Antibiotic stewardship interventions in hospitals in low-and middle-income countries: a systematic review

Abstract Objective To review the effectiveness of antibiotic stewardship interventions in hospitals in low- and middle-income countries. Methods We searched MEDLINE®, Embase®, Cochrane Central Register of Controlled Trials and regional indexes for studies of interventions to improve appropriate prescribing and use of antibiotics for hospitalized patients in low- and middle-income countries. We included controlled trials, controlled before-and-after studies and interrupted time-series studies published up to December 2017. We report prescribing, clinical and microbiological outcomes using a narrative approach. Findings We screened 7342 original titles and abstracts, assessed 241 full-text articles and included 27 studies from 2 low-income and 11 middle-income countries. We found a medium (11 studies) or high risk (13 studies) of bias. Generally, all types of interventions (structural, persuasive and enabling) and intervention bundles were reported to improve prescribing and clinical outcomes. However, the studied interventions and reported outcomes varied widely. The most frequent intervention was procalcitonin-guided antibiotic treatment (8 of 27 studies, all randomized controlled trials). The intervention was associated with a relative risk for patients receiving antibiotics ranging between 0.40 and 0.87. Conclusion The majority of studies reported a positive effect of hospital antibiotic stewardship interventions. However, we cannot draw general conclusions about the effectiveness of such interventions in low- and middle-income countries because of low study quality, heterogeneity of interventions and outcomes, and under-representation of certain settings. To strengthen the evidence base, action needs to be taken to address these shortcomings.


Introduction
Antibiotic resistance is a problem of global importance. 1 Representative data on the extent of the problem in low-and middle-income countries are relatively scarce, but high levels of resistance are increasingly being reported worldwide. [2][3][4] Misuse and overuse of antibiotics in humans and animals is one of the main drivers of antibiotic resistance. 5,6 Antibiotic stewardship, that is, interventions designed to optimize use of antibiotics, is therefore one of the key actions of the World Health Organization (WHO) Global Action Plan to contain antibiotic resistance. 5,7 Stewardship interventions are typically classified as structural (such as the introduction of new diagnostic tests to guide antibiotic treatment), persuasive (such as expert audit of prescriptions and feedback advice to prescribers), enabling (such as guidelines or education on antibiotic use) or restrictive (such as expert approval for use of certain antibiotics). 8 Often, different interventions are combined in antibiotic stewardship bundles.
Several systematic reviews showed that antibiotic stewardship interventions for hospitalized patients increased compliance with local antibiotic policies and improved clinical patient outcomes. [8][9][10] These reviews included mainly or exclusively papers from high-income countries. Whether these results also apply to low-and middle-income countries is unclear. The organization of health-care system, availability of diagnostic testing and appropriate antibiotics, infection prevention and control practices and prescribing practices (such as over-the-counter availability of antibiotics) differs markedly between high-income countries and low-and middle-income countries. 11 These differences may affect the implementation and effectiveness of antibiotic stewardship interventions in these settings.
Many hospitals in low-and middle-income countries are setting up antibiotic stewardship programmes. 12 To better inform the selection of antibiotic stewardship interventions, we systematically reviewed the literature for studies that describe the effect of these interventions on clinical, microbiological or antibiotic prescribing outcomes in hospitalized patients in low-and middle-income countries.

Methods
The review protocol including the complete search strategy has been registered at the PROSPERO international prospective register of systematic reviews (CRD42016042019). 13 We included studies on antibiotic stewardship interventions for hospitalized patients in low-and middle-income countries. Stewardship interventions were defined as any intervention aiming to improve appropriate prescribing of antibiotics. A summary of the search strategy is shown in Box 1. Low-and middle-income countries were defined according to the World Bank criteria. 14 To be included, studies had to report at least one prescribing outcome (such as defined daily doses per 100 bed-days), clinical outcome (such as mortality) or microbiological outcome (such as proportion of bacterial isolates with antibiotic resistance). We included (non)randomized controlled trials, cluster randomized controlled trials, controlled before-after studies and interrupted time-series studies if these contained at least three points of comparison Objective To review the effectiveness of antibiotic stewardship interventions in hospitals in low-and middle-income countries. Methods We searched MEDLINE®, Embase®, Cochrane Central Register of Controlled Trials and regional indexes for studies of interventions to improve appropriate prescribing and use of antibiotics for hospitalized patients in low-and middle-income countries. We included controlled trials, controlled before-and-after studies and interrupted time-series studies published up to December 2017. We report prescribing, clinical and microbiological outcomes using a narrative approach. Findings We screened 7342 original titles and abstracts, assessed 241 full-text articles and included 27 studies from 2 low-income and 11 middle-income countries. We found a medium (11 studies) or high risk (13 studies) of bias. Generally, all types of interventions (structural, persuasive and enabling) and intervention bundles were reported to improve prescribing and clinical outcomes. However, the studied interventions and reported outcomes varied widely. The most frequent intervention was procalcitonin-guided antibiotic treatment (8 of 27 studies, all randomized controlled trials). The intervention was associated with a relative risk for patients receiving antibiotics ranging between 0.40 and 0.87. Conclusion The majority of studies reported a positive effect of hospital antibiotic stewardship interventions. However, we cannot draw general conclusions about the effectiveness of such interventions in low-and middle-income countries because of low study quality, heterogeneity of interventions and outcomes, and under-representation of certain settings. To strengthen the evidence base, action needs to be taken to address these shortcomings.
pre-and post-intervention. Studies were excluded if they included residents of long-term health-care or nursing facilities; studied malaria, human immunodeficiency virus, mycobacterial or fungal infections, Helicobacter pylori eradication, or care pathways (such as malnutrition bundles); compared antibiotic regimens; were written in language other than English, Dutch, French, German, Portuguese or Spanish; or had no full-text article available.
Titles and abstracts were independently screened for eligibility by two authors. In case of disagreement, consensus was sought after reading the full-text article. The study selection was piloted by screening 630 abstracts and 44 full-text articles. These results were discussed among a panel of experts, after which the eligibility criteria were fine-tuned.
Two researchers extracted the data using an electronic form. The authors of original studies were not contacted in cases of incomplete or missing data. Data that were analysed inappropriately in the original studies were excluded. The quality of the studies was evaluated at the study level by two researchers independently. We used the 2017 quality criteria for randomized controlled trials and quasi-experimental studies of the Effective Practice and Organisation of Care Review Group. 15 Reporting was done in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. 16 For controlled trials, intention-to-treat analyses were reported unless indicated otherwise. If the original paper did not mention a relative risk (RR), we calculated a RR and 95% confidence interval (CI) if the necessary data were available. Due to the heterogeneity of the interventions and their reported outcomes, we present our findings using a narrative approach. Because of the large number of reported outcomes, we were unable to report all. We therefore selected the outcomes that were reported most frequently across the studies. We grouped studies by intervention type: structural, persuasive, enabling or intervention bundle.

Results
We screened 7342 abstracts, selected 241 full-text articles and included 27 studies: 17-43 12 interrupted time-series, 9 randomized controlled trials, 3 cluster randomized controlled trials and 3 non-randomized controlled trials (Fig. 1). The studies were performed between 1996 and 2015 in 13 different countries. Two countries were considered low-income at the time of the study, one country transitioned from low to lower-middle income and the remaining were middle-income countries. Nine studies were conducted in multiple hospitals (range 2-65) but the majority was single-centre (18 studies). The interventions were implemented hospitalwide (10 studies) or on specific wards (17 studies) and targeted therapeutic prescriptions (20 studies), surgical prophylaxis (3 studies) or a combination of those (4 studies; Table 1).

Risk of bias assessment
For the 12 interrupted time-series studies the risk of bias was low (3 studies), medium (8 studies) or high (1 study; Fig. 2). The main risks of bias were that the intervention was not independent of other changes (5 studies) and that incomplete data were not adequately addressed (5 studies). For the 15 (non) randomized trials the risk of bias was medium (3 studies) or high (12 studies). The main risks of bias included the absence of baseline outcome measurement (14 studies), lack of protection against contamination (prescribers could have been involved in treatment of both the intervention and control group; 11 studies), non-random or unclear randomization methods (8 studies) and incomplete data not being adequately addressed (7 studies).

Box 1. Search strategy for the review of antibiotic stewardship interventions in hospitals in low-and middle-income countries
We searched the following databases from inception to 5 December 2017: Cochrane Central Register of Controlled Trials, EMBASE ® , MEDLINE ® , regional databases of the Global Index Medicus and the World Health Organization's Virtual Health Library. The combination of the following and related terms was used: "low-and middle-income country", "antibiotic", "stewardship", "inpatient" and terms related to study design such as "clinical trial", "randomized controlled trial", "interrupted time series", "controlled before after". Syntax and wording was adapted to the different libraries. Moreover, we searched reference lists of selected studies and of relevant reviews and consulted experts for additional literature. The full search strategy can be viewed online. 13  Five of these studies reported antibiotic use as the outcome. All of them found a significant decrease in the percentage of patients receiving antibiotics in the procalcitonin group compared with routine care or C-reactive protein testing. RR ranged between 0.40 and 0.87. [17][18][19][20][21] Five studies reported patient deaths as the outcome and found no significant effect of procalcitonin-guided antibiotic use on in-hospital or 30-day mortality. 17,20,[22][23][24] A non-randomized controlled trial among 97 patients in a Turkish emergency department studied the effect of introducing a rapid diagnostic test for influenza-like disease. 26 A lower percentage of tested patients were prescribed antibiotics compared with patients given clinical examination only (RR: 0.68; 95% CI: 0.56 to 0.82). In a randomized controlled trial among 201 patients in a Peruvian emergency department, use of a rapid test for rotavirus was associated with fewer patients receiving antibiotics (RR: 0.59; 95% CI: 0.41 to 0.84). 25 In a cluster-randomized controlled trial in Mexico and Thailand health-care staff were given access to the WHO's online Reproductive Health Library and workshops on its use. 27 Thereafter, it was left open to the 22 participating hospitals whether certain activities, including antibiotic stewardship, were implemented. After 10-12 months, no significant difference was found in the proportion of caesarean sections in which antibiotic prophylaxis was given, when comparing the 22 intervention hospitals to the 18 control hospitals (difference in adjusted rate in Mexico was 19.0%; 95% CI: −8.0 to 46.0% and in Thailand was 4.6%; 95% CI: −17.7 to 26.9%).
One interrupted time-series study evaluated the implementation of an antibiotic treatment guide through a free-of-charge mobile application (Table 3). Twenty-four months after the intervention there were significant increases in the defined daily doses per 1000 bed-days of recommended antibiotics (amikacin and cefepime) and a significant decrease in non-recommended antibiotics (piperacillin; P = 0.02). Use of other non-recommended antibiotics (meropenem, ciprofloxacin and polymyxin) did not decrease significantly. 28 High risk of bias Unclear risk of bias Low risk of bias Not applicable to this study type a The criteria were: A: intervention independent of other changes; B: shape of intervention pre-specified; C: intervention unlikely to affect data collection; D: knowledge of allocated interventions adequately prevented during study; E: seasonality taken into account; F: incomplete outcome data adequately addressed; G: study free from selective outcome reporting; H: adequate allocation sequencing; I: adequate allocation concealment; J: baseline outcome measures similar; K: baseline characteristics similar; L: any blinding reported; M: study protected against contamination. b The risk of bias was considered low if all criteria were scored as low, medium if one or two criteria were scored as medium or high, and high if more than two criteria were scored as medium or high. 15 Systematic reviews Antibiotic stewardship in low-and middle-income countries Christophe Van Dijck et al.

Persuasive interventions
Four studies evaluated the effect of audit and feedback to prescribers on individual patient cases by pharmacists (3 studies) or infectious diseases specialists (1 study): 29,30,32,33 A non-randomized controlled trial including 577 patients in eight intensive care units reported a decrease of duration of antibiotic treatment of −1.0 day (P = 0.03) ( Table 2). 30 Another non-randomized controlled trial of 948 patients in a public university hospital reported a decrease of duration on antibiotic treatment of −3.7 days (P < 0.01) and a decrease in mean length of hospital stay of −1.6 days (P = 0.03). 32 A cluster randomized trial found no significant difference in mean length of hospital stay among 436 patients (0.3 days; P = 0.8). 33 An interrupted time-series study in 47 private hospitals in South Africa found a decreasing trend of antibiotic use during the implementation phase of the intervention (−0.56 defined daily doses per 100 bed-days per month; P < 0.01; Table 3). 29 The trend was sustained in the 20 months post-implementation (−0.20 defined daily doses per 100 bed-days per month; P < 0.05).
An interrupted time-series study evaluated the effect of audit and feedback at the departmental level in 35 surgical wards. Three months after the intervention a significant decrease in defined daily doses per 100 bed-days was reported in 3 out of 35 wards (immediate decreases of −66.5%, −46.1% and −26.4% respectively; P < 0.05). 31

Enabling interventions
Two interrupted time-series studied the effect of enabling interventions on antibiotic prescribing (Table 3). 34,35 A study in an Indonesian hospital subsequently studied the development of treatment guidelines which were officially presented, followed by education and then refresher education. The authors reported a significant decrease of −31.9 defined daily doses per 100 bed-days (P = 0.03) after guideline development and a significant increase of +38.2 defined daily doses per 100 bed-days (P < 0.05) after education. The net effect of the intervention remains unclear. 34 Another study in an Indian hospital evaluated the effect of an antibiotic policy guideline which was first developed and introduced, then revised and made available as booklet and lastly revised and made available through the intranet. The authors initially reported a baseline rising trend in antibiotic use of +0.95 defined daily doses per 100 bed-days per month (P < 0.01) which levelled off after the first two interventions and declined by −0.37 defined daily doses per 100 bed-days per month (P < 0.01) after the last intervention. 35

Intervention bundles
Eight studies evaluated bundles combining different interventions. [36][37][38][39][40][41][42][43] A cluster randomized controlled trial in eight Kenyan hospitals compared a bundle containing guidelines, education and face-to-face feedback to prescribers with a similar, but less intensive bundle (fewer hours of training, written feedback; Table 2). 37 Comparing prescriptions for 594 children in intervention hospitals and 566 children in control hospitals showed that the intensive bundle was associated with a non-significant absolute risk reduction in inappropriate use of antibiotics for non-bloody diarrhoea of 41% (95% CI: −6 to 88%).
The other seven studies all used an interrupted time-series design ( (. . .continued)

Systematic reviews
Antibiotic stewardship in low-and middle-income countries Christophe Van Dijck et al. Table 3.  guidelines for caesarean sections, immediate availability of antibiotics in the operating theatre and feedback to surgeons about surgical site infections. 39 The study reported a significant increase in the percentage of caesarean section births in which prophylaxis was administered (immediate increase by +31.6% in hospital A; P < 0.01 and gradual increase by +5.4% per month in hospital B; P < 0.01), an increase in antibiotic administration within 1 hour of delivery (immediate increase by 62.2% in hospital A only; P < 0.01) and a significant decrease in the monthly rate of surgical site infections with 9.8% (P < 0.01) in hospital A.

Outcomes of interventions to improve appropriate prescribing and use of antibiotics in hospitals in low-and middle-income countries: interrupted time-series studies
In another study in a Kenyan hospital, surgical antibiotic prophylaxis guidelines were implemented, combined with training, personal feedback to prescribers and patient information posters. 36 The proportion of operations with incorrect timing of antibiotic prophylaxis significantly decreased (no values reported) and the percentage of surgical site infections decreased after the intervention by −0.7% per month (P = 0.03).
Another Colombian study introduced an antibiotic prescription form containing a list of restricted antibiotics with information on dosing intervals and an educational campaign. 40 The study found a decrease of 20% (P < 0.01) in the proportion of operations with incorrect timing of surgical prophylaxis.
In a Chinese study, guidelines and antibiotic restrictions were introduced, followed by individual prescriber audit and feedback, with financial penalties and revocation of prescribing privileges in case of non-compliance. 38 Before the intervention the proportion of patients on antibiotic treatment was decreasing significantly by −3% per month from a baseline level of 59% (P = 0.01). After the first intervention, no significant changes were reported. After the second intervention, a sudden drop of −9% (P = 0.01) was observed, followed by a steady increase of +3% per month (P = 0.01) in the next 14 months. The net effect of the intervention bundle remains unclear.
A study in a Brazilian cardiology hospital first introduced restriction of certain antibiotics with individual audit and feedback to prescribers by an infectious diseases specialist and subsequently more comprehensive audit and feedback by a pharmacist. Before the intervention, the total antibiotic consumption significantly increased during 30 months (+1.2 defined daily doses per 100 bed-days per month; P < 0.01). This trend decreased after the first intervention (−2.7 per month; P < 0.01) and increased after the second (+1.2 per month; P < 0.01). The net effect of the intervention bundle remains unclear. 41 Two Chinese studies looked at the implementation of a multifaceted national antibiotic stewardship programme, containing structural changes, antibiotic restriction, education, guidelines, and audit and feedback, in 65 and 15 secondary and tertiary public hospitals respectively. 42,43 Participation was compulsory and financial punishment for hospitals and disciplinary actions for individual prescribers could be imposed. Both studies reported a significant decrease in antibiotic use after the intervention. One study reported a decreasing trend of −2.2 defined daily doses per 100 bed-days per month (P < 0.01). 42 The other study reported a decrease in the proportion of patients receiving antibiotics (−7.3%; P = 0.04). 43

Discussion
In this systematic review the majority of the included studies reported a positive effect of antibiotic stewardship interventions for hospitalized patients. This is in line with previously published systematic reviews on stewardship interventions in hospitals, which did not focus specifically on low-and middleincome countries. 8-10 However, we cannot make general recommendations to guide the selection of antibiotic stewardship interventions due to limitations of the included studies, including the low quality of methods, variations and shortcomings in outcome reporting, under-representation of certain settings, heterogeneity of the interventions and variations in implementation strategy.
When screening titles and abstracts, we found 153 articles that reported on stewardship activities in a hospital setting, but 126 of those were excluded because of the study design (mainly bias-prone uncontrolled before-after studies). So, although antibiotic stewardship is taking place and is being studied in low-and middle-income countries, most studies fall short methodologically. The studies we did include were also generally of low quality. For those with a randomized study design, a major risk of bias was contamination, meaning that prescribers could be involved in treatment of both the intervention and control groups. Because it may not be feasible to randomize individual prescribers, wards or hospitals to overcome this bias, interrupted time-series design has been recommended as an alternative. In interrupted time-series, data are collected continuously, and trends and outcome levels are compared before and after the intervention. To minimize bias and confounding, interrupted-timeseries should meet certain requirements: a minimum of 12 data points before and after intervention, 100 observations per data point and the use of analytic techniques or models. 45 These requirements were seldom met by the included studies. Poor quality of methods is a consistent theme among reviews of antibiotic stewardship in countries of all income levels and this issue needs to be addressed to strengthen the evidence base. 8,9,46 Many of the included studies focused on a quantitative reduction in antibiotic prescribing. However, stewardship is not merely concerned with a reduction in antibiotic use, but in finding the balance between the potency of antibiotics and their potentially hazardous effects. The goal is to improve patient outcomes, decrease antibiotic resistance and increase cost-effectiveness of care. Therefore, it is recommended that clinical outcomes (including adverse events), microbiological and cost-effectiveness outcomes are reported in all stewardship studies. 8,47 Most of the studies included in this review failed to do so. There is an ongoing debate about which parameters should be reported to accurately reflect the above-mentioned outcomes. 48,49 This generally leads to a wide variety of reported parameters, as we observed in our review. This lack of uniformity limits comparison and aggregation of data. Also, for low-and middle-income settings, the measurement of certain clinical or microbiological outcomes, for example infection with Clostridium difficile, may be challenging if not impossible. Defining feasible outcome measures that can be uniformly applied in low-and middle-income countries should be prioritized. In the meantime, parameters that are easy to assess, such as mortality or hospital length of stay, should be reported by every stewardship study.

Systematic reviews
Antibiotic stewardship in low-and middle-income countries Christophe Van Dijck et al.
The majority of studies were performed in tertiary care centres in urban areas in middle-income countries, which limits the generalizability of the results. Large differences exist in terms of resources, organization, prescription practices and financing between countries and between facilities within countries. 11 The intervention most frequently studied in our review was the implementation of procalcitonin testing. Although this intervention showed promising results, it may not be feasible to implement in many health-care settings in low-and middle-income countries. In addition, good quality evidence from non-tertiary or rural hospitals in low-income countries is lacking. Studies focusing on these settings should therefore be prioritized.
The effectiveness of the interventions varied across the studies, even those that implemented similar interventions. This is likely due to differences in the intervention or the implementation strategy, which may have been adapted to fit local circumstances. A detailed description of the intervention and the implementation strategy is therefore mandatory to interpret the study findings. Stewardship interventions in hospitals usually aim to change individual prescriber's behaviour. This behaviour is influenced by social norms, attitudes and beliefs. 50 These are there-fore important determinants of the effectiveness of the intervention and should be an integral part of studies of stewardship interventions. For this reason, collaboration with behavioural scientists has been recommended. 46 None of the included studies reported behaviour determinants.
Our review has several limitations. We defined a broad search strategy, allowing different settings, participants, interventions and outcomes to be included. This strategy provides a good overview of what evidence is available, but limits the generalizability of the findings. Moreover, to ensure the validity of the results, studies had to fulfil high methodological standards to be included. This led to discarding numerous lower quality studies. Also, we did not include studies that only reported cost (effectiveness) as an outcome, as these require a different analysis model. Lastly, due to publication bias (not reporting negative results) and language restrictions we may have missed certain studies.
We conclude that, based on the currently available evidence, general recommendations regarding the effectiveness of antibiotic stewardship interventions in low-and middle-income countries cannot be made. As many hospitals in low-and middle-income countries are setting up antibiotic stewardship programmes, what should be the way forward? On the basis of our findings, we suggest the following actions should be prioritized to strengthen the evidence base: (i) provision of methodological and statistical support for commonly used, complex study designs such as interrupted-time-series; (ii) seeking consensus on relevant and feasible outcome measurements for low-and middle-income countries; (iii) performing methodologically solid studies in settings such as non-tertiary, rural and public hospitals in low-income countries; and (iv) accurate descriptions of interventions, implementation strategies and inclusion of behavioural aspects. While awaiting the effect of these actions, the current lack of evidence should not prevent health-care workers from engaging in stewardship. Evidence and examples both from high-and low-and middle-income countries can inspire and provide guidance in the meantime. 8