Increasing antimicrobial resistance (AMR) is directly linked with intense use of antimicrobials (AMs).1,2 This has led to the development of an antimicrobial stewardship (AS) movement aimed at the rational use of AMs.3 Neonates and children are prescribed AMs very frequently and exhibit different AMR patterns compared with other patient groups.2,4 AS has proved successful in reducing AM use without negatively affecting patient mortality, for example, in neonatal intensive care, and there are now clear opportunities to improve its global applicability.2,5,6
Although there has been progress in the implementation of AS activities in well-resourced settings, AS remains rudimentary in many resource-limited settings.5,7 Traditional AS approaches have evolved in the context of clearly structured and regulated healthcare systems, with high initial and ongoing costs, even if ultimately cost effective.
The aim of this review is to outline the basic principles and strategies of pediatric AS and to discuss how these may be applied in a range of different settings. This has been framed within the consideration of access to AMs versus their excess use. Specific recommendations for the implementation of AS programs are available elsewhere and will only be touched on to illustrate the importance of local integration of AS activities.3,8
KEY AS PRINCIPLES AND GENERAL APPROACHES
In every setting, the same core questions are being addressed by AS: Who should be treated when (indication) with what (drug) and how (dose, duration and route)? Hyun et al8 recently defined key principles of pediatric AS, which relate to these aspects (Table 1). Certain features are central to the successful implementation of these AS principles in all settings. General approaches have to be translated into context-specific strategies when determining what interventions or activities are most appropriate locally.2,5
Buy-in and Engagement From Front-line Clinicians Managing Patients
This is paramount regardless of scale, context or type of AS activity. An example of how this can be achieved in a resource-limited setting is the Viet Nam Resistance (VINARES) program in Viet Nam.9 This initiative aims to bring together and streamline interventions that are compatible with ongoing healthcare. VINARES empowers local antibiotic champions with appropriate training and expertise to pursue AS strategies that can be implemented with minimal funding and can therefore be delivered despite resource constraints.9 These champions are directly coordinating the implementation of local and regional AS activities, for example, manning of an e-mail help-desk that provides advice, support and feedback to all participants. The program organizers stress the importance of not expecting rapid impacts on AMR but instead focus on building network capacity.9 The VINARES program has already been successful in carrying out an in-depth analysis of AM use and AMR across Viet Nam.10
Dividing a Complete AS Program into Small Stand-alone Components
A characteristic of successful AS is the ability to break down activities into discrete interventions that can be more easily implemented, monitored and evaluated. This approach is also exhibited in the VINARES program.9 Feasible and effective measures are rapidly introduced based on existing expertise and infrastructure. Overall, this reduces cost and increases motivation to engage in and deliver AS.
ACCESS VERSUS EXCESS: PARTICULAR PROBLEMS FOR NEONATES AND CHILDREN
One key consideration of AS is balancing access to AMs with avoiding excess use.2 Access to AMs should certainly take precedent for patients presenting with infections associated with a high morbidity and mortality. However, all stakeholders need to be aware that excess AM use can have direct and indirect negative impacts on patient health.2 Adverse drug reactions resulting directly from AM exposure are common in neonates and children, both in hospital and the community. Longer inpatient stays for prolonged or unnecessary parenteral administration of antibiotics expose patients to the risk of hospital-acquired infections, which can be caused not only by resistant bacteria but also by viruses or fungi (eg, candidemia). Such infections are costly and complex and lead to additional broad-spectrum AM exposure. One core aim of AS should be to break this cycle for every patient.
Particular challenges exist when attempting to achieve the right balance of improving access to AMs and reducing excess AM use in neonates and children.7
* Severe childhood infections often present with nonspecific signs and symptoms, especially in neonates and infants. Given that in many settings most childhood mortality is due to infections, rapid and direct access to AMs is particularly important in this group. New rapid point-of-care microfluid diagnostic approaches and surrogate inflammatory biomarkers may help in the future with early diagnosis.2,7 Novel diagnostics differentiating viral and bacterial infections and providing rapid information on the presence or absence of bacterial resistance may allow for more selective AM use as well as targeted use of narrower spectrum AMs.
* Current standard microbiological evaluation, if available, needs a few days to confirm the presence or absence of suspected bacterial infection. Clinical and microbiological review of patients on AMs at 48–72 hours is therefore central to optimal AM management. Where there is frequent AM pretreatment hampering diagnostic work-up or where microbiological tests are infrequently used, this re-evaluation is limited to the information available to the clinician. Even in resource-rich settings, the challenges of obtaining appropriate samples from children, such as sputum or even blood cultures, can make diagnosis difficult.
* Once AM therapy is initiated and continued after review, there is a lack of evidence regarding efficacy, dosing and duration of therapy for children, with much extrapolation from adult trials.7 The clinical spectrum and epidemiology of severe bacterial infection, including observed resistance patterns, as well as physiology and pharmacokinetics, differ between adults and children. More work is needed to evaluate all aspects of AM treatment in the childhood population. This must include studies in highly resourced settings as well as lower-income and middle-income countries.
* There are practical challenges in delivering AMs to children. Appropriate formulations or doses may not be available, leading to incorrect dosing or manipulation of AMs into extemporaneous formulations.7 This may affect the pharmacokinetic and pharmacodynamic properties of AMs in unpredictable ways and lead to underdosing or overdosing. The dispensing of medication in pack sizes not appropriate for neonates and children may encourage keeping of left-overs that can be used in the future.
ONE SIZE DOES NOT FIT ALL—CHALLENGES OF AS ACTIVITIES IN DIFFERENT HEALTHCARE SETTINGS
To achieve its aims, AS must take account of local healthcare structures and context and strike the appropriate balance between limiting excess AM use while ensuring targeted application of AMs when needed. In general, all principles outlined in Table 1 should be addressed regardless of the specific setting under consideration.8 As each AS strategy is nested within a complex contextual network, a careful balance needs to be achieved between regulatory and local initiatives. Although the former may be seen to achieve a rapid impact, the latter may be more sustainable in the longer term.
AMs as prescription medications can be considered as an example. In many countries with poorly resourced healthcare systems, AMs are available over-the-counter, leading to excess use.2 One obvious AS measure would be the regulatory enforcement of prescribing of AMs. However, although patients may be able to attend the nearest pharmacy or dispensing unit, they may be unable to travel to the next healthcare provision facility that can issue a prescription. An approach that in highly structured and regulated healthcare settings would be considered essential to reduce excess AM use may therefore result in reduced access to AMs in another setting.2 Equally, enforcing the use of AMs as prescription drugs only reduces excess use if it involves an uncoupling of prescribing and dispensing. Incentives to prescribe AMs, such as contribution of drug sales to healthcare provider income, the use of provisions for drug sales by pharmaceutical companies and, more indirectly, competition between providers with perceived consumer pressure to obtain AMs need to be tackled.2
An identical strategy may address slightly different challenges depending on the context in which it takes place. AM batching, for example, has been proposed as a means of dealing with the provision of very expensive AMs.11 In a less well-resourced healthcare system, batching could also be used to provide courses of AMs of a specific duration. This could reduce costs to patients with minimum waste and prevent stockpiling of AMs. Similarly, although restriction is generally used to limit empiric use of “reserve” or “critically important” AMs, it can also be used at the point of transition from empiric to definitive therapy (usually around 48 to 72 hours after treatment initiation) to encourage review of AMs and promote de-escalation strategies.11
Finally, thinking of AS as “access versus excess” will, by necessity, result in discussions about areas of patient care where evidence to inform AS activities is insufficient, and many important questions remain unanswered for neonates and children. Collaboration like in VINARES may lead to innovative approaches that are only identified when there is an exchange with other centers or groups.9,10 In Europe, the Antibiotic Resistance and Prescribing in European Children project aimed to address the paucity of surveillance data on AM consumption and AMR in neonates and children.4 Similarly, the Global Antimicrobial Resistance, Prescribing and Efficacy among Children project brings together interested stakeholders to help define feasible and reliable methods of evaluating AM prescribing and AMR patterns globally (www.garpec.org).
Local and regional networks that enable the rapid sharing of knowledge regarding the successful AS measures are likely to facilitate the development, implementation and evaluation of activities to reach a wider group of neonates and children.5,8
1. World Health Organization. Antimicrobial Resistance: Global Report on Surveillance. 2014 Geneva, Switzerland World Health Organization
2. Laxminarayan R, Duse A, Wattal C, et al. Antibiotic resistance—the need for global solutions. Lancet Infect Dis. 2013;13:1057–1098
3. Society for Healthcare Epidemiology of America; Infectious Diseases Society of America; Pediatric Infectious Diseases Society. . Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol. 2012;33:322–327
4. Versporten A, Sharland M, Bielicki J, et al.ARPEC Project Group Members. The antibiotic resistance and prescribing in European Children project: a neonatal and pediatric antimicrobial web-based point prevalence survey in 73 hospitals worldwide. Pediatr Infect Dis J. 2013;32:e242–e253
5. Brett A, Bielicki J, Newland JG, Rodrigues F, Schaad UB, Sharland M. Neonatal and Pediatric Antimicrobial Stewardship Programs in Europe—Defining the Research Agenda. Pediatr Infect Dis J. 2013;32:e456–e465
6. Zingg W, Pfister R, Posfay-Barbe KM, Huttner B, Touveneau S, Pittet D. Secular trends in antibiotic use among neonates: 2001–2008. Pediatr Infect Dis J. 2011;30:365–370
7. Le Doare K, Barker CI, Irwin A, Sharland M. Improving antibiotic prescribing for children in the resource-poor setting. Br J Clin Pharmacol. 2014 doi: 10.1111/bcp.12320.
8. Hyun DY, Hersh AL, Namtu K, et al. Antimicrobial stewardship in pediatrics: how every pediatrician can be a steward. JAMA Pediatr. 2013;167:859–866
9. Wertheim HF, Chandna A, Vu PD, et al. Providing impetus, tools, and guidance to strengthen national capacity for antimicrobial stewardship in Viet Nam. PLoS Med. 2013;10:e1001429
10. Nguyen KV, Thi Do NT, Chandna A, et al. Antibiotic use and resistance in emerging economies: a situation analysis for Viet Nam. BMC Public Health. 2013;13:1158
11. Goff DA, Bauer KA, Reed EE, Stevenson KB, Taylor JJ, West JE. Is the “low-hanging fruit” worth picking for antimicrobial stewardship programs? Clin Infect Dis. 2012;55:587–592