1. Introduction.

Increasing rates of resistance to antimicrobials among hospital pathogens is a worldwide problem that has been recognized for more than 20 years. The spread within the last 10 years of Extended Spectrum Beta Lactamase producing Enterobacteriaceae (ESBL-PE), and recently Carbapenemase producing Enterobacteriaceae (CPE) and the role of antimicrobial consumption (ref) in the increasing of this phenomenon, underline the emergency of implementation of antimicrobial stewardship program before and during outbreak episodes concomitantly with infection control measures. Patterns of consumption of different classes of antibiotics classes have been closely correlated with the emergence of bacteria resistant to those classes [1,2].Consequently, many publications have suggested the importance of antimicrobial stewardship to avoid [3] and to control [4,5] the emergence of antibiotic resistance.
The main purpose of antimicrobial stewardship programs is to improve how antibiotics are used, in order to optimize clinical outcomes while minimizing unintended consequences of antimicrobial use, including toxicity, the selection of pathogenic organisms (such as Clostridium difficile), and the emergence of resistance [6]. Since at least a third of antibiotic use is usually inappropriate or unnecessary in most hospital settings, antibiotic stewardship programs lead to reductions in total antibiotic consumption.

2. Antimicrobial stewardship programs: definitions and objectives.

Several terms have been used to describe antimicrobial stewardship programs (ASPs) such as antibiotic policies, antibiotic management programs or antibiotic control policies. They all refer to an effort by the healthcare institution (as a whole) to optimize antimicrobial use among hospitalized patients in order to improve patient outcomes and to reduce antimicrobial resistance.

The main objectives of ASPs could be summarised as:

  • optimizing antimicrobial use for treatment and prophylaxis of infections among hospitalized patients in order to improve clinical outcomes, ensure cost-effective therapy and reduce adverse effects associated with antimicrobial use [7];
  • prevention and control of antimicrobial resistance by reducing the use of antibiotics;
  • avoiding the occurrence of difficult-to-treat infections and reducing the incidence of multidrug-resistant microorganisms.

An advisable step before development of any program is to first attempt to define the most important issues that exist with respect to antimicrobial use within a given healthcare institution. Once institution-specific problems have been identified, it is important to evaluate potential causes and solutions. As part of this, any existing antibiotic recommendations and policies should be reviewed.

3. Antimicrobials stewardship components.

  • Structure: the structure of institutional antimicrobial stewardship programs has been defined in different guidelines and publications [5,8]. It should be multidisciplinary, typically with a core team consisting of an infectious disease physician or clinical microbiologist, and a clinical pharmacist with training infectious diseases. It is important to obtain the support from the hospital administration. All of these individuals should be full-time employees of the institution in which the stewardship program resides. The administration should give core team members the authority to enforce stewardship tactics [9]. Close collaboration with the microbiology department, an information system specialist, an infection control practitioner and hospital epidemiologist is also recommended. The role of staff nurses can be important, but is currently less defined: nurses are often antibiotic first responders, central communicators, coordinators of care, as well as 24-hour monitors of patient status, safety, and response to antibiotic therapy[10].
  • Components: many different strategies have been employed in ASP interventions. These are often introduced simultaneously, as multifaceted interventions, and no single type of intervention appears to be much more effective than others. The ASP should foster appropriate antimicrobial use and include monitoring of resistance, in collaboration with an effective infective control program. Here we detail examples of commonly used interventions.
  • Audit and feedback: this is one of the two core ASP strategies recommended by the Infectious Diseases Society of America (IDSA). It has been shown to reduce the inappropriate use of antimicrobials [11]. In a one-step prospective method, targeted antibiotics are directly audited by an ID physician or clinical microbiologist during clinical rounds with immediate feedback provided to the responsible team. In a two-step review method, all cases are initially reviewed by a pharmacist or nurse member of the ASP team, and then selected cases meeting criteria for further review are discussed with an ID physician or clinical microbiologist, who will then provide recommendations for changing or discontinuing antibiotics. Since acceptance of recommendations is voluntary, the clinical teams responsible for patient care do not perceive a loss of prescribing autonomy.
  • Formulary restriction or preapproval for specific antibiotics: restriction strategies that target one or several classes or antibiotic shave been shown to contribute to the control of outbreaks of many specific resistant bacteria. Preapproval requires the prescriber to indicate the appropriate rationale for the selection of a particular agent, either electronically or on paper, before use of specific antibiotics is permitted. Clinicians may inappropriately circumvent this type of restriction by listing an unconfirmed diagnosis or a differential diagnosis that meets the required criteria for use [12].
  • Guidelines with or without feedback: many before/after studies [13] conducted in hospitals suggest that improvements in appropriateness and reductions in antibiotic consumption can occur in response to the implementation of local and regional antibiotic guidelines for specific infections.
  • Many other strategies are employed in ASPs, including education of prescribers, implementation of clinical pathways and use of computerised clinical decision support systems. Education efforts in isolation appear to be marginally effective and tend not to have a sustained effect without repetition. Computer assisted surveillance, and clinical decision support systems have shown promising improvements in antibiotic prescribing resulting in more appropriate dosing and fewer adverse drug events [14]. 

3.1. In case of an outbreak, when should we implement an ASP?

Many publications suggest that ASPs can help to control the spread of resistant microorganisms. The most convincing evidence of an effect on antimicrobial resistance rates was provided by studies aimed at reducing the incidence of Clostridium difficile associated disease [15]. However, use of specific antibiotic classes seems to be correlated with a higher incidence of certain microorganisms, suggesting that close monitoring of their specific consumption could help to contain outbreaks [2,16].

4. Evaluating antimicrobial stewardship programs.

From an infection control point of view, the most relevant goal to be assessed may be the ecological effects of the ASP. In this context, the main objectives of the ASP may be to reduce antimicrobial collateral damage, such as Clostridium difficile associated diarrhea, or avoiding multi drug resistance microorganisms.

A major consideration when measuring resistance is choosing which types of specimens to include. Four main options are possible:

  • surveillance cultures that detect colonization and are the only surveillance cultures that will identify asymptomatic carriers;
  • cultures taken during routine care of the patient;
  • microbiologically and clinically documented infections;
  • site specific cultures

Measurements of antibiotic use are an essential component of ASPs, and provide data for assessing the impact of ASP interventions. The most commonly used metric for measuring aggregated antibiotic use is the defined daily dose (DDD) proposed by the World Health Organization, expressed as DDD per 1000 patient-days. This measure allows comparisons between institutions. However, it underestimates the real consumption in some populations, such as children and patients with renal failure. Others methods that can be used include days of therapy for each antibiotic administered, and total length of therapy.

Studies [17] have shown that early reassessment of antibiotic therapy after 24-48 hours is an important step towards appropriate use of antibiotics. This may be focused on appropriateness of antibiotics used according to local clinical guidelines or available microbiological results. Rates of early switching to oral antibiotic therapies can also be used to evaluate ASPs.

All of these data may be collected on a hospital-wide basis as part of regular point prevalence studies within the ASP.

References:

  1. Neuhauser MM, Weinstein RA, Rydman R, Danziger LH, Karam G, Quinn JP. Antibiotic resistance among gram-negativebacilli in US intensive care units: implications for fluoroquinolone use. JAMA. 2003 19;289:885-8.
  2. Lepper PM, Grusa E, Reichl H, Högel J, Trautmann M. Consumption of imipenem correlates with beta-lactam resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2002;46:2920-5.
  3. Paterson DL. The role of antimicrobial management programs in optimizing antibiotic prescribing within hospitals. Clin Infect Dis. 2006;42 Suppl2:S90-5. 
  4. Anderson DJ, Kaye KS. Controlling antimicrobial resistance in the hospital. Infect Dis Clin North Am. 2009;23: 847-64
  5. Gould IM. Antibiotic policies to control hospital-acquired infection. J Antimicrob Chemother. 2008;61:763-5.
  6. Dellit TH, Owens RC, McGowan JE Jr, Gerding DN, Weinstein RA, Burke JP, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 2007; 44:159–177.
  7. MacDougall C, Polk RE. Antimicrobial stewardship programs in healthcare systems. Clin Microbiol Rev 2005; 18:638–656.
  8. Lesprit P, Brun-Buisson C. Hospital antibiotic stewardship. Curr Opin Infect Dis. 2008;21:344-9.
  9. Drew RH. Antimicrobial stewardship programs: how to start and steer a successful program. J Manag Care Pharm. 2009;15:S18-23.
  10. Olans RN, Olans RD, DeMaria A Jr. The Critical Role of the Staff Nurse in Antimicrobial Stewardship-Unrecognized, but Already There. Clin Infect Dis. 2016; 62:84-9.
  11. Chung GW, Wu JE, Yeo CL, Chan D, Hsu LY. Antimicrobial stewardship: a review of prospective audit and feedback systems and an objective evaluation of outcomes. Virulence. 2013;4:151-7.
  12. Reed EE, Stevenson KB, West JE, Bauer KA, Goff DA. Impact of formulary restriction with prior authorization by an antimicrobial stewardship program. Virulence. 2013;4:158-62.
  13. Zahar JR, Rioux C, Girou E, Hulin A, Sauve C, Bernier-Combes A et al. Inappropriate prescribing of aminoglycosides: risk factors and impact of an antibiotic control team. J Antimicrob Chemother. 2006; 58 :651-6.
  14. Evans RS, Pestotnik SL, Classen DC, Clemmer TP, Weaver LK, Orme JF Jr, et al. A computer-assisted management program for antibiotics and other antiinfective agents. N Engl J Med. 1998;338 :232-8.
  15. Valiquette L, Cossette B, Garant MP, Diab H, Pépin J. Impact of a reduction in the use of high-risk antibiotics on the course of an epidemic of Clostridium difficile-associated disease caused by the hypervirulent NAP1/027 strain. Clin Infect Dis. 2007;45:S112-21.
  16. Kaier K, Frank U, Hagist C, Conrad A, Meyer E. The impact of antimicrobial drug consumption and alcohol-based hand rub use on the emergence and spread of extended-spectrum beta-lactamase-producing strains: a time-series analysis. J Antimicrob Chemother. 2009;63:609-14.
  17. Lesprit P, Landelle C, Brun-Buisson C. Clinical impact of unsolicited post-prescription antibiotic review in surgical and medical wards: a randomized controlled trial. Clin Microbiol Infect. 2013;19: E91-7.

Original contribution from Jean Ralph Zahar (Unitéd' Hygiène Hospitalière, CHU Angers)