High-strength resorbable brushite bone cement with controlled drug-releasing capabilities

Brushite cements differ from apatite-forming compositions by consuming a lot of water in their setting reaction whereas apatite-forming cements consume little or no water at all. Only such cement systems that consume water during setting can theoretically produce near-zero porosity ceramics. This study aimed to produce such a brushite ceramic and investigated whether near elimination of porosity would prevent a burst release profile of incorporated antibiotics that is common to prior calcium phosphate cement delivery matrices. Through adjustment of the powder technological properties of the powder reactants, that is particle size and particle size distribution, and by adjusting citric acid concentration of the liquid phase to 800 mM, a relative porosity of as low as 11% of the brushite cement matrix could be achieved (a 60% reduction compared to previous studies), resulting in a wet unprecompacted compressive strength of 52 MPa (representing a more than 100% increase to previously reported results) with a workable setting time of 4.5 min of the cement paste. Up to 2 wt.% of vancomycin and ciprofloxacin could be incorporated into the cement system without loss of wet compressive strength. It was found that drug release rates could be controlled by the adjustable relative porosity of the cement system and burst release could be minimized and an almost linear release achieved, but the solubility of the antibiotic (vancomycin > ciprofloxacin) appeared also to be a crucial factor.

Hospital pharmacists' awareness of a new antibiotic guideline in the UK:implications for practice

Objectives: Pharmacists play an important role in the review of local hospital guidelines. British Thoracic Society (BTS) guidelines for the management of patients with community-acquired pneumonia (CAP) were updated in 2001, and it is important that individual hospital recommendations are based upon this national guidance. The aim of this study was to identify UK Chief Pharmacists' awareness of these updated guidelines one year after their publication. Secondary aims were to identify whether pharmacists had subsequently initiated revision of institutional CAP guidelines, and what roles different professional staff had performed in this process. Method: A self-completion postal questionnaire was sent to the Chief Pharmacist (or their nominated staff) in 253 UK NHS hospitals in November 2002. This aimed to identify issues relating to their awareness of the 2001 BTS guidelines and subsequent revision of their hospital's guidelines. Results:188 questionnaires were returned (a response rate of 74%), of which 164 hospitals had local antibiotic prescribing guidelines. Respondents in 29% of these hospitals were unaware of the 2001 BTS publication and institutional guidelines had been revised in only 51% of hospitals where the Chief Pharmacist was purportedly aware of the new BTS guidance. Generally, more staff types were involved in revising guidelines than initiating revision. Conclusions:Variability existed in both Chief Pharmacists' awareness of new national guidance and subsequent review processes operating in individual hospitals. A lack of proactive reaction to new national guidance was identified in some hospitals, and it is hoped that the establishment of specialist "infectious diseases pharmacists" will facilitate the review of institutional antibiotic prescribing guidelines in the future. © Springer 2005.

Development of a prescribing indicator for objective quantification of antibiotic usage in secondary care

Objectives: To compare the recognized defined daily dose per 100 bed-days (DDD/100 bed-days) measure with the defined daily dose per finished consultant episode (DDD/FCE) in a group of hospitals with a variety of medicines management strategies. To compare antibiotic usage using the above indicators in hospitals with and without electronic prescribing systems. Methods: Twelve hospitals were used in the study. Nine hospitals were selected and split into three cohorts (three high-scoring, three medium-scoring and three low-scoring) by their 2001 medicines management self-assessment scores (MMAS). An additional cohort of three electronic prescribing hospitals was included for comparison. MMAS were compared to antibiotic management scores (AMS) developed from a questionnaire relating specifically to control of antibiotics. FCEs and occupied bed-days were obtained from published statistics and statistical analyses of the DDD/100 bed-days and DDD/FCE were carried out using SPSS. Results: The DDD/100 bed-days varied from 81.33 to 189.37 whilst the DDD/FCE varied from 2.88 to 7.43. The two indicators showed a high degree of correlation with r = 0.74. MMAS were from 9 to 22 (possible range 0-23) and the AMS from 2 to 13 (possible range 0-22). The two scores showed a high degree of correlation with r = 0.74. No correlation was established between either indicator and either score. Conclusions: The WHO indicator for medicines utilization, DDD/100 bed-days, exhibited the same level of conformity as that exhibited from the use of the DDD/FCE indicating that the DDD/FCE is a useful additional indicator for identifying hospitals which require further study. The MMAS can be assumed to be an accurate guide to antibiotic medicines management controls. No relationship has been found between a high degree of medicines management control and the quantity of antibiotic prescribed. © The British Society for Antimicrobial Chemotherapy; 2004 all rights reserved.

Documentation of antibiotic prescribing controls in UK NHS hospitals

Objectives: To identify the types, prevalence and nature of antibiotic prescribing control documents within NHS hospitals in the UK. Methods: A self-completion postal questionnaire was sent to each Chief Pharmacist at 465 NHS hospitals in 2001/2002. This contained questions covering hospital demographics, and hospital antibiotic prescribing control documentation, including format, dissemination, approval and review processes. Results: In total, 253 (54%) completed questionnaires were returned. Of these, 168 respondents' hospitals had an antibiotic formulary, 107 had a policy for antibiotic prescribing and 216 had guidelines on antibiotic use. All three types of antibiotic prescribing documents were used by 82 hospitals but 18 did not have any documents; 44% of formularies, 45% of policies and 35% of guidelines were available electronically. The Drug and Therapeutics Committee was the most frequently cited body for document approval and approximately one-third of documents had been approved during the current year of the questionnaire. Only about one-half of responding hospitals had an annual review of documents. Conclusions: Despite publication of high-profile national guidance in response to growing concerns regarding antimicrobial resistance, there has been little increase in the use of antibiotic prescribing control documents in NHS hospitals over the past decade. It is clear that appropriate controls for antibiotic prescribing are not yet universally applied in the UK and recommendations for action have been proposed. © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.

Control of antibiotic prescribing in UK NHS hosptials. Available in 2 volumes.

This thesis is an evaluation of practices to control antibiotic prescribing in UK NHS hospitals. Within the past ten years there has been increasing international concern about escalating antibiotic resistance, and the UK has issued several policy documents for pmdent antibiotic prescribing. Chief Pharmacists in 253 UK NHS hospitals were surveyed about the availability and nature of documents to control antibiotic prescribing (formularies, policies and guidelines), and the role of pharmacists and medical microbiologists in monitoring prescribers' compliance with the recommendations of such documents. Although 235 hospitals had at least one document, only 60% had both an antibiotic formulary and guidelines, and only about one-half planned an annual revision of document(s). Pharmacists were reported as mostly checking antibiotic prescribing on every ward whilst medical microbiologists mostly visited selected units only. Response to a similar questionnaire was obtained from the Chief Medical Microbiologists in 131 UK NHS hospitals. Comparisons of the questionnaires indicated areas of apparent disagreement about the roles of pharmacists and medical microbiologists. Eighty three paired-responses received from pharmacists and medical microbiologists in the same hospital revealed poor agreement and awareness about controls. A total of 205 institutional prescribing guidelines were analysed for recommendations for the empirical antibiotic prescribing of Community-Acquired Pneumonia (CAP). Variation was observed in recommendations and agreement with national guidance from the British Thoracic Society (BTS). A questionnaire was subsequently sent to 235 Chief Pharmacists to investigate their awareness of this new guidance from the BTS, and subsequent revision of institutional guidelines. Documents had been revised in only about one-half of hospitals where pharmacists were aware of the new guidance. An audit of empirical antibiotic prescribing practices for CAP was performed at one hospital. Although problems were experienced with retrieval of medical records, diagnostic criteria were poorly recorded, and only 57% of prescribing for non-severe CAP was compliant with institutional guidelines. A survey of clinicians at the same hospital identified that almost one-half used the institutional guidelines and most found them useful. However, areas for improvement concernmg awareness of the guidelines and ease of access were identified. It is important that hospitals are equipped to react to changes in the hospital environment including frequent movement of junior doctors between institutions, the employment of specialist "infectious diseases pharmacists" and the increasing benefits offered by information technology. Recommendations for policy have been suggested.

The suitability of biodegradable poly(dl-lactide-co-glycolide)75:25 microspheres for the sustained release of antibiotics

Post-operative infections resulting from total hip arthroplasty are caused by bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa entering the wound perioperatively or by haemetogenous spread from distant loci of infection. They can endanger patient health and require expensive surgical revision procedures. Gentamicin impregnated poly (methyl methacrylate) bone cement is traditionally used for treatment but is often removed due to harbouring bacterial growth, while bacterial resistance to gentamicin is increasing. The aim of this work was to encapsulate the antibiotics vancomycin, ciprofloxacin and rifampicin within sustained release microspheres composed of the biodegradable polymer poly (dl-lactide-co-glycolide) [PLCG] 75:25. Topical administration to the wound in hydroxypropylmethylcellulose gel should achieve high local antibiotic concentrations while the two week in vivo half life of PLCG 75:25 removes the need for expensive surgical retrieval operations. Unloaded and 20% w/w antibiotic loaded PLCG 75:25 microspheres were fabricated using a Water in Oil emulsification with solvent evaporation technique. Microspheres were spherical in shape with a honeycomb-like internal matrix and showed reproducible physical properties. The kinetics of in vitro antibiotic release into newborn calf serum (NCS) and Hank's balanced salt solution (HBSS) at 37°C were measured using a radial diffusion assay. Generally, the day to day concentration of each antibiotic released into NCS over a 30 day period was in excess of that required to kill St. aureus and Ps. auruginosa. Only limited microsphere biodegradation had occurred after 30 days of in vitro incubation in NCS and HBSS at 37°C. The moderate in vitro cytotoxicity of 20% w/w antibiotic loaded microspheres to cultured 3T3-L1 cells was antibiotic induced. In conclusion, generated data indicate the potential for 20% w/w antibiotic loaded microspheres to improve the present treatment regimens for infections occurring after total hip arthroplasty such that future work should focus on gaining industrial collaboration for commercial exploitation.

A novel and rational approach towards designing aluminium chelators

Aluminium (Al) is known to be neurotoxic and has been associated with the aetiology of Alzheimer's Disease. To date, only desferrioxamine (DFO), a trihydroxamic acid siderophore has been used in the clinical environment for the removal of Al from the body. However, this drug is expensive, orally inactive and is associated with many side effects. These studies employed a theoretical approach, with the use of quantum mechanics (QM) via semi-empirical molecular orbital (MO) calculations, and a practical approach using U87-MG glioblastoma cells as a model for evaluating the influence of potential chelators on the passage of aluminium into cells. Preliminary studies involving the Cambridge Structural Database (CSD) identified that Al prefers binding to bidentate ligands in a 3:1 manner, whereby oxygen was the exclusive donating atom. Statistically significant differences in M-O bond lengths when compared to other trivalent metal ions such as Fe3+ were established and used as an acceptance criterion for subsequent MO calculations. Of the semi-empirical methods parameterised for Al, the PM3 Hamiltonian was found to give the most reliable final optimised geometries of simple 3:1 Al complexes. Consequently the PM3 Hamiltonian was used for evaluating the Hf of 3:1 complexes with more complicated ligands. No correlation exists between published stability constants and individual parameters calculated via PM3 optimisations, although investigation of the dicarboxylates reveals a correlation of 0.961 showing promise for affinity prediction of closely related ligands. A simple and inexpensive morin spectrofluorescence assay has been developed and optimised producing results comparable to atomic absorption spectroscopy methods for the quantitative analysis of Al. This assay was used in subsequent in vitro models, initially on E. coli, which indicated that Al inhibits the antimicrobial action of ciprofloxacin, a potent quinolone antibiotic. Ensuing studies using the second model, U87-MG cells, investigated the influence of chelators on the transmembrane transport of Al, identifying 1,2-diethylhydroxypyridin-4-one as a ligand showing greatest potential for chelating Al in the clinical situation. In conclusion, these studies have explored semi-empirical MO Hamiltonians and an in-vitro U87-MG cell line, both as possible methods for predicting effective chelators of Al.

Antibiotic and biocide resistance in Salmonella enterica and Escherichia coli 0157

Bacterial resistance to antibiotics and biocides is a prevalent problem, which may be exacerbated by the commonplace and often unnecessary inclusion of biocides into domestic products. Addition of antimicrobials, to domestic disinfectants has raised concern about promoting microbial resistance and potential cross-resistance to therapeutic antibiotics. This study investigated the potential for resistance in Salmonella enterica serovars Enteritidis, Typhimurium, Virchow and Escherichia call 0157 to commonly used biocides, to identify mechanisms underlying resistance and whether these provided cross-resistance to antibiotics. Salmonella enterica and E. coli 0157 strains were serially exposed to sub-inhibitory. concentrations of erythromycin (ERY), benzalkonium chloride (BKC), chlorhexidine hydrochloride (CHX)and triclosan (TLN). Once resistance was achieved permeability changes in the outer membrane, including LPS, cell surface charge and hydrophobicityand the presence of,an active efflux were investigated as possible resistance candidates. Thin layer chromatography (TLC) and Gas chromatography (GC) were carried out to examine fatty acid and lipid changes in E. coli 0157 isolates with reduced susceptibility to TLN. Cross-resistance was studied by the Stoke's method and standard microdilution assays. Examination of the outer membrane proteins and LPS did not reveal any significant changes between parent and resistant strains. The hydrophobicity of the cells increased as the cells were passaged and became less. susceptible. An active efflux system was the most likely mechanism of resistance in all strains tested and a fab1 mutation was associated with E. coli 0157 resistant to TLN isolates. In all isolates investigated the resistance was stable for over 30 passages in biocide-free media. A high degree of cross-resistance was obtained in TLN-resjstant Escherichia coli 0157 strains, which repeatedly exerted decreased susceptibility to various antimicrobials, including chloramphenicol, erythromycin, imipenem, tetracycline and trimethoprirn:, as well as to various biocides. The results of this laboratory-based investigation suggest that it is possible for microorganisms to become resistant to biocides when repeatedly exposed to sublethal concentrations. This may be especially the case in the domestic environment where administration of biocides is poorly controlled. Eventually it could lead to the undesirable situation of resident strains becoming resistant to disinfection and cross resistant to other antimicrobials.

Development and validaton of an indicator to compare antibiotic usage in secondary care in England

The use of antibiotics was investigated in twelve acute hospitals in England. Data was collected electronically and by questionnaire for the financial years 2001/2, 2002/3 and 2003/4. Hospitals were selected on the basis of their Medicines Management Self-Assessment Scores (MMAS) and included a cohort of three hospitals with integrated electronic prescribing systems. The total sample size was 6.65% of English NHS activity for 2001/2 based on Finished Consultant Episode (FCE) numbers. Data collected included all antibiotics dispensed (ATC category J01), hospital activity FCE's and beddays, Medicines Management Self-assessment scores, Antibiotic Medicines Management scores (AMS), Primary Care Trust (PCT) of origin of referral populations, PCT antibiotic prescribing rates, Index of Multiple Deprivation for each PCT. The DDD/FCE (Defined Daily Dose/FCE) was found to correlate with the DDD 100beddays (r = 0.74 pAntibiotic use increased from a mean 4.16 DDD/FCE in 2001/2 to 4.35 DDD/FCE in 2003/4. Antibiotic use in the electronic prescribing cohort was found to be lower, than the sample mean at 3.48 DDD/FCE in 2001/2 and 3.34 DDD/FCE in 2003/4. The MMAS and AMS were found to correlate (r = 0.74 pantibiotic use. No correlation was found between the MMAS and a range of qualitative indicators of antibiotic use. A number of indicators are proposed as triggers for further investigation including a proportion of 0.24 for the ratio of third generation to first/second generation cephalosporin use, and five percent as the limit for parenteral quinolone DOD of total quinolone DOD usage. It was possible to demonstrate a correlation between the IMD 2000 and primary care antibiotic prescribing rates but not between primary and secondary care antibiotic prescribing rates for the same referral population or between the weighted mean IMD 2000 for each hospital's referral population and the hospital antibiotic prescribing rate.

Studies on survival of Pseudomonas aeruginosa 6750

The growth of Pseudomonas aeruginosa 6750 as a biofilm was investigated using a novel system based on that of Gilbert et al (1989). The aim was to test the effect of controlled growth of the organism on antibiotic susceptibility and examine the survival of the organism as a biofilm. During the investigations it became clear that, because of the increasing growth of P.aeruginosa and production of exopolysaccharide, a growth rate controlled monolayer could not be achieved and so the method was not used further. The data, however, showed that there was an increase in the smooth colony type of the organism during growth. Investigations were focused on the survival of P.aeruginosa in batch and chemostat studies. Survival or percentage culturability, as measured by total and colony count ratio, was found to decrease both in extended batch culture and for chemostat cells with decreasing growth rate. Extended batch culture, however, did not exhibit further increases in resistance to ciprofloxacin and polymyxin B. Survival was also measured using other parameters namely the direct viable count, vital staining, effect of temperature downshift and measurement of lag. In batch culture, the most notable change was a decrease in cell size along the growth curve. This was accompanied by an increase in the cellular protein content. Protein per volume was calculated from the data which showed a marked increase in batch culture, which was not demonstrated for chemostat cells with decreasing growth rate. Outer membrane protein profiles were obtained for batch and chemostat cells. An LPS profile of batch culture cells was also demonstrated. In general, there was little difference in the outer membrane protein profiles of cells from early and late stationary phases.The result of the LPS profile showed that there appeared to be an increase in the B-band of the region of the LPS in the older stationary phase cultures.

The need for continued monitoring of antibiotic resistance patterns in clinical isolates of Staphylococcus aureus from London and Malta

Antibiotic resistance is an increasing problem in isolates of Staphylococcus aureus (S. aureus) worldwide. In 2001 The National Health Service in the UK introduced a mandatory bacteraemia surveillance scheme for the reporting of S. aureus and methicillin-resistant S. aureus (MRSA). This surveillance initiative reports on the percentage of isolates that are methicillin resistant. However, resistance to other antibiotics is not currently reported and therefore the scale of emerging resistance is currently unclear in the UK. In this study, multiple antibiotic resistance (MAR) profiles against fourteen antimicrobial drugs were investigated for 705 isolates of S. aureus collected from two European study sites in the UK (London) and Malta.

Professionals' awareness of operational antibiotic prescribing controls in UK NHS hospitals

In recent years, there have been increasing recommendations for multidisciplinary collaboration between clinical pharmacists and medical microbiologists in an attempt to control the quality (and quantity) of antibiotic prescribing. A questionnaire addressing the utilization of antibiotic prescribing controls was sent to the chief pharmacist and medical microbiologist in UK NHS hospitals. Responses were received from both the chief pharmacist and the medical microbiologist employed in the same hospital from 83 hospitals (a 30% response rate from two independent studies). A high level of disagreement and poor awareness was identified between the interprofessional staff groups regarding the existence of antibiotic formulary (with disagreement between the two groups, or not known by one or both respondents, in 46% of the paired hospitals, N=38) and guideline documents (13%, N=11), performance of antibiotic prescribing audits (40%, N=33), and whether pharmacists (52%, N=43) and medical microbiologists (77%, N=64) monitored physician compliance with antibiotic prescribing control documents. This study has identified poor knowledge of the existence of basic antibiotic prescribing control mechanisms and the role of professional colleagues. It is suggested that there is some way to go before 'Agenda for Change' principles of flexible and collaborative roles are met. © 2004 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved.

Delivery of the antibiotic gentamicin sulphate from precipitation cast matrices of polycaprolactone

Microporous, poly(ε-caprolactone) (PCL) matrices were loaded with the aminoglycoside antibiotic, gentamicin sulphate (GS) using the precipitation casting technique by suspension of powder in the PCL solution prior to casting. Improvements in drug loading from 1.8% to 6.7% w/w and distribution in the matrices were obtained by pre-cooling the suspension to 4°C. Gradual release of approximately 80% of the GS content occurred over 11 weeks in PBS at 37°C and low amounts of antibiotic were measured up to 20 weeks. The kinetics of release could be described effectively by the Higuchi model with the diffusion rate constant (D) increasing from of 1.7 to 5.1 μg/mg matrix/day0.5 as the drug loading increased from 1.4% to 8.3% w/w. GS-loaded PCL matrices retained anti-bacterial activity after immersion in PBS at 37°C over 14 days as demonstrated by inhibition of growth of S. epidermidis in culture. These findings recommend further investigation of precipitation-cast PCL matrices for delivery of hydrophilic molecules such as anti-bacterial agents from implanted, inserted or topical devices. © 2005 Elsevier B.V. All rights reserved.