Global antimicrobial resistance: from surveillance to stewardship. Part 2: stewardship initiatives

Abstract

22nd European Congress of Clinical Microbiology and Infectious Diseases

London, UK, 31 March–3 April 2012

Twelve months after the WHO launched its World Health Day 2011 campaign to combat antimicrobial resistance, antibiotic stewardship initiatives were a major focus at the annual meeting of the European Society of Clinical Microbiology and Infectious Diseases, in London, UK. In the second part of their report from the Congress, the authors review the impact of some of these initiatives in achieving their goals of reducing overall antibiotic usage, ensuring timely, appropriate prescribing and avoiding sub-optimal dosing and unnecessarily prolonged treatment. The authors also report new data on antibiotic prescribing in primary care and latest research in the development of novel antibiotics for the future.

Keywords::

• antimicrobial resistance
• antimicrobial stewardship
• Gram-negative organisms
• resistance surveillance

Stewardship strategies

Over half of hospitals now have an Antimicrobial Stewardship (AMS) Program, but only a third of these have formally assessed their impact, according to preliminary results of a global AMS survey, carried out on behalf of the European Society of Clinical Microbiology and Infectious Diseases Study Group for Antimicrobial Policies and International Society of Chemotherapy Working Party on AMS [1]. The initial data, from 324 centers in six continents show that 55% have an AMS Program and 26% are planning a scheme. Most common reasons for setting up a program were to reduce or stabilize resistance, improve clinical outcomes, reduce Clostridium difficile and other healthcare-acquired infection and reduce antibiotic prescribing. Among the 34% of centers which had formally assessed their program, most AMS schemes had been shown to reduce expenditure, inappropriate prescribing and use of broad-spectrum agents, but had not reduced length of hospital stay.

A number of the AMS Programs on show at the European Congress of Clinical Microbiology and Infectious Diseases demonstrated this sort of impact. Restricting ciprofloxacin use in a large tertiary teaching hospital was associated with improved susceptibility of Pseudomonas aeruginosa to group two carbapenems, according to results of an antibiotic de-escalation strategy, described by Cook et al. (Brody School of Medicine, East Carolina University, SC, USA). Ciprofloxacin use was reduced by 90% between 2000 and 2010, with an accompanying reduction in carbapenem-resistant P. aeruginosa from approximately 25 to 10–15%, despite an increase in carbapenem use from 12 daily defined doses (DDDs)/1000 patients in 2004 to 28 DDDs/1000 patients in 2010 [2]. Cook explained that the introduction of electronic medical records had facilitated rapid review of antibiotic usage and correction of inappropriate prescribing. A doubling of antimicrobial recommendations from infection control specialists was associated with a 29% decrease in the use of 41 commonly used antibacterial agents (p < 0.0001), a 19% decrease in nosocomial C. difficile (p = 0.07) and a 45% fall in nosocomial methicillin-resistant Staphylococcus aureus infection (p < 0.0001).

Hospital physicians in English hospitals are given regular feedback on antibiotic usage, but more emphasis is placed on costs than DDDs or prescriptions/pack use. These findings from a national electronic audit of antimicrobial hospital pharmacists were reported by Wickens et al. (Imperial College Healthcare Trust, London, UK)[3]. The audit also showed that antibiotic point prevalence studies were conducted by 86% of hospitals, but results fed back to clinicians less frequently than expenditure or DDD data.

A survey of 36 French intensive care units (ICUs) in France, discussed by Dumartin et al. (University of Bordeaux, Bordeaux, France), demonstrated the value of training for new prescribers in reducing antibiotic use [4]. An antibiotic advisor was in place in 75% of ICUs, and antibiotic guidelines were in used in approximately half of ICUs. Specific training for new prescribers was in place in half of ICUs, and was associated with lower use of ciprofloxacin.

Incorporating review of intravenous antimicrobial prescriptions into weekly medical ward rounds at a large UK hospital has had a significant impact on antibiotic usage and costs [5]. Vaghela et al. (West Hertfordshire Hospitals, National Health Service Trust, Herts, UK) reported that over a 5-month period, 107 intravenous antimicrobial courses relating to 69 patients were reviewed by a multidisciplinary team composed of an antimicrobial pharmacist, consultant microbiologist and the medical team. As a result, 23% of courses were stopped, 24% had a stop date recommended, 14% required a switch to oral antimicrobials and 14% had a review date recommended. In 11% of courses, further investigations were advised, and 14% of courses were deemed to be appropriate. Antimicrobial expenditure declined by GB£13,850.

Given the well-recognized reservoir of antimicrobial resistance in residential home facilities, research showing the impact of resident antimicrobial management plans (RAMPs) is timely. In a randomized control trial of over 3000 residents in 30 nursing homes in London, UK, RAMP implementation was associated with a significant reduction in antibiotic consumption between 2010 and 2011 (4.9%; p = 0.02) compared with a significant increase of 5.1% (p = 0.04) in patients where RAMPs were not used [6].

Much of the success of AMS Programs will depend on the commitment of clinicians making everyday treatment decisions, so it is important to monitor adherence and address barriers to implementation. Martin et al. (Hospital Universitario Son Espases, Palma de Mallorca, Spain) assessed the impact of over 11,000 recommendations made to clinicians at a Spanish teaching hospital between 2006 and 2010, to stop, change or maintain antibiotic treatment following chart review [7]. Adherence in orthopedic, gastroenterology, neurology and neurosurgery was twice that in the urology department (85 vs 40%), and clinicians were more likely to follow recommendations to de-escalate antibiotic treatment or to stop treatment following course completion than to fit prescriptions to local guidelines or to stop treatment due to lack of indication (61, 56, 40 and 40%, respectively). Encouragingly, adherence did improve during the 3-year follow-up.

Lessons on antibiotic prescribing in primary care

Primary care physicians have been encouraged to reduce antibiotic prescribing for common infections, but evidence from Greece and France suggests that there is still room for improvement. Katsarolis et al. (University Hospital, Athens, Greece) reported that only 55% of 1185 physicians working in the community said they restricted antibiotic prescriptions for sore throat and 26% used a strep-test to guide antibiotic use [8]. For sinusitis, 52% of respondents would not prescribe an antibiotic upon presentation and 64% would wait for symptoms to persist for 7 days before prescribing an antibiotic. Eighty nine percent of respondents prescribed antibiotics for chronic obstructive pulmonary disease exacerbations, but only 17% applied the widely accepted Anthonisen criteria.

French research showed that only 21% of primary care prescriptions for urinary tract infection followed antibiotic treatment guidelines (i.e., correct drug, dose and duration of treatment) [9]. Nearly half of prescriptions for nephritis were wrong, as were a quarter of those for prostatitis. Seventy percent of cases of asymptomatic bacteriuria were treated with antibiotics, and inappropriate treatment of cystitis was associated with significant unnecessary costs.

Sick leave regulations across Europe have been shown to have a significant impact on antibiotic prescribing. Cortoos et al. (Catholic University, Leuven, Belgium) related antibiotic consumption to the length of time that people could take on sick leave without need for a medical certificate (median: 3 days; range: 1–14 days) in 30 European countries [10]. He showed a clear inverse correlation between sick leave without certification and antimicrobial consumption (p = 0.035), and concluded that to reduce antimicrobial consumption the different legislative bodies and healthcare regulators should screen their regulations for inadvertent counter-productive effects.

Novel developments in antibiotics

The research pipeline for novel antibiotics is almost dry and, as Ursula Theuretzbacher (Center for Anti-Infective Agents, Vienna, Austria) explained, the outlook is particularly gloomy for treatment of Gram-negative infections, about which there is greatest concern [11]. She explained that novel, multi-target agents are needed in order to minimize the risk of resistance but, as most new agents have a single target, the most common approach is to test antibacterial combinations.

Theuretzbacher reported that the novel agent most advanced in development is the β-lactamase inhibitor, avibactam which has been shown to have welcome inhibitory activity against both Klebsiella pneumoniae carbapenemase- and OXA-producing carbapenemases, but not metallo-β-lactamases. In combination studies, it has been shown that the success of combining avibactam and ceftaroline depends on achieving long, steady concentrations at levels which require three-times daily dosing, and Theuretzbacher expressed concern that some current trials may not be using optimal dosing schedules.

Other compounds discussed in her presentation included ME 1071, which potentiates the activity of ceftazadime and carbapenems against class B metallo-carbapenemase producers [12], ceftolozane, a novel cephalosporin whose activity against Amp-C cephalosporinase producers is being optimized by combining it with tazobactam, and the monobactam, BAL 30072, which has shown promising activity against NDM-producing isolates.

Turning to the potential of non-β-lactam antibiotics against Gram-negative infections, Theuretzbacher reported that the next-generation aminoglycoside, plazomicin, has demonstrated activity against both Gram-negative and Gram-positive organisms, including isolates with clinically relevant aminoglycoside-modifying enzymes [13]. Also promising is TP-434, a novel, broad-spectrum fluorocycline antibiotic in early development, which has activity against bacteria expressing resistance mechanisms, including tetracycline-specific efflux and ribosomal protection [14]. However, as Theuretzbacher pointed out, none of these approaches can address all the problems associated with the current upsurge in Gram-negative resistant organisms.

Conclusion

Given the paucity of novel antibiotics development, the need to preserve the effectiveness of our current antimicrobial armamentarium has never been greater. There is an urgent requirement to reduce selection pressure on today’s agents by more prudent choice of antibiotic, by reducing transmission of multi-drug resistant organisms through effective infection-control systems, and by optimizing drug exposure through better adherence to proven treatment regimens. How well we are achieving this three-pronged approach will become clearer at next year’s European Congress of Clinical Microbiology and Infectious Diseases, to be held in Berlin, Germany (27–30 April 2013).

Financial & competing interests disclosure

R Cantón has participated in educational programs sponsored by MSD and AstraZeneca. R Cantón did not receive an honorarium to participate in preparing this manuscript. J Bryan received payment from MSD for attendance at the conference and manuscript preparation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.