Consensus generation

In November 2016, a panel of 11 expert infectious disease (ID) clinicians, researchers, and opinion leaders from Asia met to discuss and formulate a consensus statement on AMS programs for acute-care hospitals in the Asian region. In a pre-meeting survey, the experts answered questions relating to AMS program goals and outcome measures, team structure, AMS interventions, the importance of information technology systems, the strategy of combining AMS and infection control, and stakeholder advocacy. At the 2-day meeting, the experts reviewed the available medical literature then discussed the results of the survey in relation to gaps and challenges in Asia. After the meeting, draft consensus statements based on this discussion were distributed to each panel member for review and comment, and these statements were revised accordingly. This process was repeated until final consensus was reached in November 2017.

Search strategy and selection criteria

A system adapted from the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to rate the strength of recommendations for AMS program interventions and the quality of the supporting evidence (Table 1).Reference Barlam, Cosgrove and Abbo ⁸ Evidence for these recommendations was primarily based on updated Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) guidelines and recent systematic reviews and meta-analyses of interventions, including from hospitals in the Asia-Pacific region.Reference Barlam, Cosgrove and Abbo ^{8 ,} Reference Baur, Gladstone and Burkert ^{16 –} Reference Schuts, Hulscher and Mouton ¹⁸ We also searched PubMed for relevant English language articles using terms such as “antimicrobial resistance,” “antimicrobial stewardship,” and “Asia” from 2000 through August 2017.

Table 1 Grading System Used to Rate the Strength of Guideline Recommendations and Quality of Supporting EvidenceFootnote ^a

^a Based on the US Grading of Recommendations Assessment, Development and Evaluation (GRADE) system used in current IDSA/SHEA guidelines.Reference Tiong, Loo and Mai ¹²

Gaps and challenges facing implementation of AMS in Asia

The common gaps and challenges that can hinder implementation of AMS programs in Asia and potential solutions to overcoming them are listed in Table 2. A critical concern is the lack of routinely collected epidemiological AMR data in Asian countries, which makes planning difficult.Reference Lai, Lee and Xiao ^{4 –} Reference Suwantarat and Carroll ⁷ A paucity of epidemiological data contributes to low awareness of the scale of the problems associated with the misuse of antibiotics. ⁵

Table 2 Common Gaps and Challenges in Relation to Implementing AMS Programs in Hospitals in Asia

Note. AMR, antimicrobial resistance; AMS, antimicrobial stewardship.

^a See Supplementary Material S1 for an AMS program assessment checklist, for Asian hospitals to assess which aspects of the AMS programs are in place and what gaps need to be addressed.

^b See Supplementary Material S2 for a flowchart of potential next steps and solutions to overcome gaps and challenges in AMS programs in Asian hospitals.

Compounding the low awareness of AMS program benefits, hospital administrators and prescribers in overworked and overcrowded, resource-poor hospitals often do not prioritize AMS because they perceive themselves to have more immediate challenges, primarily patient care and potentially infection control. ^{2 ,} Reference Howard, Pulcini and Levy Hara ^{9 ,} Reference Teng, Lee and Yeo ^{11 ,} Reference Tiong, Loo and Mai ^{12 ,} Reference Levy Hara ^{19 ,} Reference Nguyen, Thi Do and Chandna ²⁰ The pharmaceutical industry can support discussion among the stakeholders, which occurred during the preparation of this document, but the industry is often seen as a negative influence, especially when financial incentives are offered for prescribing antibiotics. ^{2 ,} Reference Teng, Lee and Yeo ^{11 ,} Reference Tiong, Loo and Mai ^{12 ,} Reference Levy Hara ^{19 –} Reference Wang, Zhang, Liang and Bloom ²¹ Provider resistance is another important barrier to the widespread implementation of hospital AMS programs.Reference Howard, Pulcini and Levy Hara ^{9 ,} Reference Teng, Lee and Yeo ^{11 ,} Reference Levy Hara ¹⁹

Resource constraints pose a major barrier to the implementation of AMS programs in many Asian hospitals. ^{2 ,} Reference Sing, Boo, Mukhlis, Chin and Hoo ^{10 ,} Reference Wertheim, Chandna and Vu ^{13 ,} Reference Levy Hara ^{19 ,} Reference Nguyen, Thi Do and Chandna ^{20 ,} Reference Hadi, Keuter, van Asten and van den Broek ²² Ongoing training and education should encourage and emphasize the importance of AMS activities.Reference Teng, Lee and Yeo ^{11 ,} Reference Wertheim, Chandna and Vu ^{13 ,} Reference Nguyen, Thi Do and Chandna ^{20 ,} Reference Om, Daily, Vlieghe, McLaughlin and McLaws ²³ Strengthening microbiology laboratory and information technology capacity to deliver reliable and timely data on causative pathogens and antibiotic susceptibility is particularly important for implementation of AMS. ^{2 ,} Reference Wertheim, Chandna and Vu ¹³

As hospitals differ in terms of AMS program status, we recommend that each hospital assess the AMS gaps using an AMS assessment checklist (Supplementary Material S1) and prioritize actionable steps (Supplementary Material S2) to overcome the barriers.

AMS program goals

The primary objective of a hospital AMS program is to achieve best clinical outcomes related to antibiotic use while minimizing toxicity and limiting the selective pressure on bacterial populations that drive the emergence of AMR.Reference Dellit, Owens and McGowan ²⁴

AMS process and outcome measures

Before an AMS program is implemented, outcome measures need to be chosen that prospectively evaluate the efficiency of the AMS program in relation to its goals.Reference Dellit, Owens and McGowan ^{24 ,} Reference Doron and Davidson ²⁵ We recommend selecting a combination of commonly used process and outcome measures (Table 3) and accounting for data and resource availability.Reference Akpan, Ahmad, Shebl and Ashiru-Oredope ²⁶ Process measures, such as antibiotic consumption and appropriate antibiotic use, should be evaluated to confirm compliance with the AMS program. An effective AMS program can improve outcomes, such as length of hospital stay, rates of MDR bacterial infection or colonization, and treatment-related costs.Reference Baur, Gladstone and Burkert ^{16 –} Reference Schuts, Hulscher and Mouton ^{18 ,} Reference Davey, Marwick and Scott ^{27 ,} Reference Karanika, Paudel, Grigoras, Kalbasi and Mylonakis ²⁸

Table 3 Suggested Process-Related Measures and Outcome Measures for AMS Programs

Note. AMS, antimicrobial stewardship; DDT, defined daily dose; DOT, days of therapy; ICU, intensive care unit; IV, intravenous; MDR, multidrug resistant.

All AMS programs should focus on classes of antibiotics and MDR pathogens that are most relevant to their own region and hospital.Reference Barlam, Cosgrove and Abbo ⁸ In Asian hospitals, this will include carbapenem consumption, with a focus on carbapenem-resistant A. baumannii and carbapenemase-producing, carbapenem-resistant Enterobacteriaceae infection.

How to build a multidisciplinary AMS team and define roles and responsibilities

In agreement with IDSA/SHEA guidelines,Reference Barlam, Cosgrove and Abbo ^{8 ,} Reference Dellit, Owens and McGowan ²⁴ we believe that AMS teams should include an ID specialist, clinical pharmacist (with ID training, if possible), a clinical microbiologist, an infection control specialist, and an information technology expert as core team members (Fig. 1). In this AMS team scenario, the ID specialist leads the team, and is responsible for implementation and evaluation of the program, and the clinical pharmacist/pharmacologist performs many daily AMS program tasks and supports the team leader. Clinical microbiologists, clinicians with expertise in infection control and epidemiology, and information technology experts should also have key roles in AMS teams.

Fig. 1 An ideal hospital antimicrobial stewardship (AMS) program team structure.

Although AMS programs may be best led by ID physicians with additional AMS training,Reference Barlam, Cosgrove and Abbo ^{8 ,} Reference Dellit, Owens and McGowan ²⁴ many hospitals in Asia do not have adequate personnel to make up the AMS team.Reference Levy Hara ¹⁹ In these cases, hospitals should work within their resources to create the most effective team possible.Reference Doron and Davidson ^{25 ,} Reference Kim, Craft and Katzman ²⁹ For example, the team leader could be an interested clinician from another specialty or a clinical pharmacist.Reference Sing, Boo, Mukhlis, Chin and Hoo ^{10 ,} Reference Waters ³⁰ External ID specialist advice and AMS training could be obtained from other hospitals to support the local AMS team.Reference Duguid and Cruickshank ^{31 ,} Reference Wu, Chen and Lee ³² The minimum personnel for an effective AMS team should include an interested clinician, a pharmacist, and a collaborating microbiologist.Reference Kim, Craft and Katzman ²⁹ However, because of the value ID training offers to hospital AMS programs,Reference Apisarnthanarak, Lapcharoen, Vanichkul, Srisaeng-Ngoen and Mundy ^{33 –} Reference Schmitt, McQuillen and Nahass ³⁵ we encourage all hospitals to commit to ID specialty training for AMS team members.

Several stages are involved in building and establishing a successful AMS team. First, a business plan should be developed, and formal approval and financial support should be obtained from hospital administration, followed by the appointment of a team leader and core team members with clearly defined roles and responsibilities (Table 4). The team should then start working within their budget and existing resources to decide on measurable clinical outcomes and feasible interventions that achieve short- and long-term AMS program goals. After implementing these interventions, the team should begin monitoring AMS program processes and outcomes. Regular team meetings must be scheduled to review AMS program activities and AMR data and to modify the program. One strategy is to incorporate serial plan-do-study-act (PDSA) cycles to evaluate the effects of AMS interventions and implement further changes as required to improve processes and achieve outcomes.Reference Kanter, Connelly and Fitzgerald ³⁶

Table 4 AMS Core Team Member Roles and Responsibilities

Note. AMS, antimicrobial stewardship; IV, intravenous; MDR, multidrug resistant.

^a If no ID specialists are available, another physician or pharmacist with an interest in infectious diseases can assume responsibility for this role.

AMS program interventions

A recent systematic review and meta-analysis of AMS programs in hospitals in Asia showed that AMS implementation was associated with reduced carbapenem and overall antimicrobial consumption, reduced antibiotic expenditure, and trends toward reductions in the incidence of MDR pathogens.Reference Honda, Ohmagari, Tokuda, Mattar and Warren ¹⁷ Many programs implemented bundled interventions, making it difficult to determine which individual interventions contributed to the success of the AMS program.Reference Honda, Ohmagari, Tokuda, Mattar and Warren ¹⁷ However, on the basis of these and other reports,Reference Barlam, Cosgrove and Abbo ^{8 ,} Reference Baur, Gladstone and Burkert ^{16 ,} Reference Schuts, Hulscher and Mouton ¹⁸ we recommend a range of AMS strategies (Table 5), any number of which can be selected to form AMS programs.

Table 5 Recommended physician-, pharmacist- and microbiology-driven AMS program interventions.

AMS, antimicrobial stewardship; IV, intravenous; NA, not available; PK/PD, pharmacokinetic/pharmacodynamic

Recommended physician-driven interventions

Implementation of local guidelines for surgical prophylaxis and empiric antibiotic therapy of common infection syndromes (strong recommendation, low-quality evidence). As has occurred in China and Vietnam, Asian countries should work toward establishing their own national or regional guidelines for antibiotic therapy.Reference Wertheim, Chandna and Vu ^{13 ,} Reference Xiao, Zhang, Zheng, Zhao, Li and Li ³⁷ Facility-specific guidelines for infection syndromes commonly treated in hospitals can be adapted from pre-existing national, regional, or international guidelines to suit the types of infection commonly seen at the local facility.Reference Levy Hara ^{19 ,} Reference Loo, Liew, Lee, Chlebicki and Kwa ^{38 ,} Reference Liew, Lee and Cai ³⁹

Use of monotherapy instead of combination antibiotics (strong recommendation, high-quality evidence). For many common infections, monotherapy is often one of the most practical, straightforward approaches to reducing antibiotic consumption.Reference Gupta, Hooton and Naber ^{40 –} Reference Stevens, Bisno and Chambers ⁴³ Evidence indicates that routine use of combination therapy is not superior to monotherapy in terms of outcome for sepsis, endocarditis, neutropenia, and gram-negative infections, or for preventing AMR, and that more toxicity is seen with combination therapy.Reference Falagas, Matthaiou and Bliziotis ^{44 –} Reference Falagas, Matthaiou, Karveli and Peppas ⁴⁹ Where appropriate, guidelines should advocate monotherapy as a first-line option, especially for those who are not critically ill.

Use of antibiotic diversity (eg, multiple agents and classes) (strong recommendation, low-quality evidence). A quantitative relationship between the volume of antibiotics consumed and the development of AMR has been demonstrated; resistance to specific drugs increases when consumption of those drugs passes a critical threshold.Reference Austin, Kristinsson and Anderson ^{50 ,} Reference Peterson, Samia, Skinner, Chopra and Smith ⁵¹ Therefore, strategies promoting antibiotic diversity should be encouraged, such as changing the first-line antibiotic in consecutive patients or prescribing according to patient characteristics.Reference Sandiumenge, Lisboa, Gomez, Hernandez, Canadell and Rello ^{52 ,} Reference Sandiumenge, Diaz and Rodriguez ⁵³ In line with IDSA/SHEA guidelines,Reference Barlam, Cosgrove and Abbo ⁸ we do not recommend antibiotic cycling as an AMS strategy.

Formulary restriction and preauthorization and/or prospective audit and feedback (strong recommendation, moderate-quality evidence). All AMS programs should include some form of prospective audit and/or formulary restriction. With restriction and preauthorization, approval of restricted agents must be granted by an ID expert or another authorized clinician (eg, if ID specialists are unavailable) before they can be prescribed. With prospective audit and feedback, which has similar effects to formulary restriction and preauthorization, the prescription is reviewed by appropriate staff members after empiric antibiotic therapy has been initiated, and recommendations are made based on factors such as hospital guidelines, potential for misuse (spectrum of antibiotic activity), hospital AMR patterns, and the availability of microbiologic test results. Many physicians in Asian countries practice social bedside medicine and like to be personally involved in patient care, so prospective audit and feedback is better suited to such prescribing culture than preauthorization.Reference Davey, Marwick and Scott ^{27 ,} Reference Teo, Kwa, Loh, Chlebicki and Lee ^{54 ,} Reference Apisarnthanarak, Danchaivijitr and Khawcharoenporn ⁵⁵

Formulary restriction and preauthorization can be conducted on a small scale by evaluating antimicrobial usage patterns and resistance trends, then devising interventions targeted at a single antibiotic agent or class thought to be misused. For example, an intervention focused on carbapenems in response to endemic carbapenem-resistant A. baumannii may be more practical than wide-ranging formulary restriction in many Asian hospitals.

Education (weak recommendation, low-quality evidence). Passive educational activities, such as quarterly or yearly lectures, should not be solely relied upon to improve antibiotic prescribing, but they should be used to complement other AMS activities. Presenting the positive impact of the hospital AMS program can encourage participation by all providers. An education program in combination with ongoing feedback as part of the audit/feedback process is an example of an inexpensive and highly effective AMS program that could be easily applied to many hospitals and is well suited to the Asian bedside prescribing culture.Reference Teo, Kwa, Loh, Chlebicki and Lee ^{54 –} Reference Teng, Ng and Tan ⁵⁷

Recommended pharmacist-driven interventions

De-escalation (strong recommendation, low-quality evidence). With this approach, once the pathogen and its susceptibility are known, empiric prescribing should be changed to a narrow-spectrum, pathogen-directed treatment as soon as possible. Carbapenem de-escalation is an example of a beneficial strategy in settings of endemic gram-negative resistance and high rates of carbapenem prescription often found in Asian hospitals.Reference Lew, Ng and Tan ⁵⁸

Choice of antibiotics for de-escalation during empirical therapy should be based on hospital guidelines, while that for pathogen-directed therapy is based on microbiology results. However, as a caution, the prescriber needs to understand that microbiology results can be confusing as to whether the isolated pathogen is causing the infection or is just a contaminant or colonizer.Reference Levy Hara, Kanj and Pagani ⁵⁹

Dose optimization (using pharmacokinetic/pharmacodynamic models and therapeutic drug monitoring) (strong recommendation, low-to-moderate–quality evidence). Dose optimization does not necessarily require therapeutic drug monitoring, and can be implemented on the basis of identifying deviations from recommended dosing schedules, making recommendations to optimize dosing based on pharmacokinetic/pharmacodynamic principles.Reference Teo, Kwa, Loh, Chlebicki and Lee ^{54 ,} Reference Lew, Ng and Tan ⁵⁸ In patients who are critically ill, with fluctuating hemodynamic parameters, and with sepsis from infection caused by MDR pathogens, dose-optimization via therapeutic drug monitoring will help ensure adequacy of treatment.Reference Cotta, Roberts and Lipman ⁶⁰

IV to oral switching (strong recommendation, moderate-quality evidence). Intravenous to oral conversion of the same antibiotic is a relatively simple intervention and applicable to many settings.Reference Barlam, Cosgrove and Abbo ⁸ During the prospective audit process, pharmacists should encourage the appropriate use of oral formulations.

Recommended microbiology-driven interventions

Use of rapid diagnostic testing in addition to conventional diagnostic testing (strong recommendation, moderate-quality evidence). Delayed (≥72 hours) conventional bacterial culture and antimicrobial susceptibility testing results are barriers to optimizing therapy.Reference Morency-Potvin, Schwartz and Weinstein ⁶¹ Few hospitals in Asia use rapid diagnostic testing, and many are not in a position to deliver accurate and reliable conventional pathogen-defining testing. It is essential to strive toward strengthening laboratory capacity that can deliver such services. In the meantime, early AMS review and prospective interventions, such as use of monotherapy, de-escalation, and IV-to-oral switch, can be implemented to help optimize empiric antibiotic therapy.Reference Liew, Lee and Tay ⁶²

Selective antibiotic susceptibility reporting (strong recommendation, low-quality evidence). Some evidence suggests an association between antibiotics listed in susceptibility reports and their prescription. When feasible, reporting susceptibility to broader-spectrum drugs only when isolates are resistant to narrow-spectrum agents may guide physicians to select the more appropriate narrow-spectrum drugs.Reference Levy Hara, Kanj and Pagani ^{59 ,} Reference Morency-Potvin, Schwartz and Weinstein ⁶¹ Although the practice of reporting susceptibility results for a limited number of antibiotics instead of all tested antibiotics may promote appropriate antibiotic use, it requires the specialized expertise of a clinical microbiologist and could be difficult to implement in many Asian hospitals. This reporting needs to be carefully monitored so that errors are not made (eg, no active antibiotic treatment is found in the laboratory report).

Site-specific hospital antibiograms with or without active surveillance testing (strong recommendation, low-quality evidence). Active surveillance testing and availability of hospital antibiograms can present unique susceptibility patterns that help AMS programs develop optimized treatment guidelines and recommendations for empiric treatment.Reference Loo, Liew, Lee, Chlebicki and Kwa ^{38 ,} Reference Teng, Ng and Tan ⁵⁷ In resource-constrained settings, targeted and strategic surveillance testing (eg, point-prevalence surveys for resistant gram-negative bacteria) may be more feasible than continuous active surveillance of all bacterial isolates.

Use of computer systems to support AMS programs

As hospitals move toward adopting electronic health records, there are increasing opportunities to integrate surveillance and decision support into information technology systems.Reference Doron and Davidson ^{25 ,} Reference Baysari, Lehnbom, Li, Hargreaves, Day and Westbrook ⁶³ A recent systematic review has shown that using information technology systems to streamline AMS program processes and guide prescribing decisions can help to improve appropriate antibiotic use in acute-care hospitals.Reference Baysari, Lehnbom, Li, Hargreaves, Day and Westbrook ⁶³

Computer-assisted AMS strategies, ranging from computerized systems for data analysis and recording to online AMS systems and computerized decision support systems, are being implemented in various hospitals across Asia.Reference Apisarnthanarak, Danchaivijitr and Khawcharoenporn ^{55 ,} Reference Cheon, Kim, Yun, Moon and Kim ^{64 –} Reference Chow, Ang and Chow ⁶⁷ However, these can be costly and time-consuming to implement and maintain, and they may not be readily accepted.Reference Chow, Ang and Chow ^{67 ,} Reference Chow, Lye and Arah ⁶⁸ If a hospital does not have the infrastructure to set up information technology systems to support an AMS program, a paper-based system can be used in conjunction with syndrome-specific guidelines.

How to combine AMS programs and infection control

Implementation of AMS programs alone may not reduce rates of MDR pathogens.Reference Lai, Lee and Xiao ^{4 ,} Reference Baur, Gladstone and Burkert ^{16 ,} Reference Levy Hara, Kanj and Pagani ^{59 ,} Reference Cheon, Kim, Yun, Moon and Kim ^{64 ,} Reference Guo, He and Wang ^{65 ,} Reference Apisarnthanarak, Pinitchai and Thongphubeth ⁶⁹ Infection control measures, including hand hygiene, contact precaution, environmental cleaning, and disinfection, are critical for controlling MDR pathogens in hospitals. Practices to prevent common healthcare-associated infections (eg, central-line–associated blood stream infection and catheter-associated urinary tract infection) are also important.Reference Nagel, Kaye, LaPlante and Pogue ^{70 ,} Reference Apisarnthanarak, Ratz, Greene, Khawcharoenporn, Weber and Saint ⁷¹ We strongly recommend that AMS and infection control teams work together under the same leadership to achieve the goal of reducing the rate of MDR infections.Reference Dellit, Owens and McGowan ^{24 ,} Reference Nagel, Kaye, LaPlante and Pogue ⁷⁰

How can organizations and stakeholders work together to advocate for AMS?

The World Health Organization (WHO) is positioned to promote worldwide antimicrobial stewardship, and it acknowledges the roles of the Asia-Pacific Economic Cooperation (APEC) and the Association of Southeast Asian Nations (ASEAN) for successful implementation of AMS in the Asia-Pacific region. ⁵ The Vietnam Resistance Project (VINARES) is an example of a national project that addresses hospital-related priorities in the WHO policy package on antimicrobial resistance,Reference Wertheim, Chandna and Vu ¹³ and a national campaign to enforce Ministry of Health regulations for the rational use of antibiotics has been conducted with a positive effect in China.Reference Xiao, Zhang, Zheng, Zhao, Li and Li ^{37 ,} Reference Zhou, Luo, Tang, Zou, Zhao and Fang ^{72 ,} Reference Zou, Fang and Min ⁷³ The VINARES project and Chinese Ministry of Health initiatives are models for similar healthcare settings. ^{2 ,} Reference Xiao, Zhang, Zheng, Zhao, Li and Li ³⁷

To operate successfully, AMS programs require buy-in from hospital administration and local stakeholders, and adequate financial support.Reference Wertheim, Chandna and Vu ^{13 ,} Reference Pollack and Srinivasan ^{15 ,} Reference Doron and Davidson ^{25 ,} Reference Trivedi and Kuper ⁷⁴ Formal statements of support for AMS should be given by organizational leadership.Reference Pollack and Srinivasan ¹⁵ AMS-related duties should be included in job descriptions, and staff should be given sufficient time and financial support to contribute to AMS activities.Reference Pollack and Srinivasan ¹⁵

Making AMS programs sustainable

The foundation of a sustainable AMS program lies in starting small and progressively building capacity, with regular monitoring and reporting AMS program performance, modifying and adapting the AMS program, and continuing AMS education. Tracking of long-term trends of pre-specified AMS program process and outcome measures are as important as initial changes. A timeline for reporting progress toward AMS program goals should be specified to clarify expectations from stakeholders because some outcomes take longer to show noticeable changes from baseline.Reference Doron and Davidson ²⁵

In conclusion, we also recommend that AMS team members stay up-to-date with the latest AMS guidelines from relevant professional societies and that they modify and/or add AMS program strategies as appropriate. The AMS team can test, evaluate, and modify interventions using a plan-do-study-act cycle.Reference Duguid and Cruickshank ³¹ Regular meetings should be scheduled with the AMS team and clinical staff most affected by the AMS program to make necessary changes to the program.Reference Teng, Lee and Yeo ^{11 ,} Reference Duguid and Cruickshank ³¹

Ongoing training and departmental feedback sessions are also important, where the purpose, evidence-based importance, and positive outcomes of the AMS program can be emphasized.Reference Teng, Lee and Yeo ^{11 ,} Reference Duguid and Cruickshank ³¹ Finally, education about the AMS program should be provided as part of orientation for new staff, with regular updates to keep all staff informed about any changes to the antibiogram and the AMS program.