Drug delivery strategies for photodynamic antimicrobial chemotherapy: From benchtop to clinical practice

Light and photosensitizer-mediated killing of many pathogens, termed photodynamic antimicrobial chemotherapy (PACT), has been extensively investigated in vitro. A wide range of organisms from the Gram-positive Staphylococcus aureus to the Gram-negative Pseudomonas aeruginosa have been proven to be susceptible to PACT. Multidrug-resistant strains are just as susceptible to this treatment as their naive counterparts. Both enveloped and non-enveloped viruses have demonstrated susceptibility in vitro, in addition to fungi and protozoa. Significantly, however, no clinical treatments based on PACT are currently licensed. This paper provides a comprehensive review of work carried out to date on delivery of photosensitizers for use in PACT, including topical, intranasal and oral/buccal delivery, as well as targeted delivery. We have also reviewed photo-antimicrobial surfaces. It is hoped that, through a rational approach to formulation design and subsequent success in small-scale clinical trials, more widespread use will be made of PACT in the clinic, to the benefit of patients worldwide. (C) 2009 Elsevier B.V. All rights reserved.

Modelling the impact of antibiotic use and infection control practices on the incidence of hospital-acquired methicillin-resistant Staphylococcus aureus: a time-series analysis

Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen worldwide. A wide range of factors have been suggested to influence the spread of MRSA. The objective of this study was to evaluate the effect of antimicrobial drug use and infection control practices on nosocomial MRSA incidence in a 426-bed general teaching hospital in Northern Ireland.

Methods: The present research involved the retrospective collection of monthly data on the usage of antibiotics and on infection control practices within the hospital over a 5 year period (January 2000–December 2004). A multivariate ARIMA (time-series analysis) model was built to relate MRSA incidence with antibiotic use and infection control practices.

Results: Analysis of the 5 year data set showed that temporal variations in MRSA incidence followed temporal variations in the use of fluoroquinolones, third-generation cephalosporins, macrolides and amoxicillin/clavulanic acid (coefficients = 0.005, 0.03, 0.002 and 0.003, respectively, with various time lags). Temporal relationships were also observed between MRSA incidence and infection control practices, i.e. the number of patients actively screened for MRSA (coefficient = -0.007), the use of alcohol-impregnated wipes (coefficient = -0.0003) and the bulk orders of alcohol-based handrub (coefficients = -0.04 and -0.08), with increased infection control activity being associated with decreased MRSA incidence, and between MRSA incidence and the number of new patients admitted with MRSA (coefficient = 0.22). The model explained 78.4% of the variance in the monthly incidence of MRSA.

Conclusions: The results of this study confirm the value of infection control policies as well as suggest the usefulness of restricting the use of certain antimicrobial classes to control MRSA.

Perturbed frequency-selective surfaces fabricated on large thin polymer membranes for multiband infrared applications

The design, fabrication, and characterization of single-screen perturbed frequency-selective surfaces (FSS) at infrared frequencies for single and multiband applications are reported. Single-band FSS based on parallel strips have been perturbed by decreasing the length of every second strip within the array in order to achieve dual band-stop responses. The same principle has been extended to design FSS exhibiting tri- and quadreflection bands. In addition, strip FSSs have been perturbed by replacing every second strip for a metallic ring, resulting in dual-band filters with different polarization responses of the bands. These designs have been fabricated on large thin polyimide membranes using sacrificial silicon wafers. An oxide interlayer between the sacrificial silicon wafer and the polyimide membrane is employed to stop the silicon etching and is wet etched subsequently by a solution of ammonium fluoride and acetic acid that does not attack either the polyimide membrane or the aluminium FSS elements. Fourier transform infrared spectroscopy measurements are presented to validate the predicted responses of the fabricated prototypes.

Effect of the metabolic inhibitor, methimazole on the drug susceptibility of a triclabendazole-resistant isolate of Fasciola hepatica

A study has been carried out to investigate whether the action of triclabendazole (TCBZ) is altered in the presence of a metabolic inhibitor. The flavin monooxygenase system (FMO) was inhibited using methimazole (MTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-sensitive isolates Were used for these experiments. The FMO system was inhibited by a 2-h pre-incubation in methimazole (100 mu M). Flukes were then incubated for I further 22 h in NCTC medium containing either MTZ; MTZ+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nm); MTZ+NADPH+TCBZ (15 mu g/ml); or MTZ+NADPH+triclabendazole sulphoxide (TCBZ.SO) (15 mu g/ml). Morphological changes resulting from drug treatment and following metabolic inhibition were assessed Using scanning electron microscopy'. After treatment with either TCBZ or TCBZ.SO alone, there was greater surface disruption to the triclabendazole-susceptible than -resistant isolate. However, co-incubation with MTZ and TCBZ/TCBZ.SO lead to more severe surface changes to the TCBZ-resistant isolate than with each drug oil its own; this was not seen for the TCBZ-susceptible Cullompton isolate. Results of this study support the concept of altered drug metabolism in TCBZ-Resistant flukes and this process may play a role in the development of drug resistance.

Potentiation of triclabendazole sulphoxide-induced tegumental disruption by methimazole in a triclabendazole-resistant isolate of Fasciola hepatica

A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of drug metabolism. The flavin monooxygenase system (FMO) was inhibited using methimazole (MTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The FMO system was inhibited by a 2-h pre-incubation in methimazole (100 mu M), then incubated for a further 22 h in NCTC medium containing either MTZ; MTZ+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM); MTZ+NADPH+TCBZ (15 mu g/ml); or MTZ+NADPH+triclabendazole sulphoxide (TCBZ.SO) (15 mu g/ml). Changes to fluke ultrastructure following drug treatment and metabolic inhibition were assessed using transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than triclabedazole-resistant isolate. However, co-incubation with MTZ+TCBZ, but more particularly MTZ+TCBZ.SO, led to more severe changes to the TCBZ-resistant isolate than with each drug on its own, with severe swelling of the basal infolds and mucopolysaccharide masses in the syncytium, accompanied by a reduction in numbers of secretory bodies. The synthesis and production of secretory bodies in the tegumental cells was severely affected as well. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action. The results support the concept of altered drug metabolism in TCBZ-resistant flukes, and this process may play a role in the development of drug resistance.

Efficacy of a standard meticillin-resistant Staphylococcus aureus decolonisation protocol in routine clinical practice

Summary

Decolonisation may reduce the risk of meticillin-resistant Staphylococcus aureus (MRSA) infection in individual carriers and prevent transmission to other patients. The aims of this prospective cohort study were to determine the long-term efficacy of a standardised decolonisation regimen and to identify factors associated with failure. Patients colonised with MRSA underwent decolonisation, which was considered to be successful if there was no growth in three consecutive sets of site-specific screening swabs obtained weekly post treatment. If patients were successfully decolonised, follow-up cultures were performed 6 and 12 months later. Of 137 patients enrolled, 79 (58%) were successfully decolonised. Of these 79, 53 (67%) and 44 (56%) remained decolonised at 6 and 12 months respectively. Therefore only 44/137 (32%) patients who completed decolonisation were MRSA negative 12 months later. Outcome was not associated with a particular strain of MRSA. Successful decolonisation was less likely in patients colonised with a mupirocin-resistant isolate (adjusted odds ratio: 0.08; 95% confidence interval: 0.02–0.30), in patients with throat colonisation (0.22; 0.07–0.68) and in patients aged >80 years (0.30; 0.10–0.93) compared with those aged 60–80 years. These findings suggest that although initially successful in some cases, the protocol used did not result in long-term clearance of MRSA carriage for most patients.