An international cross-sectional survey of antimicrobial stewardship programmes in hospitals.

OBJECTIVES: To report the extent and components of global efforts in antimicrobial stewardship (AMS) in hospitals. METHODS: An Internet-based survey comprising 43 questions was disseminated worldwide in 2012. RESULTS: Responses were received from 660 hospitals in 67 countries: Africa, 44; Asia, 50; Europe, 361; North America, 72; Oceania, 30; and South and Central America, 103. National AMS standards existed in 52% of countries, 4% were planning them and 58% had an AMS programme. The main barriers to implementing AMS programmes were perceived to be a lack of funding or personnel, a lack of information technology and prescriber opposition. In hospitals with an existing AMS programme, AMS rounds existed in 64%; 81% restricted antimicrobials (carbapenems, 74.3%; quinolones, 64%; and cephalosporins, 58%); and 85% reported antimicrobial usage, with 55% linking data to resistance rates and 49% linking data to infection rates. Only 20% had electronic prescribing for all patients. A total of 89% of programmes educated their medical, nursing and pharmacy staff on AMS. Of the hospitals, 38% had formally reviewed their AMS programme: reductions were reported by 96% of hospitals for inappropriate prescribing, 86% for broad-spectrum antibiotic use, 80% for expenditure, 71% for healthcare-acquired infections, 65% for length of stay or mortality and 58% for bacterial resistance. CONCLUSIONS: The worldwide development and implementation of AMS programmes varies considerably. Our results should inform and encourage the further evaluation of this with a view to promoting a worldwide stewardship framework. The prospective measurement of well-defined outcomes of the impact of these programmes remains a significant challenge.

A cross-sectional survey of antimicrobial stewardship strategies in UK hospitals.

WHAT IS KNOWN AND OBJECTIVE: Antimicrobial stewardship programmes describe strategies to optimize antimicrobial prescribing and utilization, minimize resistance and improve patient outcomes. Strategies in hospitals are usually implemented by multidisciplinary antimicrobial teams (AMTs). The objective of this study was to describe the profile and activities of AMTs within hospitals in the United Kingdom (UK). METHOD: All hospitals within the UK (n = 836) were included, and a prepiloted questionnaire was mailed to the 'Director of Pharmacy'. Non-respondents were mailed up to two reminder questionnaires at two-weekly intervals. Main outcome measures are as follows: existence and remit of the AMTs; availability of antimicrobial-prescribing policies, aims, scope and methods of dissemination; and monitoring and feedback provided on antimicrobial policy adherence. RESULTS: Response rate was 33% (n = 273). Completed questionnaires analysed were n = 226. Eighty-two (n = 186) of respondents indicated the presence of an AMT within the hospital, with 95% of these (n = 177) reporting an antimicrobial pharmacist as part of the team. All AMTs (n = 186) were involved in development of an antimicrobial policy and almost all (99% n = 184) promoted adherence and restricting use of specific antimicrobials (97% n = 180). Ninety-eight per cent of respondents (n = 222) reported the availability of a local antimicrobial-prescribing policy within the hospital with this disseminated mainly through the hospital intranet (98% n = 217). Adherence to policy was measured mainly through audits measuring the appropriateness of antimicrobial use against the local policy (76% n = 169). Hospitals in England (P = 0·010), tertiary care hospitals (P = 0·021) and bed capacity >500 (P < 0·001) were more likely to have an AMT, as were hospitals with an accident and emergency department (P < 0·001), an infectious diseases unit (P = 0·019) and a microbiology department (P < 0·001). Audits to measure policy adherence were more likely (P < 0·001) if an AMT was present. The only variable retained in bivariate logistic regression was the presence of a microbiology unit, with an odds ratio of 14·1 (95% CI 6·02-33·33, P < 0·001). WHAT IS NEW AND CONCLUSIONS: Although most respondents reported an antimicrobial-prescribing policy, less had an AMT. Despite recent government and regional initiatives, further improvements in antimicrobial stewardship are still required.

Combination antimicrobial susceptibility testing of multidrug-resistant Stenotrophomonas maltophilia from cystic fibrosis patients.

Stenotrophomonas maltophilia is increasingly being isolated from the respiratory tract of individuals with cystic fibrosis, and, because of its multidrug-resistant nature, the selection of suitable treatment regimens can be problematical. Etest methodology was used to facilitate MIC and antimicrobial combination testing on 80 isolates of S. maltophilia cultured from the respiratory tract of Scottish individuals with cystic fibrosis between 2001 and 2010. The overall rate of susceptibility for the 1,410 MIC tests was 23.1%, and resistance was 68.9%. The most active antimicrobials were minocycline, co-trimoxazole, and doxycycline, with 92.4%, 87.3%, and 58.8% of isolates being susceptible, respectively. Of the 517 combinations, 13.2% were synergistic, with the most synergistic being ticarcillin/clavulanate plus aztreonam (91.7% synergistic), ticarcillin/clavulanate plus colistin (40%), and ticarcillin/clavulanate plus levofloxacin (19.4%). Colistin plus tobramycin was the only antagonistic combination (0.2%). By the median susceptible breakpoint index, the most active combinations were minocycline plus co-trimoxazole (median index, 20), minocycline plus piperacillin-tazobactam (median, 20), and co-trimoxazole plus ceftazidime (median, 16.5). The increasing problem of multidrug resistance in organisms recovered from the respiratory tracts of individuals with cystic fibrosis is not going to go away. Current susceptibility testing methods do not address the slow-growing organisms associated with chronic infection, and interpretive standards are based on achievable blood levels of antimicrobials. Addressing these issues specifically for organisms recovered from the respiratory tracts of individuals with cystic fibrosis should lead to better therapeutic outcomes and improved wellbeing of individuals with cystic fibrosis.

Is vancomycin MIC "creep" method dependent? Analysis of methicillin-resistant Staphylococcus aureus susceptibility trends in blood isolates from North East Scotland from 2006 to 2010.

This study investigated "creep" in vancomycin and daptomycin MICs among methicillin-resistant Staphylococcus aureus (MRSA) isolates from blood cultures over a 5-year period in a hospital in the United Kingdom, using different susceptibility testing methods. Trends in vancomycin and daptomycin susceptibility were evaluated by using Etest performed prospectively on isolates in routine clinical practice from December 2007 to December 2010 (n = 102). Comparison was made to results from prospective testing of subcultures at the Scottish MRSA Reference Laboratory, using an automated system (Vitek 2) and retrospective testing (Etest and CLSI reference broth microdilution [BMD] method) of stored isolates from 2006 to 2010 (n = 208). Spearman's rank correlations revealed a significant increase in vancomycin MIC (P = 0.012) and a significant decrease in daptomycin MIC (P = 0.03) by year of study for Etest results from the time of isolation. However, neither trend was replicated in MICs from automated or retrospective testing. The Friedman test revealed a significant difference between vancomycin MICs obtained from the same samples by different testing methods (χ(2) [3 degrees of freedom] = 97; P < 0.001). MICs from automated testing and Etest analysis of stored isolates were significantly lower than those from Etest analysis at the time of isolation for both antibiotics (P < 0.001). Effects of storage on the MIC appeared within the first 6 months of storage. Inconsistent evidence on vancomycin MIC creep and the relevance of the MIC to clinical outcome may arise from differences in susceptibility testing methods, including storage of isolates. There is a need to standardize and streamline susceptibility testing of vancomycin against MRSA.

Antimicrobial stewardship: lessons from human healthcare.

This paper focuses on antimicrobial stewardshipin human healthcare, and some concepts possibly transferable to veterinary medicine. Antimicrobial stewardship is a multidisciplinary effort to reduce antimicrobial resistance in human pathogens, when future drug development is dwindling. These strategies encourage healthcare staff to use antimicrobials prudently and, when needed, for as short a duration and with as narrow a spectrum as possible. Various methods are involved in stewardship within the healthcare setting, often implemented simultaneously, which sometimes makes evaluation of specific measures difficult. All healthcare workers must accept responsibility for stewardship, although the role of infectious diseases physicians, microbiologists, pharmacists and infection control practitioners is crucial, as are appropriate surveillance systems and information technology. Support from management and government is also beneficial. Considering the frequent use of antimicrobials in animals, it would seem sensible to apply a similarly critical approach to conserve the efficacy of the antimicrobials still available, now and in the future.

Methicillin-resistant Staphylococcus aureus in Northeastern Scotland in 2003 to 2007: evolving strain distribution and resistance patterns.

This study explored strain distribution and resistance patterns of methicillin-resistant Staphylococcus aureus (MRSA) over a 5-year period in northeastern Scotland. We noted a shift in the relative rates of epidemic strains and an increase in community-associated strains. Use of oral antibiotics to eradicate throat carriage may have contributed to trimethoprim resistance, which was observed to increase 10-fold.

Epidemiology and management of candidaemia--a retrospective, multicentre study in five hospitals in the UK.

Candidaemia is associated with high mortality. Despite the fact that Candida species account for close to 10% of all nosocomial bloodstream infections, relatively few studies have investigated the management of candidaemia in hospitals. Our objective was to find out how candidaemia is managed in hospitals. Data relating to all episodes of candidaemia for the year 2008 were retrospectively collected in five centres in Scotland and Wales. A total of 96 candidaemic episodes were recorded in the year 2008, yielding 103 isolates of Candida. Fifty candidaemic episodes were caused by Candida albicans. Fluconazole was the most common agent prescribed for the treatment of candidaemia. There was great variation in the prescribed dose of fluconazole. Forty per cent of patients who survived received <2 weeks of systemic antifungal therapy. Central venous catheters (CVC) were removed in 57% of patients. CVC removal was not associated with better survival. The overall mortality was 40.4%. Management of candidaemia varies between the UK centres and is often inadequate. There is need to have consensus on the dosages of antifungal agents and the duration of therapy. The current guidance on removal of CVC in all cases of candidaemia should be reviewed.

Combination testing of multidrug-resistant cystic fibrosis isolates of Pseudomonas aeruginosa: use of a new parameter, the susceptible breakpoint index.

OBJECTIVES: The microbiology laboratory at Aberdeen Royal Infirmary operates an extended susceptibility testing service for multidrug-resistant Gram-negative non-fermenting isolates from the sputum of Scottish cystic fibrosis patients. The service aims to provide clinicians with useful treatment options and developed the use of a novel parameter-the susceptible breakpoint index (SBPI), which allows easy ranking of the antimicrobial combinations in order of their possible in vivo effectiveness. METHODS: Three hundred and fifteen isolates of Pseudomonas aeruginosa were submitted for testing. MICs of 14 antimicrobials were determined using the Etest and the results categorized using CLSI guidelines. Usually, six antimicrobial pairs were tested in combination also using the Etest. The results were assessed using the fractional inhibitory concentration index (FICI) and also by a novel parameter, the SBPI. RESULTS: Some 4173 MICs and 1663 combination pairs were performed. The most active individual antimicrobials were colistin, tobramycin and amikacin, with 84%, 69% and 32% of isolates susceptible, respectively. Twenty-eight of 44 antimicrobial combinations were tested >10 times. Of the combinations, 3.6% were synergistic (FICI < or = 0.5) and 0.1% were antagonistic (FICI > 4.0). Amikacin + ceftazidime (17%), ciprofloxacin + ceftazidime (12.9%) and ciprofloxacin + piperacillin/tazobactam (12%) were the most synergistic combinations. By median SBPI, the most effective combinations in vitro were colistin + ticarcillin/clavulanate, colistin + piperacillin/tazobactam and colistin + meropenem. CONCLUSIONS: The Etest is a useful tool for determining MICs and testing antimicrobial combinations. The SBPI is more discriminatory than the FICI, allowing easy ranking of the combinations, and is likely to have clinical relevance.

A computational study of Anthracyclines interacting with lipid bilayers: Correlation of membrane insertion rates, orientation effects and localisation with cytotoxicity.

Anthracyclines interact with DNA and topoisomerase II as well as with cell membranes, and it is these latter interactions that can cause an increase in their cytotoxic activity. In the present study a detailed computational analysis of the initial insertion, orientation and nature of the interaction occurring between Anthracyclines and two different lipid bilayers (unsaturated POPC and saturated DMPC) is explored through molecular dynamics (MD) simulations; four Anthracyclines: Doxorubicin (DOX), Epirubicin (EPI), Idarubicin (IDA) and Daunorubicin (DAU) were examined. The results indicate that the increased cytotoxicity of DOX, in comparison to the other three analogues, is correlated with its ability to diffuse at a faster rate into the bilayers. Additionally, DOX exhibited considerably different orientational behaviour once incorporated into the bilayer and exhibited a higher propensity to interact with the hydrocarbon tails in both lipids indicating a higher probability of transport to the other leaflet of the bilayer.

Who's winning the war?

Traditionally, methicillin-resistant Staphylococcus aureus (MRSA) has been seen as an infection control problem in healthcare communities. It is now clear that antibiotic use is also an important factor in the control of MRSA, both in the treatment of infection and also, paradoxically perhaps, as a cause of the MRSA problem, in the same way that antibiotic use causes Clostridium difficile disease. At both levels, major improvements in the quality of our antibiotic use are required, particularly antibiotic stewardship to reduce the selection, maintenance and transmission of MRSA strains. In addition, new agents are required to reduce our reliance on glycopeptides for the treatment of serious MRSA infections. Daptomycin has great promise in this regard as its rapid bactericidal activity makes it particularly suitable for the treatment of bacteraemia and endocarditis.

Antibiotic policies to control hospital-acquired infection.

Antibiotic use is widely accepted as being responsible for the selection and maintenance of antibiotic resistance. It is less obvious, however, that it is also responsible for increasing transmissibility and pathogenicity of many multiresistant bacteria and may actually be increasing the number of hospital-acquired infections (HAIs). Antibiotic stewardship should be given much more emphasis in the fight against HAI.

The epidemiology of antibiotic resistance.

Antibiotic resistance has reached crisis point in many hospitals around the world. The majority are swamped with meticillin-resistant Staphylococcus aureus (MRSA), and many with multidrug-resistant (MDR) Gram-negatives. Whilst there are good treatment alternatives available for serious infections due to MRSA, mortality rates remain high. For MDR Gram-negatives the situation is more complex and worrying. There are few, if any, new agents in development that can be expected to benefit the situation in the next decade. Moreover, extreme (or extensive) drug-resistant and even pandrug-resistant Gram-negative infections are increasingly being described. Although definitions are confused in this area, reports suggest that patients in some intensive care units are dying from lack of availability of any antibiotic active against certain strains of Pseudomonas aeruginosa and Acinetobacter baumannii. A better understanding of the molecular basis of resistance is urgently needed if it is to be successfully overcome. Moreover, we urgently need better global early warning systems to detect new resistances and put mechanisms in place for their control.

Current and future treatment options for community-associated MRSA infection.

INTRODUCTION: Community-associated MRSA (CA-MRSA) represents a global epidemic which beautifully encapsulates the fascinating ability of bacterial organisms to adapt quickly on an evolutionary basis to the extreme selective pressure of antibiotic exposure. In stark contrast to Healthcare-associated MRSA (HA-MRSA), it has become apparent that CA-MRSA is less straight forward of a challenge in terms of controlling its transmission, and has forced clinicians to adjust empiric management of clinical syndromes such as skin and soft tissue infection (SSTI) as well as pneumonia. AREAS COVERED: This review details the history and epidemiology of CA-MRSA, while covering both current and future treatment options that are and may be available to clinicians. The authors reviewed both historic and more recent literature on this ever-evolving topic. EXPERT OPINION: While development of new anti-MRSA agents should be encouraged, the importance of antimicrobial stewardship in the battle to stay ahead of the curve with regards to the ongoing control of the MRSA epidemic should be emphasised.

Antimicrobial drug use and infection control practices associated with the prevalence of methicillin-resistant Staphylococcus aureus in European hospitals.

Major regional variations in the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) are observed across Europe. This study investigated hospital MRSA prevalence in relation to patterns of antimicrobial use and infection control policies in an observational, cross-sectional study that used retrospective data from 2001 and linear regression to model relationships. MRSA prevalence (median 20.8%, n = 173 hospitals) and antimicrobial consumption (median 55.2 defined daily doses/100 bed-days, n = 140 hospitals) both varied significantly according to geographical region (p <0.001). MRSA prevalence and antimicrobial consumption data were provided by 128 hospitals, and showed a strong statistical relationship between macrolide use and MRSA prevalence. Use of (i) third-generation cephalosporins, (ii) all antimicrobial agents, and (iii) all antimicrobial agents except glycopeptides was also associated with MRSA prevalence. Up to 146 hospitals provided data on MRSA prevalence and key infection control parameters. Adjusted linear regression modelling provided strong evidence that infection control policy recommendations associated with lower MRSA prevalence rates were (i) use of alcohol-based solutions for hand hygiene (mean difference 10.3%, 99% CI 1.2-10.3), and (ii) placement of MRSA patients in single rooms (mean difference 11.2%, 99% CI 1.4-20.9). Hospitals with problems in implementing isolation policies had higher resistance levels (mean difference 12%, 99% CI 3.8-20.1). Additional recommendations showed less evidence of association with a low MRSA prevalence. Overall, this study highlighted significant associations between MRSA prevalence, antimicrobial use and various key infection control parameters, all of which showed significant individual variations according to geographical region.

Systematic review of the effectiveness of preventing and treating Staphylococcus aureus carriage in reducing peritoneal catheter-related infections.

OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of (1) alternative strategies for the prevention of Staphylococcus aureus carriage in patients on peritoneal dialysis (PD) and (2) alternative strategies for the eradication of S. aureus carriage in patients on PD. DATA SOURCES: Major electronic databases were searched up to December 2005 (MEDLINE Extra up to 6 January 2006). REVIEW METHODS: Electronic searches were undertaken to identify published and unpublished reports of randomised controlled trials and systematic reviews evaluating the effectiveness of preventing and treating S. aureus carriage on peritoneal catheter-related infections. The quality of the included studies was assessed and data synthesised. Where data were not sufficient for formal meta-analysis, a qualitative narrative review looking for consistency between studies was performed. RESULTS: Twenty-two relevant trials were found. These fell into several groups: the first split is between prophylactic trials, aiming to prevent carriage, and trials which aimed to eradicate carriage in those who already had it; the second split is between antiseptics and antibiotics; and the third split is between those that included patients having the catheter inserted before dialysis started and people already on dialysis. Many of the trials were small or short-term. The quality was often not good by today's standards. The body of evidence suggested a reduction in exit-site infections, but this did not seem to lead to a significant reduction in peritonitis, although to some extent this reflected insufficient power in the studies and a low incidence of peritonitis in them. The costs of interventions to prevent or treat S. aureus carriage are relatively modest. For example, the annual cost of antibiotic treatment of S. aureus carriage per identified carrier of S. aureus was estimated at 179 pounds (73 pounds screening and 106 pounds cost of antibiotic). However, without better data on the effectiveness of the interventions, it is not clear whether such costs are offset by the cost of treating infections and averting changes from peritoneal dialysis to haemodialysis. Although treatment is not expensive, the lack of convincing evidence of clinical effectiveness made cost-effectiveness analysis unrewarding at present. However, consideration was given to the factors needed in a hypothetical model describing patient pathways from methods to prevent S. aureus carriage, its detection and treatment and the detection and treatment of the consequences of S. aureus (e.g. catheter infections and peritonitis). Had data been available, the model would have compared the cost-effectiveness of alternative interventions from the perspective of the UK NHS, but as such it helped identify what future research would be needed to fill the gaps. CONCLUSIONS: The importance of peritonitis is not in doubt. It is the main cause of people having to switch from peritoneal dialysis to haemodialysis, which then leads to reduced quality of life for patients and increased costs to the NHS. Unfortunately, the present evidence base for the prevention of peritonitis is disappointing; it suggests that the interventions reduce exit-site infections, but not peritonitis, although this may be due to trials being in too small numbers for too short periods. Trials are needed with larger numbers of patients for longer durations.

Impact of infection control interventions and antibiotic use on hospital MRSA: a multivariate interrupted time-series analysis.

Hospitals in the northeast of Scotland have experienced methicillin-resistant Staphylococcus aureus (MRSA) outbreaks since 1997. Several infection control measures were introduced sequentially to control MRSA, and antibiotic use has been monitored. From January 1997 to December 2004, data on the monthly percentage of non-duplicate MRSA infections (%MRSA) were collated from an intervention hospital (IH) and a control hospital (CH). Both hospitals introduced the use of alcohol hand gel in November 2002. Furthermore, the IH introduced an environmental MRSA swabbing programme in March 2001, chlorine disinfection of the environment in September 2001, discharge screening in December 2001, admission screening in November 2003 and environmental audits in March 2004. Multivariate dynamic regression analysis was used to evaluate the longitudinal effects of these interventions as measured by new clinical cases of MRSA. At the IH, the %MRSA increased between January 1998 and January 2001 and then decreased. At the CH, the %MRSA increased from January 1997 to December 2004. Introduction of alcohol hand gel was associated with an absolute decrease in %MRSA of 21% and 30%, respectively, for the IH and CH. At the IH, introduction of chlorine disinfection and environmental swabbing were, respectively, associated with a decrease in %MRSA of 27% immediately and 32% 3 months later. Discharge screening and environmental audit did not significantly affect %MRSA, whereas admission screening was associated with a 22% decrease in %MRSA 4 months later. Increasing macrolide use was associated with increasing %MRSA in both hospitals, and increasing quinolone use was associated with increasing %MRSA in the CH. Implementation of stepwise infection control measures was associated with a decrease in %MRSA in the IH. Introduction of an alcohol gel for hand hygiene was associated with a decrease in %MRSA in both hospitals. Antibiotic use also affects %MRSA, in particular that of macrolides and quinolones.

Temporal relationship between prevalence of meticillin-resistant Staphylococcus aureus (MRSA) in one hospital and prevalence of MRSA in the surrounding community: a time-series analysis.

We studied the relationship between meticillin-resistant Staphylococcus aureus (MRSA) prevalence in the Aberdeen Royal Infirmary and in the surrounding community (Grampian region: 500 000 inhabitants). We calculated the monthly %MRSA for both hospital and community from January 1996 to February 2002. A dynamic regression model was adjusted to measure any relationship between both series. The monthly %MRSA in the community was strongly related to the monthly %MRSA observed one month before in the hospital (R(2)=90.8%). We found no relationship with antimicrobial community use, although we have previously reported a strong correlation between prior use of antibiotics and incidence of MRSA in the hospital. By using time-series analysis techniques, we demonstrated that variations in MRSA prevalence in the hospital are quickly followed by similar variations in MRSA prevalence in the surrounding community. These results suggest that the reason for the increase in MRSA prevalence in the community was a hospital MRSA outbreak. Screening at patient discharge should be evaluated as a new measure to control spread of MRSA in the community.