Archive for September 1, 2014

Impact of bacterial biofilm on the treatment of prosthetic joint infections

Journal of Antimicrobial Chemotherapy SEPT 2014 V.69 Suppl.1

Cédric Jacqueline* and Jocelyne Caillon

Université de Nantes, Faculté de Médecine, UPRES EA 3826, 1 rue Gaston Veil, Nantes, F-44000 France

*Corresponding author. Tel: +33-240-41-2854; Fax: +33-240-41-2854; E-mail: cedric.jacqueline@univ-nantes.fr

Microbial biofilm contributes to chronic infection and is involved in the pathogenesis of prosthetic joint infections.

Biofilms are structurally complex and should be considered a dynamic system able to protect the bacteria from host defence mechanisms and from antibacterial agents.

Despite the use of antibiotics recognized as effective against acute infections, prosthetic joint infections require long-term suppressive treatment acting on adherent bacteria.

Conventional in vitro susceptibility testing methods are not suitable for biofilm-associated infections given that these tests do not take into account the physiological parameters of bacterial cells in vivo.

Most anti-staphylococcal drugs are able to inhibit in vitro the adhesion of bacteria to a surface, considered to be the first step in biofilm formation.

Recent studies suggest that the lack of activity of antibiotics against biofilm-embedded bacteria seems to be more related to the decreased effect of the drug on the pathogen than to the poor penetration of the drug into the biofilm.

Eradication of biofilm-embedded bacteria is a very difficult task and combination therapy is required in the treatment of persistent infections involving biofilm. Although several combinations demonstrate potent efficacy, rifampicin is the most common partner drug of effective combinations against staphylococcal biofilms.

Considering the complexity of biofilm-related infections, further studies are needed to assess the activity of new therapeutic agents in combination with antibiotics (quorum-sensing inhibitors, biofilm disruptors and specific anti-biofilm molecules).

PDF

http://jac.oxfordjournals.org/content/69/suppl_1/i37.full.pdf+html

September 1, 2014 at 9:07 pm

Single-Tablet Regimens in HIV Therapy.

Infect Dis Ther. 2014 Jun;3(1):1-17.

Astuti N1, Maggiolo F.

Author information

1Unit of Antiviral Therapy, Division of Infectious Diseases, AO Papa Giovanni XXIII, Bergamo, Italy.

Abstract

Combined antiretroviral therapy (cART) has evolved considerably over the past decades leading to a better control of human immunodeficiency virus replication.

Recently, regimens have evolved so as to simplify dosing frequency and reduce pill burden to improve adherence. Several national and international guidelines suggest antiretroviral (ARV) regimen simplification as a method of improving adherence. Decreased cART adherence has been associated with both patient-related factors and regimen-related factors.

Adherence rates are statistically higher when simpler, once-daily (OD) regimens are combined with smaller daily regimen pill burdens. The avoidance of selective non-adherence, where a patient takes part of a regimen but not the full regimen, is a further potential benefit offered by single-tablet regimens (STRs).

Simplification of cART has been associated with a better quality of life (QoL). Although tempered by other factors, better adherence, higher QoL and patients’ preferences are all key points which might combine to assure long-lasting efficacy and durability of cART. All studies underlined the favorable tolerability profile of newer STRs. Three STRs are currently available.

Tenofovir (TDF) plus emtricitabine (FTC)/efavirenz (EFV) was the first OD complete ARV regimen available as a STR. TDF plus FTC/rilpivirine is a second-generation STR. The most recently approved STR, TDF plus FTC/cobicistat/elvitegravir, is the first non-nucleoside reverse transcriptase inhibitor-based STR. All of them have shown excellent efficacy; safety and tolerability have been improved by more recent formulations.

Several other STRs are anticipated both combining completely different drugs, abacavir (ABC) plus lamivudine (3TC)/dolutegravir, utilizing innovative formulations of older drugs, tenofovir alafenamide fumarate, or taking advance of bioequivalent drugs, lamivudine (3TC) plus ABC/EFV.

The future challenge would be to develop completely alternative STRs (including for example protease inhibitors or new molecules) to extend the advantages of simplicity to heavily pre-treated individuals.

PDF

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108118/pdf/40121_2014_Article_24.pdf

September 1, 2014 at 8:59 pm

Oritavancin microbiologic features and activity results from the surveillance program in the United States.

Clin Infect Dis. 2012 Apr;54 Suppl 3:S203-13.

Mendes RE1, Farrell DJ, Sader HS, Jones RN.

Author information

1JMI Laboratories, North Liberty, Iowa 52317, USA. rodrigo-mendes@jmilabs.com

Abstract

Oritavancin is in the final stages of clinical development for treatment of acute bacterial skin and skin structure infections.

This drug has demonstrated potent activity against staphylococci (minimum inhibitory concentration [MIC] for which 90% of isolates are inhibited [MIC(90)], 0.06 μg/mL), enterococci (MIC(90), ≤ 0.008 to 0.5 μg/mL), and streptococci (MIC(90), ≤ 0.008 to 0.12 μg/mL), including enhanced potency against vancomycin-resistant enterococci.

During the clinical development of oritavancin, it was demonstrated that this molecule binds to plastic labware surfaces and that this feature was likely responsible for interlaboratory variability observed from in vitro investigations before 2006.

Therefore, reference broth microdilution methods and MIC ranges for quality control strains were reestablished using media supplemented with a surfactant (polysorbate-80, 0.002%). These were followed by numerous experiments to reassess the in vitro characteristics of oritavancin; the results originating from those studies are summarized here.

The oritavancin activity tested against a resistance surveillance collection of 12,367 Gram-positive clinical pathogens and resistant subsets from the United States (2008-2009) is also presented, with the highest MIC among staphylococci at only 0.25 μg/mL. In vitro results for oritavancin indicate wide potential use against Gram-positive pathogens.

PDF

http://cid.oxfordjournals.org/content/54/suppl_3/S203.full.pdf+html

September 1, 2014 at 8:55 pm

Comparison of the efficacy and safety of oritavancin front-loaded dosing regimens to daily dosing: an analysis of the SIMPLIFI trial.

Antimicrob Agents Chemother. 2011 Jul;55(7):3476-84.

Dunbar LM1, Milata J, McClure T, Wasilewski MM; SIMPLIFI Study Team.

Collaborators (42)

Author information

1LSU Health Sciences Center, School of Medicine at New Orleans, New Orleans, Louisiana 70112, USA. laladunbar@msn.com

Abstract

Oritavancin is a novel lipoglycopeptide with demonstrated effectiveness against complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens, including those caused by methicillin-resistant Staphylococcus aureus (MRSA).

The pharmacokinetic and pharmacodynamic profile of oritavancin is favorable for single or infrequent dosing. A phase 2, multicenter, randomized, double-blind, parallel, active-comparator study (ClinicalTrials.gov identifier, NCT00514527) of single and infrequent dosing of intravenous (i.v.) oritavancin for the treatment of cSSSI caused by Gram-positive pathogens (wound infections, major abscess, and cellulitis) was undertaken to evaluate the noninferiority of front-loaded dosing regimens compared to a daily-dosing regimen.

A total of 302 patients ≥ 18 years of age were randomized equally to one of three oritavancin treatment groups, receiving either a daily dose (200 mg) administered for 3 to 7 days, a single dose (1,200 mg), or an infrequent dose (800-mg dose, with the option for an additional 400 mg on day 5).

The primary efficacy was defined as a clinical response in clinically evaluable (CE) patients assessed at days 21 to 29 (test of cure [TOC]).

The cure rates in the CE population were 72.4% (55/76) in the daily-dose group, 81.5% (66/81) in the 1,200-mg-single-dose group, and 77.5% (55/71) in the infrequent-dose group. In patients with MRSA at baseline, the cure rates were 78.3% (18/23), 73.0% (27/37), and 87.0% (20/23) in the daily-, 1,200-mg-single-, and infrequent-dose groups, respectively; however, the study was not powered to assess outcomes in the MRSA subpopulation, and given the heterogeneity of the types of infection and the small sample size, these do not suggest any true differences in efficacy rates for these pathogens.

The frequencies of adverse events were similar among treatment groups.

The results of this study show that single- and infrequent-dosing schedules of oritavancin were as efficacious as daily administration and had a similar safety profile in treating cSSSI caused by Gram-positive pathogens, including MRSA.

PDF

http://aac.asm.org/content/55/7/3476.full.pdf+html

September 1, 2014 at 8:52 pm


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