliermondii and C. parapsilosis complexes and episodes of polyfungal fungemia. The overall percentage of fluconazole-resistant isolates was 5%, although this was higher in C. glabrata (8.6%), and non-Candida yeast isolates (47.4%). The rate of resistance to echinocandins was 4.4% and was mainly due to the presence of intrinsically resistant non-Candida species. Resistance mainly affected non-Candida yeasts. The rate of resistance to fluconazole and echinocandins did not change considerably during the study period.

PMID: 24867979 [PubMed – as supplied by publisher]

‘Breakthrough invasive fungal disease in patients receiving posaconazole primary prophylaxis: a four year study’

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‘Breakthrough invasive fungal disease in patients receiving posaconazole primary prophylaxis: a four year study’

Clin Microbiol Infect. 2014 May 26;

Authors: Lerolle N, Raffoux E, Socie G, Touratier S, Sauvageon H, Porcher R, Bretagne S, Bergeron A, Azoulay E, Molina JM, Lafaurie M

Abstract
Posaconazole (PSC) is currently recommended as primary prophylaxis in neutropenic patients with acute myeloid leukemia (AML) and in allogenic hematopoietic stem cell transplantation (AHSCT) recipients with graft-versus-host-disease (GVHD). Studies focusing on breakthrough invasive fungal disease (IFD) upon PSC prophylaxis show disparate results. In order to evaluate IFD incidence in patients on PSC prophylaxis and identify IFD risk factors, we carried out a retrospective study of all consecutive patients on PP from 01/2007 to 12/2010 in our hospital. Breakthrough IFD were identified from the database of the central pharmacy and the French administrative database (PMSI), registering final medical diagnoses of hospitalized patients. Medical data were reviewed to study proven or probable IFD, according to EORTC/MSG definition. PSC plasma concentrations (PPC) were also retrieved. Poisson models were used for statistical analysis. Two hundred and seventy nine patients received PSC prophylaxis for a median duration of 1.4 months (range 0.2-17.9). Proven (n=6) or probable (n=3) IFD were diagnosed in 9 cases (3.2%). IFD incidence rate per 100 person-month was 1.65 (95% CI 0.79-2.97). IFD were candidemia (Candida glabrata n=2), pulmonary invasive aspergillosis (n=3), disseminated fusariosis (n=2) and pulmonary mucormycosis (n=2). Seven deaths were reported, directly related to IFD in 3 patients (33.3%). First dosage of PPC under 0.3μg/ml was the single significant risk factor for IFD (RR 7.77, 95% CI 1.30-46.5, p=0.025). Breakthrough IFD in patients receiving PSC prophylaxis is rare but associated with a poor outcome. Low PSC plasma concentrations are associated with an increased risk of IFD This article is protected by copyright. All rights reserved.

PMID: 24861577 [PubMed – as supplied by publisher]

New epidemiology of Staphylococcus aureus infections in the Middle East.

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New epidemiology of Staphylococcus aureus infections in the Middle East.

Clin Microbiol Infect. 2014 May 26;

Authors: Tokajian S

Abstract
Staphylococcus aureus is a bacterial pathogen distributed worldwide and is an increasing problem both in hospitals and the community. Global transmission of methicillin-resistant S. aureus (MRSA) has been the subject of many studies. The incidence of colonization with community acquired (CA) MRSA of hospitalized and outpatient was the aim of several studies conducted in the Middle East (Western Asia). The local epidemiology within countries in this region is changing due to the introduction of new strains with the intercontinental exchanges of several clones. ST80-MRSA-IV is one common clone detected in different countries within the region showing country-based differences and hence more likely forming clonal lineages. MRSA is endemic in this region, and is increasing the burden and the difficulty of detecting imported strains. This is also increasing the risk for domestic and global transmission. To counter the threat associated with the high incidence of MRSA carriage and infections, systematic surveillance of both hospital and community isolates is required along with taking appropriate measures designed to limit their spread. Additionally, antibiotic stewardship is needed to contain the further development of the observed resistance and to help in preserving antibiotics as precious therapeutic resources. It is critical for countries in this region to establish national, as well as international initiatives towards better measurements designed to limit and control the spread of infections. Finally more sequence-based studies are needed to better understand the pathogenicity and epidemiology of these important pathogens. This article is protected by copyright. All rights reserved.

PMID: 24861893 [PubMed – as supplied by publisher]